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Contributors
Robert A. Adler, Hunter Holmes McGuire VA Medical Center and Virginia Commonwealth University School of Medicine, Richmond, VA, USA
of Internal Medicine, Katholieke Universiteit Leuven, Leuven, Belgium Adele L. Boskey, Starr Chair in Mineralized Tissue Research and Director, Musculoskeletal Integrity Program, Hospital for Special Surgery, New York; Professor of Biochemistry, Weill Medical College of Cornell University; Professor, Field of Physiology, Biophysics and Systems Biology, Graduate School of Medical Sciences of Weill Medical College of Cornell University; Professor, Field of Biomedical Engineering, Sibley School, Cornell Ithaca; Adjunct Professor, School of Engineering, City College of New York, NY, USA
Matthew R. Allen, Departments of Anatomy and Cell Biology, Indiana University School of Medicine, Indianapolis, IN, USA Shreyasee Amin, Division of Rheumatology, College of Medicine, Mayo Clinic, Rochester, MN, USA Diana M. Antoniucci, University of California, San Francisco; Physicians Foundation of California Pacific Medical Center, Division of Endocrinology, Diabetes and Osteoporosis, San Francisco, CA, USA
Roger Bouillon, Laboratory of Experimental Medicine and Endocrinology (LEGENDO), Katholieke Univeriteit Leuven (KUL), Leuven, Belgium
Andre B. Araujo, New England Research Institutes, Inc., Watertown, MA, USA
David B. Burr, Departments of Anatomy and Cell Biology and Orthopaedic Surgery, Indiana University School of Medicine; Department of Biomedical Engineering, IUPUI, Indianapolis, IN, USA
Laura A.G. Armas, Creighton University Osteoporosis Research Center, Omaha, NE, USA
Melonie Burrows, Department of Orthopaedics, University of British Columbia; Centre for Hip Health and Mobility, Vancouver, Canada
Giampiero I. Baroncelli, Department of Obstetrics, Gynecology and Pediatrics, 2nd Pediatric Unit, ‘S. Chiara’ Hospital, Azienda Ospedaliero-Universitaria Pisana, Pisa, Italy
Filip Callewaert, Center for Musculoskeletal Research, Leuven University Department of Experimental Medicine, Katholieke Universiteit Leuven, Leuven, Belgium
Silvano Bertelloni, Department of Obstetrics, Gynecology and Pediatrics, 2nd Pediatric Unit, ‘S. Chiara’ Hospital, Azienda Ospedaliero-Universitaria Pisana, Pisa, Italy
Geert Carmeliet, Laboratory of Experimental Medicine and Endocrinology (LEGENDO), Katholieke Univeriteit Leuven (KUL), Leuven, Belgium
Shalender Bhasin, Section of Endocrinology, Diabetes and Nutrition, Boston University School of Medicine and Boston Medical Center, Boston, MA, USA
Luisella Cianferotti, Department of Endocrinology and Metabolism, University of Pisa, Pisa, Italy
John P. Bilezikian, Department of Medicine, Division of Endocrinology, Metabolic Bone Diseases Unit, College of Physicians and Surgeons, Columbia University, New York, NY, USA
Juliet Compston, University of Cambridge School of Clinical Medicine, Cambridge, UK Felicia Cosman, Regional Bone Center Helen Hayes Hospital, West Haverstraw, New York; Department of Medicine, Division of Endocrinology, Metabolic Bone Diseases Unit, College of Physi cians and Surgeons, Columbia University, New York, NY, USA
Neil C. Binkley, University of Wisconsin, School of Medicine and Public Health, Madison, WI, USA Steven Boonen, Center for Musculoskeletal Research, Department of Experimental Medicine, Katholieke Division of Geriatric Medicine, Leuven University Hospital, Department
Serge Cremers, Division of Endocrinology, Department of Medicine, Columbia University, New York, NY, USA
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Contributors
K. Shawn Davison, Laval University, Quebec City, PQ, Canada David W. Dempster, Department of Pathology, College of Physicians and Surgeons, Columbia University, New York, NY, USA
Deborah T. Gold, Duke University Medical Center, Durham, NC, USA X. Edward Guo, Department of Biomedical Engineering, Columbia University, New York, NY, USA
John A. Eisman, Bone and Mineral Research Program, Garvan Institute of Medical Research; University of New South Wales; St Vincent’s Hospital, Sydney, NSW, Australia
Patrick Haentjens, Center for Outcomes Research, University Hospital Brussels, Vrije Universiteit Brussel, Brussels, Belgium
Ghada El-Hajj Fuleihan, Calcium Metabolism and Osteo porosis Program, American University of Beirut Medical Center, Beirut, Lebanon
Johan Halse, Department of Endocrinology and Internal Medicine, Aker University Hospital, Oslo; Spesialistsenteret Pilestredet Park, Oslo, Norway
Erik Fink Eriksen, Department of Endocrinology and Internal Medicine, Aker University Hospital, Oslo; Spesialistsenteret Pilestredet Park, Oslo, Norway
David J. Handelsman, Department of Andrology, ANZAC Research Institute, Concord Hospital, University of Sydney, Sydney, NSW, Australia
Murray J. Favus, Section of Endocrinology, Diabetes, and Metabolism, University of Chicago, Chicago, IL, USA
Elizabeth M. Haney, Oregon Health and Science University, Portland, OR, USA
Dieter Felsenberg, Zentrum Muskel- & Knochenforschung, Charité-Universitätsmedizin Berlin, Campus Benjamin Franklin, Freie Universität & Humboldt-Universität Berlin, Berlin, Germany Serge Ferrari, Service of Bone Diseases, Department of Rehabilitation and Geriatrics, WHO Collaborating Center for Osteoporosis Prevention, Geneva University Hospital, Geneva, Switzerland David P. Fyhrie, David Linn Chair of Orthopaedic Surgery, Lawrence J. Ellison Musculoskeletal Research Center, Department of Orthopaedic Surgery, The University of California, Davis; The Orthopaedic Research Laboratories, Sacramento, CA, USA Patrick Garnero, INSERM Research unit 664 and Synarc, Lyon, France
David A. Hanley, University of Calgary, Calgary, AB, Canada Robert P. Heaney, Creighton University Osteoporosis Research Center, Omaha, NE, USA Ravi Jasuja, Section of Endocrinology, Diabetes and Nutrition, Boston University School of Medicine and Boston Medical Center, Boston, MA, USA Helena Johansson, WHO Collaborating Centre for Metabolic Bone Diseases, University of Sheffield Medical School, Sheffield, UK John A. Kanis, WHO Collaborating Centre for Metabolic Bone Diseases, University of Sheffield Medical School, Sheffield, UK
Luigi Gennari, Deparment of Internal Medicine, Endocrine, Metabolic Sciences, and Biochemistry, University of Siena, Italy
Jean-Marc Kaufman, Ghent University Hospital, Department of Endocrinology and Unit for Osteoporosis and Metabolic Bone Diseases, Gent, Belgium
Piet Geusens, Department of Internal Medicine, Subdivision of Rheumatology, Maastricht University Medical Center, Maastricht, The Netherlands; Biomedical Research Institute, University Hasselt, Belgium
Robert Klein, Bone and Mineral Unit, Oregon Health & Science University and Portland VA Medical Center, Portland, OR, USA
Vicente Gilsanz, Director, Childrens Imaging Research Program, Childrens Hospital Los Angeles, Professor of Radiology and Pediatrics, University of Southern California, Los Angeles, CA, USA Monica Girotra, Memorial Sloan-Kettering Cancer Center; Joan and Sanford I. Weill Medical College of Cornell University, New York, NY, USA Andrea Giusti, Department of Gerontology & Musculo Skeletal Sciences, Galliera Hospital, Genoa, Italy
Stavroula Kousteni, Division of Endocrinology, Department of Medicine, College of Physicians and Surgeons, Columbia University, New York, NY, USA Diane Krueger, University of Wisconsin, Madison, WI, USA Kishore M. Lakshman, Section of Endocrinology, Dia betes, and Nutrition, Division of Endocrinology & Metabolism, Boston University School of Medicine, Boston Medical Center, Boston, MA, USA
Andrea Giustina, Department of Endocrinology & Metabolic Diseases, Leiden University Medical Center, Leiden, The Netherlands
Thomas F. Lang, Professor in Residence, Department of Radiology and Biomedical Imaging, and Joint Bioengineering Graduate Group, University of California, San Francisco, San Francisco, CA, USA
Stefan Goemaere, Ghent University Hospital, Department of Endocrinology and Unit for Osteoporosis and Metabolic Bone Diseases, Gent, Belgium
Bruno Lapauw, Ghent University Hospital, Department of Endocrinology and Unit for Osteoporosis and Metabolic Bone Diseases, Gent, Belgium
Contributors Joan M. Lappe, Creighton University Osteoporosis Research Center, Omaha, NE, USA Benjamin Z. Leder, Endocrine Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA Willem Lems, Department of Rheumatology, Vrije Universiteit Amsterdam; VU Medisch Centrum, Amsterdam, The Netherlands X. Sherry Liu, Departments of Medicine and Biomedical Engineering, College of Physicians and Surgeons, Columbia University, New York, NY, USA Shi S. Lu, Regional Bone Center, Helen Hayes Hospital, West Haverstraw, New York, NY, USA Heather M. Macdonald, Schulich School of Engineering, University of Calgary, Calgary, Canada Christa Maes, Laboratory of Experimental Medicine and Endocrinology (LEGENDO), Katholieke Universiteit Leuven (KUL), Leuven, Belgium Ann E Maloney, Maine Medical Center Research Institute, Scarborough, ME, USA Peggy Mannen Cawthon, San Francisco Coordinating Center, California Pacific Medical Center Research Institute, San Francisco, CA, USA Claudio Marcocci, Department of Endocrinology and Metabolism, University of Pisa, Pisa, Italy Lynn Marshall, Department of Medicine, Bone and Mineral Unit, Department of Public Health and Preventive Medicine, Oregon Health & Science University, Portland, OR, USA Gherardo Mazziotti, Department of Medical and Surgical Sciences, University of Brescia, Italy Eugene V. McCloskey, WHO Collaborating Centre for Metabolic Bone Diseases, University of Sheffield Medical School, Sheffield, UK Heather A. McKay, Department of Orthopaedics, University of British Columbia; Centre for Hip Health and Mobility; Department of Family Practice, University of British Columbia, Vancouver, Canada Christian Meier, Division of Endocrinology, Diabetes and Clinical Nutrition, University Hospital Basel, Basel, Switzerland Paul D. Miller, University of Colorado Health Sciences Center, Medical Director, Colorado Center for Bone Research, Lakewood, CO, USA Bismruta Misra, College of Physicians and Surgeons, Columbia University, New York, NY, USA
xi
Stefano Mora, Departments of Radiology and Pediatrics, Childrens Hospital Los Angeles, Los Angeles, California, USA; Laboratory of Pediatric Endocrinology, BoNetwork, San Raffaele Scientific Institute, Milan, Italy Tuan V. Nguyen, Bone and Mineral Research Program, Garvan Institute of Medical Research; University of New South Wales; St Vincent’s Hospital, Sydney, NSW, Australia Anders Oden, WHO Collaborating Centre for Metabolic Bone Diseases, University of Sheffield Medical School, Sheffield, UK Claes Ohlsson, Center for Bone Research, Department of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden Terence W. O’Neill, Epidemiology arc Unit, University of Manchester, Manchester, UK Eric S. Orwoll, Bone and Mineral Unit, Oregon Health & Science University, Portland, OR, USA Socrates E. Papapoulos, Department of Endocrinology & Metabolic Diseases, Leiden University Medical Center, Leiden, The Netherlands René Rizzoli, Division of Bone Diseases [WHO Collaborating Center for Osteoporosis Prevention] Department of Rehabilitation and Geriatrics, Geneva University Hospitals and Faculty of Medicine, Geneva, Switzerland Clifford J. Rosen, Maine Medical Center Research Institute, Scarborough, ME, USA Martin Runge, Aerpah Clinic Esslingen, Esslingen, Germany John T. Schousboe, Park Nicollet Health Services, Minneapolis; Division of Health Policy & Management, School of Public Health, University of Minnesota, MN, USA Ego Seeman, Endocrine Centre, Heidelberg Repatriation Hospital/Austin Health, Department of Medicine, University of Melbourne, Melbourne, Victoria, Australia Markus J. Seibel, Bone Research Program, ANZAC Research Institute, The University of Sydney, Sydney, NSW, Australia Deborah E. Sellmeyer, Metabolic Bone Center, The Johns Hopkins Bayview Medical Center, Baltimore, MD, USA Elizabeth Shane, Columbia University College of Physi cians & Surgeons, New York, NY, USA Jay R. Shapiro, Bone and Osteogenesis Imperfecta Programs, Kennedy Krieger Institute; Department of Physical Medicine and Rehabilitation, Johns Hopkins University, Baltimore, MD, USA Shonni J. Silverberg, Division of Endocrinology, Department of Medicine, College of Physicians and Surgeons, Columbia University, New York, NY, USA
xii
Contributors
Stuart L. Silverman, Cedars-Sinai/UCLA and the OMC Clinical Research Center, Los Angeles, CA, USA Rajan Singh, Section of Endocrinology, Diabetes and Nutrition, Boston University School of Medicine and Boston Medical Center, Boston, MA, USA Emily M. Stein, Columbia University College of Physicians & Surgeons, New York, NY, USA Thomas W. Storer, Section of Endocrinology, Diabetes and Nutrition, Boston University School of Medicine and Boston Medical Center, Boston, MA, USA Pawel Szulc, INSERM Research Unit 831, Hôspital Edouard Heriot, Lyon, France Mahmoud Tabbal, Calcium Metabolism and Osteoporosis Program, American University of Beirut Medical Center, Beirut, Lebanon Youri Taes, Ghent University Hospital, Department of Endocrinology and Unit for Osteoporosis and Metabolic Bone Diseases, Gent, Belgium Charles H. Turner, Department of Orthopaedic Surgery, Indiana University School of Medicine, Indianapolis; Department of Biomedical Engineering, IUPUI, IN, USA Liesbeth Vandenput, Center for Bone Research, Department of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden Dirk Vanderschueren, Center for Musculoskeletal Research, Leuven University Department of Experimental Medicine, Katholieke Universiteit Leuven, Leuven, Belgium
Katrien Venken, Center for Musculoskeletal Research, Leuven University Department of Experimental Medicine, Katholieke Universiteit Leuven, Leuven, Belgium Lieve Verlinden, Laboratory of Experimental Medicine and Endocrinology (LEGENDO), Katholieke Universiteit Leuven (KUL), Leuven, Belgium Annemieke Verstuyf, Laboratory of Experimental Medicine and Endocrinology (LEGENDO), Katholieke Universiteit Leuven (KUL), Leuven, Belgium Qingju Wang, Endocrine Centre, Heidelberg Repatriation Hospital/Austin Health, Department of Medicine, University of Melbourne, Melbourne, Victoria, Australia Connie M. Weaver, Department of Foods and Nutrition, Purdue University, West Lafayette, IN, USA Felix W. Wehrli, Department of Radiology, University of Pennsylvania, Philadelphia, PA, USA Sunil J. Wimalawansa, Professor of Medicine, Endo crinology & Metabolism; Director, Regional Osteoporosis Center, Department of Medicine, Robert Wood Johnson Medical School, New Brunswick, NJ, USA Kristine M. Wiren, Bone and Mineral Unit, Oregon Health & Science University; Portland VA Medical Center, Portland, OR, USA Roger Zebaze, Department of Endocrinology and Medicine, Austin Health, University of Melbourne, Melbourne, Victoria, Australia Hua Zhou, Regional Bone Center, Helen Hayes Hospital, West Haverstraw, New York, NY, USA
Foreword
The field of osteoporosis has grown enormously over the last 4 decades, with a focus upon the issues that relate to skeletal health in women. It was only about 15 years ago that the scientific community began to acknowledge that osteoporosis in men is also important. The first edition of Osteoporosis in Men, published in 2001, was a seminal event in that it called attention to the problem in an organized series of articles on male skeletal health and bone loss. Now, with this second edition of Osteoporosis in Men, further progress in this area is emphasized with particular emphasis on new knowledge that has appeared during the last decade. Osteoporosis in men is heterogeneous with many etiologies to consider besides the well known roles of aging (Sections 1-4) and sex steroids (Sections 6-8). The roots of the problem in some individuals can be back dated to the pre-pubertal and pubertal growth periods that determine the acquisition of peak bone mass. In addition, Osteoporosis in Men, second edition, deals exhaustively with important clinical issues. Nutritional considerations, the clinical and economic burden of fragility fractures, and diagnostic approaches are particularly strong aspects of the text (Sections 5, 7, 9). These chapters transcend, in part, the specific focus of the volume, making it a useful resource and a valuable reference for an audience not necessarily well-informed in bone and mineral disorders. The last section of Osteoporosis in Men, second edition, highlights therapeutic approaches. Treatment options are less well defined in men than in women because virtually all of the clinical trials involving men have been much smaller and
shorter in duration with surrogate, instead of fracture, endpoints. With this smaller database, it nevertheless appears that men respond to available pharmacological approaches to osteoporosis in a similar manner to women (Section 10). Available clinical data support the efficacy of these therapies in men with both primary and secondary osteoporosis. Finally, Osteoporosis in Men, second edition provides a view of the future, underscoring a number of unresolved issues to be included in the agenda for future research in this area. These include discussions related to an appropriate BMD-based definition for male osteoporosis, a further understanding of the factors implicated in age-related bone loss and idiopathic osteoporosis in men, and randomized-controlled studies directly assessing fracture risk reduction, particularly for non vertebral fracture. In all these areas, more definitive information is needed. This thorough and comprehensive book integrates new, accessible and informative material in the field. It will help investigators, as well as practitioners and students, to improve their understanding of male skeletal health and bone loss. The additional knowledge, assembled in such a readable manner, should help us achieve one of our ultimate goals-better care of men with osteoporosis. Gerolamo Bianchi, MD Department of Locomotor System Division of Rheumatology Azienda Sanitaria Genovese Genova, Italy
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Preface to the Second Edition
The first edition of Osteoporosis in Men was published in 1999, about 15 years after the earliest publications on the subject. Over the past decade, we have witnessed a surge of further interest in the subject of male osteoporosis. This second edition of Osteoporosis in Men is, thus, timely. In the second edition, we have made major additions to reflect increased areas of new knowledge, including genetics and inherited disorders. Previous topics are updated and extended to make them timely also. New topics include:
The increased scope of the book is the result of contributions from prominent experts in the field, including many who contributed chapters to the first edition. New authors also have provided novel insights for the second edition. Editorial responsibilities were shared by the three of us. As was the goal before, Osteoporosis in Men, Second Edition, is meant to be useful to a broad audience, including students of the field as well as those already knowledgeable. We have sought to summarize a compendium of information intersecting general and specific areas of interest. This volume will make apparent that information available concerning osteoporosis in men still lags behind what we know about osteoporosis in women. On the other hand, major advances in our understanding of the male skeleton in health and in disease are being translated into practical approaches to their clinical management. We hope this second edition provides a valuable reference source for you and that it also will serve to stimulate further advances in the field.
Important basic processes including bone biochemistry and remodeling Mechanical properties and structure Genetics and inherited disorders Growth and puberty Nutrition, including calcium, vitamin D, protein and other factors Sex steroids in muscle and bone Assessment of bone using DXA, CT, ultrasound, biochemical markers Sarcopenia and frailty Diagnostic approaches Treatment approaches including bisphosphonates, parathyroid hormone, androgens and SARMS and newer agents.
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Eric Orwoll Portland, Oregon
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John Bilezikian New York, New York
A key element of the book continues to be sex differences in bone biology and pathophysiology that can inform our understanding of osteoporosis in both men and women.
Dirk Vanderschueren Leuven, Belgium
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Chapter
1
The Biochemistry of Bone: Composition and Organization Adele L Boskey Starr Chair in Mineralized Tissue Research and Director, Musculoskeletal Integrity Program, Hospital for Special Surgery, New York; Professor of Biochemistry, Weill Medical College of Cornell University; Professor, Field of Physiology, Biophysics and Systems Biology, Graduate School of Medical Sciences of Weill Medical College of Cornell University; Professor, Field of Biomedical Engineering, Sibley School, Cornell Ithaca; Adjunct Professor, School of Engineering, City College of New York, USA
Introduction
tubular (long and short) bones such as the femur and digits, respectively, and the flat bones, such as the calvaria in the skull. Slightly better resolved, at the millimeter level, are the components of the bones, the cortices that surround the marrow cavity, the cancellous bone within the marrow cavity, the marrow cavity itself, the cartilaginous ends, etc. At the micrometer to millimeter level are the individual interconnecting struts of the trabeculae, the lamellae and the osteons that surround the vascular canals. The cells and the composite matrices also can be visualized as part of this microstructure. Finally, at the nanometer level, bone consists of an organic matrix made mainly from collagen fibrils and noncollagenous proteins, lipids, nanometer size mineral crystals (discussed below) and water. There is also heterogeneity in both the size of the collagen fibrils and the composition and sizes of the crystals deposited on this matrix [3, 4]. This heterogeneity is important for the mechanical competence of the tissue [5]. To understand the process of mineralization, knowledge of the cells and the extracellular matrices of bone is required.
As detailed throughout this book, osteoporosis is characterized by increased risk of fracture due to changes in the ‘quality’ of bone [1]. To appreciate why bone becomes weaker or less resilient to fracture with age in both men and women and in individuals of different races, a general knowledge of bone development and age-dependent changes is necessary. In line with the theme of this book, it is noted that there are both age- and sex-dependent differences in bone properties and composition, some related to the rate at which bones develop in boys and girls, some related to the impact of genes on the X-chromosome which produce proteins important for bone development and/or metabolism and some due to the direct effect of sex steroids on bone cells [2]. To appreciate the discrete differences between bone structure and composition in men and women this chapter reviews the basics of bone composition and organization and the mineralization process from the point of view of sexual dimorphism, where such differences between men and women are recognized. Emphasis is placed on those factors that contribute to bone strength; geometry, architecture, mineralization, the nature of the organic matrix and tissue heterogeneity.
Bone Cells Within the bone matrix are the cells that are responsible for bone formation and bone turnover. Three key cells are of mesenchymal origin – chondrocytes, osteoblasts and osteocytes. The chondrocytes that form cartilage within the epiphysial growth plates produce a matrix that can be mineralized, regulate the flux of ions that facilitate the mineralization of that matrix and orchestrate the remodeling of that matrix and its replacement by bone [6]. The other mesenchymal derived bone cells are the osteoblasts and osteocytes [7]. As seen in the electron micrograph in Figure 1.1,
Bone organization Bone Heterogeneity The structure of bone appears different depending on the scale at which it is examined. At the centimeter level, whole bone can be viewed as an organ, for example, the Osteoporosis in Men
Copyright 2009, 2010 Elsevier, Inc. All rights of reproduction in any form reserved.
Osteoporosis in Men
Osteoclasts
Osteoblast
Bone 50 Microns
0.5 µm
Osteocyte
Figure 1.1 Transmission electron micrograph showing osteoblasts lining the bone surface in an adult male Sprague-Dawley rat. Inside the bone are the osteocytes, connected to one another by canaliculae. The banded pattern of the collagen is also visible. Magnification is marked on the figure. Courtesy of Dr Stephen B. Doty, Hospital for Special Surgery, New York.
osteoblasts line the surface of the mineralized bone. They synthesize new matrix and regulate the mineralization and turnover of that matrix. Once these osteoblasts become engulfed in mineral they become osteocytes and connect with one another by long processes (canaliculae) (see Figure 1.1). The osteocytes are the cells that sense mechanical signals and then convey them through the matrix. Osteocytes produce many of the same proteins as osteoblasts, but the relative concentrations of these proteins are not the same and the ways in which these cells use regulatory pathways differ. As reviewed in detail elsewhere [8], the osteoblasts use the WNT/beta-catenin pathway [9] to regulate synthesis of new bone; the osteocytes use the WNT/beta-catenin pathway to convey mechanical signals. Osteoblasts synthesize more alkaline phosphatase, more type I collagen and more bone sialoprotein than osteocytes, while osteocytes specifically produce sclerostin, a glycoprotein that is a WNT and BMP antagonist, and produce high levels of dentin matrix protein 1 [8]. Sclerostin, an osteocytes specific protein, inhibits osteoblast differentiation and, based on the significant increase in bone mineral density in the sclerostin knockout mouse [10], is believed to be important in determining the high bone mass phenotype [11]. This increase in bone mass was noted to be comparable for both sexes [10]. There is sexual dimorphism in the density of osteocytes, as females gain osteoclast lacunar density with increasing age, while males show a decrease in this parameter [12]. This may explain why bone loss in women results in a decrease
Figure 1.2 Transmission electron micrograph of an osteoclast on the bone surface of a 70-year-old woman. The ruffled borders sealing the cell to the mineralized surface are indicated along with the magnification. Courtesy of Dr Stephen B. Doty, Hospital for Special Surgery, New York.
in trabecular number, while in males there is a thinning of trabeculae [13]. Some of the other functions of osteoblasts and osteocyte proteins will be discussed later. The cells responsible for the turnover of bone, the osteoclasts, are of hematologic and macrophage origin [14]. As seen in the electron micrograph in Figure 1.2, these multinucleated giant cells attach to the surface of the bone via a ‘ruffled border’. They receive signals from osteoblasts that control bone remodeling and regulate the turnover of the mineralized matrix. They remove bone by producing acid and couple that with the transport of chloride out of the cell. The acid dissolves the mineral (see below) and, after the mineral is removed, release proteolytic enzymes that degrade the matrix. During the dissolution of the matrix, signaling molecules communicate with the osteoblasts and new bone formation is triggered. Androgens and estrogens inhibit osteoclast activity to different extents [15] explaining some of the sexual dimorphism in osteoclast activity. There are a number of other cells in bone, marrow stromal cells, pericytes, vascular endothelial cells, fibroblasts, etc that function as stem cells [16] but their properties are beyond the scope of this chapter and will not be discussed here.
Skeletal Development The shapes of male and female adult bones are different and, for archeologists, form the basis for the identification of sexes in skeletal remains [17]. The early development of the skeleton contributes markedly to these sexual differences. During development, bone structure changes in length and width and there is a concomitant alteration in tissue density, resulting in a bone that is optimally designed to bear the loads imposed on it [18]. In the long and short tubular bones, endochondral
C h a p t e r 1 The Biochemistry of Bone: Composition and Organization l
ossification, in which a cartilage model becomes calcified and is replaced by bone, provides the basis for longitudinal growth, while widening of the bones takes place by apposition on already formed bone in the periosteum concurrent with removal of the inner (endosteal) surfaces. Endochondral ossification starts during embryogenesis and continues throughout childhood and into adolescence, peaking during the ‘growth spurt’. The rate at which changes in bone geometry occur depends on genetics, the environment and hormonal signals [19, 20]. With the exception of individuals with rare genetic mutations, the process of endochondral ossification terminates during adolescence with the closing of the growth plate. This generally occurs in girls around age 13 and in boys around age 18 [21]. In contrast, there is a report of a man who had a bone age of 15, based on bone mineral density (BMD), at age 28 and lacked closed epiphyses and had continued linear growth into adulthood due to a mutation in his estrogen-receptor alpha (ERalpha) gene [22]. His testosterone levels were reported as normal. Other related cases with abnormalities in the ability to synthesize estrogen (aromatase deficiency) had a similar phenotype, but longitudinal growth could be modulated with estrogen treatment [23]. During aging, at least in mice [24] and, most likely, in humans [25], there is a decrease of bone formation (osteogenesis) and an increase of fat cell formation (adipogenesis) in bone marrow. There is also a difference between aging patterns in bones of men and women. In general, in both sexes, bone strength is maintained by the process of remodeling, removal of bone by osteoclasts and formation of new bone by osteoblasts. These coupled processes [26] are not equivalent in men and women. Testosterone decreases this pathway in men [27], perhaps contributing to the delayed start of agedependent bone loss in males relative to females. In women, menopause-related estrogen deficiency leads to increased remodeling [28] and, with age, bone loss is accelerated and bone loss exceeds formation, causing cortices to being thinner and more porous and trabeculae to become disconnected and thinner. In men, the changes in remodeling lead to bone loss occurring later in life [29]. Concurrent bone formation on the periosteal surface during aging occurs to a greater extent in men than in women, thus diminishing some of the bone loss [30]. In a cross-sectional study of older men and women [29], men had significantly larger cross-sectional bone sizes than women which, in turn, was associated with decreased compressive strength indices at the spine, femoral neck and trochanter and bending strength indices at the femoral neck.
Bone composition: the bone composite Independent of age, state of development, race and sex, bone is a composite material consisting of mineral crystals
1.5 µm
Figure 1.3 Transmission electron micrograph of a section of bone from the tibia of an adult male mouse. The electron dense mineral crystals can be seen to lie parallel to the collagen fibril axis. Courtesy of Dr Stephen B Doty, Hospital for Special Surgery, New York.
deposited in an oriented fashion on an organic matrix. The organic matrix is predominately type I collagen, but there are also non-collagenous proteins and lipids present. The non-collagenous proteins account for a small percentage of the bone matrix, yet they are important for regulating cell– matrix interactions, matrix structure, matrix turnover and the biomineralization process. Knowledge about the functions and critical status of these proteins has come from studies of mutant animals (naturally occurring and those made by genetic manipulation), cell culture studies [31] and analyses of the proteins’ activity in the absence of cells.
The Mineral The mineral component of the bone composite is an analogue of the naturally occurring mineral hydroxyapatite. Bone hydroxyapatite is comprised of nanometer sized crystals [32]. These crystals have the approximate chemical composition Ca5(PO4)3OH but are carbonate-substituted and calcium and hydroxide deficient [33]. The individual crystals have a broad range of sizes, depending on the age of the bone and the health of the subject, but are always oriented parallel to the long fiber axis of the collagenous matrix (Figure 1.3). There is a broad distribution of the amount of mineral in the matrix, again varying with age, environment and disease. The average amount of mineral in the matrix can be measured by burning off the organic matrix (ash weight) or by radiographic measurement of density (bone mineral density or bone mineral content). There is some sexual dimorphism in the ash weight in bones of egg-laying
Osteoporosis in Men
chicks, with males having, on average, a greater mineral content in any given bone than age matched female bones [34] but, in humans of the same race, the ash content of adult male and female bones is similar [35], perhaps because there is a well defined maximum amount of mineral that can fit into the bone matrix. Only in osteomalacia and related diseases is the mineral content reduced and that occurs in both sexes. Bone mineral density measured by computed tomography, tends to be higher in males than females at each stage of life, but differences are removed when corrected for bone length and cortical thickness [29, 36, 37]. The composition of bone hydroxyapatite varies with age, diet and health due to the substitution of foreign ions and vacancies into the crystal lattice and to the absorption of these ions on the surface of the crystals. The substituted ions also have been reported to differ when male and female mouse bones are compared, although the number of such studies is limited. When attention is paid to the sex of the animal, compositional studies show differences in mineral content and composition [38]. The effects of sex steroids on bone development can explain many of these differences. For example, assessing the effects of sex hormones on bone composition Ornoy et al. [39] compared a variety of compositional parameters in gonadectomized mice treated with male and female sex steroids. While the investigators found that tibial mineral content (ash weight) was comparable in all the groups, Ca and P content increased after ovariectomy. Estradiol treatment increased mineral content and bone Ca and P in ovariectomized and in intact females and orchiectomized mice, while testosterone had smaller effects.
The Extracellular Matrix Collagen provides the oriented template or scaffold upon which these mineral crystals are deposited. The collagen is predominately type I, a triple helical collagen, with the individual chains having the amino acid sequence (X-YGly)n, where X and Y are any amino acids, often proline and hydroxyproline, and glycine is the only amino acid small enough to fit in the center of the triple helix [40]. The importance of type I collagen for the proper mineralization of the matrix is seen in the different osteogenesis imperfecta diseases, a set of diseases, reviewed elsewhere [41], caused by mutations that lead to altered quantity or quality (composition) of type I collagen and result in brittle bones. There are also other collagen types in bone, including fibrillar type III collagen and non-fibrillar type V collagens [42]. No sex dependent differences in the distribution of collagen types have been reported, however, there are differences in the non-collagenous proteins that are found associated with the collagen matrix. In the next section, these non-collagenous proteins will be presented as families, with emphasis on their roles in mineral formation and turnover and other ways in which they might affect sexual dimorphism in bone strength.
The Non-Collagenous Proteins: Gla Proteins The most abundant non-collagenous protein in vertebrates is a small protein, osteocalcin, also known as bone gla protein [40]. This small (5.7 kDa) protein has three gammacarboxy-glutamic acid residues, with a high affinity for hydroxyapatite and calcium as demonstrated by its crystal and nuclear magnetic resonance (NMR) structures [43, 44]. Osteocalcin is frequently used as a biomarker for bone formation [45], although it is also released from bone and hence can reflect remodeling rather than only formation. In studies where bone tissue osteocalcin levels and serum osteocalcin levels were compared as a function of age and sex, the levels in men exceeded those in women at all ages until age 60, when levels in women increased and then decreased, reflecting age-dependent increases in bone remodeling [46, 47]. This most likely is an estrogendetermined effect as, in the rat, estrogen treatment is associated with a decrease in osteocalcin [48]. Knockout mice lacking osteocalcin have thickened bones and, thus, it was initially suggested that osteocalcin was important for bone formation [49]. Further studies led to the suggestion that osteocalcin was important for osteoclast recruitment [50], a suggestion supported by in vitro and in vivo assays [40]. Most recently, Karsenty’s group has suggested, from studies in wildtype as well as osteocalcin knockout mice, that the uncarboxylated form of osteocalcin acts as a hormone, regulating glucose levels in cultures of pancreatic cells and in the skeleton [51]. The role of osteocalcin in glucose metabolism is suggested by the observation that osteoblastic bone formation is negatively regulated by the hormone leptin. Leptin, secreted by fat cells (adipocytes), has multiple hormonal functions including, but not limited to: appetite suppression, initiation of puberty in girls and acceleration of longitudinal bone growth in mice, although the data on bone formation have suggested a bimodal pattern [52]. In humans, a recent report showed postmenopausal women with type 2 diabetes had reduced osteocalcin levels [53]. In addition to the identification of osteocalcin as a hormone with a postulated role in metabolic syndrome, readers are reminded that the osteocalcin knockout has a bone phenotype, there is some sex specificity to osteocalcin’s action in bone [48] and polymorphisms in the osteocalcin gene have been associated with osteoporosis [54–56]. The second gamma-carboxyglutamic acid containing protein in bone (predominantly in cartilage) and in soft tissues is matrix-gla protein (MGP). MGP is a hydrophobic protein [40] containing five gamma-carboxyglutamate residues that is important for inhibition of soft tissue calcification, as can be seen in the knockout mice where, when MGP is ablated, the animals have excessive cartilage calcification, denser bones and young animals succumb to calcification of the blood vessels and esophagus [57, 58]. Both the full length protein and its component peptides can inhibit hydroxyapatite formation and growth in culture [59]. MGP is more abundant in
C h a p t e r 1 The Biochemistry of Bone: Composition and Organization l
soft tissues than in bone, hence it is not surprising that polymorphisms in MGP are not associated with bone density or fracture risk [56].
Non-Collagenous Proteins: Siblings There is a family of proteins found in bone that have been named the SIBLING proteins (small integrin binding ligand N-glycosylated) [60]. These proteins are all located on the same chromosome, all have RGD-cell binding domains, all are anionic and all are subject to multiple post-translational modifications including phosphorylation and dephosphorylation, cleavage and glycosylation [61]. Each is found in multiple tissues in addition to bone and each has signaling functions in addition to interacting with hydroxyapatite and regulating mineralization (Table 1.1). The SIBLING proteins include osteo pontin (bone sialoprotein 1), dentin matrix protein 1 (DMP1), bone sialoprotein (BSP2), matrix extracellular phosphoglycoprotein (MEPE) and the products of the dspp gene, dentin sialoprotein (DSP) and dentin phosphoprotein (DPP).
Osteopontin is the most abundant of the SIBLING proteins and has the most widespread distribution. In solution [73, 74], in a variety of cell culture systems [75, 76], in animals in which gene expression has been ablated [71] and in models of pathologic calcifications [77], bone osteopontin is an inhibitor of mineralization. When this glycoprotein is highly phosphorylated it can promote hydroxyapatite formation, most likely due to small conformational changes occurring on binding to the mineral surface [78]. Osteopontin is also involved in the recruitment of osteoclasts and in regulating the immune response [79]. Bone specific conditional knockout of osteopontin results in impaired osteoclast activity at all ages [72], but sexual dimorphism was not noted. Dentin matrix protein 1 is a synthetic product of growth plate chondrocytes and of osteocytes, although it was first cloned from dentin [40]. DMP1 is not usually found in an intact form but rather it is found as three smaller peptides, an N-terminal peptide, a C-terminal peptide and an N-terminal protein that has a glycosaminoglycan chain attached [65]. It is the only one of the SIBLING proteins to date that has been
Table 1.1 Bone non-collagenous matrix proteins* whose modification (deletion (KO) or overexpression (TG)) creates a bone phenotype Protein or gene
Genotype
Bone phenotype
Proposed function
Biglycan [62]
KO
Decreased mineral content Increased crystal size in young animals Females less affected
Regulation of mineralization
Bone sialoprotein [63]
KO
Variable
Decorin [62]
KO
Dentin matrix protein-1 [64, 65]
KO
Weaker bones Thinner collagen fibrils Impaired mineralization Altered osteocyte function
Dentin sialophosphoprotein gene (dspp) [66] Matrix gla protein [57]
KO
Initiation of mineralization Signaling Regulation of collagen fibrillogenesis Regulation of mineralization Signaling response to load Phosphate regulation Regulation of initial calcification
Matrix extracellular phosphoglycoprotein [67, 68]
KO
KO
Osteocalcin [49, 50]
TG KO
Osteonectin [69, 70]
KO Bone specific KO
Osteopontin [71, 72]
KO Bone specific KO
*
Increased collagen maturity and crystallinity in young male and female mice Excessive vascular and cartilage Prevent excessive calcification calcification Hypermineralization Regulation of PHEX activity
Hypomineralization Thicker bones, smaller crystals suggest impaired turnover Males/females differ Altered collagen maturity Decreased bone density, increased bone fragility Increased bone density, larger crystals, resistant to turnover Increased bone density
Enzymes, growth factors and cytokines that affect bone are excluded from this table.
Regulation of mineralization Regulation of bone turnover Glucose regulation Regulation of collagen fibrillogenesis Regulation of bone formation Osteoclast recruitment Inhibition of mineralization Osteoclast recruitment
Osteoporosis in Men
associated with a bone disease (autosomal hypophosphatemic rickets) [80]. The intact protein appears to inhibit mineralization, as does the glycosylated N-terminal fragment, but the phosphorylated cleaved fragments can promote mineralization [81, 82]. The knockout mouse has defective mineralization, supporting a role for DMP1 as a nucleator [64], although it appears equally important as a signaling molecule [8]. Bone sialoprotein (BSP) is a specific product of bone forming cells. There are low levels in other mineralized tissues, such as calcified cartilage and dentin. In solution, BSP is a hydroxyapatite nucleator [83, 84], implying a role in in situ mineralization. In culture, BSP facilitates osteo blast differentiation and maturation [85] and thereby stimulates mineralization. The BSP knockout is viable, but has a variable phenotype. In the youngest animals, the bones are shorter, narrower and less mineralized, supporting the in vitro findings. As the animals age, the mineralization normalizes, but the mice have impaired osteoclast activity, as they are resistant to bone loss by hind-limb suspension [63]. These data support the hypothesis that because mineralization is such an important process, it is crucial to have multiple pathways to support mineralization. BSP activity may be different in males and females as knockdown of the estrogen receptor alpha gene in a model of cartilage induced osteoarthritis resulted in decreased expression of BSP, implying some gender specificity to the expression of this protein [86] and studies in chick osteoblasts had previously demonstrated a response of BSP expression to estrogen-like molecules [87]. Matrix extracellular phosphoglycoprotein (MEPE) is made in bone, dentin and also exists in serum as smaller peptides [67]. The MEPE peptides are effective inhibitors of hydroxyapatite formation and growth, while unpublished studies show the intact protein, in phosphorylated form, promotes hydroxyapatite formation. Following gene ablation, the knockout animals have excessive mineralization while the transgenic animal, in which MEPE is overexpressed is hypomineralized [67]. This protein is one of the substrates for PHEX (phosphate regulating hormone with analogy to endopeptidase on the X-chromosome). PHEX is defective in hypophosphatemic rickets, presumably because where normally PHEX binds to MEPE and degrades its inhibitory peptides, in the mutant, this ability to degrade the peptides is absent and the inhibition persists [68]. Thus, MEPE is an important regulator of calcification. Because PHEX is on the X-chromosome, hypophosphatemic rickets is more prevalent and more severe in males than in females, although the female HYP mice have a bone phenotype, but it is less severe than that of the males [88]. Dentin sialophosphoprotein is expressed as a gene, dspp, but an intact protein has not yet been isolated. Its major components, dentin sialoprotein (DSP) and dentin phosphophoryn (DPP) are found mainly in dentin, but the gene is expressed in bone [61], and the dspp gene knockout has a detectable bone phenotype [66]. Both DSP and DPP can
regulate mineralization in vitro, thus it is not surprising that the knockout has impaired mineralization both in bone and in dentin.
Non-Collagenous Proteins: SLRPS Small leucine rich proteoglycans (SLRPS) are the major bone glycoproteins [40]. While small amounts of large aggregating proteoglycans (such as aggrecan and epiphican) are resident in bone as part of residual calcified cartilage, the majority of the bone proteoglycans are smaller. These SLRPS include decorin (the major SLRP produced by osteoblasts), biglycan, osteoadherin, lumican, fibromodulin and mimecan [89]. Each of these proteins binds to collagen and regulates collagen fibrillogenesis, thus they have an important effect on the bone composite and the mechanical strength of bone. In addition, biglycan and decorin are important for regulating cellular activity, perhaps due to the binding of growth factors, and decorin, biglycan and mimecan can regulate hydroxy apatite formation [90]. The properties and functions of these proteins in bone as adapted from these reviews are summarized in Table 1.2, while Table 1.1 includes the properties of the knockouts that had bone phenotypes.
Non-Collagenous Proteins: Matricellular Proteins Another protein family whose members are found in bone are the so-called ‘matricellular proteins’, named so because they regulate the interactions between the cells and the extracellular matrix. The members of this family found in mineralized bone (as distinct from cartilage) include: osteonectin (SPARC), the matrillins, the thrombospondins, the tenascins, the galectins, periostin and osteopontin and BSP (SIBLINGs). Each of these proteins is expressed in higher amounts during development than in adult life, but they are all upregulated during wound repair (callus formation) in the adult. As noted from studies of mice lacking these proteins, or combinations thereof, matricellular proteins affect postnatal bone structure and turnover when animals are challenged by aging, ovariectomy, mechanical loading and fracture healing regeneration but do not have a visible phenotype during normal development [96].
Non-Collagenous Proteins: Other In addition to the families of bone matrix proteins noted above, there are other extracellular matrix proteins that are found in glycosylated and phosphorylated form in bone. These include BAG-75 (which is found at the initial sites of mineralization in culture) [97], SPP24 (that regulates the formation of bone via inhibition of BMP-induced osteoblast differentiation) [98] and others proteins that serve as signaling molecules or have other functions that are still being investigated [40].
C h a p t e r 1 The Biochemistry of Bone: Composition and Organization l
Table 1.2 Small leucine rich proteoglycans (SLRPs) found in bone* Protein
Structure
Proposed functions
Biglycan
2 GAG chains/protein core
Decorin
Generally 1 GAG chain/protein core
Osteoadherin [91]
Keratan sulfate proteoglycan
Fibromodulin
4 Keratan sulfate chains in its leucine rich domain Possesses a unique stretch of aspartate residues at its N terminus Derived from bone tumor Also called osteogenic factor
Binds and releases growth factors Cell differentiation Initiates mineralization Expression depressed in patient’s with Turner’s syndrome Regulates collagen fibrillogenesis Binds and releases growth factors Facilitates osteoblast differentiation and maturation Regulates HA proliferation Regulation of collagen fibrillogenesis
Asporin [92] Osteoglycin/mimecan
Lumican
Keratan sulfate proteoglycan
Osteomodulin [93] Periostin (osteoblasts-specific factor 2) [94]
Keratan sulfate proteoglycan SLRP made in primary osteoblasts
Tsukushin [95]
353 amino acid protein upregulated by estrogen – has phosphorylation sites
Negative regulator of osteoblast maturation and mineralization Induces osteogenesis Regulation of collagen fibrillogenesis Regulation of mineralization Regulation of collagen fibrillogenesis Regulation of mineralization Regulates osteoblast maturation Regulates intramembranous bone formation Regulates collagen fibrillogenesis BMP inhibitor Regulates mineralization
*
Adapted from OMIM: On Line Mendelian Inheritance in Man: http://www.ncbi.nlm.nih.gov/sites/entrez/OMIM unless otherwise noted.
Other Matrix Components Within the extracellular matrix are other proteins including enzymes (Table 1.3), growth factors and other signaling molecules, as well as lipids that are important for regulating cell–cell communication and mineral deposition. The actions of lipids in bone are reviewed in detail elsewhere [40, 103, 104]. The importance of lipid rafts (caveolin) is seen in the caveolin knockout mouse that has increased bone density and matures more rapidly than control mice [105]. There have not yet been reports of sex-dependent differences in these mice, although lipid metabolism is different in men and women.
How bones change with age A key event in the transition from the embryo to the adult is the development of mineralized structures. The cells that deposit the matrix, regulate the flux of ions and control the interaction between the matrix components orchestrate these processes. As shown by Figure 1.3, the mineral in bone is deposited in an oriented fashion on the collagen matrix. It is widely recognized, as reviewed elsewhere [33, 40], that the collagen provides a template for mineral deposition, but the extracellular matrix proteins regulate
the sites of initial mineral deposition and control the extent to which the crystals can grow in length and in width. The collagenous matrix is mineralized to a certain extent during development (primary mineralization) and, as the individual ages, the rest of the matrix becomes mineralized (secondary mineralization). A variety of signals, discussed elsewhere in this book, activate the osteoclast to remove bone and this removal exposes stimuli that activate osteo blasts to lay down a new bone matrix, with the matrix proteins mentioned above regulating these processes. With age, the resorption process exceeds the formative one and this occurs earlier in women then in men. Mouse models in which specific matrix proteins are ablated or inserted provide information both on the sexual dimorphic responses of these proteins, but also on the age-related changes. Mice, in general, achieve their peak bone mass at 16–18 weeks of age, depending on the sex and background. Although the functions of many of these proteins are redundant, because they are so essential for the development of the animal, examining knockout and transgenic animals (see Table 1.1) and the phenotypic appearance of their bones provides clues into the activities of these proteins. The only knockouts that totally lack bone are the osterix [106] and the Runx2 knockouts [107], although the retinoblastoma tumor suppressor gene knockout has severely impaired osteogenesis [108]. The knockout
Osteoporosis in Men
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Table 1.3 Some key enzymes* involved in modifying bone structure in health and disease Enzyme
Substrate/activity
Effect on bone properties
Bone specific alkaline phosphatase [99] Hydrolyzes phosphate esters Bone morphogenetic protein 1/tolloid Cleaves matrix proteins including [100] removing pro-peptides form fibrillar collagens Cathepsin K [101] Demineralized matrix Cl-channel and ATPase [101] PHEX [67, 68] Protein kinases [31] Phosphoprotein phosphatases [31] Procollagen peptidases [48] Tartrate resistant acid phosphatase [102]
Transports Cl ions out of osteoclasts Cleaves ASARM peptides Add phosphate moieties Removes phosphate moieties Removes terminal peptides from collagen Phosphoesters
Stimulates new bone formation Modulates activity of matrix proteins – turning inhibitors into activators and vice versa preparing matrix for mineral deposition Osteoclast enzyme – when defective results in osteopetrosis When blocked get osteopetrosis Removes inhibitors of mineralization Activates some proteins/inactivates others Activates some proteins/inactivates others When defective bone fails to cross-link properly resulting in reduced mechanical strength Marker of osteoclast activity
*
Excludes enzymes involved in protein synthesis.
and overexpression of other bone proteins and ‘critical’ signaling pathways have altered bone properties but none seem to be mandatory, most likely due to the redundancy of the function of these proteins. However, from the analyses of the cell culture and altered phenotype in the animals having too little or too much of these proteins, the following can be identified as important for the formation of the mineralized matrix: type I collagen, bone sialoprotein, dentin matrix protein1, BAG-75, osteopontin, PHEX and alkaline phosphatase. The sequence in which they act is not yet clear.
Acknowledgments Dr Boskey’s data as reported in this review were supported by NIH Grants DE04141, AR037661, AR041325 and AR046121. Dr Boskey appreciates the collaboration of Dr Steven B Doty who provided the images for this chapter.
References 1. E. Seeman, P.D. Delmas, Bone quality – the material and structural basis of bone strength and fragility, N. Engl. J. Med. 354 (2006) 2250–2261. 2. L.L. Tosi, B.D. Boyan, A.L. Boskey, Does sex matter in musculoskeletal health? The influence of sex and gender on musculoskeletal health, J. Bone Joint Surg. 87 (A) (2005) 1631–1647. 3. A.L. Boskey, L. Spevak, R.S. Weinstein, Spectroscopic markers of bone quality in alendronate-treated postmenopausal women, Osteoporos. Int. 20 (2009) 793–800. 4. A. George, A. Veis, Phosphorylated proteins and control over apatite nucleation, crystal growth, and inhibition, Chem. Rev. 108 (2008) 4670–4693.
5. D. Ruffoni, P. Fratzl, P. Roschger, K. Klaushofer, R. Weinkamer, The bone mineralization density distribution as a fingerprint of the mineralization process, Bone 40 (2007) 1308–1319. 6. E.J. Mackie, Y.A. Ahmed, L. Tatarczuch, K.S. Chen, M. Mirams, Endochondral ossification: how cartilage is converted into bone in the developing skeleton, Int. J. Biochem. Cell Biol. 40 (2008) 46–62. 7. B. Clarke, Normal bone anatomy and physiology, Clin. J. Am. Soc. Nephrol. 3 (Suppl 3) (2008) S131–S139. 8. L.F. Bonewald, ML. Johnson, Osteocytes, mechanosensing and Wnt signaling, Bone 42 (2008) 606–615. 9. S.C. Manolagas, M. Almeida, Gone with the Wnts: betacatenin, T-cell factor, forkhead box O, and oxidative stress in age-dependent diseases of bone, lipid, and glucose metabolism, Molec. Endocrinol. 21 (2007) 2605–2614. 10. X. Li, M.S. Ominsky, Q.T. Niu, et al., Targeted deletion of the sclerostin gene in mice results in increased bone formation and bone strength, J. Bone Miner. Res. 23 (2008) 860–869. 11. P. ten Dijke, C. Krause, D.J. de Gorter, C.W. Löwik, R.L. van Bezooijen, Osteocyte-derived sclerostin inhibits bone formation: its role in bone morphogenetic protein and Wnt signaling, J. Bone Joint Surg. 90 (A Suppl 1) (2008) 31–35. 12. D. Vashishth, G.J. Gibson, DP. Fyhrie, Sexual dimorphism and age dependence of osteocyte lacunar density for human vertebral cancellous bone, Anat. Rec. Part A, Discov. Molec. Cell. Evol. Biol. 282 (2005) 157–162. 13. L. Mosekilde, The effect of modelling and remodelling on human vertebral body architecture, Technol. Hlth. Care: Offic. J. Eur. Soc. Eng. Med. 6 (1998) 287–297. 14. D.V. Novack, SL. Teitelbaum, The osteoclast: friend or foe? Ann. Rev. Pathol. 3 (2008) 457–484. 15. H. Michael, P.L. Härkönen, H.K. Väänänen, TA. Hentunen, Estrogen and testosterone use different cellular pathways to inhibit osteoclastogenesis and bone resorption, J. Bone Miner. Res. 20 (2005) 2224–2232. 16. R.S. Tare, J.C. Babister, J. Kanczler, R.O. Oreffo, Skeletal stem cells: phenotype, biology and environmental niches informing tissue regeneration, Molec. Cell. Endocrinol. 288 (2008) 11–21.
C h a p t e r 1 The Biochemistry of Bone: Composition and Organization l
17. L.S. Cowal, RF. Pastor, Dimensional variation in the proximal ulna: evaluation of a metric method for sex assessment, Am. J. Phys. Anthropol. 135 (2008) 469–478. 18. D.R. Carter, T.E. Orr, D.P. Fyhrie, Relationships between loading history and femoral cancellous bone architecture, J. Biomech. 22 (1989) 231–244. 19. S.A. Kontulainen, J.M. Hughes, H.M. Macdonald, J.D. Johnston, The biomechanical basis of bone strength development during growth, Med. Sports Sci. 51 (2007) 13–32. 20. A.D. Rogol, J.N. Roemmich, P.A. Clark, Growth at puberty, J. Adolesc. Hlth. 31 (6 Suppl) (2002) 192–200. 21. P.V. Hamill, T.A. Drizd, C.L. Johnson, R.B. Reed, A.F. Roche, WM. Moore, Physical growth: National Centers for Health statistics percentiles, Am. J. Clin. Nutr. 32 (1979) 607–629. 22. E.P. Smith, J. Boyd, G.R. Frank, et al., Estrogen resistance caused by a mutation in the estrogen-receptor gene in a man, N. Engl. J. Med. 331 (1994) 1056–1061. 23. S. Khosla, Estrogen and bone: insights from estrogen-resistant, aromatase-deficient, and normal men, Bone 43 (2008) 414–417. 24. K. Kawaguichi, Molecular backgrounds of age-related osteoporosis from mouse genetic approaches, Rev. Endocrine. Metabol. Disord. 7 (2006) 17–22. 25. G. Duque, BR. Troen, Understanding the mechanisms of senile osteoporosis: new facts for a major geriatric syndrome, J. Am. Geriatr. Soc. 56 (2008) 935–941. 26. T.C. Phan, J. Xu, MH. Zheng, Interaction between osteoblast and osteoclast: impact in bone disease, Histol. Histopathol. 19 (2004) 1325–1344. 27. C. Moretti, G.V. Frajese, L. Guccione, et al., Androgens and body composition in the aging male, J. Endocrinol. Invest. 28 (3 Suppl) (2005) 56–64. 28. H.K. Väänänen, PL. Härkönen, Estrogen and bone metabolism, Maturitas 23 (Suppl) (1996) S65–S69. 29. G. Sigurdsson, T. Aspelund, M. Chang, et al., Increasing sex difference in bone strength in old age: The Age, Gene/ Environment Susceptibility-Reykjavik study (AGESREYKJAVIK), Bone 39 (2006) 644–651. 30. E. Seeman, Pathogenesis of bone fragility in women and men, Lancet 359 (2002) 1841–1850. 31. A.L. Boskey, R. Roy, Cell culture systems for studies of bone and tooth mineralization, Chem. Rev. 108 (2008) 4716–4733. 32. W. Tong, M.J. Glimcher, J.L. Katz, L. Kuhn, S.J. Eppell, Size and shape of mineralites in young bovine bone measured by atomic force microscopy, Calcif. Tissue Int. 72 (2003) 592–598. 33. A. Boskey, Mineralization of bones and teeth, Elem. Mag. 3 (2007) 387–393. 34. A.L. Boskey, IR. Dickson, Influence of vitamin D status on the content of complexed acidic phospholipids in chick diaphyseal bone, Bone Miner. 4 (1988) 365–371. 35. K. Ostrowski, A. Dziedzic-Gocławska, A. Sicinski, et al., Evaluation of the amount of crystallinity of bone mineral in the course of the aging process in man, Acta. Biol. Acad. Sci. Hung. 31 (1980) 227–232. 36. F. Rivadeneira, M.C. Zillikens, C.E. De Laet, et al., Femoral neck BMD is a strong predictor of hip fracture susceptibility in elderly men and women because it detects cortical bone instability: the Rotterdam Study, J. Bone Miner. Res. 22 (2007) 1781–1790.
11
37. W. Högler, C.J. Blimkie, C.T. Cowell, et al., A comparison of bone geometry and cortical density at the mid-femur between prepuberty and young adulthood using magnetic resonance imaging, Bone 33 (2003) 771–778. 38. S.M. Nordstrom, S.M. Carleton, W.L. Carson, M. Eren, C.L. Phillips, D.E. Vaughan, Transgenic over-expression of plasminogen activator inhibitor-1 results in age-dependent and gender-specific increases in bone strength and mineralization, Bone 41 (2007) 995–1004. 39. A. Ornoy, S. Giron, R. Aner, M. Goldstein, B.D. Boyan, Z. Schwartz, Gender dependent effects of testosterone and 17 beta-estradiol on bone growth and modelling in young mice, Bone Miner. 24 (1994) 43–58. 40. W. Zhu, P.G. Robey, A.L. Boskey, Sexual dimorphism and age dependence of osteocyte lacunar density for human vertebral cancellous bone, in: R. Marcus, D. Feldman, D. Nelson, C. Rosen (Eds.) Osteoporosis, third ed., vol. 1, Academic Press, San Diego, 2007, pp. 191–240. 41. R.D. Blank, A.L. Boskey, Genetic collagen diseases: influence of collagen mutations on structure and mechanical behavior, in: P. Fratzl (Ed.), Collagen: Structure and Mechanics, Springer Science Business Media, LLC, 2008, pp. 447–474. 42. S.H. Liu, R.S. Yang, R. al-Shaikh, JM. Lane, Collagen in tendon, ligament, and bone healing. A current review, Clin. Orthopaed. Rel. Res. 318 (1995) 265–278. 43. Q.Q. Hoang, F. Sicheri, A.J. Howard, DS. Yang, Bone recognition mechanism of porcine osteocalcin from crystal structure, Nature 425 (2003) 977–980. 44. T.L. Dowd, J.F. Rosen, L. Li, CM. Gundberg, The threedimensional structure of bovine calcium ion-bound osteocalcin using 1H NMR spectroscopy, Biochemistry 42 (2003) 7769–7779. 45. P. Garnero, Biomarkers for osteoporosis management: utility in diagnosis, fracture risk prediction and therapy monitoring, Molecul. Diagn. Ther. 12 (2008) 157–170. 46. C.M. Gundberg, A.C. Looker, S.D. Nieman, M.S. Calvo, Patterns of osteocalcin and bone specific alkaline phosphatase by age, gender, and race or ethnicity, Bone 31 (2002) 703–708. 47. D. Vanderschueren, G. Gevers, G. Raymaekers, P. Devos, J. Dequeker, Sex- and age-related changes in bone and serum osteocalcin, Calcif. Tissue Int. 46 (1990) 179–182. 48. R.T. Turner, D.S. Colvard, T.C. Spelsberg, Estrogen inhibition of periosteal bone formation in rat long bones: downregulation of gene expression for bone matrix proteins, Endocrinology 127 (1990) 1346–1351. 49. P. Ducy, C. Desbois, B. Boyce, et al., Increased bone formation in osteocalcin-deficient mice, Nature 382 (1996) 448–452. 50. A.L. Boskey, S. Gadaleta, C. Gundberg, S.B. Doty, P. Ducy, G. Karsenty, Fourier transform infrared microspectroscopic analysis of bones of osteocalcin-deficient mice provides insight into the function of osteocalcin, Bone 23 (1998) 187–196. 51. M. Ferron, E. Hinoi, G. Karsenty, P. Ducy, Osteocalcin differentially regulates beta cell and adipocyte gene expression and affects the development of metabolic diseases in wild-type mice, Proc. Natl. Acad. Sci. USA 105 (2008) 5266–5270. 52. V. Cirmanová, M. Bayer, L. Stárka, K. Zajícková, The effect of leptin on bone: an evolving concept of action, Physiol. Res/Acad. Sci. Bohemoslov. 57 (Suppl 1) (2008) S143–S151.
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53. J.A. Im, B.P. Yu, J.Y. Jeon, S.H. Kim, Relationship between osteocalcin and glucose metabolism in postmenopausal women, Clin. Chim. Acta. 396 (2008) 66–69. 54. A. Gustavsson, P. Nordström, R. Lorentzon, U.H. Lerner, M. Lorentzon, Osteocalcin gene polymorphism is related to bone density in healthy adolescent females, Osteoporos. Int. 11 (2000) 847–851. 55. H.Y. Chen, H.D. Tsai, W.C. Chen, J.Y. Wu, F.J. Tsai, C.H. Tsai, Relation of polymorphism in the promotor region for the human osteocalcin gene to bone mineral density and occurrence of osteoporosis in postmenopausal Chinese women in Taiwan, J. Clin. Lab. Anal. 15 (2001) 251–255. 56. J.G. Kim, S.Y. Ku, D.O. Lee, et al., Relationship of osteocalcin and matrix Gla protein gene polymorphisms to serum osteocalcin levels and bone mineral density in postmenopausal Korean women, Menopause 13 (2006) 467–473. 57. G. Luo, P. Ducy, M.D. McKee, et al., Spontaneous calcification of arteries and cartilage in mice lacking matrix GLA protein, Nature 386 (1997) 78–81. 58. M. Murshed, T. Schinke, M.D. McKee, G. Karsenty, Extracellular matrix mineralization is regulated locally; different roles of two gla-containing proteins, J. Cell Biol. 165 (2004) 625–630. 59. L.J. Schurgers, H.M. Spronk, J.N. Skepper, et al., Posttranslational modifications regulate matrix Gla protein function: importance for inhibition of vascular smooth muscle cell calcification, J. Thromb. Haemost. 5 (2007) 2503–2511. 60. N.S. Fedarko, A. Jain, A. Karadag, L.W. Fisher, Three small integrin binding ligand N-linked glycoproteins (SIBLINGs) bind and activate specific matrix metalloproteinases, FASEB J. 18 (2004) 734–736. 61. C. Qin, O. Baba, WT. Butler, Post-translational modifications of sibling proteins and their roles in osteogenesis and dentinogenesis, Crit. Rev. Oral. Biol. Med. 15 (2004) 126–136. 62. A.L. Boskey, M.F. Young, T. Kilts, K. Verdelis, Variation in mineral properties in normal and mutant bones and teeth, Cells Tissues Organs 181 (2005) 144–153. 63. L. Malaval, N.M. Wade-Guéye, M. Boudiffa, et al., Bone sialoprotein plays a functional role in bone formation and osteoclastogenesis, J. Exp. Med. 205 (2008) 1145–1153. 64. Y. Ling, H.F. Rios, E.R. Myers, Y. Lu, J.Q. Feng, A.L. Boskey, DMP1 depletion decreases bone mineralization in vivo: an FTIR imaging analysis, J. Bone Miner. Res. 20 (2005) 2169–2177. 65. C. Qin, R. D’Souza, J.Q. Feng, Dentin matrix protein 1 (DMP1): new and important roles for biomineralization and phosphate homeostasis, J. Dent. Res. 86 (2007) 1134–1141. 66. K. Verdelis, Y. Ling, T. Sreenath, et al., Dspp effects on in vivo mineralization, Bone 43 (2008) 983–990. 67. PS. Rowe, The wrickkened pathways of FGF23, MEPE and PHEX, Crit. Rev. Oral. Biol. Med. 15 (2004) 264–281. 68. W.N. Addison, Y. Nakano, T. Loisel, P. Crine, M.D. McKee, MEPE-ASARM peptides control extracellular matrix mineralization by binding to hydroxyapatite: an inhibition regulated by PHEX cleavage of ASARM, J. Bone Miner. Res. 23 (2008) 1638–1649. 69. A.L. Boskey, D.J. Moore, M. Amling, E. Canalis, A.M. Delany, Infrared analysis of the mineral and matrix in bones of osteonectin-null mice and their wildtype controls, J. Bone Miner. Res. 18 (2003) 1005–1011.
70. F.C. Mansergh, T. Wells, C. Elford, et al., Osteopenia in Sparc (osteonectin)-deficient mice: characterization of phenotypic determinants of femoral strength and changes in gene expression, Physiol. Genomics 32 (2007) 64–73. 71. A.L. Boskey, L. Spevak, E. Paschalis, S.B. Doty, M.D. McKee, Osteopontin deficiency increases mineral content and mineral crystallinity in mouse bone, Calcif. Tissues Int. 71 (2002) 145–154. 72. A. Franzén, K. Hultenby, F.P. Reinholt, P. Onnerfjord, D. Heinegård, Altered osteoclast development and function in osteopontin deficient mice, J. Orthopaed. Res. 26 (2008) 721–728. 73. A.L. Boskey, M. Maresca, W. Ullrich, S.B. Doty, W.T. Butler, C.W. Prince, Osteopontin-hydroxyapatite interactions in vitro: inhibition of hydroxyapatite formation and growth in a gelatin-gel, Bone Miner. 22 (1993) 147–159. 74. G.K. Hunter, C.L. Kyle, H.A. Goldberg, Modulation of crystal formation by bone phosphoproteins: structural specificity of the osteopontin-mediated inhibition of hydroxyapatite formation, Biochem. J. 300 (1994) 723–728. 75. S. Jono, C. Peinado, C.M. Giachelli, Phosphorylation of osteo pontin is required for inhibition of vascular smooth muscle cell calcification, J. Biol. Chem. 275 (2000) 20197–20203. 76. A.L. Boskey, S.B. Doty, V. Kudryashov, P. Mayer-Kuckuk, R. Roy, I. Binderman, Modulation of extracellular matrix protein phosphorylation alters mineralization in differentiating chick limb-bud mesenchymal cell micromass cultures, Bone 42 (2008) 1061–1071. 77. W. Jahnen-Dechent, C. Schäfer, M. Ketteler, M.D. McKee, Mineral chaperones: a role for fetuin-A and osteopontin in the inhibition and regression of pathologic calcification, J. Molec. Med. 86 (2008) 379–389. 78. A. Gericke, C. Qin, L. Spevak, et al., Importance of phosphorylation for osteopontin regulation of biomineralization, Calcif. Tissues Int. 77 (2005) 45–54. 79. M. Scatena, L. Liaw, C.M. Giachelli, Osteopontin: a multifunctional molecule regulating chronic inflammation and vascular disease, Arterioscler. Thromb. Vasc. Biol. 27 (2007) 2302–2309. 80. J.Q. Feng, L.M. Ward, S. Liu, et al., Loss of DMP1 causes rickets and osteomalacia and identifies a role for osteocytes in mineral metabolism, Nat. Genet. 38 (2006) 1310–1315. 81. G. He, S. Gajjeraman, D. Schultz, et al., Spatially and temporally controlled biomineralization is facilitated by interaction between self-assembled dentin matrix protein 1 and calcium phosphate nuclei in solution, Biochemistry 44 (2005) 16140–16148. 82. P.H. Tartaix, M. Doulaverakis, A. George, et al., In vitro effects of dentin matrix protein-1 on hydroxyapatite formation provide insights into in vivo functions, J. Biol. Chem. 279 (2004) 18115–18120. 83. G.K. Hunter, H.A. Goldberg, Nucleation of hydroxyapatite by bone sialoprotein, Proc. Natl. Acad. Sci. USA. 90 (1993) 8562–8565. 84. G.S. Baht, G.K. Hunter, H.A. Goldberg, Bone sialoproteincollagen interaction promotes hydroxyapatite nucleation, Matrix Biol. 27 (2008) 600–608. 85. J.A. Gordon, C.E. Tye, A.V. Sampaio, T.M. Underhill, G.K. Hunter, H.A. Goldberg, Bone sialoprotein expression enhances osteoblast differentiation and matrix mineralization in vitro, Bone 41 (2007) 462–473.
C h a p t e r 1 The Biochemistry of Bone: Composition and Organization l
86. E. Bonnelye, N. Laurin, P. Jurdic, D.A. Hart, J.E. Aubin, Estrogen receptor-related receptor-alpha (ERR-alpha) is dysregulated in inflammatory arthritis, Rheumatology (Oxf) 47 (2008) 1785–1791. 87. R. Yang, L.C. Gerstenfeld, Structural analysis and characterization of tissue and hormonal responsive expression of the avian bone sialoprotein (BSP) gene, J. Cell. Biochem. 64 (1997) 77–93. 88. A. Boskey, K. Verdelis, A. Frank, Y. Fujimoto, L. Spevak, T. Carpenter, PHEX transgene corrects mineralization defects in 9 month old hypophosphatemic mice, Calcif. Tissues Int 84 (2009) 126–127. 89. M.F. Young, Y. Bi, L. Ameye, et al., Small leucine-rich proteoglycans in the aging skeleton, J. Musculoskelet. Neuron. Interact. 6 (2006) 364–365. 90. R.J. Waddington, H.C. Roberts, R.V. Sugars, E. Schänherr, Differential roles for small leucine-rich proteoglycans in bone formation, Eur. Cells Mater. 6 (2003) 12–21. 91. A.P. Rehn, R. Cerny, R.V. Sugars, N. Kaukua, M. Wendel, Osteoadherin is upregulated by mature osteoblasts and enhances their in vitro differentiation and mineralization, Calcif. Tissues Int. 82 (2008) 454–464. 92. S. Chakraborty, J. Cheek, B. Sakthivel, B.J. Aronow, K.E. Yutzey, Shared gene expression profiles in developing heart valves and osteoblast progenitor cells, Physiol. Genomics 35 (2008) 75–85. 93. K. Ninomiya, T. Miyamoto, J. Imai, et al., Osteoclastic activity induces osteomodulin expression in osteoblasts, Biochem. Biophys. Res. Commun. 362 (2007) 460–466. 94. T.G. Kashima, T. Nishiyama, K. Shimazu, et al., Periostin, a novel marker of intramembranous ossification, is expressed in fibrous dysplasia and in c-Fos-overexpressing bone lesions, Hum. Pathol. (15 September, 2008) [Epub ahead of print]. 95. K. Ohta, G. Lupo, S. Kuriyama, et al., Tsukushi functions as an organizer inducer by inhibition of BMP activity in cooperation with chordin, Dev. Cell 7 (2004) 347–358. 96. A.I. Alford, K.D. Hankenson, Matricellular proteins: extracellular modulators of bone development, remodeling, and regeneration, Bone 38 (2006) 749–757.
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97. R.J. Midura, A. Wang, D. Lovitch, D. Law, K. Powell, J.P. Gorski, Bone acidic glycoprotein-75 delineates the extracellular sites of future bone sialoprotein accumulation and apatite nucleation in osteoblastic cultures, J. Biol. Chem. 279 (2004) 25464–25473. 98. C. Sintuu, S.S. Murray, K. Behnam, et al., Full-length bovine spp24 [spp24 (24-203)] inhibits BMP-2 induced bone formation, J. Orthopaed. Res. 26 (2008) 753–758. 99. J.L. Millán, Alkaline phosphatases: structure, substrate specificity and functional relatedness to other members of a large superfamily of enzymes, Purinerg. Signal. 2 (2006) 335–341. 100. D.R. Hopkins, S. Keles, DS. Greenspan, The bone morphogenetic protein 1/Tolloid-like metalloproteinases, Matrix Biol. 26 (2007) 508–523. 101. H.K. Väänänen, T. Laitala-Leinonen, Osteoclast lineage and function, Arch. Biochem. Biophys. 473 (2008) 132–138. 102. J.D. Kaunitz, D.T. Yamaguchi, TNAP, TrAP, ecto-purinergic signaling, and bone remodeling, J. Cell. Biochem. 105 (2008) 655–662. 103. M. Goldberg, A.L. Boskey, Lipids and biomineralizations, Prog. Histochem. Cytochem. 31 (1996) 1–187. 104. K. Podar, K.C. Anderson, Caveolin-1 as a potential new therapeutic target in multiple myeloma, Cancer Lett. 233 (2006) 10–15. 105. J. Rubin, Z. Schwartz, B.D. Boyan, et al., Caveolin-1 knockout mice have increased bone size and stiffness, J. Bone Miner. Res. 22 (2007) 1408–1418. 106. K. Nakashima, X. Zhou, G. Kunkel, et al., The novel zinc finger-containing transcription factor osterix is required for osteoblast differentiation and bone formation, Cell 108 (2002) 7–29. 107. Q. Tu, J. Zhang, J. Paz, K. Wade, P. Yang, J. Chen, Haploinsufficiency of Runx2 results in bone formation decrease and different BSP expression pattern changes in two transgenic mouse models, J. Cell Physiol. 217 (2008) 40–47. 108. S.D. Berman, T.L. Yuan, E.S. Miller, E.Y. Lee, A. Caron, J.A. Lees, The retinoblastoma protein tumor suppressor is important for appropriate osteoblast differentiation and bone development, Molec. Cancer Res. 6 (2008) 1440–1451.
Chapter
2
Bone Remodeling: Cellular Activities in Bone Hua Zhou1, Shi S Lu1 and David W. Dempster2 1
Regional Bone Center, Helen Hayes Hospital, West Haverstraw, New York, NY, USA Department of Pathology, College of Physicians and Surgeons, Columbia University, New York, NY, USA
2
Introduction
where removal of old bone is coupled in space and in time by replacement by new bone [6, 7].
Bone remodeling is a fundamental process by which the mammalian skeleton tissue is continuously renewed to maintain the structural, biochemical and biomechanical integrity of bone and to support its role in mineral homeostasis. The process of bone remodeling is achieved by the cooperative and sequential work of groups of functionally and morphologically distinct cells, termed basic multicellular units (BMUs) or bone remodeling units (BRUs). Changes in the population and/or activities in any component of the BMUs disrupts the harmony of the cellular efforts and leads to changes in bone mass and strength. The cellular activities of bone remodeling units vary within and among the different bones of the skeleton and this variation changes with age, underlying the mechanism of agerelated bone loss. This chapter reviews current concepts of bone remodeling with respect to its cellular mechanism, physiological functions and anatomic variation in cellular behavior.
Activation Activation is the term used to describe the process of converting a resting bone surface into a remodeling surface. In the human adult skeleton, a new BRU is activated about every ten seconds [3]. Activation involves recruitment of mononuclear osteoclast precursors from hematopoietic origin, penetration by osteoclast precursors through gaps in the bone lining cell layer, fusion of the precursor cells to form multinucleated osteoclasts and functional osteoclasts adhering to mineralized bone matrix [8, 9]. Two cytokines, receptor activator of nuclear factor kappa B ligand (RANKL) and macrophage colony-stimulating factor (M-CSF), are essential and sufficient for osteoclastogenesis [10–12]. RANKL and M-CSF are produced by marrow stromal cells and their derivative osteoblasts in response to pro-resorption stimuli, such as parathyroid hormone (PTH), 1,25(OH)2D, interleukin-1 (IL-1) and interleukin-6 (IL-6), and play a crucial role in the formation, activation, activity and life span of osteoclasts (Figure 2.2). The activation of sites on the bone surface is either targeted or random. Selective remodeling targets specific sites where the osteocytes have sensed a change in mechanical strain or matrix damage in the form of microcracks and have conveyed signals to the surface to initiate targeted remodeling. However, most remodeling sites are likely to be random [13, 14].
Cellular mechanism of bone remodeling Bone remodeling takes place on bone surfaces and is achieved by multicellular units, BMUs [1, 2] or bone remodeling units, BRUs [3], the latter term being used here. The process of remodeling consists of four sequential and distinct phases of cellular events: activation, resorption, reversal and formation [2, 4, 5] (Figure 2.1A–E). The microanatomic basis of BRUs is osteonal units in intracortical bone (Figure 2.1G) and discrete osteonal units or packets in endocortical and cancellous bone (Figure 2.1F),
Osteoporosis in Men
Resorption Osteoclasts affix themselves to the bone matrix through integrins such as 3 [15, 16]. The adherence to bone induces ruffled membrane formation and creates an annular
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Copyright 2009, 2010 Elsevier, Inc. All rights of reproduction in any form reserved.
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Osteoporosis in Men (A)
(B)
(C)
(D) O L MB
(E)
Cancellous bone remodeling unit
(F)
(G)
Resorption
Reversal
Formation
Cortical bone remodeling unit
Figure 2.1 Light photomicrographs of the principal phases of the remodeling cycle in cancellous bone of human iliac crest biopsy specimens. (A) Resorption. Several multinucleated osteoclasts are seen in excavating a Howship’s lacuna. (B) Reversal. The Howship’s lacuna contains no osteoclasts but small mononucleated cells in contact with the scalloped surface. (C) Formation. A sheet of plump osteo blasts is seen depositing osteoid (O) on top of mineralized bone (MB). Note the reversal line (L) and osteocyte lacunae (arrowheads) in the mineralized matrix. (D) A later stage of formation where the osteoblasts have become flattened lining cells. Matrix production has ceased, but a thin layer of osteoid still remains to be mineralized. (E) Resting. No remodeling activity is in progress but a layer of attenuated cells lines the surface. Cross-sectional diagrams of BRUs in cancellous bone (F) and cortical bone (G). The arrows indicate the direction of movement through space. Note that the cancellous BRU is essentially one half of the cortical BRU. (A–E, from Dempster DW. Bone remodeling. In Disorders of bone and mineral metabolism. 2nd edn, (eds) Coe F, Favus MJ, pp 315–343, 2002. Lippincott Williams & Wilkins, Philadelphia: with permission. F,G, from Seibel MJ, Robins SP, Bilezikian JP. (eds) Dynamics of bone and cartilage metabolism, 2nd edn, pp 377–389, 2006. Academic Press, New York with permission).
C h a p t e r 2 Bone Remodeling: Cellular Activities in Bone l
17
Prostaglandins, multiple hormones, cytokines, ILs and vitamin D E2 Stromal/osteoblastic cells
GCs
T T
TGFβ IFNγ
T OPG, RANKL, M-CSF
TNFα, IL-1, IL-6, IL-7, other ILs
RANKL TNFα
HSC M-CSF c-Fms– RANK–
c-Fms+ RANK–
c-Fms+ RANK+
M-CSF + RANKL T OPG
Figure 2.2 Role of cytokines, peptide and steroid hormones and prostaglandins in the osteoclast formation and activation. Hematopoietic stem cells (HSCs) express c-Fms (receptor for M-CSF) and RANK (receptor for RANKL) and differentiate to osteoclasts. Marrow mesenchymal cells respond to a range of stimuli by secreting a mixture of pro- and anti-osteoclastogenic factors, the latter consisting primarily of OPG. (From Ross FP. Osteoclast biology and bone resorption. In Primer on the metabolic bone diseases and disorders of mineral metabolism, 6th edn, (ed.) Favus MJ, pp 30–35, 2006. American Society for Bone and Mineral Research, Washington, with permission).
sealing zone, forming a hemivacuole between the osteoclast itself and the bone matrix and isolated from the surrounding extracellular space (Figure 2.3A, B). By means of membrane-bound proton pumps and chloride channels, the osteoclast secretes hydrochloric acid, as well as acidic proteases such as cathepsin K, TRACP, MMP9, MMP13 and gelatinase into the hemivacuole (see Figure 2.3A, B) [17, 18]. The acidified solution in the resorbing compartment mobilizes the mineralized component of the matrix and the proteolytic enzymes, which are most active at low pH, degrade the organic constituents of the matrix. This pro cess creates the crescent-shaped resorption cavities called Howship’s lacunae on the cancellous bone surface (see Figure 2.1A and F) and the cutting cones of the evolving Haversian systems within cortical bone (see Figure 2.1G). Generally, the resorption is accomplished by multinucleated osteoclasts, but both in vivo and in vitro evidence suggests that mononucleated cells are also capable of excavating bone and forming resorption cavities and cutting cones [19, 20]. The fate of the osteoclast at the conclusion of the resorption phase is unclear, but at least some undergo apoptosis [21].
Reversal During this phase, the resorption lacuna is occupied by mononuclear cells, including monocytes, osteocytes that
were liberated from bone by osteoclasts and pre-osteoblasts that are being recruited to couple the resorption phase with the formation phase (see Figure 2.1B, F, G) [22]. The mechanism of osteoblast coupling and the exact nature of the coupling signals are currently undefined, but there are a number of interesting hypotheses. One plausible theory is that osteoclastic bone resorption liberates growth factors from the bone matrix and that these factors serve as chemo attractants for osteoblast precursors and then enhance osteoblast proliferation and differentiation. Bone matrixderived growth factors, such as transforming growth factor- (TGF-), insulin-like growth factors I and II (IGF-I and II), bone morphogenetic proteins (BMPs), platelet-derived growth factors (PDGF) and fibroblast growth factor (FGF) are all possible contenders for such coupling factors [23–27]. Another attractive premise is that the coupling of bone formation to resorption is a strain-regulated phenomenon [28]. As bone remodeling units penetrate through cortical bone, strain levels are reduced in front of the osteoclasts, but are increased behind them. Similarly, in cancellous bone, strain is posited to be higher at the base of the Howship’s lacunae and lower in the surrounding bone. It is argued that this gradient of strain leads to sequential activation of osteoclasts and osteoblasts, with osteoclasts being activated by reduced strain and osteoblasts, in turn, by increased strain. This hypothesis may account for alignment of osteons along the dominant loading direction of the
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Osteoporosis in Men
bone [29, 30]. Furthermore, osteoclast to osteoblast forward and reverse signaling has recently been implicated in the coupling mechanism [31, 32].
Formation
Sealing zone (A)
Ruffled border
Sealing zone
Bone
HCO3-Cl-
Cath K
H+HCO3-Cl-
αvβ3
H+ ClBone
Nuclei
TGN Microtubles
Signaling ruffled membrane
αvβ3
(B)
Bone
Figure 2.3 (A) Transmission electron microphotograph of a multinucleated osteoclast in rat bone. Note the extensive ruffled border, sealing zones and the partially degraded matrix between the sealing zones. (B) Diagram illustrating the primary mechanisms of osteoclastic bone resorption. (From Ross FP. Osteoclast biology and bone resorption. In Primer on the metabolic bone diseases and disorders of mineral metabolism, 6th edn, (ed.) Favus MJ, pp 30–35, 2006. American Society for Bone and Mineral Research, Washington, with permission).
Osteoblasts are recruited and differentiate from mesenchymal precursors. There is a gradient of differentiation as the osteoblastic precursors reach the bone surface to refill the resorption cavity and the osteoblast phenotype becomes fully expressed (Figure 2.4A) [33]. Bone matrix formation is a two-stage process in which osteoblasts initially synthesize the organic matrix, called osteoid, and then regulate its mineralization (Figure 2.4B). Osteoid consists of collagenous proteins, predominantly type I collagen, accounting for 90% of the organic matrix, with non-collagenous proteins making up the remaining 10%, including glycoproteins (i.e. alkaline phosphatase and osteonectin), Gla-containing proteins (i.e. osteocalcin and matrix Gla protein) and others (e.g., proteolipids) [34]. Osteoid is deposited on the bone surface in curved sheets called osteoid lamellae, following the contours of the underlying mineralized bone (see Figure 2.4B). Once the collagenous organic matrix is synthesized, osteoblasts trigger the mineralization process, which occurs after a delay of about 20 days, called the mineralization lag time. This is accomplished by the release of small, membranebound matrix vesicles that establish suitable conditions for initial mineral deposition by concentrating calcium and phosphate ions and enzymatically degrading inhibitors of mineralization, such as pyrophosphate and proteoglycans that are present in the extracellular matrix [35]. During this period, the osteoid undergoes a variety of biochemical changes that render it mineralizeable. The mineral content of the matrix increases rapidly to 75% of the final mineral content over the first few days, called primary mineralization, but it may take as long as a year for the matrix to reach its maximum mineral content, called secondary mineralization [36]. The mineral crystals within bone are analogous to the naturally occurring geologic mineral, hydroxyapatite (Ca10[PO4]6[OH]2), including numerous ions which are not found in pure hydroxyapatite, such as HPO42, CO32, Mg2, Na, F and citrate, adsorbed to the hydroxyapatite crystals [34]. As bone formation continues, osteoblasts that have reached the end of their synthetic activity embed themselves in the matrix, becoming osteocytes (see Figure 2.4A). Osteocytes are regularly dispersed throughout the mineralized matrix and maintain intimate contact with each other, as well as to the cells on the bone surface, through gap junctions between their slender, cytoplasmic processes or dendrites, which pass through the bone in small canals called canaliculi (Figure 2.5). Osteocytes function as an extensive 3-dimensional network of sensor cells, or ‘syncytium’, which can detect a change in mechanical strain in bone and respond by transmitting signals to the lining
C h a p t e r 2 Bone Remodeling: Cellular Activities in Bone l
19
OS MS MB
pOB OB OS pOCY OCY
MB
(A)
(B)
Figure 2.4 (A) Light photomicrograph of a human bone biopsy stained with Goldner’s trichrome. Osteoblastic lineage in a gradient differentiation: osteoblastic precursors (pOB) reach the bone surface → mature osteoblasts (OB) filling in a resorption cavity → pre-osteocytes (pOCY) become incorporated into osteoid (OS) matrix → osteocytes (OCY) embedded within the mineralized bone (MB). (B) Fluorescent photomicrograph of dog bone. Two steps of bone formation: osteoid matrix forming on bone surface (OS), mineralizing surface (MS) and mineralized bone (MB). (See color plate section).
(A)
(B)
Figure 2.5 (A) Transmission and (B) scanning electron micrographs showing osteocyte processes communicating with cells on the bone surface. (From Marotti G. et al. The structure of bone tissues and the cellular control of their deposition. Ital J Anat Embryol 1996;101:25-79, with permission).
cells on the bone surface to initiate targeted remodeling or to regulate resorption and formation in the newly initiated bone remodeling cycle [37]. Osteocytes die by apoptosis, which occurs with aging, immobilization, microdamage, lack of estrogen, glucocorticoid excess and in association with pathological conditions, such as osteoporosis and osteoarthritis [38]. Osteocyte apoptosis has also been suggested to play an important role in targeting bone remodeling following the observation that osteocyte apoptosis occurs in association with areas of microdamage and that this is followed by osteoclastic resorption to begin the replacement of the mechanically challenged bone [39]. Osteoblasts suffer one of three fates during and at the end of the bone formation phase of the remodeling cycle: many become incorporated into the matrix they formed and differentiate into osteocytes; some convert into lining
cells on the bone surface at the termination of formation; and the remainder die by apoptosis. Bone lining cells were once thought to serve primarily to regulate the flow of ions into and out of the bone extracellular fluid serving as the blood–bone barrier. It has recently been appreciated that, under certain circumstances, for example, stimulation by PTH or mechanical force, bone lining cells can revert back to functional osteoblasts [40, 41]. Another recently discovered important function of the lining cells is to create specialized compartments in cancellous and cortical bone where bone remodeling takes place [42] (Figure 2.6). The end result of a completed remodeling cycle by a BRU is the production of a new osteon (Figure 2.7A, B). The remodeling process is similar in cancellous and cortical bone with the remodeling unit in cancellous bone being equivalent to half of a cortical remodeling unit [43] (see Figure 2.1F, G).
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The difference between the volume of bone removed by osteoclasts and replaced by osteoblasts during BRU remodeling cycle is termed ‘bone balance’. As will be discussed later, the bone balance varies with the anatomical location of the bone surface as well as with gender, age and disease.
Physiological functions of bone remodeling The primary functions of bone remodeling are presumed to be maintenance of the mechanical competence of bone by continuously replacing fatigued bone with new, mechanically sound bone and to preserve mineral homeostasis by continuously mobilizing the skeletal stores of calcium and phosphorus
OC
Figure 2.6 Light photomicrograph of a human bone biopsy stained with toluidine blue. An osteoclast (OC) is resorbing bone within a specialized compartment formed by a dome-shaped layer of lining cells (arrows). (See color plate section).
(A)
to the circulation. It has also been suggested that there must be other, as yet known functions or reasons why the human skeleton undergoes such extensive remodeling [44]. Like all load-bearing structural materials, the skeleton is subjected to fatigue damage as it ages and undergoes repetitive mechanical challenges. Older bone displays increased mineralization density as secondary mineralization continues and the water content diminishes, which causes the matrix to become more brittle [45]. In addition, aging is associated with biochemical changes in the bone matrix constituents, such as accumulation of non-enzymatic glyca tion end products [46] and increased cross-linking of collagen [47]. These changes render the bone more susceptible to mechanical damage and fracture. It has also been demonstrated that osteocytes that have undergone apoptosis leave empty lacuna that may become occluded by mineralized debris [48] and that fatigue microcracks increase in number with bone age and are spatially associated with missing osteocytes [49]. Moreover, the fact that resorption cavities are frequently located close to bone microcracks [50, 51] provides compelling evidence that targeted remodeling is activated in response to the appearance of such microcracks. The skeleton is the greatest repository of mineral ions, such as Ca, Mg and P, in the human body and plays an important role in mineral homeostasis by coordinated interplay with the intestine, the site of net ionic absorption, and the kidney, the site of net ionic excretion. Longterm mineral homeostasis is achieved by the BRUs, which mobilize skeletal mineral to blood during bone resorption and return the mineral back to the skeleton during bone formation. However, at least two other mechanisms allow the skeleton to participate in mineral homeostasis: the blood– bone barrier maintained by the bone lining cells and the percolation of bone extracellular fluid through osteocyte lacuno-canalicular network.
(B)
Figure 2.7 (A) Completed basic structural units in cancellous bone and (B) cortical bone. The arrowheads delineate reversal lines. (From Dempster DW. Bone remodeling. In Osteoporosis: etiology, diagnosis, and management, 2nd edn, (eds) Riggs BL, Melton LJ, pp 67–91, 1995. Raven Press, New York, with permission.) (See color plate section).
C h a p t e r 2 Bone Remodeling: Cellular Activities in Bone l
In the regulation of calcium homeostasis, a fall in serum Ca2 concentration is detected by the parathyroid cell plasma membrane Ca-sensing receptor (CaSR), which leads to an increase in parathyroid hormone release. Parathyroid hormone acts to mobilize calcium by three mechanisms: PTH regulates the outflow of calcium from bone by stimulating the resorptive activity in existing BRUs, an acute response, and by stimulating the activation of new BRUs and increasing bone turnover, a long-term response [52]. PTH also stimulates renal tubular reabsorption of calcium and regulates the calcium blood–bone equilibrium through the lining cells on quiescent bone surfaces. Finally, PTH increases intestinal absorption of calcium by enhancement of 1,25 dihydroxyvitamin D synthesis [53, 54]. The involvement of the skeleton in phosphate homeo stasis is achieved in a similar manner. A fall in plasma phosphate concentration stimulates 1,25-dihydroxyvitamin D production in the kidney which, in addition to increasing phosphate absorption from gut, stimulates bone remodeling to mobilize phosphate from the skeleton. Clearly, phosphate cannot be withdrawn from the skeleton without being accompanied by calcium and vice versa. However, the unnecessary increase in calcium or phosphate, respectively, can be compensated by the enhanced renal excretion of calcium or phosphate. As discussed earlier in the chapter, minerals are transferred into bone during the formation phase of the remodeling cycle. Because bone formation is usually tightly coupled with bone resorption, bone remodeling does not generally lead to a net transfer of mineral to or from the blood in the long run. However, an increase in remodeling rate does transiently mobilize significant amounts of mineral into the blood, because it takes a much longer time for newly formed bone to reach the same mineral content as that removed during bone resorption [55]. By analogy to financial transactions, when calcium is urgently needed, it may be withdrawn rapidly from the bone bank and then paid back gradually later. This allows the skeleton to participate in calcium homeostasis without permanently compromising its structural integrity. However, with advancing age, the intestinal absorption of calcium declines and, ultimately, the mechanical competence of the skeleton is compromised to maintain an adequate serum calcium level.
Variation in bone remodeling activity throughout the skeleton The bone turnover rate varies substantially within and among the different bones of the skeleton. It has often been asserted that cancellous bone has higher turnover than cortical bone [56], which is true when one compares central cancellous bone with peripheral cortical bone. This is generally attributed to the four to five times higher surface-to-volume
21
ratio in the typical cancellous bone than in the typical cortical bone [57, 58] and to the close correspondence in cancellous bone tissue between marrow cellularity, blood flow and remodeling activity [59]. But this view fails to consider the geometrical and biological factors that influence bone turnover [56, 59]. The subdivisions within the bone consist of four distinct surfaces or ‘envelopes’: periosteal, Haversian or intracortical, cortical-endosteal or endocortical and cancellous [4, 56]. The evaluation of the activity of BRUs on each subdivision provides a histological estimation of bone turnover with the measurement and calculation of the tetracycline-based bone formation rate and activation frequency. Such data are available for the ilium and the rib in the human skeleton. In the iliac bone of healthy postmenopausal white women, bone turnover is 8.4% per year in the subperiosteal envelope, 5.9% per year in the intracortical envelope and 33.7% per year in the subendocortical envelope. The bone turnover in the total cortical bone is 7.7% per year and in the cancellous bone it is 17.7% per year [56, 58, 60, 61]. In the cortical bone of the sixth rib, mean bone turnover after 50 years is 4% per year [62]. Differences in cellular activity in BRUs among the anatomic subdivisions within the bone determines the net difference between the volume of bone removed and replaced by each BRU. In the Haversian or intracortical envelope, the net bone balance is slightly negative, particularly in the inner half of the cortex, which leads to a decrease in the radial rate of closure of osteons [62], an increase in the Haversian canal diameter, a decrease in osteon wall thickness and an increase in the number of resorption cavities that are abandoned in the reversal phase and remain unfilled [63–66]. In the periosteal envelope, each BRU deposits slightly more bone than it removes. Conversely, in the endocortical envelope, less bone is laid down than resorbed and the deficit here is greater than the slight positive balance in the periosteal envelope, which reduces the thickness of cortex [60, 67, 68]. In the cancellous bone envelope, there is a shortfall in the amount of bone replaced compared to that removed, which causes thinning of trabeculae making them more vulnerable to perforation by osteoclasts [60, 67, 68]. With aging, the effects of these small increments and decrements of bone mass accumulate. The net bone balance on each envelope provides a BRUbased explanation for the long-established facts concerning the changes in three-dimensional geometry of bones as a function of age [4]. Both the positive bone balance on the periosteal surface and the negative balance on the endocortical surface increase their respective circumferences, with the latter moving outward at a greater rate than the former, which consequently reduces cortical thickness. The cortical porosity increases by 1–2% in the outer half of the cortex and by 5–10% in the inner half due to the negative bone balance on the Haversian surface. The increase in the osteoclast resorption cavity depth, together with the negative bone balance on the endocortical surface and the
22
Osteoporosis in Men
increase in cortical porosity, leads to the creation of large voids in the inner third to half of the cortex. Ultimately, the inner cortex resembles the cancellous bone in structure, a process called cortical bone cancellization, which contributes to the thinning of cortex. In cancellous bone, the negative bone balance in BRUs is manifested in a reduction of the completed wall thickness of cancellous bone packets, which is partially the cause of the gradual age-related bone loss that occurs in both sexes [69, 70]. There have been relatively few assessments of the regional variation in bone remodeling and turnover throughout the skeleton. Some attention has been given to the relationship between the standard biopsy site in the iliac crest and other skeletal sites [71]. As evaluated by histomorphometry, the bone turnover rate in ilium is about double that in the vertebral body [3]. Based on the measurement of osteoid and osteoblast-covered surface, Krempien and colleagues found a marked disparity among four different skeletal sites, with an implied rank order of remodeling rate as follows: iliac crest lumbar vertebra femoral head distal femur [72]. The histomorphometric analysis of tetracycline-labeled bone samples has been the most reliable way to assess regional differences in remodeling rate but, obviously, is not practical for studies in living subjects. However, there is one case report [73] of an elderly osteo porotic woman who died suddenly before a scheduled bone biopsy for which she had been pre-labeled with tetracycline. Twenty-four skeletal sites were sampled at autopsy and bone formation rates were found to vary widely from a high of 37% per year in the iliac crest to a low of less than 2% per year in the 10th thoracic vertebra. Significant variations were also found between bones within fairly localized regions of the skeleton, e.g. from one vertebra to the next, or between the right and left iliac crest. The tetracyclinebased bone formation rate in cortical bone of rib, a oncefavored biopsy site, is 3–4% year, which is about twice that in cortical bone elsewhere in the skeleton [3].
References 1. H.M. Frost, Dynamics of bone remodeling, in: H.M. Frost (Ed.), Bone Biodynamics, Little Brown & Co, Boston, 1964. 2. H.M. Frost, Bone Remodeling and Its Relationship to Metabolic Bone Disease, Charles C Thomas, Springfield, 1973. 3. A.M. Parfitt, The physiological and clinical significance of bone histomorphometric data, in: R.R. Recker (Ed.), Bone Histomorphometry: Techniques and Interpretation, CRC Press, Boca Raton, 1983, pp. 143–223. 4. H.M. Frost, Intermediary Organization of the Skeleton, CRC Press, Boca Raton, 1986. 5. R. Baron, Importance of the intermediate phases between resorption and formation in the measurement and understanding of the bone remodeling sequence, in: P.J. Meunier (Ed.), Bone Histomorphometry. Proceedings of the 2nd International workshop, Société de la Nouvelle Imprimerie Fournie, Toulouse, 1977, pp. 179–183.
6. H.M. Frost, Bone Remodeling Dynamics, Charles C Thomas, Springfield, 1963. 7. H.M. Frost, The Laws of Bone Structure, Charles C Thomas, Springfield, 1964. 8. P. Tran Van, A. Vignery, R. Baron, An electron microscopic study of the bone-remodeling sequence in the rat, Cell Tissue Res. 225 (1982) 283–292. 9. P. Tran Van, A. Vignery, R. Baron, Cellular kinetics of the bone remodeling sequence in the rat, Anat. Rec. 202 (1982) 441–451. 10. W.J. Boyle, W.S. Simonet, D.L. Lacey, Osteoclast differentiation and activation, Nature 423 (2003) 337–342. 11. T. Suda, N. Takahashi, N. Udagawa, E. Jimi, M.T. Gillespie, T.J. Martin, Modulation of osteoclast differentiation and function by the new members of the tumor necrosis factor receptor and ligand families, Endocr. Rev. 20 (1999) 345–357. 12. F.J. Pixley, E.R. Stanley, CSF-1 regulation of the wandering macrophage: complexity in action, Trends Cell Biol. 14 (2004) 628–638. 13. D.B. Burr, Targeted and nontargeted remodeling, Bone 30 (2002) 2–4. 14. A.M. Parfitt, Targeted and nontargeted bone remodeling: relationship to basic multicellular unit origination and progression, Bone 30 (2002) 5–7. 15. R.O. Hynes, Integrins: bidirectional, allosteric signaling machines, Cell 110 (2002) 673–687. 16. F.P. Ross, S.L. Teitelbaum, 3 and macrophage colonystimulating factors: partners in osteoclast biology, Immunol. Rev. 208 (2005) 88–105. 17. S.L. Teitelbaum, F.P. Ross, Genetic regulation of osteoclast development and function, Nat. Rev. Genet. 4 (2003) 638–649. 18. J.M. Delaisse, T.L. Andersen, M.T. Engsig, K. Henriksen, T. Troen, L. Blavier, Matrix metalloproteinases (MMP) and cathepsin K contribute differently to osteoclastic activities, Microsc. Res. Tech. 61 (2003) 504–513. 19. E.F. Eriksen, Normal and pathological remodeling of human trabecular bone: three-dimensional reconstruction of the remodeling sequence in normals and in metabolic bone disease, Endocr. Rev. 7 (1986) 379–408. 20. D.W. Dempster, C. Hughes-Begos, K. Plavetic-Chee, et al., Normal human osteoclasts formed from peripheral blood monocytes express PTH type 1 receptors and are stimulated by PTH in the absence of osteoblasts, J. Cell Biochem. 95 (2005) 139–148. 21. H.C. Blair, S. Simonet, D.L. Lacey, M. Zaidi, Osteoclast biology, in: R. Marcus, D. Feldman, D.A. Nelson, C.J. Rosen (Eds.) Osteoporosis, third ed., Elsevier Academic Press, Burlington, 2008, pp. 71–89. 22. R. Baron, A. Vignery, P. Tran Van, The significance of lacunar erosion without osteoclasts: studies on the reversal phase of the remodeling sequence, Metab. Bone. Dis. Relat. Res. 2S (1980) 35–40. 23. L.F. Bonewald, G.R. Mundy, Role of transforming growth factor beta in bone remodeling, Clin. Orthoped. Relat. Res. 250 (1990) 261–276. 24. S. Mohan, D.J. Baylink, Insulin-like growth factor system components and the coupling of bone formation to resorption, Hormone. Res. 45 (Suppl. 1) (1996) 59–62. 25. J.M. Hock, M. Centrella, E. Canalis, Insulin-like growth factor I (IGF-I) has independent effects on bone matrix formation and cell replication, Endocrinology 122 (1998) 254–260.
C h a p t e r 2 Bone Remodeling: Cellular Activities in Bone l
26. J. Fiedler, G. Roderer, K.P. Gunther, R.E. Brenner, BMP-2, BMP-4, and PDGF-bb stimulate chemotactic migration of primary human mesenchymal progenitor cells, J. Cell Biochem. 87 (2002) 306–312. 27. H. Tanaka, A. Wakisaka, H. Ogasa, S. Kawai, C.T. Liang, Effects of basic fibroblast growth factor on osteoblast-related gene expression in the process of medullary bone formation induced in rat femur, J. Bone. Miner. Metab. 21 (2003) 74–79. 28. T.H. Smit, E.H. Burger, Is BMU-coupling a train-regulated phenomenon? A finite element analysis, J. Bone Miner. Res. 15 (2000) 301–307. 29. T.H. Smit, E.H. Burger, J.M. Huyghe, A case for straininduced fluid flow as a regulator of BMU-coupling and osteonal alignment, J. Bone Miner. Res. 17 (2002) 2021–2029. 30. E.H. Burgher, J. Klein-Nulend, T.H. Smit, Strain-derived, canalicular fluid flow regulates osteoclast activity in a remodelling osteon – a proposal, J. Biomech. 36 (2003) 1453–1459. 31. T.J. Martin, N.A. Sims, Osteoclast-derived activity in the coupling of bone formation to resorption, Trends. Molec. Med. 11 (2005) 76–81. 32. M.A. Karsdal, K. Henriksen, M.G. Sorensen, et al., Acidification of the osteoclastic resorption compartment provides insight into the coupling of bone formation to bone resorption, Am. J. Pathol. 166 (2005) 467–476. 33. J.B. Lian, G.S. Stein, Osteoblast biology, in: R. Marcus, D. Feldman, D.A. Nelson, C.J. Rosen (Eds.) Osteoporosis, Elsevier Academic Press, London, 2008, pp. 93–150. 34. W. Zhu, P.G. Robey, A. Boskey, The regulatory role of matrix proteins in mineralization of bone, in: R. Marcus, D. Feldman, D.A. Nelson, C.J. Rosen (Eds.) Osteoporosis, Elsevier Academic Press, London, 2008, pp. 191–240. 35. H.C. Anderson, Matrix vesicles and calcification, Curr. Rheumatol. Rep. 5 (2003) 222–226. 36. R. Amprino, A. Engstrom, Studies on x-ray absorption and diffraction of bone tissue, Acta. Anat. 15 (1952) 1–22. 37. L.F. Bonewald, M.L. Johnson, Osteocytes, mechanosensing and Wnt signaling, Bone 42 (2008) 606–615. 38. L.F. Bonewald, Osteocytes, in: R. Marcus, D. Feldman, D.A. Nelson, C.J. Rosen (Eds.) Osteoporosis, Elsevier Academic Press, London, 2008, pp. 169–189. 39. B.S. Noble, N. Peet, H.Y. Stevens, et al., Mechanical loading: biphasic osteocyte survival and targeting of osteoclasts for bone destruction in rat cortical bone, Am. J. Physiol. Cell. Physiol. 284 (2003) C934–C943. 40. H. Dobnig, R.T. Turner, Evidence that intermittent treatment with parathyroid hormone increases bone formation in adult rats by activation of bone lining cells., Endocrinology 136 (1995) 3632–3638. 41. J.W. Chow, A.J. Wilson, T.J. Chambers, S.W. Fox, Mechanical loading stimulates bone formation by reactivation of bone lining cells in 13-week-old rats, J. Bone Miner. Res. 13 (1998) 1760–1767. 42. E.M. Hauge, D. Qvesel, E.F. Eriksen, L. Mosekilde, F. Melsen, Cancellous bone remodeling occurs in specialized compartments lined by cells expressing osteoblastic markers, J. Bone Miner. Res. 16 (2001) 1575–1582. 43. A.M. Parfitt, Osteonal and hemiosteonal remodeling: the spatial and temporal framework for signal traffic in adult bone, J. Cell Biochem. 55 (1994) 273–276.
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44. J.D. Currey, Bone: Structure and Mechanics, Princeton University Press, Princeton, 2002. 45. H.M. Frost, Micropetrosis, J. Bone Joint Surg. 42 (1980) 138–143. 46. D. Vashishth, G.J. Gibson, J.L. Khoury, M.B. Schaffler, J. Kimura, DP. Fyhrie, Influence of nonenzymatic glycation on biomechanical properties of cortical bone, Bone 28 (2001) 195–201. 47. A.J. Bailey, Changes in bone collagen with age and disease, J. Musculoskelet Neuron Interact. 2 (2002) 529–531. 48. S. Qiu, S. Palnitkar, D.S. Rao, A.M. Parfitt, Age and distance from the surface but not menopause reduce osteocyte viability in human cancellous bone, Bone 31 (2002) 313–318. 49. S. Qiu, D.S. Rao, D.P. Fyhrie, S. Palnitkar, A.M. Parfitt, The morphological association between microcracks and osteocyte lacunae in human cortical bone, Bone 37 (2005) 10–15. 50. S. Mori, D.B. Burr, Increased intracortical remodeling following fatigue damage, Bone 14 (1993) 103–109. 51. D.B. Burr, M.R. Forwood, D.P. Fyhrie, R.B. Martin, M.B. Schaffler, C.H. Turner, Perspective: bone microdamage and skeletal fragility in osteoporotic and stress factures, J. Bone Miner Res. 12 (1997) 6–15. 52. A.M. Parfitt, Renal bone disease: a new conceptual framework for the interpretation of bone histomorphometry, Curr. Opin. Nephrol. Hypertension. 12 (2003) 387–408. 53. AM. Parfitt, Calcium homeostasis, J. Musculoskelet Neuron Interact. 4 (2004) 109–110. 54. A.M. Parfitt, Misconceptions (3): calcium leaves bone only by resorption and enters only by formation, Bone 33 (2003) 259–263. 55. D.W. Dempster, Bone remodeling, in: F. Coe, M.J. Favus (Eds.) Disorders of Bone and Mineral Metabolism, second ed., Lippincott Williams & Wilkins, Philadelphia, 2002, pp. 315–343. 56. A.M. Parfitt, Misconceptions (2): turnover is always higher in cancellous than in cortical bone., Bone 30 (2002) 807–809. 57. J. Foldes, A.M. Parfitt, M.-S. Shih, D.S. Rao, M. Kleerekoper, Structural and geometric changes in iliac bone: relationship to normal aging and osteoporosis, J. Bone Miner. Res. 6 (1991) 759–766. 58. Z.H. Han, S. Palnitkar, D.S. Rao, D. Nelson, AM. Parfitt, Effect of ethnicity and age or menopause on the structure and geometry of iliac bone, J. Bone Miner Res. 11 (1996) 1967–1975. 59. A.M. Parfitt, Skeletal heterogeneity and the purposes of bone remodeling: implications for the understanding of osteo porosis, in: R. Marcus, D. Feldman, D.A. Nelson, C.J. Rosen (Eds.) Osteoporosis, third ed., Elsevier Academic Press, Burlington, 2008, pp. 71–89. 60. Z.H. Han, S. Palnitkar, D.S. Rao, D. Nelson, A.M. Parfitt, Effects of ethnicity and age or menopause on the remodeling and turnover of iliac bone: implications for mechanisms of bone loss, J. Bone Miner Res. 12 (1997) 498–508. 61. R. Balena, M.S. Shih, A.M. Parfitt, Bone resorption and formation on the periosteal envelope of the ilium: a histomorphometric study in healthy women, 7 (1992) 1475–1482. 62. H.M. Frost, Tetracycline-based histological analysis of bone remodeling, Calcif. Tissue Res. 3 (1969) 211–237. 63. R.B. Martin, J.C. Picket, S. Zinaich, Studies of skeletal remodeling in aging men., Clin. Orthoped. 49 (1980) 268–282. 64. J.S. Arnold, M.H. Bartley, S.A. Tont, DP. Jenkins, Skeletal changes in aging and disease, Clin. Orthoped. 49 (1966) 17–38.
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65. J. Jowsey, Studies of Haversian system in man and some animals, J. Anat. 100 (1966) 857–864. 66. Z.F. Jaworski, P. Meunier, H.M. Frost, Observations on 2 types of resorption cavities in human lamellar cortical bone., Clin. Orthoped. Relat. Res. 83 (1972) 279–285. 67. A.M. Parfitt, Bone remodeling: relationship to the amount and structure of bone, and the pathogenesis and prevention of fractures, in: B.L. Riggs, L.J. Melton (Eds.) III Osteoporosis: Etiology, Diagnosis and Management, Raven Press, New York, 1988, pp. 45–93. 68. A.M. Parfitt, The cellular basis of bone remodeling: the quantum concept re-examined in the light of recent advances in cell biology, Calcif. Tissue. Int. 36 (1984) 537–545. 69. P. Lips, P. Courpron, P.J. Meunier, Mean wall thickness of trabecular bone packets in the human iliac crest: changes with age., Calcif. Tissue Res. 26 (1978) 13–17.
70. J. Kragstrup, F. Melsen, L. Mosekilde, Thickness of bone formed at remodeling sites in normal human iliac trabecular bone: variations with age and sex, Metabol. Bone Dis. Relat. Res. 5 (1983) 17–21. 71. D.W. Dempster, The relationship between iliac crest bone biopsy and other skeletal sites, in: M. Kleerekoper, S. Krane (Eds.) Clinical Disorders of Bone and Mineral Metabolism, Mary Ann Liebert, New York, 1988. 72. B. Krempien, F.M. Lemminger, E. Ritz, E. Weber, The reaction of different skeletal sites to metabolic bone disease – a micromorphometric study, Klin. Wochenschr. 56 (1978) 755–759. 73. J. Podenphant, U. Engel, Regional variations in histomorphometric bone dynamics from the skeleton of an osteoporotic women, Calcif. Tissue Int. 40 (1987) 184–188.
Chapter
3
Assessment of Bone Turnover in Men Using Biochemical Markers Patrick Garnero1,2 and Pawel Szulc3 1
INSERM Research Unit 664, Lyon, France Synarc, Lyon, France 3 INSERM Research Unit 831, Lyon, France 2
Introduction
New biochemical markers of bone metabolism and new assays
Bone remodeling is the result of two opposite activities, the production of new bone matrix by osteoblasts and the destruction of old bone by osteoclasts. The rate of bone production and destruction can be evaluated by either measuring predominantly osteoblastic or osteoclastic enzyme activities or by assaying bone matrix components released into the bloodstream and eventually excreted in the urine. They have been separated into markers of formation and resorption, but it should be kept in mind that, in diseases where both events are coupled in time and space at the level of the basic multicellular unit and change in the same direction, any marker will reflect overall rate of bone turnover. The clinical utility of biochemical markers has been extensively evaluated in postmenopausal osteoporosis [1, 2], but data in men osteoporosis are more limited. At present, the biochemical markers which are the most specific and established for bone formation include serum osteocalcin, bone alkaline phosphatase (bone ALP) and the procollagen type I N-terminal propeptide (PINP) [1, 2]. For the evaluation of bone resorption, most assays are based on the detection in serum or urine of type I collagen fragments, which account for 90% of the organic bone matrix. These include the cross-links pyridinoline (PYD) and deoxypyridinoline (DPD), the telopeptides of type I collagen generated by cathepsin K (CTX, NTX) and by matrix-metalloproteases (CTX-MMP or ICTP) and fragments of the helical portion of type I collagen molecule (helical peptide) [2]. The individual measurement of most of these biochemical markers can be achieved with high throughput and analytical precision on automated platforms [3, 4].
Osteoporosis in Men
Although current biochemical markers have demonstrated clinical utility in the differential diagnosis of metabolic bone diseases and in predicting fracture risk and response to treatment in postmenopausal osteoporosis, they do have some limitations. Current biochemical markers of bone resorption are based primarily on type I collagen, which is not bone-specific but rather widely distributed in several other body tissues. Some of the type I collagen-based bone resorption markers are characterized by significant intrapatient variability, which impairs their use in individual patients. The systemic levels of biochemical markers reflect global skeletal turnover and do not provide distinct information on the remodeling of different bone envelopes, i.e. trabecular, cortical and periosteal. Further, their relative contribution to skeletal turnover may vary with aging, disease and treatment. Finally, current markers mostly reflect quantitative changes of bone turnover and do not provide information on the structural abnormalities of bone matrix properties which are an important determinant of bone fragility, especially toughness. Recently, new biochemical markers have been investigated to address some of these limitations (Table 3.1), although their clinical utility in assessment of bone turnover abnormalities in postmeno pausal and male osteoporosis is limited.
Non-Collagenous Bone Proteins Although the vast majority of bone matrix is composed of type I collagen molecules, about 10% of the organic phase is comprised of non-collagenous proteins, some of them
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Osteoporosis in Men Table 3.1 New candidate biochemical markers of bone metabolism by category
Non-collagenous proteins of bone matrix and fragments
Osteoclastic enzymes
Regulators of osteoclast-osteoblast differentiation/activity
Bone sialoprotein Osteopontin
TRAPC5b
OPG/ RANK-L (osteoclast)
Periostin Urinary mid-molecule osteocalcin fragments
Cathepsin K Wnt signaling molecules (Dkkl/sFRP) Sclerostin (osteoblast)
Collagen posttranslational modifications Non enzymatic glycation – mediated modifications of collagen (eg. pentosidine, vesperlysine, GOLD, MOLD, CML)
Type I collagen C-telopeptide isomerization (/ CTX ratio)
TRACP5b: tartrate resistant acid phosphatase isoenzyme 5b OPG: osteoprotegerin; RANK-L: receptor activator of nuclear factor kB ligand; Wnt Wingless, Dkk-1: Dicckops-1, sERP: soluble Frizzled-related protein, GOLD (glyoxal-derived lysine dimer), MOLD (methylglyoxal-derived lysine dimer), CML (carboxymethyllysine).
being almost specific for bone tissue. It has been suggested that the measurement of these proteins or fragments thereof could represent specific biochemical markers of bone turnover. Bone sialoprotein (BSP) is an acidic, phosphorylated glycoprotein of 33 kDa (glycosylated: 70–80 kDa) which contains an RGD integrin binding site. Although BSP is relatively restricted to bone, it is also expressed by tropho blasts and is strongly upregulated in a variety of human primary cancers, particularly those that metastasize to the skeleton [5]. A small amount of BSP is released in the circulation and, as such, is a potential marker of bone turnover [6]. Serum BSP levels are increased in malignant bone diseases, in postmenopausal osteoporosis and are decreased by antiresorptive treatments [6]. However, because of its tight association with circulating factor H, accurate measurement of serum BSP remains challenging. Other non-collagenous proteins include osteopontin, which belongs to the small integrin-binding ligand N-linked glycoprotein (SIBLING) family like BSP [7] and periostin, a secreted glutamic acid (Gla) adhesion molecule with preferential distribution in the periosteum envelope. They have been identified specifically as potentially useful in cancer-induced bone diseases [8]. Clinical data in other metabolic bone diseases, including male osteoporosis, are currently unavailable. Although most of the newly synthesized osteocalcin is captured within bone matrix, a small fraction is released into the blood where it can be detected by immunoassays. Circulating osteocalcin comprises different immunoreactive forms including the intact molecule and fragments of different sizes [9]. The majority of these fragments is generated from in vivo degradation of the intact molecule and, thus, also reflects bone formation. In vitro studies suggest, however, that some osteocalcin fragments could also be released from osteoclastic degradation of bone matrix [10] and, thus, may reflect, in part, bone resorption. Elevated levels of urinary osteocalcin fragment levels were reported in
osteoporotic postmenopausal women and values decreased after one month of treatment with the bisphosphonate alendronate [11]. This contrasts with the absence of significant change in serum total osteocalcin levels. Urinary osteocalcin fragment levels were found to be associated with BMD loss and fracture risk in older post-menopausal women [12, 13], but no data have been reported in men.
Osteoclastic Enzymes TRACP 5b Acid phosphatase is a lysosomal enzyme which is present primarily in bone, prostate, platelets, erythrocytes and spleen. Bone acid phosphatase is resistant to L ()-tartrate (TRACP), whereas the prostatic isoenzyme is inhibited by TRACP. Acid phosphatase circulates in blood and shows higher activity in serum than in plasma because of the release of platelet phosphatase activity during the clotting process. In normal plasma, TRACP corresponds to isoenzyme 5. Isoenzyme 5 is represented by two subforms, 5a and 5b. TRACP 5a derives mainly from macrophages and dendritic cells, whereas TRACP 5b is more specific for osteoclasts [14]. These two subforms differ by their carbohydrate content including sialic acid and mannose residues [15], optimal pH and specific activity. TRACP 5a is a monomeric protein, whereas TRACP 5b is cleaved into two subunits. Total plasma TRACP activity is measured by colorimetric assays. However, the lack of specificity of plasma TRACP activity for the osteoclast, its instability in frozen samples and the presence of enzyme inhibitors in serum are drawbacks which have limited the development of clinically useful enzymatic TRACP assays. To overcome these limitations, different immunoassays for serum tartrate TRACP, which preferentially detect isoenzymes 5a and 5b, have been developed. The first assay for TRACP 5b which was developed uses antibodies that recognize both intact and fragmented TRACP 5a and 5b. The selectivity of this assay
C h a p t e r 3 Assessment of Bone Turnover in Men Using Biochemical Markers l
for TRACP 5b is partly achieved by performing measurements at optimal pH for TRACP 5b activity [16]. More recently, a new immunoassay using two monoclonal antibodies raised against purified bone TRACP 5b with limited cross-reactivity for TRACP 5a has been described [17]. One antibody captures active intact TRACP 5b while the second eliminates interference of inactive fragments. We found that this new enzyme-linked immunosorbent assay (ELISA) for TRACP 5b is highly sensitive to detect increased bone turnover following menopause and is also very responsive to alendronate therapy [18]. Serum TRACP 5b is likely to reflect mostly the number and the activity of the osteoclasts. It may thus provide information on the bone resorption process which is complementary to that provided by collagen-related markers [19]. Another advantage of serum TRAPC 5b relates to its limited diurnal variation and negligible effect of food intake. These features result in lower intra-patient variability for TRACP 5b than for collagen-based biochemical markers. However, the magnitude of changes observed following bisphosphonate treatment in postmenopausal women is also lower for TRACP 5b than for collagen markers [16]. Data on serum TRACP 5a isoenzyme are more limited and there is no yet commercially available assay. A recent study showed that serum TRACP 5a was significantly increased in patients with rheumatoid arthritis (RA), especially in those presenting with nodules, whereas TRACP 5b was only marginally increased and was not associated with nodules [20]. It has also been reported that the alendronate induced a marked decrease in serum TRACP 5b, but had no effect on serum TRACP 5a [21]. These data indeed support the view that TRACP 5a is likely to reflect inflammatory macrophage activity, whereas TRACP 5b is an indicator of osteoclast activity. Cathepsin K The enzyme cathepsin K is a member of the cysteine protease family that, unlike other cathepsins, has the unique ability to cleave both helical and telopeptide regions of type I collagen [22]. The enzyme is produced as a 329 amino acid precursor procathepsin K, which is cleaved into its active form with a length of 215 amino acids. This cleavage event takes place in vivo within the low pH bone resorption lacunae. Commercially, two assays measuring respectively the enzymatic activity and the protein concentration of cathepsin K in serum are available. Clinical data on serum cathepsin K are still limited. In both healthy women and men, serum cathepsin K decreases with age, contrasting with age-associated increased bone resorption [23]. Increased serum cathepsin K levels have been reported in patients with active RA [24], patients with Paget’s disease of bone [25] and in postmenopausal women with fragility fractures [26]. Because circulating concentrations of cathepsin K are very low and current available assays lack
27
sensitivity, accurate measurements of this enzyme remain challenging.
Regulators of Osteoclastic and Osteoblastic Activity RANK-L AND OPG The RANK-L/RANK/OPG system is one of the main regulators of osteoclast formation and function [27]. In healthy men, serum OPG increases with age and modestly correlates with parathyroid hormone (PTH) and total deoxy pyridinoline, but not with BMD [28]. Although the major contribution of this pathway in postmenopausal bone loss has been clearly established in various animal and clinical models, the serum measurement of RANK-L and OPG remains difficult. Indeed, at present it remains unclear what proportion of circulating OPG is monomeric, dimeric or bound to RANK-L and which of these forms is the most biologically relevant to measure. The same issues arise for the measurements of circulating RANK-L which, in its free form, has barely detectable levels in healthy individuals. It is also unlikely that circulating levels of OPG and RANK-L reflect adequately local bone marrow production. These limitations probably explain the conflicting data available on the association of circulating OPG and RANK-L with BMD and biochemical markers of bone turnover in postmenopausal women and elderly men [29]. Wnt signaling molecules The Wnt signaling pathway plays a pivotal role in the differentiation and activity of osteoblastic cells [30]. There are 19 closely related Wnt genes that have been identified in humans. The primary receptors of Wnt molecules are the seven-transmembrane Frizzled related proteins (FRP), each of which interacts with a single transmembrane low density lipid (LDL) receptor-related protein 5/6 (LRP5/6). Different secreted proteins, including soluble FRP-related proteins (sFRP), Wnt inhibitory factor-1 (WIF1) and Dickkopfs (Dkk) – isoforms 1, 2, 3, and 4 – prevent ligand-receptor interactions and consequently inhibit the Wnt signaling pathway. Alterations of the Wnt signaling pathway and its regulatory molecules including Dkk-1 and sFRP have been shown to play an important role in bone turnover abnormalities associated with osteoporosis, arthritis, multiple myeloma and bone metastases from prostate and breast [31]. Immunoassays for circulating Dkk-1 have recently been developed. Serum Dkk-1 levels have been reported to be increased in clinical situations characterized by depressed bone formation such as multiple myeloma [32]. Circulating levels are also higher in diseases characterized by focal osteolysis, such as multiple myeloma [32], bone metastases from breast or lung cancer [33, 34] and RA [35]. In RA patients, we found that increased levels were associated with a faster radiological progression [36]. Conversely, in
28
Osteoporosis in Men Helical domain
N-telopeptide
N+ α1 α1
OH
C-telopeptide
PYD DPD
K
CTX sequence: EKAHDGGR
O
OH
O OH N N α H H O
O
OH
α CTX (native)
H N
β
N H
OH
O
O
β CTX (isomerized)
Figure 3.1 Schematic representation of C-telopeptide isomerization in type I collagen molecules. Type I collagen is constituted by the association in triple helix of two alpha 1 and one alpha 2 chains except of the two ends (N and C-telopeptides). In bone matrix, type I collagen is subjected to different post-translational modifications including (1) the trivalent crosslinks by pyridinoline (PYD) and deoxypyridinoline (DPD) which make bridges between 2 hydroxylysine residues within the telopeptides of one collagen molecule and one hydroxylysine (PYD) or lysine (DPD) in the helical region of a second collagen molecule and the non-enzymatic isomerization of aspartic acid (D) occurring in the 8 amino acid sequence (CTX) within the C-telopeptides of alpha 1 chains. Isomerization is a spontaneous posttranslational modification which converts the native CTX (CTX) to its isomerized (CTX) form in which the peptide bond between D and the adjacent glycine (G) is made through the carboxyl group in position . The urinary ratio / CTX provides a biological index of type I collagen maturation.
patients with osteoarthritis of the hip, a clinical situation characterized by focal sclerosis of subchondral bone, lower serum Dkk-1 levels have been shown to be associated with a decreased risk of joint destruction [37]. At the present time there are no data on circulating Dkk-1 in postmenopausal or male osteoporosis. Similar to the assessment of OPG and RANK-L, it is possible that circulating Dkk-1 does not reflect adequately local bone dynamics. Another issue with the determination of serum Dkk-1 is the fact that Dkk-1 is in platelets and, thus, can be released in the serum during the process of clotting [38], confounding the interpretation of circulating levels. More recently, an immunoassay measuring sclerostin, an osteocyte secreted factor inhibiting the Wnt signaling pathway, has been developed on a multiplex platform (Meso Scale Discovery, Gaithersburg, MA), but no data on circulating levels have yet been reported.
Post-Translational Modifications of Bone Type I Collagen Post-translational modifications of type I collagen, especially those derived from non-enzymatic age-related processes, have been suggested to reflect age-related changes of
the mechanical properties of bone tissue. Non-enzymatic modifications include the advanced glycation end products (AGE) such as the cross-link pentosidine and the isomerization of aspartic acid residues. This latter modification results in the conversion of the native alpha form of CTX ( CTX) to its beta isomerized peptide ( CTX) (Figure 3.1). A series of ex-vivo studies [39] performed on animal or human bone specimens has shown that changes in pentosidine and CTX isomerization were associated with mechanical properties independently of BMD. The ratio between urinary CTX and CTX provides a non-invasive tool which allows for the detection of alterations in bone matrix maturation. Increased urinary / CTX ratio has been reported in conditions characterized by localized increased bone turnover, such as Paget’s disease and metastatic bone diseases [40, 41], consistent with the presence of ‘younger’ poorly matured type I collagen molecules in the affected bone sites. Immunohistochemistry studies also showed altered CTX isomerization in the abnormal woven matrix, which is comprised of younger, poorly matured collagen molecules [40, 41]. A recent study found increased urinary / CTX ratio in the type I collagen genetic disorder osteogenesis imperfecta, which may be indicative of the qualitative defects of bone tissue observed in these
C h a p t e r 3 Assessment of Bone Turnover in Men Using Biochemical Markers l
29
Table 3.2 Type I collagen and the risk of fracture in older men: The Mr Os study RR of fracture (95% Cl), age and clinic adjusted
RR of fracture, age, clinic and hip BMD adjusted
Non-spine
Non-spine
Hip
Hip
CTX/cr
1.43(1.10;1.86)
1.91(1.14;3.20)
1.10(0.83;1.50)
1.02(0.56;1.85)
CTX / CTX ratio
1.11(0.84;1.48) 1.40(1.07;1.82)
1.22(0.70;2.11) 1.93(1.14;3.28)
0.89(0.66;1.18) 1.37(1.05;1.80)
0.72(0.39;1.33) 1.85(1.00;3.40)
Mr Os study included 5995 men (mean age at baseline: 73.7 years). During the 5 yr follow-up, 431 men documented non-spine fractures. Baseline urine was available on 427 fracture cases, including 80 hip fractures and on 1013 randomly selected subjects. The table shows the risk of non-spine and hip estimated by Cox models for baseline urinary excretion of CTX corrected for creatinine, CTX corrected for creatinine and the / CTX ratio. From Bauer et al. Osteoporosis Int 2008; 19, supp. 2;S244 (with permission).
patients [42]. In postmenopausal women, it was found that increased urinary / CTX ratio was significantly associated with increased fracture risk independently of both hip BMD and overall bone turnover. More recently, a high / CTX ratio was shown to be predictive of non-spine and hip fracture, independent of hip BMD, in elderly men participating in the Mr Os study (Table 3.2) [43]. The effects of antiresorptive therapy and PTH on urinary / CTX ratio in postmenopausal women have recently been investigated in post hoc analyses of interventional studies. The bisphosphonates, alendronate at a dose of 10 or 20 mg/ day and ibandronate, both induce a decrease of / CTX ratio, suggesting increased bone collagen maturation [44]. Such changes were not observed with treatments that are less potent suppressors of bone turnover, such as raloxifene [44] or calcitonin [45]. Conversely, treatment with PTH 1-84 for 1 year, followed by 1 year of placebo or alendronate was associated with an increase of / CTX ratio [46], suggesting the formation of younger, less mature bone matrix with PTH. All together, these data suggest that the urinary / CTX ratio may indeed reflect alterations of bone collagen maturation in women and men with osteoporosis and provide additional information on bone strength that is not captured by BMD or conventional bone turnover markers.
New technologies for discovery and assay bone markers The currently available bone markers have been developed using a conventional candidate approach based on known physiopathological pathways, enzymes from osteoblast or osteoclast and proteins purified from bone matrix. It is likely that the improvement of proteomic technologies, such as surface enhanced laser desorption ionization (SELDI) and matrix-assisted laser desorption time-of-flight mass spectrometry (MALDI-TOF), coupled with bioinformatics, will provide a means to analyze a broad array of proteins and to identify novel markers. Such a strategy has recently been applied to define a serum biomarker profile which was able to differentiate postmenopausal women with high
or low bone turnover [47]. Ultimately, such strategies may result in identifying a panel of a few independent markers which, when combined, may improve the sensitivity and specificity to detect patients at high fracture risk. Multiplex automated technologies allowing the simultaneous measurement of these biochemical markers in a low sample volume will then be required for easy use. Illustrating this point, an automated platform with high analytical precision has been recently developed for the simultaneous measurements of osteocalcin, CTX, PINP and PTH in only 20 microliters of serum [48].
Factors influencing BTM levels in men Bone turnover is subject to the influence of many factors, some of which have been comprehensively examined. Strong correlations between bone turnover marker (BTM) levels in male twins indicate that hereditary factors are an important determinant of the bone turnover rate in men [49]. By contrast, ethnic differences in the BTM levels are relatively weak [50]. Bone turnover demonstrates circadian variation. For most BTM, acrophase (peak time) is similar in both sexes. In contrast, the average concentration (mesor) and magnitude of diurnal variation (amplitude) vary between men and women [51]. Levels of most BTMs increase during the night and attain highest values between 04:00 and 06:00 hours. Circadian variation is greater for bone resorption than for bone formation. In men, diurnal variation is similar for different bone resorption markers. Variation of bone formation is lower – 5 to 20%. Mechanisms that govern circadian variability of BTM are not known. Food consumption accentuates circadian variation of bone resorption, whereas fasting significantly attenuates the circadian pattern probably due to the increased secretion of glucagon-like peptide-2 which is stimulated by food intake [52]. It suggests that the circadian variation of bone resorption is only partly inherent and, to a major extent, determined by the exogenous nutritional regulation.
30
Osteoporosis in Men
Data on the seasonal variation of BTM in men are limited. However, some studies show increased bone resorption in winter in older but not in younger men [53]. The winter increase in bone turnover is believed to be related to vitamin D deficiency and secondary hyperparathyroidism. Therefore, it is more prominent in the elderly who are more likely to become vitamin D deficient. Low 25-hydroxyvitamin D and high PTH levels are also associated with higher BTM levels regardless of the season in older men. This association is observed especially in institutionalized persons who have severe vitamin D deficiency, high PTH concentration and markedly increased BTM levels [54]. Sex steroid hormones are major determinants of bone turnover in older men. Low concentration of the bioavailable fraction of 17-estradiol is strongly associated with higher levels of the markers of bone formation and bone resorption and this effect is observed in men from the general population [55, 56]. In contrast to the bioavailable fraction, total 17-estradiol is not correlated with BTM levels. Men with overt hypogonadism, as defined by a decreased concentration of total, free or bioavailable testosterone, had slightly higher levels of bone resorption markers but not of bone formation markers [57]. By contrast, in the general population, the association between the testosterone level (free, bioavailable) and the BTM levels is weak or not significant. Interventional studies also show that 17-estradiol inhibits bone resorption in men much more strongly than testosterone [58]. In this short-term study (3 weeks), it could also be shown that 17-estradiol and, to a lesser extent, testosterone are direct stimulators of bone formation. Tobacco smoking was associated with slightly higher levels of bone resorption markers but not of bone formation markers [59]. It suggests that elevated bone resorption not matched by a parallel increase in bone formation could underlie tobacco-induced bone loss. However, specific mechanisms responsible for the increase in bone resorption in smokers are not elucidated. This mechanism could include vitamin D deficiency, hypercortisolemia, increased catabolism of 17-estradiol, stimulation of bone resorbing cytokines by components of smoke, as well as other factors which are more frequently observed in smokers, although not induced by smoking itself (e.g. low body mass index, high alcohol intake, sedentary lifestyle). Most studies show that alcohol abuse is associated mainly with the inhibition of bone formation (confirmed by bone histomorphometry) and lower concentrations of bone formation markers (especially OC) [60, 61]. By contrast, data on bone resorption markers levels are divergent. These data suggest that an imbalance between bone resorption and lowered bone formation may underlie the low BMD observed in those who abuse alcohol. However, data on bone resorption should be interpreted cautiously. Heavy drinkers often have lower muscle mass associated with lower urinary creatinine excretion. In these persons, adjustment of the urinary excretion of bone resorption markers for urinary creatinine may falsely increase their levels. Ethanol withdrawal results in
a progressive normalization of bone turnover rate [62]. The actions of alcohol on bone include the following potential mechanisms: a direct effect of ethanol on bone cells, undernourishment, hepatic cirrhosis, hypogonadism, vitamin D deficiency, hypercortisolemia [63]. Any one or combination of these discrete mechanisms could be responsible for negative calcium balance in alcoholism. Immobilization is associated with an acceleration of bone turnover, especially of bone resorption. The rapid increase in bone resorption is observed very early during experimental bed rest in young healthy men and is not followed by a parallel increase in bone formation [64]. During the first weeks after acute spinal cord injury, bone resorption increases dramatically to several times higher than the upper limit of the normal range, whereas bone formation increases only slightly [65]. It suggests a severe imbalance between these two processes which probably underlies the rapid bone loss associated with immobilization. In elderly persons with prolonged, very low physical activity (including the sick and bedridden), bone turnover rate is higher – both bone formation and bone resorption [66, 67]. In this group, there are probably several mechanisms responsible for the increase in bone turnover: immobility itself, underlying diseases, undernourishment or vitamin D deficiency due to a very low sunlight exposure. Leisure daily physical activity has no major effect on bone turnover. By contrast, regular intensive sport training in young healthy men (long distance runners, premier league soccer players) is associated with accelerated bone turnover [68, 69]. Prostate cancer is frequent in men. During its natural course, bone metastases often develop and are associated with higher BTM levels, mainly ICTP, bone ALP, NTX and --CTX (native non-isomerized CTX-I reflecting the most recently synthesized type I collagen molecules) and, to a lesser extent, P1NP, -CTX or OC [70]. In these patients, bone resorption is increased to a greater extent than bone formation. High ICTP levels suggest an important role of matrix metalloproteinases in the formation of bone metastases [71]. BTM levels increase sharply with the spread of bone metastases. Elevated BTM levels (NTX, bone ALP) were associated with a higher risk of the skeletal-related events (e.g. pathological fractures, spinal cord compression) regardless of the presence of bone metastases or treatment status [70, 72]. Some kinds of androgen deprivation therapy (ADT) used in the therapy of prostate cancer (analogues of luteinizing hormone-releasing hormone, orchiectomy) promptly increase bone turnover resulting in rapid bone loss. In men without bone metastases, BTM increases during the first months, then stabilize at the higher level [73]. Bone resorption increases more than bone formation. Anti-resorptive treatment (neridronate, pamidronate) initiated simultaneously with ADT prevented the increase in BTM [74]. In men who had previously received ADT, bisphosphonates decreased elevated BTM levels in men who did not have
C h a p t e r 3 Assessment of Bone Turnover in Men Using Biochemical Markers l
progression of bone disease, but not in men who experienced a progression of disease [75, 76]. Other anti-resorptive medications (estrogens, raloxifene, diethylstilbesterol) also decreased BTM (or prevented their increase) in men on ADT. Also, in men with metastatic prostate cancer treated with ADT, bisphosphonates induced rapid and protracted inhibition of bone resorption [77]. Corticosteroids are the principal group of drugs increasing the risk of osteoporosis. They promptly inhibit bone formation, a fall in the OC concentration being consistently most significant and most rapid followed by a delayed and weaker decrease in the levels of PICP, PINP and bone ALP [78, 79]. Bone resorption can increase, especially after treatment exceeding 3 months, but data are less consistent. Interestingly, OC concentration increased significantly and normalized after withdrawal of the long-term corticosteroid therapy [80]. Inhaled corticosteroids induced a small but statistically significant decrease in the OC concentration but did not influence other BTM levels [81]. In the analysis of the effect of corticosteroids on BTM, it should be noted that their effect depends on the age of patients and the underlying disease. In bronchial asthma, changes in the BTM reflect the undesirable effect of corticosteroids on bone turnover, while chronic inflammatory diseases, such as rheumatoid arthritis, may themselves induce changes in bone turnover. In these patients, higher bone resorption may confound the effect of corticosteroids on BTM. Corticosteroid-treated patients usually have more severe underlying disease than patients who do not receive corticosteroids. In the longitudinal studies, changes in BTM reflect mainly both the pharmacologic effect of corticosteroids and the severity of the disease at baseline.
Clinical applications of bone turnover markers in male osteoporosis Association of bone mineral density and bone loss with the BTM levels Young men achieve their peak areal bone mineral density (aBMD) in young adulthood. Attainment of peak BMD (growth arrest, consolidation) is associated with a reduction in bone turnover and a decrease in BTM levels. However, the age of peak aBMD varies according to the skeletal site (from 20 to 25 years at the hip, up to 40 years at distal radius). This is probably the reason why, in young men, the correlation of BTM with aBMD and trabecular microarchitectural parameters is weak or, most frequently, not significant [82, 83]. In older men, who are in the phase of bone loss, BTM levels are weakly but significantly correlated with aBMD [82, 83]. The older the age group, the stronger is the correlation, probably signifying age-related acceleration of bone loss in men. The difference between average aBMD in men with low and high BTM levels was greater at the predominantly trabecular
31
skeletal sites than for the predominantly cortical sites. In this group, BTM correlated weakly but negatively with trabecular bone volume and trabecular number. In older men, higher BTM levels are associated with slightly more rapid bone loss in some [84, 85], but not all [86] studies. These data suggest that bone loss in men is determined mainly by an acceleration of bone turnover driven by a slight increase in bone resorption which is not matched by a parallel increase in bone formation. This imbalance results in age-related bone loss. However, the link between BTM levels and remodeling events were studied mainly in women and it is not certain that they can be directly extrapolated in men. In some men, osteoblast insufficiency may be a main determinant of bone loss. To our knowledge, no study has reported lower aBMD and slower bone loss in men with low concentrations of bone formation markers. Continuous periosteal apposition influences bone size, aBMD and calculated rates of bone loss. However, it is not reflected by BTM levels. Therefore, increased BTM levels seem to reflect mainly bone loss at endosteal surfaces [84]. However, methodological limitations of the applied approach should be recognized. The calculation of endosteal bone loss has been based on the geometric approximations and has not been confirmed by a more direct method. In men, bone loss is slow, especially before the age of 70. Therefore, its individual values during a short-term follow up may be biased by a measurement error, especially in men less than 70. By contrast, a single BTM measurement does not necessarily reflect the bone turnover rate during a long-term follow up. BTM levels reflect the overall rate of bone turnover, whereas the rate of bone loss may vary according to the skeletal site. At every skeletal site, bone metabolism is influenced by systemic factors (e.g. hormones) and by local factors (e.g. mechanical load) which may differently affect the bone turnover and the rate of bone loss according to the skeletal site. Furthermore, data concerning the lumbar spine are inconclusive because its aBMD increases with age due to progression of osteoarthritis. Thus, the weak overall correlation between bone loss and BTM in men may result from both biological determinants and methodological limitations.
Prediction of the Fragility Fractures by BTM in Elderly Men Few studies have assessed the use of BTM for the prediction of osteoporotic fractures in men. In a prospective nested case-control study from the Dubbo cohort (cases – 50 men with incident symptomatic low trauma fractures; controls – 101 men free of any bone disease who did not take any medication affecting bone disease and had not had fractures in the past), increased serum ICTP concentration (fourth quartile) was associated with an almost threefold higher risk of fracture [87]. ICTP remained predictive of fractures after adjustment for aBMD and other confounders. It predicted all fractures analyzed jointly as well as
32
Osteoporosis in Men
hip fractures, vertebral fractures and other fractures analysed separately. Serum CTX and PINP concentrations did not predict fractures. However, this study has several limitations. Exclusion from the control group of men with prevalent fractures and concomitant major diseases, mainly bone diseases, can overestimate the difference between the groups. Ascertainment of the incident vertebral fractures was suboptimal. Time of blood sampling was not standardized, which can affect markedly CTX levels. In the MINOS cohort composed of 790 men aged 50–85 years and followed up from 3 to 90 months, 77 incident fractures (including 27 radiographically determined vertebral fractures) occurred in 74 men [84]. None of the large panel of BTM measured at baseline (OC, bone ALP, PINP, serum and urinary CTX, free and total DPD) predicted fractures regardless of the statistical model used (continuous log-transformed BTM levels, various thresholds, adjustment for confounders including aBMD, analysis limited to major fragility fractures). The principal limitation of this study was the low number of the incident fractures. The large dropout for longitudinal spine x-rays could underestimate the number of incident vertebral fractures. In two prospective nested case-control analyses from the Mr OS cohort composed of men aged 65 years and older and followed up for 5 years on average (cases – 427 men with incident non-spine fractures; controls – 943 and 1013 randomly selected men, respectively), increased serum concentrations of PINP, TRACP5b and CTX as well as increased urinary excretion of CTX and of CTX (highest quartile) were each not independently associated with the risk of hip or non-spine fractures in multivariate models adjusted for other confounders including femoral neck aBMD [43, 85]. By contrast, as previously indicated, increased / CTX ratio was associated with a twofold higher risk of hip and non-spine fracture also after adjustment for BMD [43]. BTM levels reflect overall bone turnover rate, whereas the / CTX ratio is supposed to reflect the degree of collagen maturation. The fact that the increased / CTX ratio, but not the conventional BTM, predicted fracture suggests that impaired collagen maturation may be associated with an increased bone fragility in elderly men independent of BMD and overall bone turnover rate. Increased levels of conventional BTM do not seem to be useful to predict fractures in older men in contrast to women. Several possible hypotheses can be put forward to explain this observation. Negative results may be related to the markers themselves. In older men, bone formation markers remain stable or increase only in very old men and are much lower than in postmenopausal and older women [88]. Importantly, even in women, bone formation markers were less predictive of fracture than bone resorption markers [1, 2]. Bone resorption increases with age in men, but urinary DPD excretion is markedly lower in older men than in women of similar age [88]. It suggests that few men can have BTM levels sufficiently high to affect substantially
bone strength. Thus, the so-called ‘increased bone turnover’ defined by the highest quartile may correspond to lower BTM levels and lower rate of bone turnover in absolute terms (e.g. number of bone remodeling units) and, consequently, to a lower damage of bone tissue in men than women (smaller bone loss from the peak bone mass, less cortical thinning, less deterioration of the trabecular microarchitecture, smaller deficit in bone mineralization). Furthermore, it has not yet been proven that the relationship between bone turnover rate and the loss of bone mass and strength is the same in men and in women. It is not clear whether the same BTM reflect similarly the degradation of bone matrix in both sexes. Urinary DPD excretion increases with age in men. This increase is also observed for DPD adjusted for the glomerular filtrate volume, which indicates that it is not an apparent increase due to the agerelated decrease in muscle mass and urinary creatinine [83]. By contrast, age-related increase in the serum and urinary levels of NTX and CTX is weaker or not significant in men (in contrast to women) [83, 89], whereas serum ICTP increases [86]. Thus, enzymatic mechanisms and principal products of degradation of bone type I collagen may be different in men and in women. Bone turnover rate reflects mainly metabolic status of the trabecular bone. However, men have larger bones and higher cortical mass which can have a strong protective effect but is not reflected by the BTM levels. The peri osteal apposition can also reduce the loss of bone strength and again, it is not reflected by the BTM levels [84]. Furthermore, the above studies have assessed mainly or exclusively non-spine fractures. However, vertebral fractures may be more dependent on bone fragility, whereas non-spine fractures may depend more on the trauma. It should be also recognized that a fracture is a rare event and a long-term follow up is needed to collect a number of fractures high enough to attain sufficient statistical power. However, the predictive power of a single BTM measurement may decrease with time in long-term studies. Other studies also need to be mentioned. In men aged 70 and over, baseline carboxylated OC (COC) to total OC ratio (COC/TOC) was lower in those who subsequently sustained a fracture than in men who did not [90]. In men and women analyzed jointly, low COC/TOC predicted fractures in a short-term but not in long-term study, however, these data were not adjusted for aBMD. Vitamin K is necessary for the gammacarboxylation of OC. Therefore, decreased COC/TOC may reflect vitamin K deficit. However, it is not clear if this association reflects the effect of vitamin K on bone metabolism or is a by-stander of the association between nutritional deficits and increased bone fragility. Homocysteine (Hcy) is not a marker of bone turnover, however, it has appeared as an indicator of fracture risk and this association was stronger in men than women [91, 92]. However, high Hcy concentration was predictive of fractures mainly in old and frail elderly. High Hcy concentration
C h a p t e r 3 Assessment of Bone Turnover in Men Using Biochemical Markers
33
l
was associated mainly with increased risk of hip fracture and some of these analyses were not adjusted for aBMD. Thus, Hcy may simply reflect poor health status, unhealthy lifestyle and nutritional deficits that influence aBMD, risk of fall and mortality. Hcy has been supposed to be a marker of the ultrastructure of collagen, because it inhibits lysyl oxidase, an enzyme necessary for the synthesis of cross-links [93]. Impairment of collagen cross-linking may interfere with bone mineralization, compromise trabecular organization and reduce bone strength [94]. Hcy also stimulates differentiation and function of osteoclasts [95]. Thus, the mechanism underlying the association between the Hcy level and fracture risk remains to be elucidated: impairment of the ultrastructure of bone collagen matrix, increased bone turnover, lower aBMD, nutritional deficits, or frailty due to the poor general health status and propensity to fall? In summary, the currently available BTM levels are not independently related to the risk of fragility fracture in men. From the pathophysiological point of view, it suggests that higher bone turnover rate (as assessed in comparison with the levels observed in older men) is not associated with the increased fragility in older men. From the clinical point of view, it means that the measurement of BTM levels cannot be recommended for the assessment of the fracture risk in older
men in clinical practice. Biochemical assessment of qualitative modifications of bone matrix, which may be associated with higher bone fragility in men, needs further studies.
Effect of anti-osteoporotic treatment on BTM in men Data on the changes induced by anti-osteporotic treatment in men are limited because there are few studies on the pharmacological treatment of osteoporosis in men.
Testosterone Replacement Therapy (TRT) Effect of testosterone replacement therapy (TRT) on bone turnover in hypogonadal men depends on the initial hormonal status, normalization of testosterone level during treatment and the treatment duration. TRT is efficient in men with overt hypogonadism, but not in men with borderline decreased testosterone concentration. TRT is not efficient if testosterone level has not been normalized. The effect of TRT may also depend on the initial BMD and bone turnover rate. TRT reduces bone resorption moderately but promptly and significantly (Figure 3.2) [96, 97]. The decrease was
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Figure 3.2 Effect of transdermal testosterone (T) gel and testosterone patch treatment on urinary N-terminal crosslinking telopeptide of type I collagen / creatinine ratio and serum osteocalcin concentration in 227 hypogonadal men aged 19 to 68 (mean SE). The subjects were initially (days 0 to 90) randomized to three groups: T patch (closed triangles), T gel 50 mg/day (closed squares), and T gel 100 mg/day (closed circles) (left panel of each graph). Based on the serum T levels, the dose of T gel was adjusted upwards or downwards to 75 mg/day at day 90 if the serum T level was below or above the adult male range, respectively: T gel 50 to 75 mg/day (open squares), T gel 100 to 75 mg/day (open circles) (right panel of each graph). (Wang et al. Effects of transdermal testosterone gel on bone turn over markers and bone mineral density in hypogonadal men. From Wang et al., Clin Endocrinol 2001; 54:739–750 (with permission).
Osteoporosis in Men
Anti-Resorptive Treatment Studies in men concern principally alendronate and risedronate, which increase aBMD and decrease BTM. Both eugonadal and hypogonadal men were recruited for these studies. Bisphosphonates induce a rapid decrease in BTM levels, detected after 1 month of treatment [99, 100]. After 3–12 months, decrease in BTM levels attains 50–60% for bone resorption and 15–40% for bone formation (Figure 3.3) [99, 101]. Then, BTM levels remain stable. Decrease in BTM is comparable for 5 and 10 mg alendronate and 5 mg risedronate. In osteoporotic men, treatment with 35 mg risedronate weekly decreased serum bone ALP concentration by 25–30%, serum CTX concentration by about 50% and urinary NTX excretion by about 35% [102]. This decrease was observed after 3 months of treatment (earliest time point tested), then BTM levels remained relatively stable. In patients receiving at least 7.5 mg oral prednisone daily, alendronate and risedronate decreased BTM in patients receiving glucocorticoids for less than 3 months and in patients treated for more than 6 months. However, BTM were analyzed jointly in both sexes. In hypogonadal osteoporotic men receiving an adequate TRT, alendronate decreased urinary DPD excretion promptly and rapidly [103]. In men with Klinefelter’s syndrome, intravenous ibandronate decreased the bone turnover rate and increased
Placebo 5 mg of alendronate 10 mg of alendronate
50 Urinary N-Telopeptides of Types I Collagen (pmol of bone collagen equivalents/µmol of creatinine)
significant for more specific bone resorption markers such as DPD or NTX-I, but not for hydroxyproline which is not specific for bone and poorly sensitive. Decrease in the urinary excretion of bone resorption markers per mg urinary creatinine is partly related to the increase in muscle mass induced by testosterone. Therefore, data expressed per glomerular filtrate volume and serum markers of bone resorption can be more reliable, although experimental data are limited. The overall effect of TRT on bone formation markers, as presented in the metaanalysis of Isidori et al., was not significant [98]. However, these data should be interpreted cautiously. Apart from the aforementioned general limitations, the dynamics of bone formation during TRT should be taken into account. Bone formation markers increase during the first months of TRT, then plateau [96, 97]. This increase may reflect the direct stimulatory effect of TRT on bone formation. Later, TRT-induced decrease in bone resorption was followed by a decrease in bone formation which may reflect general slow down of bone turnover. These studies present certain limitations. Groups are small and heterogeneous (etiology, age of diagnosis of hypogonadism, age at the beginning of the study, duration of TRT before the study, doses of TRT and way of administration, degree of normalization of the testosterone level, duration of TRT during the study). A placebo group is not always included. TRT-induced increase in aBMD may reflect mainly the stimulation of bone formation in young men and the inhibition of bone resorption in the elderly.
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Figure 3.3 Effects of alendronate on biochemical markers of bone resorption in 259 patients (top panel) and bone formation in 264 patients (bottom panel) receiving an average daily dose of at least 7.5 mg of prednisone (or its equivalent). All values are means (SE). The solid horizontal lines indicate the mean reference values for premenopausal women, and the dotted horizontal lines 1 SD above and below the mean. The values were significantly decreased at 48 weeks in the patients receiving 5 mg of alendronate and those receiving 10 mg (P 0.001). From Saag et al. N Engl J Med. 1998; 339:292–299 (with permission).
aBMD [104]. However, after withdrawal of the treatment, BTM levels returned to the pretreatment levels and aBMD decreased. In a group of human immundeficiency virus (HIV)-infected men treated with highly active antiretroviral therapy who had BMD T-score 0.5, annual zoledronate administration decreased urinary NTX excretion by about 60% and serum concentrations of OC and CTX by 50–60% compared to the placebo group (OC and CTX-I were not measured at baseline) [105]. In 28 men with idiopathic osteoporosis, nasal calcitonin 200 IU daily administered for 1 year reduced bone turnover [106]. Decrease in bone resorption was significant after 3 months and attained 50% after 12 months. It was followed by a milder decrease in bone formation markers which became significant after 6 months.
C h a p t e r 3 Assessment of Bone Turnover in Men Using Biochemical Markers l
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P � 0.001 TPTD20 vs 40 (Bone ALP, PICP, NTX, CTX); P < 0.01 (TDPD) at all timepoints after baseline
Figure 3.4 Median percent changes from baseline in biochemical markers of bone formation (top) and resorption (bottom) from baseline to endpoint for observed cases at 1, 3, 6, and 12 months. (Bone ALP – bone alkaline phosphatase, PlCP – procollagen I carboxy-terminal, NTX/CR – urinary N-telopeptide/creatinine ratio, fDPD/CR – free deoxypyridinoline/creatinine ratio, TPTD20 – teriparatide 20 g; TPTD40 – teriparatide 40 g). From Orwoll et al. J Bone Miner Res 2003; 18:9–17 (with permission).
Treatment with Bone Formation Stimulating Agents Effect of recombinant human parathyroid hormone (1–34) (rhPTH-[1–34]) on BTM levels was assessed in two randomized placebo-controlled studies [107, 108]. Markers of bone formation increase rapidly with a significant increment of PINP after 1 month of treatment followed by an increase in bone resorption markers (Figure 3.4). This rapid increase in bone formation indicates that rhPTH-(1–34) directly stimulates osteoblastic cells. After 6–9 months of treatment, BTM attain the maximum (50–250% above baseline), then slightly decrease but remain elevated. By contrast, during combined treatment (alendronate and rhPTH-[1–34]) started 6 months after the beginning of the anti-resorptive treatment, the increase in the serum concentrations of the bone formation markers induced by rhPTH(1–34) were lower and the increase in aBMD at the spine
and femoral neck was less than after rhPTH-(1–34) alone [109] (Figure 3.5). In growth hormone (GH) deficient men, recombinant human GH increases bone resorption and bone formation [110, 111]. BTM increase after 4 days of treatment, attain peak values (50–300% above baseline) after 6– 12 months, then decrease. BTM decrease despite sustained elevated histomorphometric parameters of bone formation and resorption. During GH therapy, changes in BTM and aBMD did not correlate, probably because BTM increase from the beginning of treatment, whereas aBMD decreases slightly then increases. A similar pattern of changes in BTM levels (increase then decrease) was found in adults independent of the etiology of GH deficiency. The studies on GH treatment present several limitations including small groups, both sexes analyzed jointly, no placebo group in most cases, different doses of GH, different regimens and treatment duration. Thus, these results should be interpreted cautiously.
Osteoporosis in Men
36
Serum osteocalcin
400
Serum PNP 1200
300 Percent change
Serum N-telopeptide
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1000 800
200
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100
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12 18 24 Time (months)
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–100
–100 0
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Figure 3.5 Mean percent change from baseline for serum OC, P1NP, and NTX in men receiving alendronate alone (square), human PTH(1–34) alone (rhombus), or both (circle). PTH was begun at month 6. Data are plotted as the mean (SE). Error bars that are not seen are contained within the symbols. From Finkelstein JS et al. J Clin Endocrinol Metab 2006; 91:2882–2887 (with permission).
The data on the BTM levels during the anti-osteoporotic treatment are limited. Overall, they show that the treatmentinduced changes in the BTM levels are similar in men and women. However, potential use of the BTM in the monitoring of the anti-osteoporotic treatment in clinical practice has not been studied specifically in men. For instance, it has not been assessed if the change in the BTM levels can be used for the prediction of the increase in BMD or the decrease in the fracture risk during the treatment. There is also no study which has assessed the potential use of BTM to improve the compliance to the anti-osteoporotic treatment in men.
Conclusion Studies carried out during recent years have improved our knowledge about BTM in men and their age-related changes. Bone loss in men is correlated significantly with the BTM levels at baseline. It indicates that high bone turnover is a determinant of the accelerated bone loss in men. This correlation is poor and BTM measurements cannot be used for the prediction of the accelerated bone loss in men similarly to the data found in women. Weakness of the association between the BTM levels and the rate of bone loss can depend on the methodological problems. However, it can also reflect the weakness of the concept of bone loss calculated using BMD meaured by dual-energy x-ray absorptiometry (DXA). Conventional BTM do not predict fractures in older men. However, it is not clear if it reflects the real lack of the impact of the bone turnover rate on bone fragility in men. Men have higher skeletal mass and a milder age-related acceleration of bone turnover than women. Thus, it is plausible that only a few men attain the bone turnover rate which is dangerous for bone solidity, however, in this group, high bone turnover may be a real determinant of the increase in bone fragility. Data on
the biochemical bone markers which reflect qualititative aspects of bone tissue are scanty. Few studies concern the effect of the anti-osteoporotic medications on BMD and fracture risk specifically in men. Overall, the effect of these drugs on BTM levels is similar in men as in women. However, there are no studies which have assessed the potential utility of the BTM in the evaluation of the efficacy of the anti-osteroporotic treatment in men, e.g. is the treatment-induced change in the BTM levels predictive of the subsequent increase in BMD and of the subsequent decrease in the fracture incidence (as it has been observed in post-menopausal women)? In particular, it is not known if the BTM can be used to improve persistence with the anti-osteoporotic treatment in men.
References 1. P. Garnero, P.D. Delmas, Investigation of bone: biochemical markers, in: M.C. Hochberg, A.J. Silman, J.S. Smolen, M.E. Weinblatt, M.H. Weisman (Eds.) Rheumatology, fourth ed., vol. 2, Harcourt Health Sciences Ltd, London, 2007, pp. 1943–1953. 2. P. Szulc, P.D. Delmas, Biochemical markers of bone turn over: potential use in the investigation and management of post-menopausal osteoporosis, Osteoporos. Int. 19 (2008) 1683–1704. 3. P. Garnero, O. Borel, P.D. Delmas, Evaluation of a fully automated serum assay for C-terminal cross-linking telopeptide of type I collagen in osteoporosis, Clin. Chem. 47 (2001) 694–702. 4. P. Garnero, P. Vergnaud, N. Hoyle, Evaluation of a fully automated serum assay for total N terminal propeptide of type I collagen in post-menopausal osteoporosis, Clin. Chem. 54 (2008) 188–196. 5. N.S. Fedarko, A. Jain, A. Karadag, M.R. Van Eman, L.W. Fisher, Elevated serum bone sialoprotein and osteopontin in colon, breast, prostate, and lung cancer, Clin. Cancer Res. 7 (2001) 4060–4066. 6. M. Seibel, H. Woitge, M. Pecherstorfer, et al., Serum immunoreactive bone sialoprotein as a new marker of bone turnover
C h a p t e r 3 Assessment of Bone Turnover in Men Using Biochemical Markers l
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
21.
22.
in metabolic and malignant bone disease, J. Clin. Endocrinol. Metab. 81 (1996) 3289–3294. A. Ramankulov, M. Lein, G. Kristiansen, S.A. Loening, K. Jung, Plasma osteopontin in comparison with bone markers as indicator of bone metastasis and survival outcome in patients with prostate cancer, Prostate 67 (2007) 330–340. Y. Kudo, B.S. Siriwardena, H. Hatano, I. Ogawa, T. Takata, Periostin: novel diagnostic and therapeutic target for cancer, Histol. Histopathol. 22 (2007) 1167–1174. P. Garnero, M. Grimaux, P. Seguin, P.D. Delmas, Characterization of immunoreactive forms of human osteocalcin generated in vivo and in vitro, J. Bone Miner Res. 9 (1994) 255–264. K.K. Ivaska, T.A. Hentunen, J. Vääräniemi, H. Ylipahkala, K. Pettersson, H.K. Väänänen, Release of intact and fragmented osteocalcin molecules from bone matrix during bone resorption in vitro, J. Biol. Chem. 279 (2004) 18361–18369. A.K. Srivastava, F.R. Mohan, F.R. Singer, D.J. Baylink, A urine midmolecule osteocalcin assay shows higher discriminatory power than a serum midmolecule osteocalcin assay during short-term alendronate treatment of osteoporotic patients, Bone 31 (2002) 62–69. J. Lenora, K.K. Ivaska, K.J. Obrant, P. Gerdhem, Prediction of bone loss using biochemical markers of bone turnover, Osteoporos. Int. 18 (2007) 1297–1305. P. Gerdhem, K.K. Ivaska, S.L. Alatalo, et al., Biochemical markers of bone metabolism and prediction of fracture in elderly women, J. Bone Miner. Res. 19 (2004) 386–393. A.J. Janckila, R.N. Parthasarathy, L.K. Parthasarathy, et al., Properties and expression of human tartrate resistant acid phosphatase isoform 5a by monocyte-derived cells, J. Leukoc. Biol. 77 (2005) 209–218. T. Kawaguchi, T. Nakano, K. Sasagawa, T. Ohashi, T. Miura, T. Komoda, Tartrate-resistant acid phosphatase 5a and 5b contain distinct sugar moieties, Clin. Biochem. 41 (2008) 1245–1249. J.M. Halleen, S.L. Alatalo, H. Suominen, S. Cheng, A.J. Janckila, H.K. Väänänen, Tartrate-resistant acid phosphatase 5b: a novel serum marker of bone resorption, J. Bone Miner. Res. 15 (2000) 1337–1345. T. Ohashi, Y. Igarashi, Y. Mochiuki, et al., Development of a novel fragment absorbed immunocapture enzyme assay system for tartrate-resistant acid phosphatase 5b, Clin. Chim. Acta. 376 (2007) 205–212. Y. Lhoste, P. Vergnaud, P. Garnero, A new specific immuno assay for intact serum TRACP5b demonstrates increased sensitivity in osteoporosis, J. Bone Miner. Res. 22 (Suppl. 1) (2007) S192. A. Nenonen, S. Cheng, K. Ivaska, et al., Serum TRACP5b is a useful marker for monitoring alendronate treatment: comparison with other markers of bone turnover, J. Bone Miner. Res. 20 (2005) 1804–1812. A.J. Janckila, D.H. Neustadt, L.T. Yam, Significance of serum TRACP in rheumatoid arthritis, J. Bone Miner. Res. 23 (2008) 1287–1295. K.M. Fagerlund, A.J. Janckila, H. Ylipahkala, et al., Clinical performance of six different serum tartrate-resistant acid phosphatase assays for monitoring alendronate treatment, Clin. Lab. 54 (2008) 347–354. P. Garnero, O. Borel, I. Byrjalsen, et al., The collagenolytic activity of cathepsin K is unique among mammalian proteinases, J. Biol. Chem. 273 (1998) 32347–32352.
37
23. K. Kerschan-Schindl, G. Hawa, S. Kudlacek, W. Woloszczukand, P. Pietschmann, Serum levels of cathepsin K decrease with age in both women and men, Exp. Gerontol. 40 (2005) 532–535. 24. M. Skoumal, G. Haberhauer, G. Kolarz, G. Hawa, W. Woloszczuk, A. Klingler, Serum cathepsin K levels of patients with longstanding rheumatoid arthritis: correlation with radiological destruction, Arthritis. Res. Ther. 7 (2005) R65–R70. 25. C. Meier, U. Meinhardt, J.R. Greenfield, et al., Serum cathepsin K concentrations reflect osteoclast activity in women with post-menopausal osteoporosis and patients with Paget’s disease of bone, Clin. Lab. 21 (2006) 1–10. 26. G. Holzer, H. Noske, T. Lang, L. Holzer, U. Willinger, Soluble cathepsin K: a novel marker for the prediction of nontraumatic fractures? J. Lab. Clin. Med. 146 (2005) 13–17. 27. A.E. Kearns, S. Khoslal, P. Kostenuik, RANKL and OPG regulation of bone remodeling in health and disease, Endocr. Rev. 29 (2008) 155–192. 28. P. Szulc, L.C. Hofbauer, A.E. Heufelder, S. Roth, P.D. Delmas, Osteoprotegerin serum levels in men: correlation with age, estrogen, and testosterone status, J. Clin. Endocrinol. Metab. 86 (2001) 3162–3165. 29. A. Rogers, R. Eastell, Circulating osteoprotegerin and receptor activator for nuclear factor kappaB ligand: clinical utility in metabolic bone disease assessment, J. Clin. Endocrinol. Metab. 90 (2005) 6323–6331. 30. T.F. Day, X. Guo, L. Garrett-Beal, Y. Yang, Wnt/beta-catenin signaling in mesenchymal progenitors controls osteoblast and chondrocyte differentiation during vertebrate skeletogenesis, Dev. Cell 8 (2005) 739–750. 31. M.L. Johnson, MA. Kamel, The Wnt signaling pathways and bone metabolism., Curr. Opin. Rheum. 19 (2007) 376–382. 32. E. Tian, F. Zhan, R. Walker, et al., The role of the Wntsignaling antagonist DKK1 in the development of osteolytic lesions in multiple myeloma, N. Engl. J. Med. 349 (2003) 2483–2494. 33. N. Voorzanger-Rousselot, D. Goehrig, F. Journe, et al., Increased dickkopf-1 (Dkk-1) expression in breast cancer bone metastases, Br. J. Cancer 97 (2007) 964–970. 34. T. Yamabuki, A. Takano, S. Hayama, et al., Dikkopf-1 as a novel serologic and prognostic biomarker for lung and esophageal carcinomas, Cancer Res. 67 (2007) 2517–2525. 35. D. Diarra, M. Stolina, Polzer, et al., Dickkopf-1 is a master regulator of joint remodeling., Nat. Med. 13 (2007) 156–163. 36. P. Garnero, N.C. Tabassi, N. Voorzanger-Rousselot, Circulating dickkopf-1 and radiological progression in patients with early rheumatoid arthritis treated with etanercept, J. Rheumatol. 35 (2008) 2313–2315. 37. N.E. Lane, M.C. Nevitt, L.Y. Lui, P. de Leon, M. Corr, Study of Osteoporotic Fractures Research Group. Wnt signaling antagonists are potential prognostic biomarkers for the progression of radiographic hip osteoarthritis in elderly Caucasian women, Arthritis. Rheum. 56 (2007) 3319–3325. 38. N. Voorzanger-Rousselot, D. Goehrig, T. Facon, P. Clézardin, P. Garnero, Platelets is a major contributor to circulating levels of Dickkopf-1 (Dkk-1): clinical implications in patients with multiple myeloma. Brit. J. Hematol. (in press). 39. P. Garnero, New biochemical markers of bone turnover, BoneKEy 5 (2008) 84–102. 40. P. Garnero, C. Fledelius, E. Gineyts, C.M. Serre, E. Vignot, PD. Delmas, Decreased -isomerisation of C-telopeptides
38
41.
42.
43.
44.
45.
46.
47.
48.
49.
50.
51.
52.
53.
54.
55.
56.
Osteoporosis in Men of type I collagen in Paget’s disease of bone, J. Bone Miner. Res. 12 (1997) 1407–1415. D.J. Leeming, G. Delling, M. Koizumi, et al., Alpha CTX as a biomarker of skeletal invasion of breast cancer: immunolocalization and the load dependency of urinary excretion, Cancer Epidemiol. Biomarkers. Prev. 15 (2006) 1392–1395. P. Garnero, A.M. Schott, D. Prockop, G. Chevrel, Bone turn over and type I collagen C-telopeptide isomerization in adult osteogenesis imperfecta: associations with collagen gene mutations, Bone (21 November 2008) [Epub ahead of print]. D.C. Bauer, P. Garnero, S. Litwak, et al., Type I collagen isomerization (alpha/beta CTX) and the risk of hip and nonspine fracture in men: a prospective study, Osteoporos. Int. 19 (Suppl. 2) (2008) S233–S250. I. Byrjalsen, D.J. Leeming, P. Qvist, C. Christiansen, M.A. Karsdal, Bone turnover and bone collagen maturation in osteoporosis: effects of antiresorptive therapies, Osteoporos. Int. 19 (2008) 339–348. M.A. Karsdal, I. Byrjalsen, D.J. Leeming, P.D. Delmas, C. Christiansen, The effects of oral calcitonin on bone collagen maturation: implications for bone turnover and quality, Osteoporos. Int. 19 (2008) 1355–1361. P. Garnero, D.C. Bauer, E. Mareau, et al., Effects of PTH and alendronate on type I collagen isomerization in post-menopausal women with osteoporosis: the PaTH study, J. Bone Miner. Res. 23 (2008) 1442–1448. S. Bhattacharyya, E.R. Siegel, S.J. Achenbach, S. Khosla, L.J. Suva, Serum biomarker profile associated with high bone turnover and BMD in post-menopausal women, J. Bone Miner. Res. 23 (2008) 1106–1117. A. Claudon, P. Vergnaud, C. Valverde, A. Mayr, U. Klause, P. Garnero, A new automated multiplex assay for bone turnover markers in osteoporosis, Clin. Chem. 54 (2008) 1554–1563. O.S. Donescu, M.C. Battié, J. Kaprio, et al., Genetic and constitutional influences on bone turnover markers: a study of male twin pairs, Calcif. Tissue. Int. 80 (2007) 81–88. B.Z. Leder, A.B. Araujo, T.G. Travison, J.B. McKinlay, Racial and ethnic differences in bone turnover markers in men, J. Clin. Endocrinol. Metab. 92 (2007) 3453–3457. S.L. Greenspan, R. Dresner-Pollak, R.A. Parker, D. London, L. Fergusson, Diurnal variation of bone mineral turnover in elderly men and women, Calcif. Tissue. Int. 60 (1997) 419–423. D.B. Henriksen, P. Alexandersen, N.H. Bjarnason, et al., Role of gastrointestinal hormones in postprandial reduction of bone resorption, J. Bone Miner. Res. 18 (2003) 2180–2189. P. Szulc, F. Munoz, F. Marchand, M.C. Chapuy, P.D. Delmas, Role of vitamin D and parathyroid hormone in the regulation of bone turnover and bone mass in men: the MINOS study, Calcif. Tissue. Int. 73 (2003) 520–530. R. Theiler, H.B. Stähelin, M. Kränzlin, A. Tyndall, H.A. Bischoff, High bone turnover in the elderly, Arch. Phys. Med. Rehabil. 80 (1999) 485–489. L. Gennari, D. Merlotti, G. Martini, et al., Longitudinal association between sex hormone levels, bone loss, and bone turnover in elderly men, J. Clin. Endocrinol. Metab. 88 (2003) 5327–5333. P. Szulc, F. Munoz, B. Claustrat, et al., Bioavailable estradiol may be an important determinant of osteoporosis in men: the MINOS study, J. Clin. Endocrinol. Metab. 86 (2001) 192–199.
57. P. Szulc, B. Claustrat, F. Marchand, P.D. Delmas, Increased risk of falls and increased bone resorption in elderly men with partial androgen deficiency: the MINOS study, J. Clin. Endocrinol. Metab. 88 (2003) 5240–5247. 58. A. Falahati-Nini, B.L. Riggs, E.J. Atkinson, W.M. O’Fallon, R. Eastell, S. Khosla, Relative contributions of testosterone and estrogen in regulating bone resorption and formation in normal elderly men, J. Clin. Invest. 106 (2000) 1553–1560. 59. P. Szulc, P. Garnero, B. Claustrat, F. Marchand, F. Duboeuf, P.D. Delmas, Increased bone resorption in moderate smokers with low body weight: the Minos study, J. Clin. Endocrinol. Metab. 87 (2002) 666–674. 60. A. Diez, J. Puig, S. Serrano, et al., Alcohol-induced bone disease in the absence of severe chronic liver damage, J. Bone Miner. Res. 9 (1994) 825–831. 61. T. Diamond, D. Stiel, M. Munzer, M. Wilkinson, S. Posen, Ethanol reduces bone formation and may cause osteoporosis, Am. J. Med. 86 (1989) 282–288. 62. F. Nyquist, S. Jlunghall, M. Berglund, K. Obrant, Biochemical markers of bone metabolism after short and long time ethanol withdrawal in alcoholics, Bone 19 (1996) 51–54. 63. D.A. Chakkalaka, Alcohol-induced bone loss and deficient bone repair, Alcohol. Clin. Exp. Metab. 29 (2005) 2077–2090. 64. M. Inoue, H. Tanaka, T. Moriwake, M. Oka, C. Sekiguchi, T. Seino, Altered biochemical markers of bone turnover in humans during 120 days of bed rest, Bone 26 (2000) 281–286. 65. D. Roberts, W. Lee, R.C. Cuneo, et al., Longitudinal study of bone turnover after acute spinal cord injury, J. Clin. Endocrinol. Metab. 83 (1998) 415–422. 66. J.S. Chen, I.D. Cameron, R.G. Cumming, et al., Effect of age-related chronic immobility on markers of bone turnover, J. Bone Miner. Res. 21 (2006) 324–331. 67. Y. Sato, Y. Honda, J. Iwamoto, T. Kanoko, K. Satoh, Abnormal bone and calcium metabolism in immobilized Parkinson’s disease patients, Mov. Disord. 20 (2005) 1598–1603. 68. M.L. Hetland, J. Haarbo, C. Christiansen, Low bone mass and high bone turnover in male long distance runners, J. Clin. Endocrinol. Metab. 77 (1993) 770–775. 69. K.M. Karlsson, C. Karlsson, H.G. Ahlborg, Ö. Valdimarsson, S. Ljunghall, The duration of exercise as a regulator of bone turnover, Calcif. Tissue. Int. 73 (2003) 350–355. 70. K. Jung, M. Lein, C. Stephan, et al., Comparison of 10 serum bone turnover markers in prostate carcinoma patients with bone metastatic spread: diagnostic and prognostic implications, Int. J. Cancer 111 (2004) 783–791. 71. P. Garnero, M. Ferreras, M.A. Karsdal, et al., The type I collagen fragments ICTP and CTX reveal distinct enzymatic pathways of bone collagen degradation, J. Bone Miner. Res. 18 (2003) 859–867. 72. J.E. Brown, R.J. Cook, P. Major, et al., Bone turnover markers as predictors of skeletal complications in prostate cancer, lung cancer, and other solid tumors, J. Natl. Cancer Inst. 97 (2005) 59–69. 73. D. Mittan, S. Lee, E. Miller, R.C. Perez, J.W. Basler, JM. Bruder, Bone loss following hypogonadism in men with prostate cancer treated with GnRH analogs, J. Clin. Endocrinol. Metab. 87 (2002) 3656–3661. 74. M.R. Smith, F.J. McGovern, A.L. Zietman, M.A. Fallon, D.L. Hayden, D.A. Schoenfeld, P.W. Kantoff, J.S. Finkelstein,
C h a p t e r 3 Assessment of Bone Turnover in Men Using Biochemical Markers l
75.
76.
77.
78.
79.
80.
81.
82.
83.
84.
85.
86.
87.
88.
89.
Pamidronate to prevent bone loss during androgen-deprivation therapy for prostate cancer, N. Engl. J. Med. 345 (2001) 948–955. M. Lein, M. Wirth, K. Miller, et al., Serial markers of bone turnover in men with metastatic prostate cancer treated with zoledronic acid for detection of bone metastases progression, Eur. Urol. 52 (2007) 1381–1387. T.H. Diamond, J. Winters, A. Smith, et al., The antiosteo porotic efficacy of intravenous pamidronate in men with prostate carcinoma receiving combined androgen blockade. A double blind, randomized, placebo-controlled crossover study, Cancer 92 (2001) 1444–1450. R.E. Coleman, P. Major, A. Lipton, et al., Predictive value of bone resorption and formation markers in cancer patients with bone metastases receiving the bisphosphonate zoledronic acid, J. Clin. Oncol. 23 (2005) 4925–4935. J. Gram, P. Junker, H.K. Nielsen, J. Bollerslev, Effects of shortterm treatment with prednisolone and calcitriol on bone and mineral metabolism in normal men, Bone 23 (1998) 297–302. G. Pearce, D.A. Tabensky, P.D. Delmas, H.W. Baker, E. Seeman, Corticosteroid-induced bone loss in men, J. Clin. Endocrinol. Metab. 83 (1998) 801–806. C.K.T. Farmer, G. Hampson, I.C. Abbs, R.M. Hilton, C.G. Koffman, I. Fogelman, S.H. Sacks, Late low-dose steroid withdrawal in renal transplant recipients increases bone formation and bone mineral density, Am. J. Transplant. 6 (2006) 2929–2936. F. Richy, J. Bousquet, G.E. Ehrlich, et al., Inhaled corticosteroids effects on bone in asthmatic and COPD patients: a quantitative systematic review, Osteoporos. Int. 14 (2003) 179–190. S. Khosla, L.J. Melton 3rd, S.J. Achenbach, A.L. Oberg, BL. Riggs, Hormonal and biochemical determinants of trabecular microstructure at the ultradistal radius in women and men, J. Clin. Endocrinol. Metab. 91 (2006) 885–891. P. Szulc, P. Garnero, F. Munoz, F. Marchand, P.D. Delmas, Cross-sectional evaluation of bone metabolism in men, J. Bone Miner. Res. 16 (2001) 1642–1650. P. Szulc, A. Montella, P.D. Delmas, High bone turnover is associated with accelerated bone loss but not with increased fracture risk in men aged 50 and over: the prospective MINOS study, Ann. Rheum. Dis. 67 (2008) 1249–1255. D.C. Bauer, P. Garnero, S.L. Harrison, et al., Biochemical markers of bone turnover, hip bone loss and non-spine fracture in men: a prospective study, J. Bone Miner. Res. 22 (Suppl. 1) (2007) S21. Abstract 1074. T.V. Nguyen, C. Meier, J.R. Center, J.A. Eisman, M.J. Seibel, Bone turnover in elderly men: relationships to change in bone mineral density, BMC Musculoskelet. Disord. 8 (2007) 13. C. Meier, T.V. Nguyen, J.R. Center, M.J. Seibel, J.A. Eisman, Bone resorption and osteoporotic fractures in elderly men: the Dubbo Osteoporosis Epidemiology Study, J. Bone Miner. Res. 20 (2005) 579–587. P. Szulc, J.M. Kaufman, P.D. Delmas, Biochemical assessment of bone turnover and bone fragility in men, Osteoporos. Int. 18 (2007) 1451–1461. T. Sone, M. Miyake, N. Takeda, M. Fukunaga, Urinary excretion of type I collagen crosslinked N-telopeptides in healthy Japanese adults: age- and sex-related changes and reference limits, Bone 17 (1995) 335–339.
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90. H. Luukinen, S.M. Kakonen, K. Pettersson, et al., Strong prediction of fractures among older adults by the ratio of carboxylated to total serum osteocalcin, J. Bone Miner. Res. 15 (2000) 2473–2478. 91. R.R. McLean, P.F. Jacques, J. Selhub, et al., Homocysteine as a predictive factor for hip fractures in elderly persons, N. Engl. J. Med. 350 (2004) 2042–2049. 92. R.A.M. Dhonukshe-Rutten, S.M.F. Pluijm, L.C.P.G.M. de Groot, P. Lips, J.H. Smit, W.A. van Staveren, Homocysteine and vitamin B12 status relate to bone turnover markers, broadband ultrasound attenuation, and fractures in healthy elderly people, J. Bone Miner. Res. 20 (2005) 921–929. 93. B. Raposo, C. Rodriguez, J. Martinez-Gonzalez, L. Badimon, High levels of homocysteine inhibit lysyl oxidase (LOX) and downregulate LOX expression in vascular endothelial cells, Atherosclerosis 177 (2004) 1–8. 94. M. Khan, M. Yamauchi, S. Srisawasdi, et al., Homocysteine decreases chondrocyte mediated matric mineralization in differentiating chick limb-bud mesenchymal cell micro-mass cultures, Bone 28 (2001) 387–398. 95. M. Herrmann, T. Widmann, G. Colaianni, S. Colucci, A. Zallone, W. Herrmann, Increased osteoclast activity in the presence of increased homocysteine concentrations, Clin. Chem. 51 (2005) 2348–2353. 96. J.K. Amory, N.B. Watts, K.A. Easley, et al., Exogenous testosterone or testosterone with finasteride increases bone mineral density in older men with low serum testosterone, J. Clin. Endocrinol. Metab. 89 (2004) 503–510. 97. C. Wang, R.S. Swerdloff, A. Iranmanesh, et al., Effects of transdermal testosterone gel on bone turnover markers and bone mineral density in hypogonadal men, Clin. Endocrinol. 54 (2001) 739–750. 98. A.M. Isidori, E. Giannetta, E.A. Greco, et al., Effects of testosterone on body composition, bone metabolism and serum lipid profile in middle-aged men: a meta-analysis, Clin. Endocrinol. 63 (2005) 280–293. 99. K.G. Saag, R. Emkey, T.J. Schnitzer, et al., Alendronate for the prevention and treatment of glucocorticoid-induced osteoporosis, N. Engl. J. Med. 339 (1998) 292–299. 100. S. Wallach, S. Cohen, D.M. Reid, et al., Effects or risedronate treatment on bone density and vertebral fracture in patients on corticosteroid therapy, Calcif. Tissue. Int. 67 (2000) 277–286. 101. E. Orwoll, M. Ettinger, S. Weiss, et al., Alendronate treatment of osteoporosis in men, N. Engl. J. Med. 343 (2000) 604–610. 102. S. Boonen, E.S. Orwoll, D. Wenderoth, K. Stoner, R. Eusebio, P.D. Delmas, Once-weekly risedronate in men with osteoporosis: results of a 2-year, placebo-controlled, doubleblind, multicenter study, J. Bone Miner. Res. 24 (2009) 719–725. 103. I. Shimon, V. Eshed, R. Doolman, B.A. Sela, A. Karasik, I. Vered, Alendronate for osteoporosis in men with androgenrepleted hypogonadism, Osteoporos. Int. 16 (2005) 1591–1596. 104. J.J. Stepan, P. Burckhardt, V. Hána, The effects of threemonth intravenous ibandronate on bone mineral density and bone remodeling in Klinefelter’s syndrome: the influence of vitamin D deficiency and hormonal status, Bone 33 (2003) 589–596.
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105. M.J. Bolland, A.B. Grey, A.M. Horne, et al., Effects of intravenous zoledronate on bone turnover and BMD persist for at least 24 months, J. Bone Miner. Res. 23 (2008) 1304–1308. 106. G.P. Trovas, G.P. Lyritis, A. Galanos, P. Raptou, E.A. Constantelou, A randomized trial of nasal spray salmon calcitonin in men with idiopathic osteoporosis: effects on bone mineral density and bone markers, J. Bone Miner. Res. 17 (2002) 521–527. 107. E.S. Orwoll, W.H. Scheele, S. Paul, et al., The effect of teriparatide [human parathyroid hormone (1–34)] therapy on bone density in men with osteoporosis, J. Bone Miner. Res. 18 (2003) 9–17. 108. E.S. Kurland, F. Cosman, D.J. McMahon, C.J. Rosen, R. Lindsay, J.P. Bilezikian, Parathyroid hormone as a therapy
for idiopathic osteoporosis in men: effects on bone mineral density and bone markers, J. Clin. Endocrinol. Metab. 85 (2000) 3069–3076. 109. J.S. Finkelstein, B.Z. Leder, S.A. Burnett, et al., Effects of teriparatide, alendronate, or both on bone turnover in osteoporotic men, J. Clin. Endocrinol. Metab. 91 (2006) 2882–2887. 110. N. Bravenboer, P.J. Holzmann, J.C. ter Maaten, L.M. Stuurman, J.C. Roos, P. Lips, Effect of long-term growth hormone treatment on bone mass and bone metabolism in growth hormonedeficient men, J. Bone Miner. Res. 20 (2005) 1778–1784. 111. A.M. Ahmad, J. Thomas, A. Clewes, et al., Effects of growth hormone replacement on parathyroid hormone sensitivity and bone mineral metabolism, J. Clin. Endocrinol. Metab. 88 (2003) 2860–2868.
Chapter
4
Fundamentals of Mineral Homeostasis K. SHAWN Davison1 and DAvid A. Hanley2 1
Laval University, Quebec City, PQ, Canada University of Calgary, Calgary, AB, Canada
2
Introduction
secretion, nerve conduction, muscular contraction, glycogen metabolism, coagulation and plasma membrane adhesion. P is a fundamental component of cellular structure and activity, involved in most energy releasing (adenosine tri phosphate → adenosine diphosphate) or producing (adeno sine diphosphate → adenosine triphosphate) biochemical interactions. Mg acts as an essential cofactor in a number of biological systems that regulate enzyme activities and neuromuscular function. The intricate maintenance of homeostasis often calls for rapid, minute changes in mineral concentration both inside and outside the cells. Given adequate dietary intakes, bone, the intestine and the kidneys are primarily responsible for the maintenance of ECF mineral concentrations within appropriate limits, with both parathyroid hormone (PTH) and 1,25(OH)2 vitamin D3 (1,25D or calcitriol) playing important roles in regulation of these tissues. The precise control of mineral balance afforded from this system per sonifies biological elegance.
The skeleton is a resilient composite of organic and inorganic materials intricately intertwined into a dynamic structure that serves essential mechanical and metabolic functions. The organic materials, most notably type I collagen, pro vide a ductile lattice to which the inorganic components adhere to provide stiffness and resistance to compression. The purpose of this chapter is briefly to review the body’s acquisition and maintenance of the inorganic minerals that compose the skeleton and identify aspects relevant to male skeletal physiology. For the most part, the differences between male and female mineral physiology occur during adolescent growth and after menopause, so most of what is detailed here will not emphasize differences in bone home ostasis between men and women. Of the inorganic constituents of bone, three minerals stand alone in their importance: calcium (Ca), phosphorus (P) and magnesium (Mg). In this discussion, concentra tions of P will be substituted by concentrations of inorganic phosphate (PO4 or Pi) since P does not exist freely in the body. The maintenance of homeostasis for Ca, Pi and Mg is of paramount importance, because these minerals function as essential cofactors and regulators of numerous metabolic processes within the body. The skeleton plays a leading role as a vast, accessible storehouse that ensures essential metabolic functions can continue normally in the blood, extracellular fluid (ECF) and soft tissues. The hydroxy apatite crystal (HAP) is the fundamental inorganic build ing block of bone and is composed primarily of Ca and Pi [Ca10(Pi)6(OH2)]. Mg, while not integrated within the HAP crystal, is found adhering to it, often in a state of equili brium with ECF Mg. Ca is a critical constituent for several important meta bolic functions including cell division, cell adhesion, protein Osteoporosis in Men
Total body stores of essential minerals Calcium The total body stores of Ca for a healthy adult man or woman are approximately 1 kg, ranging higher or lower depending on an individual’s body size and overall degree of bone mineralization. The skeleton possesses about 99% of the body’s calcium within its HAP crystals, with the remainder found in the ECF and soft tissues (10 g). During normal states of bone turnover, approximately 500 mg of Ca is liberated from the skeleton daily with roughly an equal amount reinvested. The ionized fraction 41
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Osteoporosis in Men
42
↑ PTH
Releases calcium and phosphate
Bone
Parathyroid glands sense low blood Ca++ ↑Calcitriol (1,25(OH)2D)
Increased blood Ca++
Sunlight or diet Vitamin D
25(OH)D
Kidney
Calcitriol (1,25(OH)2D)
Liver ♦ Increases calcitriol formation ♦ Decreases excretion of calcium ♦ Increases excretion of phosphate
G-I tract
Increased absorption of calcium and phosphate
Figure 4.1 Hormonal regulation of extracellular calcium. Ca, calcium; PTH, parathyroid hormone; G-I tract, gastrointestinal tract.
of Ca is the metabolically significant fraction responsible for its biologic action.
Phosphate In the healthy adult, there is approximately 550 g of Pi in the total body, with approximately 85% of the total bound with Ca in the HAP crystal and the remaining 15% found in the soft tissues as phosphate esters. A relatively small amount of Pi is found in the ECF – approximately 0.1% of the total.
Magnesium Total body stores of Mg are approximately 25 g in a healthy adult with about 66% located within the skele ton, 33% found in intracellular fluid and 1% in the ECF. Approximately 55% of Mg is in the ionized state, 30% is bound onto a protein and 15% is complexed with other anions. Ionic Mg is primarily responsible for the majority of biochemical activity within the body. Intracellular, soft tissue or total body Mg status is difficult to ascertain within an individual since serum ionized or total Mg reflects only ECF Mg, a miniscule fraction of the total.
Extracellular mineral metabolism – circulating levels Calcium Approximately 900 mg of Ca is found within the different compartments of the extracellular pool in a healthy adult. Ca is purposefully transported among dynamic pools of Ca in blood, bone and from within cells depending on the
particular metabolic needs at any given moment. The move ment of Ca through the ECF is tightly controlled through the coordination of endocrine cells which express the cal cium-sensing receptor (CaSR), modulating the production of hormones which then act on specific cells in kidney, bone and gut to allow for coordinated maintenance of ECF Ca concentrations (Figure 4.1). The prime regulator of ECF Ca is PTH. In optimum (zero) balance within the adult skeleton, bone resorption and formation are equivalent at about 500 mg/d and the net quantity of Ca absorbed by the intes tine each day (200 mg) is also excreted by the kidney into urine (Figure 4.2). Thus, under normal circumstances, net Ca absorption provides a surplus of Ca that considerably exceeds systemic requirements. Dietary intake and the skeletal requirements for Ca fluc tuate widely daily and throughout the lifespan. There is an active coordination of Ca among the intestine, kidneys and the skeleton while the concentration of Ca within the blood is maintained within a narrow range under normal circum stances since serum Ca concentration plays a large role in cellular function. In the ECF compartment, both the ionized and complexed Ca are ultrafilterable which means that they can easily cross semi-permeable membranes. Intestinal Absorption of Calcium Ingestion of Ca-containing foods or supplements is the singular source of Ca for the body. In a typical North American or European diet, dairy products make up the bulk of foods that are responsible for providing Ca to the body, although Ca is found, in lower concentrations, in many other food sources. The intake of Ca can vary widely as can the body’s requirements for this mineral. About 20–60% of the ingested Ca is absorbed, depending on skel etal requirements, age, calcium intake, vitamin D status and
C h a p t e r 4 Fundamentals of Mineral Homeostasis l
43
Ca 1000 mg/d
Dietary intake
Bone (1 kg Ca)
Bone formation and resorption Ca 500 mg/d
Intestine
Extracellular fluid Ca
Intestinal absorption Ca 200 mg/d
Fecal excretion Ca 800 mg/d
Tubular reabsorption Ca 9,800 mg/d Kidney Filtered load Ca 10,000 mg/d
Urinary excretion Ca 200 mg/d Ca 1000 mg/d
Figure 4.2 Calcium balance. Ca, calcium.
the bioavailability of Ca from foods [1]. The duodenum and the jejunum provide vast surface area for the absorption of dietary Ca, accounting for an estimated 90% of the total Ca absorbed. As an individual ages past young adulthood, there is a decrease in the efficiency of the intestinal absorption of Ca, with only an approximate 20–45% of the dietary load of Ca absorbed in older men and women [2]. This decreased abil ity to absorb Ca with aging necessitates increasing dietary intakes as one ages in order to ensure a relatively constant Ca absorption, which is reflected in Ca intake guidelines. Conversely, during periods of very high demand of Ca, such as during rapid skeletal growth and mineralization during childhood and adolescence and during pregnancy and lacta tion in women, the intestinal absorption efficiency can be increased dramatically with as high as 55–70% of dietary calcium absorbed in children and young adults. Generally, when Ca intake falls below 200 mg/d, a nega tive Ca balance occurs where more Ca is leaving the body through the bowels and kidneys than is being absorbed through the intestines. In adults, at least 400 mg/d is needed to obtain zero Ca balance. There is a curvilinear relationship between net calcium absorption and calcium intake which reflects the sum of two absorptive mechanisms – a cellmediated, 1,25D-dependent saturable active transport mecha nism and a passive, diffusional paracellular absorption that is driven by transepithelial electrochemical gradients [1]. When Ca intake is increased past zero balance, there is a decrease in absorption efficiency, with absorption begin ning to plateau at approximately 1000 mg/d. When dietary intake of Ca drops, there is a subsequent increase in the Ca
absorption efficiency causing a greater proportion of the ingested dietary Ca to be retained. In periods of reduced dietary intake or increased skeletal or metabolic demand, 1,25D stimulates the small intestine to increase its effi ciency of Ca absorption. This stimulation involves upregu lation of the active transport of Ca across the duodenum and jejunum. During these periods of upregulation of intestinal absorption, efficiency can shift from 25–45% to 55–70% and result in absorption of a far greater propor tion of the dietary load. Conversely, when dietary Ca intake is high and skeletal and metabolic demands are being met, there is a consequent decrease in the Ca absorption in the intestines. The Ca passed in the feces contains both the unab sorbed fraction of dietary intake, but also Ca that is secreted as part of pancreatic and bile juices as well as through mucosal secretion. Estrogens or hormonal changes during pregnancy or lactation have distinct, vitamin D-independ ent effects at the genomic level on active duodenal calcium absorption mechanisms, mainly through a major upregula tion of the calcium influx channel CaT1. The estrogen effects seem to be mediated solely by estrogen receptor alpha [3]. Renal Transport of Calcium The kidney plays a critical role in the maintenance of Ca homeostasis and over 270 mmol (10 g) of Ca is filtered each day, which represents a larger volume than the entire Ca composition of the ECF and far more than net intesti nal calcium absorption of about 200 mg/d. Of this 10 g of calcium, approximately 1000 mg is directly under the con trol of PTH-regulated reabsorption in the distal nephron
44
Osteoporosis in Men
allowing for intricate control of calcium concentrations within the ECF. In order for a neutral Ca balance to be obtained, approximately 98% of the filtered load must be reabsorbed along the renal tubule. The ultrafilterable com partment of Ca is the complexed and ionized fraction and is freely filtered by the glomerulus, with a Ca concentration of about 1.5 mmol/L. Within the kidney, approximately 70% of the filtered Ca load is passively reabsorbed, following sodium, in the proxi mal tubule. Approximately 20% is reabsorbed in the loop of Henle, with very little reabsorbed in the thin descend ing and the thin ascending limb – the majority occurs in the thick ascending limb (TALH) where paracellular Ca reabsorption is mediated by Na-K-2 Ca transporter. In the TALH, Ca concentration is monitored via the basolateral membrane cells which contain CaSRs. When the CaSR senses an increase in the peritubular Ca, a lumen positive voltage is induced, which then results in reduced Ca reab sorption, thereby decreasing urinary Ca concentration. The major site of physiologic regulation of urine Ca excretion by PTH is the distal convoluted tubule (DCT), which can reabsorb about 8% of the filtered Ca load. In the DCT, there is active Ca reabsorption moving against an electrochemical gradient. This active transport is respon sive to a low Ca diet, 1,25D and low levels of estradiol to elicit increased Ca conservancy in the kidney and also is the process in which PTH plays a pivotal role. The Ca enters across the apical membrane through the highly selec tive renal epithelial calcium channel 1 (TRPV5), which is selectively more permeable to Ca as opposed to sodium. Once within the cell, cytosolic Ca diffusion is facilitated by Ca binding to calbindin 28 kDa and calbindin 9 kDa. Active release of Ca across the distal nephron plasma membrane is accomplished by the Na–Ca exchanger and a Ca-ATPase (PMCA1b). While Ca generally mirrors Na movement throughout the kidney, in the DCT, reabsorption and excre tion of the two can be actively dissociated if metabolic demands warrant (PTH stimulation in response to low ECF Ca), or treatment with a thiazide diuretic is initiated. The collecting duct absorbs 5% of the filtered load with the final urine content ending up with about 2% of the fil tered load, which can be higher or lower depending on the metabolic and skeletal needs of the body. If dietary Ca is increased, approximately 6–8% of the increase appears in the urine. Reabsorption in the kidney can be affected by a number of factors allowing for intricate control of Ca balance. Volume expansion increases urine Ca and Na excretion through decreased proximal tubule ion reabsorption; volume contraction causes the opposite reactions. Hypercalcemia increases ultrafilterable Ca, decreases the glomerular fil tration rate (GFR) and decreases proximal tubule, TALH and distal convoluted tubule Ca reabsorption resulting in a greater Ca than Na excretion. Ca activation of CaSR in the TALH also decreases Ca reabsorption.
Skeletal Calcium One of the most metabolically important roles that the skele ton plays is as a ‘calcium bank’ which can be drawn upon for maintenance of ionized Ca in the serum. Ultimately, mechanisms of mineral homeostasis will operate to main tain ECF Ca which occurs at the expense of reduced bone mineral content. Serum Calcium Ca is brought into the serum through ingestion of Cacontaining foods by way of intestinal absorption or through bone resorption in the event of low dietary availability or by renal reabsorption. Excess Ca is eliminated from the serum primarily through filtration through the renal glomer ulus and secreted along various segments of the nephron. Modest amounts are secreted into the intestine and skin losses are minimal. The other major repository for calcium is bone and, failing that, precipitation with an anion (usually phosphate) into soft tissues. The concentration of ECF calcium is approximately 103 M, with 50% of the fraction ionized, 40% protein-bound and 10% complexed with citrate or Pi ions. About 90% of the protein-bound Ca is bound to albumin, with the remain der bound to globulins. Total Ca concentration in normal serum is between 8.5 and 10.5 mg/dL (2.12–2.62 mmol/L in SI units), above which is considered hypercalcemic and below hypocalcemic. The normal concentration of ionized Ca is 4.65–5.25 mg/dL (1.16–1.31 mmol/L). Of the two meas ures of serum Ca, the more reliable, and biologically active, measure of is that of ionized Ca: total Ca concentration is easily affected by changes in serum protein concentrations, whereas ionized Ca remains relatively stable during fluctua tions in serum protein levels. Since 90% of the protein-bound Ca is bound to albumin, alterations in serum albumin result in dramatic changes in serum calcium measurements. Further, since Ca is prima rily bound to the carboxyl group in albumin, its binding is highly pH dependent. Thus, when acute acidosis is present, this decreases the binding of Ca to albumin which results in increased ionized Ca; the opposite is seen in acute alkalo sis. At pH 7.4, each gram per deciliter (10 g/L in SI units) of albumin binds 0.8 mg/dL (0.2 mmol/L) of Ca and this calculation can be used to correct the total serum Ca con centration in patients with abnormally low levels of circu lating albumin. Major shifts in serum protein or pH require direct measurement of the ionized Ca level to determine the true level of physiologically relevant serum Ca.
Phosphorus The extracellular pool of P (orthophosphate) is approxi mately 550 mg. Like Ca, this pool is in dynamic equilib rium with entry and exit via the intestine, kidney, bone and soft tissues (Figure 4.3). An adequate serum P is needed to
C h a p t e r 4 Fundamentals of Mineral Homeostasis l
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P 1240 mg/d
Dietary intake
Bone
Bone formation and resorption P279 mg/d Secretion Intestine Net intestinal absorption P 868 mg/d
Extracellular fluid P
Tubular reabsorption P 4,960 mg/d Kidney Filtered load P 5,828 mg/d
Urinary excretion P 868 mg/d
Fecal excretion P 372 mg/d P 1240 mg/d
Figure 4.3 Phosphorus balance. P, phosphorus.
ensure sufficient ions to be available for normal mineraliza tion. In zero balance, fractional net phosphorus absorption is about two-thirds of P intake; this amount represents the vast excess over systemic requirements and this excess is excreted into the urine. Concentrations of Pi are less rigidly maintained than that of Ca and Mg. Pi serum fluctuates widely based on sex, age, diet, growth rate and hormone levels. Serum levels of Pi are primarily regulated via changes in the efficiency of reabsorption of filtered Pi in the kidneys and are hormo nally mediated. Intestinal Absorption of Phosphorus Phosphate is found in almost all food groups, as it is a major constituent of all cells. Intake of Pi is seldom less than 620 mg/d as absorption is directly related to dietary Pi ingestion. Pi negative balance typically occurs at intakes lower than 310 mg/d, which is usually only observed during strict caloric restriction. With typical dietary intakes (775– 1860 mg/d) approximately 60–80% of ingested Pi is absorbed in the intestine and passed into the circulatory system. The absorption of phosphate in the intestine is far less rigidly regulated than that of Ca. Passive transport in the intestine is mediated via luminal Pi concentration as well as an active, cell-mediated Pi transport that is regulated by 1,25D. Transepithelial Pi transport must overcome existing electrochemical gradients as the ion moves from the intes tinal lumen into the enterocyte. Entry through the brush border is through an energy dependent transport process or through a secondary active transport process coupled to the flux of another ion such as sodium.
Renal Transport of Phosphorus The concentration of ECF Pi is primary regulated via the kidney with about 85% being ultrafiltrable. In the kid neys, the threshold Pi reabsorption in the proximal tubule is essentially the setpoint that defines the fasting serum Pi concentration, which is also, not coincidentally, the set point regulated by PTH. Urine Pi excretions total about 750–1000 mg/d depending on dietary intake and metabolic demand. Approximately 85% of the Pi reabsorption occurs in the proximal tubule with the rate-limiting step located in the apical domain of the proximal tubule cells, which is also the site of active Na–Pi transport. Thus, about 12.5% glomerular filtrate is excreted in the urine. Skeletal Phosphorus Low Pi concentrations may create suboptimal concentra tions and impair mineralization. Adequate Pi is needed to maintain Pi Ca ion product sufficient to support bone mineralization. Pathologically high Pi leads to extraskeletal ossification. Serum Phosphorus P in serum is primarily as inorganic Pi. Within the blood, 55% of the Pi is ionized, 10% is protein-bound and the remaining complexed with sodium, Ca, and Mg.
Magnesium ECF Mg is approximately 250 mg and in bidirectional equilibrium with Mg fluxes across the intestine, kidney,
46
Osteoporosis in Men Mg 300 mg/d
Dietary intake
Bone and soft tissues Net 0 mg/d
Secretion Intestine Net intestinal absorption Mg 100 mg/d
Extracellular fluid Mg
Tubular reabsorption Mg 1,900 mg/d Kidney Filtered load Mg 2,000 mg/d
Urinary excretion Mg 100 mg/d
Fecal excretion Mg 200 mg/d
Mg 300 mg/d
Figure 4.4 Magnesium balance. Mg, magnesium.
bone and soft tissues (Figure 4.4). In zero balance, the Mg derived from the net intestinal absorption, approximately 100 mg/day, represents a systemic surplus and is quantita tively excreted. The protein-bound fraction of Mg is bound to the carboxyl groups of albumin and is influenced by pH, similarly to that of calcium. The ionized fraction of Mg is biologically active. Intestinal Absorption of Mg As a major intracellular cation, Mg is found in many food sources and Mg intake is generally adequate, as it is proportional to caloric intake. Net intestinal Mg absorp tion increases in direct proportion to dietary Mg intake. It takes 28 mg/d of Mg of absorption to exceed excretion. During usual intake (168–720 mg/d) fractional absorption is 35–40%. Pi forms a non-absorbable complex with Mg and thereby decreases Mg absorption. Reductions in Mg intestinal absorption can also occur with disease or chronic laxative abuse. Different from Ca and P intake, Mg intake is not under significant regulation by 1,25D. In the small intestine and colon, absorptive and secretory Mg fluxes have voltage dependent and independent components – both through cel lular and paracellular pathways. In the intestinal lumen, Mg concentration drives passive diffusional absorption along the paracellular pathway. Renal Transport of Mg Ionized and complexed Mg is about 70% of the total serum Mg and constitutes the ultrafilterable portion. Urinary Mg
averages about 24 mmol/d, therefore about 95% GFR is reabsorbed before excretion. The kidney is responsible for regulating the serum Mg concentration by a setpoint trans port maximum (Tm)-limited process similar to the setpoint for Pi, except that the TmMg is not hormonally regulated. ECF concentration of ionized Mg is tightly regulated by the tubular threshold or maximum for Mg in the nephron. About 15% of the reabsorption of Mg occurs at the proxi mal tubule and about 70% at the cortical TALH. Mg may stimulate the basolateral membrane CaSR which decreases renal Mg reabsorption. The distal convoluted tubule accounts for about 10% of Mg resorption through a trans cellular transport process. Renal Mg reabsorption is highly regulated, with a number of factors that may increase or decrease tubular resorption. Since there is little distal tubule reabsorption, ECF volume expansion decreases Mg reabsorption and increases urine Mg excretion. Hypermagnesemia increases urine Mg excretion at least in part through activation of CaSR. Skeletal Mg Although a significant portion of total body magnesium resides in the skeleton, the skeleton does not play a major role in magnesium regulation. Serum Mg Blood levels of Mg are not as tightly regulated as Ca, but rather fluctuate with the influx and efflux across the ECF with changes in intestinal Mg absorption, net renal reab sorption and resorption and formation of bone mineral.
C h a p t e r 4 Fundamentals of Mineral Homeostasis l
Intracellular mineral metabolism Calcium Intracellular Ca functions include contributing stability to plasma membranes by binding to phospholipids in the lipid bilayer and by regulating the permeability of plasma membranes to sodium ions. A reduction in ionized Ca con centration increases sodium permeability and enhances the excitability of all excitable tissues; an increase in sodium content has the opposite effect. The function of the cell largely dictates the cell Ca homeostasis with differences in cells responsible for muscle excitation and contraction, signal transduction, mediating signals from an activated plasma membrane receptor for the synthesis and release of hormones, neurotransmitters and kinase phosphorylation. Serum Ca concentration of ionized Ca is approximately 103 M, while the ionized cytosolic Ca concentration is approximately 106 M, resulting in an approximate 1000fold gradient that strongly favors the movement of calcium from the ECF to within the cell. Further, the cell interior possesses a slightly negative charge with a differential elec tric charge across the plasma membrane (50 mV) gradi ent, further supporting diffusion to the cell. In order for the cell to maintain this gradient, a strong system of active transport exists to maintain cellular Ca concentrations at an optimal level to avoid cell death, which occurs if intracellu lar Ca is not maintained in the micromolar range. The maintenance of optimal intracellular Ca concen trations is regulated by a number of intracellular func tions. A system of energy-dependent active transport exists across the plasma membrane as an ATP-driven calcium pump quickly to expunge Ca from within the cell once concentrations become elevated beyond normal levels. A separate system of sodium–calcium exchangers is also employed to ensure that Ca concentrations remain in the normal range. Further, active uptake of Ca into organelles, such as the endoplasmic reticulum and the mitochondria, occurs to remove Ca from the cytosol; in fact, the mito chondria and microsomes can contain up to 99% of the intracellular Ca, bound largely to organic and inorganic phosphates. Should Ca concentration levels drop below optimal within the cytosol, Ca can be rapidly released from the organelles to facilitate a rebalancing of cytosolic Ca. The Ca capacity of these organelles is such that it can replenish cytosolic Ca levels approximately 500 times. There are also receptors on the plasma membrane that, when activated, result in the pulsed release of Ca from the organelles. Movement of Ca to within the organelles occurs through both cell-binding proteins and calcium transport proteins. Lastly, within the cytosol, there is a system of Ca buffering, where Ca binds to other cytoplasmic constitu ents or a specific Ca-binding protein to deal with elevated levels of Ca.
47
At the intestinal cellular level, transcellular calcium trans port is stimulated by 1,25D and upregulation of the vitamin D receptor (VDR). VDR-mediated increased expression of a number of vitamin-D dependent genes produce proteins that participate in the active transport process. Calcium influx across the brush border membrane is facilitated by the channel created by the calcium transport protein I (TRPV6) which is induced by 1,25D and estradiol, independently through their cognate receptors.
Phosphorus The gradients for Pi across the plasma membrane are mod est with an ECF concentration of Pi approximately 104 M and cytosolic Pi approximately 2 104 M. The trans port of Pi ions across the plasma membrane and across the membranes of the organelles is passive, but largely depends on the concomitant movement of cations, in most cases Ca2. Serum Pi decreases postprandially and during IV glu cose infusion, therefore, there is insulin-mediated Pi entry into the cells as well. While the concentration of Pi ions within the cytosol is quite low, the mitochondrial concen tration is quite high, generally as calcium Pi salts, reflective of the importance of the mitochondria in ATP energy pro duction. Intracellularly, Pi is almost always bound or exists as phospholipids forming cell membranes, organic phos phate esters or as phosphorylated intermediate molecules involved in a large number of cellular processes – the most common being that of ADP–ATP. Phosphate esters play a very important role in cellular metabolism: purine nucle otides provide the cell with stored energy; phosphorylated intermediates are involved in energy conservation and transfer; phospholipids are major constituents of cell mem branes; and the phosphorylation of proteins is an important means of regulating their function.
Magnesium Within the cell, Mg is the most abundant divalent cation and the second most abundant intracellular cation after potas sium. Mg concentration is strictly controlled within the cytosol and ECF at approximately 5 104 M, both con centrations controlled by factors that currently are not well understood. Cytosolic unbound, ionized Mg constitutes 5–10% of the total cellular Mg. Similar to Ca, Mg concen tration within the cells is partially regulated by its uptake into the organelles. Approximately 60% of cellular Mg is found within the mitochondria where it acts as an essential cofactor in a number of enzyme systems including almost all enzymes involved in the transfer of phosphate groups, transport and all functions that require ATP. Outside the mitochondria, Mg is involved as a cofactor in enzyme sys tems for replication, transcription and translation of genetic information.
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Mineral ion balance Mineral exchange systems in the intestine, kidney and bone are required in order to ensure precise control and sufficient concentrations of essential minerals. A number of hormone systems, most notably PTH and 1,25D, play primary roles in the regulation of these mineral-balancing systems. There is increasing evidence that fibroblast growth factor-23 is a major Pi-regulating hormone. In general, there are states of neutral, positive or negative mineral ion balance. In neutral (or zero) balance, mineral intake and bone accretion are equal to bone resorption and the losses excreted. Neutral mineral balances are generally observed in men who are under 65 years of age and in nonpregnant premenopausal women after peak bone mass had been achieved. Early studies have suggested that a thresh old of Ca intake (approximately 1000 mg/day) is needed to maintain a neutral or positive calcium balance and that menopause may increase that requirement [6]. Full Ca bal ance studies are rarely done today and differences in cal cium balance between adult men and women have not been consistently documented. As children progress through adolescence, however, males seem to have a higher Ca intake [7, 8] and also retain more Ca. One recent study of 3week dietary Ca retention in adolescent boys [9] suggested greater retention for the same intake than was seen in a similar study of adolescent girls [10]. In a study of children from Saskatchewan [11], daily Ca retention during the ado lescent growth spurt was estimated to be 359 mg/d for boys (199–574 mg/d) and 284 mg/d for girls (171–459 mg/d). In states of positive balance, mineral intake and accre tion exceed mineral losses. Positive mineral balance is only observed during skeletal growth and during recovery from periods of bone loss. Lastly, in negative balance, min eral losses exceed mineral intake and accretion. Negative mineral balance occurs often during the menopause and in estrogen deficiency, during chronic glucocorticoid ther apy, with hyperthyroidism and with vitamin D deficiency. A common consequence of negative mineral balance is bone loss. With a normal diet, the supply of minerals through absorption in the intestine is more than sufficient for met abolic and accretion needs. The primary regulator of ECF mineral homeostasis is the renal tubule through alterations in the amounts of mineral reabsorbed.
Calcium Balance Serum Ca concentration is tightly regulated by hormonal activity and PTH is the primary regulator of serum Ca. The integrated actions of PTH on distal tubule calcium reabsorp tion, bone resorption and vitamin D mediated intestinal Ca absorption finely regulate ionized Ca concentration to the extent that there is rarely a fluctuation of more than 0.1 mg/dL from the setpoint value at any given time of the day.
The parathyroid chief cell is exquisitely sensitive to ionized serum Ca concentration, through its CaSR on the plasma membrane, and is capable of responding to decreases in Ca concentration by releasing PTH to elicit increases in serum Ca. If Ca concentration is too high in the serum (hypercalcemia), there is a suppression of CaSR signaling and a subsequent decrease in PTH release, with increased intracellular degradation of PTH to biologi cally inactive fragments [12]. There is also stimulation of the distal nephron CaSR which then reduces the net tubule reabsorption of Ca resulting in increased Ca losses into the urine. Sustained hypocalcemia can eventually lead to par athyroid (PT) cell proliferation and an increase in the total secretory capacity of the PT gland, whereas vitamin D reduces PTH synthesis and PT cell proliferation. Distal tubule reabsorption and osteoclastic bone resorption are the primary players in minute-to-minute calcium homeos tasis. Of the two, the impact of PTH on the kidney is quan titatively more important: approximately 1000 mg of Ca is daily under the control of PTH as it passes through the distal nephron. PTH has a major role in ensuring Ca balance and fine tuning by stimulating both renal Ca reabsorption (prima rily the proximal tubule) and excretion (distal tubule). This is a classical short loop system where the Ca that is released via PTH is immediately sensed by the PT where adjustments in PTH secretion can then be made to bring the system into bal ance; these adjustments in reabsorption of Ca can occur within minutes of sensing low concentrations of Ca. PTH causes Ca sparing in the kidney by way of enhanced renal tubule rea bsorption of Ca with concomitant inhibition of Pi reabsorp tion resulting in phosphaturia. PTH related peptide (PTHrP) mimics the action of PTH in the nephron. PTH increases the net Ca reabsorption, but patients with primary hyperparathy roidism are often hypercalciuric, because increased tubule Ca reabsorption leads to hypercalcemia and an increased filtered load of Ca resulting in hypercalciuria. Pi administration can reduce urine Ca excretion though an increased distal calcium reabsorption and stimulation of PTH. Dietary Pi deprivation causes hypercalciuria in part by actions in the distal nephron. PTH increases bone resorption resulting in Ca and Pi release from the skeleton. There has been speculation that part of the impact of PTH on bone resorption is through activation of the osteocytes which, in turn, may act on either the osteoblast or osteoclast cell lines. These changes in Ca availability in the serum via the bone can occur in minutes to hours following stimulation. There is also a long-loop system that increases Ca con centration with vitamin-D mediated Ca absorption from the intestine providing feedback to the PT cells. When PTH rises in response to hypocalcemia, in the proximal tubule, PTH promotes 1- hydroxylase conversion of 25-OH vitamin D to 1,25D, which then increases intestinal Ca absorption and, to a lesser extent, renal phosphate reabsorption. Renal 1- hydroxylase is also stimulated directly by hypocalcemia and hypophosphatemia. This system is important for bringing
C h a p t e r 4 Fundamentals of Mineral Homeostasis l
dietary Ca and phosphate into the system, but maximal adjustments via 1,25D and the intestinal absorption system take 24–48 hours to manifest fully and have little to do with minute-to-minute regulation of ECF Ca. 1,25D action in the kidney is not well understood, although it is recognized that deficiencies in 1,25D decrease Ca reabsorption independent of PTH. Calcitriol increases expression of CaSR which then decreases calcium reab sorption. Calbindin 28 kDa levels increase and may also increase Ca reabsorption. 1,25D is responsible for miner alization of bone and for intestinal absorption of Ca and Pi and for maintaining them at levels that facilitate deposi tion into the bone matrix in appropriate quantities. A major indirect role of 1,25D is to mobilize Ca stores when dietary Ca is insufficient to maintain normal ECF calcium concen tration. Calcitriol enhances osteoclastic bone resorption by binding with receptors in the pre-osteoblastic stromal cell line and stimulating the RANK/RANKL system to enhance the proliferation, differentiation and activation of the osteo clastic system from its monocyte precursors. Acute and chronic metabolic acidosis increases urine Ca excretion and alkalosis decreases urine Ca excretion. Endogenous acid production from metabolism of sulfurcontaining amino acids found in animal proteins contrib utes to post-prandial increases in urine Ca. Although these short-term changes in calcium excretion may cause a nega tive Ca balance and increases in bone turnover in the short term, there is little evidence for long-term reduction in bone mass due to dietary acid load [13].
Phosphorus Balance The kidney plays the dominant role in systemic Pi homeo stasis and holds the serum Pi concentration at a value very close to the tubular P threshold or TmP/GFR. Since the normal efficiency and lack of fine regulation of Pi absorp tion in the intestine, only in unusual circumstances is the systemic supply of Pi a limiting factor in Pi homeostasis. With a normal dietary intake, 1,25D does not stimulate jejunal Pi absorption, however, during states of vitamin D deficiency or with chronic renal failure with impaired 1,25D production, administration of 1,25D can stimulate net Pi absorption. 1,25D supports net intestinal Pi absorp tion through enhanced cellular brush border Pi uptake. This uptake process is saturable with an affinity coefficient of 1.0 mM and is present in the proximal duodenum, jejunum and, to a lesser extent, the distal ileum. Net Pi absorption does not occur in the colon. In hypophosphatemia, there is a stimulation of 1,25D production in the kidney, an enhanced mobilization of P and Ca from the bone and an increase in TmP/GFR. The increased 1,25D leads to increased Pi and Ca absorption in the intestine and provides additional stimulus for Pi and Ca mobilization from bone. The increased flow of Ca and Pi from the bone inhibits the release of PTH which diverts the
49
flow of Ca into the urine and further increases TmP/GFR. The net change is an increase in serum Pi without a change in ionized Ca concentration in the serum. There are two major mechanisms whereby the renal loss of phosphate will protect against hyperphosphatemia. Recently, FGF-23 has been identified as a phosphate-regu lating hormone. It is produced primarily in bone by cells of the osteoblast lineage (osteoblast progenitors, osteoblasts, and osteocytes) and regulates renal phosphate transport and 1,25D synthesis. In response to hyperphosphatemia, increased FGF-23 secretion from bone results in increased phosphate excretion and decreased renal synthesis of 1,25D [4]. Hyperphosphatemia is also corrected by increased PTH secretion djue to the effect of phosphate on serum Ca. The mineral ion product (Ca P) is generally a biologic con stant in the sense that an increase in the concentration of one mineral will result in the reciprocal change in the other. Thus, an acute increase in serum Pi concentration produces a transient decrease in Ca concentration and a stimulation of PTH secretion, which then reduces the TmP/GFR and leads to a readjustment in serum Pi and Ca concentrations.
Magnesium Balance Mg serum levels are regulated primarily by the quantitative influx and efflux of Mg rather than an elaborate hormonal system like that which has evolved for Ca. There appears to be no important systemic or hormonal regulation of Mg con centration in the ECF. Blood ionized Mg is less potent than Ca concentration in regulating PTH secretion. The levels are regulated primarily in the kidney at the level of renal tubu lar reabsorption. Instead, control seems to be as fluxes at the intestine, kidney, intracellular fluids and perhaps the skeleton. The kidney is the prime regulator of serum Mg concentration. Absorptive and secretory Mg fluxes across both the small intestine and colon are largely voltage dependent. Therefore, there are large paracellular pathways of Mg transport that are primarily driven by the luminal Mg concentration. The Mg ion channel TRPM6 is important in the regulation of Mg homeostasis, but the regulator of TRPM6 is unknown. Fractional absorption of Mg is approximately 30%. In dietary Mg excess, a smaller proportion may be absorbed and, in times of deficiency, the opposite. Mg absorption in the small intestine is not well understood, but appears to happen via both passive and facilitated, but not active, elements. These elements do not seem to be sensitive to PTH, calcitonin or 1,25D; thus, net Mg absorbed appears to primarily be a function of dietary Mg intake.
Summary Homeostasis of Ca, Pi and Mg is essential for normal functioning of the body. The gut, kidneys, bone and cells work in a coordinated fashion to ensure that mineral
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levels remain stable whenever possible. PTH and 1,25D play critical roles in the maintenance of specific mineral concentrations despite frequently changing dietary intakes and metabolic and growth demands.
References 1. R.C. Khanal, I. Nemere, Regulation of intestinal calcium transport, Annu. Rev. Nutr. 28 (2008) 179–196. 2. J.M. Wishart, F. Scopacasa, M. Horowitz, et al., Effect of perimenopause on calcium absorption: a longitudinal study, Climacteric 3 (2) (2000) 102–108. 3. S.J. Van Cromphaut, K. Rummens, I. Stockmans, et al., Intestinal calcium transporter genes are upregulated by estrogens and the reproductive cycle through vitamin D receptor-independent mechanisms, J. Bone Miner. Res. 18 (10) (2003) 1725–1736. 4. S.M. Burnett, S.C. Gunawardene, F.R. Bringhurst, H. Juppner, H. Lee, J.S. Finkelstein, Regulation of C-terminal and intact FGF-23 by dietary phosphate in men and women, J. Bone Miner. Res. 21 (8) (2006) 1187–1196. 5. J. Marks, L.J. Churchill, E.S. Debnam, R.J Unwin, Matrix extracellular phosphoglycoprotein inhibits phosphate trans port, J. Am. Soc. Nephrol. 19 (12) (2008) 2313–2320. 6. R.P. Heaney, J.C. Gallagher, C.C. Johnston, R. Neer, A.M. Parfitt, G.D. Whedon, Calcium nutrition and bone health in the elderly, Am. J. Clin. Nutr. 36 (5 Suppl.) (1982) 986–1013.
7. K. Bialostosky, J.D. Wright, J. Kennedy-Stephenson, M. McDowell, CL. Johnson, Dietary intake of macronutrients, micronutrients, and other dietary constituents: United States 1988–94, Vital Health Stat. 11 (245) (2002) 1–158. 8. R.B. Ervin, C.Y. Wang, J.D. Wright, J. Kennedy-Stephenson, Dietary intake of selected minerals for the United States pop ulation: 1999–2000., Adv. Data 27 (341) (2004) 1–5. 9. M. Braun, B.R. Martin, M. Kern, et al., Calcium retention in adolescent boys on a range of controlled calcium intakes, Am. J. Clin. Nutr. 84 (2) (2006) 414–418. 10. L.A. Jackman, S.S. Millane, B.R. Martin, et al., Calcium retention in relation to calcium intake and postmenarcheal age in adolescent females, Am. J. Clin. Nutr. 66 (2) (1997) 327–333. 11. D.A. Bailey, A.D. Martin, H.A. McKay, S. Whiting, R. Mirwald, Calcium accretion in girls and boys during puberty: a longitudinal analysis, J. Bone Miner. Res. 15 (11) (2000) 2245–2250. 12. D.A. Hanley, K. Takatsuki, J.M. Sultan, A.B. Schneider, L.M. Sherwood, Direct release of parathyroid hormone fragments from functioning bovine parathyroid glands in vitro, J. Clin. Invest. 62 (6) (1978) 1247–1254. 13. T.R. Fenton, M. Eliasziw, A.W. Lyon, S.C. Tough, D.A. Hanley, Meta-analysis of the quantity of calcium excretion associated with the net acid excretion of the modern diet under the acid-ash diet hypothesis, Am. J. Clin. Nutr. 88 (4) (2008) 1159–1166.
Chapter
5
The Mechanical Properties of Bone David P. Fyhrie David Linn Chair of Orthopaedic Surgery, Lawrence J. Ellison Musculoskeletal Research Center, Department of Orthopaedic Surgery, The University of California, Davis; The Orthopaedic Research Laboratories, Sacramento, California, USA
The idea of hierarchy in bone mechanics
Introduction The mechanical properties of bone include all of the properties measured and all of the mathematical complexities developed by engineers to understand and use solid materials to build houses, cars and electronics. Fortunately, only some of the mechanical properties and almost none of the mathematical complexity are needed to understand the important functional properties of bone. In life, the important mechanical properties result in a bone that is strong, tough and sufficiently long lived that it does not hurt or break when we use it! Whole bone properties come both from the structure (the anatomy) and the material properties of the hard tissue. This chapter will consider the effects of anatomy first and then examine key mechanical properties of the hard tissue that are essential to function. The goal for this chapter is to understand the mechanical properties of bone without the engineering complexity. The chapter uses example mechanical tests as illustrations and relegates mathematical analysis to separate sections. If you do not need to understand how to calculate a modulus or failure stress, you can skip the mathematics and (I hope!) the examples will ensure that the concepts are still clear. This is an idiosyncratic attempt to provide a guide to the important bone mechanical properties. It is not a listing of measured properties, nor a complete mathematical treatment of the subject. Rather, I sought to provide examples and explanations to help with understanding how bone mechanical properties arise from the molecular constituents. The reference list is not intended as a review of the literature, but I have tried to be topical, up-to-date and fair to the many investigators working in the field. Osteoporosis in Men
A detailed understanding of the effect of structure on mechanical properties of a bone is as variable as their shapes. From the bones of the inner ear to the femur, the shape (the anatomy) and loading on the bones determine the average stresses and strains in the hard tissue. At a smaller level, the structures of the hard tissue itself (the histological microstructure and molecular ultrastructure) determine how the average stress and strain in the tissue are distributed in the molecular elements. Consequently, the sizes of the structures from gross anatomy down to the molecular organization affect the stress and strain distribution at smaller and smaller levels. The observation that a descending series of sizes in the structures (e.g. anatomical, histological, molecular) all contribute to the mechanical properties is often presented in shorthand as, ‘Bone is a hierarchical material’ [1, 2]. This is a useful concept and helps with the understanding of bone mechanics since there is a large literature on the properties of man-made hierarchical composites. A weakness of the analogy is that the hierarchy in man-made composites is designed into the material and design is a concept inappropriate for an evolved structure such as bone. In evolved materials, the different sized patterns in the molecular components survive from generation to generation for unknown reasons. What can be said with certainty is that the mechanical properties created from the material patterns we see in bone do not (usually) contribute to death before successful reproduction. Bone as an evolved material simultaneously uses all structural sizes from the quantum mechanical to the anatomical in order to provide sufficient function to the organism. 51
Copyright 2009, 2010 Elsevier, Inc. All rights of reproduction in any form reserved.
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Osteoporosis in Men 140 120
Load (N)
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0
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Figure 5.1 Load (force) displacement curve for three-point bending of a canine rib. This curve is typical of not only bending but most other mechanical test methods.
Anatomical structural effect Understanding (or analyzing) how the anatomical structure of each particular bone provides function to the body is far beyond this chapter. Fortunately, bending of a tubular cortical bone and compression or tension of a bone specimen are fairly easy to present mathematically and cover a large fraction of the cases where a bone fails during function.
Long Bone in Bending There are many cases of bending of bones in the skeleton. In most cases, the bending is very complex, such as for the femoral shaft when running. Simple bending, such as of the femoral neck during standing, is the rare exception. To illustrate the effect of anatomical structure on the bending properties of a bone, I shall resort to a simplified form called three-point bending. Three-point bending is a mechanical test where an isolated long bone (or a beam-like specimen of tissue) is pressed between one central point and two evenly spaced lateral points (Figure 5.1). The loading points can be knife edges, cylinders or rollers (to choose between these options for bone see [3]). The configuration of the loading causes bending of the specimen and, usually, failure at the midpoint. For the example here, (data provided by Matt Allen, Indiana University), the rib of a dog was compressed in displacement control while simultaneously recording the force and displacement of the test (see Figure 5.1). These are the only data needed to determine the structural properties of the bone during the test. The slope (the stiffness) of the force-displacement test is nearly constant (the linear
region) when the material is not damaging (Figure 5.2). The force and displacement at which significant damage initiates (the yield point) can be estimated by various means [4, 5] and the maximum load point is determined directly from the force data. The events in the load-displacement data are predictable. Initially, the load increases non-linearly, caused by settling of the specimen against the grips. These data are artifacts and were removed from the graph. Then, there is a nearly linear region where the load and the displacement increase proportionally. When damage begins, the load and displacement cease being proportional. This region begins at the yield point (or the proportional limit). (If the specimen is unloaded after the yield point it will have a reduced stiffness, but will unload to close to the original length. This is a material behavior called ‘Elastic-perfect damage’ [6, 7]. Finally, the maximum load is achieved and (in displacement control) the load decreases. The linear region, yield point and maximum load are present in many different mechanical tests, regardless of their geometry. This is because they result from characteristics of the material, rather than from the shape of the specimen. The dependence of the sequence of events in the test of the whole rib on the material means that almost all that you need to know about bone during a single load is revealed by the bending test: 1. if you load bone below the yield point it is not damaged and it acts as a linear spring that has deformation proportional to the load 2. loading beyond the yield point (the proportional limit) permanently damages the material, reducing stiffness
C h a p t e r 5 The Mechanical Properties of Bone l
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Constant slope (linear) region.
95% secant line.
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Figure 5.2 The force–displacement curve (black) from initial contact till just past maximum load. The dashed line is the slope of the curve calculated using Excel. The stiffness is the slope of a linear fit to the straight part of the curve and the 95% secant line is that line with the slope reduced by 5%. The yield point and maximum point are determined from the intersection of the secant line with the load line and the maximum force, respectively.
3. with continued loading a maximum load is reached, after which there is a reduction in the highest load that the bone can support.
strain.) For a normal stress applied to a linear material, stress is proportional to the strain as:
These observations are valid both at the structural and the material level of the bone. If all we cared about was how stiff and strong the rib was as a structure in three-point bending, we would be done. But, of course, this bending test example is too specific to one bone and one testing laboratory to be generally useful. Therefore, further analysis of the data is needed in order to estimate the mechanical properties of cortical bone in the rib. The next section is such an analysis – but you can skip it if you are not interested in calculating material properties from a bending test.
Stress, Strain, Toughness and Linear Isotropic Moduli To convert the force and displacement of a specific structural test of a bone into material properties that can be compared between different laboratories, three important concepts are needed. The first two are normalizations of the force and displacement. The normalization of force is stress (Figure 5.3) defined as the force-per-unit-area. The normalization of the displacement is the strain which is the displacement divided by the appropriate size of the specimen (see Figure 5.3). There are three normal stresses and three shear stresses at each point in a material. Similarly, there are three normal strains and three shear strains (see [8] for outstanding detail on stress and
Stress (Young’s Modulus) Strain. Similarly, for a simple shear stress:
Stress (Shear Modulus) Strain.
The Young’s modulus (E) is related to the shear modulus (G) through the formula,
E 2G(1 ν)
where is the Poisson’s ratio. For most materials, when a compressive normal stress is applied to a cube, the compressive strain is accompanied by a lateral expansion of the material. Poisson’s ratio is the ratio of the lateral to the normal strain under a normal stress. Only two of the linear isotropic properties (E, G, ) are independent of each other, so if you know two, the third is easily calculated. A very important property of bone is the energy absorbed prior to failure, which is called toughness. From basic physics, the energy absorbed is the integration of the applied force as a function of the displacement. The units of energy are: 1 Joule 1 Newton-meter. On a force versus displacement curve (see Figure 5.1), the toughness (or energy) is the area under the curve. The same integration can be performed for a stress–strain curve, but then the energy units are in Joules/m3. The concept tough is paired with brittle. This pair of words
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Osteoporosis in Men Normal Force δn
Shear Area
δs
Height
Normal Stress = Normal force/Area δn Strain
Shear stress = Shear force/Area δs Strain
Figure 5.3 The simple engineering definitions of stress and strain. Stress and strain are normalizations of force and displacement.
refers to materials that absorb large or small amounts of energy before failure, respectively. The concept of toughness is needed later to understand the importance of different components of bone ultrastructure. Material Properties from A Three-point Bending Test To calculate material properties from a mechanical test, it is always necessary to perform a stress analysis. For the threepoint bending test, the model for the structure is a simply supported beam loaded in the center. To convert the force and displacement of the mechanical test into stress and strain, the experimental data are matched to a theoretical stress analysis and the material properties are calculated. A three-point bending test is often analyzed using linear beam theory [9]. To do this, three structural measurements are needed: 1. the distance between the loading points (L) 2. the distance from the centroid of the cross-section to the outer fiber of the beam (c) 3. the second moment of the area around the centroid in the direction of bending (Ic). (This parameter is also called the cross-sectional moment of inertia and often abbreviated CSMI.) From the force (F) and deflection of the beam (), the axial normal strain (e, see Figure 5.3), axial normal stress (, see Figure 5.3) and Young’s modulus (E) are calculated using: Mc Ic M ( F/ 2)( L/ 2) c Dy / 2 Ee
E
FL3 48 I c
where L is the distance between the loading points, Dy is the diameter of the cross-section in the direction of bending and Ic is the second moment of area of the cross-section in
Figure 5.4 The shaft of the femur can be approximated as a cylinder with inner radius RI and outer radius RO. The second moment of area (Ic) is proportional to the difference between the 4th power of the bone’s outer and inner radii: Ic (/4) (RO4 RI4). An interesting exercise is to prove to yourself that a small change in the outer radius has a much larger effect on the second moment than the same change in the inner radius because of the fourth power. As a result, as endosteal expansion occurs during life, the bending stiffness of the bone can be restored by placing a smaller amount of bone tissue at the periosteum.
the direction of bending. To use these equations, the diameter and the second moment must be measured. Second Moment of Area The second moment of the area of the cross-section (Ic) and the diameter of the cross-section (Dy) are measurements from the bone that contribute to structural stiffness. The diameter does not require any explanation, but the second moment of area is not intuitive. A detailed explanation of the second moment should remain in a book on strength of materials [9]. A brief description is that the second moment is proportional to the integrated moment over the area caused by the stresses when it is assumed that the stresses are linearly distributed. There are two key observations: 1. the second moment scales as the fourth power of the diameter of the bone (Figure 5.4) 2. there are computer programs available to calculate the second moment from digital images of a bone cross-section (http://www.hopkinsmedicine.org/fae/MMacro.htm).
C h a p t e r 5 The Mechanical Properties of Bone l
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Lower Threshold
Figure 5.5 Using the program MomentMacro (provided by Dr Chris Ruff, http://www.hopkinsmedicine.org/fae/MMacro.htm), the second moment of inertia of the canine rib was calculated for a range of lower image thresholds, keeping the upper threshold at 255. This demonstrates the strong dependence of second moment on the thresholds used to prepare the bone image. This is very important, since the accuracy of all calculated values from the bending test are strongly dependent on an accurate second moment.
The second moment of area has a very large effect on the modulus calculated from a bending test. Therefore, accurately measuring the second moment is very important. A primary effect on the value of the second moment is the threshold used to create the binary digital image used in the calculation. For the rib of our example, the image had grayscale values from 0 to 255. The second moment of the cortical bone is sensitive to the lower threshold even when the upper threshold is fixed at 255 (pure white; Figure 5.5). The threshold used by the contributors of these data (Allen et al. 2008) (thanks to Drs Allen and Burr) resulted in Ic 9.62 mm4. Since the second moment is very sensitive to the shape of the cross-section, it is important to understand how investigators choose their image threshold when interpreting bone mechanical property data. The Final Calculations For the three-point test of the example rib, the collected data were: L 25 mm; Ic 9.62 mm4; Dy 4.44 mm; Fyield 82 N; yield 0.40 mm; Fmaximum 116 N. Therefore, the properties are: E yield (82 N)(25 mm)3 /[ 48(9.62 mm 4 )(0.40 mm ) yield
6936 N/mm 2 6.9 GPa [(82 N)(25 mm)/ 4][(4.44 mm)/ 2]/ 9.62 mm 4 118 N/mm 2 118 MPa
e 118 MPa/(6936 MPa) 0.017 2% yield maximum [(116 N)(25 mm ) / 4][(4.44 mm)/ 2] / 9.62 mm 4 167 N/mm 2 167 MPa. This analysis assumed that strain () was linearly distributed across the cross-section, that the material was uniform, with stress () proportional to strain ( E), that the neutral axis of the cross-section passes through the centroid and that the Young’s modulus (E) was uniform. These assumptions may or may not be appropriate for any particular mechanical test and errors caused by the actual experiment violating the assumptions can be large. To understand the detailed bases of these assumptions and to discover other mechanical analysis methods with fewer assumptions, please see a good book on beam theory [9]. (Also consider working with an experienced mechanical engineer to develop experiments!) A final note for the bending test is that the stress calculated from the maximum load and displacement is called the modulus of rupture. The modulus of rupture is always larger than the actual stress in the tissue because, at the time of maximum load, the distribution of stress in the cross-section is no longer linear. As a result, maximum stresses calculated using a bending test can only be compared between identical tests – they are not actually material properties. On the other hand, the stress, strain and modulus at yield
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are consistent estimates of the material properties and can be compared between different tests and laboratories. Further Complications in the Relationship Between Stress and Strain For a linear material that follows Hooke’s Law (Ut tensio, sic vis: or, E), the Young’s modulus (E) is a constant, but it does not necessarily have the same value for different loading directions. Imagine that the normal stress cube of Figure 5.3 is turned so that the load is applied to a different face. For a linear material, the stress will be proportional to strain, but E (Young’s modulus) can be different for each direction of loading. This is true for all the normal loading directions and for all the shear loading directions. If all of the possible combinations of loading direction are accounted for, there can be 21 independent material properties! This is more than we can measure effectively and more than are actually needed for most bone tissue. The most generally useful model for bone is the orthotropic model, which has nine independent material properties. This is still too many for easy measurement and the transversely isotropic (five material constants) and cubic (three independent properties) are occasionally used. However, the overwhelmingly most popular model is the isotropic model, with only two independent material properties. Unfortunately, the isotropic model is not a very good approximation of the direction dependence of material properties, but it is easier to use in calculations. Some of the interesting details of these material models are available in a good book on composite materials [11] or in a large number of papers published in the biomechanics literature [12–15].
Vertebra in Compression The main observations from the bending test, that there is a linear region and a damage region for the tissue separated
by a yield point, are also valid for compression of bones. As an example, the force and displacement in compression for the T12, L1 and L2 vertebral centra from an individual are presented in Figure 5.6. Although the magnitudes of the displacements and forces in these compression tests are different from those of the three-point bending test of the canine rib, the main features of the test – linear region, yield point and maximum load – are identical. Therefore, the mechanical behavior of a vertebral centrum in compression, a structure filled almost completely with cancellous bone, is homologous to the behavior of a tube of cortical bone (the rib) in bending. The similarity is because the mechanical behavior of cancellous bone in compression is largely determined by the hard tissue of the trabeculae. The hard tissue of the trabeculae is essentially identical to cortical bone at the molecular level, therefore, the main features of failure of the vertebrae are the same as those of the rib. A significant difference between compression of a vertebra and bending of a rib, however, is that there is not any simple method to calculate the stress and strain in the trabeculae. Many investigators have worked to develop the computational methods needed to estimate stress and strain in cancellous bone tissue [16–22], but these calculations are not important to our goal of understanding the main features of bone’s mechanical properties.
Cancellous Tissue in Simple Compression and Tension One way to simplify the analysis of cancellous bone is to cut small specimens from the tissue, then compress or pull on them until they break. The force displacement curves for tests from small specimens of cancellous bone look very similar to the results for whole vertebral centra. The material properties are calculated from the force and
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Figure 5.6 Force and displacement for three human vertebrae compressed to failure. The data were kindly provided by Yener Yeni, Henry Ford Hospital. The same features of nearly linear region, yield and ultimate points appear as in the test of the canine rib.
C h a p t e r 5 The Mechanical Properties of Bone l
d isplacement data as if there are no holes in the cancellous tissue. Material properties calculated in this way are called apparent mechanical properties. There is a huge literature on the apparent mechanical properties of cancellous bone [23–26]. As an example, Weaver and Chalmers [27] measured the apparent compressive strength for a single ½ inch cube (1.25 cm) from the center of the third lumbar vertebra collected post-mortem from 137 individuals. Their results clearly show the dependence of the apparent compressive strength on age (Figure 5.7). An important observation is that cancellous bone is similar to an engineering foam. These are materials created by ‘foaming’ a solid engineering material – e.g. bubbling gas through molten metal while it cools. There are standardized testing protocols for foams, such as the cube compression test. In addition, there is a specialized literature on cancellous bone testing that presents methods for accurate testing [24, 27–30]. Regardless of the details of the testing protocol, however, almost all of the mechanical properties of foams (and of cancellous bone) are power functions of the apparent density which is defined as the weight of the specimen divided by its volume. Young’s modulus, yield and maximum stress of cancellous bone all can be approximated by a power function of apparent density: Property K(Apparent density)B, where K and B are fitting constants. The values of these fitting constants depend on animal species, the anatomical site from which the specimen was cut, direction of loading, the mineralization of the tissue, whether the specimen was loaded in compression, tension or shear and many other factors [23, 24, 26, 31]. (Cancellous bone tissue has differing strength in tension and compression [32], so direction of loading is quite important. See below for an example for cortical bone.) Analysis of foams suggests that 2 B 3 [33]
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and values of the exponent in this range are often observed for experimental data from cancellous bone. Even with the simplification of ignoring the holes, any further progress on explaining the mechanical properties of cancellous bone immediately leads to a great proliferation of details that are not relevant here. However, a final point to make is that the radiodensity of cancellous bone is directly related to the apparent density of the tissue. This is why a computed tomography (CT) scan (which measures the radiodensity using x-rays) can be used to predict material properties using a function such as: Property k(radio density)b. Where the constants k and b differ from the formula based on apparent density. The relationship between radiodensity and apparent density of bone is part of the explanation of why bone mineral density (BMD) measured using dual-energy x-ray absorptiometry (DXA) is correlated to bone mechanical properties and to a fracture risk.
Cortical Tissue in Simple Compression and Tension: Asymmetry of Strength An example of mechanical testing that illustrates strength asymmetry is from a pair of cylindrical ‘dog bone’ specimens of bovine cortical bone in compression and tension, respectively (Figure 5.8). Results for this pair of specimens are typical and consistent with the previous examples. For both compression and tension, there is a linear region, a point where non-linearity becomes significant (yield point) and a peak load. An important similarity between the specimens is that the slope of the linear region (the Young’s modulus) is the same in compression and tension (this is a generally observed phenomenon). An important difference between the specimens is that the yield and peak stresses are larger in compression than in tension. This is not an
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Figure 5.7 Ultimate stress for ½ inch (1.25 cm) cubes of human vertebral cancellous bone in compression (data hand digitized from [27]). Male and female specimens are mixed, but showed no differences. This illustrates the concept of apparent failure stress and also the strong dependence of bone strength on age before and after the years of peak strength.
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the microscopic organization of the molecules into trabeculae, marrow spaces, osteons and the other features of bone tissue that many are familiar with. In the first part of this section we shall discuss how the ultrastructure affects material properties and then briefly discuss the role of microstructure on mechanical properties.
250 Compression
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Figure 5.8 Stress and strain for bovine cortical bone specimens in tension and compression. The slopes of the linear region (Young’s modulus) are similar, but the yield and ultimate stresses are different. Also, notice that the total area under the curves is very different.
accident of the two particular specimens used to make the figure. Cortical bone is stronger in compression than in tension [13, 23, 26] – it is asymmetric in strength. Similar to cancellous bone, the mechanical properties of cortical bone are a power function of the apparent mineral percentage of the tissue. Mineral percentage is often measured as the ash fraction of the tissue, which is the weight of the specimen after ashing in a muffle furnace divided by the dry weight of the specimen before ashing. The exponent for the power law for cortical bone mechanical properties is reported as variably between 2.79 and as high as 10.27, depending on testing conditions and covariates that are measured [34]. The key observation is that very small changes in mineralization cause very large changes in mechanical properties. As an aside, these data for cortical bone (kindly provided by Deepak Vashishth, Rensellaer Polytechnic University) are from bovine specimens loaded slowly. The slow loading allows the organic matrix to stretch (to creep) in tension. In compression, the mineral crystals constrain the creep, reducing the maximum strain. The mechanical properties of bone are affected by cross-linking of the organic matrix [35–37] which is an ultrastructural phenomenon.
Ultrastructure and microstructure and effects on mechanical properties The mechanical properties of bone seen in the force displacement examples are expressions of the mechanical properties of the hard tissue. The properties of the hard tissue arise from the molecular structure and, at a larger size,
The hard tissue of bone is a composite of a protein matrix, a mineral matrix and water, bonded together largely by covalent, ionic and hydrogen bonds [31]. The protein matrix is largely composed of type I collagen, the mineral is a highly substituted form of hydroxyapatite and the water is, of course, actually a complex solution containing many different species of ions, large and small proteins. (As a matter of definition, the word ‘composite’ is reserved for combinations of at least two distinct materials that have recognizable interfaces between them.) The relative importance of the mineral, collagen and water to bone mechanical properties is easily illustrated with simple experiments.
Experiment 1 Demineralization The role of mineral is revealed using dog-bone tensile specimens demineralized using ethylenediaminetetra-acetic acid (EDTA) or other means [38–40]. The resulting collagenous bone matrix specimens were broken wet in tension (Figure 5.9). For comparison, results for an undemineralized specimen are also presented (unpublished data, D Vashishth, Resellaer Polytechnic University). The demineralized tissue is fairly strong, fairly tough (the absorbed energy was 2500 J/ m3 versus 4100 J/m3 for the two specimens of Figure 5.9), has a far larger failure strain and is much more compliant. This simple comparison suggests that the collagen fibers are a primary source of bone strength and toughness, analogous to man-made continuous fiber composites.
Experiment 2 Deproteinization (Ashing) The importance of the protein matrix is emphasized again when 2 mm 2 mm square beams of equine cortical bone are broken in three-point bending with a 20 mm length between the knife edges (Figure 5.10). Removal of the organic material and water by ashing a specimen reduced the strength of the remaining mineral matrix by about a factor of 5, the failure displacement by about a factor of 10 and the energy to failure (toughness) by a factor of about 100. This is a profound effect considering that the stiffness of the ashed bone beam was similar to that of untreated bone.
C h a p t e r 5 The Mechanical Properties of Bone l
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180 160 Mineralized bovine cortical bone Energy density to failure: 4100 J/m3
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Figure 5.9 Tensile failure of a mineralized (data from Deepak Vashishth, RPI) and demineralized (data digitized from [39]) dog-bone specimens of bovine cortical bone. Demineralization greatly reduces modulus (slope) and reduces ultimate strength, but greatly increases the maximum strain. The toughness (energy absorbed before failure) is lower in the demineralized specimen by a factor of about two.
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Figure 5.10 2 mm 2 mm 20 mm equine cortical bone beams in bending to failure. Drying makes a specimen somewhat stiffer and stronger. Ashing makes the specimen much weaker but leaves the stiffness roughly unchanged. The absorbed energy to failure is reduced by about 100-fold by ashing. These data are similar to those published by Yan et al [41].
Experiment 3 Drying Removing the water from a three-point bending specimen using 16 hours of vacuum increased the peak strength approximately 20%, increased the stiffness, decreased the toughness (energy absorption) by about a factor of three and greatly decreased the post-yield deformation of the specimen (see Figure 5.10). Water is a solvent and acts as a plasticizer for the collagen fibrils, making them more flexible than when dry. Similar to drying, substituting a less polar solvent, such as alcohol, for the water causes the tissue to
be stronger and more brittle [42, 43], [Jordan McCormack, unpublished data]. The nature of the non-covalent bonding between collagen and mineral is another topic of significant interest [44–48] but beyond the goals here.
Synthesis of the Experiments The different results of the three illustrative experiments are summarized in a tri-axial plot of the weight fraction of the components of cortical bone specimens (Figure 5.11) [89]. Removing the mineral from human femoral tissue would
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1.0
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0.5 Galapagos tortoise femur
Dry: Strong, Stiff and Brittle Human femur Strong, stiff and tough
Demineralize: strong, flexible and tough
Bovine Tibia Ash+Dry: Weak, stiff and brittle
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Figure 5.11 A tri-axial illustration of how drying, ashing or demineralization would move a specimen as a function of composition and the effects of the modification of strength, modulus and toughness. Redrawn after Zioupos et al. [89].
move the specimen to the right onto the ‘Demineralized’ axis, where it would be very flexible, yet fairly strong and tough. Removing the collagen and water would move the specimen to the lower left corner of the ‘Ashed’ axis and make it stiff, very weak and very brittle. Removing just the water would displace the specimen leftward to the ‘Dry’ axis where it would be stiff, strong and relatively brittle. The conclusions are:
link of bone, so when bone is loaded, the mineral fails first. Despite inherent mechanical weakness in tension, the mineral protects the collagen fibrils from the hostile environment of the body, keeps the fibers in the appropriate position so that load is efficiently distributed and provides stiffness to the composite that permits load-bearing without undue deformation.
1. the collagenous matrix is essential for strength and toughness 2. water enhances the plasticity of the collagenous matrix, increasing the post-yield strain 3. mineral is the primary contributor to stiffness, but is very weak and brittle in the absence of the collagen matrix.
The Key Role of the Collagenous Bone Matrix
The ultrastructure of bone is similar to a high-performance continuous fiber composite. In continuous fiber composites, almost all of the load carrying capacity is provided by the fibers. In bone, the collagen fibrils are the continuous fiber phase and the mineral is the matrix that binds the fibrils together. The functions of the mineral matrix in bone (and the matrix of man-made composites) are to hold the fibers together and to distribute the loading among the fibers to prevent local overloading. The mineral matrix is the weak
Removing any of the components of bone had a significant effect on the mechanical properties, but the runaway ‘winner’ for the size of its effect was the organic matrix. This is consistent with the highly increased risk-of-fracture in patients with collagen I defects, such as osteogenesis imperfecta [49] and also with the strong deleterious effect on bone strength of high doses of gamma radiation [50–52]. A critical role of the collagenous matrix of bone in determining mechanical properties may help explain why x-ray determination of bone shape and density can only explain a portion of fracture risk – the quality of the protein matrix is invisible to these methods. As a result, any genetic, exogenous or age-related effect that weakens the collagenous matrix can be expected to have a highly deleterious effect on bone strength.
C h a p t e r 5 The Mechanical Properties of Bone l
Covalent cross-linking among the collagen molecules and fibrils has a strong effect on the mechanical properties of the collagenous matrix. There are various cross-link types, including the pyridinoline cross-links formed consequent to action of the lysyl oxidase enzyme. These cross-links are very important to bone functional properties and tend to: 1. increase the ultimate stress 2. decrease the ultimate strain of the protein matrix. Blocking the action of lysyl oxidase significantly affects bone, skin and other tissues containing pyridinoline crosslinks [53]. As a general observation, any cross-link reduces the extractability of bone collagen [54–56] (i.e. makes it less soluble). It is not surprising, therefore, that the action of cross-linking is opposite of the action of water, resulting in bone matrix that is less plastic. Other covalent cross-links, for example those consequent to age-related non-enzymatic glycation [57, 58] have similar effects on collagen mechanical properties. This could help explain the significant decrease in the extractability of the protein matrix of bone with age. Of course, there are a very large number of other ultrastructural features that change the ability of the collagen matrix to carry load. These include the number and size of collagen fibrils [59, 60], whether the collagen is lamellar or woven [61] and the organization of collagen fibrils in the lamellae [62]. For example, unpublished data from my laboratory suggest that osteoporotics with fractures have poorly defined lamellae compared to normals. The importance of collagen organization to bone mechanical properties and disease is currently an area of active research.
Mineral Crystals and An Ultrastructural Model for Bone The typical single mineral crystal that can be extracted from bone is very small, approximately 5 nm 5 nm 40 nm [31]. The nanometer size and regular shape of the single crystals attracts engineers to theoretical models where crystals interact with the organic matrix by shear stresses [63]. Since the individual crystals are stiff and very strong, these shear lag models have adjustable parameters in the thickness and strength of the organic (shear) interface to tune the model to fit real bone mechanical behavior. This approach to modeling bone is very similar to models of nacre, where the crystals are much larger than in bone and the organic component is very thin relative to the crystal thickness. The shear lag model is a powerful, mechanistic model for nacre [64]. It is not clear, however, that the actual mechanisms of stress transfer in bone mimic those in nacre. For example, if the crystals in bone were truly separated from each other, then deproteinization by ashing might tend to create a nanosand rather than a ceramic-like mineral matrix with nearly the same modulus as whole bone.
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My opinion is that it is very revealing that ashing destroys the strength and toughness of normal bone, but that the stiffness of the remnant mineral ceramic remains similar to normal bone. A model that is consistent with these observations is that a continuous, open-celled, nano-porous mineral matrix creates the bone stiffness and the organic matrix acts to bridge nano-cracks in the mineral, preventing crack propagation and creating the toughness and strength missing from the mineral alone [65, 66]. The organic matrix weaves through the entire mineral volume at the nanoscopic level. In other words, bone is a high performance continuous-fiber nano-composite with the collagen matrix as the fiber and nano-porous mineral as the matrix. The doublenetwork model for crack propagation [67] and mechanical properties [68, 69] may be the appropriate starting point for mathematically modeling the properties of bone as opposed to starting with a shear lag approach. The effect of drying on bone properties suggests that the intimate bonding between the mineral and protein matrices might be by hydrogen bonds, but calcium bonds and ‘glue’ have also been proposed [46]. The mathematical behavior of this type of composite structure is similar to a shear lag model, but the details of stress transfer rely upon the tensile properties of the bridging collagen fibers rather than upon their shear properties. The key to this model is that the fibers bridge nanocracks in the mineral and cause propagation to become more difficult as the crack extends. This property of increasing resistance to crack propagation with crack extension is important to bone function and will be further discussed below.
Cancellous Microstructure An immense amount of research has been done in the last 50 years on the effects of cancellous bone microstructure on bone mechanical properties. A key and repeated observation is: the microstructural features of normal cancellous bone are very highly correlated to apparent density. Why apparent density is such a powerful predictor of microstructure and mechanical properties is tied up with very interesting details of how stress and strain are distributed in mechanical foams [33], how the trabecular organization creates mechanical anisotropy that orients with the habitual loading directions [70, 71] and a vast number of other topics of both biological and mechanical interest. I recommend starting with the excellent book of Currey [26]. There is a lifetime of reading available. One potentially useful observation is that cancellous bone strength is predicted fairly well by Young’s modulus [26, 72]. It is, in principle, possible to measure bone modulus non-destructively in vivo. Therefore, there is a potential to predict bone strength using the correlation between the two material properties. Unfortunately, the relationship between modulus and strength does not hold when the bone
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ultrastructure is abnormal. For example, in patients with collagen defects, such as osteogenesis imperfecta or with other collagen damage (or, for that matter, for ashed bone), the relationship between modulus and strength is not normal. Since apparent density (or volume fraction) of bone is highly correlated to the microstructural morphology, the universal age-related decline in bone density causes significant changes in tissue microstructure [73]. From the mechanical properties point-of-view, about the most detrimental change is transection of trabecular elements by osteoclastic resorption [74]. Cutting trabecular elements has a much greater effect in decreasing mechanical properties than does the thinning of elements. Preventing trabecular perforation is, therefore, one of the best means to slow the loss of mechanical properties with aging. Because of the different age-dependent histories of remodeling activation with age between men and women, treatment to reduce remodeling activation and element perforation will occur at different ages between the sexes. Perforation is only one example of how the history of remodeling affects cancellous bone strength. Other changes in the cancellous structure affected by remodeling include trabecular thickness, mean age of the tissue, degree of mineralization, density of cement lines and accumulation of other changes in the bone ultrastructure resulting from differences in osteoblast function in the aged organism.
Microstructural Effects in Cortical Bone As noted earlier in the chapter, the mechanical properties of normal cortical bone are related to the mineral content of the tissue as: Mechanical properties C(Ash Fraction)D, where ash fraction is the weight of the bone after ashing divided by the dry weight. The mineralization of osteoid increases nonlinearly to a near steady state over time in living bone [31], but mineralization increases further if the osteocytes die [75, 76]. This occurs in both cancellous and cortical bone: the interiors of trabeculae are more highly mineralized than the surfaces [77] and the interstitial regions of cortical bone are more mineralized than the osteons [78]. Therefore, for any particular bony site the mechanical properties are in constant flux due to (at least) changes in the local mineralization. In reality, the empirical power law for mechanical properties subsumes a huge number of details of how the mechanical properties arise from the complex interplay of collagen, mineral, lamellae, osteons, cement lines and the other features of cortical bone. One of the important features of cortical bone mechanical properties is that primary bone is typically stronger and stiffer but has a shorter fatigue life and lower toughness than does remodeled secondary bone [31]. As a consequence, remodeling is a causal factor in the age-related changes in cortical bone mechanical properties. Although the changes in morphology caused by remodeling are different in cortical bone than in cancellous bone, the rate
at which changes accumulate in both tissues depends upon the remodeling activation frequency. Sex, genetics, general health and other factors such as diet and exercise all affect remodeling activation. Therefore, remodeling related mechanical changes will differ between individuals and sites within a particular bone. An important consequence of Haversian remodeling in cortical bone is the creation of cement lines between the new osteon and the older tissue. The cement line is a weak interface in the tissue and cracks in the bone matrix will tend to be trapped by the cement line interface [31]. When trapped, cracks turn to run along the length of the osteon, preventing the formation of a larger crack that might grow into a macroscopic fracture. This power of osteons and cement lines to control damage and provide enhanced tolerance of bone to damage was recognized many years ago by F. Gaynor Evans [79]. His concept was that osteons in remodeled (secondary) cortical bone are analogous to a ‘bundle of sticks’ in bending. In bending, the ‘sticks’ shear relative to each other and dissipate energy by rupture of the cement lines and by friction [80]. The detailed mechanism is redirection of cracks down the long axis of osteons. A larger number of osteons is associated with larger bending toughness and longer fatigue life [26, 31]. In a long bone, the osteons are largely aligned with the axis of the bone. As a consequence, the weak cement-line interfaces are also lined up with the bone axis. Due to the alignment of the weak interfaces, the strength of remodeled cortical bone is more anisotropic (i.e. it is weaker in lateral and radial tension) than is primary bone. Primary bone is also weaker in radial and lateral tension compared to axial, but this arises from the inherent properties of the primary lamellae as opposed to the cement lines. Mathematical descriptions of the anisotropy of strength can become quite challenging [81, 82] and will not be reviewed here.
Strain rate, fracture propagation toughness and fatigue Much of bone function is explained by modulus and strength under a single load. For a better understanding, however, there are several other important mechanical properties to examine. In this section, three will be presented.
Strain Rate Bone mechanical properties are significantly affected by loading rate. With increase in loading from slow (0.08/s) to fast loading (17/s), modulus tended to increase, yield and failure strength increased up to 1/s then fell and the strain at yield remained unchanged up to 10/s, but decreased subsequently [83]. These strain rate effects can be significant and are often represented mathematically as an additional factor
C h a p t e r 5 The Mechanical Properties of Bone l
in apparent density power laws for properties: Property A(strain rate)B(apparent density)C. The strain rate exponent is usually fairly small. With B 0.05 [84], the predicted relative effect of strain rates 1/s and 0.08/s is a 13% increase in the mechanical properties ((1/0.08)0.05 1.13). The effect of strain rate is reduced by ovariectomy in sheep [85], but it is unknown whether this is important in humans.
Fracture Toughness and Damage Fracture toughness is the resistance of bone to the propagation of an existing crack. This is a different property from toughness, which is the amount of energy absorbed before failure. There are three fracture toughness values for initiation of crack propagation (two in shear and one in tension) and, also, three fracture toughness values related to the continuation of crack propagation once it is initiated. A very important property of bone is that the force to propagate a crack increases as the crack grows [86]. Technically, this is called a rising R-curve, which always struck me as about the most obscurant phrase in the mechanical properties lexicon. Regardless, the benefit to an organism of a rising R-curve is that as a crack elongates, it becomes more and more difficult to continue propagation. For tensile cracks, increasing resistance to crack propagation comes from unbroken ligaments that pass between the crack faces (Figure 5.12). At the tip of the crack, the protein matrix also bridges across the faces. If the crack in the mineral is small enough, it will be completely bridged by the protein matrix. Most fracture toughness theories were developed for metals and do not include the concept of propagating
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compression cracks. In bone, however, compressive cracks form by collapse of the ultrastructure in apparent kink bands (Figure 5.13) [80]. The density of a compressive crack appears to be lower than the adjacent material, suggesting that the kink bands open voids in the tissue. Microporous materials, such as snow, fracture in compression along an anti-crack [87], but this has not been tested for applicability to the nano-porous structure of bone. Both the initiation and propagation fracture toughness of bone are highly dependent upon properties of the collagenous matrix. Damage to the collagen matrix can reduce fracture toughness and, particularly, propagation toughness, to such an extent that normal function is essentially impossible. The examples of osteogenesis imperfecta and ashing discussed above demonstrate this. Any other agerelated degradation of the collagen matrix, such as cleavage by oxygen free radicals or increased cross-linking by non-enzymatic glycation, can be expected significantly to change bone fracture properties from those of a normal young adult.
Fatigue and Fatigue Damage The last of the three more complex mechanical properties to discuss here is fatigue. In essentially all materials, stresses far below the yield stress create changes in the molecular structure of the material that are small, but permanent. For any single small load, the change in the material is so small that it is not detectable by our mechanical test systems. However, with a sufficient number of small loads the changes accumulate and a degradation of the material properties becomes
Figure 5.12 A relatively large tensile crack in iliac cancellous bone imaged by quantitative backscattered electron imaging. Arrows indicate unbroken ligaments (bridges) that slow crack propagation and toughen the bone material.
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Figure 5.13 Compressive microcracks in iliac cancellous bone imaged by quantitative backscattered electron imaging. Arrows indicate three sites where cracks cause bulging of the matrix into the marrow space. The linear portions of the crack are lighter than the remainder of the matrix consistent with micro-voids opening in the tissue due to kink-band formation in the compressive failure zone.
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Figure 5.14 Number of cycles to failure in reversed tension as a function of stress. Cycles of life increase very quickly with decreased stress. Data digitized from Currey [26].
detectable. Details of this process are complex and depend on the material type, but a repeated observation for bone is that even very small loads cause the accumulation of microcracks in the hard tissue. The accumulated damage reduces the modulus and strength of bone tissue relatively slowly at first but, eventually, a critical number of loadings have passed and the material degrades extremely rapidly. The total number of loading cycles to cause failure depends on the magnitude of the load (Figure 5.14) in a highly non-linear fashion.
The importance of fatigue loading and damage to bone function are hard to overstate. A condition where bone damage accumulates is after avascular necrosis of the femoral head. In a few months or years, the dead cancellous bone of the femoral head fails in fatigue, creating the classic crescent sign. The importance of this is that the dead bone was not weaker than living bone – at least initially. The failure of the dead tissue is caused by the accumulation of damage that occurs under normal function but which would
C h a p t e r 5 The Mechanical Properties of Bone l
be repaired in a living bone. The prevention of damage accumulation by bone turnover is the last, and perhaps one of the more important, topics to discuss.
The complete dependence on damage repair for mechanical function In itself, repair is not a mechanical property of bone. However, it is a key property of the living bone that makes it difficult to predict fracture risk. For example, consider a pair of identical twins who live similar lives. If one suffers an occult avascular necrosis of the femoral head, he will accrue a femoral head fracture and the other brother will not. This is not surprising, but it is unpredictable without knowing that one brother has a dead femoral head. Next consider a case of identical quintuplets: one receives a sufficient dose of bisphosphonate to eliminate completely all remodeling; one receives no bisphosphonate and the other three brothers receive intermediate drug doses. The greatly overdosed brother has a virtual avascular necrosis of the femoral head and an eventual fracture would be expected. However, of the three brothers with intermediate doses, who will fracture his femoral head and who will not? Whatever the correct answer, it is not determined by the mechanical properties of their identical femoral heads. Clearly, damage repair is crucial to bone strength. Fortunately, clinical results and animal experiments [10, 88] show that significant reduction of remodeling by bisphosphonates can be tolerated. However, if remodeling is completely suppressed, damage accumulation is uncontrolled and fracture can result. To date, the effects of remodeling suppression are not fully understood.
References 1. J.Y. Rho, L. Kuhn-Spearing, et al., Mechanical properties and the hierarchical structure of bone, Med. Eng. Phys. 20 (2) (1998) 92–102. 2. K.J. Jepsen, O.J. Akkus, et al., Hierarchical relationship between bone traits and mechanical properties in inbred mice, Mamm. Genome 14 (2) (2003) 97–104. 3. L.V. Griffin, J.C. Gibeling, et al., Artifactual nonlinearity due to wear grooves and friction in four-point bending experiments of cortical bone, J. Biomech. 30 (2) (1997) 185–188. 4. C.H. Turner, D.B. Burr, Basic biomechanical measurements of bone: a tutorial, Bone 14 (4) (1993) 595–608. 5. C.L. Malik, J.C. Gibeling, et al., Compliance calibration for fracture testing of equine cortical bone, J. Biomech. 35 (5) (2002) 701–705. 6. T.M. Keaveny, E.F. Wachtel, et al., Mechanical behavior of human trabecular bone after overloading, J. Orthop. Res. 17 (3) (1999) 346–353. 7. V. Kosmopoulos, T.S. Keller, Predicting trabecular bone microdamage initiation and accumulation using a non-linear perfect damage model, Med. Eng. Phys. 30 (6) (2008) 725–732.
65
8. Y.C. Fung, P. Tong, Classical and Computational Solid Mechanics (Advanced Series in Engineering Science), World Scientific Publishing Company Pte Ltd, Singapore, 2001. 9. S.M. Gere, S.P. Timoshenko, Mechanics of Materials, third ed., PWS-KENT Publsihing Company, Boston, 1990. 10. M.R. Allen, S. Reinwald, et al., Alendronate reduces bone toughness of ribs without significantly increasing micro damage accumulation in dogs following 3 years of daily treatment, Calcif. Tissue Int. 82 (5) (2008) 354–360. 11. R.M. Jones, Mechanics of Composite Materials, Taylor & Francis, Inc, Philadelphia, 1998. 12. R.B. Ashman, J.Y. Rho, et al., Anatomical variation of orthotropic elastic moduli of the proximal human tibia, J. Biomech. 22 (8–9) (1989) 895–900. 13. S.C. Cowin, C.H. Turner, On the relationship between the orthotropic Young’s moduli and fabric, J. Biomech. 25 (12) (1992) 1493–1494. 14. G. Yang, J. Kabel, et al., The anisotropic Hooke’s law for cancellous bone and wood, J. Elast. 53 (2) (1998) 125–146. 15. M. Pithioux, P. Lasaygues, et al., An alternative ultrasonic method for measuring the elastic properties of cortical bone, J. Biomech. 35 (7) (2002) 961–968. 16. A. Odgaard, J. Kabel, et al., Fabric and elastic principal directions of cancellous bone are closely related, J. Biomech. 30 (5) (1997) 487–495. 17. J. Kabel, B. van Rietbergen, et al., Constitutive relationships of fabric, density, and elastic properties in cancellous bone architecture, Bone 25 (4) (1999) 481–486. 18. D.P. Fyhrie, S.J. Hoshaw, et al., Shear stress distribution in the trabeculae of human vertebral bone, Ann. Biomed. Eng. 28 (10) (2000) 1194–1199. 19. Y.N. Yeni, F.J. Hou, et al., Trabecular shear stress in human vertebral cancellous bone: intra- and inter-individual variations, J. Biomech. 34 (10) (2001) 1341–1346. 20. Y.N. Yeni, F.J. Hou, et al., Trabecular shear stresses predict in vivo linear microcrack density but not diffuse damage in human vertebral cancellous bone, Ann. Biomed. Eng. 31 (6) (2003) 726–732. 21. E. Verhulp, B. van Rietbergen, et al., Indirect determination of trabecular bone effective tissue failure properties using microfinite element simulations, J. Biomech. 41 (7) (2008) 1479–1485. 22. E. Verhulp, B. Van Rietbergen, et al., Micro-finite element simulation of trabecular-bone post-yield behaviour – effects of material model, element size and type, Comput. Methods Biomech. Biomed. Engin. 11 (4) (2008) 389–395. 23. FG. Evans, Mechanical Properties of Bone, Charles C. Thomas, Springfield, 1973. 24. S.C. Cowin, Bone Mechanics Handbook, CRC Press LLC, Boca Raton, 2001. 25. TM. Keaveny, E.F. Morgan, et al., Biomechanics of trabecular bone, Annu. Rev. Biomed. Eng. 3 (2001) 307–333. 26. JD. Currey, Bones: Structure & Mechanics, Princeton University Press, Princeton, 2006. 27. I. Hvid, P. Christensen, et al., Compressive strength of tibial cancellous bone. Instron and osteopenetrometer measurements in an autopsy material, Acta Orthop. Scand. 54 (6) (1983) 819–825. 27. J.K. Weaver, J. Chalmers, Cancellous bone: its strength and changes with aging and an evaluation of some methods for measuring its mineral content, J. Bone Joint Surg. 48A (2) (1966) 289–298.
66
Osteoporosis in Men
28. T.M. Keaveny, R.E. Borchers, et al., Theoretical analysis of the experimental artifact in trabecular bone compressive modulus, J. Biomech. 26 (4–5) (1993) 599–607. 29. T.M. Keaveny, R.E. Borchers, et al., Trabecular bone modulus and strength can depend on specimen geometry, J. Biomech. 26 (8) (1993) 991–1000. 30. T.M. Keaveny, T.P. Pinilla, et al., Systematic and random errors in compression testing of trabecular bone, J. Orthop. Res. 15 (1) (1997) 101–110. 31. R.B. Martin, D.B. Burr, et al., Skeletal Tissue Mechanics, Springer-Verlag, New York, 1998. 32. W.C. Chang, T.M. Christensen, et al., Uniaxial yield strains for bovine trabecular bone are isotropic and asymmetric, J. Orthop. Res. 17 (4) (1999) 582–585. 33. L.J. Gibson, Biomechanics of cellular solids, J. Biomech. 38 (3) (2005) 377–399. 34. C.J. Hernandez, G.S. Beaupre, et al., The influence of bone volume fraction and ash fraction on bone strength and modulus, Bone 29 (1) (2001) 74–78. 35. S. Lees, D. Hanson, et al., Comparison of dosage-dependent effects of beta-aminopropionitrile, sodium fluoride, and hydrocortisone on selected physical properties of cortical bone, J. Bone Miner. Res. 9 (9) (1994) 1377–1389. 36. C.J. Hernandez, S.Y. Tang, et al., Trabecular microfracture and the influence of pyridinium and non-enzymatic glycationmediated collagen cross-links, Bone 37 (6) (2005) 825–832. 37. S. Viguet-Carrin, D. Farlay, et al., An in vitro model to test the contribution of advanced glycation end products to bone biomechanical properties, Bone 42 (1) (2008) 139–149. 38. A.H. Burstein, J.M. Zika, et al., Contribution of collagen and mineral to the elastic-plastic properties of bone, J. Bone Joint Surg. 57A (7) (1975) 956–961. 39. S.M. Bowman, J. Zeind, et al., The tensile behavior of demineralized bovine cortical bone, J. Biomech. 29 (11) (1996) 1497–1501. 40. J. Catanese 3rd, E.P. Iverson, et al., Heterogeneity of the mechanical properties of demineralized bone, J. Biomech. 32 (12) (1999) 1365–1369. 41. J. Yan, A. Daga, et al., Fracture toughness and work of fracture of hydrated, dehydrated, and ashed bovine bone, J. Biomech. 41 (9) (2008) 1929–1936. 42. R.K. Nalla, M. Balooch, et al., Effects of polar solvents on the fracture resistance of dentin: role of water hydration, Acta Biomater. 1 (1) (2005) 31–43. 43. R.K. Nalla, J.H. Kinney, et al., Role of alcohol in the fracture resistance of teeth, J. Dent. Res. 85 (11) (2006) 1022–1026. 44. J.B. Thompson, J.H. Kindt, et al., Bone indentation recovery time correlates with bond reforming time, Nature 414 (6865) (2001) 773–776. 45. Y.N. Yeni, D.G. Kim, et al., Do sacrificial bonds affect the viscoelastic and fracture properties of bone? Clin. Orthop. Relat. Res. 443 (2006) 101–108. 46. G.E. Fantner, J. Adams, et al., Nanoscale ion mediated networks in bone: osteopontin can repeatedly dissipate large amounts of energy, Nano. Lett. 7 (8) (2007) 2491–2498. 47. J. Adams, GE. Fantner, et al., Molecular energy dissipation in nanoscale networks of dentin matrix protein 1 is strongly dependent on ion valence, Nanotechnology 19 (38) (2008) 384008.
48. B. Zappone, P.J. Thurner, et al., Effect of Ca2 ions on the adhesion and mechanical properties of adsorbed layers of human osteopontin, Biophys. J. 95 (6) (2008) 2939–2950. 49. P. Chavassieux, E. Seeman, et al., Insights into material and structural basis of bone fragility from diseases associated with fractures: how determinants of the biomechanical properties of bone are compromised by disease, Endocr. Rev. 28 (2) (2007) 151–164. 50. O. Akkus, RM. Belaney, Sterilization by gamma radiation impairs the tensile fatigue life of cortical bone by two orders of magnitude, J. Orthop. Res. 23 (5) (2005) 1054–1058. 51. O. Akkus, R.M. Belaney, et al., Free radical scavenging alleviates the biomechanical impairment of gamma radiation sterilized bone tissue, J. Orthop. Res. 23 (4) (2005) 838–845. 52. O. Akkus, CM. Rimnac, Fracture resistance of gamma radiation sterilized cortical bone allografts, J. Orthop. Res. 19 (5) (2001) 927–934. 53. K.R. Wilmarth, J.R. Froines, In vitro and in vivo inhibition of lysyl oxidase by aminopropionitriles, J. Toxicol. Environ. Hlth. 37 (3) (1992) 411–423. 54. J.M. Mbuyi-Muamba, J. Dequeker, Biochemical anatomy of human bone: comparative study of compact and spongy bone in femur, rib and iliac crest, Acta Anat. (Basel) 128 (3) (1987) 184–187. 55. J.M. Mbuyi-Muamba, G. Gevers, et al., Studies on EDTA extracts and collagenase digests from osteoporotic cancellous bone of the femoral head, Clin. Biochem. 20 (3) (1987) 221–224. 56. G.K. Reddy, L. Stehno-Bittel, et al., Glycation-induced matrix stability in the rabbit achilles tendon, Arch. Biochem. Biophys. 399 (2) (2002) 174–180. 57. S.Y. Tang, U. Zeenath, et al., Effects of non-enzymatic glycation on cancellous bone fragility, Bone 40 (4) (2007) 1144–1151. 58. S.Y. Tang, A.D. Sharan, et al., Effects of collagen crosslinking on tissue fragility, Clin. Biomech. 23 (1) (2008) 122–123 author reply 124–126. 59. M. Tzaphlidou, P. Berillis, Collagen fibril diameter in relation to bone site. a quantitative ultrastructural study, Micron 36 (7–8) (2005) 703–705. 60. P. Berillis, D. Emfietzoglou, et al., Collagen fibril diameter in relation to bone site and to calcium/phosphorus ratio, Sci. World Jl. 6 (2006) 1109–1113. 61. P.L. Leong, EF. Morgan, Measurement of fracture callus material properties via nanoindentation, Acta Biomater. 4 (5) (2008) 1569–1575. 62. M.G Ascenzi, A. Ascenzi, et al., Structural differences between ‘dark’ and ‘bright’ isolated human osteonic lamellae, J. Struct. Biol. 141 (1) (2003) 22–33. 63. S.P. Kotha, N. Guzeslu, Modeling the tensile mechanical behavior of bone along the longitudinal direction, J. Theor. Biol. 219 (2) (2002) 269–279. 64. Y. Hamamoto, K. Okumura, Analytical solution to a fracture problem in a tough layered structure, Phys. Rev. E Stat. Nonlin. Soft Matter Phys. 78 (2 Pt 2) (2008) 026118. 65. Y.N. Yeni, D.P. Fyhrie, A rate-dependent microcrack-bridging model that can explain the strain rate dependency of cortical bone apparent yield strength, J. Biomech. 36 (9) (2003) 1343–1353.
C h a p t e r 5 The Mechanical Properties of Bone l
66. R.K. Nalla, J.S. Stolken, et al., Fracture in human cortical bone: local fracture criteria and toughening mechanisms, J. Biomech. 38 (7) (2005) 1517–1525. 67. Y. Tanaka, Y. Kawauchi, et al., Localized yielding around crack tips of double-network gels(a), Macromolec. Rapid Commun. 29 (18) (2008) 1514–1520. 68. Y. Tanaka, R. Kuwabara, et al., Determination of fracture energy of high strength double network hydrogels, J. Phys. Chem. B 109 (23) (2005) 11559–11562. 69. T. Nakajima, T. Kurokawa, et al., Super tough gels with a double network structure, Chin. J. Polym. Sci. 27 (1) (2009) 1–9. 70. S.C. Cowin, Wolff’s law of trabecular architecture at remodeling equilibrium, J. Biomech. Eng. 108 (1) (1986) 83–88. 71. D.P. Fyhrie, DR. Carter, A unifying principle relating stress to trabecular bone morphology, J. Orthop. Res. 4 (3) (1986) 304–317. 72. Y.N. Yeni, X.N. Dong, et al., The dependence between the strength and stiffness of cancellous and cortical bone tissue for tension and compression: extension of a unifying principle, Biomed. Mater. Eng. 14 (3) (2004) 303–310. 73. L. Mosekilde, Mechanisms of age-related bone loss, Novartis Found. Symp. 235 (2001) 150–166 discussion 166–171. 74. M.J. Silva, LJ. Gibson, Modeling the mechanical behavior of vertebral trabecular bone: effects of age-related changes in microstructure, Bone 21 (2) (1997) 191–199. 75. HM. Frost, Micropetrosis, J. Bone Joint Surg. 42A (1960) 144–150. 76. L.S. Bell, M. Kayser, et al., The mineralized osteocyte: a living fossil, Am. J. Phys. Anthropol. 137 (4) (2008) 449–456. 77. T.E. Ciarelli, D.P. Fyhrie, et al., Effects of vertebral bone fragility and bone formation rate on the mineralization levels of cancellous bone from white females, Bone 32 (3) (2003) 311–315. 78. P. Zioupos, M. Gresle, et al., Fatigue strength of human cortical bone: age, physical, and material heterogeneity effects, J. Biomed. Mater. Res. A 86 (3) (2008) 627–636.
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79. F.G. Evans, M.L. Riolo, Relations between the fatigue life and histology of adult human cortical bone, J. Bone Joint Surg. 52A (8) (1970) 1579–1586. 80. T.M. Boyce, D.P. Fyhrie, et al., Damage type and strain mode associations in human compact bone bending fatigue, J. Orthop. Res. 16 (3) (1998) 322–329. 81. H. Cezayirlioglu, E. Bahniuk, et al., Anisotropic yield behavior of bone under combined axial force and torque, J. Biomech. 18 (1) (1985) 61–69. 82. T.M. Keaveny, E.F. Wachtel, et al., Application of the TsaiWu quadratic multiaxial failure criterion to bovine trabecular bone, J. Biomech. Eng. 121 (1) (1999) 99–107. 83. U. Hansen, P. Zioupos, et al., The effect of strain rate on the mechanical properties of human cortical bone, J. Biomech. Eng. 130 (1) (2008) 011011. 84. D.R. Carter, WC. Hayes, Bone compressive strength: the influence of density and strain rate, Science 194 (4270) (1976) 1174–1176. 85. C.M. Les, J.L. Vance, et al., Long-term ovariectomy decreases ovine compact bone viscoelasticity, J. Orthop. Res. 23 (4) (2005) 869–876. 86. R.K. Nalla, J.J. Kruzic, et al., Effect of aging on the toughness of human cortical bone: evaluation by R-curves, Bone 35 (6) (2004) 1240–1246. 87. J. Heierli, P. Gumbsch, et al., Anticrack nucleation as triggering mechanism for snow slab avalanches, Science 321 (5886) (2008) 240–243. 88. M.R. Allen, DB. Burr, Three years of alendronate treatment results in similar levels of vertebral microdamage as after one year of treatment, J. Bone Miner. Res. 22 (11) (2007) 1759–1765. 89. P. Zioupos, J.D. Currey, et al., Exploring the effects of hypermineralisation in bone tissue by using an extreme biological example, Connect. Tissue Res. 41 (3) (2000) 229–248.
Chapter
6
Essentials of Bone Biology: Assessment of Bone Architecture Thomas F. Lang Professor in Residence, Department of Radiology and Biomedical Imaging, and Joint Bioengineering Graduate Group, University of California, San Francisco, San Francisco, CA, USA
Introduction
two dimensional, such as DXA or radiography. Volumetric imaging methods, such as quantitative computed tomography or magnetic resonance imaging, can capture the threedimensional bone structure with resolution sufficient to differentiate the cortex from the medullary cavity or, in the case of high resolution peripheral quantitative computed tomography (HR-pQCT) or high resolution magnetic resonance imaging (HR-MR), to depict the network of trabecular bone and the thickness of the cortical bone. Until relatively recently, non-invasive imaging of bone has focused on density measurement. Areal bone mineral density (aBMD) measurements by DXA provide the primary clinical surrogate measure for bone strength. In DXA studies, a one standard-deviation (SD) reduction in femoral BMD compared to age-matched normal BMD was found to result in an approximately threefold increase in fracture risk, depending on the femoral subregion assessed [9, 10]. In addition to BMD, geometric measurements, such as hip axis length or increased trochanteric width, extracted from DXA images and pelvic radiographs [11, 12], have also been documented to confer risks for hip fracture. Compared to DXA, which is an estimate of total areal bone density, QCT provides measurements of cortical and trabecular volumetric bone density [13]. Individual subregions based on trabecular and cortical compartments have been established in epidemiologic studies as independent predictors of hip fracture risk [14] and have been shown to demonstrate differential responses to pharmacologic interventions in osteo porosis [15]. Although BMD measures, whether by DXA or QCT, have strong associations with incident and prevalent fracture, they are poor fracture predictors on an individual basis. Many individuals with high BMD sustain fractures and many with low BMD do not. Further, changes in BMD do not appear to account for the large changes in fracture
Osteoporosis is one of the major public health problems facing the elderly population [1] and it results in an annual cost of 2.4 billion dollars in the state of California alone [2]. Hip fractures are the most serious manifestation of osteoporosis. Hip fracture alone affects over 250 000 elderly in the USA annually, resulting in a 20% mortality rate and substantial loss of quality of life [3]. The number of osteoporotic fractures is expected to increase as the population ages. Skeletal fractures occur when the loading forces exerted on bone exceed the strength of the bone structure. The risk factors for fractures tend to center around three different mechanisms of action: the risk of a fall or another event exerting a large force on the skeletal structure; the nature of the applied load; and the structural strength of the bone with respect to that loading condition. Bone strength under any loading scenario depends on the three-dimensional distribution of material properties, essentially the bone size, the bone shape and the material properties, elastic modulus and material strength, at each point in the structure [4]. Image-based methods, in that they provide information on both bone material properties and geometry, have become the primary method for assessment of bone strength. Imaging-based methods can be used to capture measures of bone size and architecture, such as cross-sectional area, volume, width or network connectivity, which act as surrogates rather than estimators of bone strength, or methods such as dual-energy x-ray absorptiometry (DXA) hip strength analysis [5] or finite element modeling [4, 6–8], which use point estimates of material properties across the bone structure directly to calculate mechanical properties such as moment of inertia, section modulus or whole bone strength. These methods can be
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risk associated with pharmacologic interventions. Over time, these findings and others have led to the investigation of other skeletal factors not captured in BMD measurements, including measures of bone macroarchitecture, such as bone shape and size, and microarchitecture related to the microstructure of trabecular and cortical bone. This review shall focus on imaging methods for quantification of bone architecture and estimation of strength and other mechanical properties. The review will be structured by imaging modality, starting with two-dimensional DXA and radiographic imaging and continuing to CT and MRI. Each section will be divided into measures of bone geometry and architecture and methods by which the images can be used to estimate bone strength and mechanical properties.
DXA and radiographic imaging Dual x-ray absorptiometry (DXA) was introduced in the late 1980s and has become the mainstay of osteoporosis diagnosis and clinical evaluation worldwide. In the DXA concept, x-rays with a bimodal energy spectrum, obtained either by rare-earth filtration [16] of an x-ray tube, or rapid switching of kVp [17], is passed through the body. By measuring the attenuation of x-rays within each energy and referring these measurements to calibration standards, it is possible to measure the mass of bone in grams at each point or pixel of the projectional image. An areal bone density in g/cm2 is obtained by determining a region of interest, such as the lumbar spine or the femoral neck, and dividing the total mass in g summed across all the pixels in the region by the region’s area in cm2. Starting in the early 1990s, prospective studies have documented the association of areal BMD with incident osteoporotic fracture and have documented therapy responses to anti-resorptives and other osteoporosis medications [18]. DXA has been widely adopted in the clinical setting due to its low cost, high reliability and a radiation dose which is close to daily background radiation and much smaller than that received during a transatlantic flight. Although it is a versatile technique with wide clinical acceptance, DXA is hindered by several technical limitations which compromise its clinical efficacy and utility for research studies. First, the projectional nature of DXA results in areal BMD measures that scale with bone size: of two bones with the same volumetric BMD but different volumes, the larger bone will have the greater apparent areal BMD. Second, the areal BMD measure integrates cortical and trabecular compartments, which QCT studies have shown to have distinct associations with incident hip fracture and with therapy. Third, DXA is unable to account for sclerotic deposits which may overlay bone, such as osteophytes in the vertebrae and hips. Finally, DXA is unable to take into account trabecular microstructure, both because of the projectional nature of the imaging and particularly
because of the limited spatial resolution. Because of these and other limitations, DXA is a relatively poor fracture risk estimator for individuals in so far as there are a large number of subjects with areal BMD consistent with healthy status who incur fractures and others considered osteoporotic who remain fracture-free. Some of the limitations of DXA are addressed in the new FRAX calculations of fracture risk, which take into account both areal BMD as well as a host of clinical factors that may affect skeletal properties not measured by DXA.
Hip Strength Analyses (HSA) HSA techniques are employed to derive estimates of bone dimensions and strength using DXA images. There are two extant HSA approaches which are implemented on commercial DXA systems: Hologic DXA machines use the implementation developed by Beck and co-workers [19] and GE-Lunar systems employ the methodology described by Yoshikawa et al [20]. Based on the cross-sectional moment of inertia (CSMI), which is obtained from the supero-lateral antero-medial profile through the femoral neck, and indices of femoral neck length and neck-shaft angle, both techniques can estimate indices of femoral neck bending rigidity. By dividing the distance between the femoral neck neutral axis position and the periosteal neck edge into the CSMI, it is also possible to estimate a section modulus, another estimate of femoral neck bending rigidity. The Hologic program also estimates a cross-sectional area (CSA) and an endosteal diameter, which are derived parametrically from the areal BMD. These estimates are based on assumptions of a constant mineralization, a circular femoral neck shape and a fixed proportion of bone mass distributed between the cortical and trabecular compartments. The assumptions implicit in HSA signify that caution should be used in interpreting changes in such indices as a function of treatment, as parathyroid hormone (PTH) treatment or anti-resporptive treatment can change the areal BMD and mineralization of bone as well as differentially alter the trabecular and cortical envelopes. HSA measures have been found to be associated with incident risk of hip fracture, but these measures do not appear to predict hip fractures independently of or better than BMD [21, 22]. Standard pelvic radiographs using traditional screen film systems have been used to assess proximal femoral structure since the advent of the Singh Index in the late 1980s [23, 24]. The Singh Index was developed on the premise that hip fracture risk may depend on the integrity of the bands of load-bearing trabeculae that are clearly evident in the radiographs. The Singh Index is computed as a six level grade of the integrity of five anatomic groups of trabeculae, with level VI denoting the clear visibility of all trabecular groups and level 1 denoting the clear visibility of only the principal compressive band. Data relating geometric measurements from pelvic radiographs to incident
C h a p t e r 6 Essentials of Bone Biology: Assessment of Bone Architecture l
hip fracture were obtained in the early 1990s in the Study of Osteoporotic fractures. Glüer et al compared baseline pelvic radiographs in 162 women who had incurred an incident hip fracture to 162 randomly selected non-fractured controls and observed that subjects with fractures had lower indices of cortical thickness in the femoral shaft and neck, a wider trochanteric region and lower Singh scores for the tensile groups of proximal femoral trabeculae [11]. A multi variate model composed of all four measures predicted hip fractures as well as hip BMD. By digitizing standard radiographs, or using digital radiography systems, it is possible to employ image processing and segmentation to extract information on the trabecular network and cortical parameters that can be used to predict femoral strength. Some of this work is currently under clinical evaluation to be introduced commercially. This not only includes a computer system for analysis of femoral radiographs, but radiographic analyses based on x-rays of the hand and wrist, which have also been found to yield variables that are predictive of hip and other osteoporotic fractures.
Computed tomography (CT) CT is a three-dimensional x-ray absorptiometric measurement which provides the distribution of linear attenuation coefficient in a thin cross-section of tissue. The cross-section of the object being scanned is contained within a fan of xrays defined between the edges of the detector array and an x-ray point source. The x-ray attenuation of the patient is measured along ray-paths corresponding to the lines defined between individual detector elements and the x-ray source. Along the length of the scanning system, the x-ray beam is shaped to radiate a relatively thin ‘slice’ of tissue, ranging from m in the case of micro CT, hundreds of m in the case of high resolution CT systems and millimeters in the case of clinical scanners. The fan of x-rays circumscribes a circular field of view, which is itself contained within a square image matrix, which typically consists of two-dimensional arrays of square pixel elements, or ‘pixels’. Because the image represents a slice of tissue, the picture elements have a thickness and, thus, are volume elements, or ‘voxels’. The dimensions of the voxels may be adjusted depending on the size of the organ being imaged. Depending on the type of scanner, the voxel dimensions range from the m level to roughly 1 mm ‘in plane’ and up to several mm in slice thickness. The CT image is acquired when the x-ray source and detector rotate around the patient and the absorption is continuously measured for each detector element. Through a 360-degree source-detector rotation, each voxel is intersected by several ray-paths. The x-ray absorption measurements taken at the different angles are recorded in a computer and combined in a process known as back-projection to calculate the linear attenuation coefficient at each voxel. In the resulting
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CT image, the voxel values are based on the linear attenuation coefficients. Because these linear attenuation coefficients depend on the effective x-ray energy (which varies between CT scanner models and different kVp settings of the same scanner), a simple scale, known as the Hounsfield scale, is used to standardize them. The gray-scale value of each voxel is represented as a Hounsfield Unit (HU), which is defined as the difference of the linear attenuation coefficient of a given voxel from that of water, divided by the linear attenuation coefficient of water. The HU scale is a linear scale in which air has a value of 1000, water 0, muscle 30, with bone typically ranging from 300 to 3000 units. The value of the Hounsfield unit for a given tissue type depends on several technical factors. First, if the sizes of the structures in the tissue are smaller than the dimensions of the voxel, the HU value is subject to partial volume averaging, in which the HU value is the average HU of the constituent tissues of the voxel, weighted by their volume fractions. For example, a 0.78 mm 0.78 mm 10 mm voxel of trabecular bone is a mixture of bone, collagen, cellular marrow and fatty marrow and HU is the volume-weighted average of these four constituents. Beam hardening is a second source of variation in HU. In a CT image, the result of this is that for the same tissue, attenuation coefficients at the outside of the patient are systematically higher than those in the interior. Although manufacturers of CT equipment have implemented beam-hardening corrections, the efficacy of these corrections varies between manufacturers and between technical settings on different machines. Image data for multiple slices are acquired with motion of the patient table through the CT gantry. In older models of CT scanners, the patient table stepped in discrete increments and a 360° rotation of the source/detector was performed at each position. Helical CT scanning was introduced in the early 1990s. In this scanning approach, the detector and x-ray tube rotates while the table moves continuously, resulting in acquisition of a volume of data. The x-ray spot describes a spiral trajectory, with use of interpolation to fill in data between the arms of the spiral. Introduction of this technology resulted in significant reductions in image acquisition time [25, 26] and, combined with the advent of powerful, inexpensive computer workstations, has enabled the clinical development of volumetric QCT analyses of the spine and hip as will be discussed in the following sections. In the late 1990s and early 2000s, the first multidetector CT systems were introduced and are expected to have an important impact in skeletal assessment. In multidetector systems, the single detector array is replaced by a series of detector segments, allowing for the reduction of imaging time and improved usage of radiation dose. Initial multidetector systems featured 4–16 detector rows and the newer systems feature 64 rows of detector data, with recent introduction of 256-detector systems. The newest multidetector systems allow for acquisition of CT cross-sections of submillimeter thickness, resulting in the ability to acquire high quality
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volumetric scans with the resolution along the table axis comparable to the in-plane spatial resolution. As will be described later, this technology will allow for improved analyses of skeletal sites such as the proximal femur, which must be resampled through oblique reformations of the scan data.
Assessment of bone mineral density: quantitative computed tomography (QCT) CT BMD assessment is based on quantitative analysis of the HU in volumes of bone tissue. Typically, the BMD is quantified using a bone mineral reference phantom that is scanned simultaneously with the patient. In order to minimize the impact of beam hardening, the calibration phantom is placed as close as possible to the vertebrae and is normally located under the lumbar spine of the patient. The calibration standard originally developed by Cann et al at UCSF, and which is currently marketed by Mindways (South San Francisco, CA, USA) consists of an acrylic wedge containing cylinders of solutions with varying concentrations (200 mg/cm3, 100 mg/cm3, 50 mg/cm3, 0 mg/cm3) of dipotassium hydrogen phosphate in water [27]. An additional cylinder contained alcohol as a reference material for fat. A solid calcium hydroxyapatite-based calibration standard was later developed by Image Analysis (Columbia, KY, USA) and by Siemens Medical Systems (Erlangen, Germany). The Image Analysis standard consists of rods with varying concentrations (200 mg/cm3, 100 mg/cm3 and 50 mg/cm3) of calcium hydroxyapatite mixed in a waterequivalent solid resin matrix [28]. During the analysis of the QCT image, regions of interest are placed in each of the calibration objects and linear regression analysis is used to determine a relationship between the mean HU measured in each region and the known concentrations of bone-equivalent material. This calibration relationship is then used to convert the mean HU in the patient region of interest (e.g. vertebra or proximal femur) into a concentration (reported in mg/cm3, i.e. the mass of bone per unit tissue volume) of bone equivalent material in the region of interest. Unlike areal bone mineral density, the QCT density measurement is independent of bone size and, thus, is more robust measure for comparisons of bone density between populations and potentially for growing children as well. The major source of error in the QCT bone measurement is the phenomenon of partial volume averaging. Because the voxel dimensions in QCT measurements (0.8–1.0 mm in the imaging plane, 3–10 mm slice thicknesses) are larger than the dimensions and spacing of trabeculae, a QCT voxel includes both bone and marrow constituents. Thus, a QCT measurement is the mass of bone in a volume containing bone, red marrow and marrow fat. A single-energy QCT measurement is capable of determining the mass of bone in a volume
consisting of two components (e.g. bone and red marrow), but not in a three-component system. Resolving the mass fractions of bone, red marrow and marrow fat in the QCT voxel requires a dual-energy QCT measurement. Because fat has a HU value of 200, compared to 30 HU for red marrow and 300–3000 HU for bone, the presence of fat in the QCT volume reduces the depresses the HU measurement. Thus, the presence of marrow fat causes single-energy QCT to underestimate the mass of bone per unit tissue volume, an error which can be corrected using dual-energy acquisitions. The effect of marrow fat on QCT measurements is larger at the spine than at the hip or peripheral skeletal sites. Whereas the conversion from red to fatty marrow tends to finish by the mid-20s in the hip and peripheral skeleton, the vertebrae show a gradual age-related increase in the proportion of fat in the bone marrow which starts in youth and continues through old age [29]. The inclusion of fatty marrow in the vertebral BMD measurement results in accuracy errors ranging from 5 to 15% depending on the age group. However, because the increase in marrow fat is age-related, single energy CT data can be corrected using age-related reference databases and the residual error is not considered to be clinically relevant. Provided that the QCT scan is acquired at low effective energies (i.e. 80–90 kVp), the population SD in marrow fat accounts for roughly 5 mg/cm3 of the 25–30 mg/cm3 population SD in spinal trabecular BMD. This residual error is not considered large enough to merit clinical use of dualenergy techniques, which are more accurate, but which have larger radiation doses and precision errors.
Measurement of structure and BMD using volumetric CT images of the spine and hip Almost all CT scanners in current clinical practice are multidetector models, allowing acquisition of multiple crosssectional images, or ‘slices’, in a single rotation of the detector array. Multidetector systems in current clinical use range from 4- and 8-detector systems up to 256 detector systems with total widths up to 15 cm. The advent of multidetector CT allows for acquisition of large scan volumes within time periods of seconds. The speed of scanning reduces the procedure time to the time required to position the patient on the table and define an anatomic volume for acquisition. The ability rapidly to image and reconstruct large volumes of tissue has made feasible the application of threedimensional (3D) CT-based analytic methods to clinical osteoporosis assessment and to research in osteoporosis. For assessment of the central skeleton, analytic methods have been developed which quantify structural and density measurements from 3D reconstructions of whole vertebrae and proximal femora. One of the most powerful applications of helical CT scanning and three-dimensional image analysis
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is for assessment of bone mineral density, geometry and strength of the proximal femur. Analysis approaches range from assessment of density, geometry and macrostructural processes based on reconstruction of cross-sections and volumes of femoral neck tissue to finite element modeling approaches to model the strength of the hip based on bone geometry and material properties mapped from CT image values. Densitometric and structural assessments based on volume reconstructions of the proximal femur based on CT scans have been developed at the University of California, San Francisco (UCSF) [30, 31], the University of Erlangen [32, 33], the Mindways Company [34], Image Analysis [35] and the Mayo Clinic [36]. The approaches developed at UCSF and University of Erlangen involve reformatting of the QCT scans along the femoral neck axis and segmentation of the entire proximal femoral envelope, with combinations of mathematical morphology and thresholding, and edge detection approaches to derive the cortical envelope for volume and thickness assessments. The computer algorithm described by Kang et al carries out volumetric analyses of the femoral neck [32, 33] and the approach described by Lang et al at UC San Francisco (Figure 6.1) processes three-dimensional CT images of the proximal femur to measure bone mineral density in the femoral neck, the total femur and in a region which combines the trochanteric and intertrochanteric subregions similar to those of DXA systems [30, 31]. Within each anatomic subregion, the density, mass and volume are computed for the cortical and trabecular components as well as for the integral bone envelope. For trabecular BMD measurements, the precision of this method in vivo was found to range from 0.6% to 1.1% depending on the volume of interest assessed [30]. Both the Erlangen and UCSF approaches carry out geometric and structural analyses of the minimum femoral neck cross-section, computing crosssectional area, estimates of cortical volume and thickness
Femoral neck
Trochanteric
Total femur
Figure 6.1 Proximal femoral integral regions of interest derived from volumetric QCT (red) overlaid on a 3D reconstruction of CT scan data (green). (See color plate section).
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and moments of inertia for strength estimation. The approach for proximal femoral analysis developed at the Mayo clinic [36, 37] does not reconstruct the whole proximal femoral volume, a single cross-section of the femoral neck is reconstructed and measures of integral, cortical and medullary density and cross-sectional area are computed in addition to bending and axial compressive strength indices.
Findings based on volumetric QCT analyses While earlier studies using QCT have documented that density and structural measures are associated with proximal femoral strength in vitro [30], recent data have confirmed that measures of density and structure are associated with hip fracture in vivo. A recent cross-sectional study comparing women imaged within 48 hours of a hip fracture to age and body-size matched controls, showed that hip fracture was significantly associated with reduced vBMD in the cortical, integral and trabecular compartments, as well as reduced measures of cortical volume and thickness [38]. Two interesting findings of the study were that fracture status was associated with increased femoral neck cross-sectional area, consistent with an earlier finding of increased proximal femoral intertrochanteric width from pelvic radiographs in the Study of Osteoporotic Fractures [39]. The study also found that measures of cortical geometry and trabecular vBMD were independently associated with hip fracture. QCT was also employed to characterize the association of femoral neck density and geometry parameters with incident hip fracture in men in the prospectively designed Mr Os study. Black et al reported that the percentage of proximal femoral tissue volume occupied by cortical tissue, a measure of cortical thickness, and the cross-sectional area of the femoral neck, were both associated with incident hip fracture in men aged 69–90 years, independently of BMD measured either volumetrically by QCT or areally by DXA [14]. The percentage cortical volume in the femoral neck was a particularly powerful predictor, with a one standard deviation reduction increasing the relative risk of fracture nearly three-fold. Interestingly, however, the predictive power for incident hip fracture of QCT BMD and the independently associated geometric parameters in a multivariate model were not better than that of hip DXA. This may be because, as described earlier, areal BMD by hip DXA comprises information regarding bone density and bone size, both of which are hip fracture risk factors. A new approach to incorporating both hip BMD and 3D geometric information into the prediction of hip fracture risk has been proposed by Li et al [40]. Using the CT scans from the cross-sectional study in Chinese women described above, they first employed an intersubject image registration approach to register all of the scans onto a common
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hip coordinate system, creating a voxelized 3D model of the entire cohort. Li et al then divided the cohort into training and test subgroups, with each subgroup containing half of the fracture and control subjects, and with a voxel-based model for each subgroup. Within the training subgroup, they carried out an analysis of variance (ANOVA) to determine which voxels in the training 3D model were most highly correlated with hip fracture status. This resulted in a region of interest corresponding to voxels with highest association with hip fracture. They then mapped this region into the scans of the test subject and compared BMD measured in that region between the fracture subjects and control, observing that it tended to be more strongly associated with hip fracture status than standard regions of BMD assessment, such as femoral neck or total femur [41]. In addition to fracture status, recent studies have delineated the correlation of these measures to age [37, 42], drug treatment [15, 43] and changes in mechanical loading [44]. Using volumetric QCT in a seminal cross-sectional study of aging, Riggs et al compared measures of proximal femoral volumetric density, cortical geometry and femoral neck cross-sectional area between young normal and aging subjects of the Rochester Study [37]. In addition to powerful age-related declines across multiple indices of volumetric cortical and trabecular bone mineral density and cortical thickness, they observed higher femoral neck cross-sectional areas in the older subjects, supporting the idea of periosteal apposition as a compensation for age-related bone loss [37, 45, 46]. Consistent findings of age-related increases in measures of femoral neck, femoral shaft and vertebral cross-sectional area were supported by other cross-sectional studies reported by Sigurdsson et al, who studied a cohort of Icelandic men and women aged 66–90 years [45], by Marshall et al, who studied aging American men [46, 47] and by Meta et al, who compared young and elderly American women [42]. At the present time, several studies have documented the response of bone density and structure variables measured by QCT to pharmacologic interventions. There have been several studies in which QCT has been employed to characterize the differential effects of PTH treatment on cortical and trabecular bone. In the proximal femur, studies of PTH 1-84 and teriparatide (12 and 18 months respectively) have shown concurrent increases in trabecular volumetric BMD and decreases in cortical volumetric BMD [15, 43]. Black et al have reported that one year of PTH 1-84 therapy resulted in an increase of cortical tissue volume consistent with increased amount of cortical tissue having low mineralization [15, 43]. Studies of anti-resorptive medications have reported smaller increases in proximal femoral trabecular and cortical bone mineral density by QCT, although, in these cases, positive changes have been associated with increases in both compartments. QCT based studies of information regarding the response of proximal femoral density and structure variables to changes in mechanical loading have been provided by two
longitudinal studies of astronauts undergoing and recovering from spaceflights of roughly six-month duration on the International Space Station. Lang et al reported that crews on long-duration spaceflight lose, on average, 1–2.7% of their proximal femoral bone mass per month of spaceflight, depending on anatomic subregion and compartment [31]. A study following the same subjects one year after their return from their mission observed that, while indices of bone mass recovered nearly completely, indices of volumetric bone mineral density only recovered to a small extent and that this discrepancy could be explained by an increase in the bone size during the year after flight, supporting the idea that periosteal apposition could be a response to resumed weight bearing after the loss of large amounts of bone during the flight [44].
3D QCT of the vertebrae In the spine, the use of volumetric QCT measurements impacts precision more than discriminatory capability. Their ability to improve the precision of spinal measurements relates to the use of three-dimensional anatomic landmarks to guide the placement of volumes of interest and to correct for differences in patient positioning which affect single slice scans. Currently, single-slice QCT techniques are highly operator dependent, requiring careful slice positioning and angulation as well as careful region of interest placement. Lang et al developed a volumetric spinal QCT approach in which an image of the entire vertebral body (Figure 6.2) is acquired and anatomic landmarks such
3Dtrab
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Figure 6.2 QCT vertebral regions of interest. Top row of images are three-dimensional regions and bottom row are standard trabecular and integral bone regions defined on the mid-vertebral cross-section. (See color plate section).
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as the vertebral endplates and the spinous process are used to fix the 3D orientation of the vertebral body, allowing for definition of new trabecular and integral regions which contain most of the bone in the vertebral centrum, as shown in Figure 6.2 [48]. Although measuring a larger volume of tissue may enhance precision, these new regions are highly correlated with the mid-vertebral subregions assessed with standard QCT techniques and may not contain significant new information about vertebral strength. Consequently, volumetric studies of regional BMD, which examine specific subregions of the centrum that may vary in their contribution to vertebral strength, and studies of the cortical shell, the condition of which may be important for vertebral strength in osteoporotic individuals, are of interest for future investigation.
Finite element modeling (FEM) FEM is a mathematical technique used by engineers to evaluate the strength of complex structures such as engine parts, bridges and, more recently, bones. The structure is divided into ‘finite elements’ (discrete pieces of the structure) to form an ‘FE mesh’ so that it can be analyzed. The advantage of using FEM in this study is that this method can account for the material heterogeneity and irregular geometry of the femur, factors that cannot be considered using other approaches. Until recently, it has not been possible to analyze individual bones due to the extraordinary amount of labor involved in generating the FE mesh. Not only does the complex 3-D geometry need to be defined, but the material properties, which vary dramatically within the bone, must be specified. As a result, researchers have often spent months, or even years, to create just one FE model and, even then, the model often lacked adequate refinement. To address this problem, researchers have developed methods to derive finite element models from CT scans of the hip and spine. These methods involve volumetric QCT whole hip [4, 49–52] or whole vertebra images [6, 7, 53] obtained with 1-mm or 3-mm slice thickness. The finite element modeling application involves three steps. First, the bone geometry information is obtained by determining the outer boundaries of the proximal femora or vertebra on each imaged crosssection on the stack of cross-sections which encompass the bone. Next, material properties, such as elastic modulus and strength, are computed for each voxel within the bone boundaries. These are computed using parametric relationships between BMD and material properties obtained by scanning and then mechanically testing samples of trabecular and cortical bone. Once the material properties and bone geometry have been defined, load vectors are applied, which simulate the forces applied to bone in normal loading, or in traumatic events such as falls. Keyak et al have developed an automated, CT scan-based method of generating patientspecific FE models of the hip [4, 49, 50]. This method takes
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advantage of the voxel-based nature of quantitative CT scan data to achieve fully automated mesh generation and, more significantly, to allow heterogeneous material properties to be specified. The FE models can be analyzed using a loading condition simulating a load on the femur in a single-legged gait or a fall backwards and to the side with an impact on the greater trochanter. For each voxel, elastic modulus and strength are estimated as material properties and the factor of safety (FOS) is determined as the strength at each element divided by the stress, with FOS 1 representing mechanical failure. A fracture is considered to occur if 15 contiguous elements fail. The outcome variable produced by the modeling technique is failure load, which is defined as the load magnitude required to produce a fracture. This procedure has been extensively tested in vitro, with high correlations to measured failure load for both loading conditions (r 0.95 and 0.96 for fall and stance loading conditions, respectively [4]). In addition to their close correlation with fracture load, the FE models depict areas of high strain which occur at the sites where the bones fracture in vitro and where fractures occur in vivo. The application of FEM to clinical studies has been limited in the past, but is now growing with the wide employment of CT scanning in clinical osteoporosis research. Orwoll et al recently reported that proximal femoral strength and the ratio of applied load to proximal femoral strength were strongly associated with incident hip fracture in elderly men [8]. In particular, load to strength ratio remained strongly and significantly associated with incident hip fracture even after areal BMD was taken into account. Keaveny et al reported on the use of FEM to estimate changes of proximal femoral strength associated with one year’s administration of PTH 1-84, alendronate, and a combination of these two therapies [54]. In the second year of the study, the PTH group was split into alendronateand placebo-treated subgroups and the combination and alendronate groups were also followed up with alendronate. For the first year of treatment, both the PTH and alendronate group showed small but significant increases of femoral strength from baseline and, in the second year, femoral strength continued to increase for all groups but the placebo group, with the group initially treated by PTH showing the largest overall change in strength. It seems that the relatively modest increases in strength reported for the PTH group are consistent with the idea that PTH treatment has an initially negative effect on cortical bone, which counteracts the large increases in trabecular bone mineral density. Keaveny et al recently applied FEM to compare the effects of teriparatide and alendronate on estimated vertebral strength and vertebral bone density [7] and Lian et al employed FEM to compare estimated proximal femoral strength between subjects with glucorticoid-induced osteoporosis and age-matched controls [55]. In addition to studies of fracture risk and drug treatment, FEM of the hip has also been used to study the effect of mechanical unloading of the proximal femur in long-duration spaceflight. Keyak et al reported that crew
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members undergoing International Space Station missions of 6 months average length showed loss of proximal femoral strength on the order of 2–2.6%/month of flight, which is roughly double the rate of bone loss reported for studies of integral bone density by DXA and QCT [56]. Figure 6.3 shows an example of the application of single-legged stance and posterolateral fall loading conditions to a finite element model of the proximal femur, as computed by Keyak.
been employed to gain insight into the effects of aging [59, 60], menopause [61] and drug treatments [62–67]. In addition to benchtop devices capable of imaging human bone specimens and whole animal bones in vitro and rodents in vivo, there are also systems available for imaging the structure of peripheral bones in humans in vivo. Norland-Stratec have developed devices that can image skeletal sites such as the forearm, femur and tibia at voxel sizes of 200–800 MA and radiation doses from 2 to 30 Sv, depending on the site being imaged [68–69]. Although not capable of imaging trabecular architecture, these systems have been widely used to study structural properties of peripheral skeletal sites such as cross-sectional moment of inertia, cross-sectional area and cortical area [70–72]. More recently, Scanco has developed a peripheral QCT system which can obtain an isotropic spatial resolution of 100 M with an effective radiation dose less than 10 mSv per measurement [58]. This device can assess compartmental bone density as well as indices of apparent trabecular and cortical microstructure with good precision (4%). For a typical scan session of 9 mm with 110 sections, the scan time is on the order of 3 minutes, which can result in motion artifacts that may require rescanning. Recent studies have shown cross-sectional association between indices of trabecular and cortical structure assessed at the distal radius and tibia with prevalent femoral neck [71] and vertebral fracture [72] which were independent of areal BMD of the spine. At this juncture, this device does not yet have data confirming ability to predict fracture in the prospective setting, nor are there any published studies of response of the trabecular and cortical microstructure parameters to drug treatment. Figure 6.4 shows images obtained by a desktop microCT device and by the high resolution pQCT device developed by Scanco. Magnetic resonance imaging (MRI) provides a method for imaging bone structure in primarily peripheral skeletal sites that does not require ionizing radiation [73–77]. In MRI
MicroCT methods While QCT using whole body CT scanners allows for differential assessment of the cortical and trabecular compartments and estimates of bone strength using the information on material properties and geometry derived from the scans, these images do have sufficient spatial resolution to quantify accurately the properties of the thin proximal femoral cortices and cannot be used to study the characteristics of trabecular microarchitecture. Specialized scanners have been developed to measure trabecular and cortical properties at extremely high spatial resolutions (5–20 M) in specimens and animals and at somewhat lower resolution (50–100 M) at peripheral skeletal sites in vivo in humans. Benchtop microCT scanners have been developed for characterization of human and animal bone specimens as well as live animals [57, 58]. These scans may be employed to derive morphologic properties of the trabecular network, including bone volume/total volume, trabecular surface area, trabecular size and spacing, as well as porosity. The parameters quantified from microCT images have been based on histomorphometric definitions proposed by Parfitt and studies have shown a high correlation between measurements from 3D microCT images and parameters assessed by standard histomorphometry. Trabecular structure measures based on biopsies have
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Figure 6.3 Proximal femoral finite element models showing (A) application of loading forces (red arrows) in a single legged stance and (B) a fall to the side with an impact on the posterolateral aspect of the lesser trochanter (Courtesy of J Keyak University of California, Irvine). (See color plate section).
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imaging, the body part of interest is placed in a strong external magnetic field and protons contained in the body’s tissues are excited by a series of pulses from a radiofrequency coil placed on the site of interest. An image is generated by detection of the pulses of energy produced by the protons as they decay back from the excited state. The strength of MRI is its ability to depict soft tissues, which contain lipids and other components which are proton rich. Since hydrocarbons and other proton-rich compounds are scarce in skeletal tissue, bone manifests as a signal void in MRI images.
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For high-resolution skeletal imaging, MRI is most often applied at peripheral skeletal sites where a high signal to noise ratio is obtained because of the thin soft tissue layer interposed between the bone of interest and the radiofrequency coil. Thus, for skeletal structure assessment, MRI has generally been performed for the calcaneus [74, 75, 78], distal radius [79], phalanges [80] and, more recently, the trochanteric portion of the proximal femur [81–83]. Using surface coils in conjunction with 1.5 T and 3 T whole body scanners, voxels sizes of 150–300 M in plane and 300–500 M slice thickness are typically obtained. Because the trabecular thickness is of the order of 150 mM with a spacing on the order of 300 mM, these measurements are used to derive apparent rather than direct estimates of trabecular structure. Studies have shown these measures to correlate strongly with microCT measures obtained at higher spatial resolution and MRI has been widely used in clinical research studies. MRI based indices of trabecular structure obtained at the distal radius, calcaneus and phalanges have been shown to reflect menopause-, age- and treatmentrelated changes and limited cross-sectional studies have shown associations between alterations of indices of apparent trabecular microstructure and prevalent vertebral fracture [84, 85]. The development of new radiofrequency coils and sequences have made possible imaging of trabecular structure of trabeculae in the region of the hip close to the body surface. Further improvements may become possible through imaging at 7 T and use of parallel imaging to increase efficiency of data collection. Figure 6.5 shows high-resolution MRI images of the distal radius and proximal femur.
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Figure 6.4 Micro CT image (Scanco 40) of cubic specimens from the distal radius from a non-osteoporotic (A) and (B) osteo porotic human donors obtained at 10 M spatial resolution; (C) shows a scan through the distal radius in a young healthy volunteer obtained with the ScanCo XtremeCT at 82 M voxel size. (Courtesy of Dr. G. Kazakeia, University of California, San Francisco).
Improvements in imaging technology and image processing techniques have made it possible to extend clinical osteoporosis research beyond bone mineral density into indices of bone structure. These techniques range from estimates made on relatively crude imaging technologies, such as DXA and radiographic imaging, to more sophisticated approaches based on images from volumetric CT acquisitions. These measures range from estimates of sectional strength estimates from cross-sections through the femoral neck and indices of apparent cortical thickness and volume, to finite element modeling methods which take into account the full 3D information on the bone geometry and material properties to estimate the whole bone strength. Although the resolution of CT scanners has improved greatly due to the introduction of multidetector systems, the images are still not of sufficient quality directly to assess trabecular microstructure and cortical thickness. To this end, microCT has become available for high-resolution scanning of bone specimens and live animals and high-resolution devices such as the XtremeCT HR-PQCT device have been developed
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Figure 6.5 High-resolution MRI images obtained through the distal radius for (A) a young normal subject and (B) a 76-year old osteoporotic subject; (C) shows an example of an MRI image through the proximal femur employed for structural assessments which are currently in an exploratory stage. (Courtesy of Dr. S. Majumdar, University of California, San Francisco).
for estimates of trabecular texture and cortical structure at peripheral skeletal sites.
References 1. A.C. Sasser, M.D. Rousculp, H.G. Birnbaum, E.F. Oster, E. Lufkin, D. Mallet, Economic burden of osteoporosis, breast cancer, and cardiovascular disease among postmenopausal women in an employed population, Womens Hlth. Issues 15 (2005) 97–108. 2. L.S. Orsini, M.D. Rousculp, S.R. Long, S. Wang, Health care utilization and expenditures in the United States: a study of osteoporosis-related fractures, Osteoporos. Int. 16 (2005) 359–371. 3. S.R. Cummings, M.C. Nevitt, W.S. Browner, et al., Risk factors for hip fracture in white women. Study of Osteoporotic Fractures Research Group [see comments], N. Engl. J. Med. 332 (1995) 767–773. 4. J.H. Keyak, T.S. Kaneko, J. Tehranzadeh, H.B. Skinner, Predicting proximal femoral strength using structural engineering models, Clin. Orthop. Relat. Res. (2005) 219–228. 5. T.J. Beck, C.B. Ruff, K.E. Warden, W.W. Scott Jr, G.U. Rao, Predicting femoral neck strength from bone mineral data. A structural approach, Invest. Radiol. 25 (1990) 6–18.
6. R.P. Crawford, W.S. Rosenberg, T.M. Keaveny, Quantitative computed tomography-based finite element models of the human lumbar vertebral body: effect of element size on stiffness, damage, and fracture strength predictions, J. Biomech. Eng. 125 (2003) 434–438. 7. T.M. Keaveny, D.W. Donley, P.F. Hoffmann, B.H. Mitlak, E. V. Glass, J.A. San Martin, Effects of teriparatide and alendronate on vertebral strength as assessed by finite element modeling of QCT scans in women with osteoporosis, J. Bone Miner. Res. 22 (2007) 149–157. 8. E.S. Orwoll, L.M. Marshall, C.M. Nielson, et al., Finite element analysis of the proximal femur and hip fracture risk in older men, J. Bone Miner. Res. (2008). 9. S.R. Cummings, D.M. Black, M.C. Nevitt, et al., Bone density at various sites for prediction of hip fractures: the study of osteoporotic fractures, Lancet 341 (1993) 72–75. 10. A.M. Schott, C. Cormier, D. Hans, et al., How hip and wholebody bone mineral density predict hip fracture in elderly women: the EPIDOS prospective study, Osteoporos. Int. 8 (1998) 247–254. 11. C.C. Glüer, S.R. Cummings, A. Pressman, et al., Prediction of hip fractures from pelvic radiographs: the study of osteo porotic fractures, J. Bone Miner. Res. 9 (1994) 671–677. 12. K.G. Faulkner, S.R. Cummings, C.C. Glüer, L. Palermo, D. Black, H.K. Genant, Simple measurement of femoral
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13.
14.
15.
16.
17.
18.
19.
20.
21.
22.
23.
24.
25. 26.
27.
28.
29.
geometry predicts hip fracture: the study of osteopotic fractures, J. Bone Miner. Res. 8 (1993) 1211–1217. H.K. Genant, C.E. Cann, B. Ettinger, G.S. Gordan, Quantitative computed tomography of vertebral spongiosa: a sensitive method for detecting early bone loss after oophorectomy, Ann. Int. Med. 97 (1982) 699–705. D.M. Black, M.L. Bouxsein, L.M. Marshall, et al., Proximal femoral structure and the prediction of hip fracture in men: a large prospective study using QCT, J. Bone Miner. Res. 23 (2008) 1326–1333. D.M. Black, S.L. Greenspan, K.E. Ensrud, et al., The effects of parathyroid hormone and alendronate alone or in combination in postmenopausal osteoporosis, N. Engl. J. Med. 349 (2003) 1207–1215. R.B. Mazess, B. Collick, J. Trempe, H. Barden, J. Hanson, Performance evaluation of a dual energy x-ray bone densitometer, Calcif. Tissue Int. 44 (1989) 228–232. J.A. Stein, J.L. Lazewatsky, A.M. Hochberg, Dual energy x-ray bone densitometer incorporating an internal reference system, Radiology 165 (P) (1987) 313. D. Black, S. Cummings, D. Karpf, et al., Randomised trial of effect of alendronate on risk of fracture in women with existing vertebral fractures, Lancet 348 (1996) 1535–1541. T.J. Beck, B.R. Christopher, K.E. Warden, W.W. Scott, G.U. Rao, Predicting femoral neck strength from bone mineral data: a structural approach, Invest. Radiol. 25 (1990) 6–18. T. Yoshikawa, C.H. Turner, M. Peacock, et al., Geometric structure of the femoral neck measured using dual-energy x-ray absorptiometry, J. Bone Miner. Res. 9 (1994) 1053–1064. S. Kaptoge, T.J. Beck, J. Reeve, et al., Prediction of incident hip fracture risk by femur geometry variables measured by hip structural analysis in the study of osteoporotic fractures, J. Bone Miner. Res. 23 (2008) 1892–1904. F. Rivadeneira, M.C. Zillikens, C.E. De Laet, et al., Femoral neck BMD is a strong predictor of hip fracture susceptibility in elderly men and women because it detects cortical bone instability: the Rotterdam study, J. Bone Miner. Res. 22 (2007) 1781–1790. S.H. Patel, K.P. Murphy, Fractures of the proximal femur: correlates of radiological evidence of osteoporosis, Skeletal Radiol. 35 (2006) 202–211. Y.M. Singh, A.R. Nagrath, P.S. Maini, Changes in trabecular pattern of the upper end of the femur as an index of osteoporosis, J. Bone Joint Surg. 52A (1970) 457–467. W.A. Kalender, A. Polacin, Physical performance of spiral CT scanning, Med. Phys. 18 (1991) 910–915. W.A. Kalender, W. Seissler, E. Klotz, P. Vock, Spiral volumetric CT with single-breath-hold technique, continuous transport and continuous scanner rotation, Radiology 176 (1990) 181–183. C.E. Cann, H.K. Genant, Precise measurement of vertebral mineral content using computed tomography, J. Comp. Assist. Tomogr. 4 (1980) 493–500. K.G. Faulkner, C.C. Glüer, S. Grampp, H.K. Genant, Cross calibration of liquid and solid QCT calibration standards: corrections to the UCSF normative data, Osteo. Int. 3 (1993) 36–42. M. Dunnill, J. Anderson, R. Whitehead, Quantitative histological studies on age changes in bone, J. Pathol. Bacteriol. 94 (1967) 275–291.
79
30. T.F. Lang, J.H. Keyak, M.W. Heitz, et al., Volumetric quantitative computed tomography of the proximal femur: precision and relation to bone strength, Bone 21 (1997) 101–108. 31. T. Lang, A. LeBlanc, H. Evans, Y. Lu, H. Genant, A. Yu, Cortical and trabecular bone mineral loss from the spine and hip in long-duration spaceflight, J. Bone Miner. Res. 19 (2004) 1006–1012. 32. Y. Kang, K. Engelke, W.A. Kalender, A new accurate and precise 3-D segmentation method for skeletal structures in volumetric CT data, IEEE Trans. Med. Imaging 22 (2003) 586–598. 33. Y. Kang, K. Engelke, C. Fuchs, W.A. Kalender, An anatomic coordinate system of the femoral neck for highly reproducible BMD measurements using 3D QCT, Comput. Med. Imaging Graph. 29 (2005) 533–541. 34. Mindways Software Inc.2009. www.qct.com 35. Image Analysis. 2009. www.image-analysis.com 36. J.J. Camp, R.A. Karwoski, M.C. Stacy, et al., A system for the analysis of whole-bone strength from helical CT images, Proc. SPIE 5369 (2004) 74–88. 37. B.L. Riggs, L.J. Melton 3rd, R.A. Robb, et al., Populationbased study of age and sex differences in bone volumetric density, size, geometry, and structure at different skeletal sites, J. Bone Miner. Res. 19 (2004) 1945–1954. 38. X. Cheng, J. Li, Y. Lu, J. Keyak, T. Lang, Proximal femoral density and geometry measurements by quantitative computed tomography: association with hip fracture, Bone 40 (2007) 169–174. 39. C.C. Gluer, S.R. Cummings, A. Pressman, et al., Prediction of hip fractures from pelvic radiographs: the study of osteoporotic fractures. The Study of Osteoporotic Fractures Research Group, J. Bone Miner. Res. 9 (1994) 671–677. 40. W. Li, I. Kezele, D.L. Collins, et al., Voxel-based modeling and quantification of the proximal femur using inter-subject registration of quantitative CT images, Bone 41 (2007) 888–895. 41. W. Li, J. Kornak, T. Harris, et al., Identify fracture-critical regions inside the proximal femur using statistical parametric mapping, Bone 44 (2009) 596–602. 42. M. Meta, Y. Lu, J.H. Keyak, T. Lang, Young-elderly differences in bone density, geometry and strength indices depend on proximal femur sub-region: a cross sectional study in Caucasian-American women, Bone 39 (2006) 152–158. 43. M.R. McClung, J. San Martin, P.D. Miller, et al., Opposite bone remodeling effects of teriparatide and alendronate in increasing bone mass, Arch. Intern. Med. 165 (2005) 1762–1768. 44. T.F. Lang, A.D. Leblanc, H.J. Evans, Y. Lu, Adaptation of the proximal femur to skeletal reloading after long-duration spaceflight, J. Bone Miner. Res. 21 (2006) 1224–1230. 45. G. Sigurdsson, T. Aspelund, M. Chang, et al., Increasing sex difference in bone strength in old age: the age, gene/environment susceptibility-Reykjavik study (AGES-REYKJAVIK), Bone 39 (2006) 644–651. 46. L.M. Marshall, T.F. Lang, L.C. Lambert, J.M. Zmuda, K.E. Ensrud, E.S. Orwoll, Dimensions and volumetric BMD of the proximal femur and their relation to age among older US men, J. Bone Miner. Res. 21 (2006) 1197–1206. 47. L.M. Marshall, J.M. Zmuda, B.K. Chan, et al., Race and ethnic variation in proximal femur structure and BMD among older men, J. Bone Miner. Res. 23 (2008) 121–130.
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48. T.F. Lang, J. Li, S.T. Harris, H.K. Genant, Assessment of vertebral bone mineral density using volumetric quantitative CT, J. Comput. Assist. Tomogr. 23 (1999) 130–137. 49. J.H. Keyak, Improved prediction of proximal femoral fracture load using nonlinear finite element models, Med. Eng. Phys. 23 (2001) 165–173. 50. J.H. Keyak, S.A. Rossi, K.A. Jones, C.M. Les, H.B. Skinner, Prediction of fracture location in the proximal femur using finite element models, Med. Eng. Phys. 23 (2001) 657–664. 51. D.D. Cody, G.J. Gross, F.J. Hou, H.J. Spencer, S.A. Goldstein, D.P. Fyhrie, Femoral strength is better predicted by finite element models than QCT and DXA, J. Biomech. 32 (1999) 1013–1020. 52. D.D. Cody, F.J. Hou, G.W. Divine, D.P. Fyhrie, Short term in vivo precision of proximal femoral finite element modeling, Ann. Biomed. Eng. 28 (2000) 408–414. 53. K.G. Faulkner, C.E. Cann, B.H. Hasegawa, Effect of bone distribution on vertebral strength: assessment with patientspecific nonlinear finite element analysis, Radiology 179 (1991) 669–674. 54. T.M. Keaveny, P.F. Hoffmann, M. Singh, et al., Femoral bone strength and its relation to cortical and trabecular changes after treatment with PTH, alendronate, and their combination as assessed by finite element analysis of quantitative CT scans, J. Bone Miner. Res. 23 (2008) 1974–1982. 55. K.C. Lian, T.F. Lang, J.H. Keyak, et al., Differences in hip quantitative computed tomography (QCT) measurements of bone mineral density and bone strength between glucocorticoid-treated and glucocorticoid-naive postmenopausal women, Osteoporos. Int. 16 (2005) 642–650. 56. J.H. Keyak, A.K. Koyama, A. Leblanc, Y. Lu, T.F. Lang, Reduction in proximal femoral strength due to long-duration spaceflight, Bone 44 (2009) 449–453. 57. A. Laib, O. Barou, L. Vico, et al., 3D micro-computed tomography of trabecular and cortical bone architecture with application to a rat model of immobilisation osteoporosis, Med. Biol. Eng. Comput. 38 (2000) 326–332. 58. A. Laib, H.J. Häuselmann, P. Rüegsegger, In vivo high resolution 3D-QCT of the human forearm, Technol. Hlth. Care 6 (1998) 329–337. 59. W.Q. Cui, Y.Y. Won, M.H. Baek, et al., Age-and regiondependent changes in three-dimensional microstructural properties of proximal femoral trabeculae, Osteoporos. Int. 9 (2008) 1579–1587. 60. D.M. Cooper, C.D. Thomas, J.G. Clement, A.L. Turinsky, C.W. Sensen, B. Hallgrimsson, Age-dependent change in the 3D structure of cortical porosity at the human femoral midshaft, Bone 40 (2007) 957–965. 61. M.P. Akhter, J.M. Lappe, K.M. Davies, R.R. Recker, Transmenopausal changes in the trabecular bone structure, Bone 41 (2007) 111–116. 62. R.R. Recker, P.D. Delmas, J. Halse, et al., Effects of intravenous zoledronic acid once yearly on bone remodeling and bone structure, J. Bone Miner. Res. 23 (2008) 6–16. 63. R.R. Recker, L.G. Ste-Marie, B. Langdahl, D. Masanauskaite, D. Ethgen, P.D. Delmas, Oral ibandronate preserves trabecular microarchitecture: micro-computed tomography findings. From the Oral Ibandronate Osteoporosis Vertebral Fracture Trial in North America and Europe Study, J. Clin. Densitom. 12 (2009) 71–76.
64. J. Fox, M.A. Miller, R.R. Recker, S.P. Bare, S.Y. Smith, I. Moreau, Treatment of postmenopausal osteoporotic women with parathyroid hormone 1-84 for 18 months increases cancellous bone formation and improves cancellous architecture: a study of iliac crest biopsies using histomorphometry and micro computed tomography, J. Musculoskelet. Neuronal Interact. 5 (2005) 356–357. 65. B. Borah, T.E. Dufresne, E.L. Ritman, et al., Long-term risedronate treatment normalizes mineralization and continues to preserve trabecular architecture: sequential triple biopsy studies with micro-computed tomography, Bone 39 (2006) 345–352. 66. B. Borah, E.L. Ritman, T.E. Dufresne, et al., The effect of risedronate on bone mineralization as measured by micro-computed tomography with synchrotron radiation: correlation to histomorphometric indices of turnover, Bone 37 (2005) 1–9. 67. T.E. Dufresne, P.A. Chmielewski, M.D. Manhart, T.D. Johnson, B. Borah, Risedronate preserves bone architecture in early postmenopausal women in 1 year as measured by three-dimensional microcomputed tomography, Calcif. Tissue Int. 73 (2003) 423–432. 68. JL. Ferretti, Perspectives of pQCT technology associated to biomechanical studies in skeletal research employing rat models, Bone 17 (1995) 353S–364S. 69. J.L. Ferretti, R.F. Capozza, J.R. Zanchetta, Mechanical validation of a tomographic (pQCT) index for noninvasive estimation of rat femur bending strength, Bone 18 (1996) 97–102. 70. P. Schneider, C. Reiners, G.R. Cointry, R.F. Capozza, J.L. Ferretti, Bone quality parameters of the distal radius as assessed by pQCT in normal and fractured women, Osteoporos. Int. 12 (2001) 639–646. 71. L. Vico, M. Zouch, A. Amirouche, et al., High-resolution pQCT analysis at the distal radius and tibia discriminates patients with recent wrist and femoral neck fractures, J. Bone Miner. Res. 23 (2008) 1741–1750. 72. E. Sornay-Rendu, J.L. Cabrera-Bravo, S. Boutroy, F. Munoz, P.D. Delmas, Severity of vertebral fractures is associated with alterations of cortical architecture in postmenopausal women, J. Bone Miner. Res. 24 (2009) 737–743. 73. S. Majumdar, Magnetic resonance imaging for osteoporosis, Skeletal Radiol. 37 (2008) 95–97. 74. S. Majumdar, H. Genant, A. Gies, G. Gugliemi, Regional variations in trabecular structure in the calcaneus assessed using high resolution magnetic resonance images and quantitative image analysis, J. Bone Miner. Res. 8 (1993) s351. 75. S. Majumdar, M. Kothari, P. Augat, et al., High-resolution magnetic resonance imaging: three-dimensional trabecular bone architecture and biomechanical properties, Bone 22 (1998) 445–454. 76. F.W. Wehrli, J.C. Ford, C. Kaut-Watson, Quantitative MR: a new method for in vivo characterization of trabecular bone structure, Radiology 177 (P) (1990) 245. 77. F.W. Wehrli, H.K. Song, P.K. Saha, A.C. Wright, Quantitative MRI for the assessment of bone structure and function, NMR Biomed. 19 (2006) 731–764. 78. J.S. Bauer, R. Monetti, R. Krug, et al., Advances of 3T MR imaging in visualizing trabecular bone structure of the calcaneus are partially SNR-independent: analysis using simulated noise in relation to micro-CT, 1.5T MRI, and biomechanical strength, J. Magn. Reson. Imag. 29 (2009) 132–140.
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79. M. Hudelmaier, A. Kollstedt, E.M. Lochmuller, V. Kuhn, F. Eckstein, T.M. Link, Gender differences in trabecular bone architecture of the distal radius assessed with magnetic resonance imaging and implications for mechanical competence, Osteoporos. Int. 16 (2005) 1124–1133. 80. B. Stampa, B. Kuhn, C. Liess, M. Heller, C.C. Gluer, Characterization of the integrity of three-dimensional trabecular bone microstructure by connectivity and shape analysis using high-resolution magnetic resonance imaging in vivo, Top. Magn. Reson. Imag. 13 (2002) 357–363. 81. R. Krug, S. Banerjee, E.T. Han, D.C. Newitt, T.M. Link, S. Majumdar, Feasibility of in vivo structural analysis of highresolution magnetic resonance images of the proximal femur, Osteoporos. Int. 16 (2005) 1307–1314. 82. J. Blumenfeld, C. Studholme, J. Carballido-Gamio, D. Carpenter, T.M. Link, S. Majumdar, Three-dimensional
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image registration of MR proximal femur images for the analysis of trabecular bone parameters, Med. Phys. 35 (2008) 4630–4639. 83. T.M. Link, V. Vieth, R. Langenberg, et al., Structure analysis of high resolution magnetic resonance imaging of the proximal femur: in vitro correlation with biomechanical strength and BMD, Calcif. Tissue Int. 72 (2003) 156–165. 8 4. T.M. Link, S. Majumdar, P. Augat, et al., In vivo high resolution MRI of the calcaneus: differences in trabecular structure in osteoporosis patients, J. Bone Miner. Res. 13 (1998) 1175–1182. 85. S. Majumdar, T.M. Link, P. Augat, et al., Trabecular bone architecture in the distal radius using magnetic resonance imaging in subjects with fractures of the proximal femur. Magnetic Resonance Science Center and Osteoporosis and Arthritis Research Group, Osteoporos. Int. 10 (1999) 231–239.
Chapter
7
Skeletal Growth in Males Qingju Wang and Ego Seeman Endocrine Centre, Heidelberg Repatriation Hospital/Austin Health, Department of Medicine, the University of Melbourne, Melbourne,Victoria, Australia
Introduction
2. age-related decay of the skeleton affects a smaller proportion of the male population than it does in the female population because men do not undergo a comparable midlife reduction in sex hormone levels [12, 13]. Therefore, their skeletons are not exposed to the high bone remodeling that drives structural decay in the face of a negative bone multicellular unit (BMU) balance.
Fewer men than women sustain fractures during advancing age, but fragility fractures are common in men and confer a sufficiently high morbidity, mortality and cost to the community to regard this as a public health problem [1–3]. The reasons underlying the lower incidence of fractures in men than in women are incompletely understood because the reasons why any individual sustains a fracture are poorly understood. For example, the majority of fragility fractures in the population occur in persons without osteoporosis [4, 5]. Over 60% of all fractures occur in men without osteoporosis and the structural basis underlying this bone fragility has received limited attention in women and none in men [4, 5]. While sex differences in bone size are said to explain differences in fracture incidence, this has not been tested experimentally [6]. Indeed, larger bones are loaded by larger muscles so that, at least in young adulthood, the stress imposed on bone is no different in males and females [7]. Asians have a smaller skeleton and lower bone mineral density (BMD) even after adjusting for height and weight, yet fracture rates in Asians are lower, not higher than in Caucasians [8, 9] and women with hip fractures and their daughters have larger femoral neck diameter than age matched controls [10]. When comparing women and men with fractures with their corresponding controls, or with each other, little insight into structural differences are present that explain the sex differences in fragility – both men and women with fractures have comparable deficits in bone structure relative to controls without fractures and bone morphology in men and women with fractures is similar [11]. The two most reasonable explanations for the lower incidence of fractures in men than in women are that:
As a consequence of growth-related and age-related factors, there are fewer men than women in the population susceptible to fractures should a fall occur. This chapter is confined largely to a discussion of the attainment of structural differences in males relative to females that we propose will protect their skeleton from net age-related bone loss which, although less than in women, is still substantial.
Growth in stature Stature increases due to the growth of the trunk and lower extremities of different growth velocities. In prepubertal years, growth velocity of leg length is twice that of sitting height increasing the proportion of stature in favor of the lower extremities [14]. Growth velocity of tibia and femur remains unchanged after entering puberty and decelerates later in puberty while that of trunk accelerates [15–17]. The pubertal growth spurt (11 years in girls and 13 years in boys) is largely truncal and postpubertal growth is mostly growth in the trunk (Figure 7.1) [15, 16, 18]. The upper extremities follow a similar growth pattern as the lower extremities [17, 19]. The growth velocity of tibia or femur is not greater in boys than girls [15–17, 20]. The longer extremities in adult males is due to the 2 years longer prepubertal growth than in females, not due to more rapid growth [20]. By contrast, the tempo of trunk growth may be slightly greater in pubertal boys than girls (Table 7.1) [20].
1. peak structural features achieved during growth in men makes their skeleton less susceptible to age-related decay Osteoporosis in Men
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Copyright 2009, 2010 Elsevier, Inc. All rights of reproduction in any form reserved.
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Figure 7.1 The growth velocity of stature, sitting height, femur and tibia length. The pubertal growth spurt is truncal. (From Anderson J Bone Joint Surg 1965;47A:1554-64 [16] and J Bone Joint Surg 1963;45A:1–14 [15]). Table 7.1 Sex-difference in pubertal growth of stature and segments (mean 6 SD) Height
Age at take off (yr) Age at peak velocity (yr) Peak velocity (size/yr) Size at take off (size) Adult size (cm) Adolescent gain (cm)
Sitting Height
Leg-Length
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Female
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Female
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Female
12.05 0.85 13.91 0.84 8.80 1.05 146.09 6.33 173.64 6.11 27.56 3.54
10.30 0.95 11.89 0.90 8.13 0.78 137.91 7.02 163.16 5.94 25.25 4.14
12.12 0.86 14.25 0.87 4.54 0.67 77.31 3.22 92.71 3.26 15.40 2.34
10.38 1.00 12.21 0.96 4.02 0.47 74.07 2.93 87.60 2.92 13.53 2.42
12.01 0.90 13.58 0.79 4.25 0.70 68.83 3.81 80.94 3.87 12.11 2.25
10.18 0.94 11.59 0.93 4.25 0.62 64.03 4.83 75.53 3.96 11.50 2.55
Modified from Tonner JM et al. Annals of Human Biology 3(2): 109–26.
The elongation of a long bone differs proximally and distally. Serial measurement of the distance of the distal and proximal ends of long bones to their nutrient foramina in the diaphyseal cortex showed that the growth plates of the tibia and femur at the knee contribute more to their elongation. In the upper extremities, the growth plates distant from the elbow contribute more to long bone growth [17, 19]. The different growth patterns of axial and peripheral skeleton have clinical implications. The effects of illness during growth depend on the maturational stage at the time of exposure, not just the ‘severity’ of the illness. As longitudinal growth is more rapid in the appendicular than axial skeleton before puberty, illness may produce greater deficits in appendicular morphology [21]. Illness during late puberty may produce greater deficits in the axial than the appendicular morphology. This regional specificity in growth and the effects of illness are obscured by the study of standing height or BMD alone. Disease interrupting
growth may be more deleterious on morphology at the proximal than distal humerus and distal femur than proximal femur by preferentially blocking more of the growth at regions growing faster.
Growth in bone structure As long as bone elongates, bone diameter also increases by periosteal apposition. Variance in bone length, like standing height, is largely genetically determined. For reasons that are unclear, bone lengths do not differ between children with cerebral palsy and controls after adjustment of bone age [22]. This is not the case for bone diameter. Binkely et al report that tibial length did not differ, but tibial shaft periosteal circumference was reduced by one-third in nonambulatory patients with cerebral palsy relative to controls
C h a p t e r 7 Skeletal Growth in Males l
[23]. This suggests that mechanical stimulation plays a role in the growth of bone width. Racket sport players training during or before puberty have a larger humeral midshaft diameter, while those starting training after puberty have no larger humeral diameter but a smaller medullar cavity suggesting periosteal apposition, while still active, can respond to loading during growth, but later, loading has little effect while endocortical apposition or prevention of endocortical resorption by loading may benefit cortical thickness [24–26]. Whether the benefit of greater periosteal apposition and greater net cortical thickness achieved by the latter or by endocortical modeling/remodeling is sustained into adulthood is uncertain, but evidence is available suggesting maintenance for some years after cessation of sporting activity [27, 28]. Loading is accommodated by modifying the shape of bone during growth, not just its mass [29, 30]. More mass means greater weight, greater maintenance cost and reduced mobility so lightness is an advantage and is achieved by modifying bone shape, varying the distribution of mass in space, not just increasing mass. Variance in bone shape, while believed to be largely the result of differing loading patterns is probably also largely explained by genetic variation. Difference in rates of focal periosteal apposition around a bone perimeter modifies its shape [31]. For example, the cross-section of the tibial shaft becomes more elliptical with advanced age in pubertal girls, due to greater periosteal apposition at anterior and posterior regions than at the medial and lateral regions. Similarly, the shape of the radius in growing goats is more circular and becomes elliptical in adulthood [29, 30]. No study has examined the bone shape under different loading circumstances. It is also not clear,
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whether the shape of bone can be modified after completion of growth when periosteal apposition has slowed down. As males have a 2-year longer growth period than females, their bone cross-sectional size becomes larger mainly after puberty (some differences in bone diameter may be present at birth) [32, 33]. The difference in duration of prepubertal growth accounts for the majority of the sex differences in bone mass, because for a given pubertal stage, periosteal apposition rate differs little, if any, by sex [34]. Despite the larger bone size in males, cortical thickness of the long bone does not differ substantially by sex before or after puberty, owing to the medullar contraction in females in late puberty and continued medullar expansion in males during puberty [32, 33]. Unlike the diaphysis, where bone diameter increases by periosteal apposition, periosteal resorption models the flasklike shape of the metaphysis while cortical thickening occurs by trabecular condensation [35]. The wide metaphysis is resorbed on its periosteal surface by resorptive modeling or remodeling to fit the slender diaphysis, a process that may increase metaphyseal cortical porosity (Figure 7.2). This increased cortical porosity with a temporary decrease in cortical thickness may contribute to fracture risk during the pubertal growth spurt [36, 37]. Although bone size increases during childhood and puberty, trabecular morphology remains relatively constant during growth. For example, Rauch et al and Moyer-Mileur et al reported that the trabecular vBMD of the distal radius and tibia, measured using peripheral quantitative computed tomography (pQCT), did not increase from 5 to 20 years of age [38, 39]. Byers et al examined the histomorphometry of the growth plate at the costochondral junction from birth to adolescence and reported bone volume fraction in the
A B
C D
A: Metaphyseal site of periosteal resorption B: Metaphyseal site of endocortical apposition C: Diaphyseal site of periosteal apposition D: Diaphyseal site of endocortical resorption
Figure 7.2 Different cortical morphology at the metaphysis and diaphysis due to different osteogenesis. Metaphyseal cortex is derived from coalesced trabeculae at the endocortical surface, while diaphyseal cortex is formated by periosteal apposition (P and E in the right panel represent periosteal and endocortical surface. (From Cadet et al J Bone Joint Surg 2003;85A(9):1739–48 [35]. Reprinted with permission).
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secondary spongiosa was stable from 3 years of age onwards [40] (Figure 7.3). These observations draw attention to the complexities of the formation of trabecular bone at this region. Further studies are needed to elucidate the development of trabecular structure during childhood. We reported trabecular bone fraction (BV/TV), measured using high-resolution pQCT, in the distal radius is independent of age from 7 up to 20 years of age in females with only modest increases in males (unpublished observations). Trabecular BV/TV was greater in males than females after puberty due to greater trabecular thickness in males, with no difference in trabecular number between the sexes [41]. Thicker trabeculae are more connected, there is less surface available for remodeling, protecting the trabeculae from being resorbed (because remodeling requires a surface to be initiated upon). A similar situation is seen between races. African Americans have thicker trabeculae, less surface and lower bone remodeling [42]. Thicker trabeculae are also more likely to thin than perforate during aging; this will result in less loss of strength because a reduction in trabecular density by loss of connectivity has more deleterious effects on strength than the same loss of trabecular density by thinning of trabeculae [13]. The origin of sex differences in trabecular thickness is not known. Whether this is the result of differences in growth plate-derived primary trabeculae or due to differences in the synthesis of secondary trabeculae is not known.
Trabecular BV/TV (%)
In contrast to little or no sex difference in long bone diameter before puberty, vertebral body cross-section is larger in boys than girls before puberty (15%) and the sex difference increases at maturity (25%) due to a longer prepubertal growth period as well as a later growth deceleration within their puberty in males [6, 43, 44]. The sex difference in axial bone diameter but less so at the appendicular sites before puberty may be due to differing prenatal sex steroid exposure as supported by the longer axial but not limb length in male than female neonates [45, 46]. Vertebral vBMD does not increase until late puberty and there is no difference in total or trabecular vBMD of the vertebral body between sexes at any growing stage [6, 43, 44], implying similar trabecular architecture in the vertebral body, contrasting to appendicular sites where males have thicker trabeculae [41].
Skeletal fragility has its origin early in life Bone traits such as size, shape, vBMD and cortical thickness track during adulthood. Differences in these traits in adulthood originate during growth [47, 48]. The magnitude of the variance or dispersion of bone traits around their age-specific mean is large; 1 SD is about 10–15% of the mean. Thus,
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Figure 7.3 Secondary spongiosa at the costochondral junction underneath the growth plate. There is little change in the architecture of the secondary spongiosa from early in life. (Modified from Byers et al Bone 27:495–501 [40]. Reprinted with permission).
C h a p t e r 7 Skeletal Growth in Males l
individuals at the 95th and 5th percentiles for bone size or mass differ by 50%. The variance in the rate of bone loss is about an order of magnitude less (1 SD 1% of the mean) [49]. So the difference in the percentile location of a trait established at the completion of growth is likely to be a more important determinant of fracture risk in old age than differences in rates of bone loss for many years. The position of an individual’s bone trait in the population distribution is established early in life – probably before puberty. In the study by Loro et al, percentile ranking of traits including size and vBMD of vertebral body, total cross-sectional area and cortical bone area of femoral midshaft at Tanner stage 2 was unchanged in the next 3 years and 60–90% of the variance at maturity was accounted for by the variance before puberty [50]. Ruff examined the tracking of femoral and humeral strength from infancy through adolescence in 10 boys and girls. Although sample size was small, ranking at 17 years was established at least before 6 years of age [51]. Similarly, Cheng et al report that an individual’s peak bone mass (PBM) correlated to the body length at 1 year of age and this correlation was not different to that between PBM and peak body height suggesting that the individual’s PBM was largely determined during the first year of life [52]. Twin and family studies suggest that genetic factors explain 60–80% of the variance in PBM, the amount of mass present at completion of linear and radial bone growth [53]. Whether this is the case for bone size, cortical thickness and trabecular BV/TV is not known. Physical activity during growth may contribute to the variance in bone traits but individuals differ more in their genetic makeup than differences in physical activity so the latter is still likely to only account for a small proportion of total variance. Nevertheless, intermittent skeletal stresses caused by muscular contractions in utero modulate cartilage growth, ossification and bone modeling and remodeling [54, 55]. Low skeletal mass and strength in newborns with neuromuscular disease-induced fetal immobility is well documented [56, 57]. In children with cerebral palsy, the trabecular bone structure and bone width are underdeveloped [58]. Ruff studied the femoral and humeral length and strength from early in life and found that the ratio of femoral and humeral length in human infants is close to that in adults, while the ratio of femoral and humeral strength only started to develop at 1 year of age, when walking begins, and increased rapidly from 1 to 3 years, then more slowly to mid- adolescence [59].
Modeling and remodeling – machinery of tracking Variance in bone remodeling as determined using circulating bone markers is largely genetically determined [60]. During aging, the lower the remodeling rate the lower the rate of
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loss [61]. During growth, low remodeling rate is associated with higher vBMD and high remodeling associated with the opposite. Slemenda et al demonstrated that black children accumulated approximately 10% greater bone mass by the end of puberty and had 50% lower concentration of osteocalcin and tartrate-resistant acid phosphatase (TRAP) throughout growth than white children; within a race, children with a lower concentration of these bone resorption markers had greater bone mass, while there was no difference left after controlling for TRAP between or within races, indicating remodeling rate during growth accounts for the difference in bone mass and structure between races and within a race [62]. Mora et al reported that high resorption markers pyridinoline and deoxypyridinoline were associated with low vertebral cancellous vBMD, low femoral mid-shaft cortical vBMD and smaller femoral mid-shaft cross-section in children. Serum osteocalcin was negatively associated with cortical vBMD [63]. Using pQCT, we found that high TRAP level was associated with larger marrow size and low vBMD of the tibial midshaft in a given bone cross-section [31]. Thus, the rate of bone modeling and remodeling during growth contributes to peak structural development and the position of bone traits in their population distribution; a high rate of remodeling constructs a more ‘empty’, lighter bone with thinner cortices and perhaps thinner, less connected trabeculae with a large surface area. While this may be advantageous in producing a lighter skeleton, as age advances, this structural design may be disadvantageous and the larger surface area exposes the bone to more intense remodeling and so bone loss as each remodeling event removes bone.
Bone growth and GH-IGF-I/sex hormones Growth hormone (GH) augments longitudinal bone growth by binding to its receptor at two main sites: the liver and the growth plate. In liver, it stimulates the production of insulinlike growth factor I (IGF-I) which is transported to the growth plates via the circulation to stimulate the proliferation and hypertrophy of chondrocytes. At the growth plate, GH stimulates the proliferation of prochondrocytes and the local production of IGF-I. Thus, direct effects and indirect effects via its systemic or local production of IGF-I are necessary for optimal growth [64]. IGF-I is the essential factor for the maintenance of intra uterine growth independently of GH, as seen in the severely compromised growth in mice and human fetuses with a mutated IGF-I gene, in contrast to normal weight and length at birth in mice and human with GH deficiency [65–67]. IGF-II also plays critical roles during intrauterine growth, especially at the early stage of gestation [68].
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In the first year of life, GH is elevated, decreases in midchildhood and reaches a peak at mid-puberty, at 11–12 years in girls and at 13–14 years in boys [69], coinciding with the two periods of rapid growth. The infancy growth spurt is mainly the result of growth in the legs, while the growth spurt in puberty is mainly truncal. The higher growth potential of long bones during infancy than puberty and the increased sex hormone levels during puberty promoting truncal growth may partly explain the different growth patterns of the axial and appendicular skeleton under high levels of GH. Growth in the leg and trunk are similarly associated with IGF-I in boys and diminished in children with GH deficiency or GH resistance [14]. The GH/IGF-I axis is likely to be one of the major mediators in the prepubertal growth in which there is no difference between normal children and children with androgen/estrogen receptor insensitivity [70, 71]. After entering puberty, testosterone directly, or indirectly via estradiol, stimulates the excretion of GH which induces the pubertal growth spurt in the spine. The direct effect, if any, of testosterone on the growth plate is unclear. Testosterone exerts no effect on the longitudinal bone growth in gonadohypophysectomized growing rats with or without GH while exerting a dose-dependent effect in gonadectomized rats suggesting testosterone affects longitudinal growth mainly via GH by modulating the hypothalamopituitary function [72–74]. Testosterone does not affect the production of IGF-I or the abundance of IGF-I receptor in liver or the growth plate [75]. Testosterone may modulate the effect of GH on the growth plate, but this remains controversial. The cessation of longitudinal growth in later puberty is not due to GH/IGF-I or testosterone, but the direct effect of estradiol (E2) on the growth plate in both sexes [73]. E2 at high levels in puberty promotes epiphyseal fusion, probably by inhibiting the proliferation of chondrocytes and promoting apoptosis [76]. Linear growth into adulthood continues in male and female patients with estrogen receptor resistance or aromatase deficiency, and aromatase inhibitors in pubertal boys with short stature increase their predicted adult height by delaying bone age [70, 77–79]. E2 promotes the pituitary production of GH [80, 81]. The effect of E2 on systemic and local production of IGF-I remains controversial. Ovariectomy in rats increases serum IGF-I and E2 administration reduces it [82]. Moreover, acute and chronic exposure to E2 may have a different effect. GH-induced hepatic IGF-I production is not affected by acute E2 but is reduced by chronic E2 administration [83]. Inconsistent with this, one recent study reported that E2 promotes the hepatic production of IGF-I independent of GH [84]. In the growth plate, local production of IGF-I is reported not to be affected by E2 which contrasts to its effect in utero [76, 82] . GH/IGF-I promotes periosteal apposition, as seen in acromegaly [85]. Exercise has profound effects on periosteal apposition during growth but not thereafter [86], perhaps partly due to interaction with this axis. GH deficiency
does not appear to affect the cortical vBMD in prepubertal children or apparent vBMD of diaphysis [87]. It is unclear whether GH/IGF-I affects the growth in trabecular architecture. In adult and animal studies, trabecular structure dose not differ between GH deficient patients or animals and controls, suggesting GH/IGF-I has little effect on the internal bone structure [84, 88]. The lower aBMD in GH deficiency children is almost, if not totally, due to their shorter stature than controls. As GH modifies body composition, with relatively more fat mass in GH deficiency children, their aBMD is also likely to be underestimated [89]. The increased rate of bone remodeling associated with GH/IGF-I excess, such as in acromegalic patients, does not appear to be associated with increased or decreased vertebral vBMD [90]. The changed bone status in patients with GH deficiency or excess can be more attributable to comorbidities than GH/IGF-I itself. Further study with advanced high-resolution imaging modalities is needed to investigate the effect of GH on the trabecular structure in children.
Summary There is little difference in skeletal structure in prepubertal males and females. As bone length increases during growth, the diameter of a bone cross-section increases with expansion of the medullary cavity so that there is little change in apparent vBMD in the vertebral body or long bones. Trabecular architecture, such as its BV/TV, thickness, number and separation may remain largely unchanged from as early as 2 years of age. At puberty, due to a longer duration of prepubertal growth in males than in females, sex differences in bone size appear, but not in cortical thickness. Trabecular architecture also differs by sex at maturity in favor of males having thicker trabeculae. An individual’s position of bone structural traits, such as bone size, cortical thickness and especially the trabecular BV/TV in their population distribution probably is established before puberty. That is, an individual’s position for their bone structural strength, whether at the 95th or 5th percentile at the completion of growth has its origin before puberty. The variance in bone traits is an order magnitude greater than the variance in rates of structural decay so that peak structural strength established at the completion of growth is likely to be an important determinant of skeletal fragility in adulthood.
References 1. M. Van der Klift, C.E. De Laet, E.V. McCloskey, A. Hofman, H.A. Pols, The incidence of vertebral fractures in men and women: the Rotterdam Study, J. Bone Miner. Res. 17 (6) (2002) 1051–1056. 2. J.A. Kanis, O. Johnell, A. Oden, et al., Long-term risk of osteoporotic fracture in Malmo, Osteoporos. Int. 11 (8) (2000) 669–674.
C h a p t e r 7 Skeletal Growth in Males l
3. E. Seeman, Osteoporosis in men: epidemiology, pathophysiology, and treatment possibilities, Am. J. Med. 95 (5A) (1993) 22S–28S. 4. S.C. Schuit, M. van der Klift, A.E. Weel, et al., Fracture incidence and association with bone mineral density in elderly men and women: the Rotterdam Study, Bone 34 (1) (2004) 195–202. 5. K.M. Sanders, G.C. Nicholson, J.J. Watts, et al., Half the burden of fragility fractures in the community occur in women without osteoporosis, Bone 38 (5) (2006) 694–700. 6. V. Gilsanz, M.I. Boechat, T.F. Roe, M.L. Loro, J.W. Sayre, W.G. Goodman, Gender differences in vertebral body sizes in children and adolescents, Radiology 190 (3) (1994) 673–677. 7. Y. Duan, E. Seeman, C.H. Turner, The biomechanical basis of vertebral body fragility in men and women, J. Bone Miner. Res. 16 (12) (2001) 2276–2283. 8. E.M. Lau, H. Lynn, J. Woo, L.J. Melton 3rd, Areal and volumetric bone density in Hong Kong Chinese: a comparison with Caucasians living in the United States, Osteoporos. Int. 14 (7) (2003) 583–588. 9. L. Xu, A. Lu, X. Zhao, X. Chen, S.R. Cummings, Very low rates of hip fracture in Beijing, People’s Republic of China the Beijing Osteoporosis Project, Am. J. Epidemiol. 144 (9) (1996) 901–907. 10. A. Tabensky, Y. Duan, J. Edmonds, E. Seeman, The contribution of reduced peak accrual of bone and age-related bone loss to osteoporosis at the spine and hip: insights from the daughters of women with vertebral or hip fractures, J. Bone Miner. Res. 16 (6) (2001) 1101–1107. 11. H. Kroger, M. Lunt, J. Reeve, et al., Bone density reduction in various measurement sites in men and women with osteoporotic fractures of spine and hip: the European quantitation of osteoporosis study, Calcif. Tissue Int. 64 (3) (1999) 191–199. 12. E. Seeman, The structural basis of bone fragility in men, Bone 25 (1) (1999) 143–147. 13. E. Seeman, P.D. Delmas, Bone quality – the material and structural basis of bone strength and fragility, New Engl. J. Med. 354 (21) (2006) 2250–2261. 14. I. Rogers, C. Metcalfe, D. Gunnell, P. Emmett, D. Dunger, J. Holly, Insulin-like growth factor-I and growth in height, leg length, and trunk length between ages 5 and 10 years, J. Clin. Endocrinol. Metab. 91 (7) (2006) 2514–2519. 15. M. Anderson, W.T. Green, M.B. Messner, Growth and predictions of growth in the lower extremities, J. Bone Joint Surg. 45A (1) (1963) 1–14. 16. M. Anderson, S.C. Hwang, W.T. Green, Growth of the normal trunk in boys and girls during the second decade of life; related to age, maturity, and ossification of the iliac epiphyses, J. Bone Joint Surg. 47A (8) (1965) 1554–1564. 17. J.W. Pritchett, Longitudinal growth and growth-plate activity in the lower extremity, Clin. Orthop. Relat. Res. 275 (1992) 274–279. 18. S. Bass, P.D. Delmas, G. Pearce, E. Hendrich, A. Tabensky, E. Seeman, The differing tempo of growth in bone size, mass, and density in girls is region-specific, J. Clin. Invest. 104 (6) (1999) 795–804. 19. J.W. Pritchett, Growth and predictions of growth in the upper extremity, J. Bone Joint Surg. 70A (4) (1988) 520–525. 20. J.M. Tanner, R.H. Whitehouse, E. Marubini, L.F. Resele, The adolescent growth spurt of boys and girls of the Harpenden growth study, Ann. Hum. Biol. 3 (2) (1976) 109–126.
91
21. E. Seeman, M.K. Karlsson, Y. Duan, On exposure to anorexia nervosa, the temporal variation in axial and appendicular skeletal development predisposes to site-specific deficits in bone size and density: a cross-sectional study, J. Bone Miner. Res. 15 (11) (2000) 2259–2265. 22. C.K. Kong, P.W. Tse, W.Y. Lee, Bone age and linear skeletal growth of children with cerebral palsy, Dev. Med. Child Neurol. 41 (11) (1999) 758–765. 23. T. Binkley, J. Johnson, L. Vogel, H. Kecskemethy, R. Henderson, B. Specker, Bone measurements by peripheral quantitative computed tomography (pQCT) in children with cerebral palsy, J. Pediatr. 147 (6) (2005) 791–796. 24. S. Kontulainen, H. Sievanen, P. Kannus, M. Pasanen, I. Vuori, Effect of long-term impact-loading on mass, size, and estimated strength of humerus and radius of female racquet-sports players: a peripheral quantitative computed tomography study between young and old starters and controls, J. Bone Miner. Res. 17 (12) (2002) 2281–2289. 25. P. Kannus, H. Haapasalo, M. Sankelo, et al., Effect of starting age of physical activity on bone mass in the dominant arm of tennis and squash players, Ann. Intern. Med. 123 (1) (1995) 27–31. 26. S.L. Bass, L. Saxon, R.M. Daly, et al., The effect of mechanical loading on the size and shape of bone in pre-, peri-, and postpubertal girls: a study in tennis players, J. Bone Miner. Res. 17 (12) (2002) 2274–2280. 27. S. Bass, G. Pearce, M. Bradney, et al., Exercise before puberty may confer residual benefits in bone density in adulthood: studies in active prepubertal and retired female gymnasts, J. Bone Miner. Res. 13 (3) (1998) 500–507. 28. S. Kontulainen, P. Kannus, H. Haapasalo, et al., Changes in bone mineral content with decreased training in competitive young adult tennis players and controls: a prospective 4-yr follow-up, Med. Sci. Sports Exerc. 31 (5) (1999) 646–652. 29. R.P. Main, A.A. Biewener, Ontogenetic patterns of limb loading, in vivo bone strains and growth in the goat radius, J. Exp. Biol. 207 (Pt 15) (2004) 2577–2588. 30. A.A. Biewener, J.E. Bertram, Structural response of growing bone to exercise and disuse, J. Appl. Physiol. 76 (2) (1994) 946–955. 31. Q. Wang, M. Alen, S. Cheng, E. Seeman, Bone structural diversity in adulthood is established before puberty, J. Clin. Endocrinol. Metab. (2009) (In press). 32. S.M. Garn, R.L. Miller, K.E. Larson, Metacarpal lengths, cortical diameters and areas from 10-state nutrition survey, Center for Human Growth and Development, University of Michigan, 1976. 33. J.M. Tanner, P.C. Hughes, R.H. Whitehouse, Radiographically determined widths of bone muscle and fat in the upper arm and calf from age 3–18 years, Ann. Hum. Biol. 8 (6) (1981) 495–517. 34. K. Kimura, Growth of the second metacarpal according to chronological age and skeletal maturation, Anat. Rec. 184 (2) (1976) 147–157. 35. E.R. Cadet, R.I. Gafni, E.F. McCarthy, et al., Mechanisms responsible for longitudinal growth of the cortex: coalescence of trabecular bone into cortical bone, J. Bone Joint Surg. 85A (9) (2003) 1739–1748. 36. A.M. Parfitt, The two faces of growth: benefits and risks to bone integrity, Osteoporos. Int. 4 (6) (1994) 382–398.
92
Osteoporosis in Men
37. S. Kirmani, D. Christen, G.H. van Lenthe, et al., Microfinite element modeling reveals that transient deficits in cortical bone may underlie the adolescent peak in forearm fracture, J. Bone Miner. Res. 23 (Suppl.) (2008) S51. 38. F. Rauch, E. Schoenau, Peripheral quantitative computed tomography of the distal radius in young subjects – new reference data and interpretation of results, J. Musculoskelet. Neuron Interact. 5 (2) (2005) 119–126. 39. L.J. Moyer-Mileur, J.L. Quick, M.A. Murray, Peripheral quantitative computed tomography of the tibia: pediatric reference values, J. Clin. Densitom. 11 (2) (2008) 283–294. 40. S. Byers, A.J. Moore, R.W. Byard, N.L. Fazzalari, Quantitative histomorphometric analysis of the human growth plate from birth to adolescence, Bone 27 (4) (2000) 495–501. 41. S. Khosla, B.L. Riggs, E.J. Atkinson, et al., Effects of sex and age on bone microstructure at the ultradistal radius: a populationbased noninvasive in vivo assessment, J. Bone Miner. Res. 21 (1) (2006) 124–131. 42. Z.H. Han, S. Palnitkar, D.S. Rao, D. Nelson, A.M. Parfitt, Effect of ethnicity and age or menopause on the structure and geometry of iliac bone, J. Bone Miner. Res. 11 (12) (1996) 1967–1975. 43. A.B. Schultz, S.E. Sorensen, G.B. Andersson, Measurement of spine morphology in children, ages 10–16, Spine 9 (1) (1984) 70–73. 44. A.G. Veldhuizen, P. Baas, P.J. Webb, Observations on the growth of the adolescent spine, J. Bone Joint Surg. 68B (5) (1986) 724–728. 45. M. Zatorska, Values of somatic traits and of body proportion indices in male and female newborns of Lublin, Stud. Hum. Ecol. 10 (1992) 75–82. 46. H. Greil, Ontogenetic aspects of dimensions and proportions in sitting posture, Coll. Antropol. 21 (2) (1997) 367–386. 47. N. Emaus, G.K. Berntsen, R. Joakimsen, V. Fonnebo, Longitudinal changes in forearm bone mineral density in women and men aged 45–84 years: the Tromso Study, a populationbased study, Am. J. Epidemiol. 163 (5) (2006) 441–449. 48. N. Emaus, G.K. Berntsen, R.M. Joakimsen, V. Fonnebo, Longitudinal changes in forearm bone mineral density in women and men aged 25–44 years: the Tromso study: a populationbased study, Am. J. Epidemiol. 162 (7) (2005) 633–643. 49. H.G. Ahlborg, O. Johnell, C.H. Turner, G. Rannevik, M.K. Karlsson, Bone loss and bone size after menopause, N. Engl. J. Med. 349 (4) (2003) 327–334. 50. M.L. Loro, J. Sayre, T.F. Roe, M.I. Goran, F.R. Kaufman, V. Gilsanz, Early identification of children predisposed to low peak bone mass and osteoporosis later in life, J. Clin. Endocrinol. Metab. 85 (10) (2000) 3908–3918. 51. C. Ruff, Growth tracking of femoral and humeral strength from infancy through late adolescence, Acta Paediatr. 94 (8) (2005) 1030–1037. 52. S. Cheng, Q. Wang, A. Lyytikainen, et al., Peak bone mass is determined at 1 year-old: evidence from growth charts, J. Bone Miner. Res. 23 (Suppl.) (2008) S131. 53. E. Seeman, J.L. Hopper, N.R. Young, C. Formica, P. Goss, C. Tsalamandris, Do genetic factors explain associations between muscle strength, lean mass, and bone density? A twin study, Am. J. Physiol. 270 (2 Pt 1) (1996) E320–E327. 54. D.R. Carter, T.E. Orr, D.P. Fyhrie, D.J. Schurman, Influences of mechanical stress on prenatal and postnatal skeletal development, Clin. Orthop. Relat. Res. 219 (1987) 237–250.
55. M. Wong, D.R. Carter, A theoretical model of endochondral ossification and bone architectural construction in long bone ontogeny, Anat. Embryol. (Berl.) 181 (6) (1990) 523–532. 56. Z.A. Ralis, H.M. Ralis, M. Randall, G. Watkins, P.D. Blake, Changes in shape, ossification and quality of bones in children with spina bifida, Dev. Med. Child Neurol. Suppl. 37 (1976) 29–41. 57. J.I. Rodriguez, A. Garcia-Alix, J. Palacios, R. Paniagua, Changes in the long bones due to fetal immobility caused by neuromuscular disease. A radiographic and histological study, J. Bone Joint Surg. 70 (7) (1988) 1052–1060. 58. C.M. Modlesky, P. Subramanian, F. Miller, Underdeveloped trabecular bone microarchitecture is detected in children with cerebral palsy using high-resolution magnetic resonance imaging, Osteoporos. Int. 19 (2) (2008) 169–176. 59. C. Ruff, Ontogenetic adaptation to bipedalism: age changes in femoral to humeral length and strength proportions in humans, with a comparison to baboons, J. Hum. Evol. 45 (4) (2003) 317–349. 60. M. Harris, T.V. Nguyen, G.M. Howard, P.J. Kelly, J.A. Eisman, Genetic and environmental correlations between bone formation and bone mineral density: a twin study, Bone 22 (2) (1998) 141–145. 61. P. Szulc, P. Garnero, F. Marchand, F. Duboeuf, P.D. Delmas, Biochemical markers of bone formation reflect endosteal bone loss in elderly men – MINOS study, Bone 36 (1) (2005) 13–21. 62. C.W. Slemenda, M. Peacock, S. Hui, L. Zhou, C.C. Johnston, Reduced rates of skeletal remodeling are associated with increased bone mineral density during the development of peak skeletal mass, J. Bone Miner. Res. 12 (4) (1997) 676–682. 63. S. Mora, P. Pitukcheewanont, F.R. Kaufman, J.C. Nelson, V. Gilsanz, Biochemical markers of bone turnover and the volume and the density of bone in children at different stages of sexual development, J. Bone Miner. Res. 14 (10) (1999) 1664–1671. 64. C. Ohlsson, B.A. Bengtsson, O.G. Isaksson, T.T. Andreassen, M.C. Slootweg, Growth hormone and bone, Endoc. Rev. 19 (1) (1998) 55–79. 65. J.P. Liu, J. Baker, A.S. Perkins, E.J. Robertson, A. Efstratiadis, Mice carrying null mutations of the genes encoding insulinlike growth factor I (Igf-1) and type 1 IGF receptor (Igf1r), Cell 75 (1) (1993) 59–72. 66. K.A. Woods, C. Camacho-Hubner, M.O. Savage, A.J. Clark, Intrauterine growth retardation and postnatal growth failure associated with deletion of the insulin-like growth factor I gene, New Engl. J. Med. 335 (18) (1996) 1363–1367. 67. J.M. Wit, H. van Unen, Growth of infants with neonatal growth hormone deficiency, Arch. Dis. Child 67 (7) (1992) 920–924. 68. J. Baker, J.P. Liu, E.J. Robertson, A. Efstratiadis, Role of insulin-like growth factors in embryonic and postnatal growth, Cell 75 (1) (1993) 73–82. 69. O. Nukada, T. Moriwake, S. Kanzaki, M. Katayama, J. Higuchi, H. Kimoto, Age-related changes in urinary growth hormone level and its clinical application, Act. Paediatr. Jpn. 32 (1) (1990) 32–38. 70. E.P. Smith, J. Boyd, G.R. Frank, et al., Estrogen resistance caused by a mutation in the estrogen-receptor gene in a man, N. Engl. J. Med. 331 (16) (1994) 1056–1061.
C h a p t e r 7 Skeletal Growth in Males l
71. M. Zachmann, A. Prader, E.H. Sobel, et al., Pubertal growth in patients with androgen insensitivity: indirect evidence for the importance of estrogens in pubertal growth of girls, J Pediatr 108 (5 Pt 1) (1986) 694–697. 72. M. Simpson, W. Marx, H. Becks, H.M. Evans, Effect of testosterone propionate on the body weight and skeletal system of hypophysectomized rats. Synergism with pituitary growth hormone, Endocrinology 35 (1944) 309–316. 73. J.O. Jansson, S. Eden, O. Isaksson, Sites of action of testosterone and estradiol on longitudinal bone growth, Am. J. Physiol. 244 (2) (1983) E135–E140. 74. R.J. Borski, W. Tsai, R. DeMott-Friberg, A.L. Barkan, Regulation of somatic growth and the somatotropic axis by gonadal steroids: primary effect on insulin-like growth factor I gene expression and secretion, Endocrinology 137 (8) (1996) 3253–3259. 75. M. Phillip, T. Palese, E.R. Hernandez, C.T. Roberts Jr., D. LeRoith, A.A. Kowarski, Effect of testosterone on insulin-like growth factor-I (IGF-I) and IGF-I receptor gene expression in the hypophysectomized rat, Endocrinology 130 (5) (1992) 2865–2870. 76. B.C. van der Eerden, J. Emons, S. Ahmed, et al., Evidence for genomic and nongenomic actions of estrogen in growth plate regulation in female and male rats at the onset of sexual maturation, J. Endocrinol. 175 (2) (2002) 277–288. 77. A. Morishima, M.M. Grumbach, E.R. Simpson, C. Fisher, K. Qin, Aromatase deficiency in male and female siblings caused by a novel mutation and the physiological role of estrogens, J. Clin. Endocrinol. Metab. 80 (12) (1995) 3689–3698. 78. J.P. Bilezikian, A. Morishima, J. Bell, M.M. Grumbach, Increased bone mass as a result of estrogen therapy in a man with aromatase deficiency, N. Engl. J. Med. 339 (9) (1998) 599–603. 79. N. Mauras, L. Gonzalez de Pijem, H.Y. Hsiang, et al., Anastrozole increases predicted adult height of short adolescent males treated with growth hormone: a randomized, placebo-controlled, multicenter trial for one to three years, J. Clin. Endocrinol. Metab. 93 (3) (2008) 823–831. 80. W.B. Wehrenberg, A. Baird, S.Y. Ying, N. Ling, The effects of testosterone and estrogen on the pituitary growth hormone
81.
82.
83.
84.
85.
86.
87.
88.
89.
90.
93
response to growth hormone-releasing factor, Biol. Reprod. 32 (2) (1985) 369–375. M. Yan, M.E. Jones, M. Hernandez, D. Liu, E.R. Simpson, C. Chen, Functional modification of pituitary somatotropes in the aromatase knockout mouse and the effect of estrogen replacement, Endocrinology 145 (2) (2004) 604–612. Y. Tajima, S. Yokose, M. Kawasaki, T. Takuma, Ovariectomy causes cell proliferation and matrix synthesis in the growth plate cartilage of the adult rat, Histochem. J. 30 (7) (1998) 467–472. L.J. Murphy, H.G. Friesen, Differential effects of estrogen and growth hormone on uterine and hepatic insulin-like growth factor I gene expression in the ovariectomized hypophysectomized rat, Endocrinology 122 (1) (1988) 325–332. K. Venken, F. Schuit, L. Van Lommel, et al., Growth without growth hormone receptor: estradiol is a major growth hormone-independent regulator of hepatic IGF-I synthesis, J. Bone Miner. Res. 20 (12) (2005) 2138–2149. D. Peretianu, D. Grigorie, F. Popescu, J. Zaharescu, Bone scintigraphy in acromegaly. Preliminary report on cases, Endocrinologie 28 (3–4) (1990) 199–205. M. Cappa, C. Bizzarri, C. Martinez, et al., Neuroregulation of growth hormone during exercise in children, Int. J. Sports Med. 21 (Suppl.) (2000) S125–S128. W. Hogler, J. Briody, B. Moore, P.W. Lu, C.T. Cowell, Effect of growth hormone therapy and puberty on bone and body composition in children with idiopathic short stature and growth hormone deficiency, Bone 37 (5) (2005) 642–650. N. Bravenboer, P. Holzmann, H. de Boer, J.C. Roos, E.A. van der Veen, P. Lips, The effect of growth hormone (GH) on histomorphometric indices of bone structure and bone turnover in GH-deficient men, J. Clin. Endocrinol. Metab. 82 (6) (1997) 1818–1822. P. Tothill, D.W. Pye, Errors due to non-uniform distribution of fat in dual X-ray absorptiometry of the lumbar spine, Br. J. Radiol. 65 (777) (1992) 807–813. M. Bolanowski, W. Wielgus, A. Milewicz, R. Marciniak, Axial bone mineral density in patients with acromegaly, Acad. Radiol. 7 (8) (2000) 592–594.
Chapter
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Pubertal Growth of the Male Skeleton Stefano Mora1,2 and Vicente Gilsanz3,4 1
Departments of Radiology and Pediatrics, Children’s Hospital Los Angeles, Los Angeles, California, USA Laboratory of Pediatrics Endocrinology, BoNetwork, San Raffaele Scientific Institute, Milan, Italy 3 Children’s Imaging Research Program, Children’s Hospital Los Angeles, Los Angeles, California, USA 4 University of Southern California, Los Angeles, California, USA 2
Introduction
and physeal plates of bone to define their proximity to full maturity. Assessments of skeletal maturation are frequently used as a diagnostic tool to evaluate clinical conditions associated with generalized growth abnormalities, to monitor response to medical treatment and to determine the growth potential of children. Although measures of skeletal maturation are often confused with measures of skeletal growth, growth and maturation reflect different processes; growth represents a quantitative increase in size or mass, while maturation is a sequence of changes that lead to a highly organized, specialized and mature state. Skeletal maturation is a temporal process only loosely linked to chronological age and, while expressed in years and months, there is no constant relationship between bone and chronological age. Moreover, skeletal maturation is only related to bone size in very general terms. Indeed, children with the same bone age may have very divergent bone dimensions and chronological age associated to full skeletal maturity varies greatly among subjects. There are several methods to assess skeletal maturity, but the most commonly used in clinical practice is the atlasbased technique of Greulich and Pyle [2], followed by the Tanner–Whitehouse bone-specific scoring technique [3] and the Fels method [4]. All use left hand and wrist radiographs to estimate a bone age, but the former differs in concept and method from the latter two. The Greulich-Pyle atlas is founded on the assumption that the skeleton matures in a uniform fashion and is based on a reference collection of radiographs from normal Caucasian children of high socioeconomic status at different chronological ages [2]. With the advent of digital imaging, multiple attempts have been made to develop image-processing techniques that automatically extract the key morphological features of ossification in the bones to provide a more effective and scientific approach to skeletal maturity assessments. However, the design of computer
Puberty encompasses major physical, emotional and psychological events that guide the transition from childhood to adulthood. It is a highly variable period influenced by many genetic, hormonal, nutritional, environmental and socioeconomic factors [1]. The pubertal process includes major changes in sexual development and body composition and is the time of greatest postnatal growth after infancy stages. These changes are regulated by the interaction of several organs in the hypothalamic–pituitary end organs axis for growth hormone (GH) and insulin-like growth factor-I (IGF-I) and in the hypothalamic–pituitary–gonadal axis for gonadotropins and sex hormones. At puberty, a yet undefined set of signals promotes the pulsatile release of gonadotropin releasing hormone (GnRH) by the hypothalamus. The increase in GnRH results in the production of luteinizing hormone (LH) and follicle stimulating hormone (FSH) by the pituitary gland and increased sex steroids by the gonads. Meanwhile, the coordinated secretion of GH releasing hormone (GHRH) and somatostatin from the hypothalamus promotes the increased release of GH by the pituitary gland. GH acts on local tissues to produce IGF-I which, in conjunction with sex steroids, induces the pubertal growth spurt. Boys achieve peak velocity, at about 9 cm per year, between 13 and 14 years of age. The later onset and longer duration of the growth spurt and the higher values for peak velocity in boys, when compared with girls, results in adult males being taller than adult females at skeletal maturity, which is achieved soon after sexual development.
Skeletal maturation Skeletal maturity is a measure of development incorporating the size, shape and degree of mineralization of the epiphyses
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algorithms capable of automatically rendering bone age has been impeded by the complexity of evaluating the wide variations in bone mineralization tempo, shape and size encompassed in the large number of ossification centers in the hand and wrist. Recently, these obstacles were circumvented through the selection of an alternative approach: the creation of artificial, idealized, sex- and age-specific images of skeletal development. The models were generated through rigorous analyses of the maturation of each ossification center in the hands and wrists of healthy children and the construction of virtual images that incorporate composites of the average development for each ossification center in each age group [5]. As an alternative to atlas-based techniques, other methods were developed that independently assess the maturation of each bone. The result of such a system would provide maturity standards for each bone considered. A diffuse method based on these principles was conceived by Tanner and Whitehouse and named TW after their initials. The original system (TW1) was refined and published as TW2 and, recently, as TW3 [3]. They defined a series of eight maturity indicators for each bone of the hand and wrist and nine for the radius. These maturity indicators were then evaluated not in relation to chronological age, but in relation to their appearance within the full passage of each specific bone from immaturity to maturity. The Fels method is less frequently used and differs in the chronological ages at which assessments are possible, maturity indicators and the scale of maturity [4]. These methods for assessment of skeletal maturity are difficult to compare. A small study found that the method of Greulich and Pyle was as reproducible as the TW2 method [6]. In contrast, another study assessed 362 bone ages by the same methods and concluded that they do not give equivalent bone age estimates and that the TW2 method was more reproducible. A more recent study compared the atlas-based and bone-specific techniques using a large sample of children aged 2 to 15 years [7]. The study demonstrated that bone age was closer to chronological age using the Fels method and that the greatest difference was observed using the Greulich-Pyle method, both in boys and girls. Another issue pertains to the use of images and standards derived from populations of a specific socioeconomic and ethnic background to assess skeletal maturity of children of different origins or race. Indeed, ample data indicate significant variations in the tempo of skeletal maturity in children of different ethnic, social and economic backgrounds. The appropriateness of the old standards has been questioned [8, 9] and the need for specific standards not only for contemporary children, but also for different populations or ethnic groups within a specific geographical region became imperative for an accurate assessment of skeletal maturity. Are skeletal and pubertal maturations related events? In many pathological conditions, there is a clear association between the rate of skeletal maturation and the pubertal
stage of development. Conditions that delay skeletal maturation are associated with a postponed onset of puberty [10], while conditions that accelerate skeletal maturation advance the onset of pubertal development [10]. This synchrony between different maturational processes has suggested the concept of ‘tempo’ to refer to the whole process of maturation [11]. This concept has been challenged by the observation that the concordance between skeletal maturation and hypothalamic–pituitary–gonadal axis was not present in normal children. A recent study tried to assess whether the age at onset of puberty correlates with skeletal maturation in healthy boys, as it does in boys with abnormal maturational tempo [12]. The data showed a lack of correlation between skeletal age and chronological age at onset of puberty. This finding seems thus to contradict the notion that skeletal maturation governs the onset of puberty. Taken together, all available data seem to indicate that several diverse factors (nutritional, genetic, endocrine) may intervene in regulating skeletal and pubertal maturation. However, while they promote synchrony between maturational processes, whenever there is a perturbation of development tempo, they appear to act independently in normal physiological conditions. Further studies are needed to elucidate the mechanisms that promote concordance between growth, bone age and puberty in some cases, but not in normal boys. Females, at any age, have advanced bone age when compared with boys. The difference is present at birth and persists throughout growth, although it is slightly more pronounced after the onset of puberty [2, 8]. Moreover, the skeletal maturation process lasts longer in boys than in girls. The reasons for these gender discrepancies in skeletal maturity remain unknown. However, the description of the estrogen receptor- and - [13] and the recently reported estrogen receptor GRP30 expression [14] in human chondrocytes support the possible role of estrogen in regulating skeletal maturation in girls. The role of estrogen in girls’ skeletal maturation has been provided by a model in which patients with XY genotype carried disruptive mutations in the androgen receptor gene (AIS) and, consequently, a complete resistance to endogenous androgen, leaving estrogen the only functional sex steroid [15]. From the normal pubertal growth in individuals with complete AIS, it is clear that estrogen alone is sufficient to support normal pubertal skeletal growth. In contrast, androgen alone is not sufficient to grant a normal skeletal development, as characterized by a girl with aromatase deficiency [16].
Bone measurement techniques in children The development of precise non-invasive methods for measuring bone mineral content has significantly improved our
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ability to study the influence of genetic and environmental factors on the attainment of bone. These techniques have not only helped to quantify the loss of bone associated with the various disorders that cause osteopenia in children, but have also improved our understanding of the childhood antecedents of a condition that happens to manifest in adults – osteoporosis. Dual-energy x-ray absorptiometry (DXA) is, by far, the most widely used technique for measuring bone acquisition in children due to its low cost, minimal radiation exposure, accessibility and ease of use. The availability of DXA has resulted in many large-scale studies of the genetic and environmental determinants of areal bone mineral density (aBMD) in healthy children. Although DXA studies in pediatrics have provided much information regarding changes in aBMD over time, there is still considerable confusion over the interpretation of DXA measures. Most growth-related increases in DXA aBMD values are due to increases in the size, rather than the density, of the bone and gender differences in aBMD values are also largely due to greater bone size in males [17]. The confounding effect of skeletal geometry on DXA measures is gaining much recognition. Recently, it was suggested that major errors in interpretation occur when using this technique in pediatric populations, leading to the overdiagnosis of osteoporosis in growing subjects. Indeed, several investigators have proposed that osteoporosis should not be diagnosed based on DXA densitometry criteria alone [18, 19]. In addition, while, in adults, DXA aBMD is a powerful predictor of fracture and is used to define osteoporosis, there is insufficient pediatric evidence to determine aBMD standard deviation (SD) criteria for osteopenia and osteoporosis as indicated by the World Health Organization (WHO). Hence, it is recommended that, when reporting DXA results in subjects under 20 years of age, it is more appropriate to define a Zscore of less than 2.0 as low bone density, rather than using the WHO classification for osteoporosis [18]. Attempts to overcome this disadvantage with the use of correction factors; i.e. the squared root of the projected area, the height of the subject, the width of the bone, assuming the cross-sectional area of the vertebrae is a cube, a cylinder with a circular base or a cylinder with an elliptic base area [20], etc., are subject to error, as there is no closed formula that defines the size of the vertebrae. Similarly, formulas have been proposed for the femur and the mid-radius, which are also prone to error, especially during growth when there are changes in the size, as well as the shape, of the bone [20]. In a recent study, vertebral bone density was measured using both DXA and computed tomography (CT) in 400 children (100 each, healthy and sick boys and girls) [21]. The results indicated that DXA measures of aBMD underestimate bone accretion in children and adolescents. On average, three times as many subjects were determined to
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have low bone density (Z-score 2.0 for chronological age) by DXA than by CT; this was true for both healthy (2% versus 7%) and sick (10.5% versus 31%) children. While DXA and CT Z-scores were related, almost 50% of the variability remained even after age and anthropometric measures were taken into account. Hence, many children are identified as having low bone density by DXA, but not by CT. In contrast, quantitative CT (QCT) using conventional CT scanners or peripheral QCT (pQCT) scanners provides three-dimensional images, allowing for volumetric density measures, an evaluation of bone morphology and an independent assessment of trabecular and cortical bone. Because of its porosity and large surface area, trabecular bone has greater turnover and is a better indicator of bone remodeling than cortical bone. Trabecular bone density determinations by pQCT are commonly obtained by a single scan at a relative location, such as 4 or 8% length of the radius or tibia [22, 23], or a fixed location, such as 10 mm from the end of the growth plate [24]. Whereas available data indicate that the short-term reproducibility of these measurements is excellent [20], positioning is critical and, due to the variability of trabecular bone density throughout the metaphysis, any offset in the location to be scanned would significantly influence the values obtained [25]. Additionally, the large range of metaphyseal morphology among subjects, diseases and ages limits comparative cross-sectional studies and interpretation of the same scan location in longitudinal examinations. Previous studies using pQCT in children have investigated the effects of age or maturity related growth, gender differences, physical activity, disease, geometry and strength [22, 23, 26–28]. These studies used a variety of methods, such as measurements at 4 or 10% length of the radius or tibia or at a fixed length 10 mm distal to the growth plate. More recent studies, using high-resolution pQCT, have scanned 9-mm-thick sections of long bones to assess trabecular microarchitecture [29]. The results of a recent study highlight the limitations of current pQCT methodology using single scans as outcome measures in cross-sectional and longitudinal studies assessing trabecular bone density and highlight the need for developing pQCT acquisition techniques that provide more reproducible determinations in the appendicular skeleton of children [30]. The significant variability in metaphyseal morphology, length of the metaphysis, overall trabecular mean density and gradient in trabecular bone density from the physeal plate to the shaft of the bone among growing subjects account for the large intra- and inter-subject variability in bone density measures. Subjects in this study showed a substantial range of variability from a 1-mm offset slice positioning with an average of 6.9 mg/cm3 or 16.8%. In addition, longitudinal assessments showed that the slopes of the density curve drastically changed in some children, even over a short period of 6 months.
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Skeletal changes during puberty Longitudinal Growth Skeletal size and shape change dramatically during the pubertal period due to genetic, hormonal and mechanical influences. Bone growth involves changes in length and width by means of longitudinal bone formation and periosteal bone formation versus endosteal bone resorption, respectively. Longitudinal bone growth occurs through the addition of cartilage tissue to the growth plates at the proximal and distal ends of the long bones and vertebrae [31]. The growth plate consists of three distinct cellular layers: the resting zone; the proliferative zone; and the hypertrophic zone [32]. The resting and proliferative zones consist of chondrocytes arranged in columns parallel to the long axis of the bone. Chondrocytes replicate repeatedly in the proliferative zone. However, chondrocytes located in the farthest part from the epiphysis cease dividing and enlarge to become hypertrophic cells. Throughout the growth plate, chondrocytes synthesize and secrete cartilage matrix. The hypertrophic zone is invaded by osteoclasts and differentiating osteoblasts, coming from the adjacent metaphyseal bone, that transform the cartilage into bone tissue [31, 32]. Therefore, new bone is formed progressively at the bottom of the growth plate, resulting in bone elongation. Recent evidence indicates that the resting zone contains unipotent, chondrogenic stem-like cells that are able to generate new columnar proliferative and hypertrophic chondrocytes [33]. The major systemic hormones that regulate longitudinal bone growth during childhood are GH and IGF-I, thyroid hormones and glucocorticoids and, during puberty, sex steroids. For decades, it was accepted that estrogen, in girls, and androgen, in boys, were the primary sex steroids regulating pubertal growth. This vision has been radically changed recently and now it is clear that both androgen and estrogen play an important role in regulating boys’ longitudinal growth (see Chapter 9 for a comprehensive review).
Bone Density Bone mass increases throughout childhood and adolescence and reaches its peak shortly after sexual and skeletal maturity. The greater bone mass in men than women has been documented by means of neutron activation analysis, measurement of the calcium content of selected regions of the skeleton and the techniques of radiogrammetry and absorptiometry [34–36]. Of the two components of bone mass, bone density and bone size, the latter is responsible for the gender differences in bone mass. Neither CT measures of the tissue density of cancellous bone (a reflection of the size and number of trabeculae),
nor CT values for the material density of bone (a reflection of its degree of mineralization) differ substantially between men and women [37, 38]. Differences in morphology of cancellous and cortical bone must be considered for the appropriate interpretation of bone density data. Cancellous bone exists as a three-dimensional lattice of plates and columns (trabeculae). The trabeculae divide interior volume of the bone into intercommunicating pores, which are filled with a variable mixture of red and yellow marrow. Because of the relatively small size of trabeculae when compared to the pixel, the CT unit of measurement, values for cancellous bone density reflect not only the amount of mineralized bone and osteoid, but also the amount of marrow per pixel [39]. Similar limitations apply to in vitro determinations of the volumetric density of trabecular bone which are obtained by washing the marrow from the pores of a specimen of cancellous bone, weighing it and dividing the weight by the volume of the specimen, including the pores. Bone density determinations of cancellous bone are, therefore, directly proportional to the bone volume fraction and inversely proportional to the porosity of the bone. The relatively large coefficient of variation for values of cancellous bone density reflects the considerable variation in the dimensions of the pores throughout the vertebral body. In contrast, in young subjects with non-porous bone, measurements of cortical bone density reflect the material density of bone and are primarily based on the degree of mineralization if the cortex is sufficiently thick to circumvent volume averaging errors [40]. These measurements are analogous to in vitro determinations of the intrinsic material density of bone, which are commonly expressed as the ash weight per unit volume of bone. On average, values for cortical bone density are eight times higher than those for cancellous bone density, a finding consistent with histomorphometric studies indicating an equivalent difference in the porosity of these two forms of a structural organization of bone tissue. Otherwise, cancellous bone can be viewed as a porous structure comprised of bone tissue with the same mechanical properties and composition as cortical bone [41]. Regardless of gender, the tissue density of cancellous bone increases during puberty (Figure 8.1). Although the factors that account for the increase in cancellous bone density remain to be determined, it is reasonable to suspect that they are, in part, mediated by the actions of sex steroids. It should be stressed that neither before nor after completion of puberty does cancellous bone density (CBD) differ in men and women and that the small gender differences in the temporal sequence of CBD likely reflect gender differences in the appearance of sexual characteristics and the accelerated growth spurt. While, for both sexes, growth acceleration begins in early adolescence, typically, peak growth velocity in boys is reached 2 to 3 years later and boys continue growing for approximately 2 to 3 years longer than girls [42] (see Figure 8.1). Interestingly, the
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Figure 8.1 Mean and standard deviations of vertebral cancellous bone density (CBD) in males and females. CBD increases and reached peak values earlier in females than in males.
d ifferences between males and females in the commencement of increases in CBD parallel the differences in the tempo of peak height velocities.
Bone Size Gender differences in bone mass are a result of differences in bone size that evolve during growth [38, 43]. Several reports indicate that, throughout childhood and adolescence, girls have smaller vertebral body dimensions compared to boys of similar age, degree of sexual development and anthropometric measures [17, 43, 44]. On average, the cross-sectional area of the vertebral bodies is 11% smaller in prepubertal girls than in prepubertal boys matched for age, height and weight [17, 43]. While it is commonly believed that sex differences in skeletal morphology and physiology occur at or around puberty [45], this notion is challenged by the finding of sex differences in bone size prior to the pubertal period [46, 47]. The gender disparity increases with growth and is greatest at skeletal maturity, when the cross-sectional dimensions of the vertebrae are about 25% smaller in women than in men, even after taking into consideration differences in body size [38]. The smaller vertebral size is probably key to the four- to sevenfold higher incidence of vertebral fractures in elderly women, as compared to men [48]. Vertebral size has been demonstrated to be an important determinant of vertebral fractures in elderly women with osteoporosis. A small vertebral body imparts a mechanical disadvantage that increases
the stress within the spine and becomes increasingly important as bone density declines with age [49]. In the appendicular skeleton, cross-sectional growth is primarily related to body weight. Some reports indicate that the cross-sectional and cortical bone areas of the femoral shaft do not differ between males and females matched for age, height and weight [17], a notion consistent with analytical models proposing that long bone cross-sectional growth is strongly driven by mechanical loads [50]. In contrast, other studies suggest that boys have larger femur cross-sectional area and cortical bone area than girls, measured both with QCT and magnetic resonance imaging [51] and that the total bone cross-sectional area and the cortical area measured at the tibial midshaft by pQCT are greater in boys than in girls during puberty [27]. Even in the appendicular skeleton, larger bone dimensions confer a greater mechanical resistance to stress, thus reducing fracture risk in males. The greater male bone size primarily results from enhanced periosteal bone formation, affected by both androgen and estrogen [52]. Periosteal bone formation is significantly reduced following androgen deficiency in growing male rats, while it is increased in estrogen-deficient female rats leading to the traditional view of stimulatory androgens in males versus inhibitory estrogens in females on periosteal growth [53]. The role of estrogen and androgen in the regulation of bone accretion is review in Chapter 9. The available data indicate that periosteal bone formation in males may not be solely dependent on androgen action, but also, at least in part, on estrogen action [54].
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Peak bone mass The amount of bone in the skeleton, at any age, is the result of the amount of bone gained during growth, from uterine life to skeletal maturity, and the loss of bone that occurs with aging. Bone acquisition during adolescence is the main contributor to peak bone mass (PBM) which, in turn, is a major determinant of osteoporosis and fractures in the elderly, most commonly in the vertebrae [55]. Because current treatment for osteoporosis in elderly subjects does not significantly restore loss of bone, efforts are being directed toward developing preventive measures that increase bone mass before it reaches its peak. Because of difficulties in longitudinally studying subjects from childhood to an elderly age, the contention that senile osteoporosis is the result of inadequate bone acquisition during growth remains unproven. This notion is supported, however, by data showing that there is a strong resemblance between mother–daughter bone traits and that this resemblance is present even before the daughters have begun puberty [56, 57]. Additional support for this concept comes from the knowledge that genes associated with the normal variations in bone mass in elderly women are also related to variations in bone density in children [58–60]. If bone loss were the exclusive determinant of late life bone mass, one would not expect such a strong resemblance in bone traits between girls and their mothers or an association between candidate genes and bone mass to be depicted in childhood. Data from previous investigations showing strong correlations between yearly bone mass measurements in prepubertal girls, suggest that bone traits can be tracked during growth [56]. Thus, the genetic control of bone phenotypes associated with fragility fractures in the elderly appears to be expressed very early in life and is tightly maintained throughout childhood and adolescence. The time of life in which PBM is attained has been the subject of considerable controversy, with estimates for the axial skeleton ranging from soon after the completion of sexual and skeletal maturity at the end of the 2nd decade to the 5th decade of life. Most, but not all, indicate that bone mass does not significantly increase after the third decade [61]. However, DXA bone values are influenced by changes in body size and soft tissue composition around the bone measured [62, 63], which may account for the conflicting results of previous studies. Moreover, it is likely that the timing of peak values differs between the axial and appendicular skeletons. Bone mass achieves peak values by the end of the second decade of life. Studies in women using CT have demonstrated that the density and the size of vertebral bone reach their peak soon after the time of sexual and skeletal maturity [38, 43, 64], corroborating anatomical data indicating trabecular bone loss as early as the third decade of life and no change in the cross-sectional area of the
vertebral body from 15 to 90 years of age [37, 65, 66]. The results of a recent study in the axial skeleton indicate that CT values for vertebral bone mineral content and bone density reach their peak around the time of sexual maturity and cessation of longitudinal growth. In contrast, DXA values for vertebral bone mineral content and bone mineral density continued to increase beyond sexual and skeletal maturity (Figure 8.2). The data regarding whether vertebral size in men continues to grow after cessation of longitudinal growth is controversial; while some investigators find no change in the cross-sectional areas of the vertebral bodies after skeletal maturity, others have suggested that vertebral cross-sectional area increases with age throughout adulthood [37, 67]. In the appendicular skeleton, the range of ages published in cross-sectional studies for the timing of PBM has varied significantly, from 17–18 years of age to as late as 35 years of age [68, 69]. Longitudinal DXA studies indicate that the rate of increase in skeletal mass slows markedly in late adolescence and that peak values in the femoral neck, like those in the spine, are achieved near the end of puberty in normal females [70–72]. It should, however, be stressed that, in both men and women, the cross-sectional dimensions of the long bones in the appendicular skeleton continue to grow throughout adulthood and into old age by subperiosteal bone apposition. This increase in bone width occurs in all sample populations studied [73].
Conclusion The main areas of progress in osteoporosis research during the last decade have been the general recognition that this condition, which is the cause of so much pain in the elderly, has its roots in childhood and the identification of the structural basis accounting for much of the variations in bone strength among humans. Considerable progress has been made in elucidating the basis for the gender differences in bone strength and the greater incidence of fragility fractures in elderly women when compared to men. Available data indicate that there is very little difference in measures of cancellous bone density in the vertebral body between sexes. In contrast, females have a smaller vertebral cross-sectional area when compared with males, even after accounting for differences in body size; a gender difference that becomes most apparent after puberty. Hence, vertebral fractures are likely more common in women than in men because women have smaller vertebrae. Although at present, the reasons for the reported gender differences in the incidence of hip fractures have yet to be clearly defined, it is tempting to think that complete phenotypic characteristics responsible for variations in femoral strength will be soon delineated. Such knowledge will provide a more rational way to identify those subjects prone to develop
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Figure 8.2 Box and whisker plots of CT cancellous bone density (BD) and bone mineral content (BMC) of the third lumbar vertebra (A) and DXA values for bone mineral density (BMD) and BMC (B) showing no changes between baseline and follow-up values by CT, but highly significant changes when using DXA.
fractures and towards whom osteoporosis prevention trials should be geared.
References 1. D.S. Rosen, Physiologic growth and development during adolescence, Pediatr. Rev. 25 (6) (2004) 194–200. 2. W.W. Greulich, SI. Pyle, Radiographic Atlas of Skeletal Development of the Hand and Wrist, second ed., Stanford University Press, California, 1959. 3. J.M. Tanner, M.J.R. Healy, H. Goldstein, N. Cameron, Assessment of Skeletal Maturity and Prediction of Adult Height (TW3 method), third ed., Academic Press, London, 2001. 4. A.F. Roche, W.C. Chumlea, D. Thissen, Assessing the Skeletal Maturity of the Hand-Wrist: Fels Method, Thomas, Springfield, IL, 1988. 5. V. Gilsanz, O. Ratib, Hand Bone Age: A Digital Atlas of Skeletal Maturity, Springer Verlag, Berlin, 2005. 6. D.G. King, D.M. Steventon, M.P. O’Sullivan, et al., Reproducibility of bone ages when performed by radiology registrars: an audit of Tanner and Whitehouse II versus Greulich and Pyle methods, Br. J. Radiol. 67 (1994) 848–851.
7. G. Aicardi, M. Vignolo, S. Milani, A. Naselli, P. Magliano, P. Garzia, Assessment of skeletal maturity of the hand-wrist and knee: a comparison among methods, Am. J. Hum. Biol. 12 (5) (2000) 610–615. 8. S. Mora, M.I. Boechat, E. Pietka, H.K. Huang, V. Gilsanz, Skeletal age determinations in American children of European and African descent: applicability of the Greulich and Pyle standards, Pediatr. Res. 50 (2001) 624–628. 9. S.Y. Zhang, L.J. Liu, Z.L. Wu, et al., Standards of TW3 skeletal maturity for Chinese children, Ann. Hum. Biol. 35 (3) (2008) 349–354. 10. A. Flor-Cisneros, E.W. Leschek, D.P. Merke, et al., In boys with abnormal developmental tempo, maturation of the skeleton and the hypothalamic-pituitary-gonadal axis remains synchronous, J. Clin. Endocrinol. Metab. 89 (1) (2004) 236–241. 11. JM. Tanner, Issues and advances in adolescent growth and development, J. Adolesc. Health Care 8 (6) (1987) 470–478. 12. A. Flor-Cisneros, J.N. Roemmich, A.D. Rogol, J. Baron, Bone age and onset of puberty in normal boys, Mol. Cell Endocrinol. 254–255 (2006) 202–206. 13. S. Bord, A. Horner, S. Beavan, J. Compston, Estrogen receptors alpha and beta are differentially expressed in developing human bone, J. Clin. Endocrinol. Metab. 86 (5) (2001) 2309–2314.
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14. A.S. Chagin, L. Savendahl, GPR30 estrogen receptor expression in the growth plate declines as puberty progresses, J. Clin. Endocrinol. Metab. 92 (12) (2007) 4873–4877. 15. T.R. Brown, D.B. Lubahn, E.M. Wilson, F.S. French, C.J. Migeon, JL. Corden, Functional characterization of naturally occurring mutant androgen receptors from subjects with complete androgen insensitivity, Mol. Endocrinol. 4 (12) (1990) 1759–1772. 16. F.A. Conte, M.M. Grumbach, Y. Ito, C.R. Fisher, ER. Simpson, A syndrome of female pseudohermaphrodism, hypergonadotropic hypogonadism, and multicystic ovaries associated with missense mutations in the gene encoding aromatase (P450arom), J. Clin. Endocrinol. Metab. 78 (6) (1994) 1287–1292. 17. V. Gilsanz, A. Kovanlikaya, G. Costin, T.F. Roe, J. Sayre, F. Kaufman, Differential effect of gender on the size of the bones in the axial and appendicular skeletons, J. Clin. Endocrinol. Metab. 82 (1997) 1603–1607. 18. The writing group for the ICSD position development conference diagnosis of osteoporosis in men, premenopausal women, and children. J. Clin. Densitom. 7 (1) (2004) 17–26. 19. R.I. Gafni, J. Baron, Overdiagnosis of osteoporosis in children due to misinterpretation of dual-energy x-ray absorptiometry (DEXA), J. Pediatr. 144 (2) (2004) 253–257. 20. S. Mora, L. Bachrach, V. Gilsanz, Non-invasive techniques for bone mass measurement, in: F. Glorieux, J. Pettifor, H. Jueppner (Eds.) Pediatric Bone: Biology and Diseases, Academic Press, San Diego, 2003, pp. 303–324. 21. T.A. Wren, X. Liu, P. Pitukcheewanont, V. Gilsanz, Bone densitometry in pediatric populations: discrepancies in the diagnosis of osteoporosis by DXA and CT, J. Pediatr. 146 (6) (2005) 776–779. 22. C.M. Neu, F. Manz, F. Rauch, A. Merkel, E. Schoenau, Bone densities and bone size at the distal radius in healthy children and adolescents: a study using peripheral quantitative computed tomography, Bone 28 (2) (2001) 227–232. 23. Q. Wang, M. Alen, P. Nicholson, et al., Growth patterns at distal radius and tibial shaft in pubertal girls: a 2-year longitudinal study, J. Bone Miner. Res. 20 (6) (2005) 954–961. 24. K.A. Ward, S.A. Roberts, J.E. Adams, M.Z. Mughal, Bone geometry and density in the skeleton of pre-pubertal gymnasts and school children, Bone 36 (6) (2005) 1012–1018. 25. F. Rauch, B. Tutlewski, O. Fricke, et al., Analysis of cancellous bone turnover by multiple slice analysis at distal radius: a study using peripheral quantitative computed tomography, J. Clin. Densitom. 4 (3) (2001) 257–262. 26. H.M. Macdonald, S.A. Kontulainen, K.J. Mackelvie-O’Brien, et al., Maturity- and sex-related changes in tibial bone geometry, strength and bone-muscle strength indices during growth: a 20-month pQCT study, Bone 36 (6) (2005) 1003–1011. 27. S.A. Kontulainen, H.M. Macdonald, K.M. Khan, HA. McKay, Examining bone surfaces across puberty: a 20-month pQCT trial, J. Bone Miner. Res. 20 (7) (2005) 1202–1207. 28. T. Binkley, J. Johnson, L. Vogel, H. Kecskemethy, R. Henderson, B. Specker, Bone measurements by peripheral quantitative computed tomography (pQCT) in children with cerebral palsy, J. Pediatr. 147 (6) (2005) 791–796. 29. J.A. MacNeil, SK. Boyd, Load distribution and the predictive power of morphological indices in the distal radius and tibia by high resolution peripheral quantitative computed tomography, Bone 41 (1) (2007) 129–137.
30. D.C. Lee, V. Gilsanz, TAL. Wren, Limitations of peripheral quantitative computed tomography metaphyseal bone density measurements, J. Clin. Endocrinol. Metab. 92 (2007) 4248–4253. 31. HM. Kronenberg, Developmental regulation of the growth plate, Nature 423 (6937) (2003) 332–336. 32. B.C. van der Eerden, M. Karperien, JM. Wit, Systemic and local regulation of the growth plate, Endocr. Rev. 24 (6) (2003) 782–801. 33. V. Abad, J.L. Meyers, M. Weise, et al., The role of the resting zone in growth plate chondrogenesis, Endocrinology 143 (5) (2002) 1851–1857. 34. M. Trotter, RR. Peterson, Weight of the skeleton during postnatal development, Am J Phys Anthropol 33 (1970) 313–324. 35. S.M. Garn, J.M. Nagy, ST. Sandusky, Differential sexual dimorphism in bone diameters of subjects of European and African ancestry, Am. J. Anthropol. 37 (1972) 127–130. 36. J.A. DePriester, T.J. Cole, NH. Bishop, Bone growth and mineralization in children aged 4 to 10 years, Bone Min. 12 (1991) 57–65. 37. L. Mosekilde, L. Mosekilde, Sex differences in age-related changes in vertebral body size, density and biomechanical competence in normal individuals., Bone 11 (2) (1990) 67–73. 38. V. Gilsanz, M.I. Boechat, R. Gilsanz, M.L. Loro, T.F. Roe, WG. Goodman, Gender differences in vertebral sizes in adults: biomechanical implications, Radiology 190 (1994) 678–682. 39. H.K. Genant, K. Engelke, T. Fuerst, et al., Noninvasive assessment of bone mineral and structure: state of the art, J. Bone Miner. Res. 11 (1996) 707–730. 40. T.N. Hangartner, V. Gilsanz, Evaluation of cortical bone by computed tomography, J. Bone Miner. Res. 11 (1996) 1518–1525. 41. J.K. Gong, J.S. Arnold, SH. Cohn, Composition of trabecular and cortical bone, Anat. Rec. 149 (1964) 325–331. 42. A.V. Marcell, Adolescence, in: R.M. Kliegman, H.B. Jenson, R.E. Behrman, B.F. Stanton (Eds.) Nelson Textbook of Pediatrics, eighteenth ed., Saunders Elsevier, Philidelphia, 2007, pp. 60–65. 43. V. Gilsanz, M.I. Boechat, T.F. Roe, M.L. Loro, J.W. Sayre, WG. Goodman, Gender differences in vertebral body sizes in children and adolescents., Radiology 190 (1994) 673–677. 44. V. Gilsanz, D.L. Skaggs, A. Kovanlikaya, et al., Differential effect of race on the axial and appendicular skeletons of children, J. Clin. Endocrinol. Metab. 83 (1998) 1420–1427. 45. S.P. Garnett, W. Hogler, B. Blades, et al., Relation between hormones and body composition, including bone, in prepubertal children, Am. J. Clin. Nutr. 80 (4) (2004) 966–972. 46. E.M. Clark, A.R. Ness, JH. Tobias, Gender differences in the ratio between humerus width and length are established prior to puberty, Osteoporos. Int. 18 (4) (2007) 463–470. 47. H. Hasselstrom, K.M. Karlsson, S.E. Hansen, V. Gronfeldt, K. Froberg, LB. Andersen, Sex differences in bone size and bone mineral density exist before puberty. The Copenhagen School Child Intervention Study (CoSCIS), Calcif. Tissue. Int. 79 (1) (2006) 7–14. 48. S.R. Cummings, J.L. Kelsey, N.C. Nevitt, KJ. O’Dowd, Epidemiology of osteoporosis and osteoporotic fractures, Epidemiol. Rev. 7 (1985) 178–208.
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49. V. Gilsanz, M.L. Loro, T.F. Roe, J. Sayre, R. Gilsanz, E. Schulz, Vertebral size in elderly women with osteoporosis: mechanical implications and relationship to fractures, J. Clin. Invest. 95 (1995) 2332–2337. 50. M.C.H. Van der Meulen, G.S. Beaupre, D.R. Carter, Mechanobiologic influences in long bone cross-sectional growth, Bone 14 (1993) 635–642. 51. W. Hogler, C.J. Blimkie, C.T. Cowell, et al., A comparison of bone geometry and cortical density at the mid-femur between prepuberty and young adulthood using magnetic resonance imaging, Bone 33 (5) (2003) 771–778. 52. E. Seeman, Clinical review 137: sexual dimorphism in skeletal size, density, and strength, J. Clin. Endocrinol. Metab. 86 (10) (2001) 4576–4584. 53. R.T. Turner, G.K. Wakley, KS. Hannon, Differential effects of androgens on cortical bone histomorphometry in gonadectomized male and female rats, J. Orthop. Res. 8 (4) (1990) 612–617. 54. V. Rochira, L. Zirilli, B. Madeo, et al., Skeletal effects of long-term estrogen and testosterone replacement treatment in a man with congenital aromatase deficiency: evidences of a priming effect of estrogen for sex steroids action on bone, Bone 40 (6) (2007) 1662–1668. 55. J.P. Bonjour, G. Theintz, F. Law, D. Slosman, R. Rizzoli, Peak bone mass, Osteoporos. Int. 4 (Suppl. 1) (1994) 7–13. 56. S. Ferrari, R. Rizzoli, D. Slosman, JP. Bonjour, Familial resemblance for bone mineral mass is expressed before puberty, J. Clin. Endocrinol. Metab. 83 (1998) 358–361. 57. E. Seeman, J.L. Hopper, L.A. Bach, et al., Reduced bone mass in daughters of women with osteoporosis, N. Engl. J. Med. 320 (1989) 554–558. 58. J. Sainz, J.M. Van Tornout, M.L. Loro, J. Sayre, T.F. Roe, V. Gilsanz, Vitamin D receptor gene polymorphisms and bone density in prepubertal girls, N. Engl. J. Med. 337 (1997) 77–82. 59. J. Sainz, J.M. Van Tornout, J. Sayre, F. Kaufman, V. Gilsanz, Association of collagen type 1 a1 gene polymorphism with bone density in early childhood, J. Clin. Endocrinol. Metab. 84 (1999) 853–855. 60. S. Ferrari, R. Rizzoli, T. Chevalley, D. Slosman, J.A. Eisman, JP. Bonjour, Vitamin-D-receptor-gene polymorphisms and change in lumbar-spine bone mineral density, Lancet 345 (1995) 423–424. 61. T.A. Wren, X. Liu, P. Pitukcheewanont, V. Gilsanz, Bone acquisition in healthy children and adolescents: comparisons of DXA and CT measures, J. Clin. Endocrinol. Metab. 90 (2005) 1925–1928.
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62. P. Tothill, M.A. Laskey, C.I. Orphanidou, M. van Wijk, Anomalies in dual energy X-ray absorptiometry measurements of total-body bone mineral during weight change using Lunar, Hologic and Norland instruments, Br. J. Radiol. 72 (859) (1999) 661–669. 63. C. Formica, M.L. Loro, V. Gilsanz, E. Seeman, Inhomogeneity in body fat distribution may result in inaccuracy in the measurement of vertebral bone mass, J. Bone Miner. Res. 10 (1995) 1504–1511. 64. V. Gilsanz, D.T. Gibbens, T.F. Roe, et al., Vertebral bone density in children: effect of puberty, Radiology 166 (1988) 847–850. 65. J.K. Weaver, J. Chalmers, Cancellous bone: its strength and changes with aging and an evaluation of some methods for measuring its mineral content. I. Age changes in cancellous bone, J. Bone Joint Surg. 48A (1966) 289–298. 66. W.A. Merz, RK. Schenk, A quantitative histological study on bone formation in human cancellous bone, Acta. Anat. 76 (1970) 1. 67. M.S. Dunnill, J.A. Anderson, R. Whitehead, Quantitative histological studies on age changes in bone, J. Path. Bact. 94 (1967) 275–291. 68. R.R. Recker, K.M. Davies, S.M. Hinders, R.P. Heaney, M.R. Stegman, D.B. Kimmel, Bone gain in young adult women, J. Am. Med. Assoc. 268 (1992) 2403–2408. 69. V. Matkovic, T. Jelic, G.M. Wardlaw, et al., Timing of peak bone mass in Caucasian females and its implication for the prevention of osteoporosis, J. Clin. Invest. 93 (1994) 799–808. 70. J.P. Bonjour, G. Theintz, B. Buchs, B. Slosman, R. Rizzoli, Critical years and stages of puberty for spinal and femoral bone mass accumulation during adolescence, J. Clin. Endocrinol. Metab. 73 (1991) 555–563. 71. P.W. Lu, J.N. Briody, G.D. Ogle, et al., Bone mineral density of total body, spine, and femoral neck in children and young adults: a cross-sectional and longitudinal study, J. Bone Miner. Res. 9 (1994) 1451–1458. 72. G. Theintz, B. Buchs, R. Rizzoli, et al., Longitudinal monitoring of bone mass accumulation in healthy adolescents: evidence for a marked reduction after 16 years of age at the levels of lumbar spine and femoral neck in female subjects, J. Clin. Endocrinol. Metab. 75 (1992) 1060–1065. 73. A.M. Parfitt, Genetic effects on bone mass and turnoverrelevance to black/white differences, J. Amer. Coll. Nutr. 16 (1997) 325–333.
Chapter
9
The Effects of Sex Steroids on Bone Growth Giampiero I. Baroncelli and Silvano Bertelloni Department of Obstetrics, Gynecology and Pediatrics, 2nd Pediatric Unit, ‘S. Chiara’ Hospital, Azienda Ospedaliero-Universitaria Pisana, Pisa, Italy
Introduction
and estrogens cannot be considered as only ‘male’ or ‘female’ hormones, respectively. Indeed, androgens may act as prohormones of estrogens even within bone. Sex steroids influence not only the accrual of bone mass and bone mineral density (BMD) but also skeletal sex dimorphism [4–6]. This chapter will focus on the main effects of sex steroids on the biological processes involved in bone growth in both sexes, emphasizing gender differences.
Bone growth includes the progressive incremental changes in length, size and mass, associated with changes in bone geometry/width, that physiologically occur throughout the development of the individual (Figure 9.1). As already recognized in the 1940s by Albright and Reifenstein [1], sex steroids regulate skeletal growth and maturation in both men and women. Both androgens and estrogens and their respective receptors have specific actions on different bone envelopes during growth in both sexes [2]. Androgen receptor (AR), estrogen receptor- (ER-) and (ER-) are expressed in human, rat and mouse osteoblasts, osteoclasts, osteocytes and growth plate chondrocytes, thereby supporting the concept that the action of sex steroids on the skeleton may be exerted by a direct stimulation of their receptors [3]. However, androgens
Longitudinal and radial bone growth Longitudinal bone growth depends on endochondral bone formation which basically involves two steps. The first step is characterized by addition of cartilage tissue to the growth plates of long bones. In the second step, the cartilaginous scaffold is transformed into bone tissue at the adjacent metaphyses. The resulting primary spongiosa consists of trabeculae which contain a core of mineralized cartilage surrounded by mineralized bone tissue. This type of bone is turned over very rapidly through the coordinated action of osteoclasts and osteoblasts [7]. Radial bone growth occurs by the process of bone modeling which involves coordinated action of osteoclasts and osteoblasts sitting on opposite sites of bone. During radial growth, osteoblasts are typically located on the outer (periosteal) surface of a bone cortex, where they deposit bone matrix and later mineralize it. Thereby, the outer circumference of a long bone or vertebral body is increased. At the same time, osteoclasts located on the inner (endocortical) surface of the cortex resorb bone, increasing the marrow cavity. Net bone mass increases rapidly during modeling since osteoclasts remove less bone tissue than is deposited by osteoblasts [7–9].
Growth in width
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Figure 9.1 Physiologic processes involved in bone growth occurring in childhood and adolescence. Osteoporosis in Men
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Finally, the bone tissue produced either by endochondral ossification or by modeling is continuously turned over in a process defined remodeling [7, 9, 10]. Remodeling consists of successive cycles of bone resorption and formation on the same bone surface; the basic features of this process are the same for both trabecular and cortical bone [7, 10]. A group of osteoclasts removes a small quantity of bone tissue which, after a reversal phase, is replaced by a team of osteoblasts. The entire group of cells involved in this process is named a remodeling unit or basic multicellular unit. The link between osteoblast activity and previous osteoclast action is known as ‘coupling’. The process of bone remodeling has a crucial role in bone maintenance during life. These biological processes, as well as their effects on bone structure, are illustrated in Figure 9.2; these mechanisms are the means by which sex dimorphism may arise.
Effects of Sex Steroids (Including their Interaction with the GH-IGF-I axis) on Longitudinal Bone Growth Sex steroids may have a direct action on chondrocytes via AR, ER- or ER- [2, 11]. The AR has been found in all layers of the growth plate at different ages without significant gender variation [12–14]. Dihydrotestosterone (DHT), the 5-reduced and non-aromatizable metabolite of testosterone, regulates proliferation and differentiation of human epiphyseal chondrocytes in vitro, probably via the stimulation of local insulin-like growth factor-I (IGF-I) synthesis as well as IGF-I receptor expression [14, 15]. In rats, the sex-specific response of osteochondral growth zone chondrocytes to testosterone also requires further metabolism of the hormone to DHT [16]. ERs have been demonstrated in all maturational zones of the growth plate during
development and puberty, but there is conflicting evidence on the effect of estrogens on chondrocyte proliferation and differentiation [14]. Some of these discrepancies may be explained by the ability of chondrocytes to synthesize estrogens locally [17]. Studies in rats have shown that estrogens inhibit chondrocyte cell division in the proliferative zone of the growth plate [18] and that the age-related decrease in size of the hypertrophic chondrocytes is increased by estrogens [14, 19]. Estrogens probably have separate and independent effects on chondroblast proliferation and epiphyseal fusion. Their action on proliferation also appears to be biphasic with stimulation by low levels and inhibition by high levels of estrogen, respectively. In both males and females, the process of inhibition of chondrocyte proliferation predominates in late puberty leading to cessation of growth and epiphyseal fusion. Indeed, growth velocity rapidly decreases in tall girls treated with high-dose estrogens. During puberty, not only sex steroids, but also the pulsatile secretion of growth hormone (GH) increases (1.5- to 3-fold) along with a greater than threefold increase in serum IGF-I concentrations. Moreover, this increase of GH secretion during puberty shows a sex dimorphism that parallels the change in growth velocity [14]. GH acts on bone tissue both directly through a specific receptor on chondrocytes on the growth plate and osteoblasts, and indirectly by IGF-I. Therefore, longitudinal growth may depend on the interaction between sex steroids and GH-IGF-I axis. In fact, estrogen stimulation of longitudinal growth is largely dependent on GH and GH and estrogen levels are positively correlated in prepubertal children [14, 20] and throughout normal female puberty [21]. Moreover, in peripubertal children, estrogens also increase GH sensitivity [14, 22]. Testosterone increases growth velocity in association with an increase in
Trabecular structure
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Figure 9.2 Mechanisms by which bone growth in length and width may occur (from Schoenau et al [7], reproduced with permission).
C h a p t e r 9 The Effects of Sex Steroids on Bone Growth l
Bone mass acquisition during childhood and adolescence
the GH-IGF-I axis. However, such an action is primarily due to its conversion to estrogen following aromatization [14, 23]. On the other hand, non-aromatizable androgens (DHT and oxandrolone) may increase growth velocity independently of GH-IGF-I action, possibly via a direct action on the AR within the growth plate cartilage [3]. Sex steroids have a fundamental role in inducing sex dimorphism during puberty according to chronologic age and pubertal stage. Growth velocity spurt occurs earlier in girls than in boys (age 12.0–12.5 years and 14.0–14.5 years, respectively) with a peak at pubertal Tanner stage B2 and G3, respectively [24]. It has therefore been widely accepted that estrogens are the primary hormones that mediate pubertal bone growth in both sexes. The dimorphic pattern of body and bone growth may be related to the delayed achievement of adequate estrogen levels in boys (following aromatization of testosterone). Indeed, estrogen concentrations during peak height velocity are similar in boys and girls and correlate not only with testosterone levels in boys, but with bone age as well [25]. Some clinical and experimental data suggest that the deceleration of longitudinal growth in late puberty is not due to a systemic (hormonal) mechanism but probably related to a local (paracrine) mechanism within the growth plate [14, 26]. Nevertheless, at the end of puberty, ER- activation appears to be involved in epiphyseal growth plate closure in both sexes [2], as indicated by some observations in patients with aromatase deficiency or ER- disruption (see Chapter 5). The mechanism of ‘growth plate senescence’, as well as the role of estrogen in this process is, however, incompletely understood. According to Parfitt [27], epiphyseal fusion marks but does not determine growth cessation. In fact, epiphyseal fusion follows but does not precede cessation of growth.
In both sexes, bone mass progressively increases during childhood, with a rapid gain during puberty. However, some gender differences in the accrual of bone mass are evident. At birth and during prepubertal years, males and females have similar values of total body bone mass (bone mineral content, BMC) and lumbar BMD [28–32], measured by dual energy x-ray absorptiometry (DXA), until the age of approximately 8 years. Thereafter, the values become higher in females than in males as the result of the earlier onset of the pubertal growth spurt whereas, in the late adolescence, total bone mass in boys exceeds that measured in girls. Figures 9.3 and 9.4 show, respectively, the pattern of total body bone mass and lumbar BMD during childhood and adolescence in both sexes. 3400
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Figure 9.3 Centile curves for total body bone mass (BMC), by DXA measurements, according to age in boys (solid lines) and girls (dashed lines) during childhood and adolescence (from Mølgaard et al [30], reproduced with permission).
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Figure 9.5 Mean and standard deviations of vertebral trabecular bone density, by QCT measurements, in male and female subjects aged 7–20 years. Trabecular bone density increases and reaches peak values earlier in female than in male subjects. Because trabecular bone density does not correlate with age for male subjects aged 7–11 and 17–20 years and for female subjects aged 7–10 and 15–20 years, the values in these age groups were equalized. Values at 7 and 20 years represent the mean for subjects 5–7 years of age and 20–21 years of age, respectively (from Gilsanz et al [34], reproduced with permission). BMC TB velocity curve cubic spline 450 Boys Age of peak 14.05 Peak value 408 Size adjusted 394
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The higher bone mass in boys than in girls can be explained by differences in bone size related to gender and not to differences in bone density [6, 7, 33]. In young adulthood, men and women have similar volumetric BMD, but men have bigger bones than women due to the process of periosteal apposition [6] (see Chapter 4). Volumetric BMD is independent of age for the vertebral body, at least until puberty [34], then it increases comparably by gender (Figure 9.5). The number of trabeculae at the growth plates does not increase with age [35]. At puberty, trabecular BMD increases by increasing the size and thickness of the trabeculae plates to a similar degree in boys and girls [36]. Approximately 40% of bone mass is accumulated during adolescence [37, 38]. Moreover, on average, 26% of peak bone mass is acquired during the 2-year period across peak height velocity [37], suggesting a clear relationship between the increase of sex steroids, linear growth and bone growth. At peak height velocity, boys and girls reached 90% of their adult height but only 57% of their bone mass. Sex differences in timing and magnitude of bone mass accrual with respect to the gain of longitudinal growth during puberty have been shown. Peak total bone mass accrual occurs approximately 1.6 years earlier in girls than in boys (age 12.50.90 [meanSD] and 14.10.95 years, respectively) and is less in girls than boys (32567 g/year and 40950 g/ year, respectively) [39, 40] (Figure 9.6). In boys, the greatest difference between height and BMD gains is more pronounced at the lumbar spine and femoral neck than at the femoral midshaft; in girls, the difference appears to be of a lower magnitude than in males [41]. Furthermore, according to Forwood et al [42], peak linear growth (height and femur length) precedes the peak rate of growth in bone
Age PHV 13.44 yrs
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Figure 9.6 Total body peak bone mass velocity (BMCTB) curve illustrating velocity at peak and ages at peak BMC and peak height velocities (PHV) by chronologic age for boys and girls (from Bailey et al [39], reproduced with permission).
strength variables (cross-sectional area and subperiosteal width assessed by DXA) at femoral neck by 6.5 months and by 8.4 months for boys and girls, respectively. Therefore, the timing of axial and appendicular bone mass acquisition differs between boys and girls, apparently due to the different onset and progression of puberty [36, 43].
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Figure 9.7 Variations of periosteal and medullary diameter (upper panel of the figure) and cross-section of cortical (black) and medullary (white) areas (lower panel of the figure), from infancy to young adulthood at metacarpal bones in both sexes (modified from Seeman [6], reproduced with permission).
In both sexes, the maximal gain of BMD occurs at pubertal stages 3–4 at the lumbar spine and at pubertal stages 2–3 at the femoral neck or midshaft [37, 41, 44]. In both sexes, the accrual of bone mass abruptly decreases in late adolescence. It has been calculated, by DXA measurements, that at least 90% of peak bone mass at the lumbar spine and femoral neck is acquired within the second decade of life [37, 44, 45]. However, in other skeletal sites, such as the radius, skull or whole body, peak bone mass (assessed by DXA) is reached later, around 35 years [31, 45]. In both sexes, a similar pattern has been reported at the proximal phalanges of the hand as assessed by quantitative ultrasound measurement [46, 47].
Changes in bone size by periosteal expansion during growth Individual bone size is determined by absolute and relative movements of both periosteal and endosteal surfaces. These changes in bone size influence bone geometry, cortical bone mass and thickness, as well as the diameter of medullary cavity. At the second metacarpal bone, periosteal apposition increases bone width during the prepubertal years in both sexes, resulting in a slightly higher periosteal diameter in boys than girls, whereas only small changes occur at the medullary area up to puberty [6, 36, 48, 49]. In the first two
years life, an initial resorptive phase with a slightly greater diameter in males than in females is followed by a childhood appositive phase with a similar medullary diameter between males and females [6, 36, 48, 49]. At puberty, the development of cortical bone takes a gender-specific course. In fact, in boys, periosteal apposition and endocortical resorption continue causing enlargement of bone diameter, cortical thickening and increased medullary cavity diameter. In girls, periosteal apposition also increases, but to a lesser extent than in boys, whereas endocortical bone formation is stimulated resulting in cortical thickening and reduced medullary cavity. Although cortical thickness is similar in males and females, the cortical bone mass is greater in males because of the greater periosteal perimeter [6, 36, 48, 49]. In Figure 9.7 the pattern of periosteal and medullary diameters measured at the second metacarpal bone from infancy to young adulthood is illustrated. These observations at the second metacarpal bone are largely confirmed by peripheral quantitative computed tomography (pQCT) measurements at the 65% site of the proximal radius in children and adolescents [50]. By the age of 15 years, girls have almost completed periosteal apposition; in boys, the maximum diameter is only reached at 21 years without evident pubertal acceleration. Moreover, according to Neu et al [50] periosteal apposition rate at the proximal radius was similar to the iliac periosteal formation rate in children, as measured by histomorphometry [35]. In contrast to the results at the second metacarpal bone [48, 49] and at the femoral diaphysis [43], but in agreement with
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Figure 9.8 Mean BTT values in male and female subjects from infancy to young adulthood (A) and during prepuberty and the main periods of puberty (B) (modified from Baroncelli et al [58], reproduced with permission).
radiogrammetric measurements obtained at the proximal radius [51], no significant changes in medullary area were documented in females. In contrast to girls, medullary area increases with age in boys [50, 52]. Therefore, these data indicate that, at the proximal radius, the endocortical surface appears to remain stable in females, whereas considerable endocortical resorption occurs in males. In weight-bearing skeletal regions, such as femur, only small or no changes in cross-sectional area and cortical bone area, as assessed by QCT, have been reported in prepubertal children, with no difference between boys and girls [33, 43]. However, Högler et al [53] showed, by DXA and magnetic resonance imaging, that mid-femoral cortical thickness increased between prepuberty and adulthood in both sexes, with males having higher values of total, cortical and medullary areas than females, suggesting that periosteal expansion is slightly predominant over net endocortical resorption. The sex-specific increase in medullary area was nearly identical with the increase in mid-femoral medullary area assessed by QCT [54]. In addition, Looker et al [55] also reported gender difference in cortical thickness at the femoral neck and proximal shaft. A longitudinal study by pQCT in girls showed that growth velocity of total cross-sectional area and total bone mass at the distal radius peaked at 16 and 9 months, whereas at the tibial shaft they peaked at 20 and 10 months before menarche, respectively. The growth velocity of cortical cross-sectional area of the tibial shaft peaked at 13 months before menarche and then decreased. Moreover, during puberty, the cortical cross-sectional area/total cross-sectional
area ratio increased, whereas the medullary cross-sectional area/total cross sectional area ratio decreased [56]. These data are similar to those observed at the second metacarpal bone and at the mid-femoral shaft [43, 57]. Quantitative ultrasound (QUS) measurements at the proximal phalanges of the hand showed that the QUS variable defined as BTT (bone transmission time, expressed as s), which reflects cortical bone mass, cortical thickness and cortical area, progressively increases during childhood in both sexes, with slightly higher values in males than in females during infancy and childhood and with an earlier increase in girls at the onset of puberty compared with boys [58]. Moreover, the analysis of the BTT pattern during puberty further reveals that boys have higher values than girls, mainly in late puberty [58] (Figure 9.8), likely reflecting a greater perimeter of the bigger bone as documented earlier at the second metacarpal bone [48, 49]. In conclusion, a longer period of bone accumulation in males than in females as a consequence of a longer prepubertal longitudinal growth and a more pronounced periosteal expansion during puberty may explain the differences in bone mass between sexes [6, 36].
Mechanisms Regulating Periosteal and Endosteal Expansion During Growth The mechanism(s) regulating the sex-dependent periosteal and endosteal surface changes occurring during growth are not well defined. Some potential hypotheses are summarized in Table 9.1 [59].
C h a p t e r 9 The Effects of Sex Steroids on Bone Growth l
Table 9.1 Theories on the sex-dependent periosteal and endosteal surface changes occurring during growth Theory
Possible mechanisms
Hormonal
Sex steroids can have a different action on bone surface according to sex Mechanostat Mechanical strain regulates the morphology of bone geometry MechanoSex steroids, in particular estrogen, modulate hormonal the response of mechanical strain regulating the morphology of bone geometry Sizostat Some genetic factors can regulate bone growth in width to reach a pre-programmed size, independent of mechanical requirements
Hormonal Factors: Sex Steroids and the GH-IGF-I axis The sex dimorphism in bone mass and size suggests that sex steroids are key regulators of bone mineral accumulation and geometry during puberty. According to observations in gonadectomized rats, androgens mainly stimulate periosteal bone formation in males and estrogens inhibit periosteal expansion in females [60]. The variation in cortical bone volume after gonadectomy appears primarily related to changes in periosteal bone formation and not (or to a lesser extent) to changes of the inner endocortical perimeter [61]. Based on the skeletal response to estrogen therapy in a 17-year-old boy with congenital aromatase deficiency (see Chapter 5), Bouillon et al [62] suggested that androgens alone are not sufficient to drive periosteal expansion and that estrogen therapy is able to stimulate periosteal apposition. Therefore, exposure to estrogens appears to be essential for the male pubertal periosteal bone expansion as well. A unifying hypothesis could be that estrogens rather than androgens are driving periosteal bone apposition, with a biphasic, dose dependent effect of estrogens. Assuming a dose–response relationship between estradiol levels and bone expansion in both sexes, stimulation would occur at low levels, as is the case in males and in early pubertal girls, whereas increasing exposure to higher concentrations of estrogens, as occurs in late puberty and in adulthood in females, would inhibit periosteal growth [62]. This assumption is consistent with both the lifelong slow periosteal bone expansion in males and the resumption of bone expansion after menopause [36]. Estrogens may induce periosteal bone formation in both sexes through ER-, whereas inhibition of periosteal expansion could be primarily an ER- effect, according to observations of increased periosteal expansion in female ER- knockout mice [3, 63]. Some data indicate that testosterone and other androgens have a crucial role on periosteal growth with actions mediated by both the AR and ERs after aromatization to estrogen [23]. Compared with women, men exhibit more periosteal expansion because they are more exposed to the
111
stimulatory effects of androgens and less exposed to the inhibitory effects of estrogens. On the other hand, periosteal apposition in women may be enhanced by androgens, as it is in men [64]. This hypothesis is in keeping with the demontration of increased bone size and bone mass in women with polycystic ovary syndrome that is characterized by androgen excess [65, 66]. Wang et al [67], in a study at tibial shaft by pQCT, showed that estrogens inhibited bone resorption during the rapid growth occurring before menarche; by contrast, after menarche the higher estrogen concentrations promoted bone formation. At the periosteal surface, testosterone promoted bone formation, whereas estrogens did not affect it. Therefore, these data do not support the view that estrogens inhibit bone formation at the periosteal surface. In addition to linear growth, the GH-IGF-I axis regulates bone mass gain and bone modeling and remodeling [68] according to some studies in GH-deficient children [68, 69]. Furthermore, the interaction between GH-IGF-I axis and sex steroids plays a crucial role in regulating bone metabolism. According to a study on femoral mid-shaft geometry in rats [61], gonadectomy had no net effect on the endocortical surface in males but abolished endocortical bone acquisition in females. GH deficiency halved periosteal bone formation and had no net effect on the endocortical surface in males, but abolished bone acquisition on both surfaces in females. Therefore, periosteal growth is independently and additively stimulated by androgens and GH in males, inhibited by estrogen and stimulated by GH in females. The role of the GH-IGF-I axis in bone sex dimorphism is largely unknown in humans. The similar degree of reduction in lumbar BMD between boys and girls with GH deficiency [68] could suggest that sex dimorphism in bone mass as well as in body composition could be primarily due to sex steroids [70]. ‘Mechanostat’ Theory (The Utah Paradigm) Based on the ‘mechanostat’ theory, skeletal growth is fully regulated by a dominant feed-back system (the ‘mechanostat’) that senses mechanical strain generated by muscle contraction and skeletal loading. These mechanisms are able to adapt bone tissue to the processes of modeling and remodeling [71, 72]. Although the mechanisms of action of the ‘mechanostat’ are not defined, there is strong evidence that mechanical forces do play a major role in determining periosteal bone development via osteocytes, bone lining cells or other cells in the marrow [72]. Mechanical strain is primarily dependent on muscle mass and strength and, to a lesser extent, on body weight. During puberty, it has been demonstrated that muscle mass contributes to the variability of bone mass by 6–12% in boys and 4–10% in girls [73]. Rauch et al [74] demonstrated, by DXA scans, that muscle strength and
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Males Age PHV 13.45y
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100 BMC Age peak 14.11 y Peak value 404 g
LBM Age peak 13.75 y Peak value 8550 g
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9 10 11 12 13 14 15 16 17 18 19 Age in y
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Age PHV 11.80 y
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LBM Age peak 12.19 y Peak value 5050 g BMC Age peak 12.69 y Peak value 318 g
5000
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Total body BBC velocity in g per y
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Total body BBC velocity in g per y
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Total body LBM velocity in g per y
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0 9 10 11 12 13 14 15 16 17 18 19 Age in y
Figure 9.9 Velocities of total body lean body mass (LBM) and bone mass (BMC) accretion during the pubertal growth spurt in males (left panel) and females (right panel). The age at peak height velocity (PHV) is shown as a reference point for pubertal development (from Rauch et al [74], reproduced with permission).
bone strength are closely correlated between them and that the pubertal peak velocity in lean body mass accretion precedes the pubertal peak velocity in bone mass accretion by an average of 0.51 years in girls and by 0.36 years in boys (Figure 9.9). Moreover, Macdonald et al [75], by pQCT measurements, showed that sex dimorphism in tibial bone strength and its components (geometry and density) is already evident in pre- and early pubertal boys and girls. However, it should be taken into consideration that these data do not establish a direct cause-and-effect relationship between muscle force and bone strength. In fact, the development of muscle mass and bone mass during growth, and mainly during puberty, is influenced by several factors, including genetic and hormonal factors. Based on the ‘mechanostat theory’, sex differences in bone size may be largely explained. Mechanical loads on bones deform or strain them and larger loads cause bigger strains. Where strains exceed a modeling threshold range, modeling slowly increases bone strength to reduce later strains towards that range, otherwise mechanically controlled modeling turns off. When strains stay below a lower remodeling threshold range, disuse-mode remodeling permanently removes bone, but only next to or close to marrow. At any rate, it is possible that there is some form of positional cue that is responsible for the ‘setpoint’ threshold for mechanical loading at each location in the skeleton, so that architecture is optimized to habitual strains experienced for each of those locations. That implies that
a site-specific customary strain stimulus exists for each site within the skeleton and it is that combination of different strain parameters to which the modeling and remodeling processes are directed [76]. It is hypothesized that the setpoint of the mechanostat in girls is lower than that of boys; as a consequence, a lower mechanical strain is sufficient to activate modeling in girls [77]. ‘Mechano-Hormonal’ Theory Some observations suggest that the ‘bone–muscle unit’ could be regulated by sex steroids [78, 79] and the GH-IGFI axis [80]. Figure 9.10 shows some possible interactions between mechanical strain and hormones, as described by Rauch and Schoenau [81] and Petit et al [82]. Testosterone has a profound anabolic effect on muscle mass at puberty; this effect is mainly evident in boys who have a muscle mass gain about of 35% more than girls [83]. Skeletal muscle has many ARs and testosterone stimulates the muscle mass independently of IGF-I production [83, 84]. A regulating effect of testosterone on the setpoint of the mechanostat is not demonstrated. Some studies [77–79] suggested that the main effect of estrogens on the bone–muscle unit is in decreasing the mechanical setpoint of the mechanostat, thereby increasing the responsiveness of the periosteum to load. As a consequence, customary loading may cause a greater bone mass. Conversely, withdrawal of estrogens (due to menopause or amenorrhea) may reduce the sensitivity to loading inducing
C h a p t e r 9 The Effects of Sex Steroids on Bone Growth l
Bone strength
Mechanostat model*
Tissue strain
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Material strength
Geometry
Regulatory feedback loop Signaling pathways Osteocyte sensing
Osteoblasts
Sensitivity set-points Signaling pathways
Osteoclasts
Growth in bone length change in muscle load
Genetics, hormones, nutrition, environment
Challenges
Modulators
Figure 9.10 Possible interactions among mechanical and hormonal factors involved in bone development based on mechanostat theory (from Rauch and Schoenau [81] and Petit et al [82], reproduced with permission).
bone loss, as the concurrent loading is not sufficient to counter this change in mechanosensitivity [85]. Accordingly, the rise in estrogen levels during puberty could lead to the deposition of additional bone mass in order to satisfy the anticipated physiological needs of the subsequent reproductive period [77–79]. However, a study in mice [86] showed that the responsiveness of periosteal bone to load was decreased by estrogens and not increased. In additon, Järvinen et al [87] observed that the skeletal response of estrogen-depleted female rats to exercise was higher compared with their estrogenrepleted counterparts. In humans, some studies showed more beneficial effects on periosteal bone in prepubertal girls (low estrogen) than in postpubertal girls (high estrogen), suggesting that the responsiveness of periosteal bone to load could be reduced by estrogens [43, 88, 89]. Although the theories on the role of estrogens in periosteal bone expansion seem to be contradictory, according to Venken et al [59], they could reflect different exposure to endogenous estrogens. Low levels of estrogen could increase the mechanical sensitivity of the periosteum and/ or affect systemic IGF-I concentrations. Alternatively, higher concentrations of estrogen could inhibit periosteal bone expansion and its interaction with mechanical loading. Furthermore, it should be considered that the interaction between estrogens and mechanical loading may be not only restricted to a potential role of different exposure to estrogen concentrations, but also to the role of the ER and ER- and their different actions on male and female skeleton during loading [59]. It has been hypothesized that ER- could stimulate bone formation on the endocortical
surface, whereas ER- may act as an antimechanostat [90]. In fact, disruption of ER- increased periosteal bone formation following loading in female mice but not in male mice [86]; this may suggest that estrogen signaling through ER suppresses the loading response in the female skeleton. Therefore, periosteal bone apposition may be not only dependent on the combined action of hormonal or mechanical stimuli but also on their mutual interactions; mechanical loading is strongly stimulatory for bone but it seems to be sex steroid hormone-dependent. GH could decrease the bone mechanostat setpoint and reinforce the effect of mechanical loading on bone formation [80, 91], as suggested by the evidence that men with GH deficiency have reduced muscle mass associated with a high risk of fractures [92]. Moreover, the GH-IGF-I axis may have an important role in regulating periosteal bone expansion, as demonstrated by the fact that GH receptor and IGF-I genedisrupted mice show extremely short and thin bones [93]. Genetic Factors (‘Sizostat’ Hypothesis) The Sizostat hypothesis sustains that a master gene or a set of genes can regulate bone growth in width to reach a preprogrammed size, independent of mechanical requirements and hormonal influences [94]. As a consequence, in an individual who is genetically destined to have a wide leg, the genetic growth program will make bones and muscles grow to reach the pre-programmed size [95]. Muscle and bone growth would independently follow a genetic script but would not have a functional link.
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Table 9.2 Effects of sex steroids deficiency/action on linear growth, pubertal growth spurt, bone maturation, BMD, bone geometry and muscle mass Pubertal Unfused Bone age BMDa growth epiphyses spurt
Disorder
Hormone Clinical deficiency/ phenotype deficient action
Congenital aromatase deficiency (in men, n 7) Estrogen resistance syndrome (in a man) Complete androgen insensitivity syndrome
Estrogen deficiency
Eunuchoid Increased No proportion, genu valgum
Yes
Delayed
Reduced Reduced
Reduced
Estrogen resistance
Eunuchoid Increased No proportion, genu valgum
Yes
Delayed
Reduced Unknown
Unknown Unknown
Androgen resistance
No
Not delayed
Reduced Unknown
Unknown Normal for females, but reduced for males
5reductase deficiency
DHT deficiency
Normal female with absent pubic and axillary hair and primary amenorrhea Female/ ambiguous (at birth)d
Linear growth
Normalc
Yes
Normal
Unknown No
Cortical CrossMuscle thicknessb sectional Massa areab
Unknown Normale Unknown
Unknown
Unknown Unknownf
a
Assessed by DXA; assessed by pQCT; c intermediate between those predicted for females and males; d virilization after puberty if gonads are not removed; e in individuals raised as males, intact testes, spontaneous high-normal testosterone values and low DHT values; f male appearance after puberty in individuals raised as males and with spontaneous testosterone secretion. b
Relevant clinical observations on the sex steroids’ effect on bone growth Clinical observations in patients with altered secretion or action of sex steroids strongly support their role on bone growth, skeletal maturation and bone mass accrual. Hypogonadal patients have reduced BMD which improves following hormonal replacement therapy [5]. In untreated patients suffering from hypogonadotrophic hypogonadism, such as Kallman’s syndrome, linear growth continues until the third decade, resulting in taller than average final height and abnormal body proportions with relatively longer bones at the lower body segment [14]. Moreover, boys with primary hypogonadism, such as Klinefelter syndrome (47, XXY), have taller than average final height as well as a variable degree of BMD reduction (25–40%) that seems to be related to the degree of hypogonadism. Cortical bone appears also more affected than trabecular bone in these patients [96]. Males with estrogen insensitivity secondary to a mutation in the ER gene or impaired estrogen biosynthesis due to hereditary aromatase deficiency have reduced BMD, delayed skeletal maturation and persistent skeletal growth into adult life. These ‘experiments of nature’ show that androgens alone do not promote epiphyseal maturation and
that estrogens have a fundamental role not only in pubertal development and linear growth, but also in the acquisition of bone mass in both girls and boys [5, 23, 97]. A positive effect of estrogen treatment in improving lumbar and femoral BMD and linear growth in a boy with congenital aromatase deficiency [62] also indicates that estrogens have a critical role in male skeletal growth and bone mass acquisition and that estrogens may regulate pubertal periosteal bone expansion associated with the male bone phenotype. Complete androgen insensitivity syndrome offers a unique opportunity to assess the consequences of a total lack of androgen action on bone growth. The syndrome is caused by mutations in the AR, thereby producing complete lack of target tissue response to high-normal endogenous androgens. Despite subnormal estrogen concentrations for females, these patients are usually taller than normal males. Although estrogen concentrations are able to induce a normal pubertal growth spurt and feminization, bone mass accretion is likely impaired in these androgen resistant patients, suggesting that not only estrogen but also androgen exerts a direct role in BMD acquisition [5, 98–101]. Moreover, the evidence that lean body mass in women with complete androgen insensitivity syndrome is reduced when compared with control men [102] could indicate a role of an impaired mechano-hormonal system on bone growth
C h a p t e r 9 The Effects of Sex Steroids on Bone Growth
115
l
Table 9.3 Principal effects of sex steroids on bone growth and maturation and muscle mass independent of sex Hormone
Linear growth
Pubertal growth spurt
Body proportions
Epiphyseal closure
Bone mass acquisition
Periosteal geometry
Endosteal geometry
Muscle mass acquisition
Estrogens Androgens
/ *
/
, Stimulation; , no effect. The number of symbols reflects the degree of stimulation for comparison between estrogen and androgen only in general terms. *At least in part, this effect could be due to aromatization to estrogens.
in these subjects. In contrast, patients suffering from 5reductase deficiency do not have reduction of BMD compared with standardized male values, suggesting that testosterone itself and/or low levels of DHT are sufficient for the acquisition of a normal BMD [99]. A study by Han et al (103) of patients affected by complete androgen insensitivity syndrome and gonadal dysgenesis with 46, XY karyotype (Swyer’s syndrome) or 46, XX karyotype suggested that androgens rather than sex chromosomes may have a role in protecting BMD in women with complete androgen insensitivity syndrome and that androgens likely exert their greatest effects on bone mass acquisition in the early period of life. Table 9.2 summarizes the main effects of sex steroids deficiency/action on linear growth, pubertal growth spurt, bone maturation, BMD and bone geometry. These data indicate that, in both sexes, estrogens have a primary role on bone mass accumulation during puberty and skeletal consolidation after puberty, but an independent participation of androgens in these processes likely occurs. However, it should be considered that testosterone represents the necessary substrate for aromatization to estrogens, so that it has an important indirect role in regulating bone surfaces modeling.
Conclusions Sex steroids play a fundamental role in the regulation of bone growth and skeletal dimorphism. Estrogens appear to be important for bone development not only in girls but also in boys. Table 9.3 summarizes the principal effects of estrogens and androgens on bone growth and maturation and muscle mass. The pubertal growth spurt, epiphyseal fusion, body proportion and endosteal geometry seem to be mainly regulated by estrogens, whereas periosteal geometry and muscle mass are mainly regulated by androgens.
References 1. F. Albright, EC. Reifenstein (Eds.), Metabolic Bone Diseases, Williams and Wilkins, Baltimore, 1948, pp. 145–204. 2. K. Venken, F. Callewaert, S. Boonen, D. Vanderschueren, Sex hormones, their receptors and bone health, Osteoporos. Int. 19 (2008) 1517–1525. 3. D. Vanderschueren, L. Vandenput, S. Boonen, M.K. Lindberg, R. Bouillon, C. Ohlsson, Androgens and bone, Endocr. Rev. 25 (2004) 389–425.
4. AM. Parfitt, The two faces of growth: benefits and risks to bone integrity, Osteoporos. Int. 4 (1994) 382–398. 5. G. Saggese, S. Bertelloni, GI. Baroncelli, Sex steroids and the acquisition of bone mass, Horm. Res. 48 (Suppl. 5) (1997) 65–71. 6. E. Seeman, Clinical review 137: sexual dimorphism in skeletal size, density, and strength, J. Clin. Endocrinol. Metab. 86 (2001) 4576–4584. 7. E. Schoenau, G. Saggese, F. Peter, et al., From bone biology to bone analysis, Horm. Res. 61 (6) (2004) 257–269. 8. HM. Frost, Skeletal structural adaptations to mechanical usage (SATMU): 1. Redefining Wolff’s law: the bone modeling problem, Anat. Rec. 226 (1990) 403–413. 9. HM. Frost, Skeletal structural adaptations to mechanical usage (SATMU): 2. Redefining Wolff’s law: the remodeling problem, Anat. Rec. 226 (1990) 414–422. 10. A.M. Parfitt, Bone forming cells in clinical conditions, in: B.K. Hall (Ed.), The Osteoblasts and Osteocyte, Telford Press, Caldwell, 1990, pp. 351–429. 11. A. Juul, The effects of oestrogens on linear bone growth, Hum. Reprod. Update. 7 (2001) 303–313. 12. B. Noble, J. Routledge, H. Stevens, I. Hughes, W. Jacobson, Androgen receptors in bone-forming tissue, Horm. Res. 51 (1999) 31–36. 13. O. Nilsson, D. Chrysis, O. Pajulo, et al., Localization of estrogen receptors-alpha and -beta and androgen receptor in the human growth plate at different pubertal stages, J. Endocrinol. 177 (2003) 319–326. 14. R.J. Perry, C. Farquharson, SF. Ahmed, The role of sex steroids in controlling pubertal growth, Clin. Endocrinol. (Oxf) 68 (2008) 4–15. 15. K. Krohn, D. Haffner, U. Hugel, et al., 1,25(OH)2D3 and dihydrotestosterone interact to regulate proliferation and differentiation of epiphyseal chondrocytes, Calcif. Tissue Int. 73 (2003) 400–410. 16. P. Raz, E. Nasatzky, B.D. Boyan, A. Ornoy, Z. Schwartz, Sexual dimorphism of growth plate prehypertrophic and hypertrophic chondrocytes in response to testosterone requires metabolism to dihydrotestosterone (DHT) by steroid 5-alpha reductase type 1, J. Cell Biochem. 95 (2005) 108–119. 17. B.C. van der Eerden, J. Emons, et al., Evidence for genomic and nongenomic actions of estrogen in growth plate regulation in female and male rats at the onset of sexual maturation, J. Endocrinol. 175 (2002) 277–288. 18. S.W. Whitson, L.R. Dawson, WS. Jee, A tetracycline study of cyclic longitudinal bone growth in the female rat, Endocrinology 103 (1978) 2006–2010. 19. P.O. Gustafsson, H. Kasstrom, L. Lindberg, SE. Olsson, Growth and mitotic rate of the proximal tibial epiphyseal plate in hypophysectomized rats given estradiol and human growth hormone, Acta. Radiol. 344 (1975) 69–74.
116
Osteoporosis in Men
20. J.D. Veldhuis, J.N. Roemmich, AD. Rogol, Gender and sexual maturation-dependent contrasts in the neuroregulation of growth hormone secretion in prepubertal and late adolescent males and females: a general clinical research center-based study, J. Clin. Endocrinol. Metab. 85 (2000) 2385–2394. 21. J.M. Wennink, H.A. Delemarre-van de Waal, R. Schoemaker, G. Blaauw, C. van den Braken, J. Schoemaker, Growth hormone secretion patterns in relation to LH and estradiol secretion throughout normal female puberty, Acta. Endocrinol. 124 (1990) 129–135. 22. R. Coutant, F.B. de Casson, S. Rouleau, et al., Divergent effect of endogenous and exogenous sex steroids on the insulinlike growth factor I response to growth hormone in short normal adolescents, J. Clin. Endocrinol. Metab. 89 (2004) 6185–6192. 23. B.L. Clarke, S. Khosla, Androgens and bone, Steroids 74 (2009) 296–305. 24. J.D. Veldhuis, J.N. Roemmich, E.J. Richmond, et al., Endocrine control of body composition in infancy, childhood, and puberty, Endocr. Rev. 26 (2005) 114–146. 25. M.M. Grumbach, RJ. Auchus, Estrogen: consequences and implications of human mutations in synthesis and action, J. Clin. Endocrinol. Metab. 84 (1999) 4677–4694. 26. P.J. Simm, A. Bajpai, V.C. Russo, GA. Werther, Estrogens and growth, Pediatr. Endocrinol. Rev. 6 (2008) 32–41. 27. AM. Parfitt, Misconceptions (1): epiphyseal fusion causes cessation of growth, Bone 30 (2002) 337–339. 28. L. del Rio, A. Carrascosa, F. Pons, M. Gusinyé, D. Yeste, FM. Domenech, Bone mineral density of the lumbar spine in white Mediterranean Spanish children and adolescents: changes related to age, sex, and puberty, Pediatr. Res. 35 (3) (1994) 362–366. 29. A.M. Boot, M.A. de Ridder, H.A. Pols, E.P. Krenning, SM. de Muinck Keizer-Schrama, Bone mineral density in children and adolescents: relation to puberty, calcium intake, and physical activity, J. Clin. Endocrinol. Metab. 82 (1997) 57–62. 30. C. Mølgaard, B.L. Thomsen, A. Prentice, T.J. Cole, KF. Michaelsen, Whole body bone mineral content in healthy children and adolescents, Arch. Dis. Child. 76 (1997) 9–15. 31. R. Rizzoli, JP. Bonjour, Determinants of peak bone mass and mechanisms of bone loss, Osteoporos. Int. 9 (Suppl. 2) (1999) S17–S23. 32. T.V. Nguyen, L.M. Maynard, B. Towne, et al., Sex differences in bone mass acquisition during growth: the Fels Longitudinal Study, J. Clin. Densitom. 4 (2001) 147–157. 33. V. Gilsanz, A. Kovanlikaya, G. Costin, T.F. Roe, J. Sayre, F. Kaufman, Differential effect of gender on the sizes of the bones in the axial and appendicular skeletons, J. Clin. Endocrinol. Metab. 82 (1997) 1603–1607. 34. V. Gilsanz, F.J. Perez, P.P. Campbell, F.J. Dorey, D.C. Lee, TA. Wren, Quantitative CT reference values for vertebral trabecular bone density in children and young adults, Radiology 250 (2009) 222–227. 35. A.M. Parfitt, R. Travers, F. Rauch, FH. Glorieux, Structural and cellular changes during bone growth in healthy children, Bone 27 (2000) 487–494. 36. E. Seeman, Bone quality: the material and structural basis of bone strength, J. Bone Miner. Metab. 26 (2008) 1–8. 37. G. Theintz, B. Buchs, R. Rizzoli, et al., Longitudinal monitoring of bone mass accumulation in healthy adolescents: evidence
38. 39.
40.
41.
42.
43.
44.
45.
46.
47.
48.
49.
50.
51.
52.
53.
for a marked reduction after 16 years of age at the levels of lumbar spine and femoral neck in female subjects, J. Clin. Endocrinol. Metab. 75 (1992) 1060–1065. R.P. Heaney, S. Abrams, B. Dawson-Hughes, et al., Peak bone mass, Osteoporos. Int. 11 (2000) 985–1009. D.A. Bailey, H.A. McKay, R.L. Mirwald, P.R. Crocker, RA. Faulkner, A six-year longitudinal study of the relationship of physical activity to bone mineral accrual in growing children: the university of Saskatchewan bone mineral accrual study, J. Bone Miner. Res. 14 (1999) 1672–1679. D.A. Bailey, A.D. Martin, H.A. McKay, S. Whiting, R. Mirwald, Calcium accretion in girls and boys during puberty: a longitudinal analysis, J. Bone Miner. Res. 15 (2000) 2245–2250. P.E. Fournier, R. Rizzoli, D.O. Slosman, G. Theintz, JP. Bonjour, Asynchrony between the rates of standing height gain and bone mass accumulation during puberty, Osteoporos. Int. 7 (1997) 525–532. M.R. Forwood, D.A. Bailey, T.J. Beck, R.L. Mirwald, A. D. Baxter-Jones, K. Uusi-Rasi, Sexual dimorphism of the femoral neck during the adolescent growth spurt: a structural analysis, Bone 35 (2004) 973–981. S. Bass, P.D. Delmas, G. Pearce, E. Hendrich, A. Tabensky, E. Seeman, The differing tempo of growth in bone size, mass, and density in girls is region-specific, J. Clin. Invest. 104 (1999) 795–804. J.P. Bonjour, G. Theintz, B. Buchs, D. Slosman, R. Rizzoli, Critical years and stages of puberty for spinal and femoral bone mass accumulation during adolescence, J. Clin. Endocrinol. Metab. 73 (1991) 555–563. V. Matkovic, T. Jelic, G.M. Wardlaw, et al., Timing of peak bone mass in caucasian females and its implication for the prevention of osteoporosis: inference from a cross-sectional model, J. Clin. Invest. 93 (1994) 799–808. C. Wuster, C. Albanese, D. De Aloysio, et al., Phalangeal osteosonogrammetry study: age-related changes, diagnostic sensitivity, and discrimination power. The Phalangeal Osteosonogrammetry Study Group, J. Bone Miner. Res. 15 (2000) 1603–1614. A. Montagnani, S. Gonnelli, C. Cepollaro, et al., Quantitative ultrasound at the phalanges in healthy Italian men, Osteoporos. Int. 11 (2000) 499–504. S. Garn, The Earlier Gain and Later Loss of Cortical Bone. Nutritional Perspectives, Charles C. Thomas, Springfield, 1970 pp. 3–120. A.R. Frisancho, S.M. Garn, W. Ascoli, Subperiosteal and endosteal bone apposition during adolescence, Hum. Biol. 42 (1970) 639–664. C.M. Neu, F. Rauch, F. Manz, E. Schoenau, Modeling of cross-sectional bone size, mass and geometry at the proximal radius: a study of normal bone development using peripheral quantitative computed tomography, Osteoporos. Int. 12 (2001) 538–547. P. Virtama, T. Helela, Radiographic measurements of cortical bone: variations in a normal population between 1 and 90 years of age, Acta. Radiol. 293 (Suppl.) (1969) 1–110. E. Schoenau, C.M. Neu, F. Rauch, F. Manz, Gender-specific pubertal changes in volumetric cortical bone mineral density at the proximal radius, Bone 31 (2002) 110–113. W. Högler, C.J. Blimkie, C.T. Cowell, et al., A comparison of bone geometry and cortical density at the mid-femur between
C h a p t e r 9 The Effects of Sex Steroids on Bone Growth l
54.
55.
56.
57.
58.
59.
60.
61.
62.
63.
64.
65.
66. 67.
68.
prepuberty and young adulthood using magnetic resonance imaging, Bone 33 (2003) 771–778. V. Gilsanz, D.L. Skaggs, A. Kovanlikaya, et al., Differential effect of race on the axial and appendicular skeletons of children, J. Clin. Endocrinol. Metab. 83 (1998) 1420–1427. A.C. Looker, T.J. Beck, E.S. Orwoll, Does body size account for gender differences in femur bone density and geometry?, J. Bone Miner. Res. 16 (2001) 1291–1299. Q. Wang, M. Alén, P. Nicholson, et al., Growth patterns at distal radius and tibial shaft in pubertal girls: a 2-year longitudinal study, J. Bone Miner. Res. 20 (2005) 954–961. C. Libanati, D.J. Baylink, E. Lois-Wenzel, N. Srinvasan, S. Mohan, Studies on the potential mediators of skeletal changes occurring during puberty in girls, J. Clin. Endocrinol. Metab. 84 (1999) 2807–2814. G.I. Baroncelli, G. Federico, M. Vignolo, et al., The Phalangeal Quantitative Ultrasound Group. Cross-sectional reference data for phalangeal quantitative ultrasound from early childhood to young-adulthood according to gender, age, skeletal growth, and pubertal development, Bone 39 (2006) 159–173. K. Venken, R. Bouillon, D. Vanderschueren, Androgens versus estrogens: different theories about opposing actions on periosteal bone expansion, IBMS BoneKEy 5 (2008) 130–136 http://www.bonekey-ibms.org/cgi/content/full/ibmske; 5/4/130. R.T. Turner, G.K. Wakley, KS. Hannon, Differential effects of androgens on cortical bone histomorphometry in gonadectomized male and female rats, J. Orthop. Res. 8 (1990) 612–617. B.T. Kim, L. Mosekilde, Y. Duan, et al., The structural and hormonal basis of sex differences in peak appendicular bone strength in rats, J. Bone Miner. Res. 18 (2003) 150–155. R. Bouillon, M. Bex, D. Vanderschueren, S. Boonen, Estrogens are essential for male pubertal periosteal bone expansion, J. Clin. Endocrinol. Metab. 89 (2004) 6025–6029. S.H. Windahl, O. Vidal, G. Andersson, J.A. Gustafsson, C. Ohlsson, Increased cortical bone mineral content but unchanged trabecular bone mineral density in female ER(/) mice, J. Clin. Invest. 104 (1999) 895–901. D. Vanderschueren, K. Venken, J. Ophoff, R. Bouillon, S. Boonen, Clinical review: sex steroids and the periosteum: reconsidering the roles of androgens and estrogens in periosteal expansion, J. Clin. Endocrinol. Metab. 91 (2006) 378–382. J.V. Zborowski, J.A. Cauley, E.O. Talbott, D.S. Guzick, SJ. Winters, Clinical review 116: bone mineral density, androgens, and the polycystic ovary: the complex and controversial issue of androgenic influence in female bone, J. Clin. Endocrinol. Metab. 85 (2000) 3496–3506. M. Notelovitz, Androgen effects on bone and muscle, Fertil. Steril. 77 (Suppl. 4) (2002) S34–S41. Q. Wang, M. Alén, P.H. Nicholson, et al., Differential effects of sex hormones on peri- and endocortical bone surfaces in pubertal girls, J. Clin. Endocrinol. Metab. 91 (2006) 277–282. G.I. Baroncelli, S. Bertelloni, C. Ceccarelli, G. Saggese, Measurement of volumetric bone mineral density accurately determines degree of lumbar undermineralization in children with growth hormone deficiency, J. Clin. Endocrinol. Metab. 83 (1998) 3150–3154.
117
69. G.I. Baroncelli, S. Bertelloni, F. Sodini, G. Saggese, Acquisition of bone mass in normal individuals and in patients with growth hormone deficiency, J. Pediatr. Endocrinol. Metab. 16 (Suppl. 2) (2003) 327–335. 70. JC. Wells, Sexual dimorphism of body composition, Best Pract. Res. Clin. Endocrinol. Metab. 21 (2007) 415–430. 71. WS. Jee, Principles in bone physiology, J. Musculoskelet. Neuron. Interact. 1 (2000) 11–13. 72. HM. Frost, From Wolff’s law to the Utah paradigm: insights about bone physiology and its clinical applications, Anat. Rec. 262 (2001) 398–419. 73. A. Arabi, H. Tamim, M. Nabulsi, et al., Sex differences in the effect of body-composition variables on bone mass in healthy children and adolescents, Am. J. Clin. Nutr. 80 (2004) 1428–1435. 74. F. Rauch, D.A. Bailey, A. Baxter-Jones, R. Mirwald, R. Faulkner, The ‘muscle-bone unit’ during the pubertal growth spurt, Bone 34 (2004) 771–775. 75. H. Macdonald, S. Kontulainen, M. Petit, P. Janssen, H. McKay, Bone strength and its determinants in pre- and early pubertal boys and girls, Bone 39 (2006) 598–608. 76. TM. Skerry, One mechanostat or many? Modifications of the site-specific response of bone to mechanical loading by nature and nurture, J. Musculoskelet. Neuron. Interact. 6 (2006) 122–127. 77. H.M. Frost, E. Schönau, The ‘muscle-bone unit’ in children and adolescents: a 2000 overview, J. Pediatr. Endocrinol. Metab. 13 (2000) 550–571. 78. J.L. Ferretti, R.F. Capozza, G.R. Cointry, et al., Genderrelated differences in the relationship between densitometric values of whole-body bone mineral content and lean body mass in humans between 2 and 87 years of age., Bone 22 (1998) 683–690. 79. H. Schiessl, H.M. Frost, WS. Jee, Estrogen and bone-muscle strength and mass relationships, Bone 22 (1998) 1–6. 80. HM. Frost, Growth hormone and osteoporosis: an overview of endocrinological and pharmacological insights from the Utah paradigm of skeletal physiology, Horm. Res. 54 (Suppl. 1) (2000) 36–43. 81. F. Rauch, E. Schoenau, The developing bone: slave or master of its cells and molecules? Pediatr. Res. 50 (2001) 309–314. 82. M.A. Petit, T.J. Beck, SA. Kontulainen, Examining the developing bone: what do we measure and how do we do it?, J. Musculoskelet. Neuron. Interact. 5 (3) (2005) 213–224. 83. M. Brown, Skeletal muscle and bone: effect of sex steroids and aging, Adv. Physiol. Educ. 32 (2008) 120–126. 84. I. Zofková, Hormonal aspects of the muscle-bone unit, Physiol. Res. 57 (Suppl. 1) (2008) S159–S169. 85. H. Sievänen, Hormonal influences on the muscle-bone feedback system: a perspective., J. Musculoskelet. Neuron. Interact. 5 (2005) 255–261. 86. L.K. Saxon, A.G. Robling, A.B. Castillo, S. Mohan, CH. Turner, The skeletal responsiveness to mechanical loading is enhanced in mice with a null mutation in estrogen receptor-beta, Am. J. Physiol. Endocrinol. Metab. 293 (2007) E484–E491. 87. T.L. Järvinen, P. Kannus, I. Pajamaki, et al., Estrogen deposits extra mineral into bones of female rats in puberty, but simultaneously seems to suppress the responsiveness of female skeleton to mechanical loading, Bone 32 (2003) 642–651.
118
Osteoporosis in Men
88. S.L. Bass, L. Saxon, R.M. Daly, C.H. Turner, A.G. Robling, E. Seeman, S. Stuckey, The effect of mechanical loading on the size and shape of bone in pre-, peri-, and postpubertal girls: a study in tennis players, J. Bone Miner. Res. 17 (2002) 2274–2280. 89. R.M. Daly, L. Saxon, C.H. Turner, A.G. Robling, SL. Bass, The relationship between muscle size and bone geometry during growth and in response to exercise, Bone 34 (2004) 281–287. 90. L.K. Saxon, CH. Turner, Estrogen receptor beta: the antimechanostat? Bone 36 (2005) 185–192. 91. M.R. Forwood, L. Li, W.L. Kelly, MB. Bennett, Growth hormone is permissive for skeletal adaptation to mechanical loading, J. Bone Miner. Res. 16 (2001) 2284–2290. 92. A. Mukherjee, R.D. Murray, SM. Shalet, Impact of growth hormone status on body composition and the skeleton, Horm. Res. 62 (2004) 35–41. 93. F. Lupu, J.D. Terwilliger, K. Lee, G.V. Segre, A. Efstratiadis, Roles of growth hormone and insulin-like growth factor 1 in mouse postnatal growth, Dev. Biol. 229 (1) (2001) 141–162. 94. AM. Parfitt, Genetic effects on bone mass and turnover relevance to black/white differences, J. Am. Coll. Nutr. 16 (1997) 325–333. 95. F. Rauch, Bone growth in length and width: the yin and yang of bone stability, J. Musculoskelet. Neuron. Interact. 5 (2005) 194–201. 96. G.I. Baroncelli, S. Bertelloni, F. Sodini, G. Saggese, Osteoporosis in children and adolescents: etiology and management, Paediatr. Drugs 7 (2005) 295–323.
97. L. Zirilli, V. Rochira, C. Diazzi, G. Caffagni, C. Carani, Human models of aromatase deficiency, J. Steroid. Biochem. Mol. Biol. 109 (2008) 212–218. 98. S. Bertelloni, G.I. Baroncelli, G. Federico, M. Cappa, R. Lala, G. Saggese, Altered bone mineral density in patients with complete androgen insensitivity syndrome, Horm. Res. 50 (1998) 309–314. 99. V. Sobel, B. Schwartz, Y.S. Zhu, J.J. Cordero, J. ImperatoMcGinley, Bone mineral density in the complete androgen insensitivity and 5-reductase-2 deficiency syndromes, J. Clin. Endocrinol. Metab. 91 (2006) 3017–3023. 100. D.L. Danilovic, P.H. Correa, E.M. Costa, K.F. Melo, B.B. Mendonca, IJ. Arnhold, Height and bone mineral density in androgen insensitivity syndrome with mutations in the androgen receptor gene, Osteoporos. Int. 18 (2007) 369–374. 101. M.B. Oakes, A.D. Eyvazzadeh, E. Quint, YR. Smith, Complete androgen insensitivity syndrome. A review, J. Pediatr. Adolesc. Gynecol. 21 (2008) 305–310. 102. E. Dati, G.I. Baroncelli, S. Mora, et al., Body composition and metabolic profile in women with complete androgen insensitivity syndrome, Sex Dev. (2009) in press. 103. T.S. Han, D. Goswami, S. Trikudanathan, S.M. Creighton, GS. Conway, Comparison of bone mineral density and body proportions between women with complete androgen insensitivity syndrome and women with gonadal dysgenesis, Eur. J. Endocrinol. 159 (2008) 179–185.
Chapter
10
Nutritional Basis of Skeletal Growth CONNIE M. Weaver1 and Elizabeth M. Haney2 1
Department of Foods and Nutrition, Purdue University, West Lafayette, Indiana, USA Department of Medicine, Oregon Health and Science University, Portland, Oregon, USA
2
Introduction
energy intake from diet records average 35 20% less than true energy intake under weight stable conditions determined by doubly labeled water in overweight adolescent boys and girls [3]. If 35% of calories are underreported, associated nutrients must also be underreported. Furthermore, there are wide variations in nutrient intake, within individuals. An example of the calcium intake of a 14-year-old adolescent determined from diet records taken monthly over 3 years is given in Figure 10.1. The range in calcium intake was 30 to 2895 mg/d. The mean intake was 786 511 mg/d but the variation was so large, it could hardly be interpreted as a habitual calcium intake. For the entire 140 cohort aged 6–14 years, the variance over 2 years was 135 374 mg for within subject and 25 708 for between subjects [5]. About 22 food records would be required to limit attenuation to 90%, but accurately assessing mean reported intake is not equivalent to accuracy of actual mean intake nor does it imply that intake is in steady state. Given the variability in intake of any one nutrient or food over time and the variability of co-ingested nutrients and foods which can also impact skeletal acquisition compounded by our inability to assess accurately consumption, the premier approach to evaluating the contribution of any nutrient or food is through controlled feeding studies. Controlled feeding studies can be conducted for sufficiently long periods in animal studies to monitor changes in bone. However, it is not practical in humans to control diet sufficiently long to measure changes in bone. Subjects can be randomized to dietary supplements or diet prescriptions, but rarely are there sufficient resources or subject commitment to provide a completely controlled diet over the years required to see changes in bone mass or quality. Shorter-term approaches are available to predict impact of diet on bone. Because 99% of the calcium in the body resides in the skeleton, determining whole body calcium retention through metabolic balance studies and calcium turnover rates through calcium isotopic tracer studies are good surrogates for bone
Many factors influence skeletal growth and ultimate peak mass acquired by adulthood. Genetics is thought to contribute 60–80% of peak bone mass and lifestyle factors 20–40% [1, 2]. Genes that control body size are undoubtedly influential in controlling skeletal growth. Crude markers for genetic differences include race and gender, the focus of this book. Lifestyle factors include all of the cultural exposures and individual choices that influence skeletal growth, notably physical activity and diet, the focus of this chapter. The interplay of these nature–nurture factors is what we strive to understand, but methodological limitations thwart our attempts. In this chapter, the influence of nutrition and the interaction of diet and exercise in the development of male peak bone mass will be reviewed, recognizing that the evidence for boys is much less than for girls. Skeletal fragility, which occurs naturally during the pubertal growth spurt or due to pediatric disorders, will also be discussed.
Assessing the role of nutrition in skeletal acquisition Diet is a highly variable and complex behavior to study. There are some characteristics common to individual cultures that can greatly influence bone health, i.e. the low dairy, high salt, plant-based diets of many Asian populations in contrast to high dairy and meat-based diets of many Western populations. However, increasingly, we mix cultural menus on a regular basis as ethnic foods are so accessible. For example, Sushi bars are now common in grocery stores in the USA, a very recent phenomenon. Current diet assessment methodology is poorly equipped to determine the nutrient intake or diet patterns of individuals. Self-reported Osteoporosis in Men
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Dietary calcium mg/d
3000 2500 2000 1500 1000 500 0 0
5
10
15
20
25
30
35
40
Figure 10.1 Dietary calcium from monthly food records in a 14-year-old adolescent [4].
Relative role of nutrition in skeletal requisition In the introduction, the reported proportional contribution of genetic:lifestyle factors was 60–80:20–40%. One wonders if the inability to measure accurately lifestyle factors or their tendency to change considerably on a daily basis and throughout the lifespan relative to genetic contributors diminishes our ability to determine their relative importance. In controlled feeding metabolic studies, calcium intake explained 12.3% of skeletal calcium retention and race explained 13.7% in black and white adolescent girls [8]. Thus, this diet factor of calcium intake in an otherwise consistent 4-day cycle diet had nearly as great an impact as genetics, indicated through race, on skeletal calcium accretion. The relative influence of sex compared to other predictors of skeletal calcium accretion in puberty, including calcium intake, regulators of calcium metabolism, hormones, physical activity, measures of body size and measures of sexual maturity was recently reported [9]. This example of diet–gene contribution to skeletal calcium accretion is from metabolic balance studies in pubertal children conducted by the Weaver laboratory. The primary question addressed in the study of boys was whether boys needed more calcium than girls to achieve their larger skeletons or if they utilize calcium more efficiently. The bulk of skeletal calcium accretion occurs during the pubertal growth spurt. The higher total body bone mineral content (TB BMC) accretion rates in boys compared to girls is shown
450 400
Girls age of peak 12.54 peak value 325 g/y
350 TB BMD velocity in g per
balance and turnover rates [6, 7]. In order for bone mass to change, first, calcium metabolism must be perturbed. The metabolic balance approach is the only method that has been used to study a range of nutrient intakes in attempt to determine optimal intakes for skeletal accretion and will be described in the next section and further in the section on calcium.
Boys age of peak 14.05y peak value 400 g/y
300 250 200 150 100 50 0
9 10 11 12 13 14 15 16 17 18 19 Age in years
Figure 10.2 Total body bone mineral content (TB BMC) accretion rates, age of peak velocity, and peak value as a function of age in boys and girls [10].
in Figure 10.2. This figure is derived from the longitudinal bone densitometry data in Canadian white boys and girls of Bailey et al [10]. This shows that the average peak velocity in bone mineral acquisition is higher in boys than girls and occurs about a year and a half later. Approximately one-fourth of peak bone mass is accumulated in the two years surrounding this peak. Thus, the influence of calcium intake on calcium retention was determined in white girls aged 12–14 years and boys aged 13–15 years [11]. Calcium retention was determined through metabolic balance studies using controlled diets which varied over a range of calcium intakes supplied through fortified juice. The subjects lived on the University campus for two three-week periods separated by a washout period in which each subject received
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1300
Ca retention (mg/day)
1100 Boys
900 700 500 300
Girls
100 –100 –300 500
700
900
1100
1300
1500
1700
1900
2100
2300
Ca intake (mg/day)
Figure 10.3 Scatterplot and predicted curves of calcium retention as a function of calcium intake in adolescent white boys () and girls (). Boys retained 171 38 mg/d more calcium than girls across the range of calcium intakes. [11].
a lower and higher intake assignment. Duplicate diet composites were analyzed for calcium as well as all urine and feces in 24-hour pools. Urinary and fecal compliance was monitored by urinary creatinine and recovery of a nonabsorbable fecal marker. Calcium retention was determined by subtracting excretion from intake. Figure 10.3 shows that calcium retention in boys was higher than girls across the range of calcium intakes by a constant amount of 171 38 mg/d. Thus, boys were more efficient than girls at calcium utilization for bone acquisition throughout the range of calcium intakes studied. Because of constant differences due to sex across calcium intake, a simple gender term could be used in the non-linear regression model of the form:
Y o e L / (1 e L ) 3 g
where Y is the mean Ca retention for a given Ca intake, L 1(1 2xy), x is Ca intake and g is gender coded as 0 for girls and 1 for boys. The implication of this gender term is that boys and girls can be studied together for calcium retention without requiring two cohorts, which would double the sample size. When the value for peak TB BMC accretion per year in boys in Figure 10.2 is converted to mg Ca retention per day knowing that calcium is a constant percent of BMC, the value for calcium retention is 359 mg/d. The mean selfreported calcium intake of the boys in that cohort [12] was 1140 392 mg/d. Using our non-linear regression model, a calcium intake of 1140 mg/d would correspond to a mean Ca retention of 442 mg/d which is remarkably close to the value observed by Bailey et al [10] considering their lack of controlled diet and errors associated with self-reported intakes as well as the short-term nature of our metabolic balance studies.
A secondary analysis of this study explored predictors of calcium retention in boys [11]. Dietary calcium intake, hormonal status (parathyroid hormone (PTH), insulin-like growth factor I (IGF-I) and IGF-I binding protein (IGF-IBP), vitamin D metabolites and sex steroids), biochemical markers of bone metabolism, habitual physical activity, physical fitness, habitual calcium intake, sexual maturity, body consumption and anthropometric measures of body size were all tested in the model for their influence on calcium retention. Dietary calcium explained 21.7% of Ca retention and serum IGF-I explained an additional 11.5%. The effect of serum IGF-I is shown in Figure 10.4. For each unit increase in log IGF-I, there is a 144 mg/d increase in mean calcium retention. IGF-I is a major regulator of longitudinal bone growth through stimulating proliferation and differentiation of chondrocytes at the epiphyses [13]. Serum IGF-I closely matches peak bone accretion rates [14]. None of the other factors measured contributed additional explanation for calcium retention. Thus, diet and an indicator of sexual maturity, which is under the influence of genetic programming, explained 33.2% of the variation in Ca retention in this cohort of adolescent boys. We must look further to explain the rest of the variation in calcium retention.
Micronutrients and bone growth Bone is a living tissue and all essential nutrients are required for bone growth. In this section, the role of the major micronutrients involved will be discussed, focusing primarily on those nutrients with concern about intakes.
Osteoporosis in Men
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Mean Ca retention (mg/d)
1000
800
IGF 1 (ng/mL) 600
600
350 200
400
200
0 600
800 1000 1200 1400 1600 1800 2000 2200 Mean Ca intake (mg/d)
Figure 10.4 Predicted calcium retention across calcium intakes as a function of serum IGF-I in male adolescents. Contours describe serum IGF-I levels of 200, 350 and 600 ng/mL which correspond to z-scores of 1, 0 and 2, respectively, r2 0.332, P 0.002 [9].
Calcium Calcium is the largest contributor to bone mineral content. It exists in hydroxyapatite crystals, which contribute to bone strength, and acts as a reserve to maintain serum calcium levels within a narrow range during periods of dietary calcium inadequacy. Calcium intakes fall below recommended levels for much of the world’s population. Males consume more calcium than females because they consume more calories on average. Nevertheless, calcium intakes in males are especially inadequate during pubertal growth. In an evaluation of adequacy of calcium intakes in 20 countries, Looker [15] compared average intakes against their respective country requirements. For adolescent males, 65% on average reach their country specific calcium recommendations which range from 500 to 1300 mg/d. Calcium requirements are well established for American white boys [11, 16]. Figure 10.3 shows that the plateau intake for maximal calcium retention in adolescent boys is not significantly different from 1300 mg/d previously reported for adolescent girls [17]. Recommended calcium intakes for children aged 4–8 years is 800 mg/d, but this too was based on data in girls as no balance studies were available for boys. Calcium requirements for other subpopulations need to be determined. Most (72%) of dietary calcium comes from dairy products [18]. Children who do not choose calcium rich foods are often not compliant with supplements. Furthermore,
calcium intake is a marker for other nutrients [18], but this would not be true when calcium is ingested in the form of supplements. It is important to establish good dietary habits early because calcium intake in adolescents tracks (r 0.43) into adulthood for males [19]. There are few randomized controlled trials (RCTs) of calcium intake that include boys (Table 10.1). In the study of identical twins [20], a 3-year calcium intervention increased bone mineral density (BMD) only in the prepubertal children. Another study of white prepubertal boys showed a relatively short intervention of 800 mg calcium daily for 8.5 months showed a trend toward improved BMD [23]. In Chinese 7 year olds, a one-year calcium intervention increased lumbar spine BMC and area, but not proximal femoral neck [21]. In African children, midshaft radius BMC and BMD were significantly increased by a oneyear calcium supplementation [22]. In white boys from the UK, randomization to 1 g calcium supplementation for 13 months increased height by 0.4% (P 0.0004) and lean mass by 1.3% (P 0.02) as well as BMC 1–3% and bone area of several sites [24]. A similar study [25] in 16–18year-old girls showed calcium supplementation increased bone mineral mass, but not bone size or height, in contrast to boys. However, the effect of calcium supplement on growth may be more related to the timing of the intervention relative to peak BMC accretion rather than differences in gender responsiveness. Figure 10.2 illustrates that 16–18-year-old girls have moved past their peak accretion period unlike boys. The authors projected that the observed increases in BMC with calcium supplementation (about 0.2 SD), if maintained into adulthood, would lower fracture risk by about 15%.
Vitamin D Requirements for vitamin D have not been established by rigorous evidence of the relationship of status to a functional indicator. There has been much speculation that vitamin D insufficiency in children is widespread based on adult cut off levels for serum 25(OH)D levels [26, 27]. However, serum 25(OH)D levels have not positively predicted calcium absorption or retention in children [27–30]. There have been no vitamin D intervention trials on bone in boys.
Magnesium and Phosphorus Both of these minerals comprise substantial portions of bone mineral. There are no concerns regarding deficiencies of these minerals in children. Severe magnesium deficiency results in structural changes that diminish bone volume [31]. Phosphorus intake excess combined with a low calcium intake has been a concern, as a low Ca/P ratio alters bone mineralization and bone turnover [32]. Cola beverages contain high levels of phosphate which have been negatively
Table 10.1 Differences in mean changes in bone mineral content and bone mineral density in calcium treated versus placebo groups in randomized, controlled trials in boys Source
Ref. Subject. Age (y) Sex Race/ no. no location
Length Calcium study intake (months) Controls (mg/day)
Calcium Site intake Treatment (mg/day)
Johnston et al, 1992
20
140 twins 6–14
F/M White, IN 36
908
1612
Lee et al, 1995
21
109
F/M Asian, China
571
1363
7
18
Midshaft radius Distal radius* Lumbar spine Femoral neck Ward’s triangle Greater trochanter Distal radius Lumbar spine
22
160
8.3–11.9 F/M Black, Gambia
12
342
1056
Bass et al, 2007
23
88
7–11
8.5
934
800 (milk minerals)
24
143
16–18
M
White, Australia
White, UK
13
1283
1858
BMD BMD BMD BMD BMD BMD
17.7% 21.5% 20.1% 15.3% 15.4% 18.1%
15.2% 18.2% 19.5% 14.9% 14.2% 17.11%
BMC Area BMC Area BMC
15.92 (T) vs 14.95% (P) gain, P 0.53 7.74 (T) vs 6.00% (P) gain, P 0.081 20.92 (T) vs 16.34% (P) gain, P 0.035 11.16 (T) vs 8.71% (P) gain, P 0.049 24.19 (T) vs 23.42% (P) gain, P 0.37
Proximal femoral neck Midshaft radius BMC BMD Non-exercise: Femur Tibia–fibula Exercise: Femur Tibia–fibula Whole body Lumbar spine
Total hip Femoral neck Intertrochanter *
Placebo (P)
3.0 1.4 (T-P), P 0.034 4.5 0.9 (T-P), P 0.0001
BMC BMC
1.1% (TvsP, P 0.06 1.4% (T vs P), P 0.11
BMC BMC
2.0% (T vs P, or No exercise), P 0.03 3% (T vs P), P 0.02
BMC BMC Bone area BMC BMC BMC
1.3% (TvsP), P 0.02 2.5% (TvsP), P 0.004 1.5% (TvsP), P 0.0003 2.3% (TvsP), P 0.01 2.4% (TvsP), P 0.01 2.7% (TvsP), P 0.01
Difference between groups significant for percent increase at distal radius (3.3, 95% CI 1.2–5.5). Difference between groups for midshaft radius was 2.5 (95% CI 0–4.9) and for the average of 6 sites was 1.4 (95% CI 0–2.5). All other between group differences were not significant. T: treatment; p: placebo; BMC: bone mineral content; BMD: bone mineral density; M: male; F: female; UK: United Kingdom; IN: Indiana, USA.
l
Prentice et al, 2005
M
Treatment (T)
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Dibba et al, 2000
Measure Group mean increase
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associated with bone gain in children [33]. However, the displacement of milk by beverages which lack the nutrient package of milk is more detrimental to bone than their phosphate content.
Dietary patterns and bone growth The formative years are the period of greatest skeletal growth, but also are when lifelong eating and exercise habits are set. Food is the most adequate source of nutrients and health promoters. Penetration of supplement use among children is low. Recommended food patterns by the 2005 Dietary Guidelines Advisory Committee for Americans considered bone health [18]. Many other Western countries are influenced by these guidelines which used both an evidencebased approach to determine the relationships of dietary intakes and bone health and other measures of health as well as a food modeling approach to achieve intakes of nutrients recommended by the Institute of Medicine [16] within one’s energy requirements. Adequate energy and macronutrients as well as micronutrients previously discussed are required for optimal growth. The role of dietary protein on bone health is discussed in another chapter, but more research is needed in children. Dietary habits including salt intake and foods which contain enhancers and inhibitors of mineral absorption also play a role in bone health.
Milk and Milk Products Milk consumption is associated with overall diet quality. Adequate milk intake in children is associated with adequacy of several other micronutrients including calcium, potassium, magnesium, zinc, iron, riboflavin, vitamin A, folate and vitamin D [34]. The Dietary Guideline for Americans recommends 2 cups of milk per day for children between ages of 2 and 8 years and 3 cups per day over age 8 [18]. It is difficult to meet vitamin D, calcium and potassium requirements without milk. Among 2364 children aged 9–18 (1154 males) who reported no dairy intake in the NHANES 2001–2002 study, only one child achieved adequate calcium intake without use of calcium fortified foods. Children with dairy-free diets had approximately half the calcium intake of those whose diet included dairy products [35]. Children may avoid milk products because of intolerance or allergy, dislike and/or alternative choices (soft drinks) or religious customs. Children who avoid milk are more likely to have low calcium intakes and sustain forearm fractures [36]. Likewise, children who avoid milk demonstrate significant declines in lumbar spine BMD after 2 years of follow up [37]. The detrimental effect of low milk intake on bone may be lower for boys than it is for girls. A case control
study of 34 girls and 57 boys aged 2.5–20 with cow’s milk allergy compared to those without resulted in an odds ratio for fracture of 4.6 (P 0.013) for girls and 1.3 (NS) for boys [38]. Two large cohort studies have evaluated milk and soft drink intake by dietary assessment and reported on bone group. Among 220 boys and girls aged 8–14, replacing milk with soft drinks was more detrimental to bone gain by girls than by boys [38]. Among 591 boys and 774 girls either 12 or 15 years old, consumption of soft drinks was associated with lower BMD at the dominant heel for girls but not boys and no difference in forearm BMD for either sex, after adjustments [39]. An RCT of high milk intake versus high meat intake (identical protein amounts in the two diets) among 8-yearold boys showed that increased milk intake decreases bone turnover among boys after 7 days, likely through increased serum IGF-I. Those randomized to milk had significantly higher calcium intakes over the 7 days and serum osteocalcin and serum C-terminal cross-linking telopeptide of collagen 1 (CTX) decreased [40].
Salt Dietary salt has a detrimental effect on growing bone through increasing urinary excretion. In fact, dietary salt is the largest known predictor of urinary calcium excretion [41].
Enhancers and Inhibitors of Mineral Absorption The presence of enhancers and inhibitors of mineral absorption in diets can alter the demand for mineral important to bone. Oxalic acid, found in spinach, rhubarb and some seeds and other plant sources, is a potent inhibitor of calcium absorption. Calcium from spinach is absorbed approximately one-tenth as efficiently as milk calcium because the calcium oxalate salt in spinach is largely indigestible [42]. Phytic acid, the storage form of phosphorus in seeds, binds divalent cations, including Mg2, Zn2, Fe2 and Ca2, resulting in decreased absorption of these minerals. The inhibitory effect of phytate on calcium absorption is less than that of oxalate and is further decreased with fermentation [43]. Liberal consumption of whole grains and legumes is encouraged by the Dietary Guidelines for Americans [18], but this type of diet emphasizes the need for adequate intake of minerals. There have been numerous reports evaluating dietary constituents that might enhance mineral absorption, especially protein products or amino acids and non-digestible oligosaccharides. The most promising for growing bone has been a mixture of short- and long-chain inulin-like fructooligosaccharides [44]. A supplement of 8 g/d of the fructan product increased (P 0.03) total body BMC though enhancing calcium absorption efficiency by 8.5 1.6% (P 0.001) in pubertal adolescents. In growing rats,
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whey protein enhanced calcium absorption from a single meal, but the enhancing effect adapted away with chronic feeding [45].
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but not bone resorption (CTx), was also reduced. Similar studies in the growing skeleton need to be undertaken.
Nutrition and pediatric disorders Diet and exercise interactions Several studies provide evidence that there is a positive interaction between diet and physical activity. The most studied aspects of diet and milk and calcium intake. In one study, 28 boys were randomized to supplementing usual diet with three extra servings per day of fluid milk or non-calcium fortified juice, while engaged in a 12-week supervised resistance training program 3 hours/week [46]. Milk drinkers had higher calcium, vitamin D, vitamin A, magnesium, phosphorus and carbohydrate intakes. The milk group had higher total body (BMD) at the end of the training period. Another trial randomized 88 pre- and early pubertal boys to one of four groups: moderate exercise with and without calcium and low impact exercise with and without calcium (all exercise was 20 minutes three times per week and addition of calcium was through milk-mineral fortified foods versus non-fortified foods) [23]. After 8.5 months, femur BMD had increased more for the moderate exercise plus calcium group compared to each of the three other groups (moderate exercise plus placebo, low exercise plus calcium and low exercise plus placebo; approximately 2% increase, P 0.03). At the tibia-fibula, BMD was 3% greater (P 0.02) for the exercise plus calcium group compared to low exercise plus placebo. Although this small study was underpowered to see significant (only trends at P 0.05) effects of exercise and calcium alone, the combined intervention of calcium and exercise resulted in significant advantages to femur but not arms or spine. In contrast, a study in 9-year-old girls found main effects of exercise at the legs and calcium at the arms and an exercise-calcium interaction at the femur [47]. In the randomized trial of calcium supplementation in late adolescent boys previously discussed [24], there was a positive interaction with physical activity (4.4%, P 0.05) on BMC response at the intertrochanter, but not at other skeletal sites. The mechanism of the influence of exercise on calcium metabolism is not completely understood. Increased calcium absorption efficiency and reduced bone turnover have been reported. Fractional calcium absorption efficiency measured by a proxy, strontium, was higher in 31 exercisetrained compared to 26 age-matched sedentary young men (20.3 4.5 versus 16.3 3.1%, P 0.001) [48]. Using the same method for estimating calcium absorption efficiency in 18 male athletes, an acute bout of exercise significantly increased calcium absorption from 14.6 0.8% to 16.2 0.07% (P 0.05) and serum 1,25(OH)2D levels from 104 111 to 123 10 pmol/L (P 0.05) [49]. In this study, a biochemical marker of bone resorption (PICP),
Several pediatric disorders are associated with worsened bone health (Table 10.2), many as a result of their impact on nutritional status. Conditions affecting bone through nutritional pathways include: anorexia nervosa, celiac disease, inflammatory bowel disease and obesity. Other conditions may be primarily genetic (osteogenesis imperfect, cystic fibrosis) or idiopathic/acquired (seizure disorders); may have mechanisms that are based in alterations in bone turnover or in connective tissue; and may be associated with low bone density and BMC because of medications used to treat the condition, such as glucocorticoids, antiretrovirals and anticonvulsants.
Anorexia Nervosa Anorexia nervosa (AN) is a condition of undernutrition, low body weight and fear of gaining weight. While more common among females, 5–15% of AN patients are male [50]. Lifetime prevalence estimates for AN in US males are approximately one-third of that for females [51] and, in one study, 11% of adolescents hospitalized for eating disorders were male [52]. AN has been associated with high rates of bone resorption, bone loss and increased fracture risk among girls [53, 54]. Recently, Misra et al demonstrated that boys with AN (n 17, mean age 16.0 1.8)
Table 10.2 Conditions associated with low bone mass and/or fractures among children and adolescents Anorexia nervosa Celiac disease Craniospinal radiation Cystic fibrosis Diabetes mellitus Epilepsy (anti-convulsant medications) Gaucher disease Hemophilia HIV (antiretroviral therapy) Inflammatory bowel disease Obesity Organ transplantation (immunosuppressive medications) Osteogenesis imperfecta Osteoporosis-pseudoganglioma syndrome Nephrotic syndrome, glucocorticoid-sensitive Neurofibromatosis I Renal osteodystrophy Rheumatologic disease Turner syndrome Adapted from Gordon, 2005 [54].
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have lower BMD at lumbar spine, total hip and all subregions compared to normal, bone-age matched controls. Additionally, these boys had lower levels of PINP and CTX and lower testosterone levels compared to controls. Lower BMD was predicted by lower testosterone, body mass index (BMI) and lean mass [50, 55].
Celiac Disease Celiac disease (also referred to as celiac sprue) is an immunemediated small bowel enteropathy caused by gluten sensitivity. Celiac disease is increasingly diagnosed in children and adults, with a prevalence of 3–13 in 1000 for children and adolescents between the ages of 2.5 and 15 years [56]. Symptoms are often non-specific, including abdominal pain, diarrhea, abdominal distention and failure to thrive. Untreated, celiac disease results in malabsorption which can lead to vitamin D insufficiency, osteomalacia and fractures [57–60]. Bone disease can occur in patients without gastrointestinal symptoms [61–64]. Studies have demonstrated lower vitamin D levels, lower calcium and higher intact-parathyroid hormone levels [65, 66], as well as higher bone-specific alkaline phosphatase and n-telopeptide levels among children with untreated celiac disease compared to controls [59]. Among seropositive children with type I diabetes who also test positive for antibodies to gluten, the degree of villous atrophy seen on small bowel biopsy is associated with higher likelihood of growth failure and low bone mass [64]. When children are treated with a gluten-free diet, the absorptive problems are reversed and vitamin D levels and bone can be corrected. Among 54 children with previously untreated celiac disease, calcium, 25(OH) vitamin D and iPTH were normalized after 6 months of gluten-free diet [65]. Bone mineral content, bone area and BMD are all improved with treatment, as demonstrated by case control studies. The time it takes for treatment to improve BMD may be as little 6 months and gains have been documented at both 4.3 years and up to 10.7 years after starting treatment [59, 67]. Similar improvements in BMD have been shown in children with diabetes and celiac disease after 12 months of gluten restriction [64].
Inflammatory Bowel Disease Children with inflammatory bowel disease (IBD), either Crohn’s disease (CD) or ulcerative colitis (UC), are at risk for developing low bone mass because of the underlying inflammation, delayed maturation, concomitant malnutrition or medications (chronic use of glucocorticoids) [68]. Reduced BMD has been demonstrated in boys and girls with IBD [69–74]. This finding is at least partially explained by glucocorticoid treatment [70, 72–73]. Studies are conflicted as to gender differences, but some indicate that boys are less likely than girls to have reduced BMD [70, 71, 73, 75]. The prevalence of reduced BMD is higher among children
with CD compared to UC [70, 73]. Children with CD are also at increased risk for fracture [76]. There are several aspects of the relationship between IBD and skeletal health, including the question of whether 25-hydroxy vitamin D levels influence BMD and fracture in children/adolescents with BMD, that remain incompletely understood.
Obesity Although higher BMI is thought to be predictive of osteoporosis in adults, overweight children and adolescents may be at increased risk of fractures [77], possibly because of increased load on a developing skeleton [78]. A comparison of children who had broken a distal forearm on two separate occasions to those without prior fracture revealed low calcium intake, milk intolerance, early age at first fracture and high BMI (33% overweight versus 15.5% in control group) as risk factors, despite no difference between the groups in physical activity [77]. Several recent studies attempt to improve our understanding of the determinants of bone structure in obese versus normal weight children and adolescents. Compared with children of healthy weight, 202 overweight and obese boys had lower vertebral BMD for their bone area, body height and body weight and pubertal development. BMC and bone area relative to body weight was 2.5–10% lower than predicted (P 0.05) [79]. It may be that the obese pubertal skeleton is adapted for lean mass and muscle forces but not for fat mass [80]. However, this concept remains incompletely understood and there may be gender differences: a study of 444 girls and 482 boys aged 6–18 years showed that non-bone fat free mass was a determinant of BMD in all girls but only prepubertal boys [81]. As opposed to the effect of anorexia and low body weight on bone, the effect of weight loss in obese and overweight adolescents appears to be beneficial for bone health. Adolescents participating in medically supervised weight loss programs that included exercise and diet with or without weight-loss medication had improved BMC [82, 83].
Conclusions As with other aspects of our understanding of male osteoporosis, research on the role of nutrition in the growing male skeleton lags behind that in girls. Recently, the effect of calcium intake on calcium retention was reported for white adolescent boys as well as other predictors of calcium retention. Attention to bone health is warranted for children with conditions that may predispose to bone loss, reduced bone accrual and fractures. Studies of other age groups and racial and ethnic minorities are needed. Little systematic work has been done on nutrients other than calcium or importance of food patterns in the growing male skeleton.
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References 1. J.-P. Bonjour, T. Chevalley, Pubertal timing, peak bone mass and fragility fracture risk, Bone Key-Osteovision 4 (2) (2007) 30–48. 2. E.A. Krall, B. Dawson-Hughes, Heritable and lifestyle determinants of bone mineral density, J. Bone Miner. Res. 8 (1993) 1–9. 3. R. Singh, B.R. Martin, Y. Hickey, et al., Comparison of selfreported energy intake and measured metabolizable energy intake with total energy expenditure in overweight teens, Am. J. Clin. Nutr. (2009) in press. 4. C.M. Weaver, B.R. Martin, M. Peacock, Calcium metabolism in adolescent girls, in: P. Burckhardt, R.P. Heaney (Eds.), Nutritional Aspects of Osteoporosis, Serono Symposia Publications, 1995, pp. 123–128. 5. J.Z. Miller, T. Kimes, S. Hui, M.E. Andon, C.C. Johnston Jr., Nutrient intake variability in pediatric population: implications for study design, J. Nutr. 121 (1991) 265–274. 6. C.M. Weaver, Clinical approaches for studying calcium metabolism and its relationship to disease, in: C.M. Weaver, R.P. Heaney (Eds.), Calcium in Human Health, Humana Press, 2006, pp. 65–81. 7. M.E. Wastney, Y. Zhao, CM. Weaver, Kinetic studies, in: C.M. Weaver, R.P. Heaney (Eds.), Calcium in Human Health, Humana Press, 2006, pp. 83–93. 8. M. Braun, C. Palacios, K. Wigertz, et al., Racial differences in skeletal calcium retention in adolescent girls on a range of controlled calcium intakes, Am. J. Clin. Nutr. 85 (2007) 1657–1663. 9. K. Hill, M.M. Braun, M. Kern, et al., Predictors of calcium retention in adolescent boys, J. Clin. Endocrin. Metab. (2008) in press. 10. D.A. Bailey, H.A. McKay, R.L. Mirwald, P.R.E. Crocker, RA. Faulkner, A six-year longitudinal study of the relationship of physical activity to bone mineral accrual in growing children: the University of Saskatchewan bone mineral accrual study, J. Bone Miner. Res. 14 (1999) 1672–1679. 11. M.M. Braun, B.R. Martin, M. Kern, et al., Calcium retention in adolescent boys on a range of controlled calcium intakes, Am. J. Clin. Nutr. 84 (2006) 414–418. 12. D.A. Bailey, A.D. Martin, H.A. McKay, S. Whiting, R. Mirwald, Calcium accretion in girls and body during puberty: a longitudinal analysis, J. Bone Miner. Res. 15 (2000) 2245–2250. 13. J. Wang, J. Zhou, C.M. Cheng, J.J. Kopchick, CA. Bondy, Evidence supporting dual, IGF-I-independent and IGF-Idependent, roles for GH in promoting longitudinal bone growth, J. Endocrinol. 180 (2004) 247–255. 14. J.S. Johansen, A. Giwercman, D. Hartwell, et al., Serum bone gla-protein as a marker of bone growth in children and adolescents: correlation with age, height, serum insulin-like growth factor I, and serum testosterone, J. Clin. Endocrinol. Metab. 67 (1998) 273–278. 15. A.C. Looker, Dietary calcium: recommendations and intakes around the world, in: C.M. Weaver, R.P. Heaney (Eds.), Calcium in Human Health, Humana Press, 2006, pp. 105–128. 16. Institute of Medicine. Dietary reference intakes for calcium, phosphorus, magnesium, vitamin d, and fluoride, 1997.
17.
18.
19.
20.
21.
22.
23.
24.
25.
26.
27.
28.
29.
30.
127
Standing Committee on the Scientific Evaluation of Dietary Reference Intakes, Food and Nutrition Board, National Academy Press, Washington, DC. L.A. Jackman, S.S. Millane, B.R. Martin, et al., Calcium retention in relation to calcium intake and postmenarcheal age in adolescent females, Am. J. Clin. Nutr. 66 (1997) 327–333. US Department of Health and Human Services and US Department of Agriculture, Dietary Guidelines for Americans. US Government Printing Office, sixth ed., Washington, DC, 2005. www.healthierus.gov/dietary guidelines (accessed 12.09.06). L.A. Lytle, S. Seifert, J. Greenstein, P. McGovern, How do children’s eating patterns and food choices change over time? Results from a cohort study. Am. J. Health Promot. 14 (2003) 222–228. C.C. Johnston Jr., J.Z. Miller, C.W. Slemenda, et al., Calcium supplementation and increases in bone mineral density in children, N. Engl. J. Med. 327 (1992) 82–87. W.T.K. Lee, S.S.F. Leung, S.H. Wang, et al., Double-blind controlled calcium supplementation and bone mineral accretion in children accustomed to low calcium diet, Am. J. Clin. Nutr. 60 (1994) 744–752. B. Dibba, A. Prentice, M. Ceesay, et al., Effect of calcium supplementation on bone mineral accretion in Gambian children accustomed to a low-calcium diet, Am. J. Clin. Nutr. 71 (2) (2000) 544–549. S.L. Bass, G. Naughton, L. Saxon, et al., Exercise and calcium combined results in a greater osteogenic effect than either factor alone: a blinded randomized placebo-controlled trial in boys, J. Bone Miner. Res. 22 (3) (2007) 458–464. A. Prentice, F. Gintz, S.J. Stear, S.C. Jones, M.A. Laskey, TJ. Cole, Calcium supplementation increases stature and bone mineral mass of 16–18 year old boys, J. Clin. Endocrinol. Metab. 90 (2005) 3153–3161. S.J. Stear, A. Prentice, S.C. Jones, TJ. Cole, Effect of a calcium and exercise intervention on the bone mineral status of 16–18-y-old adolescent girls, Am. J. Clin. Nutr. 77 (2003) 985–992. G. El-Hajj Fuleihan, R. Vieth, Vitamin D insufficiency and musculoskeletal health in children and adolescents, in: P. Burckhardt, R.P. Heaney, B. Dawson-Hughes (Eds.), Nutritional Aspects of Osteoporosis, International Congress Series 1297, Elsevier, 2007, pp. 91–108. C. Gordon, K.C. DePeter, H.A. Feldman, E. Grave, SJ. Emans, Prevalence of vitamin D deficiency among healthy adolescents, Arch. Pediatr. Adolesc. Med. 158 (2004) 531–537. C.M. Weaver, L.D. McCabe, G.P. McCabe, et al., Vitamin D status and calcium metabolism in adolescent black and white girls on a range of controlled calcium intakes, J. Clin. Endocrinol. Metab. (2008) in press. S.A. Abrams, I.J. Griffin, K.M. Hawthorne, S.K. Gunn, C.M. Gundberg, T.O. Carpenter, Relationships among vitamin D levels, parathyroid hormone and calcium absorption in young adolescents, J. Clin. Endocrinol. Metab. 90 (2005) 5576–5581. W.T. Lee, J.C. Cheng, J. Jiang, P. Hu, X. Hu, DC. Roberts, Calcium absorption measured by stable calcium isotopes (42Ca, 44Ca) among northern Chinese adolescents with low vitamin D status, J. Orthop. Surg. 10 (10) (2002) 61–66.
128
Osteoporosis in Men
31. R.K. Rude, H.E. Gruber, H.J. Norton, L.Y. Wei, A. Fransto, J. Kilburn, Reduction of dietary magnesium by only 50% in the rat disrupts bone and mineral metabolism, Osteoporos. Int. 17 (2006) 1022–1032. 32. R. Masuyama, Y. Nakaya, S. Katsumata, et al., Dietary calcium and phosphorus ratio regulates bone mineralization and turnover in vitamin D receptor knockout mice by affecting intestinal calcium and phosphorus absorption, J. Bone Miner. Res. 18 (2003) 1217–1226. 33. S.J. Whiting, H. Vatanparast, A. Baxter-Jones, R.A. Faulkner, R. Miriwald, D.A. Bailey, Factors that affect bone mineral accrual in the adolescent growth spurt, J. Nutr. 134 (2004) 696S–700S. 34. C. Balleow, S. Kuester, C. Gillespie, Beverage choices affect adequacy of children’s nutrient intakes, Arch. Pediatr. Adolesc. Med. 154 (2000) 1148–1152. 35. X. Gao, P.E. Wilde, A.H. Lichtenstein, K.L. Tucker, Meeting adequate intake for dietary calcium without dairy foods in adolescents aged 9 to 18 years (National Health and Nutrition Examination Survey 2001–2002), J. Am. Diet. Assoc. 106 (2006) 1759–1765. 36. A. Goulding, J.E.P. Rockell, R.E. Black, A.M. Grant, I.E. Jones, S.M. Williams, Children who avoid drinking cow’s milk are at increased risk for prepubertal bone fractures, J. Am. Diet. Assoc. 104 (2) (2004) 250–253. 37. J.E.P. Rockell, S.M. Williams, R.W. Taylor, A.M. Grant, I.E. Jones, A. Goulding, Two-year changes in bone and body composition in young children with a history of prolonged milk avoidance, Osteoporos. Int. 16 (2005) 1016–1023. 38. J. Konstantynowicz, T.V. Nguyen, M. Kaczmarski, J. Jamiolkowski, J. Piotrowska-Jastrzebaska, E. Seeman, Fractures during growth: potential role of a milk-free diet, Osteoporos. Int. 18 (2007) 1601–1607. 39. C. McGartland, P.J. Robson, L. Murray, et al., Carbonated soft drink consumption and bone mineral density in adolescence: the Northern Ireland Young Hearts Project, J. Bone Miner. Res. 18 (9) (2003) 1563–1569. 40. A.Z. Budek, C. Hoppe, K.F. Michaelsen, C. Molgaard, High intake of milk, but not meat, decreases bone turnover in prepubertal boys after 7 days, Eur. J. Clin. Nutr. 61 (2007) 957–962. 41. V. Matkovic, J.Z. Ilich, M.B. Andon, et al., Urinary calcium, sodium, and bone mass of young females, Am. J. Clin. Nutr. 62 (1995) 417–425. 42. C.M. Weaver, R.P. Heaney, Isotopic exchange of ingested calcium between labeled sources. Evidence that ingested calcium does not form a common absorptive pool, Calcif. Tissue Intl. 49 (1991) 244–247. 43. C.M. Weaver, R.P. Heaney, Food sources, supplements and bioavailability, in: C.M. Weaver, R.P. Heaney (Eds.), Calcium in Human Health, Humana Press, 2006, pp. 129–142. 44. S.A. Abrams, I.J. Griffin, K.M. Hawthorne, et al., A combination of prebiotic short- and long-chain inulin-type fructans enhances calcium absorption and bone mineralization in young adults, Am. J. Clin. Nutr. 82 (2005) 471–476. 45. Y. Zhao, B.R. Martin, M.E. Wastney, L. Schollum, C.M. Weaver, Acute versus chronic effects of whey proteins on calcium absorption in growing rats, Exp. Biol. Med. 230 (2005) 536–542. 46. J.S. Volek, A.L. Gomez, T.P. Scheett, et al., Increasing fluid milk favorably affects bone mineral density responses to
47.
48.
49.
50.
51.
52.
53.
54. 55.
56.
57.
58.
59.
60. 61.
62.
63.
resistance training in adolescent boys, J. Am. Diet. Assoc. 103 (10) (2003) 1353–1356. S. Iuliano-Burns, L. Saxon, G. Naughton, K. Gibbons, S.L. Bass, Regional specificity of exercise and calcium during skeletal growth in girls: a randomized controlled trial, J. Bone Miner. Res. 18 (2003) 156–162. A. Zitterman, O. Sabatschus, S.P. Jantzen, et al., Exercisetrained young men have higher calcium absorption rates and plasma calcitriol levels compared with age-matched sedentary controls, Calcif. Tissue Int. 67 (2000) 215–219. A. Zittermann, O. Sabatschus, S. Jantzen, P. Platen, A. Danz, P. Stehle, Evidence for an acute rise of intestinal calcium absorption in response to aerobic exercise, Eur. J. Nutr. 41 (2002) 189–196. M. Misra, D.K. Katzman, J. Cord, et al., Percentage extremity fat, but not percentage trunk fat, is lower in adolescent boys with anorexia nervosa than in healthy adolescents, Am. J. Clin. Nutr. 88 (2008) 1478–1484. J.I. Hudson, E. Hiripi, H.G. Pope Jr., R.C. Kessler, The prevalence and correlates of eating disorders in the national comorbidity survey replication., Biol. Psychiatr. 61 (2007) 348–358. K. Robergeau, J. Joseph, T. Silber, Hospitalization of children and adolescents for eating disorders in the state of New York, J. Adolesc. Hlth. 39 (2006) 806–810. S. Zipfel, M.J. Seibel, B. Lowe, P.H. Beumont, C. Kasperk, W. Herzog, Osteoporosis in eating disorders: a follow-up study of patients with anorexia and bulimia nervosa, J. Clin. Endocrinol. Metab. 86 (11) (2001) 5227–5233. C.M. Gordon, Evaluation of bone density in children, Curr. Opin. Endrocrinol. Diabetes. 12 (2005) 444–451. M. Misra, D.K. Katzman, J. Cord, et al., Bone metabolism in adolescent boys with anorexia nervosa, J. Clin. Endocrinol. Metab. 93 (8) (2008) 3029–3036. I.D. Hill, M.H. Dirks, G.S. Liptak, et al., Guidelines for the diagnosis and treatment of celiac disease in children: recommendations of the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition, J. Pediatr. Gastroenterol Nutrit. 40 (2005) 1–19. J. Ferretti, R. Mazure, P. Tanoue, et al., Analysis of structure and strength of bones in celiac disease patients, Am. J. Gastroenterol. 98 (2) (2003) 382–390. H. Vazqeuz, R. Mazure, D. Gonzalez, et al., Risk of fractures in celiac disease patients: a cross sectional, case-control study., Am. J. Gastroenterol. 95 (1) (2000) 183–189. S. Mora, G. Barera, S. Beccio, et al., A prospective, longitudinal study of the long-term effect of treatment on bone density in children with celiac disease, J. Pediatr. 139 (2001) 516–521. S. Mora, Celiac disease in children: impact on bone health, Rev. Endocrin. Metab. Disord. 9 (2008) 123–130. K. Mustalahti, P. Collin, H. Sievanen, J. Salmi, M. Maki, Osteopenia in patients with clinically silent celiac disease warrants screening, Lancet 354 (1999) 744–745. J.L. Shaker, R.C. Brickner, J.W. Findling, et al., Hypocalcemia and skeletal disease as presenting features of celiac disease, Arch. Intern. Med. 157 (9) (1997) 1013–1016. A.G. Kalayci, A. Kansu, N. Girgin, O. Kucuk, G. Aras, Bone mineral density and importance of a gluten-free diet in patients with celiac disease in childhood, Pediatrics 108 (5) (2001) e89.
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64. E. Artz, J. Warren-Ulanch, D. Becker, S. Greenspan, M. Freemark, Seropositivity to celiac antigens in asymptomatic children with type 1 diabetes mellitus: association with weight, height, and bone mineralization, Pediatr. Diabetes 9 (4) (2008) 277–284. 65. C. Zanchi, G. di Leo, L. Ronfani, S. Martelossi, T. Not, A. Ventura, Bone metabolism in celiac disease, J. Pediatr. 153 (2008) 262–265. 66. P.L. Selby, M. Davies, J.E. Adams, EB. Mawer, Bone loss in celiac disease is related to secondary hyperparathyroidism, J. Bone Miner. Res. 14 (4) (1999) 652–657. 67. S. Mora, G. Barera, S. Beccio, et al., Bone density and bone metabolism are normal after long-term gluten-free diet in young celiac patients, Am. J. Gastroenterol. 94 (2) (1999) 398–403. 68. F. Sylvester, IBD and skeletal health: children are not small adults!, Inflamm. Bowel Dis. 11 (2005) 1020–1023. 69. D. Herzog, N. Bishop, F. Glorieux, E.G. Seidman, Interpretation of bone mineral density values in pediatric Crohn’s disease, Inflamm. Bowel Dis. 4 (4) (1998) 261–267. 70. A.M. Boot, J. Bouquet, E.P. Krenning, SMPF. de Muinck Keizer-Schrama, Bone mineral density and nutritional status in children with inflammatory bowel disease, Gut 42 (1998) 188–194. 71. F. Walther, C. Fusch, M. Radke, S. Beckert, Osteoporosis in pediatric patients suffering from chronic inflammatory bowel disease with and without steroid treatment, J. Pediatr. Gastroenterol. Nutrit. 43 (1) (2006) 42–51. 72. E.J. Semeao, A.F. Jawad, N.O. Stouffer, B.S. Zemel, D.A. Piccoli, VA. Stallings, Risk factors for low bone mineral density in children and young adults with Crohn’s disease, J. Pediatr. 135 (1999) 593–600. 73. R. Gokhale, M.J. Favus, T. Karrison, M.M. Sutton, B. Rich, B.S. Kirschner, Bone mineral density assessment in children with inflammatory bowel disease, Gastroenterology 114 (1998) 902–911.
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74. F.J. Cowan, J.T. Warner, F.D.J. Dunstan, W.D. Evans, J.W. Gregory, H.R. Jenkins, Inflammatory bowel disease and predisposition to osteopenia, Arch. Dis. Child 76 (1997) 325–329. 75. E.J. Semeao, A.F. Jawad, B.S. Zemel, K.M. Neiswender, D.A. Piccoli, VA. Stallings, Bone mineral density in children and young adults with Crohn’s disease, Inflamm. Bowel Dis. 5 (3) (1999) 161–166. 76. E.J. Semeao, V.A. Stallings, S.N. Peck, D.A. Piccoli, Vertebral compression fractures in pediatric patients with Crohn’s disease., Gastroenterology 12 (1997) 1710–1713. 77. A. Goulding, A.M. Grant, S.M. Williams, Bone and body composition of children and adolescents with repeated forearm fractures, J. Bone Miner. Res. 20 (12) (2005) 2090–2096. 78. A. Goulding, R.W. Taylor, I.E. Jones, P.J. Manning, S.M. Williams, Spinal overload: a concern for obese children and adolescents? Osteoporos. Int. 13 (2002) 835–840. 79. A. Goulding, R.W. Taylor, I.E. Jones, K.A. McAuley, P.J. Manning, S.M. Williams, Overweight and obese children have low bone mass and area for their weight, Int. J. Obesity. 24 (2000) 627–632. 80. M.A. Petit, T.J. Beck, J. Shults, B.S. Zemel, B.J. Foster, M.B. Leonard, Proximal femur bone geometry is appropriately adapted to lean mass in overweight children and adolescents, Bone 36 (2005) 568–576. 81. A. Ackerman, J.C. Thornton, J. Wang, R.N. Pierson Jr., M. Horlick, Sex differences in the effect of puberty on the relationship between fat mass and bone mass in 926 healthy subjects, 6 to 18 years old, Obesity 14 (5) (2006) 819–825. 82. N. Stettler, R.I. Berkowtiz, J.L. Cronquist, et al., Observational study of bone accretion during successful weight loss in obese adolescents, Obesity 16 (1) (2008) 96–101. 83. C.C.W. Yu, R.Y.T. Sung, R.C.H. So, et al., Effects of strength training on body composition and bone mineral content in children who are obese, J. Strength Condit. Res. 19 (3) (2005) 667–672.
Chapter
11
Physical Activity and Skeletal Growth Heather M. Macdonald1, Melonie Burrows2,3 and Heather A. McKay2,3,4 1
Schulich School of Engineering, University of Calgary, Calgary, Canada Department of Orthopaedics, University of British Columbia, Vancouver, Canada 3 Centre for Hip Health and Mobility, Vancouver, canada 4 Department of Family Practice, University of British Columbia, Vancouver, Canada 2
few exercise intervention studies have been conducted in boys. That said, it seems ‘a little goes a long way’ and short bouts of high impact physical activity over a relatively short (8–20 months) timeframe may be all that is required to enhance children’s bone mass and strength. However, the specific exercise prescription for optimal bone strength has not been clearly defined for either sex. This knowledge gap may be related in part to our limited understanding in humans of how bone structure adapts to mechanical stimuli. Two-dimensional imaging technologies, such as dual energy x-ray absorptiometry (DXA) were designed for adults and these were then used to study pediatric bone. However, more sophisticated imaging techniques, such as peripheral quantitative computed tomography (pQCT) and high resolution pQCT (HR-pQCT) now permit us to evaluate bone’s complex nature. It is only very recently that investigators have begun to evaluate the material (e.g. volumetric bone mineral density), structural (e.g. bone cross-sectional area, second moment of area and cortical thickness) and microstructural (e.g. cortical porosity, trabecular number) adaptations that underpin bone’s response to physical activity. In this chapter we review:
Introduction When on board H.M.S. ‘Beagle’, as naturalist, I was much struck with certain facts in the distribution of the inhabitants of South America... These facts seemed to me to throw some light on the origin of species – that mystery of mysteries, as it has been called by one of our greatest philosophers. Charles Darwin. On the Origin of Species, 1859 On the Origin of Species was first published on 24 November 1859 and cost fifteen shillings (84 cents US). The 6th edition published in 1872, included a section called ‘Effects of habit and the use and disuse of parts’. In this section, Darwin provided an example of how large, ground feeding birds acquired stronger legs through exercise and weaker wings from not flying ‘until, like the ostrich, they could not fly at all’ [1]. Thus, the positive role of physical activity, and the negative consequences of disuse, on bone have been known for a long time. Although the skeletal adaptations that Darwin noted were manifest over generations, the effect of weight-bearing physical activity on bone has also been noted over much shorter timeframes. Indeed, there is now compelling evidence that physical activity is integral for developing and maintaining a strong and healthy skeleton. Further, the capacity for the skeleton of children and adolescents to adapt to exercise may be much greater than older adult bone [2, 3]. Therefore, optimizing bone accrual during the crucial years of growth may well be the best means to reduce fracture risk in later life [4, 5]. Despite the many advances in our understanding of the benefits of physical activity for growing bone, relatively Osteoporosis in Men
1. the mechanisms by which bone adapts to physical activity and 2. the imaging modalities that have been used to quantify these changes. From this foundation, we critically review the influence of physical activity on bone mass accrual in boys. We then discuss the emerging data describing material and structural properties that underpin the bone strength response to physical activity. We close with a discussion of whether benefits of physical activity undertaken during the growing years are sustained across the lifespan. 131
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How does bone adapt to physical activity? The primary mechanical function of the skeleton is to provide rigid levers for muscles to act against as they work to hold the body upright in the presence of gravitational forces [6]. Consequently, the skeleton is continually exposed to a loading environment where muscle forces produce the greatest loads during voluntary activities. The mechanical stimuli encountered throughout life serve to sculpt the skeleton’s genetic blueprint to match the loading requirements. Bone adaptation to such physical loads is determined by strain, or deformation of bone tissue, and is regulated by feedback loops that serve to maintain a customary strain level [7, 8]. An increase in bone strain (e.g. through an increase in physical activity) results in bone formation which, in turn, reduces bone strain to its original customary level. Conversely, a decrease in bone strain (e.g. through physical inactivity) results in bone resorption. The customary strain level, or setpoint, is likely genetically predetermined and is thought to vary by skeletal location. Further, the theoretical setpoint may be influenced by a variety of factors including age, nutrition and hormones (Figure 11.1) [8]. During growth, bone has the capacity to adapt to activityrelated increases in strain through several mechanisms:
bone cross-sectional area can increase through the addition of new bone to the periosteal surface (periosteal apposition); cortical thickness can increase through a combination of periosteal apposition and reduced endocortical resorption (or endosteal apposition); and tissue density can increase through modifications in trabecular microarchitecture (e.g. increased trabecular thickness [9, 10]). Ultimately, these adaptations adjust bone structure and strength to match the requirements of the mechanical environment [6]. For example, at long bone shafts where bending and torsion forces predominate, small increases in bone diameter contribute exponentially to bone section modulus, an indicator of bone bending strength [11]. Evidence from animal studies suggests that the potential for such adaptations is much greater in the growing than in the non-growing skeleton [2, 3]. In this chapter, we focus on bone adaptations to physical activity in boys. However, we acknowledge the welldocumented sex differences in the tempo, timing and magnitude of the pubertal growth spurt. In addition, the associated differences in hormonal milieu result in significant differences in bone material and structural properties between boys and girls that lead to varying skeletal responses between sexes to activity [12–14]. We encourage the reader to consult the many excellent reviews [10, 13, 15–17] that highlight physical activity and bone health in girls.
BONE STRENGTH Material properties & bone geometry
Tissue Strain
Regulatory Feedback Loop Signalling Pathway
Osteocytes (sensor cells)
Setpoints Signalling Pathway
CHALLENGES Growth: Increases in bone length and muscle force
Osteoblasts
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MODULATORS Genetics, nutrition, behavioural and environmental factors
Figure 11.1 A functional model of bone development based on the mechanostat theory [7] and related approaches [8]. The central component of the regulation of bone development and adaptation is the feed-back loop between bone deformation (tissue strain) and bone strength. During growth, this homeostatic system must continually adapt to external challenges (increases in bone length and muscle force) to keep tissue strain close to a preset level (setpoint). Various modulating factors influence aspects of the regulatory system as indicated by the dashed arrows. Adapted from Rauch and Schoenau [8] with permission from Lippincott Williams & Wilkins.
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How to measure bone adaptation to physical activity The common tool used to quantify skeletal adaptations to physical activity in children is dual energy x-ray absorptiometry (DXA). DXA measures bone mineral content (BMC, g) or areal bone mineral density (aBMD, g/cm2) and is the modality of choice for many investigators due to its widespread availability, relatively short scan time, low effective radiation dose and ability to scan clinically relevant sites such as the proximal femur and lumbar spine. While DXA studies have significantly furthered our knowledge of pediatric bone and its response to exercise and other interventions, its limitations have been clearly articulated [18]. Briefly, due to the two-dimensional planar technology and low resolution, DXA is unable to capture the underlying modifications to bone geometry such as adaptations specific to the periosteal or endosteal surface that directly influence overall bone strength [18]. This has been illustrated in both animal [19] and human [20] studies where exercise-induced changes in BMC or aBMD were minimal or non-existent, yet adaptations in bone geometry and mechanical characteristics were significantly greater in the exercise group. Despite its limitations, DXA remains a valuable clinical tool for the assessment of pediatric bone. Recent guidelines published by the International Society for Clinical Densitometry provide a means to help researchers use DXA technology and report their findings in an appropriate manner [21]. Finally, the well-recognized limitations of DXA have led to a paradigm shift where the focus of pediatric bone research has broadened beyond bone mass, to encompass the key concept of bone strength – and the bone properties that underpin it. In order more accurately to capture bone structural adaptations, the use of non-invasive imaging technologies such as peripheral quantitative computed tomography (pQCT) and magnetic resonance imaging (MRI) for the assessment of bone geometry, volumetric BMD and strength has become more widespread. Further, software is available to estimate bone geometry and strength from DXA scans (hip structural analysis (HSA)) and to derive additional geometrical outcomes from pQCT images (ImageJ). With these innovative tools we can determine surface- and regionspecific responses to loading that are not possible to assess with standard DXA imaging. The most recent evolution, high-resolution pQCT (HR-pQCT, XtremeCT), evaluates bone microstructure in the adolescent skeleton [22, 23]. The higher image resolution (82 m) permits investigation of trabecular microarchitecture including direct measures of trabecular volume and derived values for trabecular number, thickness and separation at peripheral sites (distal radius and tibia). In addition, finite element analysis can be applied to HR-pQCT scans in order to estimate bone strength. Together, these tools allow us to address more complex questions and help to further our understanding of bone adaptations to physical activity during growth.
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What types of physical activity promote bone strength? Despite the many observational and intervention studies that investigated the role of physical activity for bone health during growth, we remain uncertain about the specific type of physical activity that best promotes bone strength in the growing skeleton. In the next section, we discuss intervention studies that evaluated a variety of exercise protocols, however, to date, no study has performed a head-to-head comparison of two types of interventions (jumping versus running, for example) using a randomized controlled design. Many of the exercise protocols are informed by well-designed animal studies. Dr Charles Turner eloquently summarized the findings of these studies as ‘three rules for bone adaptation’ [24]: 1. adaptation is driven by dynamic, rather than static, loading 2. short duration of loading is more osteogenic 3. adaptation is ‘error-driven’, meaning abnormal strains drive structural change. In addition, inserting rest periods between loading bouts further optimizes the bone response to loading [19]. These principles were incorporated into an ‘osteogenic index (OI)’ that predicts the effect of an exercise protocol on bone mass and strength [25]. Three parameters are required to determine the OI: intensity (load frequency), number of loads per session and time between sessions. Importantly, these rules are based on loading-related changes in bone cross-sectional geometry and cortical bone properties. It is not entirely clear whether these rules also apply to loading-related adaptations at trabecular bone sites such as the lumbar spine or distal tibia. However, a newer innovation in animal models is to apply controlled loads at trabecular bone sites [26] and, using high resolution microCT quantify changes in microarchitecture. This approach can be used to determine the optimal loading characteristics for trabecular bone that, in turn, will inform the design of physical activity interventions.
How does physical activity influence the normal pattern of bone accrual in boys? It should come as no surprise that physical activity during growth is an essential element if bones are to achieve superior mechanics and architecture. Natural experiments, where limbs were amputated or congenitally absent, illustrate the tremendous capacity for adaptation of the remaining load-bearing limb [27]. A recent editorial in the Journal of Bone and Mineral Research contends that there is substantial quality evidence to support a key role for physical activity in children’s bone health [28]. This contention is
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well supported by numerous excellent reviews published over the past decade [10, 13, 15–17, 29] as all concluded that appropriate physical activity positively influences the normal pattern of bone mass and strength accrual. However, the debate continues as to whether these adaptations during the early formative years diminish the risk of fracture later in life [5].
What have we learned from cross-sectional studies? A number of cross-sectional studies of physical activity and bone health during growth have focused on comparisons between athlete and non-athlete populations. In general, young athletes participating in weight-bearing sports had augmented bone mass, geometry and strength compared with their less active peers. Importantly, these relationships are evident in boys as early as prepuberty [30, 31]. For example, at the shaft of the radius and tibia, school-aged male gymnasts had greater pQCT-derived cortical bone area and cortical thickness than same age non-gymnasts. Differences in bone geometry translated into a 5% and 14% greater polar SSI (an estimate of bone strength in torsion) at the tibia and radius, respectively. At the distal radius and tibia, boys’ gymnastics participation was associated with significantly greater total and trabecular vBMD which would confer greater resistance to compressive loads at these sites [32]. These findings illustrate the difference in adaptive mechanisms between cortical and trabecular bone that together lead to exerciseinduced gains in whole bone strength. During adolescence, boys who participate in weightbearing sports, such as running, gymnastics, soccer and badminton, consistently demonstrate greater bone mass than their peers who are either untrained or participate in non-impact sports such as swimming [33–35]. Among male badminton players, hockey players and non-athlete controls (17 years old, on average), badminton players had greater aBMD at the trochanter of the proximal femur and the distal femur than hockey players, despite significantly lower weekly average training [34]. It is likely that the training associated with badminton confers more diverse strain patterns than ice hockey and thus, has greater osteogenic potential. Of note, the average starting age of training for both badminton and hockey players was 7 and 9 years of age. Pre- and early puberty provides a ‘window of opportunity’ when bone is most responsive to physical activity [13, 15]. The strongest evidence in support of this theory comes from unilateral loading studies of female racquet sport athletes [36, 37]. However, recent pQCT findings provide further support for the presence of this ‘window’ in boys as well. In a large cohort (n 1068) of young Swedish men (aged 18 and 19 years), cortical bone area at the tibia diaphysis and trabecular vBMD of the metaphysis as well as femoral neck (FN) aBMD were greater if training for their
current sport began before age 13 [38]. In the average boy, age 13 corresponds to the approximate age at peak height velocity (13.4 years) and occurs approximately 1 year prior to peak bone mineral accrual velocity [12]. Thus, physical activity around this period of peak growth may enhance the normal pattern of bone accrual in boys. Cross-sectional athlete studies offer insight into the relationship between physical activity and bone health during growth, however, the high levels of physical activity associated with sport training and self-selection bias hamper external validity. To overcome these limitations, one can compare bone mass and structural differences between the playing and non-playing arms of racquet sport athletes. This unilateral loading model reduces the influence of confounding factors such as genetics, hormones and nutrition. Former competitive tennis players (aged 25–30 years) who began training during childhood had significantly greater side-to-side differences in estimates of bone strength at radius and humerus than non-playing controls (23–67% versus 5–16%, respectively) [39]. Importantly, greater bone strength at the humeral shaft was due to enlarged bone area (total and cortical CSA), not greater vBMD, indicating activity-related periosteal apposition. Studies of habitual or leisure-time physical activity are more generalizeable to all children – many of whom do not engage in organized or competitive sport. Unfortunately, habitual physical activity as a behavior is multidimensional and difficult to assess, particularly in young children. To date, habitual activity is assessed most often with subjective methods such as self-report questionnaires. In a large cohort of pre- and early pubertal boys, physical activity was measured with a valid and reliable self-report questionnaire and predicted boys’ total vBMD and bone strength index (BSI, an estimate of bone strength in compression) at the distal tibia (8% site) [32, 40]. The influence of physical activity on distal tibia bone strength persisted even after accounting for muscle cross-sectional area, a surrogate of muscle force. Similar to the results reported at the tibial diaphysis in gymnasts [31] and tennis players [39], physical activity was associated with boys’ cortical area and polar SSI at the tibial midshaft (50% site). Thus, at shaft sites where bending loads predominate, the optimal structural adaptation is to increase periosteal apposition, placing bone further from the neutral axis, so as to reduce resistance to bending. Despite best efforts, accurate assessment of children’s physical activity is an ongoing challenge. Questionnaires are a cost- and time-effective tool in large studies, however, young children have limited memory and recall [41]. Further, these relatively insensitive tools are unable to differentiate weight-bearing or intense activity, which often leads to reports of weak associations between leisure-time activity and bone outcomes. More recently, accelerometery has been employed as an objective assessment of children’s leisuretime physical activity. Accelerometers are valid and reliable tools that monitor frequency, intensity and duration of
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self-report questionnaire) and boys in the upper quartile. The more active boys demonstrated a greater bone mineral accrual rate at peak and acquired more bone in the 2 years around peak growth, compared with boys in the lower quartile of physical activity (Figure 11.2). Specifically, boys in the upper quartile of physical activity gained 7–18% more BMC at the femoral neck, lumbar spine and total body than boys in the lower quartile. As a follow up, Forwood et al [49] used PBMAS data and HSA to investigate the influence of physical activity on femoral neck bone strength during adolescence. As before, maturational differences were controlled using age at PHV but within a more sophisticated statistical approach – multilevel random-effects models. In boys, everyday physical activity was a significant independent predictor of both FN CSA and Z after controlling for biological age, height and weight (Figure 11.3(A). These findings suggest that the difference in estimated bone strength between low and high active boys would be approximately 4.5%. Importantly, when leg length and leg lean mass were included in the random-effects model, physical activity was no longer a significant predictor of FN CSA or Z. In keeping with the mechanostat theory [7, 8], lean mass, a surrogate of muscle force, likely mediated the relationship between physical activity and bone strength. 16 Peak LS BMC Accrual (g/yr)
physical activity [42] and are also used to estimate the ground reaction forces (GRF) associated with weight-bearing activities [43]. Although the utility of accelerometers demands more research, they are potentially valuable instruments for estimating the force on weight-bearing bones. Recently, several cross-sectional studies used accelerometers to explore the relationship between activity intensity and bone mass and strength in boys [44–48]. Across these reports, the consistent finding was that boys engaged in vigorous physical activity had significantly greater bone mass and estimated strength at clinically relevant sites such as the femoral neck. For example, 9-year old boys in the upper quartile of physical activity (40 min/day) demonstrated 6% higher FN BMC than boys in the lower quartile (12 min/day) [47]. Boys in the third and fourth physical activity quartiles had 10–14% higher FN strength indices (estimated from DXA measurement of FN width and hip axis length) than boys in the first quartile. Therefore, there may be a weak relationship between bone outcomes and physical activity below a certain threshold [47]. As the field of objective measurement of physical activity merges with pediatric bone research, it will be crucial to define clear thresholds for physical activity and sedentary behavior, relative to their known effects on bone. In summary, results from cross-sectional studies provide valuable evidence that, in boys, sport training and leisuretime physical activity are associated with enhanced bone mass and geometric adaptations that lead to optimized bone strength. However, given the inherent bias in these studies (e.g. self-selection), it seems prudent both to temper the interpretation of findings and encourage more randomized controlled studies that address the more specific question of optimal exercise prescription for children’s bone strength.
Prospective observational studies
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Long-term, prospective observational studies capture growth velocity and, by identifying the age at peak height velocity (PHV), are able to align children on a common maturational landmark. This overcomes the limitations of cross-sectional studies that attempt to compare bone outcomes between children of the same chronological age or at a similar Tanner stage. In a landmark study, the University of Saskatchewan Pediatric Bone Mineral Accrual Study (PBMAS) [12] highlighted the importance of accounting for differences in maturation when comparing children’s bone mass. Bailey and colleagues followed 113 normally active children (60 boys) for a period of 7 years to evaluate the relationship between everyday physical activity and peak bone mass accrual during adolescence. One innovative aspect of this trial was that the age of PHV and age at peak bone mass accrual were identified for every child. Boys were aligned on PHV and bone mass accrual was compared between boys in the lower quartile of physical activity (by
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1.2 1 0.8 0.6 0.4 0.2 Inactive
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Figure 11.2 Lumbar spine (LS) and femoral neck (FN) peak bone mineral content (BMC) accrual velocity (g/year) by inactive and active physical activity groups for boys. Bars are standard deviations. *Significantly greater than inactive P 0.005; **significantly greater than inactive P 0.001. Adapted from Bailey et al [12] with permission from the American Society for Bone and Mineral Research.
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Figure 11.3 (A) Growth curve for hip structural analysis (HSA) of the femoral neck in 17 active boys (solid line, squares) and 17 inactive boys (dashed line, circles), shown according to activity category. Adjusted mean values for section modulus (Z, adjusted for height and weight) are plotted according to years from age at peak height velocity (APHV, where 0 APHV). Adapted from Forwood et al [49] with permission from Elsevier. (B) Difference in femoral neck Z between low active boys (circles; 10 min/day moderate to vigorous physical activity, MVPA) and high active boys (squares; 40 min/day MVPA) at age 5, 8 and 11 years in the Iowa Bone Development Study [50]. Figure courtesy of Kathy Janz.
The relationship between physical activity and bone strength has also been demonstrated in prepubertal children [45]. The Iowa Bone Development Study followed 468 children across six years (ages ranged from 4 to 12 years). On average, boys who participated in 40 minutes/day of MVPA had 4% greater FN CSA (by HSA) and 5% greater FN Z than boys who participated in only 10 minutes of MVPA. The influence of MVPA on bone geometry strengthened as the boys aged (Figure 11.3B). This result further supports the notion of a ‘window of opportunity’ in boys just prior to adolescence, when the skeleton readily adapts to physical activity [50]. Although fewer studies have been undertaken in adolescent boys, it is most likely that weight-bearing activity continues to promote positive skeletal adaptations. As a follow up to their cross-sectional athlete studies, Gustavsson et al [51] showed that, in boys aged 16–19 years, being a badminton or hockey player was an independent and positive predictor of 3-year change in non-dominant humerus aBMD and FN aBMD. Unfortunately, baseline differences in aBMD between athletes and controls were not controlled in the analysis of change in aBMD. Thus, well-designed prospective studies provide valuable evidence that regular physical activity enhances bone mass and strength at the clinically relevant femoral neck. However, as imaging technology advances, it is important to look beyond the limitations of two-dimensional DXA technology and evaluate three-dimensional measures of bone geometry, microarchitecture and strength.
What have we learned from exercise intervention studies? Several well-designed randomized controlled trials (RCTs) provide the highest level of evidence to support the osteogenic effects of weight-bearing physical activity on the growing skeleton. Children assigned to physical activity
intervention groups gained significantly more bone mass and enhanced their bone strength compared with children in control groups [13, 17]. However, only two of these studies in boys used technologies other than DXA to evaluate the bone structure and strength response to physical activity. Further, it is often not possible to compare results across intervention studies (summarized in Table 11.1) as exercise protocol, study design and maturational status of the participants varies considerably. Of the DXA-based studies, gains in bone mass (BMC or aBMD) in intervention boys compared with control boys ranged from 1 to 6% depending on the anatomical site measured, the length of the trial and the intensity of the intervention. The longest randomized controlled intervention trial conducted in boys was 20 months [52]. A high-impact circuit training program enhanced BMC at the weight-bearing FN by nearly 5% more in exercising boys than in controls (Figure 11.4) [52]. As a positive response at the FN was not significant after only 7 months of participation in the Healthy Bones Study, the site-specific adaptation may have be related to boys’ advanced stage of maturity and/or the intensity and duration of the intervention [53]. Further support for the site-specific nature of the response in prepubertal boys is evidenced by the lack of a response at the femoral neck in an 8-month study of prepubertal Australian boys [54] and, more recently, in the 16-month Action Schools! BC (AS! BC) study in which the majority (60%) of boys were prepubertal [55]. In contrast, an earlier study of younger boys (and girls, aged 6–10 years) reported significantly greater increases (4.5%) in FN BMC in exercising children than in controls [56]. The very high-impact jumping program was associated with ground reaction forces nine times body weight (BW) – compared with forces 2–5 BW across other studies. Thus, more intense exercise interventions may be the key to achieving positive adaptations at the clinically relevant femoral neck during prepuberty.
Table 11.1 Intervention studies of the effects of weight-bearing physical activity on bone mass and strength in boys Reference
Subjects and study design
Intervention
Statistical approach
Results (INT vs. CON)
DXA only Unpaired t-tests: 8-month change in bone Program: activities included aerobics, football, dance, gymnastics, volleyball, basketball, weight parameters (INT vs CON). training in addition to regular school physical education Frequency and duration: 30 minutes, 3 times/ week, 8 months Progression: none stated
Femoral midshaft: BMC: 5.6% (P 0.01) vBMD: NS Peri diam: NS Endo diam: 11% (P 0.01) C.Th: 6.4% (P 0.05) CSMI: NS TB aBMD: 1.2% (P 0.01) LS aBMD: 2.8% (P 0.01)
Sundberg et al [57]
Subjects: Caucasian. INT: n 40 (12–13 years at baseline, mixed maturity) CON: n 82 (12–13 years at baseline, mixed maturity) Randomization: no randomization reported Study compliance: 93%
Program: increased time spent in regular physical education. Activities included running, jumping, gymnastics and/or ball activities. One class per week was swimming Frequency and duration: 40 minutes/week, 4 times/week, 36–48 months Progression: progressed from 100 minutes/week to 160 minutes/week (4 40 minutes)
TB BMC: NS LS BMC: 9% (P 0.05) FN BMC: 8% (P 0.05) Distal radius BMC: NS TB aBMD: NS LS aBMD: NS FN aBMD: 9% (P 0.01) Distal radius aBMD: NS
ANCOVA: 36–48 month change on bone outcomes between groups (INT vs CON). Covariates were weight, height, milk intake, physical activity, smoking, socioeconomic factors and housing. The authors did not control for maturity status
DXA: Lunar DPX-L (GE Medical) MacKelvie et al [53]
FN vBMD: 9% (P 0.01) ANCOVA: 7 month change in bone outcomes TB BMC: 1.6% Subjects: 44% Asian and 56% Caucasian Program: school-based, high-impact jumping (P 0.01) program integrated in school physical education between groups (INT vs CON). Covariates classes. Ground reaction forces 3.5–5 times body were baseline weight, change in height, LS BMC: NS physical activity and age weight
l
Subjects: Caucasian INT: n 19 (10.4 years at baseline, all prepubertal) CON: n 19 (age, height and baseline aBMD matched to INT group) Randomization: 2 schools randomly allocated to INT or CON Study compliance: 96% DXA: Lunar DPX-L (GE Medical)
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Bradney et al [54]
(Continued) 137
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Table 11.1 Continued Reference
Intervention
Statistical approach
INT: n 61 (10.2 years at baseline, all prepubertal) CON: n 60 (10.3 years at baseline, all prepubertal; age, height and baseline aBMD matched to INT group) Randomization: randomized by school (stratified by number of subjects and ethnicity) Study compliance: 80% DXA: Hologic QDR 4500 W
Frequency and duration: 10–12 minutes, 3 times/ week, 7 months Progression: # of jumps and height of jump advanced every 8–10 weeks; 50 (baseline) to 100 (final) jumps
Results (INT vs. CON) PF BMC: NS FN BMC: NS TR BMC: NS LS aBMD: NS PF aBMD: 1% (P 0.05) FN aBMD: NS TR aBMD: NS FN vBMD: NS
Linden et al Subjects: Caucasian [58] INT: n 76 (7.8 years at baseline, all prepubertal) CON: n 51 (8.0 years at baseline, all prepubertal; sex and age-matched to INT group) Randomization: no randomization Study compliance: not reported DXA: Lunar DPX-L (GE Medical)
Program: increased curricular time for physical education; indoor and outdoor activities, including ball games, running, jumping and climbing Frequency and duration: 40 minutes, 5 times/ week, 12 months Progression: none stated
Student t-tests: 12-month change in bone parameters between groups (INT vs CON)
TB BMC: NS LS3 BMC: 5.9% (P 0.001) FN BMC: NS TB aBMD: NS LS3 aBMD: 2.1% (P 0.05) FN aBMD: NS FN vBMD: NS LS3 width: 2.3% (P 0.05) FN width: NS
Hasselstrom Subjects: Caucasian et al [59] INT: n 135 (6.8 years at baseline, all prepubertal) CON: n 62 (6.8 years at baseline, all prepubertal) Randomization: no randomization reported Study compliance: not reported DXA: Lunar Pixi (GE Medical)
Program: increased curricular time for physical education Frequency and duration: 90 minutes, 2 times/ week, 3 years Progression: none stated
ANCOVA: 3-year change in bone outcomes between groups (INT vs CON). Covariates were baseline height, weight, bone mass and change in height Bonferroni corrections were applied
Distal forearm BMC: NS Calcaneus BMC: NS Distal forearm aBMD: NS Calcaneus aBMD: NS
ANCOVA: 20-month change in bone outcomes between groups (INT vs CON). Covariates were baseline bone, change in height and final Tanner stage
TB BMC: NS LS BMC: NS PF BMC: NS FN BMC: 4.3% (P 0.01)
DXA and HSA MacKelvie et al [52]
Subjects: Caucasian (42%), Asian (44%), other (14%) INT: n 31 (10.2 years at baseline, all prepubertal)
Program: school-based, high-impact jumping program integrated in school physical education classes. Ground reaction forces 3.5–5 times body weight Frequency and duration: 10–12 minutes, 3 times/ week, 2 school years (20 months)
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Subjects and study design
Table 11.1 Continued Reference
CON: n 33 (10.1 years at baseline, all prepubertal) Randomization: randomized by school (stratified by number of subjects and ethnicity) Study compliance: 61% DXA: Hologic QDR 4500 W
Progression: # of jumps and height of jump advanced every 8–10 weeks Yr 1: 50 (baseline) to 100 (final) jumps Yr 2: 55 (baseline) to 132 (final) jumps
Alwis et al [60]
Subjects: Caucasian INT: n 76 (7.8 years at baseline, all prepubertal) CON: n 51 (8.0 years at baseline, all prepubertal) Randomization: no randomization reported Study compliance: 95% DXA: Lunar DPX-L (GE Medical)
Program: increased curricular time for physical education; indoor and outdoor activities, including ball games, running, jumping and climbing Frequency and duration: 40 minutes, 5 times/ week, 24 months Progression: none stated
Macdonald et al [55]
Subjects: Caucasian (35%), Asian (53%) Program: Action Schools! BC program and mixed (12%) (Classroom Action) and Bounce at the Bell; 5–12 countermovement or side-to-side jumps/session INT: n 151 (10.2 years at baseline, performed in the classroom. Ground reaction mixed maturity) force 3.5–5 times body weight Frequency and duration: Classroom Action, 15 CON: n 62 (10.3 years at baseline, minutes, 5 times/week, 16 months; Bounce at the mixed maturity) Bell, 3 minutes, 3 times/day, 4 times/week, 16 Randomization: randomized by school months (stratified by school size) Progression: # of jumps increased every month up to a maximum of 36 jumps/day Study compliance: 74% (with Bounce at the Bell) DXA: Hologic QDR 4500 W
Statistical approach
Results (INT vs. CON) TR BMC: NS NN CSA: 2.5%, NS NN SPW: 2.6%, NS NN CSMI: 12.4% (P 0.05) NN Z: 7.5% (P 0.05) NN Endo diam: 2.9%, NS NN C.Th: NS
Student t-tests: 2-year change in bone outcomes between groups (INT vs CON)
TB BMC: NS LS3 BMC: 6% (P 0.01) FN BMC: NS LS3 width: 2.6% (P 0.01) FN width: NS FN CSA: NS FN Z: NS FN CSMI: NS
Intent-to-treat approach Linear regression model with change in bone outcome as dependent variable and group (INT vs CON) as independent variable. Covariates were baseline weight, change in height and change in TB lean mass. Random effect of school accounted for with variance inflation factor
TB BMC: 1.7% (P 0.05) LS BMC: 2.7% (P 0.05) PF BMC: NS FN BMC: NS FN CSA: NS FN SPW: NS FN Z: NS
(Continued)
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Subjects and study design
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Reference
Subjects and study design
Intervention
Statistical approach
Results (INT vs. CON)
Linear mixed-effects model to compare change in bone outcomes between groups (INT vs CON) and account for random effect of school Analysis 1: Group x maturity interaction term included in mixed-effects model along with baseline bone value, change in tibial length and change in muscle CSA as covariates Analysis 2: Group x maturity interaction not included in mixed-effects model. Covariates were baseline bone value, baseline body weight, change in tibial length, maturity offset (Mirwald equation)
Analysis 1 [61] P-value for group * maturity interaction Distal tibia ToA: NS ToD: 2.3% (P 0.07) BSI: 5% (P 0.03) (prepubertal boys only) Midshaft tibia CoA: NS CoD: NS SSIp: 2.3%, NS (prepubertal boys) Analysis 2 [62] Imax: 3% (P 0.05) Imin: 2%, NS CoA & C.Th by quadrant: 1–1.4%, NS
pQCT Macdonald Subjects: Caucasian (35%), Asian (53%) et al [61, 62] and mixed (12%) INT: n 145 (10.2 years at baseline, mixed maturity) CON: n 64 (10.3 yreas at baseline, mixed maturity) Randomized by school (stratified by school size) Compliance: 74% (with Bounce at the Bell) pQCT: Stratec XCT2000 with ImageJ and MomentMacro analysis
Program: Action Schools! BC program (Classroom Action) and Bounce at the Bell; 5–12 countermovement or side-to-side jumps/session performed in the classroom. Ground reaction force 3.5–5 times body weight Frequency and duration: Classroom Action, 15 minutes, 5 times/week, 16 months; Bounce at the Bell, 3 minutes, 3 times/day, 4 times/week, 16 months Progression: # of jumps increased every month up to a maximum of 36 jumps/day
INT: Intervention; CON: Control; DXA: dual energy x-ray absorptiometry; BMC: bone mineral content; vBMD: volumetric bone mineral density; NS: not significant; Peri diam: periosteal diameter; Endo diam: endosteal diameter; C.Th: cortical thickness; CSMI: cross-sectional moment of inertia; TB: total body; aBMD: areal bone mineral density; LS: lumbar spine; ANCOVA: analysis of covariance; HAS: hip structural analysis; PF: proximal femur; FN: femoral neck; TR: trochanter; LS3: third lumbar vertebra; NN: narrow neck; CSA: cross-sectional area; SPW: sub-periosteal width; Z: section modulus; pQCT: peripheral quantitative computed tomography; ToA: total bone cross-sectional area; ToD: total bone density; BSI: bone strength index; CoA: cortical bone area; CoD: cortical bone density; SSIp: polar strength strain index; Imax: maximum second moment of area; Imin: minimum second moment of area.
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Table 11.1 Continued
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% Change FN BMC
l
20 +4.4% p < 0.01
15 10 5 0 0
5
10 Months
15
20
Figure 11.4 Percent (%) change in femoral neck bone mineral content (FN BMC) over 20 months for intervention (squares) and control (circles) boys in the Healthy Bones Study [52, 53]. After 20-months, intervention boys gained 4.4% more FN BMC than control boys.
There are a number of fundamental considerations when designing intervention trials for children. First, programs must reflect what is known about bone’s response to specific types of loading. Thus, all interventions were comprised of high-impact activities designed to impose a ‘physiologic load’ [7] on the weight-bearing skeleton. The HBS and AS! BC interventions were also based in part on Turner’s three rules [24] discussed previously and on results from animal studies that suggested short bouts of dynamic activity followed by rest periods were more effective than longer bouts of activity [19]. Second, to influence large numbers of children and to be sustained, it is important that interventions be simple so as to be delivered by trained or untrained people (often generalist teachers) within the school or community setting. The Bounce at the Bell component of AS! BC provides one example as the jumps took only a few minutes, could easily be incorporated into the daily classroom routine, did not require additional equipment or space and were associated with low teacher burden. An alternative approach within the school setting was to increase the time devoted to physical education [57–59]. The Malmo Pediatric Osteoporosis Prevention Study (POP) compared four schools where, in the one intervention school, the weekly duration of physical education was increased from 80 min/week to 200 min/week (a 40 min/day increase) [58, 60]. Children were provided an otherwise unaltered physical education curriculum and, after 2 years, prepubertal boys in the intervention school demonstrated a 6% greater gain in BMC of the third lumbar vertebra and a 2.6% greater gain in vertebra width compared with control boys. Interestingly, as in most other studies of boys who were prepubertal, the POP program did not positively affect the load-bearing femoral neck. The Copenhagen School Child Interventions Study [59] used a similar design but did not elicit a benefit as a result of increased duration of standard physical education at any skeletal site. Given the results from these trials (and others [57]) and the demands placed on teachers and schools to adapt and deliver a modified school curriculum, these studies may not be justified, feasible or sustainable in many countries.
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Together, the aforementioned studies provide convincing evidence that physical activity can positively influence the normal trajectory of bone mass accrual in young boys, although the bone response appears to be both site- and maturity-specific. Importantly, we must advance beyond DXA technology if we are better to understand changes in bone geometry or structure that underpin growing bone’s response to weight-bearing exercise. To date, only three of the studies we discussed quantified adaptations in bone geometry, volumetric BMD or bone strength [52, 54, 55, 61]. Of these, only the HBS and AS! BC trials reported significant intervention effects for HSA-derived estimates of femoral neck geometry [52] or pQCT measures of tibial bone geometry, vBMD and strength [61, 62]. In addition to the intervention-related gain in FN BMC, boys who participated in the HBS demonstrated a significantly greater increase in FN cross-sectional area after 20 months compared with boys in control schools. This apparent increase in periosteal apposition was associated with a greater gain in FN section modulus, an indicator of bone bending strength. Although exercise-related periosteal apposition is thought to occur during prepuberty, when bones undergo rapid expansion due to normal growth [10, 63], the HBS results further support the hypothesis that structural adaptations at the femoral neck may occur primarily during early puberty. Thus, a longer intervention or follow-up period that traverses early puberty may yield more significant changes in boys’ bone structure and strength at this clinically relevant site. Hip structure analysis supplements standard DXA measures of bone mass. However, estimating three-dimensional properties from two-dimensional images has known limitations and HSA results must be interpreted with these in mind. In contrast, pQCT technology is able to capture accurately adaptations in bone cross-sectional geometry with exercise. However, it is unable to evaluate the clinically relevant femoral neck, thus, weight-bearing intervention studies that used this technology focused on assessing the tibia. AS! BC used pQCT technology and was the first RCT to demonstrate that short bouts of classroom-based activity significantly impacted bone strength. At the distal tibia (8% site), the greater gain in bone strength index (BSI) in prepubertal intervention boys compared with maturity-matched controls was mainly due to greater gains in vBMD, as opposed to an increase in cross-sectional area [61]. This finding is consistent with resistance to the primarily compressive loads at this site being a function, in large part, of trabecular density [32]. In contrast, the trend for a greater increase in polar SSI in prepubertal boys at the tibial midshaft was more likely due to increased periosteal apposition. We further explored this finding using a novel analysis for pQCT scans that allowed us to evaluate the biomechanically relevant second moments of area, Imax and Imin. These indices of bone bending strength provided an estimate of how bone was distributed about the anterior-posterior and
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A
B
CAmin
C
CAmax
Anterior D
Intervention Control
1.2 mm 0.8 mm 0.4 mm Lateral
Medial
Posterior
Figure 11.5 (A) Representative baseline (top) and (B) follow-up (bottom) pQCT images of an intervention group boy’s left tibia with the principal centroidal axes (CAmax, CAmin) superimposed. (C) Superimposition of the baseline (solid) and follow-up (dashed) bone surfaces. Alignment based upon minimization of pixel gray scale differences. (D) Radial plot of bone surface changes (follow-up-baseline) for the periosteal (outer lines) and endosteal (inner lines) surfaces for intervention (solid line) and control (dashed line) boys. Lines smoothed by a three-point running average. The apparent trend for greater periosteal apposition on the anterior and posterior surfaces lead to a significantly greater gain in Imax in intervention boys compared with controls. Adapted from Macdonald et al [62] with permission from Springer.
medial-lateral axes, respectively. The trend for greater gains in torsional bone strength (SSIp) in intervention boys was associated with an approximately 3% greater gain in Imax. Patterns of bone formation also reflected the predominantly anterior-posterior bending loads at the tibial shaft [64]. That is, changes in cortical area and thickness in the anterior, medial and posterior quadrants of the bone cross-section tended to be greater in intervention boys (Figure 11.5). These region-specific adaptations were consistent with those reported in animal studies [19] and highlight how three-dimensional imaging techniques advance our understanding of bone structural adaptations to physical activity beyond what we have learned from DXA studies.
Do the benefits of physical activity persist? Taken together, observational and intervention studies provide strong support for the positive influence of physical activity on skeletal development in boys during childhood and adolescence. However, there are no (and may never be) long-term prospective trials with fracture as the outcome that demonstrate a definitive link between childhood and adolescent bone mass and strength and decreased fracture risk. That said, we present a number of ‘detraining’, epidemiological and retrospective studies that lend credence to the notion that
skeletal adaptations to loading are maintained over the longer term and that there is indeed a relationship between childhood physical activity and reduced fracture risk in older age. Detraining or deconditioning studies aim to determine if gains in bone mass and/or strength are maintained following withdrawal of the exercise stimulus. The elegant animal studies undertaken by Warden and colleagues [65] provide a benchmark that human studies can aspire to. Using pQCT, they found that exercise-related gains in bone structure and strength in growing rats following a 7-week intervention period were still evident after 92 weeks of non-training follow up. In turn, the exercised ulna’s structural advantage increased its resistance to fracture. As alluded to previously, a similar lifelong follow-up study in humans that addresses the question of whether exercise-induced bone adaptations in childhood result in reduced fracture risk may not be feasible. However, the longest human detraining study to date found that gains in proximal femur BMC evident after 7 months of a high-impact jumping program were maintained in boys 8 years later [66]. The differences between exercise and control groups were, however, of a smaller magnitude (Figure 11.6). This study spanned pubertal growth and a powerful multilevel modeling approach, similar to that used in earlier longitudinal studies [49], controlled for the repeated measures within individuals and individual growth trajectories. Other observational studies investigated the relationship between reduced training or cessation of training and
C h a p t e r 1 1 Physical Activity and Skeletal Growth l
4
*
% D Total HIP BMC over controls
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2.5
*
2
*
*
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*
1 0.5
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7
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Figure 11.6 Different in percent (%) change in total hip bone mineral content (BMC) between jumpers and controls after 7 months of exercise training, one year of detraining (19 months) and 4 through 8 years of detraining (43–91 months). The intervention participants (boys and girls) had 3.6% greater BMC than controls at the end of the intervention and 1.4% greater total hip BMC than controls after 8 years. *Results are adjusted for baseline age, height change, weight change, maturity and sports participation and results are significant at each of the seven measurement intervals (P 0.05). From Gunter et al [66] with permission from the American Society for Bone and Mineral Research.
changes in bone outcomes in young adult athletes who began their sport training during childhood. In Swedish male hockey players (aged 17 years at baseline), physical activity-related gains at the FN and humerus (dominant and non-dominant aBMD) diminished 3 years after cessation of hockey training [67, 68]. In contrast, boys who continued ice hockey training over the same 3 years, gained significantly more aBMD at the FN, PF and arms than non-playing controls [68]. Conversely, it has been consistently demonstrated that athletes who retire from their sport sustain a greater bone mass than non-athlete controls [68–70]. Only one retrospective study linked the bone mass or strength advantage from a sport career during childhood and adolescence to reduced fracture risk later in life [69]. The field has not yet undertaken enough well designed intervention studies to determine whether gains in bone geometry or strength in the appendicular skeleton are maintained with age. However, in a recent pQCT study, young men’s (mean age 19 years) previous participation in sport was associated with a larger cortical bone area and periosteal circumference at the tibial diaphysis and with increased trabecular vBMD at the metaphysis [71]. Further, cortical bone geometry was significantly enhanced in men who had ceased their training up to 6.5 years earlier compared with men who were never active. Although the authors did not report tibial bone strength, the greater cortical area in the previously active men would increase resistance to bending or torsional forces due to the exponential relationship between bone diameter and bone strength [11]. These athlete studies suggest involvement in competitive sport during childhood is linked with bone strength benefits later in life. Similarly, bone gains from leisure-time physical activity during adolescence are maintained into young adulthood [72]. The University of Saskatchewan bone mineral
accrual study was the first to follow children prospectively into young adulthood [72]. During adolescence (1 year post PHV), active boys (by self-report questionnaire) had 8–13% greater BMC at the total body, lumbar spine and proximal femur than inactive boys. In young adulthood, the bone benefit was maintained in the active group (total body, proximal femur and femoral neck BMC were 8–10% greater than inactive group). The moderate, but significant correlation between adolescent and adult physical activity scores lends support to the notion that physical activity tracks (at least moderately) from childhood to adulthood [73, 74]. Finally, continued participation in weight-bearing activities throughout adolescence and into adulthood also confers a bone strength advantage. A recent cross-sectional study of older men used Turner and Robling’s osteogenic index (OI) [25] to categorize adolescent, mid-adulthood and lifetime exposure to weight-bearing activity [75]. A greater lifetime (13–50 years) and mid-adulthood (19–50 years) OI were positive predictors of mid-femur total and cortical area, cortical BMC and polar moment of inertia (by QCT). Further, men who continued consistently to participate in weight-bearing physical activities through adolescence and into adulthood had 6–15% greater indices of bone structure and strength compared with men who did not. Together, these results highlight the importance of adopting and sustaining an active lifestyle through the growing years and into later adult life.
Summary and conclusion In summary, effective weight-bearing physical activity can be attained through a wide range of extra-curricular sports and activities and through targeted school-based programs. It is more difficult to pinpoint the ‘window of opportunity’
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when the growing skeleton is most responsive to exerciseinduced loads. Although pre- and early puberty may well be the most opportune times to maximize the positive impact of physical activity on the growing skeleton, the timing may vary by site. For example, boys’ bone strength was enhanced through exercise at the clinically relevant femoral neck (through periosteal apposition) during early puberty, whereas structural adaptations at the tibia were evident in prepuberty. While we did not address sex differences in bone’s adaptation to physical activity, the timing of the ‘window’ likely varies between boys and girls. This may be due in part to the known sex differences in the timing of the pubertal growth spurt. Further study in well-defined maturity groups would serve to elucidate the precise time during growth when exercise has its most potent effect on bone strength accrual in boys and girls. We also do not know the optimal exercise prescription to enhance bone strength accrual in boys (and girls). In schools, short bouts of high-impact activity separated by rest periods may offer an effective, feasible and sustainable model to promote children’s bone health. However, there remains a need for rigorous randomized controlled intervention trials that control for potential confounds (sex, race, maturity and anthropometry) and where the influence of mediating factors such as nutrition and hormones are considered. Exciting new advances in imaging technology that include (p)QCT, HR-pQCT and MRI allow us to drill a little deeper into bone’s hierarchical nature to enhance our understanding of how bone structure and microarchitecture adapt to physical activity in both sexes. Although the answers to these questions are fascinating to scientists, they should not distract from the clear public implications of engaging boys and girls in physical activity. That is, children should be encouraged to adopt an active lifestyle (regardless of the timing, the site or the nature of the bone response), given the known benefits of physical activity across a range of body systems.
References 1. C. Darwin, On the Origin of Species, sixth ed., John Murray, London, 1872. 2. C.H. Turner, Y. Takano, I. Owan, Aging changes mechanical loading thresholds for bone formation in rats, J. Bone Miner. Res. 10 (10) (1995) 1544–1549. 3. T.L. Jarvinen, I. Pajamaki, H. Sievanen, et al., Femoral neck response to exercise and subsequent deconditioning in young and adult rats, J. Bone Miner. Res. 18 (7) (2003) 1292–1299. 4. S.R. Cummings, D.M. Black, M.C. Nevitt, et al., Bone density at various sites for prediction of hip fractures. The Study of Osteoporotic Fractures Research Group, Lancet 341 (8837) (1993) 72–75. 5. R.A. Faulkner, D.A. Bailey, Osteoporosis: a pediatric concern? Med. Sport Sci. 51 (2007) 1–12. 6. C.H. Turner, F.M. Pavalko, Mechanotransduction and functional response of the skeleton to physical stress: the mechanisms
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10. 11.
12.
13.
14.
15.
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17.
18.
19.
20.
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22.
23.
and mechanics of bone adaptation, J. Orthop. Sci. 3 (6) (1998) 346–355. H.M. Frost, Bone ‘mass’ and the ‘mechanostat’: a proposal, Anat. Rec. 219 (1) (1987) 1–9. F. Rauch, E. Schoenau, The developing bone: slave or master of its cells and molecules?, Pediatr. Res. 50 (3) (2001) 309–314. M.A. Petit, H.A. McKay, K.J. MacKelvie, A. Heinonen, K.M. Khan, T.J. Beck, A randomized school-based jumping intervention confers site and maturity-specific benefits on bone structural properties in girls: a hip structural analysis study, J. Bone Miner. Res. 17 (3) (2002) 363–372. R.M. Daly, The effect of exercise on bone mass and structural geometry during growth., Med. Sport Sci. 51 (2007) 33–49. E.S. Orwoll, Toward an expanded understanding of the role of the periosteum in skeletal health, J. Bone Miner. Res. 18 (6) (2003) 949–954. D.A. Bailey, H.A. McKay, R.L. Mirwald, P.R. Crocker, R.A. Faulkner, A six-year longitudinal study of the relationship of physical activity to bone mineral accrual in growing children: The University of Saskatchewan Bone Mineral Accrual Study, J. Bone Miner. Res. 14 (10) (1999) 1672–1679. K.J. MacKelvie, K.M. Khan, H.A. McKay, Is there a critical period for bone response to weight-bearing exercise in children and adolescents? A systematic review, Br. J. Sports Med. 36 (4) (2002) 250–257. S.A. Kontulainen, J.M. Hughes, H.M. Macdonald, J.D. Johnston, The biomechanical basis of bone strength development during growth., Med. Sport Sci. 51 (2007) 13–32. K. Khan, H.A. McKay, H. Haapasalo, et al., Does childhood and adolescence provide a unique opportunity for exercise to strengthen the skeleton? J. Sci. Med. Sport 3 (2) (2000) 150–164. M.A. Petit, H.M. Macdonald, H.A. McKay, Growing bones: how important is exercise? Curr. Opin. Orthop. 17 (2006) 431–437. K. Hind, M. Burrows, Weight-bearing exercise and bone mineral accrual in children and adolescents: a review of controlled trials, Bone 40 (1) (2007) 14–27. T.L. Jarvinen, P. Kannus, H. Sievanen, Have the DXAbased exercise studies seriously underestimated the effects of mechanical loading on bone? J. Bone Miner. Res. 14 (9) (1999) 1634–1635. A.G. Robling, F.M. Hinant, D.B. Burr, C.H. Turner, Improved bone structure and strength after long-term mechanical loading is greatest if loading is separated into short bouts, J. Bone Miner. Res. 17 (8) (2002) 1545–1554. S. Adami, D. Gatti, V. Braga, D. Bianchini, M. Rossini, Sitespecific effects of strength training on bone structure and geometry of ultradistal radius in postmenopausal women, J. Bone Miner. Res. 14 (1) (1999) 120–124. C.M. Gordon, L.K. Bachrach, T.O. Carpenter, et al., Dual energy X-ray absorptiometry interpretation and reporting in children and adolescents: the 2007 ISCD Pediatric Official Positions, J. Clin. Densitom. 11 (1) (2008) 43–58. S. Kirmani, D. Christen, G.H. van Lenthe, et al., Bone structure at the distal radius during adolescent growth, J. Bone Miner. Res. (2008). M. Burrows, D. Liu, Y. Ahamed, S. Braid, H. McKay, Evaluating bone microstructure at the distal tibia in children: a HR-pQCT study, J. Bone Miner. Res. 23 (S1) (2008) S111.
C h a p t e r 1 1 Physical Activity and Skeletal Growth l
24. C.H. Turner, Three rules for bone adaptation to mechanical stimuli, Bone 23 (5) (1998) 399–407. 25. C.H. Turner, A.G. Robling, Designing exercise regimens to increase bone strength, Exerc. Sport Sci. Rev. 31 (1) (2003) 45–50. 26. M.C. van der Meulen, T.G. Morgan, X. Yang, et al., Cancellous bone adaptation to in vivo loading in a rabbit model, Bone 38 (6) (2006) 871–877. 27. D.A. Bailey, R.M. Malina, R.L. Rasmussen, The influence of exercise, physical activity and athletic performance on the dynamics of human growth, in: F. Falkner, J.M. Tanner (Eds.) Human Growth: A Comprehensive Treatise, Plenum, New York, 1978. 28. H. McKay, E. Smith, Winning the battle against childhood physical inactivity: the key to bone strength? J. Bone Miner. Res. 23 (7) (2008) 980–985. 29. M.R. Forwood, Physical activity and bone development during childhood: insights from animal models, J. Appl. Physiol. 105 (1) (2008) 334–341. 30. G. Vicente-Rodriguez, J. Jimenez-Ramirez, I. Ara, J.A. Serrano-Sanchez, C. Dorado, J.A. Calbet, Enhanced bone mass and physical fitness in prepubescent footballers, Bone 33 (5) (2003) 853–859. 31. K.A. Ward, S.A. Roberts, J.E. Adams, M.Z. Mughal, Bone geometry and density in the skeleton of pre-pubertal gymnasts and school children, Bone 36 (6) (2005) 1012–1018. 32. R.B. Martin, Determinants of the mechanical properties of bones, J. Biomech. 24 (Suppl. 1) (1991) 79–88. 33. S.K. Grimston, N.D. Willows, D.A. Hanley, Mechanical loading regime and its relationship to bone mineral density in children, Med. Sci. Sports Exerc. 25 (11) (1993) 1203–1210. 34. P. Nordstrom, U. Pettersson, R. Lorentzon, Type of physical activity, muscle strength, and pubertal stage as determinants of bone mineral density and bone area in adolescent boys, J. Bone Miner. Res. 13 (7) (1998) 1141–1148. 35. F. Ginty, K.L. Rennie, L. Mills, S. Stear, S. Jones, A. Prentice, Positive, site-specific associations between bone mineral status, fitness, and time spent at high-impact activities in 16- to 18-year-old boys, Bone 36 (1) (2005) 101–110. 36. P. Kannus, H. Haapasalo, M. Sankelo, et al., Effect of starting age of physical activity on bone mass in the dominant arm of tennis and squash players, Ann. Intern. Med. 123 (1) (1995) 27–31. 37. H. Haapasalo, P. Kannus, H. Sievanen, et al., Effect of longterm unilateral activity on bone mineral density of female junior tennis players, J. Bone Miner. Res. 13 (2) (1998) 310–319. 38. M. Lorentzon, D. Mellstrom, C. Ohlsson, Association of amount of physical activity with cortical bone size and trabecular volumetric BMD in young adult men: the GOOD Study, J. Bone Miner. Res. 20 (11) (2005) 1936–1943. 39. H. Haapasalo, S. Kontulainen, H. Sievanen, P. Kannus, M. Jarvinen, I. Vuori, Exercise-induced bone gain is due to enlargement in bone size without a change in volumetric bone density: a peripheral quantitative computed tomography study of the upper arms of male tennis players, Bone 27 (3) (2000) 351–357. 40. S. Kontulainen, H. Sievanen, P. Kannus, M. Pasanen, I. Vuori, Effect of long-term impact-loading on mass, size, and estimated strength of humerus and radius of female racquet-sports players: a peripheral quantitative computed tomography study between
41.
42.
43.
44.
45.
46.
47.
48.
49.
50.
51.
52.
53.
54.
55.
145
young and old starters and controls, J. Bone Miner. Res. 17 (12) (2002) 2281–2289. J.F. Sallis, B.E. Saelens, Assessment of physical activity by self-report: status, limitations, and future directions, Res. Q. Exerc. Sport. 71 (Suppl. 2) (2000) S1–S14. S.G. Trost, D.S. Ward, S.M. Moorehead, P.D. Watson, W. Riner, J.R. Burke, Validity of the computer science and applications (CSA) activity monitor in children, Med. Sci. Sports Exerc. 30 (4) (1998) 629–633. A.W. Garcia, C.R. Langenthal, R.M. Angulo-Barroso, M.M. Gross, A comparison of accelerometers for predicting energy expenditure and vertical ground reaction force in schoolage children, Meas. Phys. Ed. Exerc. Sci. 8 (3) (2004) 119–144. K.F. Janz, T.L. Burns, J.C. Torner, et al., Physical activity and bone measures in young children: the Iowa bone development study, Pediatrics 107 (6) (2001) 1387–1393. K.F. Janz, T.L. Burns, S.M. Levy, et al., Everyday activity predicts bone geometry in children: the Iowa bone development study, Med. Sci. Sports Exerc. 36 (7) (2004) 1124–1131. J.H. Tobias, C.D. Steer, C.G. Mattocks, C. Riddoch, A.R. Ness, Habitual levels of physical activity influence bone mass in 11-year-old children from the United Kingdom: findings from a large population-based cohort, J. Bone Miner. Res. 22 (1) (2007) 101–109. L.B. Sardinha, F. Baptista, U. Ekelund, Objectively measured physical activity and bone strength in 9-year-old boys and girls, Pediatrics 122 (3) (2008) e728–e736. S. Kriemler, L. Zahner, J.J. Puder, et al., Weight-bearing bones are more sensitive to physical exercise in boys than in girls during pre- and early puberty: a cross-sectional study, Osteoporos. Int. 19 (12) (2008) 1749–1758. M.R. Forwood, A.D. Baxter-Jones, T.J. Beck, R.L. Mirwald, A. Howard, D.A. Bailey, Physical activity and strength of the femoral neck during the adolescent growth spurt: A longitudinal analysis, Bone 38 (4) (2006) 576–583. K.F. Janz, J.M. Gilmore, S.M. Levy, E.M. Letuchy, T.L. Burns, T.J. Beck, Physical activity and femoral neck bone strength during childhood: the Iowa Bone Development Study, Bone 41 (2) (2007) 216–222. A. Gustavsson, K. Thorsen, P.A Nordstrom, 3-year longitudinal study of the effect of physical activity on the accrual of bone mineral density in healthy adolescent males, Calcif. Tissue Int. 73 (2) (2003) 108–114. K.J. MacKelvie, M.A. Petit, K.M. Khan, T.J. Beck, H.A. McKay, Bone mass and structure are enhanced following a 2-year randomized controlled trial of exercise in prepubertal boys, Bone 34 (4) (2004) 755–764. K.J. MacKelvie, H.A. McKay, M.A. Petit, O. Moran, K.M. Khan, Bone mineral response to a 7-month randomized controlled, school-based jumping intervention in 121 prepubertal boys: associations with ethnicity and body mass index, J. Bone Miner. Res. 17 (5) (2002) 834–844. M. Bradney, G. Pearce, G. Naughton, et al., Moderate exercise during growth in prepubertal boys: changes in bone mass, size, volumetric density, and bone strength: a controlled prospective study, J. Bone Miner. Res. 13 (12) (1998) 1814–1821. H.M. Macdonald, S.A. Kontulainen, M.A. Petit, T.J. Beck, K.M. Khan, H.A. McKay, Does a novel school-based physical activity model benefit femoral neck bone strength in preand early pubertal children? Osteoporos. Int. (2008).
146
Osteoporosis in Men
56. R.K. Fuchs, J.J. Bauer, C.M. Snow, Jumping improves hip and lumbar spine bone mass in prepubescent children: a randomized controlled trial, J. Bone Miner. Res. 16 (1) (2001) 148–156. 57. M. Sundberg, P. Gardsell, O. Johnell, et al., Peripubertal moderate exercise increases bone mass in boys but not in girls: a population-based intervention study, Osteoporos. Int. 12 (3) (2001) 230–238. 58. C. Linden, G. Alwis, H. Ahlborg, et al., Exercise, bone mass and bone size in prepubertal boys: one-year data from the pediatric osteoporosis prevention study, Scand. J. Med. Sci. Sports 17 (4) (2007) 340–347. 59. H.A. Hasselstrom, M.K. Karlsson, S.E. Hansen, V. Gronfeldt, K. Froberg, L.B.A. Andersen, 3-year physical activity intervention program increases the gain in bone mineral and bone width in prepubertal girls but not boys: the prospective copenhagen school child interventions study (CoSCIS), Calcif. Tissue Int. 83 (4) (2008) 243–250. 60. G. Alwis, C. Linden, H.G. Ahlborg, M. Dencker, P. Gardsell, M.K. Karlsson, A 2-year school-based exercise programme in pre-pubertal boys induces skeletal benefits in lumbar spine, Acta. Paediatr. 97 (11) (2008) 1564–1571. 61. H.M. Macdonald, S.A. Kontulainen, K.M. Khan, H.A. McKay, Is a school-based physical activity intervention effective for increasing tibial bone strength in boys and girls?, J. Bone Miner. Res. 22 (3) (2007) 434–446. 62. H.M. Macdonald, D.M. Cooper, H.A. McKay, Anteriorposterior bending strength at the tibial shaft increases with physical activity in boys: evidence for non-uniform geometric adaptation, Osteoporos. Int. 20 (1) (2009) 61–70. 63. C.B. Ruff, A. Walker, E. Trinkaus, Postcranial robusticity in Homo. III: Ontogeny, Am. J. Phys. Anthropol. 93 (1) (1994) 35–54. 64. M.M. Peterman, A.J. Hamel, P.R. Cavanagh, S.J. Piazza, N.A. Sharkey, In vitro modeling of human tibial strains during exercise in micro-gravity, J. Biomech. 34 (5) (2001) 693–698. 65. S.J. Warden, R.K. Fuchs, A.B. Castillo, I.R. Nelson, C.H. Turner, Exercise when young provides lifelong benefits to bone structure and strength, J. Bone Miner. Res. 22 (2) (2007) 251–259.
66. K. Gunter, A.D. Baxter-Jones, R.L. Mirwald, et al., Impact exercise increases BMC during growth: an 8-year longitudinal study, J. Bone Miner. Res. 23 (7) (2008) 986–993. 67. A. Gustavsson, T. Olsson, P. Nordstrom, Rapid loss of bone mineral density of the femoral neck after cessation of ice hockey training: a 6-year longitudinal study in males, J. Bone Miner. Res. 18 (11) (2003) 1964–1969. 68. A. Nordstrom, T. Olsson, P. Nordstrom, Bone gained from physical activity and lost through detraining: a longitudinal study in young males, Osteoporos. Int. 16 (7) (2005) 835–841. 69. A. Nordstrom, C. Karlsson, F. Nyquist, T. Olsson, P. Nordstrom, M. Karlsson, Bone loss and fracture risk after reduced physical activity, J. Bone Miner. Res. 20 (2) (2005) 202–207. 70. L. Van Langendonck, J. Lefevre, A.L. Claessens, et al., Influence of participation in high-impact sports during adolescence and adulthood on bone mineral density in middleaged men: a 27-year follow-up study, Am. J. Epidemiol. 158 (6) (2003) 525–533. 71. M. Nilsson, C. Ohlsson, D. Mellstrom, M. Lorentzon, Previous sport activity during childhood and adolescence is associated with increased cortical bone size in young adult men, J. Bone Miner. Res. 24 (1) (2009) 125–133. 72. A.D. Baxter-Jones, S.A. Kontulainen, R.A. Faulkner, D.A. Bailey, A longitudinal study of the relationship of physical activity to bone mineral accrual from adolescence to young adulthood, Bone 43 (6) (2008) 1101–1107. 73. W.C. Taylor, S.N. Blair, S.S. Cummings, C.C. Wun, R.M. Malina, Childhood and adolescent physical activity patterns and adult physical activity, Med. Sci. Sports Exerc. 31 (1) (1999) 118–123. 74. R. Telama, X. Yang, J. Viikari, I. Valimaki, O. Wanne, O. Raitakari, Physical activity from childhood to adulthood: a 21-year tracking study, Am. J. Prev. Med. 28 (3) (2005) 267–273. 75. R.M. Daly, S.L. Bass, Lifetime sport and leisure activity participation is associated with greater bone size, quality and strength in older men, Osteoporos. Int. 17 (8) (2006) 1258–1267.
Chapter
12
The Genetics of Peak Bone Mass Luigi Gennari1, Robert Klein2 and Serge Ferrari3 1
Deparment of Internal Medicine Endocrine Metabolic Sciences and Biochemistry, University of Siena, Italy Bone and Mineral Unit, Oregon Health & Science University and Portland VA Medical Center, Portland, Oregon, USA 3 Service of Bone Diseases, Department of Rehabilitation and Geriatrics, WHO Collaborating Center for Osteoporosis Prevention, Geneva University Hospital, Geneva, Switzerland 2
Introduction
history of fracture has been consistently associated with fracture risk, much less information exists about the heritability of fracture, with reported estimates of 25–35% or less, depending on the skeletal site and population studied [1].
Heritable Influences on the Osteoporosis Phenotype Genetic factors play a key role in the pathogenesis of skeletal fragility and osteoporosis in both genders. Several studies using twin pairs or parent–offspring models have shown high levels of heritability of bone mineral density (BMD), the most commonly used skeletal trait to evaluate the genetic basis of bone strength and, ultimately, osteoporotic fractures. In particular, twin studies have provided an efficient tool for detecting the influence of genetic factors on quantitative traits, including BMD. This model involves a comparison of intrapair differences between monozygtic and dizygotic twins. Since monozygotic twins are genetically identical, their intrapair differences in any given trait are assumed to arise exclusively from environmental factors. Conversely, intrapair differences in dizygotic twins can arise because of both genetic and environmental differences. If a significantly larger variation of intrapair differences can be demonstrated in dizygotic than monozygotic twins, it may be inferred that genetic factors exert a consistent contribution to the observed variation. By this approach, it has been estimated that 50% and 80% of the variance in BMD is genetically determined [1]. Other twin studies have shown similarly high degrees of heritability for other skeletal (i.e. quantitative ultrasound properties of bone, femoral neck geometry, bone loss and bone turnover markers) or extraskeletal (i.e. body mass index, muscle strength) determinants of osteoporotic fracture risk [1, 2]. Some concerns have been raised that the classic twin model overestimates heritability because of shared environmental covariates. This hypothesis is also supported by most of the family studies generally showing lower heritability estimates for BMD than twin studies. Moreover, even though a family Osteoporosis in Men
Heritability of Peak Bone Mass Theoretically, inheritance could affect bone strength and fracture risk in at least two ways. Genetic factors could influence skeletal growth and the amount of bone mass attained in early adulthood (peak bone mass) and subjects with genetically determined low bone mass might be more susceptible to develop osteoporosis with subsequent aging. Alternatively, or in conjunction with the above, genetic factors could influence the rate of age-related bone loss. To date, twin and family studies have shown a predominant genetic effect on peak bone mineral mass acquisition rather than on age-related bone loss. In fact, both male and female offspring of subjects with osteoporosis have reduced bone mass well before age-related or postmenopausal bone loss [3, 4], suggesting the expression of inherited determinants of osteoporotic risk from an early age. Moreover, a threegeneration study in males demonstrated that sons of men with osteoporosis have reduced bone size and reduced volumetric BMD, despite normal markers of bone remodeling, further reinforcing the view that the effect of genetics on bone is mainly growth-related rather than age-related [5]. Consistent with this postulate, a study on male twins of different ages revealed that intrapair differences in radial bone mass and width were highest in young subjects but increased with age both in monozygotic and dizygotic pairs [6] (Figure 12.1). Conventional heritability estimates suggested a low degree of genetic determination of bone mass in the adult twins. Thus, the genetic component appears primarily to affect peak bone mass, while its role progressively declines 149
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Intrapair variance in bone mass
0.02 P < 0.025 0.015
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Figure 12.1 Intrapair variance in bone mass between monozygotic (MZ) and dizygotic (DZ) pairs in juvenile and adult twins. (Adapted from Smith et al J Clin Invest 1973;52:2800–8).
with aging as a result of the accumulation of non-inherited (environmental) factors. Indeed, in a longitudinal study on premenopausal women and their prepubertal daughters, a familial resemblance in several different bone traits (areal and volumetric BMD, bone mineral content, bone area) was already present before puberty and remained unchanged during pubertal growth, indicating that genetic susceptibility to osteoporosis may already be detectable in early childhood [7]. Even though similar studies have not been performed in men, these results might also be applicable to the male, since before puberty, there is no consistent gender-related difference in bone mass or size. A separate, cross-sectional study in premenopausal women and their prepubertal male and female children confirmed a significant heritability of BMD in both genders before puberty [8]. In this study, heritability was generally higher for mother–daughter pairs (57% and 79% for lumbar and femoral BMD, respectively) than for mother–son pairs (24% and 51% for lumbar and femoral BMD, respectively). There was also some evidence of site specificity with poorer correlation coefficients if skeletal sites other than the corresponding maternal anatomical site were used for prediction. Taken together, these data indicate genetic factors play a major role in determining inherent bone structural characteristics and skeletal size. Most of these heritable effects appear to be programmed before attainment of peak bone mass or, for that matter, even before puberty. Importantly, these studies also suggest that the best population to investigate the genetic component of osteoporosis may not be older subjects but rather younger subjects with low bone mass.
Gender-Specific Heritability of Bone Mass Sexual dimorphism in the structural components of bone strength (i.e. skeletal dimensions, cortical thickness and
trabecular microstructure) is marked in both skeletal development and aging [9]. This has raised the hypothesis of different genetic effects on the male or female skeleton or, more likely, of gender-specific interactions modulating the expression or penetrance of common genetic factors (i.e. due to different exposure to gonadal steroids, differences in muscle strength, exercise or other risk factors for bone fragility) [10]. Several studies identified significant differences in the heritability between the sexes, including genotype-by-sex and environment-by-sex interactions on BMD. For example, in a study of dizygotic twins, the correlations between BMD of the opposite-sex twin pairs were lower than those of same-sex twin pairs [11], suggesting such differences arise at least in part from genetic imprinting and different environments in males and females. Moreover, genderrelated differences in the percentage of variance explained by additive genetic effects suggest that, at least in part, different genes may regulate bone mass in men as compared to women [10].
Identification of Osteoporosis Susceptibility Genes Segregation analysis in families has shown regulation of BMD and other osteoporosis-related phenotypes is polygenic and determined by the effects of several genes, each with relatively small effects rather than by a small number of genes with large effects [1]. Some genes with relatively larger effects may be also involved in at least some populations and particularly in men [12, 13], even though substantial residual polygenic effects were also in evidence in most of these studies. Irrespective of the contribution made by individual genetic variants, it is clear that osteoporosis is a complex, multifactorial disorder in which genetic determinants regulating bone remodeling, BMD, bone geometry and susceptibility to fracture are modulated by hormonal, environmental and nutritional factors. The genetic control of bone strength may also vary across skeletal sites, period of life (with different genes regulating bone growth and bone loss), gender and ethnicity [10, 14]. Moreover, the possibility that a significant part of the heritability of bone mass is related to shared genetic contributions to skeletal size and body composition cannot be excluded. Over the last 20 years, researchers seeking to find genes that influence osteoporosis and fracture risk have taken separate but complementary approaches: family studies of rare monogenic skeletal fragility disorders, linkage analysis in pedigrees, association studies in population samples and experimental crosses in animal models. In most of the studies, BMD (with the 2.5 SD diagnostic threshold for osteoporosis) was studied as a major surrogate phenotype, because it is highly heritable and represents an important and measurable clinical predictor of fracture risk. Most human studies have been performed in postmenopausal women or in mixed male and female population-based samples, while
C h a p t e r 1 2 The Genetics of Peak Bone Mass l
few studies were specifically designed to investigate the genetic determinants of peak bone mass in men.
Linkage studies Classic, parametric linkage analysis has been particularly successful in identifying the genes that are responsible for rare, monogenic disorders such as osteogenesis imperfecta and sclerosing bone dysplasias. In these studies, a genomewide set of a few hundred or a few thousand markers spaced millions of bases apart was typed in families with multiple affected or unaffected relatives. Genotype data were then analyzed to look for evidence of segregation of alleles with the phenotype according to the specified disease model (i.e. dominant or recessive). A slightly different approach (nonparametric linkage analysis) has been generally used for complex disorders, where no disease model is specified and the evidence of allele sharing in relation to sharing of the disease phenotype (i.e. low BMD) is investigated. Results are typically expressed as lod scores (LOD) that are defined as the logarithm of the odds that the disease locus and marker locus are linked. In parametric analysis, linkage is considered to be ‘suggestive’ when the LOD is greater than 1.9 and ‘significant’ when the LOD is greater than 3.3. For non-parametric analysis, higher thresholds are used and a suggestive or significant linkage is defined by a LOD greater than 2.2 and 3.6, respectively [1]. Overall, linkage studies have the advantage of being an unbiased, comprehensive search across the genome for susceptibility alleles and has been successfully applied to find the genes for many single gene disorders. However, linkage analysis has been less successful for polygenic diseases and quantitative traits, perhaps in part because of a limited power to detect the effect of common alleles with modest effects on disease.
Rare Monogenic Disorders Associated With Low Bone Mass In rare instances, low bone mass and multiple fractures in young males are found to be inherited in a simple Mendelian manner. Examples of this include osteogenesis imperfecta and other familial osteoporotic syndromes due to inactivating mutations in the aromatase (CYP19A1), estrogen receptor alfa (ESR1), lipoprotein receptor-related protein 5 (LRP5) and 6 (LRP6) genes. Mutations affecting the collagen type 1, 1 (COL1A1) or 2 (COL1A2) genes were the first to be associated with bone fragility and increased fracture risk in humans. These mutations are in fact responsible for the vast majority of cases of osteogenesis imperfecta, a hereditary disorder of connective tissue [15]. A heterogeneous nature of this disorder has been described, spanning from extremely severe, early onset and often lethal conditions to milder forms.
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The presence of osteoporosis was also described in a single case of a disruptive mutation in the ESR1 gene in a 28-year-old man with unfused epiphyses and continued linear growth [16]. The gene defect was inherited as an autosomal recessive from his consanguineous parents who were heterozygotes for the mutation. A cytosine to thymidine transition at exon 2, codon 157 resulted in a stop codon and a severely truncated alpha estrogen receptor that cannot bind estrogen. He had no detectable response to administration of large doses of exogenous estrogen despite achieving serum concentrations of estradiol 10-fold higher than the typical male. A similar skeletal phenotype has been observed in nine different cases of inactivating mutations at the aromatase CYP19A1 gene in young males [17]. The disorder occurs in an autosomal recessive pattern and, in at least six of the nine described subjects, parental consanguinity was evident. All known mutations exhibit no or minimal enzyme activity in transient expression systems. Accordingly, circulating estrogen levels are markedly low or undetectable while androgens are normal or elevated. Common skeletal characteristics of these men include tall stature, continued longitudinal growth, unfused epiphyses, delayed bone age, lack of pubertal growth spurt, eunuchoid skeletal proportions, genu valgum, elevated bone resorption markers and reduced bone mass. Estrogen treatment in all these cases of aromatase deficiency was associated with an increase in BMD and epiphyseal closure. Taken together these rare cases of mutations in ESR1 and CYP19A1 genes emphasized the dominant effect of estrogen in the attainment of peak bone mass. Major disruption of the LRP5 gene due to homozygous nonsense or frame-shift mutations, resulting in loss-offunction, is responsible for the osteoporosis pseudoglioma syndrome (OPPG), a rare disorder characterized by juvenile onset osteoporosis and blindness [18]. LRP5 encodes for a transmembrane co-receptor that is involved in the Wnt signaling pathway, a major regulator of osteoblast proliferation and activity. To date, more than 50 cases of OPPG have been reported, most with onset of fractures after age 2 years. Heterozygous carriers of LRP5 mutations have also been shown to have reduced BMD and osteoporotic fractures, without eye pathology. Moreover, LRP5 mutations have been reported in some cases of idiopathic juvenile osteoporosis [19, 20]. In one of these studies, functional in vitro analyses clearly showed an inhibitory effect of mutations on Wnt signal transduction [20]. A recent report identified an inherited mutation in lipoprotein receptor-related protein 6 (LRP6) linked to coronary heart disease as well as low BMD and fragility fractures [21]. Conversely, a number of dominantly inherited gain-offunction mutations in the LRP5 gene result in high bone mass (HBM) phenotypes [22] and autosomal dominant osteopetrosis type 1 [23]. Other syndromes have been described in which affected individuals have high bone mass and are protected against osteoporotic fractures.
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Examples are the recessive syndromes of sclerosteosis and Van Buchem disease that are caused by inactivating mutations in the sclerostin (SOST) gene [24, 25]. Interestingly, individuals who are heterozygous for disease-causing mutations in SOST also have high bone mass [26]. Even though such cases of single gene mutations in men with low or high bone mass represent extreme conditions, they indicate the possibility that more subtle functional differences in those genes (i.e. due to less functional polymorphisms) could predispose some men to osteoporosis.
Linkage Studies on Osteoporosis in Men To date, several linkage studies (some covering the entire genome, others just focusing on smaller intervals) have been conducted in a variety of populations. A number of chromosome regions have demonstrated at least suggestive evidence for linkage, but only a few regions have shown significant evidence for linkage and been replicated in multiple studies [1, 2]. Moreover, a recent collaborative metaanalysis including nine major genome-wide linkage studies and involving 11 842 subjects failed to detect evidence of genome-wide significance for any tested quantitative trait locus (QTL), even though many loci with suggestive linkage with lumbar or femoral BMD were identified [27]. Even though a consensus on QTLs associated with osteoporosis has not been reached, these studies (as well as linkage studies in inbred strains of mice) clearly indicate genes that regulate bone mass act in a gender-specific and site-specific manner. An additional potential explanation for the lack of consistency between major linkage results in different studies may be related to the wide age range of the included subjects, with few studies specifically restricted to younger individuals who had attained peak bone mass. Thus, the inclusion of older subjects could have impaired the ability to detect loci that regulate peak BMD. Indeed, some of these linkage studies confirmed that genetic effects on BMD can differ across age groups and that these differences cannot adequately be captured by simply entering age into the model [28, 29]. In the largest of these studies (performed in a European sample of 3691 individuals from 715 families), gender specific analyses were also conducted for subjects under or over the age threshold of 50 years to distinguish QTLs for peak bone mass from those that influence bone mass (and presumably bone loss) in older people. Interestingly, the suggestive or significant loci for BMD only became apparent when gender and age were taken into account [29]. In men below the age of 50 years, four major QTLs were detected, on chromosome 3q25 for lumbar BMD and on chromosomes 4q25, 10q21 and 16p13 for femoral neck BMD. An additional locus on chromosome 7p14 was associated with femoral neck BMD in elderly men. However, only one of these QTLs, 4q25, was associated with BMD in women. Weak evidence of linkage (LOD 1.31) was also indicated for a QTL on
chromosome 14q31, previously associated with lumbar BMD in a genome-wide scan performed in participants from the Framingham Osteoporosis Study [28], particularly when younger individuals (below 60 years) were considered. In this latter study, chromosomal regions on 4q34.1 and 8q24 were also associated with BMD in the male-only subsample. Recently, one linkage study was specifically designed to discover QTLs for low bone mass in pedigrees of males with idiopathic osteoporosis [30] and a single study was performed to identify QTLs for peak BMD in both sexes [31]. The first of these studies was performed in 103 pedigrees from the NEMO Family Study, ascertained through a male relative with low lumbar or femoral BMD values (Z score 2) [30]. Eight chromosomal regions with LOD score 1.5 were identified on 1q42-43, 11q12-13, 12q23-24, 17q21-23, 21q22 and 22q11 for lumbar BMD and on 5q3133 and 13q12-14 for femoral neck BMD. Four of these QTLs reached the genome-wide criteria for significant (17q21-23) or suggestive (11q12-13, 22q11 and 13q12-14) linkage. Interestingly, apart from 22q11, which is a novel QTL, all other loci provided replication for previously reported QTLs for BMD and other bone-related traits. Moreover, several of these areas encompassed prominent candidate genes for osteoporosis such as COL1A1 and the SOST genes on 17q21-23, the LRP5 gene on 11q12-13 and the RANKL gene on 13q12-14. In the second study, a sample of 2200 Caucasian men and premenopausal women aged 20–50 (supposed to reflect the genetic effects on peak BMD) from 207 pedigrees was tested [31]. In the overall analysis, two QTLs showed suggestive linkage with hip BMD (12p12 and 22q13) and four with wrist BMD (2p13, 10p14, 14q23 and Xq27). However, few of these regions identified in the overall sample overlapped with those from the gender-specific analysis. In fact, when sex-specific tests were performed, two major regions showed suggestive linkage with hip (15q26) or lumbar (7p21) BMD in men, while four regions were linked to wrist BMD in females (2p13, 6q24, 11q13 and 18q21). Additional information has been derived from a linkage analysis performed in a genetically closed sample from the Amish Osteoporosis Study, with large sibships and a relatively homogeneous lifestyle [32]. Even though no strong evidence for linkage was detected in the overall study population, secondary analyses indicated sex- and agespecific effects. For men, strong evidence for linkage was observed on chromosome 7q31 for hip BMD (LOD 4.15) and on chromosome 21q22 (LOD 3.36) for spine BMD. Different and more modest associations were detected in women (1p36 and 1q21). Moreover, suggestive QTLs on chromosomes 11q22 (LOD 2.11) for radial BMD and 14q23 (LOD 2.16) for hip BMD were evidenced when analysis was restricted in men and women below age 50. Overall, these data from different linkage studies underline the necessity to design specific and sufficiently powered
C h a p t e r 1 2 The Genetics of Peak Bone Mass l
studies in selected male or female cohorts of subjects within restricted age ranges, which may increase the ability to identify true susceptibility loci for peak bone mass or bone loss at different skeletal sites. So far, only one gene for osteoporosis susceptibility has been identified by linkage studies and subsequent positional cloning in a study in two isolated populations of Iceland, the bone morphogenetic protein 2 (BMP2) gene in chromosome 20p12.3 [33]. Three polymorphic variants in this gene were then associated with osteoporosis and fractures in the two populations from Iceland as well as in a replication study in an independent cohort of Danish postmenopausal women. A major influence of the BMP2 gene on the attainment of peak bone mass, rather than increased bone loss was also observed.
Association studies Association studies, in which polymorphic variants were correlated with BMD (or less commonly other traits) across a population rather than within families, have been widely used in the field of osteoporosis genetics. By this approach, a large number of polymorphisms in different genes have been related to the regulation of bone mass and the pathogenesis of osteoporotic fractures, even though no convincing conclusions have emerged [1, 2]. Large population based studies, retrospective meta-analyses and genomewide association studies recently confirmed some but not all of these associations [1, 2, 34, 35]. Again, most of these studies have been performed in women and less commonly in men. Moreover, despite the evidence of an increased genetic effect on the attainment of peak bone mass, a consistent number of studies was performed in postmenopausal women or elderly men.
Sex Hormones, Sex Hormone Receptors and Aromatase The role of sex hormones on male skeletal homeostasis has recently been revised and it is now clear that estrogen deficiency is a major cause of osteoporosis in males [17]. Thus, genes involved in sex steroid hormone metabolism, such as aromatase, or in mediating the estrogenic and/or androgenic response, such as estrogen and androgen receptors, are all possible contributors to the reduction of bone strength and fractures in the male. Indeed, consistent with observation of clinical syndromes in which disruptive mutations in these gene have been described, it is likely that more subtle differences in sex steroid action on bone (i.e. due to polymorphic variants) could predispose some men to osteoporosis. Importantly, despite normal estrogen levels, evidence of decreased ESR1 expression has been described in osteoblasts and osteocytes derived from young and middle-aged men with idiopathic osteoporosis [36].
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ESR1 gene polymorphisms have been analyzed extensively for associations with BMD, bone loss, turnover markers and/or fractures in women and less in men, with contrasting results [37]. Nevertheless, a large meta-analysis from 22 eligible studies (n 11 in Caucasians and n 11 in Asians), as well as a large study of 19 917 individuals from eight European centers concluded that homozygotes for the XbaI (rs9340799) XX genotype may have increased bone strength compared to xx genotype [38, 39]. While in the first of these studies a modest but significantly higher BMD (1–2%) was observed in subjects with XX genotype, a significant association with fracture risk but not BMD was observed in the second study. These data therefore suggest that ESR1 genetic variation may influence the age-related changes in bone structure that underlie bone strength/fragility, whereas the ESR1 association with bone mass may be more easily discernible in particular age ranges or above a certain estradiol threshold [10]. To date, few studies of modest size investigated the effects of ESR1 polymorphisms on bone in young or middle-aged men. In the only study specifically performed in healthy adolescent boys (mean age 16.9 years), a significant association of XbaI and PvuII polymorphisms with BMD was demonstrated cross-sectionally and longitudinally, indicating a possible role of ESR1 gene in the attainment of peak bone mass [40]. Interestingly, in a different study, the association between ESR1 polymorphisms and BMD was stronger for prepubertal than for postpubertal subjects [41]. A similar effect was observed in a preliminary study in 139 prepubertal girls and 232 prepubertal boys [42]. In this study, ESR1 genotypes were associated with BMD at most skeletal sites, but with a borderline interaction involving sex and calcium intake. A significant gene-bygene interaction between the ESR1 and VDR genes on BMD and bone mineral content (BMC) was also observed in very young children from both genders [43]. Moreover, Khosla et al [44] noted significant interactions between bioavailable estradiol and the XbaI and PvuII genotypes on rates of bone loss in men aged 22–90 years, indicating that positive or negative associations may be dependent on circulating estrogen levels. While the pp or xx genotype may be relatively estrogen-insensitive, subjects with the P or X allele appeared to benefit more from the protective effects of estrogen on bone than subjects with the p or x allele. Interpretation of all the above findings is limited by the lack of biological evidence that ESR1 intron 1 alleles affect estrogen receptor levels and/or activity. However, there is evidence that these polymorphisms may affect gene transcription [37]. Few studies have examined the polymorphisms in the estrogen receptor gene (ESR2) for association with BMD and fracture risk in young individuals. A recent analysis of ESR2 polymorphisms in 723 men and 795 women (mean age 60 years) from the Offspring Cohort of the Framingham Study found significant associations between CA repeat polymorphisms and measures of femoral BMD in both genders [45]. Consistent with other studies, the higher BMD
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Figure 12.2 Variation in circulating estradiol level in men in relation to CYP19A1 TTTAn repeat genotype. Subjects were grouped according to short (S, TTTA 9) and long (L, TTTA 9) repeats number. (Adapted from Gennari et al J Clin Endocrinol Metab 2004;89:2803–10).
values were observed in subjects who were homozygous for a lower number of repeats (CA 23) [13]. Furthermore, two common single nucleotide polymorphisms (rs1256031 and rs1256059) in strong linkage disequilibrium with one another but not with the CA repeat, showed an association with femoral BMD in men but not in women, suggesting that genetic variation in the ESR2 might play a prominent role in men. Since other ESR2 studies were mostly performed in small samples of either pre- or postmenopausal women [37], there is a need for additional studies of ESR2 alleles in males along with further meta-analysis of the results of these studies. Only a small fraction of circulating estradiol is derived directly from the testes, while up to 85% is due to peripheral aromatization of testicular and adrenal androgen precursors into estrogen. Thus, a functional aromatase enzyme is crucial for the normal development of the male skeleton. Several polymorphic regions have been detected in the human CYP19A1 aromatase gene that could be responsible for qualitative and/or quantitative differences in gene expression of aromatase activity [46]. CYP19A1 polymorphisms have been found to be associated with estrogen levels, BMD and fracture risk in postmenopausal women and elderly men in a number of studies (Figure 12.2). Subjects homozygous for short TTTA repeat number in intron 4 of the CYP19A1 gene generally exhibit lower BMD and increased rates of bone loss in comparison to subjects with longer TTTA repeat sequences [46]. Interestingly, these associations appear to be dependent on fat mass. Differences between CYP19A1 genotypes were greater in subjects with a normal body mass index (BMI), while the association progressively decreased in magnitude when overweight and obese men were analysed [46]. This
point suggests that fat mass may be a mitigating factor in the expression of CYP19A1 genotypes on bone. It is possible that, with more adipose tissue, the associated overall increase in adipose aromatase activity dominates any effect of the polymorphisms on intrinsic aromatase activity. Consistent with these clinical observations, higher in vitro aromatase efficiency and greater estrogen production were observed in fibroblasts from a high TTTA repeat sequence genotype in comparison to fibroblasts from a low TTTA repeat sequence genotype [46]. Given the importance of estrogen in bone accrual, it is likely that deleterious CYP19A1 polymorphisms exert even a greater role in young individuals. Despite an early study in 140 middleaged Finnish men that revealed an association between the number of TTTA repeat sequences and height and BMI but not with BMD [47], a more recent analysis confirmed that CYP19A1 polymorphisms significantly affect the attainment of peak bone mass [48]. In a large and well-characterized cohort of 1068 men at the age of peak bone mass (18.9 0.6 years), both the TTTA repeat variation and a silent G/A polymorphism at Val80 of the CYP19A1 gene were predictors of areal BMD of the radius, lumbar spine, total body and cortical bone size (cortical cross-sectional area and thickness) of both the radius and tibia (Figure 12.3). Although these studies, in the aggregate, provide data to argue for the importance of polymorphisms in CYP19A1 and ESRs as determinants of estrogen production or sensitivity and bone strength in men, larger and more definitive studies are needed before any firm conclusions can be drawn. Notably, a (CAG)n repeat polymorphism in the androgen receptor gene may be also important, as mRNA expression serves to be dependent on CAG repeat variations, with an inverse correlation between the length of the repeats and the extent of mRNA expression and AR protein levels. Even though some studies suggested that the number of CAG repeats may be an independent negative predictor of bone density, these studies were not well powered and the role of AR gene polymorphism in the attainment of peak bone mass remains unknown [49].
Vitamin D and Parathyroid Hormone (PTH) Receptor A common allelic variation in the VDR gene was the first to be implicated in the genetic determination of bone phenotypes [1, 2]. Several polymorphisms have been identified in the human VDR gene locus (more than 180 single nucleotide polymorphisms (SNPs) according to Celera and NCBI databases). Both exon 2 and 3-end polymorphisms of the VDR gene have been extensively investigated in women, but with conflicting results [1, 2]. These polymorphisms exert a weaker effect than that originally reported and there is now evidence to suggest that their role may be mediated by effects on body size and modulated by calcium intake [1, 50]. Some positive associations also have been described
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Figure 12.3 Differences in lumbar or femoral BMD (A) and cortical thickness (B) at the radius and ulna according to the CYP19A1 TTTAn repeat genotype in young Swedish men. Subjects were grouped according to short (S, TTTA 9) and long (L, TTTA 9) repeats number. (Adapted from Lorentzon et al J Bone Miner Res 2006;21:332–39).
in men, with 3-end VDR genotypes correlated with peak bone mass, bone size, fracture risk and intestinal calcium absorption efficiency [49]. However, most of these studies have been performed on limited samples. Although these VDR SNPs have shown a modest effect on BMD and fracture risk in recent large population surveys and no effects at all in two different genome-wide association studies [1, 34, 35], it is likely that more relevant effects may occur in response to treatments with calcium, vitamin D or its active metabolites. Direct evidence for an interaction between Bsm I VDR polymorphism and calcium intake first came from an analysis of BMD changes in elderly patients receiving calcium and vitamin D supplements, showing higher lumbar spine BMD losses in BB than in Bb or bb genotypes [51]. Different reports indicated that similar interactions also occur in younger subjects. In addition, VDR polymorphisms have been reported directly to affect parathyroid gland regulation in subjects with primary hyperparathyroidism or endstage renal disease and in normal premenopausal women [50]. Interestingly, in a study on healthy Caucasian males assigned to a high or a low calcium and phosphate diet, subjects with BB genotype displayed lower renal tubular reabsorption of phosphate and higher PTH levels, particularly during calcium and phosphate restriction (Figure 12.4), despite similar 1,25(OH)2D concentrations [52]. Taken together, these observations suggest that VDR allelic variants may assume an increased role during conditions requiring a higher calcium and vitamin D intake, such as pubertal growth and senescence. However, this hypothesis remains to be confirmed in longitudinal, large-scale studies as well as in high-risk populations (i.e. young subjects before the attainment of peak bone mass, subjects with low sunlight exposure, low vitamin D status or reduced calcium intake). In addition, combinations of haplotype blocks rather than single polymorphisms should be required to analyze systematically the possible influence of genetic variants at the VDR gene on the response to calcium supplementation and/
or treatment with vitamin D. Indeed, recent observational studies in larger samples showed that different and more complex combinations of genotypes (rather than 3-end polymorphisms) may be associated with low bone strength and increased fracture risk [53]. Recently, polymorphisms in the gene encoding for parathyroid hormone receptor type 1 (PTHR1) gene have been associated with BMD in a large study on 634 families (1236 men and 1926 women) ascertained with probands with low BMD and the Children in Focus subset of the Avon Longitudinal Study of Parents and Children [54]. Interestingly, this association was restricted to the youngest tertile of the population, suggesting a major role of this gene in determining peak BMD.
LRP5 Gene and the Wnt pathway The importance of LRP5 gene for bone homeostasis and particularly for osteoblast function was discovered following linkage studies in the OPPG and the HBM syndromes [18, 19]. Subsequent studies also provided some experimental evidence that Wnt-LRP5 signaling may be implicated in the sexual dimorphism of the skeleton [10]. Not only do rare mutations in the LRP5 gene play a major role in regulating bone mass, but more subtle polymorphisms seem also to regulate BMD in the normal population. In a casecontrol study in middle-aged men (mean age 50 years), LRP5 exon 9 V667M (rs4988321) and exon 18 A1330V (rs3736228) missense polymorphisms have been associated with an up to threefold increase risk of idiopathic osteoporosis (Figure 12.5) [55]. Moreover, vertebral bone mass and size in adult males, as well as changes over one year in lumbar spine BMD and size in prepubertal boys, were also significantly associated with these LRP5 variants [56], whereas no significant association was found in females, suggesting that LRP5 polymorphisms could mainly contribute to the risk of spine osteoporosis in men by influencing
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Figure 12.4 Influence of dietary modifications (calcium and phosphate restriction versus supplementation) on (A) serum phsosphate, (B) ionized calcium, (C) serum PTH and (D) renal tubular readsorption of phosphate (TmP/GFR) in young men with VDR BB or bb genotype (rs1544410, IVS8 284A G). (Adapted from Ferrari et al J Clin Endocrinol Metab 1999;84:2043–48). 10 9 8 7 6 5 4 3 2 1 0
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Figure 12.5 Odds ratio for LRP5 polymorphisms and idiopathic male osteoporosis. The reference group was GG for exon 9 SNP (rs4988321, G2047A) and CC for exon 18 SNP (rs3736228, C4037T). (Adapted from Ferrari et al Bone 2005;37:770–75).
vertebral bone growth during childhood. These findings were replicated in the Rotterdam Study cohort, where a significant association of LRP5 1330-valine and decreased lumbar spine area and a higher risk of fragility fractures (hip, proximal humerus and pelvis fractures) was observed in men (OR 1.6, 95% CI 1.0–2.4), but not in women [57]. Evidence of an interaction between the LRP5 A1330V variant and a coding polymorphism of LRP6 (1062V) was also suggested in this study. However, no association with bone loss was observed in this cohort, suggesting that these polymorphic variants exert most of their effects on bone growth and the attainment of peak bone mass. A more
recent study analyzed ten SNPs spanning the LRP5 gene in a large and well characterized sample of 1797 unrelated individuals from the Framingham Study [58]. Three SNPs (rs4988321, rs2306862 and rs3736228) were significantly associated with BMD in men 60 years of age, after adjustment for covariates. Even though a significant association was observed also in women (but with different SNPs than in men), an interaction of LRP5 polymorphisms with physical activity was observed only in men. In both rs2306862 and rs3736228 SNPs, the TT genotype was associated with lower spine BMD in men with higher physical activity scores, conversely with preserved BMD in men with lower physical activity scores [58]. In keeping with this observation, a study in 783 Caucasian men aged 20–30 years confirmed a significant inverse association between the number of the T alleles leading to 1330-valine in rs3736228 and BMD in the spine and whole body only in physically active men [59]. Moreover, a 6-month longitudinal study investigating exercise-induced changes in bone mass during military service in 185 Finnish men identified a slight decrease in bone mineral content of the spine in those with Ala-Val rs3736228 genotype but no change in those with Ala-Ala genotype [60]. Taken together, the gene–environment interaction observed in these studies provides support for LRP5 as a mediator of load-induced bone formation. Findings of sex-specific associations of LRP5 SNPs with BMD were further confirmed in Chinese and Caucasian populations [1, 13]. However, a more recent prospective meta-analysis of participant-level data on 37 760 individuals [61], which was focused on the A1330V (rs3736228) and V667M
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(rs4988321) polymorphisms, could not replicate the gender difference suggested in most of the above individual studies. These two polymorphisms were strongly associated with BMD and were predictive of osteoporotic fractures in Caucasians of both sexes. The BMD effects tended to be larger for Val667Met than for Ala1330Val. The interaction of LRP5 variants with physical activity in men and women, however, was not tested in this meta-analysis. Interestingly, in vitro promoter–reporter assays have indicated that different haplotypes for the V667M and A1330V polymorphisms differ in their ability to activate reporter gene transcription, indicating that they are also functional [1, 58]. A recent study in a moderate-sized cohort selected with extreme BMD (n 344), found significant associations between several members of the Wnt signaling pathway and bone densitometry measures [62]. In addition to LRP5, polymorphisms of LRP1, LRP6 and Wnt3a genes, as well as of different Wnt/LRP5 antagonists (SFRP1, SOST and DKK2), also showed association with BMD in women. Polymorphisms in the SOST gene, encoding sclerostin (a LRP5 antagonist) have been shown to be associated with BMD in male and female subjects from the Rotterdam Study [63]. In contrast to LRP5, the effect of SOST polymorphism seems to be more evident in the oldest age group.
COL1A1 Gene Type 1 collagen is the major structural protein of bone and thus the genes encoding this protein are important candidates for genetic regulation of bone mass in both males and females. An osteoporotic phenotype, without typical signs of osteogenesis imperfecta, could be the result of genetics defects in the COL1A1 and COL1A2 genes. An intronic polymorphism in the COL1A1 gene has been identified and associated with BMD and osteoporotic fracture risk in several studies on elderly women [1, 2]. This polymorphism involves a consensus binding site for the transcriptional regulator Sp-1 and there is now evidence of allelic specific differences in gene transcription, collagen protein production, bone mineralization and, most importantly, bone strength in samples derived from subjects with opposite genotypes [1]. To date, there are few studies that specifically analyzed the role of this polymorphism in males [1, 2, 49]. In larger studies or meta-analysis in mixed male and female populations, the association between COL1A1 alleles and fracture persisted even after correction for BMD and appeared stronger than would be expected on the basis of allelespecific differences in bone mass [1]. This has led to speculation that the polymorphism may principally act as a marker of bone fragility rather than of reduced BMD. The COL1A1 Sp1 polymorphism has been specifically studied in relation to BMD in children and adolescents, but the results have been contradictory. In the only study performed in a mixed male and female population (mean age 12–15 years) from Northern Ireland, no significant association was
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observed, indicating that this polymorphism may be associated with osteoporotic fractures by affecting age-related bone loss and bone fragility, rather than peak bone mass [64].
Insulin-like Growth Factor I In the past years, several lines of evidence indicated that the insulin-like growth factor I (IGF-I) gene may be a strong candidate for peak bone mass and osteoporosis in men. Low IGF-I levels have been implicated in the etiopathogenesis of idiopathic osteoporosis in young males and may account for the reduced osteoblast activity frequently observed in these subjects [49]. Moreover, heritable determinants of circulating IGF-I levels have been demonstrated [49]. This has led to the hypothesis that a particular allelic configuration of the IGF-I gene due to a (CA)n dinucleotide repeat polymorphism next to the promoter region could be associated with the observed variation in circulating IGF-I levels. In an early study by Rosen et al [65], a particular allele, defined by the presence of 19 CA repeats, was more prevalent in male patients with idiopathic osteoporosis than in controls. Interestingly, homozygosity for the same allele was also associated with low serum IGF-I levels and a trend for a lower BMD was also observed. Some preliminary observations in a larger sample of men seemed to confirm this association [49]. However, the molecular mechanism remains unknown and a large sib-pair study on premenopausal females did not confirm a significant role of this polymorphism, at least in women [66]. Thus, the effect of the (CA)n repeat polymorphism on bone mass and circulating IGF-I levels may be gender-specific, with a significant impact only in male subjects. Further large-scale studies are needed to confirm this hypothesis.
Other Polymorphic Variants A large number of other candidate genes have been studied in relation to BMD and susceptibility to osteoporotic fracture. Some polymorphisms in these genes have been also specifically associated with peak bone mass in men. These include methylene tetrahydrofolate reductase (MTHFR) [67], catechol-O-methyltransferase (COMT) [68], interleukin 6 (IL-6) [69], arachidonate 12-lipoxygenase (ALOX12) [70], receptor activator of NF-kappaB ligand (RANKL), receptor activator of NF-kappaB (RANK) and osteoprotegerin (OPG) [71] genes. In particular, the association between ALOX12 polymorphisms and BMD has been further supported by linkage studies and experimental observations in mice. The 17p13 region of the human genome containing the ALOX12 gene has been identified as a QTL for BMD of the hip, spine [72] and wrist [73]. Moreover, the murine arachidonate 15-lipoxygenase gene (Alox15) has been identified as a negative regulator of peak BMD [74]. Even though the human ALOX15 gene shares significant sequence homology with the murine Alox15 gene, the human ALOX12 gene is
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functionally more similar to the mouse Alox15 gene in terms of reaction products. Similarly, the importance of polymorphisms in RANK, RANKL and OPG genes, affecting a major pathway for the regulation of osteoclast activity and bone resorption, has been recently underlined in two large-scale, genome-wide, association studies [34, 35, 75]. The specific role of these polymorphisms in the regulation of peak BMD in men, however, needs to be further investigated. Finally, an interaction between polymorphisms in peroxisome proliferator activated receptor (PPARG) gene and dietary fat on BMD has been also described in both middle-aged men and women from the Framingham Offspring Cohort [76].
Animal studies Experimental animal models have provided a means largely to circumvent the complex effects of environmental (at least extrinsic) variations which are present in human studies [77]. Different animal models (and particularly mice, rats and non-human primates) have been the subject of experimental osteoporosis research [78]. Of the currently available options, the mouse is arguably the model of choice because: 1. mice are much cheaper to house and easier to handle 2. mouse genetic resources are quite extensive 3. once candidate genes are identified, the ability to manipulate them in mice and to deduce unambiguously their role in disease is unparalleled. Moreover, gene targeting has reached new heights in mice, but is barely on the horizon in other animals. With gene targeting perhaps as the ultimate arbiter for establishing causeand-effect relationships between candidate genes and osteoporosis susceptibility, the mouse is apt to remain the primary experimental model system for the foreseeable future [79]. Current murine research in the field of skeletal genetics is heavily dependent upon comparing inbred mice of different strains that exhibit marked differences in parameters of skeletal integrity. A strain of a species is inbred when virtually every genetic locus is homozygous. This means that all individuals within an inbred strain share a set of characteristics that uniquely define them compared to other strains. Typically, inbred strains are derived from 20 or more consecutive generations that have been brother sister mated; the strain can then be maintained with this same pattern of propagation. Individual animals within an inbred strain are virtually as identical as monozygotic twins. There are several qualities of inbred strains that make them especially valuable for research. The first is their long-term relative genetic stability. This is important because it allows researchers to build on previous investigations. Genetic change can occur only as a result of mutation within an inbred strain. A second important quality of inbred animals
is their homozygosity because inbred strains will breed true. Once the characteristics of a strain are known they can be reproduced repeatedly allowing for replicate experimentation as well as for studies by other investigators. The influence of genotype upon a particular characteristic can be investigated by placing mice from several inbred strains in a common environment. Observed differences must then be, within limits, the consequence of genetic factors. By reversing this strategy and placing mice from a single inbred strain in a variety of environments, it is possible to estimate the importance of environmental influences upon a parameter of interest. Thus, inbred animals can be used to determine whether genetic variation in the expression of a characteristic exists and the environmental malleability of the characteristic [80].
Sex-Specific Skeletal Traits and Genetics Experiments with inbred strains do have some limitations. While strain differences are easily demonstrated, it is often very difficult to attach much meaning to these differences, because the genes and gene products involved are usually unknown. Because comparisons of mice from two or more strains do not usually provide any information about the nature of the genetic differences, crosses between genotypes must be used to analyze patterns of genetic influence. Additionally, when using an inbred strain to investigate any type of phenomenon, it is important to be aware that the observations may be relevant only to that strain. Because an inbred strain differs from all others, there will be characteristics unique to it. It is therefore important to use more than one strain to confirm that any observation obtained pertains to the species and not just to the strain studied. Osteoporosis researchers have performed genotype– phenotype linkage (or quantitative trait or QTL) analyses in large populations of genetically heterogeneous mice derived from various combinations of inbred strains in the hopes of obtaining a more complete picture of the polygenic control of bone mass and an improved understanding of the complex interactions and physiological mechanisms involved. Results from these complementary studies are beginning to define the landscape of the genetic regulation of bone fragility and partition this quantitative trait into separate genetic components amenable for more detailed evaluation [81, 82]. A number of experiments on inbred mice have demonstrated evidence of sex-specific effects on skeletally-relevant traits. Using C57BL/6 J mice, Glatt and colleagues [83] found age-related changes in trabecular bone architecture occur earlier and are more dramatic in female than male mice, particularly in the secondary spongiosa of the femoral metaphysis. As described above, the study of an inbred strain usually provides very little information about specific mechanisms of gene action. The analysis of single mutant versus normal genes is often a more effective approach. Comparisons between homozygous mutant mice and their
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‘normal’ homozygous wild-type and heterozygous litter mates may provide considerable information on cellular mechanisms critical for discrete aspects of bone biology. For example, steroid receptor coactivator (SRC)-1 is critical for the maintenance of bone mass in both female and male mice. However, Mödder et al [84] recently demonstrated preserved responses to estrogen in trabecular bone in male gonadectomized SRC-1 knockout (KO) mice, in stark contrast to the deficient skeletal response to similar estrogen treatment in female gonadectomized SRC-1 KO mice. These investigators hypothesize the gender-specificity in the consequences of loss of SRC-1 for estrogen action may have to do with preferred interactions of SRC-1 with the two different ESR isoforms ( and ). Future studies with this model will likely provide insights into differential ESR and expression, utilization or interactions with SRC-1 in male versus female bones. The insulin-like growth factor (IGF) system is an important regulator of bone development. Recent studies of the skeletal phenotype of IGF binding protein 2 (IGFBP2) KO mice revealed gender- and compartment-specific effects [85]. Female IGFBP2-KO mice exhibited increased femoral cortical thickness and greater periosteal circumference compared to wild-type controls, whereas male IGFBP2-KO mice had reduced femoral cortical bone area and a 20% reduction in the trabecular bone volume fraction due to thinner trabeculae than their corresponding controls. Studies of transgenic mice bearing a mutation in LRP5 associated with an HBM phenotype in humans also indicate the presence of gender-specific effects on trabecular structural parameters [86]. The above examples demonstrate the utility of animal models in uncovering aspects of bone biology contributing to skeletal dimorphism that are currently not feasible to explore in human subjects. Just as is the case in humans, sex-specific differences in the amount of bone and the architectural arrangement of bone tissue are obvious in animals. Studies on controlled model systems are now beginning to provide some insight into putative sex-specific determinants of heritable skeletal traits. Orwoll et al [87] examined peak whole body BMD (measured by dual energy x-ray absorptiometry (DXA)) in male and female mice from a panel of recombinant inbred strains derived from C57BL/6 J (B6) and DBA/2 J (D2) progenitor mice. A significant gender by strain interaction was observed, with males having higher BMD than females in some strains but lower in others. In a follow-up linkage analysis experiment employing a genetically heterogeneous F2 (second generation offspring) population of mice (B6D2F2) derived from the same B6 and D2 progenitor strains, strong associations between peak bone mass and three chromosomal locations (chromosomes 1, 4 and 11) were identified in both male and female mice [82]. However, there was no relationship with bone mass in males at a fourth locus strongly associated with bone mass in females (chromosome 2) and the reverse situation (no relationship
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with bone mass in females at a fifth locus strongly associated with bone mass in males) was found at chromosome 7. It is informative to contrast the results obtained in these analyses to those obtained when gender is not considered in the study design [88]. When male and female animals were studied together, the association on chromosome 7 was not detected using standard criteria. Unless specifically sought, gender effects can lead to a lessened ability to detect potentially important genetic determinants. Size and shape are critical determinants of the mechanical properties of skeletal elements and can be anticipated, like BMD, to be highly heritable. Moreover, the genes responsible may be independent of those that regulate BMD. For a long bone, one of the most important geometric properties influencing its ability to resist fracture is its cross-sectional area (CSA). Companion experiments employing the same panel of recombinant inbred strains and B6D2F2 population described above [89] revealed regions on four different chromosomes that were very strongly linked to femoral mid-shaft CSA (chromosomes 6, 8, 10 and X) in both genders. Evidence of gender-specific genetic influences on femoral geometry was also identified at three other chromosomal sites (chromosomes 2, 7 and 12). Interestingly, none of these chromosomal associations with femoral CSA were identified in the previous analysis of whole body BMD in the same B6D2F2 population. Thus, the genetic determinants of bone size appear to be largely, if not entirely, distinct from those regulating BMD attainment. Furthermore, these studies strongly support the existence of sex-specific pathways engaged in the genetic regulation of peak bone mass and size – critical determinants of fracture resistance. Classical transmission genetics can also be used to transfer distinct chromosomal regions containing putative risk or protective genes onto appropriate background strains. Such congenic strains are produced by repeated backcrossing to the background inbred strain and genotypic selection of the desired allele at flanking markers at each backcross generation. The primary advantage of the congenic is that the influence of an individual chromosomal region on a given trait can be tested using the congenic versus background strain comparison at any level from the molecular to the physiological. Ultimately, congenic strains can greatly facilitate positional cloning of a causative gene. Knowing which genetic markers define a specific chromosomal region will automatically indicate which candidate genes reside within the region. In addition, congenic strains provide an invaluable resource for further defining specific genes of interest and for in depth studies of the mechanisms by which they affect skeletal phenotype. Using this experimental strategy, Turner and colleagues [90] discovered that regions of murine chromosome 1 and 18 impart sex-specific effects on femoral structure (as reflected by mid-diaphyseal polar moment of inertia) and a region of chromosome 6 imparts a sex-specific effect on femoral cortical volumetric
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BMD and femoral strength. Of particular interest, the introgressed region on chromosome 1 influenced the moment of inertia (an index of resistance to fracture) of male bones in an opposite direction from female bones. Extending these observations, subsequent studies with these chromosome 1 congenic mice found that the female congenic mice were more responsive while the male congenic mice were less responsive to mechanical loading events than their respective background littermates [91]. These findings may explain sex-specific differences in peak bone mass accrual despite similar physical activity. Edderkaoui et al [92] have explored this same region of murine chromosome 1 with congenic mice created from other inbred mouse strains and have identified three separate genetic loci influencing femoral volumetric BMD – the effects of two loci were only evident in female mice. Clearly, more studies are called for better to define the implications of these preliminary observations, but the fact that mice and humans share genetic homology between this region of mouse chromosome 1 and a region of human chromosome (1q20-24) that is associated with BMD [1] suggests the imperative to partition human data by sex to improve accuracy of mapping and genetic loci identification. In summary, data in mice suggest the presence of sexspecific genes governing bone mass, size and microstructure, which may, in part, occur via differences in skeletal responses to environment (e.g. mechanical loading, sex steroids, etc.) between males and females. Certainly, the chromosomal loci that reveal gender divergence may be related to the control of, or responsiveness to, sex steroid action. On the other hand, results thus far cannot support or refute the hypothesis that gender differences are sex steroid-independent. In fact, the presence of a clear gender divergence in the genetic basis of peak bone mass raises the intriguing possibility that there may also be other mechanisms by which gender influences gene activation. Other mechanisms that may be involved are uncertain, but include genes on X or Y chromosomes with complementary activities at autosomal sites. Since the male phenotype is associated with considerable fracture risk reduction, an elucidation of the nature of sex-specific effects on bone development could provide the basis for novel diagnostic, preventative or therapeutic approaches.
References 1. S.H. Ralston, Genetic determinants of bone mass and osteoporotic fracture, in: J.P. Bilezikian, L.G. Riggs, T.J. Martin (Eds.) Principles of Bone Biology, third ed., Elsevier, San Diego, 2008, pp. 1611–1634. 2. O.M.E. Albagha, S.H. Ralston, Genetics and osteoporosis, Rheum. Dis. Clin. N. Am. 32 (2006) 659–680. 3. E. Seeman, C. Tsalamandris, C. Formica, J.L. Hopper, J. McKay, Reduced femoral neck bone density in the daughters of women with hip fractures: the role of low peak bone density
4.
5.
6.
7.
8.
9. 10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
in the pathogenesis of osteoporosis, J. Bone Miner. Res. 9 (1994) 739–743. M.E. Cohen-Solal, C. Baudoin, M. Omouri, D. Kuntz, M.C. De Vernejoul, Bone mass in middle-aged osteoporotic men and their relatives: familial effect, J. Bone Miner. Res. 13 (1998) 1909–1914. I. Van Pottelbergh, S. Goemaere, H. Zmierczak, D. De Bacquer, J.M. Kaufman, Deficient acquisition of bone during maturation underlies idiopathic osteoporosis in men: evidence from a three-generation family study, J. Bone Miner. Res. 18 (2003) 303–311. D.M. Smith, W.E. Nance, K.W. Kang, J.C. Christian, C.C. Johnston Jr., Genetic factors in determining bone mass, J. Clin. Invest. 52 (1973) 2800–2808. S. Ferrari, R. Rizzoli, D. Slosman, J.P. Bonjour, Familial resemblance for bone mineral mass is expressed before puberty, J. Clin. Endocrinol. Metab. 83 (1998) 358–361. G. Jones, T.V. Nguyen, Association between maternal peak bone mass and bone mass in prepubertal male and female children, J. Bone Miner. Res. 15 (2000) 1998–2004. E. Seeman, Pathogenesis of bone fragility in women and men, Lancet 359 (2002) 1841–1850. D. Karasik, S.L. Ferrari, Contribution of gender-specific genetic factors to osteoporosis risk, Ann. Hum. Genet. 72 (2008) 696–714. V. Naganathan, A. Macgregor, H. Snieder, T. Nguyen, T. Spector, P. Sambrook, Gender differences in the genetic factors responsible for variation in bone density and ultrasound, J. Bone Miner. Res. 17 (2002) 725–733. H.W. Deng, G. Livshits, K. Yakovenko, et al., Evidence for a major gene for bone mineral density/content in human pedigrees identified via probands with extreme bone mineral density, Ann. Hum. Genet. 66 (2002) 61–74. C. Pelat, I. Van Pottelbergh, M. Cohen-Solal, et al., Complex segregation analysis accounting for GxE of bone mineral density in European pedigrees selected through a male proband with low BMD, Ann. Hum. Genet. 71 (2007) 29–42. Q.Y. Huang, R.R. Recker, H.W. Deng, Searching for osteoporosis genes in the post-genome era: progress and challenges, Osteoporos. Int. 14 (2003) 701–715. P.H. Byers, G.A. Wallis, M.C. Willing, Osteogenesis imperfecta: translation of mutation to phenotype, Med. Genet 28 (1991) 433–442. E.P. Smith, J. Boyd, G.R. Frank, et al., Estrogen resistance caused by a mutation in the estrogen-receptor gene in a man, N. Engl. J. Med. 331 (1994) 1056–1061. L. Gennari, J. Bilezikian, S. Khosla, Estrogen effects on bone in the male skeleton, in: J.P. Bilezikian, L.G. Riggs, T.J. Martin (Eds.) Principles of Bone Biology, third ed., Elsevier, San Diego, 2008, pp. 1819–1837. Y. Gong, R.B. Slee, N. Fukai, et al., LDL Receptor-related protein 5 (LRP5) affects bone accrual and eye development., Cell 107 (2001) 513–523. H. Hartikka, O. Makitie, M. Mannikko, et al., Heterozygous mutations in the LDL receptor-related protein 5 (LRP5) gene are associated with primary osteoporosis in children, J. Bone Miner. Res. 20 (2005) 783–789. P. Crabbe, W. Balemans, A. Willaert, et al., Missense mutations in LRP5 are not a common cause of idiopathic osteoporosis in adult men, J. Bone Miner. Res. 20 (2005) 1951–1959.
C h a p t e r 1 2 The Genetics of Peak Bone Mass l
21. A. Mani, J. Radhakrishnan, H. Wang, et al., LRP6 mutation in a family with early coronary disease and metabolic risk factors, Science 315 (2007) 1278–1282. 22. L.M. Boyden, J. Mao, J. Belsky, et al., High bone density due to a mutation in LDL-receptor-related protein 5, N. Engl. J. Med. 346 (2002) 1513–1521. 23. L. Van Wesenbeeck, E. Cleiren, J. Gram, et al., Six novel missense mutations in the LDL receptor-related protein 5 (LRP5) gene in different conditions with an increased bone density, Am. J. Hum. Genet. 72 (2003) 763–771. 24. W. Balemans, M. Ebeling, N. Patel, et al., Increased bone density in sclerosteosis is due to the deficiency of a novel secreted protein (SOST), Hum. Mol. Genet. 10 (2001) 537–543. 25. W. Balemans, N. Patel, M. Ebeling, et al., Identification of a 52 kb deletion downstream of the SOST gene in patients with van Buchem disease, J. Med. Genet 39 (2002) 91–97. 26. J.C. Gardner, R.L. van Bezooijen, B. Mervis, et al., Bone mineral density in sclerosteosis: affected individuals and gene carriers, J. Clin. Endocrinol. Metab. 90 (2005) 6392–6395. 27. J.P. Ioannidis, M.Y. Ng, P.C. Sham, et al., Meta-analysis of genome-wide scans provides evidence for sex- and site-specific regulation of bone mass, J. Bone Miner. Res. 22 (2007) 173–183. 28. D. Karasik, L.A. Cupples, M.T. Hannan, D.P. Kiel, Age, gender, and body mass effects on quantitative trait loci for bone mineral density: the Framingham study, Bone 33 (2003) 308–316. 29. S.H. Ralston, N. Galwey, I. Mackay, et al., Loci for regulation of bone mineral density in men and women identified by genome wide linkage scan: the FAMOS study, Hum. Mol. Genet 14 (2005) 943–951. 30. J.M. Kaufman, A. Ostertag, A. Saint-Pierre, et al., Genomewide linkage screen of bone mineral density (BMD) in European pedigrees ascertained through a male relative with low BMD values: evidence for quantitative trait loci on 17q2123, 11q12-13, 13q12-14 and 22q11, J. Clin. Endocrinol. Metab. 93 (2008) 3755–3762. 31. F. Zhang, P. Xiao, F. Yang, et al., A whole genome linkage scan for QTLs underlying peak bone mineral density, Osteoporos. Int. 19 (2008) 303–310. 32. E.A. Streeten, D.J. McBride, T.I. Pollin, et al., Quantitative trait loci for BMD identified by autosome-wide linkage scan to chromosomes 7q and 21q in men from the Amish Family Osteoporosis Study, J. Bone Miner. Res. 21 (2006) 1433–1442. 33. U. Styrkarsdottir, J.B. Cazier, A. Kong, et al., Linkage of osteoporosis to chromosome 20p12 and association to BMP2, PLoS. Biol. 1 (3) (2003) E69. 34. J.B. Richards, F. Rivadeneira, M. Inouye, et al., Bone mineral density, osteoporosis, and osteoporotic fractures: a genomewide association study, Lancet 371 (2008) 1505–1512. 35. U. Styrkarsdottir, B.V. Halldorsson, S. Gretarsdottir, et al., Multiple genetic loci for mineral density and fracture, N. Engl. J. Med. 358 (2008) 2355–2365. 36. I. Braidman, C. Baris, L. Wood, et al., Preliminary evidence for impaired estrogen receptor – a protein expression in osteoblasts and osteocytes from men with idiopathic osteoporosis, Bone 26 (2006) 423–427. 37. L. Gennari, D. Merlotti, V. De Paola, et al., Estrogen receptor gene polymorphisms and the genetics of osteoporosis: a huge review, Am. J. Epidemiol. 161 (2005) 307–320. 38. J.P. Ioannidis, I. Stavrou, T.A. Trikalinos, et al., ER-alpha genetics meta-analysis. Association of polymorphisms of the
39.
40.
41.
42.
43.
44.
45.
46.
47.
48.
49. 50.
51.
52.
53.
161
estrogen receptor alpha gene with bone mineral density and fracture risk in women: a meta-analysis, J. Bone Miner. Res. 17 (2002) 2048–2060. J.P. Ioannidis, S.H. Ralston, S.T. Bennett, et al., Differential genetic effects of ESR1 gene polymorphisms on osteoporosis outcomes., J. Am. Med. Assoc. 292 (2) (2004) 105–114. M. Lorentzon, R. Lorentzon, T. Backstrom, P. Nordstrom, Estrogen receptor gene polymorphism, but not estradiol levels, is related to bone density in healthy adolescent boys: a cross-sectional and longitudinal study, J. Clin. Endocrinol. Metab. 84 (1999) 4597–4601. A.M. Boot, I.M. van der Sluis, S.M. de Muinck KeizerSchrama, et al., Estrogen receptor alpha gene polymorphisms and bone mineral density in healthy children and young adults, Calcif. Tissue Int. 74 (2004) 495–500. P. Pennisi, T. Chevalley, D. Manen, et al., Genetic variation in estrogen receptor alpha and interleukin-6 is associated with bone mass acquisition in prepubertal girls and boys: interaction with calcium supplements, J. Bone Min. Res. 20 (Suppl. 1) (2005) S343. M.C. Willing, J.C. Torner, T.L. Burns, et al., Gene polymorphisms, bone mineral density and bone mineral content in young children: the Iowa Bone Development Study, Osteoporos. Int. 14 (2003) 650–658. S. Khosla, B.L. Riggs, E.J. Atkinson, et al., Relationship of estrogen receptor genotypes to bone mineral density and to rates of bone loss in men, J. Clin. Endocrinol. Metab. 89 (2004) 1808–1816. A.M. Shearman, D. Karasik, K.M. Gruenthal, et al., Estrogen receptor beta polymorphisms are associated with bone mass in women and men: the Framingham study, J. Bone Miner. Res. 19 (2004) 773–781. L. Gennari, R. Nuti, J.P. Bilezikian, Aromatase activity and bone homeostasis in men, J. Clin. Endocrinol. Metab. 89 (2004) 5898–5907. T. Remes, S.B. Vaisanen, A. Mahonen, et al., Aerobic exercise and bone mineral density in middle-aged Finnish men: a controlled randomized trial with reference to androgen receptor, aromatase, and estrogen receptor gene polymorphisms, Bone 32 (2003) 412–420. M. Lorentzon, C. Swanson, A.L. Eriksson, D. Mellström, C. Ohlsson, Polymorphisms in the aromatase gene predict areal BMD as a result of affected cortical bone size: the GOOD study, J. Bone Miner. Res. 21 (2006) 332–339. L. Gennari, M.L. Brandi, Genetics of male osteoporosis, Calcif. Tissue Int. 69 (2001) 200–204. L. Gennari, D. Merlotti, V. De Paola, G. Martini, R. Nuti, Update on the pharmacogenetics of the vitamin D receptor and osteoporosis, Pharmacogenomics 10 (2009) 417–433. S. Ferrari, R. Rizzoli, T. Chevallery, D. Slosman, J.A. Eisman, J.P. Bonjour, Vitamin D receptor gene polymorphisms and change in lumbar spine bone mineral density, Lancet 345 (1995) 423–424. S. Ferrari, D. Manen, J.P. Bonjour, D. Slosman, R. Rizzoli, Bone mineral mass and calcium and phosphate metabolism in young men: relationship with vitamin D receptor allelic polymorphisms, J. Bone Miner. Res. 84 (1999) 2043–2048. E. Grundberg, E.M. Lau, T. Pastinen, et al., Vitamin D receptor 3 haplotypes are unequally expressed in primary human bone cells and associated with increased fracture risk: the
162
54.
55.
56.
57.
58.
59.
60.
61.
62.
63.
64.
65.
66.
67.
68.
Osteoporosis in Men
MrOS Study in Sweden and Hong Kong, J. Bone Miner. Res. 22 (2007) 832–840. C. Vilariño-Güell, L.J. Miles, E.L. Duncan, et al., PTHR1 polymorphisms influence BMD variation through effects on the growing skeleton, Calcif. Tissue Int. 81 (2007) 270–278. S.L. Ferrari, S. Deutsch, C. Baudoin, et al., LRP5 gene polymorphisms and idiopathic osteoporosis in men, Bone 37 (2005) 770–775. S.L. Ferrari, S. Deutsch, U. Choudhury, et al., Polymorphisms in the low-density lipoprotein receptor-related protein 5 (LRP5) gene are associated with variation in vertebral bone mass, vertebral bone size, and stature in whites, Am. J. Hum. Genet 74 (2004) 866–875. J.B. Van Meurs, S.C. Schuit, A.E. Weel, et al., Association of 5 estrogen receptor alpha gene polymorphisms with bone mineral density, vertebral bone area and fracture risk, Hum. Mol. Genet 12 (2003) 1745–1754. D.P. Kiel, S.L. Ferrari, L.A. Cupples, et al., Genetic variation at the low-density lipoprotein receptor-related protein 5 (LRP5) locus modulates Wnt signaling and the relationship of physical activity with bone mineral density in men, Bone 40 (2007) 587–596. K. Brixen, S. Beckers, A. Peeters, et al., Polymorphisms in the low-density lipoprotein receptor-related protein 5 (LRP5) gene are associated with peak bone mass in non-sedentary men: results from the Odense Androgen Study, Calcif. Tissue Int. 81 (2007) 421–429. A. Saarinen, V.V. Välimäki, M.J. Välimäki, et al., The A1330V polymorphism of the low-density lipoprotein receptor-related protein 5 gene (LRP5) associates with low peak bone mass in young healthy men., Bone 40 (2007) 1006–1012. J.B. van Meurs, T.A. Trikalinos, S.H. Ralston, et al., Largescale analysis of association between LRP5 and LRP6 variants and osteoporosis, J. Am. Med. Assoc. 299 (2008) 1277–1290. A.M. Sims, N. Shephard, K. Carter, et al., Genetic analyses in a sample of individuals with high or low BMD shows association with multiple Wnt pathway genes, J. Bone Miner. Res. 23 (2008) 499–506. A.G. Uitterlinden, P. Arp, B. Paeper, et al., Polymorphisms in the sclerosteosis/van Buchem disease gene (SOST) region are associated with bone-mineral density in elderly whites, Am. J. Hum. Genet 75 (2004) 1032–1045. F.E. McGuigan, L. Murray, A. Gallagher, et al., Genetic and environmental determinants of peak bone mass in young men and women, J. Bone Miner. Res. 17 (2002) 1273–1279. C.J. Rosen, E.S. Kurland, D. Vereault, et al., Association between serum insulin growth factor-I (IGF-I) and a simple sequence repeat in IGF-I gene: implications for genetic studies of bone mineral density, J. Clin. Endocrinol. Metab. 83 (1998) 2286–2290. I. Takacs, D.L. Koller, M. Peacock, et al., Sibiling pair linkage and association studies between bone mineral density and the insulin-like growth factor I gene locus, J. Clin. Endocrinol. Metab. 84 (1999) 4467–4471. B. Abrahamsen, H.L. Jørgensen, T.L. Nielsen, et al., MTHFR c.677C T polymorphism as an independent predictor of peak bone mass in Danish men – results from the Odense Androgen Study, Bone 38 (2006) 215–219. M. Lorentzon, A.L. Eriksson, D. Mellström, C. Ohlsson, The COMT val158met polymorphism is associated with peak BMD in men, J. Bone Miner. Res. 19 (2004) 2005–2011.
69. M. Lorentzon, R. Lorentzon, P. Nordström, Interleukin-6 gene polymorphism is related to bone mineral density during and after puberty in healthy white males: a cross-sectional and longitudinal study, J. Bone Miner. Res. 15 (2000) 1944–1949. 70. S. Ichikawa, D.L. Koller, M.L. Johnson, et al., Human ALOX12, but not ALOX15, is associated with BMD in white men and women, J. Bone Miner. Res. 21 (2006) 556–564. 71. Y.H. Hsu, T. Niu, H.A. Terwedow, et al., Variation in genes involved in the RANKL/RANK/OPG bone remodeling pathway are associated with bone mineral density at different skeletal sites in men, Hum. Genet 118 (2006) 568–577. 72. H.W. Deng, F.H. Xu, Q.Y. Huang, et al., A whole-genome linkage scan suggests several genomic regions potentially containing quantitative trait loci for osteoporosis, J. Clin. Endocrinol. Metab. 87 (2002) 5151–5159. 73. M. Devoto, K. Shimoya, J. Caminis, et al., First-stage autosomal genome screen in extended pedigrees suggests genes predisposing to low bone mineral density on chromosomes 1p, 2p and 4q, Eur. J. Hum. Genet 6 (1998) 151–157. 74. R.F. Klein, J. Allard, Z. Avnur, et al., Regulation of bone mass in mice by the lipoxygenase gene Alox15, Science 303 (2004) 229–232. 75. J.N. Hirschhorn, L. Gennari, Bona fide genetic associations with bone mineral density, N. Engl. J. Med. 358 (2008) 2403–2405. 76. C.L. Ackert-Bicknell, S. Demissie, C. Marín de Evsikova, et al., PPARG by dietary fat interaction influences bone mass in mice and humans, J. Bone Miner. Res. 23 (2008) 1398–1408. 77. H. Allayee, A. Andalibi, M. Mehrabian, Using inbred mouse strains to identify genes for complex diseases, Front. Biosci. 11 (2006) 1216–1226. 78. R.J. Shmookler Reis, R.H. Ebert 2nd, Animal models for discovery and assessment of genetic determinants of osteoporosis, Osteoporos. Int. 14 (Suppl. 5) (2003) S100–S106. 79. D. Malakoff, The rise of the mouse, biomedicine’s model mammal, Science 288 (2000) 248–253. 80. L. Flaherty, B. Herron, D. Symula, Genomics of the future: identification of quantitative trait loci in the mouse, Genome. Res. 15 (2005) 1741–1745. 81. H. Benes, R.S. Weinstein, W. Zheng, et al., Chromosomal mapping of osteopenia-associated quantitative trait loci using closely related mouse strains, J. Bone Miner. Res. 15 (2000) 626–633. 82. R.F. Klein, A.S. Carlos, K.A. Vartanian, et al., Confirmation and fine mapping of chromosomal regions influencing peak bone mass in mice, J. Bone Miner. Res. 16 (2001) 1953–1961. 83. V. Glatt, E. Canalis, L. Stadmeyer, M.L. Bouxsein, Agerelated changes in trabecular architecture differ in female and male C57BL/6J mice, J. Bone Miner. Res. 22 (2007) 1197–1207. 84. U.I. Mödder, A. Sanyal, J. Xu, B.W. O’Malley, T.C. Spelsberg, S. Khosla, The skeletal response to estrogen is impaired in female but not in male steroid receptor coactivator (SRC)-1 knock out mice, Bone 42 (2008) 414–421. 85. V.E. DeMambro, D.R. Clemmons, L.G. Horton, et al., Gender-specific changes in bone turnover and skeletal architecture in igfbp-2-null mice, Endocrinology 149 (2008) 2051–2061. 86. S.A. Dubrow, P.M. Hruby, M.P. Akhter, Gender specific LRP5 influences on trabecular bone structure and strength, J. Musculoskelet. Neuron. Interact. 7 (2007) 166–173.
C h a p t e r 1 2 The Genetics of Peak Bone Mass l
87. E.S. Orwoll, J.K. Belknap, R.F. Klein, Gender specificity in the genetic determinants of peak bone mass, J. Bone Miner. Res. 16 (2001) 1962–1971. 88. R.F. Klein, S.R. Mitchell, T.J. Phillips, J.K. Belknap, E.S. Orwoll, Quantitative trait loci affecting peak bone mineral density in mice, J. Bone Miner. Res. 13 (1998) 1648–1656. 89. R.F. Klein, R.J. Turner, L.D. Skinner, et al., Mapping quantitative trait loci that influence femoral cross-sectional area in mice, J. Bone Miner. Res. 17 (2002) 1752–1760. 90. C.H. Turner, Q. Sun, J. Schriefer, et al., Congenic mice reveal sex-specific genetic regulation of femoral structure and strength, Calcif. Tissue Int. 73 (2003) 297–303.
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91. A.G. Robling, S.J. Warden, K.L. Shultz, W.G. Beamer, C.H. Turner, Genetic effects on bone mechanotransduction in congenic mice harboring bone size and strength quantitative trait loci, J. Bone Miner. Res. 22 (2007) 984–991. 92. B. Edderkaoui, D.J. Baylink, W.G. Beamer, K.L. Shultz, J.E. Wergedal, S. Mohan, Genetic regulation of femoral bone mineral density: complexity of sex effect in chromosome 1 revealed by congenic sublines of mice, Bone 41 (2007) 340–445.
Chapter
13
Age-related Changes in Bone Remodeling and Microarchitecture Roger Zebaze1 and Ego Seeman2 1
Department of Endocrinology and Medicine, Austin Health University of Melbourne, Melbourne, Victoria, Australia Endocrine Centre, Heidelberg Repatriation Hospital/Austin Health, Department of Medicine, University of Melbourne, Melbourne, Victoria, Australia
2
Introduction
(HSA), section modulus and cross-sectional moment of inertia, are used but these also fail to improve sensitivity and specificity in identifying individuals at high or low risk for fracture respectively, perhaps because these surrogates fail to quantify the age-related deterioration in the material composition and structure of bone in either sex [5, 6]. This chapter reviews age-related changes in bone remodeling in women and men. We focus on the sex differences in bone remodeling that are likely to produce sex differences in macro- and microarchitectural deterioration.
Fewer men sustain fractures than women during advancing age [1]. However, fragility fractures are also a public health problem in men because they are common, have a high morbidity, mortality and confer a high cost on the individual and the community [2]. Structural failure – fracture – reflects age-related changes in the material composition and structural design of bone. However, the pathogenesis and structural basis of bone fragility are not well understood in either sex and so the reasons underlying the lower incidence of fragility fractures in men than women are also not well understood. Most fractures occur in women and men without osteoporosis as defined by bone mineral density (T-score 2.5 SD) [3]. This partly reflects the occurrence of most events in the larger numbers of individuals at moderate risk for fracture occupying the ‘bell’ of the Gaussian distribution of areal bone mineral density (aBMD) rather than the smaller numbers of individuals at high fracture risk occupying the tail of the distribution (aBMD T score 2.5 SD designated as ‘osteoporosis’). In addition, individuals with normal aBMD may be at high risk for fracture due to structural abnormalities not captured by the aBMD measurement [4], while not all individuals with aBMD in the osteoporosis range have fragile bones. These limitations have consequences. Many men and women in need of treatment are not identified using conventional dual energy x-ray absorptiometry (DXA) and many who are treated on the basis of low BMD may not necessarily need to be treated with pharmacological agents. To overcome this problem, surrogates of structural strength derived from quantitative computed tomography (QCT) or densitometry-based methods, such as hip structure analysis
Osteoporosis in Men
The process and purpose of bone modeling and remodeling Bone modeling (construction) is the process by which bone is formed by osteoblasts without prior bone resorption. This process is vigorous during growth and changes bone size and shape. Bone remodeling (reconstruction) occurs throughout life. During remodeling, bone is first resorbed by osteoclasts and then formed in the same location by osteoblasts without a change in bone size or shape. These cells form the basic multicellular unit (BMU) that reconstructs bone in distinct locations on the three (endocortical, intracortical and trabecular) components of its inner (endosteal) envelope and, to a much lesser extent, on the outer (periosteal) envelope [7]. Bone modeling and remodeling during growth achieve strength for loading and lightness for mobility by strategically depositing bone in locations where it is needed, modifying bone size and shape and removing bone from where it is not needed to avoid bulk. The enormous capacity of this cellular machinery to modify structure during growth, primary a modeling period, is apparent
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in the morphological differences in the playing and nonplaying arms of tennis players [8–10]. Bone remodeling during adulthood maintains bone strength by removing damaged bone. Bone develops fatigue damage during repeated loading but contains a cellular machinery that can detect the location and magnitude of the damage, remove it, replace it with new bone and thus restore bone’s material composition, micro- and macroarchitecture [11, 12]. Bone resorption is not bad for bone unless it becomes excessive. The resorptive phase of remodeling removes damaged bone and is essential to bone health. The formation phase of the remodeling cycle restores bone’s structure provided that the volume of damaged bone removed is replaced by the same volume of normal bone. This process depends on the normal production, work and lifespan of osteoclasts and osteoblasts. A cell increasingly recognized as a major component of this cellular machinery is the osteocyte. The osteocyte plays a pivotal role in initiating and perhaps regulating bone modeling and remodeling. Osteocytes are the most numerous, longest-lived and least studied cells of bone. There are about 10 000 cells per cubic millimetre and 50 neuronal-like processes per cell [13]. These processes connect osteocytes with each other and with flattened lining cells on the endosteal surface. The dense lace-like network of osteocytes with their processes ensures that no part of bone is more than several microns from a lacuna containing its osteocyte suggesting that these cells are part of the machinery guarding the integrity of the composition and structure of bone [12]. Microcracks sever osteocyte processes in their canaliculi leading to osteocyte apoptosis [14]. Apoptotic osteocytes may also be a form of damage, perhaps reducing the energy absorbing/dissipating capacity of bone when lacunae mineralize. Estrogen deficiency and corticosteroid therapy result in apoptosis [15]. The increased remodeling rate in midlife in women may be partly the result of osteocyte death. Alternatively, or in addition, osteocyte apoptosis can produce damage to surrounding mineralized matrix producing bone fragility independent of bone loss. Whether apoptotic osteocytes are a consequence of damage, are the damage itself or produce matrix damage, the number of dead osteocytes provides the topographical information needed to identify the location and size of damage [16–18]. Osteocyte apoptosis is likely to be one of the first events signaling the need for remodeling. It precedes osteoclastogenesis [19]. The apoptotic osteocyte may stimulate the sequence of cellular events of bone remodeling. In vivo, osteocyte apoptosis occurs within 3 days of immobilization and is followed within 2 weeks by osteoclastogenesis [20]. Bone remodeling is initiated on the endocortical, trabecular and intra-cortical components of the endosteal envelope (Figure 13.1). The endocortical and trabecular surfaces are adjacent to marrow. The intracortical surface forms the wall of haversian canals. Damage may occur deep to these
surfaces within the matrix of osteons or the interstitial bone between osteons. Information concerning the location and size of matrix damage must reach these surfaces and cells involved in remodeling, originating as precursors in the marrow or in stem cell niches, must reach the site of damage beneath the endosteal surface. This anatomical arrangement makes the flattened lining cells conduits transmitting the health status of the bone matrix to the bone marrow environment. Apoptotic osteocytes signal the location and size of the damage burden to the flattened lining cells of the endosteal surface leading to the formation of a bone remodeling compartment (BRC) which confines and targets remodeling to the damage [21]. The regulatory steps between osteocyte apoptotic death and creation of the BRC are not known. Bone lining cells express collagenase mRNA [22]. An early event creating the BRC may be collagenase digestion of unmineralized osteoid to expose mineralized bone, a requirement for osteoclastic bone resorption to proceed. The flattened bone lining cells are probably osteoblasts or of the osteoblast lineage and those forming the canopy over the BRC express markers characteristic of osteoblast lineage cells [21]. These canopy cells also express markers for a range of growth factors and regulators of osteoclastogenesis, such as receptor activator of nuclear factor kappa B ligand (RANKL). Bone resorption by osteoclasts and bone formation by osteoblasts occur sequentially [23]. However, the cellular and molecular events leading to these two differentiated functions are likely to be contemporaneous and multidirectional; osteoblastogenesis and its regulators determine osteoclastogenesis and the volume of bone resorbed, while osteoclastogenesis and the products of the resorbed matrix regulate osteoblastogenesis. To some extent, and in ways not yet understood, both cells may be regulated by osteocytes and their products. Signaling from apoptotic osteocytes to cells in the canopy expressing the osteoblast phenotype may influence further differentiation towards osteoblast precursors expressing RANKL and fully differentiated osteoid-producing osteoblasts. Even at this stage, regulation of osteoclastogenesis and osteoblastogenesis is occurring simultaneously through osteoblast precursors. In the MLO-Y4 cell line, damaged osteocyte-like cells have been reported to secrete macrophage colony-stimulating factor (M-CSF) and RANKL [24]. Whether this also occurs in human subjects in vivo is not known but raises the possibility that osteocytes participate in the differentiation of monocyte–macrophage precursor cells towards the osteoclast lineage. Both osteoblast and osteoclast precursors circulate and so may arrive at the BRC via the circulation and via capillaries penetrating the canopy [25–27]. Osteoprogenitor cells are associated with vascular structures in the marrow with several studies suggesting that there may be common progenitors giving rise to cells forming the blood vessel and the perivascular cells that can differentiate towards cells of multiple lineages [28–34].
C h a p t e r 1 3 Age-related Changes in Bone Remodeling and Microarchitecture l
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Periosteal surface
6.
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Intracortical surface 2.
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Figure 13.1 (1) Osteocytes are connected to each other and to lining cells on the endosteal surface adjacent to the marrow. (2) Damage to osteocytic processes by a microcrack produces osteocyte apoptosis. (3) The distribution of apoptotic osteocytes provides the topographical information needed to target osteoclasts to the damage. Osteoclasts resorb bone and remove damage. (4) The reversal phase and formation of a cement line. (5, 6) Osteoblasts deposit osteoid and some become entombed in the osteoid to form osteocytes. (From E Seeman, with permission).
The factors regulating the cessation of resorption by teams of osteoclasts and the onset of bone formation after the reversal phase are not well defined. Products from osteoclasts independent of their resorption activity and products from the resorbed matrix are likely to contribute to the regulation of osteoblastogenesis and bone formation [35–37]. In addition, products from the osteocyte are also likely to contribute to regulation of bone formation. For example, sclerostin is secreted by osteocytes and perhaps other cells as well. It is a product of the SOST gene and inhibits bone formation. Osteoblast precursors generated before resorption may form pre-emptive teams of cells ready to deposit bone, die, become lining cells or osteocytes depend on later signals from osteoclasts, the resorbed matrix or products of the osteocyte such as sclerostin or cell–cell contact. After the reversal phase, osteoblasts deposit osteoid partly or completely filling the BMU and forming the lamellae that then undergo primary and secondary mineralization. Most osteoblasts die, others become lining cells while others are
entombed in the osteoid where they develop into the osteocyte with its osteocytic canalicular network [38].
Abnormalities in bone remodeling during aging While bone can accommodate loading circumstances by adaptive modeling and remodeling during growth, this capacity diminishes because of four age-related changes in the cellular machinery of bone modeling and remodeling that compromise bone’s material properties and structural design [39]. As growth nears completion, rapid remodeling rate slows. With the completion of longitudinal growth, the only requirement for bone formation is the repair of microand macrodamage so there is a decline in bone formation, a mechanism proposed to be responsible for bone fragility over 65 years ago (Figure 13.2).
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Figure 13.2 Endosteal bone loss is the result of: (A) a reduction in the volume of bone formed in each basic metabolic unit (BMU) reflected in a reduction in mean wall thickness with age (adapted from Lips et al 1978 [40]). (B, C) A fall or little change in the volume of bone resorbed in each BMU. This is reflected in (B) as little change in erosion depth defined by preosteoblasts, mononuclear cells or osteoclast surfaces (adapted from Ericksen et al, 1985, [43] and (C) and no change in interstitial wall thickness (females black symbols) (adapted from Vedi et al 1984 [41]). (D) Increased remodeling rate (activation frequency) (courtesy J Compston).
The first age-related change in this machinery is a reduction in bone formation at the cellular level by each BMU [40, 41]. The second abnormality is also a reduction in bone formation but at the tissue level – bone modeling on the periosteal envelope slows precipitously after completion of longitudinal growth but continues slowly so that bone diameters enlarge, but no more than a few millimeters during the next 60 years [42]. The third abnormality in remodeling is believed to be an increase in the volume of bone resorbed by the BMU, but this may be confined to a brief period following sex hormone deficiency [43, 44]. The opposite may occur across the whole of life – the volume of bone resorbed by each BMU appears to decrease as reflected in a lower resorption cavity depth and an age-related increase, rather than decrease in interstitial thickness [45]. The fourth age-related abnormality in the cellular machinery contributing to structural deterioration is an increase in the rate of bone remodeling after menopause. This is accompanied by worsening of the negative bone balance in each BMU as the volume of bone resorbed increases and the volume of bone formed decreases in
the many more BMUs now remodeling bone on the three (endocortical, intra-cortical and trabecular) components of its endosteal envelope. Variance in the negative BMU balance during aging is small compared with the variance in remodeling rate so differences in rates of bone loss between individuals are driven more by corresponding differences in remodeling rate than differences in the extent of negative BMU balance. Whatever the purpose of remodeling, whether it is initiated by damage removal, by death of osteocytes or adaptive change in response to loading, remodeling is initiated upon a surface – remodeling is a surface dependent event. A bone fashioned with a higher surface, such as thinner trabeculae in Caucasians than African Americans, or in females than males at some sites, will be ‘turned over’ more rapidly. The surface area is an independent determinant of remodeling intensity; more BMUs can be generated on a larger surface to remodel the matrix beneath and the negative BMU balance in each erodes the skeleton. In addition, the amount of bone lost is also determined by the volume available to be lost. So, trabecular bone loss may be
C h a p t e r 1 3 Age-related Changes in Bone Remodeling and Microarchitecture l
more rapid than cortical bone loss because trabeculae have a higher surface to volume ratio but, as only 20% of the skeleton is trabecular and 80% is cortical, cortical bone loss over time is greater than trabecular bone loss. Thus, between individuals within a sex, between sexes and between races, differences in the amount of bone lost with age is determined by each of these four factors. However, the structural and biomechanical consequences of bone loss depend on the underlying structure from which bone is lost and how that bone is removed. For example, thicker trabeculae and cortices can tolerate a greater amount of bone loss. Thinner trabeculae are more likely to perforate with a given loss of bone. Moreover, if bone is lost by reduced formation, the structural consequences are likely to be less than the same volume of bone lost by increased resorption depth.
Bone loss during young adulthood, menopause and advanced age At some stage in midlife or earlier, a net negative bone balance emerges as the volume of bone resorbed exceeds the volume of bone formed. The negative balance probably arises initially from a reduction in bone formation [40]. Trabecular volumetric density decreases prior to menopause. In a three-year prospective study of 553 women and men, Riggs et al reported that, before age 50 years, women lose 37% and men 42% of lifetime total trabecular bone and 6% and 15% of lifetime cortical bone [46]. The structural and biomechanical consequences are likely to be less than bone loss later in life because: 1. remodeling rate is slow 2. trabecular bone loss probably proceeds by reduced bone formation rather than increased bone resorption in the BMU 3. bone loss proceeds by trabecular thinning rather than loss of connectivity so a given decrement in trabecular BMD produces less loss of strength than produced by loss of connectivity 4. continued periosteal apposition partly offsets cortical thinning shifting the cortices radially, maintaining cortical area and resistance to bending [47]. While trabecular bone loss is more rapid than cortical bone loss in the initial postmenopausal years, trabecular bone is only 20% of the skeleton while 80% of the skeleton is cortical bone. So the slower loss of cortical bone contributes more to the net amount of bone lost across life than the loss of trabecular bone [48]. Cortical bone is regarded as being ‘compact’. However, it is traversed by myriads of haversian and Volkmann canals, the surface of which is similar to that of trabecular bone surface. It is for this reason
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that, in the first 15 years after menopause, the actual amount of bone lost is similar in absolute terms. Moreover, as remodeling on trabeculae removes them with their surfaces and endocortical and intracortical remodeling increase, the surface available for remodeling decreases in the trabecular compartment and increases in the cortical compartment, so the contribution to total bone loss from the trabecular compartment decreases while the larger volume of cortical bone becomes increasingly accessible to being remodeled and accounts for most of the bone loss with aging. The high remodeling rate itself is a most important determinant of bone loss. In the early menopause, estrogen deficiency leads to accelerated bone remodeling and so accelerated bone loss. All women become postmenopausal, not all lose bone. Women with low rates of bone remodeling lose little and are at a low risk for fracture [47]. The reasons why some women remodel their skeleton slowly while others remodel it rapidly are not understood but, in part, may be due to individual differences in the amount of surface available for remodeling. Women with slow remodeling rates may assemble a bone with a smaller cross-section and higher vBMD and, therefore, less surface, while women constructing a larger skeletal cross-section avoid bulk by assembling this with more surface and a lower vBMD. The rate of remodeling slows at completion of growth and then increases after menopause when estrogen deficiency occurs. Perhaps those women who remodel bone at a slow rate and assemble a bone with a high vBMD (with a low surface to volume ratio) may also have slow remodeling after menopause and so are protected against bone loss and bone fragility after menopause. There are two reasons for the lower fragility. First, the slow remodeling rate occurs because they have a low surface to volume ratio and second, whatever the loss, the resulting fragility is less because the thicker cortices and trabeculae are more resistant to structural decay by remodeling. Those women with high remodeling, who build a larger skeleton, excavate a correspondingly larger medullary cavity with relatively thinner cortices and perhaps thinner trabeculae, have a low vBMD. The high remodeling needed to ‘empty’ the larger skeleton during growth to avoid bulk may become a liability after menopause when high remodeling reappears. This may be double jeopardy; the high remodeling and the thinner cortices and trabeculae predispose these individuals to both more rapid bone loss and greater structural decay. Menopause is also associated with increases in the volume of bone resorbed by each BMU due to the prolonged the life span of osteoclasts and reductions in the volume of bone formed by each BMU due to shortening of the life span of osteoblasts. Whether the changes in the life span of the cells is permanent or temporary is not known but, together, these changes aggravate the negative BMU balance which, in turn, produces a greater loss of bone each time bone is remodeled and the deeper resorption cavities
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remove complete trabeculae accounting for loss of trabecular numbers in women with advancing age [15]. The rapid decline in BMD associated with menopause is the result of the above changes in the rate of remodeling and BMU imbalance. In addition, there is perturbation of the steady state and expansion of the remodeling space transient [12] (Figure 13.3). Remodeling is slow before menopause; the birth rate of new BMUs creating resorption cavities is matched by slow completion of previously created BMUs in their formation phase. At menopause, this steady state is perturbed by an increase in the birth rate of new BMUs on bone’s endosteal envelope. The now many more BMUs remove bone while the fewer BMUs created before menopause complete remodeling by depositing bone. This perturbation produces a net acceleration in bone loss and a rapid decline in BMD. This is the remodeling transient, a reversible loss of bone mass and bone mineral that is a consequence of the normal delay in onset and slower progression of the formation phase of the remodeling cycle in the many remodeling foci created after menopause. The temporary deficit in bone mass and mineral has three components: the excavation site that lacks osteoid and mineral; the osteoid that lacks mineral; and bone that has undergone primary but not secondary mineralization. Primary mineralization occurs rapidly, secondary mineralization, the slow enlargement of crystals of calcium hydroxyapatite-like mineral takes many months to years to go to completion [49]. At any time, there are
osteons created in the immediate postmenopausal period and fewer, earlier created, osteons at various stages of completing secondary mineralization. Bone fragility is also the result of stress concentrators. Excavated resorption sites are vulnerable to microdamage because these sites concentrate biomechanical stress. An example of stress risers is the etched cut in a test tube that makes it easy to snap [50]. The high remodeling rate and negative BMU balance produces trabecular thinning and complete loss of trabeculae. Increased resorption depth is more likely to produce perforation and complete loss of trabeculae than either greater numbers of resorption cavities or reduced formation in the BMU in women [51]. A 10% loss of trabecular density by perforation reduces strength more than the same loss by trabecular thinning [52]. As remodeling continues, trabeculae are lost so the trabecular surface available for resorption decreases but remodeling on endocortical and intracortical surfaces continues increasing cortical porosity [48]. Remodeling on the intracortical surface (haversian canals) increases intracortical porosity [53–56]. Increased porosity, due to increased numbers of pores and/or increased size of pores by coalescence of adjacent remodeling cavities, increases the surface available for remodeling in the cortex. As age advances and remodeling continues at the same intensity due to estrogen deficiency and perhaps secondary hyperparathyroidism, the extent of coalescence of pores
(i) Bone loss before menopause (ii) Bone loss during menopause (iii) Bone loss after menopause BMD
Time
Figure 13.3 (i) Bone loss is slow before menopause because remodeling is slow, only a few sites on the trabecular surface remove bone (open arrows). (ii) Bone loss accelerates because steady state is perturbed at menopause as remodeling rate increases. Now many basic multicellular units (BMUs) remove bone (black arrows) while the three BMUs initiated before menopause deposit bone. (iii) Bone loss after menopause slows relative to the immediate postmenopausal period because steady state is restored. The many BMUs removing bone at menopause are now in their formation phase but, as many new BMUs are created and resorb bone, bone is lost because each remodeling event removes bone from bone. (From E Seeman, with permission).
C h a p t e r 1 3 Age-related Changes in Bone Remodeling and Microarchitecture
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l
increases so the number of pores in cortical bone decreases but the total area of porosity increases, and perhaps more so in patients with hip fractures [55]. Cortical porosity reduces the ability of bone to limit crack propagation so that bone cannot absorb the energy imparted by a fall and this may result in a fracture [54]. The continued remodeling at a similar intensity with its negative BMU balance, on the same amount or more surface, removes the same amount of bone from an ever decreasing amount of bone accelerating the loss of bone and structural decay (Figure 13.4). Rapid remodeling also modifies the material properties of bone, increasing fracture risk. More densely mineralized bone is removed and replaced with younger, less densely mineralized bone, reducing stiffness [57]. Increased remodeling impairs isomerization of collagen [58]. Interstitial bone deep to surface remodeling becomes more densely mineralized and more highly cross-linked with advanced glycation products (AGEs) like pentosidine [59, 60], both processes reducing bone toughness; it is easier for microcracks to travel through homogeneously mineralized bone and lengthen. Interstitial bone (between osteons) has reduced osteocyte numbers, accumulating microdamage [61].
15
Reduced periosteal bone formation in adulthood The challenges regarding and identifying the existence of periosteal apposition during adulthood, its site specificity, magnitude and sex differences are considerable. In crosssectional studies, secular changes in bone size may obscure or exaggerate periosteal apposition. Secular increases in stature occur in one or both sexes, in some races but not others and may occur in the skeleton of the upper or lower body [62]. These secular trends can produce misleading inferences when increments or lack of increments in bone diameters are used as surrogates of periosteal apposition. For example, in cross-sectional studies, absence of an increment in periosteal diameter across age may not mean periosteal apposition was absent. Earlier born individuals (the elderly in a cross-sectional sample) may have been shorter and had more slender bones than later born individuals (young normals in a cross-sectional sample). When periosteal apposition occurs, earlier born persons with more slender bones have an increase in bone diameter that comes to equal that in later born persons (who have not yet had
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Figure 13.4 Porosity increases with age (left upper panel, Brockstedt et al 1993 [56]). This is associated with a decline in ultimate stress (adapted from Martin 1984 [53]) and reduction in toughness (adapted from Yeni et al 1997 [54]). Porosity is the result of enlargement and coalescence of intracortical pores (micrographs, Zebaze and Seeman, unpublished image).
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age-related periosteal apposition) leading to the flawed inference that there was no periosteal apposition in the cross-sectional sample. When comparisons are made between sexes (or races) in cross-sectional studies, if the truth is that periosteal apposition is greater in men than women but men have a secular increase in bone size and women do not, then the secular increase in size in men will blunt the increment in bone width across age in men and make it appear that the agerelated increase in vertebral and femoral neck diameters (and so periosteal apposition) is similar in women and men. Longitudinal studies are also problematic because changes in periosteal apposition during aging are small [42]. The precision of methods to determine bone diameter, usually bone densitometry, and problems with edge detection when bone mineral density is changing, limit the credibility of these measurements. Periosteal apposition is believed to increase as an adaptive response to compensate for the loss of strength produced by endocortical bone loss, so there will be no net loss of bone, no cortical thinning and no loss of bone strength [63]. In a seven-year prospective study of over 600 women, Szulc et al report that endocortical bone loss occurred in premenopausal women with concurrent periosteal apposition [47]. As periosteal apposition was less than endocortical resorption, the cortices thinned but there was no net bone loss because the thinner cortex was now distributed around a larger perimeter conserving total bone mass. Moreover, resistance to bending increased despite bone loss and cortical thinning because this same amount of bone was now distributed further from the neutral axis. So bone mass alone is a poor predictor of strength because resistance to bending is determined by the spatial distribution of the bone. Endocortical resorption increased during the perimenopausal period, yet periosteal apposition decreased – it did not increase as predicted if the notion that periosteal apposition is a compensatory mechanism is correct. The cortices thinned as periosteal apposition declined further. Nevertheless, bending strength remained unchanged – despite bone loss and cortical thinning because periosteal apposition was still sufficient to shift the thinning cortex outwards. Bone fragility emerged only after menopause when acceleration in endocortical bone resorption and deceleration in periosteal apposition produce further cortical thinning. As periosteal apposition was now minimal, there was little outward displacement of the thinning cortex so cortical area now declined as did resistance to bending. Endocortical resorption was reduced but not abolished in women receiving hormone replacement therapy while periosteal apposition was no different to untreated women; cortical thinning was reduced and the resistance to bending occurred but less than in untreated women. The periosteal envelope is regarded exclusively as a bone-forming surface. This is incorrect [7]. During
growth, bone resorption is critical for the in-wasting that produces the fan-shaped metaphyses [64]. Blizoites et al report that bone resorption occurs in adult non-human primates [7]. Femur specimens from 16 intact adult male and female non-human primates showed that periosteal remodeling of the femoral neck in intact animals was slower than in cancellous bone but more rapid than at the femoral shaft. Gonadectomized females showed an increase in osteoclast number on the periosteal surface compared with intact controls. If this information is correct, adult skeletal dimensions may decrease in size as age advances.
Sex differences in trabecular and cortical bone loss and fracture rates A greater proportion of women than men sustain fragility fractures during their lifetime. The reasons for this sexual dimorphism are not clear. Men have a larger skeleton than women and this is often held to be responsible for sex differences in fracture rates. The larger cross-sectional area of the vertebral body or a long bone in men does confer greater resistance to bending and torsional loads. Men and women have similar cortical thickness conferring a greater cortical area in men (because the cortex is fashioned around a larger perimeter). However, men also have larger muscle mass and greater weight so compressive stress (load/area) is similar in young adult men and women. The role of larger bone size as a cause of sex differences in fracture risk is also difficult to reconcile with finding that Asians have a smaller skeleton yet lower fracture rates than Caucasians and women with hip fractures and their premenopausal daughters have larger femoral neck diameter than controls [65]. Peak trabecular density (number and thickness) is similar in men and women. Thus, sex differences in bone size, cortical thickness or trabecular architecture do not appear to be obvious contributors to sex differences in fracture rates. The most tenable explanation for sex differences in fracture risk in old age is the sex difference in bone remodeling. BMU balance becomes negative due to a decline in the volume of bone formed by each BMU during aging in both sexes but, in women, at midlife, the volume of bone resorbed by each BMU increases. This probably does not occur in men unless they become estrogen deficient. In midlife, the intensity of remodeling increases in women due to menopause and remains elevated but not in men. Secondary hyperparathyroidism occurs in both sexes but this is superimposed on the high remodeling already present in women. Periosteal apposition is reduced in both sexes and may continue slowly but may be greater in men than in women, although this is still uncertain.
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The net structural consequences of the above changes in remodeling are as follows. For trabecular bone, the reduction in formation by the BMU without increased resorption by the BMU results in trabecular thinning in men while both reduced formation and increased resorption in women by each BMU causes loss of connectivity in women [66]. However, the same deficit in trabecular density produced by thinning (as occurs in men) produces less reduction in strength than produced by loss of connectivity (as occurs in women) [52]. The high bone remodeling with deeper excavation cavities in women produces greater numbers of stress concentrators in women than in men. If trabeculae are thicker in men, this will further protect from loss of connectivity and stress concentrating effects in men. While still unproven, a most important structural feature that is likely to account for sex differences in fracture risk is the greater structural deterioration of cortical bone in women than in men. The greater negative BMU balance and higher rater of remodeling in women on the intracortical surface is likely to produce more intracortical excavation, greater cortical thinning ‘within’ as coalescent excavated pores in cortex adjacent to the marrow produce cortical remnants and a remaining thin cortex adjacent to the periosteum has greater porosity but not to the point of producing cortical remnants. Direct evidence is still lacking because sex differences in cortical porosity have not been rigorously assessed in vivo at this time. Intracortical porosity has been reported to be lower in cortical bone in men than in women in in vitro studies [67]. As secondary hyperparathyroidism compounds the high remodeling due to sex hormone deficiency, it is also plausible that the exponential increase in intracortical surfaces is greater in women than in men so that there are more pores, more pores of irregular size and shape in women than in men and so, more stress concentrators, greater reduction in resistance to crack initiation and propagation through the cortex in women than in men. The increase in porosity has a profound negative effect on bone strength [53, 54]. Endocortical resorption is also likely to be less in men than in women for the same reasons; the number of remodeling sites on the endocortical surface will be less and each site will remove less bone in men than in women because the volume of bone resorbed is less. Marrow cavity expansion occurs in both sexes but whether it is greater in women than men is uncertain. Periosteal apposition is reported to be greater in men than in women in some [68], but not all [69], studies and it is unclear if any difference in periosteal apposition accounted for the sexual dimorphism in fragility fractures. Thus, methodological issues temper inferences possible regarding sexual dimorphism in bone strength [1]. The absolute risk for fracture in women and men of the same age and BMD is similar [70]. The lower fracture incidence in men than in women is likely to be the result of a lower proportion of elderly men than elderly women having
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material and structural properties (cortical thinning, porosity, trabecular thinning. loss of connectivity, microdamage) below the critical level at which the loads on the bone are greater than the bone’s net ability to tolerate them. Furthermore, structural failure occurs less in men because the relationship between load and bone strength is better maintained in men than in women [68].
Summary and Conclusion Modeling and remodeling are successful during growth, not aging. After completion of growth, there is a profound reduction in periosteal bone formation in both sexes. In midlife or earlier, a negative balance in the volumes of bone resorbed and formed by each basic BMU appears so remodeling on the endocortical, intracortical and trabecular components of bone’s endosteal surface produces structural decay but modestly because remodeling is slow. In midlife, remodeling rate increases and a transitory worsening of the negative BMU balance occurs as each BMU increases the volume of bone resorbed and reduces the volume of bone formed due to sex hormone deficiency in women so that structural decay accelerates, more rapidly from trabecular than cortical bone because its higher surface/volume ratio. Unlike trabecular bone where remodeling removes trabeculae and their surfaces, remodeling on intracortical and endocortical surfaces increases their surface so cortical bone becomes accessible to remodeling. Trabecular bone loss is more rapid than cortical bone loss during the first 15 years after menopause but the rapid loss of 20% of the skeleton (trabecular) and slower loss of 80% of the skeleton (cortical) results in a similar loss of each type of bone in absolute terms during the first 15 years of postmenopausal life. Men have no midlife acceleration in remodeling and the negative BMU balance is primarily due to reduced bone formation by the BMU so trabecular thinning (rather than perforation) dominates. Late in life in women, bone loss diminishes from the trabecular compartment as trabeculae and their surfaces are lost. Intracortical remodeling on haversian and Volkmann canal surfaces increases the number and area of pores, particularly in cortex adjacent to the marrow resulting in coalescence, trabecularization of the inner cortex so cortical thinning occurs from ‘within’. Thus, most bone loss during aging occurs after 60 years, is predominately cortical and originates from the intracortical (not endocortical) surface, particularly in cortex adjacent to the marrow cavity. Men have no midlife acceleration of remodeling so bone loss and structural decay proceed slowly until after 65–70 years when some men develop hypogonadism and/or secondary hyperparathyroidism. Whether the negative BMU balance is less in men than in women is unknown. The slower remodeling
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rate in men than women is probably the most important reason for the slower decay of the skeleton in men. The sex difference in fragility fractures is best explained by the earlier onset and longer duration of high remodeling in women than men. The combination of sex hormone deficiency and secondary hyperparathyroidism in women produce an additive or multiplicative effect and is the driving force behind structural decay in women. Our understanding of why or how bones fail at the material and structural level remains incomplete. This is an essential direction of inquiry if we are to identify women and men at risk for fracture, those not at risk and provide approaches to drug therapy based on the underlying structural basis of bone fragility.
References 1. E. Seeman, G. Bianchi, S. Adami, J. Kanis, S. Khosla, E. Orwoll, Osteoporosis in men – consensus is premature, Calcif. Tissue Int. 75 (2004) 120–122. 2. J.A. Kanis, F. Borgstrom, Z. Zethraeus, O. Johmell, A. Oden, B. Jonsson, Intervention thresholds for osteoporosis in men and women, Bone 36 (2005) 22–32. 3. E.S. Siris, P.D. Miller, et al., Identification and fracture outcomes of undiagnosed low bone mineral density in postmenopausal women, J. Am. Med. Assoc. 286 (2001) 2815–2822. 4. R. Sornay-Rendu, J.L. Cabrera-Bravo, S. Boutroy, F. Munoz, P.D. Delmas, Severity of vertebral fractures is associated with alterations of cortical architecture in postmenopausal women, J. Bone Miner. Res. 24 (2009) 737–743. 5. R. Zebaze, E. Seeman, Measuring femoral neck strength: lost in translation? IBMS BoneKey 5 (2008) 336–339. 6. S. Kaptoge, T.J. Beck, J. Reeve, et al., Prediction of incident hip fracture risk by femur geometry variables measured by hip structural analysis in the study of osteoporotic fractures, J. Bone Miner. Res. 23 (12) (2008) 1892–1904. 7. M. Blizoites, J.D. Sibonga, R.T. Turner, E. Orwoll, Periosteal remodeling at the femoral neck in nonhuman primates, J. Bone Miner. Res. 21 (2006) 1060–1067. 8. H. Haapasalo, S. Kontulainen, H. Sievanen, P. Kannus, M. Jarvinen, I. Vuori, Exercise-induced bone gain is due to enlargement in bone size without a change in volumetric bone density: a peripheral quantitative computed tomography study of the upper arms of male tennis players, Bone 27 (3) (2000) 351–357. 9. S.L. Bass, L. Saxon, R. Daly, C.H. Turner, A.G. Robling, E. Seeman, The effect of mechanical loading on the size and shape of bone in pre-, peri- and post-pubertal girls: a study in tennis players, J. Bone Miner. Res. 17 (12) (2002) 2274–2280. 10. E. Seeman, An exercise in geometry, J. Bone Min. Res. 17 (2002) 373–380. 11. A.M. Parfitt, Skeletal heterogeneity and the purposes of bone remodeling: implications for the understanding of osteoporosis, in: R. Marcus, D. Feldman, J. Kelsey (Eds.) Osteoporosis, Academic Press, San Diego, 1996, pp. 315–339. 12. A.M. Parfitt, Targeted and non-targeted bone remodeling: relationship to basic multicellular unit origination and progression, Bone 30 (2002) 5–7.
13. G. Marotti, V. Cane, S. Palazzini, C. Palumbo, Structurefunction relationships in the osteocyte, Ital. J. Min. Electro. Metab. 4 (1990) 93–106. 14. J.G. Hazenberg, M. Freeley, E. Foran, T.C. Lee, D. Taylor, Microdamage: a cell transducing mechanism based on ruptured osteocyte processes, J. Biomech. 39 (2006) 2096–2103. 15. S.C. Manolagas, Choreography from the tomb: an emerging role of dying osteocytes in the purposeful, and perhaps not so purposeful, targeting of bone remodeling, BoneKey osteovision. 3 (1) (2006) 5–14. 16. O. Verborgt, G.J. Gibson, M.B. Schaffler, Loss of osteocyte integrity in association with microdamage and bone remodeling after fatigue damage in vivo, J. Bone Miner. Res. 15 (2000) 60–67. 17. D. Taylor, Bone maintenance and remodeling: a control system based on fatigue damage, J. Orthop. Res. 15 (1997) 601–606. 18. M.B. Schaffler, R.J. Majeska, Role of the osteocyte in mechanotransduction and skeletal fragility. Abst 20, p 12, Proceedings of meeting, Bone Quality: What is it and can we Measure it? Maryland, Besthesda, May, 2005, 2–3. 19. W.D. Clark, E.L. Smith, K.A. Linn, J.R. Paul-Murphy, P. Muir, M.E. Cook, Osteocyte apoptosis and osteoclast presence in chicken radii 0-4 days following osteotomy, Calcif. Tissue Int. 77 (2005) 327–336. 20. J.I. Aguirre, L.I. Plotkin, S.A. Stewart, et al., Osteocyte apoptosis is induced by weightlessness in mice and precedes osteoclast recruitment and bone loss, J. Bone Miner. Res. 21 (2006) 605–615. 21. E.M. Hauge, D. Qvesel, E.F. Eriksen, I. Mosekilde, F. Melsen, Cancellous bone remodeling occurs in specialized compartments lined by cells expressing osteoblastic markers, J. Bone Miner. Res. 16 (2001) 1575–1582. 22. K. Fuller, T.J. Chambers, Localisation of mRNA for collagenase in osteocytic, bone surface and chrondrocytic cells but not osteoclasts, J. Cell Sci. 106 (1995) 2221–2230. 23. R. Hattner, B.N. Epker, H.M. Frost, Suggested sequential mode of control of changes in cell behaviour in adult bone remodeling, Nature 4963 (1965) 489–490. 24. K. Kurata, T.J. Heino, H. Higaki, H.K. Väänänen, Bone marrow cell differentiation induced by mechanically damaged osteocytes in 3D gel-embedded, J. Bone Miner. Res. 21 (2006) 605–615. 25. G.Z. Eghbali-Fatourechi, J. Lamsam, D. Fraser, D.A. Nagel, B.L. Riggs, S. Khosla, Circulating osteoblast lineage cells in humans, N. Engl. J. Med. 352 (2005) 1959–1966. 26. G.Z. Eghbali-Fatourechi, U.I. Moedder, N. Charatcharoen witthaya, et al., Characterization of circulating osteoblast lineage cells in humans, Bone 40 (2007) 1370–1377. 27. Y. Fujikawa, J.M.W. Quinn, A. Sabokbar, J.O. McGee, N.A. Athanasou, The human osteoclast precursor circulates in the monocyte fraction, Endocrinology 137 (1996) 4058–4060. 28. M.J. Doherty, B.A. Ashton, S. Walsh, J.N. Beresford, M.E. Grant, A.E. Canfield, Vascular pericytes express osteogenic potential in vitro and in vivo, J. Bone Miner. Res. 13 (1998) 828–838. 29. K.M. Howson, A.C. Aplin, M. Gelati, E.A. Alessandri, R.F. Nicosia, The postnatal rat aorta contains pericyte progenitor cells that form spheroidal colonies in suspension culture, Am. J. Cell Physiol. 289 (2005) 1396–1407.
C h a p t e r 1 3 Age-related Changes in Bone Remodeling and Microarchitecture l
30. B. Sacchetti, A. Funari, S. Michienzi, et al., Marrow sinusoids can organise a hematopoietic microenvironment, Cell 131 (2007) 324–336. 31. T. Matsumoto, A. Kawamoto, R. Kuroda, et al., Therapeutic potential of vasculogenesis and osteogenesis promoted by peripheral bood CD34 positive cells for functional bone healing, Am. J. Pathol. 169 (2006) 1440–1457. 32. S. Khosla, Skeletal stem cell/osteoprogenitor cells: current concepts, alternate hypotheses, and relationship to the bone remodeling compartment, J. Cell Biochem. 103 (2) (2008) 393–400. 33. S. Otsura, K. Tamai, T. Yamazaki, H. Yoshjkawa, Y. Kaneda, Bone marrow-derived osteoblast progenitor cells in circulating blood contribute to ectopic bone formation in mice, Biochem. Biophys. Res. Commun. 354 (2007) 453–458. 34. S. Kholsa, J.J. Westendorf, M.J. Oursler, Building bone to reverse osteoporosis and repair fractures, J. Clin. Invest. 118 (2) (2008) 421–428. 35. T. Suda, N. Takahashi, N. Udagawa, E. Jimi, M.T. Gillespie, T.J. Martin, Modulation of osteoclast differentiation and function by the new members of the tumor necrosis factor receptor and ligand families, Endocr. Rev. 20 (3) (1999) 345–357. 36. T.J. Martin, N.A. Sims, Osteoclast-derived activity in the coupling of bone formation to resorption, Trends. Molec. Med. 11 (2005) 76–81. 37. J. Lorenzo, Interactions between immune and bone cells: new insights with many remaining questions, J. Clin Invest. 106 (2000) 749–752. 38. Y. Han, S.C. Cowin, M.B. Schaffler, S. Weinbaum, Mechano transduction and strain amplification in osteocyte cell processes, Proc. Natl. Acad. Sci. 101 (47) (2004) 16689–16694. 39. E. Seeman, P.D. Delmas, Bone quality: the material and structural basis of bone strength and fragility, N. Engl. J. Med. 354 (21) (2006) 2250–2261. 40. P. Lips, P. Courpron, P.J. Meunier, Mean wall thickness of trabecular bone packets in the human iliac crest: changes with age, Calcif. Tissue Res. 10 (1978) 13–17. 41. S. Vedi, J.E. Compston, A. Webb, J.R. Tigher, Histomor phometric analysis of dynamic parameters of trabecular bone formation in the iliac crest of normal British subjects, Metab. Bone Dis. Rel. Res. 5 (1984) 69–74. 42. R. Balena, M.-S. Shih, M. Parfitt, Bone resorption and formation on the periosteal envelope of the ilium: a histomorphometric study in healthy women, J. Bone Miner. Res. 7 (1992) 1475–1482. 43. E.F. Ericksen, Normal and pathological remodeling of human trabecular bone: three dimensional reconstruction of the remodeling sequence in normals and in metabolic disease, Endoc. Rev. 4 (1986) 379–408. 44. E.F. Eriksen, S.F. Hodgson, R. Eastell, S.L. Cedel, W.M. O’Fallon, B.L. Riggs, Cancellous bone remodeling in type I (postmenopausal) osteoporosis: quantitative assessment of rates of formation, resorption, and bone loss at tissue and cellular levels, J. Bone Min. Res. 5 (1990) 311–319. 45. P.I. Croucher, N.J. Garrahan, R.W.E. Mellish, J.E. Compston, Age-related changes in resorption cavity characteristics in human trabecular bone, Osteoporos. Int. 1 (1991) 257–261. 46. B.L. Riggs, L.J. Melton III, R.A. Robb, et al., A populationbased study of age and sex differences in bone volumetric density, size, geometry and structure at different skeletal sites, J. Bone Miner. Res. 19 (2004) 1945–1954.
177
47. P. Szulc, E. Seeman, F. Duboeuf, E. Sornay-Rendu, P.D. Delmas, Bone fragility: failure of periosteal apposition to compensate for increased endocortical resorption in postmenopausal women, J. Bone Miner. Res. 21 (2006) 1856–1863. 48. R. Zebaze, A. Ghasem, A. Bohte, et al., Age-related bone loss is predominantly intracortical, not endocortical or trabecular in origin, ASBMR, oral communication, Montreal, Canada, 2008. 49. O. Akkus, A. Polyakova-Akkus, F. Adar, M.B. Schaffler, Aging of microstructural compartments in human compact bone, J. Bone Miner. Res. 18 (2003) 1012–1019. 50. C.J. Hernandez, A. Gupt, T.M. Keaveny, A biomechanical analysis of the effects of resorption cavities on cancellous bone strength, J. Bone Miner. Res. 21 (2006) 1248–1255. 51. A.M. Parfitt, Surface specific bone remodeling in health and disease, in: M. Kleerekoper, S. Krane (Eds.) Clinical Disorders of Bone and Mineral Metabolism, Mary Ann Liebert, New York, 1989, pp. 7–14. 52. J.C. Van der Linden, J. Homminga, J.A.N. Verhaar, H. Weinans, Mechanical consequences of bone loss in cancellous bone, J. Bone Miner. Res. 16 (2001) 457–465. 53. R.B. Martin, Porosity and specific surface of bone, CRC. Crit. Rev. Biomed. Eng. 10 (1984) 179–221. 54. Y.N. Yeni, C.U. Brown, Z. Wang, T.L. Norman, The influence of bone morphology on fracture toughness of the human femur and tibia, Bone 21 (1997) 453–459. 55. K.L. Bell, N. Loveridge, J. Power, N. Garrahan, B.F. Meggitt, J. Reeve, Regional differences in cortical porosity in the fractured femoral neck, Bone 24 (1999) 57–64. 56. H. Brockstedt, M. Kasse, E.F. Ericksen, L. Mosekilde, F. Melsen, Age and sex related changes in iliac cortical bone mass amd remodeling, Bone 14 (4) (1993) 681–691. 57. G. Boivin, P.J. Meunier, Changes in bone remodeling rate influence the degree of mineralization of bone, Connect. Tissue Res. 43 (2002) 535–537. 58. S. Viguet-Carrin, S.P. Garnero, P.D. Delmas, The role of collagen in bone strength, Osteoporosis. Int. 17 (2006) 319–336. 59. A.J. Bailey, T.J. Sims, E.N. Ebbesen, J.P. Mansell, J.S. Thomsen, L. Mosekilde, Age-related changes in the biochemical properties of human cancellous bone collagen: relationship to bone strength, Calcif. Tissue Int. 65 (1999) 203–210. 60. X. Banse, T.J. Sims, A.J. Bailey, Mechanical properties of adult vertebral cancellous bone: correlation with collagen intermolecular cross-links, J. Bone Miner. Res. 17 (2002) 1621–1628. 61. S. Qiu, D.S. Rao, D.P. Fyhrie, S. Palnitkar, A.M. Parfitt, The morphological association between microcracks and osteocyte lacunae in human cortical bone, Bone 37 (2005) 10–15. 62. H.V. Meredith, Secular change in sitting height and lower limb height of children, youths, and young adults of Afro-black, European, and Japanese ancestry, Growth 42 (1978) 37–41. 63. H.G. Ahlborg, O. Johnell, C.H. Turner, G. Rannevik, M.K. Karlsson, Bone loss and bone size after the menopause, N. Engl. J. Med. 349 (2003) 327–334. 64. F. Rauch, C. Neu, F. Manz, E. Schoenau, The development of metaphyseal cortex – implications for distal radius fractures during growth, J. Bone Miner. Res. 16 (2001) 1547–1555. 65. S. Filardi, R.M. Zebaze, Y. Duan, J. Edmonds, T. Beck, E. Seeman, Femoral neck fragility in women has its structural and biomechanical basis established by periosteal modeling during growth and endocortical remodeling during aging, Osteoporos. Int. 15 (2) (2004) 103–107.
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66. J.E. Aaron, N.B. Makins, K. Sagreiy, The microanatomy of trabecular bone loss in normal aging men and women, Clin. Orthop. Rel. Res. 215 (1987) 260–271. 67. V. Bousson, C. Bergot, A. Meunier, F. Bardot, Parler-Cuau, A.M. Laval-Jeantet, CT of the middiaphyseal femur: cortical bone mineral density and relation to porosity, Radiology 217 (2000) 179–187. 68. M.L. Bouxsein, L.J. Melton 3rd, B.L. Riggs, et al., Age- and sex-specific differences in the factor of risk for vertebral
fracture: a population-based study using QCT, J. Bone Miner. Res. 21 (9) (2006) 1475–1482. 69. Y. Duan, C.H. Turner, B.T. Kim, E. Seeman, Sexual dimorphism in vertebral fragility is more the results of gender differences in bone gain than bone loss, J. Bone Miner. Res. 16 (2001) 2267–2275. 7 0. J.A. Kanis, F. Borgstrom, Z. Zethraeus, O. Johmell, A. Oden, B. Jonsson, Intervention thresholds for osteoporosis in men and women, Bone 36 (2005) 22–32.
Chapter
14
Markers of Bone Remodeling and the Aging Skeleton Serge Cremers1, Christian Meier2 and Markus J. Seibel3 1
Division of Endocrinology, Department of Medicine, Columbia University, New York, USA Division of Endocrinology, Diabetes and Clinical Nutrition, University Hospital Basel, Basel, Switzerland 3 Bone Research Program, ANZAC Research Institute, The University of Sydney, Sydney, NSW, Australia 2
Introduction
variability that introduces substantial ‘background noise’. This latter fact is of particular relevance when it comes to the assessment of bone turnover in individual patients as opposed to the study of larger groups, e.g. in clinical trials. For an appropriate interpretation of any bone marker measurement, it is therefore important to identify pre-analytical (biological) and analytical (technical) factors that may affect variability. These factors often differ from marker to marker and, while some can be controlled by appropriate study design and sample handling, there always remain a number of factors that either require mathematical modeling or cannot be controlled at all [3–5, 13] (see also Chapter 3). This chapter will focus on age-related changes in markers of bone turnover in men, including their response to pharmacological interventions.
Osteoporosis has long been considered a disease which affects almost exclusively older women. However, over the past decade, we have learned to recognize bone loss and osteoporotic fractures as a growing health problem in older men [1, 2]. Given the morbidity, mortality and the cost associated with osteoporotic fractures in both genders, it is critical to identify at an early stage those individuals who may have, or soon will develop the disease. Measurement of bone mineral density (BMD) is widely used to identify men and women at risk of osteoporotic fracture. However, individual fracture risk is not determined by BMD alone but by the complex interaction of clinical risk factors, bone mineral density, bone geometry and microarchitecture, as well as bone turnover. Biochemical markers of bone turnover, i.e markers of bone formation and bone resorption, can be measured easily and non-invasively in serum and urine [3–5]. In postmenopausal women [6–10] and men [11], accelerated bone turnover (as measured by markers of bone formation and/or resorption) has been shown to be associated with increased fracture risk independent of BMD or clinical risk factors. Furthermore, as changes in bone turnover markers in response to therapeutic interventions occur much more rapidly than changes in BMD, bone markers may be useful in the monitoring of treatment, e.g. to evaluate treatment efficacy or patient compliance. One of the reasons why bone turnover markers are useful in assessing fracture risk and therapeutic efficacy is their ability quantitatively to reflect the actual rate of, and changes in, skeletal remodeling [12]. However, the simplicity, convenience and clinical sensitivity of these markers need to be balanced against a rather high degree of
Osteoporosis in Men
Age-related changes in bone marker levels Levels of most bone turnover markers are highest in the first three years of life [14], decrease during prepubertal childhood only rapidly to increase again to 4–10 times the adult levels during the pubertal growth spurt [15, 16]. In growing children and adolescents, serum and urine levels of bone turnover markers correlate well with somatic growth, thus, highest bone turnover markers are usually seen in children with the greatest growth velocity [17, 18]. Once somatic growth subsides, levels of most bone markers return to a low-level steady state. In women, bone marker levels reach a stable nadir during the age of 30–45 years. During and after menopause, bone marker levels rapidly increase to approximately 50–100%
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above premenopausal levels and, in many women, bone turnover remains elevated into the eighth and ninth decades [19–21]. This increase in bone turnover has been shown to be a major determinant of bone mass in older women [22–24]. In men, the pattern of age-related changes in bone markers is quite different from that observed in women. Markers of bone formation and resorption are high in men aged 20–30 years, which corresponds to the late phase of peak bone mass development. Thereafter, bone marker levels decrease, reaching their lowest levels between 50 and 60 years [25–29] (Figures 14.1 and 14.2). The relationship between bone remodeling and bone turnover markers becomes somewhat blurred during later stages of life, i.e. after the age of 50–60 years. Direct assessments of changes in bone mass and remodeling reveal that the pattern of age-related bone loss is remarkably different for the trabecular compartment when compared with the cortical compartment. Cross-sectional and longitudinal studies have established that, in both sexes,
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Figure 14.2 Age-related changes of 24-h urinary excretion of deoxypyridinoline (Dpyr) and its fractions; (A) tDpyr, (B) fDpyr 0 15 peptide-bound 25 35 [28]. 45 55 65 75 and (C) Dpyr 85
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trabecular bone loss begins early during adult life, whereas cortical bone loss seems to become evident later (e.g. after mid-life), with overall decreases in volumetric BMD being smaller in men compared to women. In men, there appears to be ongoing periosteal apposition with age, which leads to an increase in bone cross-sectional area. However, the pronounced increase in endocortical area results in a net decrease in cortical area [30]. Histomorphometric analyses of bone biopsies have also shown that physiological bone loss with age in males is characterized by a decrease in the cancellous bone volume as well as cortical width [31]. Trabecular separation is increased but, in contrast to postmenopausal women, trabecular connectivity seems to be preserved. Age-related bone loss in males appears to be the result of low bone formation, although a trend toward an increase in activation frequency has also been described by some authors [31]. In 43 healthy men, static histomorphometric parameters, such as cancellous bone volume and osteoblast–osteoid interface, decreased by 40% and 19%,
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C h a p t e r 1 4 Markers of Bone Remodeling and the Aging Skeleton l
respectively, between 20 and 80 years of age [32]. Dynamic bone histomorphometric parameters, such as double and single labeled osteoid surface, decreased by 18% over the same period and serum osteocalcin levels were significantly correlated with dynamic parameters of bone formation [32]. In contrast, neither static nor dynamic histomorphometric parameters of bone resorption (e.g. osteoclast surface, eroded surface) changed with age in this population sample of healthy men. Interestingly, however, these histological and histomorphometric changes were not reflected by corresponding changes in the levels of bone turnover markers. While there is general agreement on the pattern of agerelated changes of bone turnover markers in adult men between 20 and 60 years of age, data on markers in men over the age of 60 years are largely discordant. Based on recent cross-sectional studies, concentrations of bone formation markers remained either unchanged [27, 28], decreased [26, 33] or increased [25, 34, 35] with age in men 60 years or older. Most studies evaluating age-related changes in bone resorption markers observed an increase in serum and urinary indices [25–28, 35, 36] (see Figure 14.2). However, this was not confirmed in other population-based studies which reported no age-related change in resorption indices [29, 37]. Clarke et al [32] studied a cohort of healthy men by both bone histomorphometry and biochemical markers. In this study, bone resorption, as measured by urinary deoxypyridinoline (DPD), did not change with age, confirming the histomorphometric finding of unaltered osteoclast function with increasing age in these men [32]. These results are in contrast to some of the previously mentioned cross-sectional studies reporting an age-dependent increase in serum and urinary indices of bone resorption [25–28, 35, 36]. A careful analysis of the published data provides clues that may help to explain some of these discrepancies. Differences in results may be related to diverse population characteristics and sample sizes, to the use of marker assays with different specificities, to age-related changes in renal and hepatic function and, lastly, to the inclusion of men with osteoporosis [11]. Men with idiopathic osteoporosis are histomorphometrically characterized by increased bone resorption with an increase in eroded surfaces of up to 90% when compared with age-matched controls [31]. Hence, the observed increase in biochemical markers of bone resorption in population-based studies may also be caused by the heterogeneity of men investigated, including men with osteoporosis. Bone formation markers, such as serum osteocalcin, N-terminal propeptide of type I procollagen (PINP) and bone alkaline phosphatase (ALP) have been found to be negatively associated with estimates of endosteal bone loss in elderly men while being unrelated to parameters of periosteal apposition (calculated from dual energy x-ray absorptiometry (DXA)). Thus, these markers seem to reflect endosteal bone remodeling but not periosteal bone formation in elderly men [38].
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Renal function deserves special attention as certain biochemical markers of bone turnover are cleared via the kidney (e.g. collagen cross-links and cross-linked telopeptides such as C-terminal telopeptide of collagen I (ICTP), serum collagen type I cross-linked C-telopeptide (CTX) or collagen type I cross-linked N-telopeptide (NTX)). Consequently, age-associated changes in glomerular filtration rate are bound to affect the urinary and serum concentrations of such markers. Thus, a decrease in renal function will result in an artificially low urinary excretion of a marker when it is expressed as 24-hour output. Conversely, when corrected by urinary creatinine, marker levels can be falsely increased due to a decrease in both creatinine filtration and muscle mass [39]. Furthermore, serum concentrations of any marker cleared by renal mechanisms may be hard to interpret, as both changes in clearance and disease-related alterations in bone turnover can affect the actual marker level. Taken together, it remains controversial to what extent biochemical markers of bone resorption and formation change as a function of age in men over 60 years. Observational studies investigating age-dependent changes in bone marker levels indicate that there seems to be an imbalance in bone turnover in elderly men with increased bone resorption and stable bone formation after the age of 60 years. As biochemical markers have been shown to be negatively correlated with BMD [25, 28], this imbalance in bone turnover may, at least in part, be responsible for the age-related bone loss in men. However, confounding factors, such as population characteristics, specificity of bone marker assays, as well as estimates of renal and liver function, have to be taken into account when evaluating agedependent changes in bone turnover.
Bone markers, bone loss and fracture risk in aging men Prospective data generally show poor correlations between bone turnover markers and bone loss in men [40–44]. The situation is similar to that in women, where bone turnover markers have been shown to be poor predictors of bone loss [45]. Recently, however, accelerated bone turnover (assessed by biochemical markers) has been shown to be associated with greater endosteal bone mineral loss (but not with fracture risk) [46]. There are limited data on bone turnover markers and their relation to fracture risk in elderly men [11, 46–48]. Some studies have shown that the bone resorption marker ICTP in serum [11] or the ratio of carboxylated to total serum osteocalcin [46] are associated with the risk of osteoporotic fracture independent of BMD. In contrast, another study found that high bone turnover was associated with bone loss but not with the risk of incident fractures [46]. Hence, the role of bone turnover markers in the prediction of accelerated bone loss or fractures currently remains unclear.
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Figure 14.3 Mean percent change from baseline for serum osteocalcin (OC), N-terminal propeptide of type I procollagen (PINP) and collagen type I cross-linked N-telopeptide (NTX) in men receiving alendronate alone (square), human parathyroid hormone (PTH)(1–34) alone (diamond) or both (circle). PTH was commenced at month 6. Data are shown as mean and SE. Error bars that are not visible are contained within the symbols [52].
The response of bone turnover markers to pharmacological interventions in aging men Pharmacological options for therapeutic interventions in male osteoporosis include oral and intravenous bisphosphonates, teriparatide, calcitonin, thiazide diuretics, androgens and supplementation with calcium and/or vitamin D [30]. However, most of the published randomized controlled trials specifically addressing male populations are relatively small, rely on BMD endpoints and usually lack in power confidently to address drug effects on fracture risk in men. It seems, though, that for the most common osteoporosis therapies (i.e. the bisphosphonates and teriparatide), the effects in men are similar to those in women, including the effects on bone turnover markers (Figure 14.3) [28–30, 49, 50–52]. Interestingly, the response of bone turnover markers to these drugs seems independent of any of the known age-related factors in osteoporotic men, such as serum insulin-like growth factor I (IGF-I), IGF binding protein 3 (IGFBP-3), estradiol and free testosterone levels [50, 53]. Part of the changes in bone turnover markers as observed during treatment with either of these drugs is related to calcium and vitamin D supplementation. As described earlier, age-related changes in bone turnover markers show inconsistencies among studies, but they are also relatively small compared with treatment-induced changes. In men with a mean age of 63 years, daily alendronate 10 mg decreased uNTX/Cr by 59%, relative to baseline, as opposed to a reduction of only 9% in the placebo group receiving calcium and vitamin D [49]. In men aged 46–85 years, daily subcutaneous injections of teriparatide increased serum PINP concentrations by more than 1000% by month 12 (see Figure 14.3), illustrating the even more pronounced changes in BTM during anabolic treatment with parathyroid hormone (PTH) [52]. Age-related changes are thus marginal
relative to drug-induced changes and bone turnover markers can therefore be used for monitoring of treatment in men. Treatment with sex steroids or therapies that alter sex steroid levels clearly affect bone turnover markers in aging men. These changes are complex and depend, among other factors, on pre-treatment sex steroid levels and the dose administered [54–57]. (The effects of steroid treatment in aging men are discussed in Section 6).
Conclusion Aging in men affects bone turnover and its corresponding markers in a number of ways, not all of which are related to changes in skeletal metabolism. As a consequence, distinct changes are found in bone turnover and morphology in aging men, but changes in bone turnover marker data show inconsistencies among studies. At the moment, the role of bone turnover markers in predicting accelerated bone loss and fracture risk remains unclear. In contrast, bone turnover markers faithfully reflect treatment-induced changes in bone turnover and may therefore be used to monitor treatment. Additional prospective studies in larger cohorts of men are warranted further to investigate the relationship between bone turnover markers, bone loss and fracture risk. Furthermore, the clinical usefulness of bone turnover markers to assess and perhaps even predict treatment efficacy in men with osteoporosis requires further study.
References 1. P.R. Ebeling, Clinical practice. Osteoporosis in men, N. Engl. J. Med. 358 (14) (2008) 1474–1482. 2. C. Meier, P.Y. Liu, D.J. Handelsman, M.J. Seibel, Endocrine regulation of bone turnover in men, Clin. Endocrinol. (Oxf) 63 (6) (2005) 603–616.
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3. S. Cremers, P. Garnero, Biochemical markers of bone turnover in the clinical development of drugs for osteoporosis and metastatic bone disease: potential uses and pitfalls, Drugs 66 (16) (2006) 2031–2058. 4. P. Szulc, P.D. Delmas, Biochemical markers of bone turnover: potential use in the investigation and management of postmenopausal osteoporosis, Osteoporos. Int. 19 (12) (2008) 1683–1704. 5. M.J. Seibel, Biochemical markers of bone turnover: part I: biochemistry and variability, Clin. Biochem. Rev. 26 (4) (2005) 97–122. 6. P.L. Van Daele, M.J. Seibel, H. Burger, et al., Case-control analysis of bone resorption markers, disability, and hip fracture risk: the Rotterdam study, Br. Med. J. 312 (7029) (1996) 482–483. 7. P. Garnero, E. Hausherr, M.C. Chapuy, et al., Markers of bone resorption predict hip fracture in elderly women: the EPIDOS prospective study, J. Bone Miner. Res. 11 (10) (1996) 1531–1538. 8. P. Garnero, E. Sornay-Rendu, B. Claustrat, P.D. Delmas, Biochemical markers of bone turnover, endogenous hormones and the risk of fractures in postmenopausal women: the OFELY study, J. Bone Miner. Res. 15 (8) (2000) 1526–1536. 9. R.D. Chapurlat, P. Garnero, G. Breart, P.J. Meunier, P.D. Delmas, Serum type I collagen breakdown product (serum CTX) predicts hip fracture risk in elderly women: the EPIDOS study, Bone 27 (2) (2000) 283–286. 10. P.D. Ross, B.C. Kress, R.E. Parson, R.D. Wasnich, K.A. Armour, I.A. Mizrahi, Serum bone alkaline phosphatase and calcaneus bone density predict fractures: a prospective study, Osteoporos. Int. 11 (1) (2000) 76–82. 11. C. Meier, T.V. Nguyen, J.R. Center, M.J. Seibel, J.A. Eisman, Bone resorption and osteoporotic fractures in elderly men: the dubbo osteoporosis epidemiology study, J. Bone Miner. Res. 20 (4) (2005) 579–587. 12. K. Brixen, E.F. Eriksen, Validation of biochemical markers of bone turnover, in: M.J. Seibel, S.P. Robins, J.P. Bilezikian (Eds.) Dynamics of Bone and Cartilage Metabolism, second ed., Academic Press, San Diego, 2006, pp. 583–594. 13. T. Nguyen, C. Meier, M.J. Seibel, Variability of bone marker measurements, in: M.J. Seibel, S.P. Robins, J.P. Bilezikian (Eds.) Dynamics of Bone and Cartilage Metabolism, second ed., Academic Press, San Diego, 2006, pp. 565–582. 14. P. Szulc, E. Seeman, P.D. Delmas, Biochemical measurements of bone turnover in children and adolescents, Osteoporos. Int. 11 (4) (2000) 281–294. 15. A. Blumsohn, R.A. Hannon, R. Wrate, et al., Biochemical markers of bone turnover in girls during puberty, Clin. Endocrinol. (Oxf) 40 (5) (1994) 663–670. 16. J.S. Johansen, A. Giwercman, D. Hartwell, et al., Serum bone Gla-protein as a marker of bone growth in children and adolescents: correlation with age, height, serum insulin-like growth factor I, and serum testosterone, J. Clin. Endocrinol. Metab. 67 (2) (1988) 273–278. 17. F. Rauch, E. Schonau, H. Woitge, T. Remer, M. Seibel, Urinary excretion of hydroxy-pyridinium cross-links of collagen reflects skeletal growth velocity in normal children, Exp. Clin. Endocrinol. 102 (2) (1994) 94–97. 18. F. Rauch, D. Schnabel, M.J. Seibel, et al., Urinary excretion of galactosyl-hydroxylysine is a marker of growth in children, J. Clin. Endocrinol. Metab. 80 (4) (1995) 1295–1300. 19. P. Ravn, C. Fledelius, C. Rosenquist, K. Overgaard, C. Christiansen, High bone turnover is associated with low
20.
21.
22.
23.
24.
25.
26.
27. 28.
29.
30. 31. 32.
33.
34.
35.
36.
37.
183
bone mass in both pre- and postmenopausal women, Bone 19 (3) (1996) 291–298. J.D. Clemens, M.V. Herrick, F.R. Singer, D.R. Eyre, Evidence that serum NTx (collagen-type I N-telopeptides) can act as an immunochemical marker of bone resorption, Clin. Chem. 43 (11) (1997) 2058–2063. H.W. Woitge, M.J. Seibel, R. Ziegler, Comparison of total and bone-specific alkaline phosphatase in patients with nonskeletal disorder or metabolic bone diseases, Clin. Chem. 42 (11) (1996) 1796–1804. P.J. Kelly, N.A. Pocock, P.N. Sambrook, J.A. Eisman, Age and menopause-related changes in indices of bone turnover, J. Clin. Endocrinol. Metab. 69 (6) (1989) 1160–1165. P. Garnero, E. Sornay-Rendu, M.C. Chapuy, P.D. Delmas, Increased bone turnover in late postmenopausal women is a major determinant of osteoporosis, J. Bone Miner. Res. 11 (3) (1996) 337–349. R. Eastell, P.D. Delmas, S.F. Hodgson, E.F. Eriksen, K.G. Mann, B.L. Riggs, Bone formation rate in older normal women: concurrent assessment with bone histomorphometry, calcium kinetics, and biochemical markers, J. Clin. Endocrinol. Metab. 67 (4) (1988) 741–748. S. Khosla, L.J. Melton III, E.J. Atkinson, W.M. O’Fallon, G.G. Klee, B.L. Riggs, Relationship of serum sex steroid levels and bone turnover markers with bone mineral density in men and women: a key role for bioavailable estrogen, J. Clin. Endocrinol. Metab. 83 (7) (1998) 2266–2274. J.M. Wishart, A.G. Need, M. Horowitz, H.A. Morris, B.E. Nordin, Effect of age on bone density and bone turnover in men, Clin. Endocrinol. (Oxf) 42 (2) (1995) 141–146. D. Fatayerji, R. Eastell, Age-related changes in bone turnover in men, J. Bone Miner. Res. 14 (7) (1999) 1203–1210. P. Szulc, P. Garnero, F. Munoz, F. Marchand, P.D. Delmas, Cross-sectional evaluation of bone metabolism in men, J. Bone Miner. Res. 16 (9) (2001) 1642–1650. E.S. Orwoll, N.H. Bell, M.S. Nanes, et al., Collagen N-telopeptide excretion in men: the effects of age and intrasubject variability, J. Clin. Endocrinol. Metab. 83 (11) (1998) 3930–3935. S. Khosla, S. Amin, E. Orwoll, Osteoporosis in men, Endocr. Rev. 29 (4) (2008) 441–464. P. Chavassieux, P.J. Meunier, Histomorphometric approach of bone loss in men, Calcif. Tissue Int. 69 (4) (2001) 209–213. B.L. Clarke, P.R. Ebeling, J.D. Jones, et al., Changes in quantitative bone histomorphometry in aging healthy men, J. Clin. Endocrinol. Metab. 81 (6) (1996) 2264–2270. K.S. Tsai, W.H. Pan, S.H. Hsu, et al., Sexual differences in bone markers and bone mineral density of normal Chinese, Calcif. Tissue Int. 59 (6) (1996) 454–460. P. Garnero, P.D. Delmas, Assessment of the serum levels of bone alkaline phosphatase with a new immunoradiometric assay in patients with metabolic bone disease, J. Clin. Endocrinol. Metab. 77 (4) (1993) 1046–1053. J.C. Gallagher, H.K. Kinyamu, S.E. Fowler, B. wson-Hughes, G.P. Dalsky, SS. Sherman, Calciotropic hormones and bone markers in the elderly, J. Bone Miner. Res. 13 (3) (1998) 475–482. B.L. Clarke, P.R. Ebeling, J.D. Jones, et al., Predictors of bone mineral density in aging healthy men varies by skeletal site, Calcif. Tissue Int. 70 (3) (2002) 137–145. T. Sone, M. Miyake, N. Takeda, M. Fukunaga, Urinary excretion of type I collagen crosslinked N-telopeptides in healthy
184
38.
39. 40.
41.
42.
43.
44.
45.
46.
47.
Osteoporosis in Men
Japanese adults: age- and sex-related changes and reference limits, Bone 17 (4) (1995) 335–339. P. Szulc, P. Garnero, F. Marchand, F. Duboeuf, P.D. Delmas, Biochemical markers of bone formation reflect endosteal bone loss in elderly men – MINOS study, Bone 36 (1) (2005) 13–21. P. Szulc, P.D. Delmas, Biochemical markers of bone turnover in men, Calcif. Tissue Int. 69 (4) (2001) 229–234. S. Cheng, H. Suominen, K. Vaananen, S.M. Kakonen, K. Pettersson, E. Heikkinen, Serum osteocalcin in relation to calcaneal bone mineral density in elderly men and women: a 5-year follow-up, J. Bone Miner. Metab. 20 (1) (2002) 49–56. E. Dennison, R. Eastell, C.H. Fall, S. Kellingray, P.J. Wood, C. Cooper, Determinants of bone loss in elderly men and women: a prospective population-based study, Osteoporos. Int. 10 (5) (1999) 384–391. S.J.A. Goemaere, H. Zmierczak, I. van Pottelbergh, R. Demuynck, H. Myny, J.M. Kaufman, Association of bone turnover with longitudinally assessed bone loss in communitydwelling elderly men, J. Bone Miner. Res. 16 (S1) (2009) S395. F. Scopacasa, J.M. Wishart, A.G. Need, M. Horowitz, H. A. Morris, B.E. Nordin, Bone density and bone-related biochemical variables in normal men: a longitudinal study, J. Gerontol. A. Biol. Sci. Med. Sci. 57 (6) (2002) M385–M391. N. Yoshimura, T. Hashimoto, K. Sakata, S. Morioka, T. Kasamatsu, C. Cooper, Biochemical markers of bone turnover and bone loss at the lumbar spine and femoral neck: the Taiji study, Calcif. Tissue Int. 65 (3) (1999) 198–202. P.D. Delmas, R. Eastell, P. Garnero, M.J. Seibel, J. Stepan, The use of biochemical markers of bone turnover in osteoporosis, Osteoporos. Int. 11 (Suppl. 6) (2000) S2–S17. P. Szulc, A. Montella, P.D. Delmas, High bone turnover is associated with accelerated bone loss but not with increased fracture risk in men aged 50 and over: the prospective MINOS study, Ann. Rheum. Dis. 67 (9) (2008) 1249–1255. H. Luukinen, S.M. Kakonen, K. Pettersson, et al., Strong prediction of fractures among older adults by the ratio of carboxylated to total serum osteocalcin, J. Bone Miner. Res. 15 (12) (2000) 2473–2478.
48. R.R. McLean, P.F. Jacques, J. Selhub, et al., Homocysteine as a predictive factor for hip fracture in older persons, N. Engl. J. Med. 350 (20) (2004) 2042–2049. 49. E. Orwoll, M. Ettinger, S. Weiss, et al., Alendronate for the treatment of osteoporosis in men, N. Engl. J. Med. 343 (9) (2000) 604–610. 50. E.S. Orwoll, W.H. Scheele, S. Paul, et al., The effect of teriparatide [human parathyroid hormone (1-34)] therapy on bone density in men with osteoporosis, J. Bone Miner. Res. 18 (1) (2003) 9–17. 51. E.S. Kurland, F. Cosman, D.J. McMahon, C.J. Rosen, R. Lindsay, J.P. Bilezikian, Parathyroid hormone as a therapy for idiopathic osteoporosis in men: effects on bone mineral density and bone markers, J. Clin. Endocrinol. Metab. 85 (9) (2000) 3069–3076. 52. J.S. Finkelstein, B.Z. Leder, S.M. Burnett, et al., Effects of teriparatide, alendronate, or both on bone turnover in osteoporotic men, J. Clin. Endocrinol. Metab. 91 (8) (2006) 2882–2887. 53. W.M. Drake, D.L. Kendler, C.J. Rosen, E.S. Orwoll, An investigation of the predictors of bone mineral density and response to therapy with alendronate in osteoporotic men, J. Clin. Endocrinol. Metab. 88 (12) (2003) 5759–5765. 54. P.J. Snyder, H. Peachey, P. Hannoush, et al., Effect of testosterone treatment on bone mineral density in men over 65 years of age, J. Clin. Endocrinol. Metab. 84 (6) (1999) 1966–1972. 55. L. Katznelson, J.S. Finkelstein, D.A. Schoenfeld, D.I. Rosenthal, E.J. Anderson, A. Klibanski, Increase in bone density and lean body mass during testosterone administration in men with acquired hypogonadism, J. Clin. Endocrinol. Metab. 81 (12) (1996) 4358–4365. 56. J.S. Tenover, Effects of testosterone supplementation in the aging male, J. Clin. Endocrinol. Metab. 75 (4) (1992) 1092–1098. 57. C. Meier, P.Y. Liu, L.P. Ly, et al., Recombinant human chorionic gonadotropin but not dihydrotestosterone alone stimulates osteoblastic collagen synthesis in older men with partial age-related androgen deficiency, J. Clin. Endocrinol. Metab. 89 (6) (2004) 3033–3041.
Chapter
15
Alterations in Mineral Metabolism in the Aging Male Bismruta Misra and Shonni J. Silverberg College of Physicians and Surgeons, Columbia University, New York, USA
Introduction
at a slower rate than do osteoblasts (2–5%) and apoptosis reflects a cumulative view of osteocyte death, because the cellular debris cannot be removed by phagocytes. Osteocyte apoptosis precedes the recruitment of osteoclasts to regions where osteocytes have died after unloading or application of excessive strain [3]. Finally, the osteoblast–osteoclast interaction also changes with aging. Changes in physical activity and mechanical loading, as well as lower levels of sex steroids, result in diminished effects upon osteoblasts. This, in turn, results in decreased secretion of osteoprotogerin. In addition, there is increased expression and secretion of receptor activator of nuclear factor-kappa B ligand (RANKL), important interleukins such as IL-1, IL-6, IL-11, and tumor necrosis factor-alpha. In aggregate, these changes directly stimulate greater osteoclast formation and activity. The imbalance of decreased osteoprotogerin and increased RANKL permits binding of RANKL to RANK, leading to increased osteoclastogenesis and bone resorption [2]. The cumulative effect of these cellular changes in aging bone leads to an imbalance of of osteoblasts and osteoclasts, ultimately favoring increased osteoclastic activity and bone resorption.
Although osteoporosis is more common in women than in men, an increasing prevalence in men has been recognized over the past several decades. After peak bone mass is achieved, there is a decline in bone mass of approximately 0.5%/year [1]. Alterations in the synthesis, metabolism and responsiveness of vitamin D and parathyroid hormone (PTH) are intrinsic to the aging process. While such changes in vitamin D and PTH could be causally related to the age-associated changes in bone mass, some hormonal changes may be adaptive, serving to protect the aging skeleton from further weakening. This chapter will review how age-related changes in mineral metabolism, from the cellular to the hormonal level, are involved in the pathogenesis of osteoporosis in men.
Cellular changes An exhaustive review of cellular changes in bone associated with advancing age is beyond the scope of this chapter. Briefly, aging is associated with changes in the mobility and differentiation of mesenchymal stem cells. In the bone marrow, osteoblasts and adipocytes share the same precursors. With aging, adipogenesis increases at the expense of osteoblastogenesis. The reduction in osteoblastogenesis results in the formation of fewer active osteoblasts. Increasing adipogenic differentiation also leads to fewer differentiated osteoblasts. Finally, aging brings about increased osteoblast apoptosis [2]. Osteocyte apoptosis also appears to play a role in the cellular changes involved in osteoporosis. Osteocytes die
Osteoporosis in Men
Age-related hormonal changes in mineral metabolism Vitamin D Alterations in vitamin D play a key role in the development of age-related bone loss. Most, but not all, studies report a fall in the circulating concentration of vitamin D with advancing age. Although 25-hydroxyvitamin D levels
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(25(OH)D) have been reported to be significantly higher in males than females at all ages, levels decline with increasing age in both sexes [4]. The pivotal role of vitamin D in the development of osteoporosis could result from abnormalities in vitamin D availability, synthesis or metabolism, or from alterations in responsiveness to vitamin D. Possible abnormalities include deficient vitamin D intake; abnormal production of 25(OH)D or 1,25-dihydroxyvitamin D (1,25(OH)2D), the active form of the vitamin; altered intestinal vitamin D receptor number or sensitivity; and acquired resistance to vitamin D. Individuals deficient in calcium as a result of such an abnormality will be at greater risk for an imbalance in the dynamic interplay between bone formation and bone resorption. Aging is associated with reduced availability of vitamin D from its two natural sources: diet and sunlight. Although current recommendations of the National Academy of Science for those 65 years of age include a minimal daily requirement for 600 IU of vitamin D [5], many feel that significantly higher intakes are appropriate in older individuals. Despite this, many older Americans choose diets with low vitamin D content, with reports suggesting a mean intake of approximately 75–100 IU of vitamin D per day [6]. Furthermore, vitamin D absorption from the gastrointestinal tract may be impaired in the elderly. Some studies show that intestinal absorption of vitamin D does not change with age [7], while others show it to be decreased [8]. In women, a decline of up to 40% in absorption of vitamin D in the distal ileum has been reported to occur with advancing age [9]. An age-related reduction in intestinal vitamin D receptor concentration has been observed in intestinal biopsies obtained from women spanning the wide age range of 20–87 years [8]. If vitamin D receptor concentration were limiting, lower receptor abundance would lead to impaired calcium absorption. Pattanaungkul et al studied the association of 1,25(OH)2D concentrations with fractional fasting calcium absorption [10]. Interestingly, the strong relationship between the two seen in young subjects did not persist in an elderly population. Moreover, the slope of the relationship between these two indices was significantly greater in the young than in the elderly. While these observations have not been fully reproduced in men, they do support the hypothesis that the elderly may be relatively resistant to the physiological actions of 1,25(OH)2D on intestinal calcium absorption. Furthermore, aging may be associated with altered responses to vitamin D supplementation. Harris et al compared plasma 25(OH)D responses to vitamin D2 supplementation (45 g/day for three weeks) in older (age 65–73 years) and younger men (age 22–28 years). The younger men had a 90% greater increase in 25(OH)D levels than did the older men in response to the same dose of vitamin D [11]. The other important source of vitamin D is the skin, where UVB rays convert 7-dehydrocholesterol to previtamin D. Cutaneous production of vitamin D decreases
with advancing age [12]. Production of 7-dehydrocholesterol levels in the epidermis fall by 50% between 20 and 80 years of age and the response in serum vitamin D after one minimal erythemal dose of UVB radiation is reduced nearly four-fold in elderly male and female subjects [13]. In addition, the prevalent use of sunscreen and the avoidance of sun exposure compound the problem of producing vitamin D in the skin. There is no evidence that the liver loses its capacity to convert vitamin D to 25(OH)D with aging, unless there is severe, advanced liver disease [14, 15]. On the other hand, a decline in the ability of the kidney to form 1,25(OH)2D, the active metabolite of vitamin D, does occur with age and has long been implicated as a possible mechanism for agerelated osteoporosis [16]. In men, the serum 1,25(OH)2D concentration has been variously reported to decrease with age or remain unchanged [17–19]. This discrepancy may be explained by the inclusion of different proportions of sick and healthy elderly subjects in different studies. Those in poor health, who may be living in nursing homes, have both lower sun exposure and lower vitamin D levels. In healthy elderly men, the production rate and metabolic clearance were noted to be normal [19]. Even though the levels of 1,25(OH)2D may be normal in healthy elderly subjects, the sensitivity of the renal 1-alpha hydroxylase to trophic factors may be reduced [20]. Older individuals respond to the stimulatory effects of PTH on 1,25(OH)2D production less well than young subjects did (discussed in further detail below). Studies in women and osteoporotic subjects found that serum PTH and creatinine increased with age, but that 1,25(OH)2D levels did not rise as expected with parathyroid hormone increases [21, 22]. Responsiveness to PTH decreased with age, but significant reductions were not noted until after age 70 [23–25]. Halloran et al studied the response to PTH infusion in healthy elderly men. They reported that the time course of the increase in 1,25(OH)2D was delayed in older men, but that the final magnitude of the increase was similar to that seen in young men (Table 15.1) [26]. In summary, the explanation for the role of age-related alterations in vitamin D metabolism in the pathogenesis of osteoporosis is clearly multifactorial. Aging is associated with reduced availability of vitamin D from its two natural sources,
Table 15.1 Response of serum 1,25(OH)2D to exogenous infusion of hPTH(1–34) for 24 hours in healthy young and elderly men Young (n 9) Elderly (n 8) Age (year)
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Serum concentration (pg/ml) Basal 31 3 After 24-hour infusion of PTH 47 3
32 4 44 5
Values are mean SE. From Halloran et al [26]
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diet and sunlight, a reduction in intestinal vitamin D receptor concentration, possible altered responses to vitamin D supplementation and incompletely characterized alterations in renal responsiveness in the production of 1,25-dihydroxyvitamin D. Those who develop osteoporosis may have further abnormalities superimposed upon these sequelae of the aging process.
Parathyroid Hormone Parathyroid hormone levels increase with advancing age [19, 27, 28]. Secondary hyperparathyroidism is expected as a result of the age-associated decreases in vitamin D levels and declining renal function. Decreasing 1,25(OH)2D concentration as a function of impaired renal 1-alpha hydroxylation of 25(OH)D would relieve the inhibitory effects of this metabolite on the parathyroid hormone gene. Although a component of the increase in circulating levels of parathyroid hormone with aging clearly reflects declining renal
function, elevated values also occur in older individuals whose renal function remains entirely normal. Halloran et al studied young and elderly men with normal renal function in this regard. Despite normal serum ionized calcium activity, serum 1,25(OH)2D and urinary calcium excretion, basal serum parathyroid hormone was 1.5-fold higher in the elderly as compared with the younger men [19]. Most studies have demonstrated the increases in serum parathyroid hormone concentration as a continuous relationship with age (Figure 15.1) [27, 28]. PTH levels were elevated in 65% of male and female centenarians, with the average PTH concentration twice the upper limit of normal [29]. Despite the increase in PTH levels with aging, the parathyroid gland has a near constant glandular weight between the ages of 30 and 90 [30]. The rise in PTH is associated with a threefold increase in the minimum and maximum secretory rates [31, 32]. There are two hypotheses to explain the increase in parathyroid hormone concentrations with age. The first links, in a causal way, the increase in parathyroid
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Figure 15.1 The relationship of PTH and age and creatinine clearance. (Reproduced from Sherman SS, Hollis BW, Tobin JD. Vitamin D status and related parameters in a healthy population: the effects of age, sex and season. J Clin Endocrinol Metab 1990;71:405-13 [27] with permission).
Osteoporosis in Men
hormone with age-related bone loss. An alternative hypothesis suggests that the increase in hormone concentration is protective against age-related bone loss. The work of Silverberg et al provides additional evidence for altered PTH responsiveness with aging [21]. Oral phosphate was used to induce a mild hypocalcemic challenge to assess the ensuing increase in PTH concentration. The study was first conducted in younger and older subjects who had no evidence of osteoporosis. While the serum phosphorus concentration rose and the serum calcium level fell to the same extent, young subjects showed a 43% increase in PTH concentration over baseline values, whereas older women showed a much more exuberant parathyroid response, with a 2.5-fold increase over baseline levels. This protocol set up two opposing stimuli with respect to 1,25(OH)2D; increased phosphorus, which would tend to inhibit its production, and increased PTH, which stimulates the conversion of 25(OH)D to the active moiety. In both younger and older subjects, the 1,25(OH)2D concentration did not change. These data were interpreted to suggest that older, normal subjects require more PTH for a given hypocalcemic challenge to maintain 1,25(OH)2D status. Such a formulation is consistent with the reduced renal capacity to form this metabolite with age. It is also possible that the aging skeleton requires a greater amount of PTH to achieve effects that are seen at lower levels in younger subjects. When the protocol was repeated in a group of postmenopausal women with osteoporosis, the same increase in serum phosphorus concentration and reduction in serum calcium concentration was observed [22]. However, in contrast to the marked increase in PTH seen in their agematched normal counterparts, the osteoporotic women demonstrated only a modest 43% increase (Figure 15.2). Although this increase in PTH was sufficient in younger individuals to prevent the inhibitory effects of phosphorus on 1,25(OH)2D production, it did not suffice in these osteoporotic women, in whom 1,25(OH)2D concentrations fell by 50%. These observations are consistent with the presence of an abnormality in PTH secretory function in osteoporosis. Osteoporotic women thus have both agerelated reductions in their ability to form 1,25(OH)2D and a superimposed deficiency in parathyroid responsiveness. Unfortunately, similar data are not available in older men. An alternative explanation for the age-related increase in PTH could be that there is an alteration in the calcium setpoint. Ledger et al investigated this question using a provocation challenge in women and were unable to demonstrate any age-related increase in the calcium setpoint for PTH secretion [31]. When postmenopausal women with osteoporosis were studied, however, differences did emerge. Using infusions of the synthetic peptide, human parathyroid hormone (1-34) to assess suppressibility of endogenous human PTH, the data of Cosman et al were consistent with a higher calcium set point in osteoporotic women [33]. The data are somewhat different in men.
Osteoporotic Control Young normal
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Figure 15.2 The effect of a hypocalcemic stimulus on the parathyroid hormone response in osteoporotic and non-osteoporotic postmenopausal women and in young normal subjects. (Reproduced from Silverberg SJ, Shane E, de la Cruz L, Segre GV, Clemens TL, Bilezikian JP. Abnormalities in PTH secretion and 1,25-dihydroxyvitamin D3 formation in women with osteoporosis. N Engl J Med 1989;320:277-81 [22] with permission).
Portale et al demonstrated that fasting and mean 24-hour whole blood calcium concentrations were not different in healthy young and elderly men, suggesting that hypocalcemia is not required to sustain the age-related elevation in serum PTH in men. However, the age-related increase in serum PTH was associated with an increase in the concentration of calcium required to suppress half-maximally PTH release [32]. Essentially, the setpoint for PTH responsiveness to calcium was shifted to the right. These results are consistent with a protective effect of PTH in the pathogenesis of osteoporosis in men. In summary, although secondary hyperparathyroidism is expected as a result of the age associated decline in both vitamin D levels and renal function, increased parathyroid hormone concentration is seen in the elderly regardless of renal function. The increase in parathyroid hormone concentrations with age could contribute to age-related bone loss or it could be protective against age-related bone loss. The latter hypothesis is supported by data showing that non-osteoporotic elderly individuals secrete excess PTH in order to compensate for reduced renal capacity to form 1,25OHD, while osteoporotic women are unable to mount a compensatory increase in PTH. Other data, however, demonstrate that the setpoint for PTH responsiveness to calcium is shifted to the right in aging men, which suggests that PTH may play a protective role in the pathogenesis of osteoporosis in men. Efforts are ongoing to characterize more fully the role of parathyroid hormone aging males.
Sex steroids Sex steroids are important for skeletal growth and for the maintenance of both the female and the male skeleton [34, 35]. This topic is covered in detail elsewhere and discussion
C h a p t e r 1 5 Alterations in Mineral Metabolism in the Aging Male l
here is limited to interaction of sex steroids with hormones of mineral metabolism with aging. It appears that declining estrogen levels play a significant role in mediating age-related bone loss and fracture risk in men. Although serum total and free testosterone decrease with advancing age [36], because most men do not develop overt hypogonadism with aging, the prevailing opinion had been that sex steroid deficiency was not a major cause of age-related bone loss in men. It is now clear that the failure of earlier studies to document decreased serum levels of total sex steroids was caused by the failure to account for the greater than twofold rise in serum sex hormone binding globulin (SHBG) with advancing age [37]. That serum levels of free or bioavailable sex steroid do substantially decrease with aging [37, 38] was confirmed by data from the Mr Os study, demonstrating that serum free testosterone and free estradiol declined significantly with age, in association with increased serum SHBG [39]. Data have not supported the traditional assumption that bone loss in men is related to the decrease in bioavailable testosterone. Instead, bone density (BMD) in men is most closely associated with estradiol levels [37–39]. In a study of the relative contributions of testosterone and estrogen on bone in elderly men, subjects (mean age 68 years) were placed on a long-acting gonadotrophin-releasing hormone (GnRH) agonist (leuprolide) and an aromatase inhibitor (letrozole) in addition to replacement testosterone and estradiol. Then, both sex steroids, testosterone only or estrogen only were discontinued and bone turnover was evaluated in all groups. Bone resorption markers were unchanged in men receiving both hormones and increased significantly in the absence of both hormones. Estrogen prevented the increase in bone resorption markers, whereas testosterone alone had no significant effect. In contrast, while bone formation markers decreased in the absence of both hormones, either estrogen or testosterone alone maintained these levels. It appears that, in aging men, estrogen is the dominant sex steroid regulating bone resorption, whereas both estrogen and testosterone are important in maintaining bone formation [40]. There are links between the decline in sex steroids with aging and alterations in hormones of mineral metabolism. The age-related increase in serum PTH is eliminated in postmenopausal women receiving long-term estrogen therapy. In a comparison of premenopausal and estrogendeficient postmenopausal women, serum PTH increased as a function of age [41]. However, this age-related increase in PTH was not seen in the postmenopausal women receiving long-term estrogen therapy. Additionally, estrogen treatment led to a similar suppression of markers of bone formation and resorption in both the early (20 years) and late (20 years) postmenopausal women. Estrogen deficiency could therefore be responsible not only for the increase in bone turnover in early postmenopausal women, but also indirectly for the secondary hyperparathyroidism and increase in bone turnover found in late postmenopausal
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women. Residual serum estrogen levels are thus important determinants of bone resorption in postmenopausal women. Recently, Leder et al evaluated the effects of male hypogonadism on PTH sensitivity and response [42]. They studied men (age 50–82) with locally advanced prostate cancer but no bone metastases. Subjects received PTH infusions both prior to initiation of GnRH agonist therapy and again after confirmation of GnRH agonist-induced hypogonadism. Bone formation markers and serum 1,25(OH)2D showed similar increases in response to PTH before and after leuprolide therapy. However, the bone resoprtion marker, urinary N-telopeptide (NTX), increased to a greater extent in the hypogonadal state. The authors conclude that, in elderly men, suppressed sex steroids increase responsiveness to the bone resorbing effects of PTH. A follow-up study by the same group assessed both testosterone and estrogen withdrawal on PTH sensitivity in younger men [43]. Healthy men (age 20–45) were treated with GnRH agonist, an aromatase inhibitor and subsequent hormone replacement, creating four study groups: testosterone and estradiol sufficient subjects, testosterone and estradiol deficient subjects, testosterone sufficient but estradiol deficient subjects and testosterone deficient but estradiol sufficient subjects. The groups received 24-hour PTH infusions at baseline and after 6 weeks of therapy. In all but the eugonadal group, serum NTX measured before PTH infusion was significantly higher after 6 weeks of therapy. Pre-infusion concentrations of osteocalcin and procollagen I N-terminal propeptide (PINP) fell significantly in the group that was testosterone sufficient but estrogen deficient. All groups demonstrated increases in NTX and C-terminal collagen cross-links (CTX) during PTH infusion. In the group that was both testosterone and estrogen sufficient, bone resorption increased to similar extents at week 0 and week 6. However, in all of the other groups, the increases in NTX were significantly greater at week 6 than baseline. This study suggests that deficiencies in either or both sex steroids increase the skeletal sensitivity to PTH, a finding that may play a role in the pathogenesis of osteoporosis in men. There are limited data on parathyroid hormone levels or glandular function in hypogonadal men treated with testosterone. Early studies of testosterone replacement in elderly hypogonadal men found no effect on serum PTH, but did show significant increases in osteocalcin levels [44]. A meta-analysis of randomized clinical trials of men treated with testosterone concluded that testosterone had a modest effect in reducing bone resorption markers and no significant effects on bone formation markers [45]. Alterations in sex steroids with aging could also affect vitamin D status in the elderly. A recent cross-sectional study found that vitamin D binding protein levels were higher in women than in men, although women had lower 25(OH)D levels. Most other cross-sectional studies have demonstrated no differences in vitamin D binding protein levels with aging in either men or women [46]. Estrogen
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increases serum vitamin D binding protein, thereby reducing the fraction of free 1,25(OH)2D [47]. Whether testosterone has similar effects and whether the fall in estrogen and testosterone with age influences the circulating levels of vitamin D binding protein and free 1,25(OH)2D is unknown. In summary, serum free testosterone and free estradiol decrease significantly with age and declining estrogen levels in particular play a significant role in mediating agerelated bone loss and fracture risk in men. The decline in sex steroids with aging is also associated with the increased skeletal sensitivity to PTH, which may be important in the pathogenesis of osteoporosis in men.
Growth Hormone, Insulin-like Growth Factor system Aging is associated with alterations in other hormones that could impact upon skeletal integrity. Growth hormone (GH), insulin-like growth factor (IGF-I) and insulin-like growth factor binding protein-II (IGFBP-II) decrease with advancing age in men and women [48–50]. The amplitude and frequency of GH secretory pulses also diminish with aging, leading to decreased hepatic IGF-I production [51]. While serum IGF-I decreases markedly with age, there are less dramatic declines in serum IGF-II [52]. Moreover, in men between the ages of 20 and 40 years, changes in trabecular microstructure, particularly the conversion of thick trabeculae into more numerous, thinner trabeculae, are closely associated with declining IGF-I levels [53]. Although agerelated decreases in circulating IGF-I levels and/or the activity of the IGF system may contribute to impaired bone formation with aging, these changes may also explain, at least in part, the age-related increase in circulating sex hormone binding globulin (SHBG) levels [37]. IGF-I inhibits in vitro SHBG production by hepatocytes [54]. In men, serum SHBG levels are inversely correlated with IGF-I levels [55]. It is therefore possible that age-related changes in the GH/IGF system could influence the activity of sex steroids through its effect on circulating SHBG levels. It has been hypothesized that the reduced bone density in both male and female patients with adult growth hormone deficiency (AGHD) is mediated by reduced parathyroid gland sensitivity. White et al compared AGHD patients with low and normal bone mineral density. Those with low bone density had significantly lower mean PTH and 1,25(OH)2D levels, consistent with reduced renal PTH effect [56]. Postmenopausal osteoporotic women had lower than expected IGF-I levels, which increased significantly with growth hormone administration. In addition, with treatment, PTH levels declined and PINP concentration increased, consistent with the hypothesis that GH may influence PTH sensitivity [57]. The effect of the growth hormone-IGF system on the skeleton could also, in part, be mediated by its effect on vitamin D production. GH and IGF-I treatment in vivo stimulate
1,25(OH)2D production. This action of GH appears to be mediated through IGF-I. IGF-I administration in vitro enhances 1,25(OH)2D synthesis, while administration of GH does not [58]. Serum calcitriol levels increase in both male and female elderly subjects treated with GH [59].
Calcitonin Serum calcitonin levels are higher in men than in women and have been reported either to decrease [60, 61] or remain unchanged with advancing age [62]. There is a greater increase in serum calcitonin in young compared to elderly women in response to a calcium challenge, but there are no studies evaluating this in men [61]. Gennari et al evaluated the relationship between estrogen and calcitonin in postmenopausal osteoporosis in a double-blind placebo-controlled study [63]. They evaluated the effects of l-year estrogen–progesterone treatment on calcitonin secretory reserve, as evaluated by calcium infusion test. Blood levels of calcitonin showed a progressive increase during the study period in the hormone-treated group, with a significant increase in the response to the calcium stimulation test. This was taken to suggest that estrogen may modulate calcitonin secretion, but more data are obviously needed in this regard. No similar data are available in men.
Summary Mineral metabolism changes in important ways in the aging male and some of these changes are implicated in the pathogenesis of osteoporosis. Age-associated alterations in vitamin D status are caused by decreased formation in the skin, decreased gastrointestinal absorption and decreased conversion to the active moiety in the aging kidney. Aging is also associated with increased and altered sensitivity to PTH. Some of these changes are adaptive and loss or absence of these adaptations may be associated with accelerated bone loss. The decline in sex steroids with aging has direct skeletal consequences. In addition, these declines may mediate an exaggerated response to parathyroid hormone, leading to enhanced bone resorptive activity. Age-related reductions in growth hormone/IGF-I may also have skeletal consequences, via effects on sex hormone binding globulin as well as through other mechanisms that are yet to be elucidated. Many questions remain with regard to the nature and consequences of hormonal changes on mineral metabolism in the aging male. First, it is not clear whether the data on hormonal changes in aging collected in women are applicable to the aging male. Clarification is also needed as to what constitutes the ‘normal’ physiologic responses of aging and what further changes are associated with the development of accelerated bone loss, or osteoporosis. In this regard, the aging male remains a fertile ground for further research.
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References 1. A. Tenenhouse, L. Joseph, N. Kreiger, et al., Estimation of the prevalence of low bone density in Canadian women and men using a population-specific DXA reference standard: the Canadian Multicentre Osteoporosis Study(CaMos), Oseoporosis. Int. 11 (2000) 897–904. 2. G. Duque, B.R. Troen, Understanding the mechanisms of senile osteoporosis: new facts for a major geriatric syndrome, J. Am. Geriatr. Soc. 56 (2008) 935–941. 3. R. Jilka, R.S. Weinstein, A.M. Parfitt, S.C. Manolagas, Quantifying osteoblast and osteocyte apoptosis: challenges and rewards, J. Bone Miner. Res. 22 (2007) 1492–1501. 4. A.C. Looker, C.M. Pfeiffer, D.A. Lacher, R.L. Schleicher, M.F. Picciano, E.A. Yetley, Serum, 25-hydroxyvitamin D status of the US population: 1988–1994 compared with 2003–2004, Am. J. Clin. Nutr. 88 (2008) 1519–1527. 5. NIH Osteoporosis Prevention, Diagnosis, and Therapy. NIH Consensus Development Conference, NIH, Washington, DC, 2000. 6. B. Dawson-Hughes, Regulation of parathyroid hormone by dietary calcium and vitamin D, in: J.P. Bilezikian, R. Marcus, M.A. Levine (Eds.) The Parathyroids, Raven Press, New York, 1994, pp. 55–65. 7. T.L. Clemens, X.Y. Zhou, M. Myles, D. Endres, R. Lindsay, Serum vitamin D3 and vitamin D2 concentrations and absorption of vitamin D2 in elderly subjects, J. Clin. Endocrinol. Metab. 63 (1986) 656–660. 8. P.R. Ebeling, M.E. Sandgren, E.P. DiMagno, et al., Evidence of an age-related decrease in intestinal responsiveness to vitamin D: relationship between serum 1,25 dihydroxyvitamin D3 and intestinal vitamin D receptor concentrations in normal women, J. Clin. Endocrinol. Metab. 75 (1992) 176–182. 9. J.M. Baggary, M.W. France, D. Corless, et al., Intestinal cholecalciferol absorption in the elderly and in young adults, Clin. Sci. Mol. Sci. 55 (1978) 213–220. 10. S. Pattanaungkul, B.L. Riggs, A.L. Yergey, N.E. Vieira, W.M. O’Fallon, S. Khosla, Relationship of intestinal calcium absorption to 1,25 dihydroxyvitamin D levels in young versus elderly women: evidence for age-realted intestinal resistance to 1,25 dihydroxyvitamin D action, J. Clin. Endocrinol. Metab. 85 (2001) 4023–4027. 11. S.S. Harris, B. Dawson-Hughes, G.A. Perrone, Plasma 25hydroxyvitamin D responses of younger and older men to three weeks of supplementation with 1800IU/day of vitamin D, J. Am. Coll. Nutr. 18 (1999) 470–474. 12. J. MacLaughlin, M.F. Holick, Aging decreases the capacity of human skin to produce vitamin D3, J. Clin. Invest. 76 (1985) 1536–1538. 13. M.F. Holick, L.Y. Matsuoka, J. Wortsman, Age, vitamin D and solar ultraviolet, Lancet 2 (1989) 1104–1105. 14. D.S. Rao, M. Honasoge, Metabolic bone disease in gastrointestinal, hepatobiliary, and pancreatic, in: M.J. Favus (Ed.), Primer on the Metabolic Bone Diseases and Disorders of Mineral Metabolism, third ed., Lippincott-Raven, New York, 1996, pp. 306–310. 15. L.M. Siegel, J.P. Bilezikian, Metabolic bone diseases and disorders of the gastrointestinal tract, in: Proceedings of the Falk Symposium: Gastrointestinal Tract and Endocrine System, Walter Kluwers, The Netherlands, 1995.
191
16. J.C. Gallagher, The pathogenesis of osteoporosis, Bone Miner. 9 (1990) 215–227. 17. S. Epstein, G. Bryce, J. Hinman, The influence of age on bone mineral regulating hormones, Bone 7 (1986) 421–425. 18. E.S. Orwoll, D. Meier, Alterations in calcium, vitamin D and PTH physiology in normal men with aging, J. Clin. Endocrinol. Metab. 63 (1986) 1262–1269. 19. B.P. Halloran, A. Portale, E.T. Lonergan, R.C. Morris, Production and metabolic clearance of 1,25 dihydroxyvitamin D in men: effect of advancing age, J. Clin. Endocrinol. Metab. 53 (1990) 833–835. 20. D.M. Slovick, J.S. Adams, R.M. Neer, M.F. Hollick, J.T. Potts, Deficient production of 1,25dihydroxyvitamin D in elderly osteoporotic patients, N. Engl. J. Med. 305 (1981) 372–374. 21. S.J. Silverberg, E. Shane, T.L. Clemens, et al., The effects of oral phosphate on major indices of skeletal metabolism in normal subjects, J. Bone Miner. Res. 1 (1986) 383–388. 22. S.J. Silverberg, E. Shane, L. de la Cruz, G.V. Segre, T.L. Clemens, J.P. Bilezikian, Abnormalities in PTH secretion and 1,25-dihydroxyvitamin D3 formation in women with osteoporosis, N. Engl. J. Med. 320 (1989) 277–281. 23. H.K. Kinyamu, J.C. Gallagher, K.M. Petranick, K.L. Ryschon, Effect of parathyroid hormon (hPTH[1-34]) infusion on serum 1,25 dihydroxyvitamin D and parathyroid hormone in normal women, J. Bone Miner. Res. 11 (1996) 1400–1405. 24. B. Riggs, A. Hamstra, H. DeLuca, Assessment of 25-hydroxyvitamin D 1-alpha hydroxylase reserve in postmenopausal osteoporosis by administration of parathyroid extract, J. Clin. Endocrinol. Metab. 53 (1981) 833–835. 25. K. Tsai, H. Heath, R. Kumar, B. Riggs, Impaired vitamin D metabolism with aging in women, J. Clin. Invest. 3 (1984) 1668–1672. 26. B.P. Halloran, E.T. Lonergan, A.A. Portale, Aging and renal responsiveness to PTH in healthy men, J. Clin. Endocrinol. Metab. 81 (1996) 2192–2197. 27. S.S. Sherman, B.W. Hollis, J.D. Tobin, Vitamin D status and related paratmeters in a healthy population: the effects of age, sex and season, J. Clin. Endocrinol. Metab. 71 (1990) 405–413. 28. S. Khosla, L.J. Melton, B.L. Riggs, Parathyroid function in the normal aging process, in: J.P. Biliezikian, R. Marcus, M.A. Levine (Eds.) The Parathyroids, Academic Press, San Diego, 2001. 29. G. Passeri, R. Vescovini, P. Sansoni, C. Galli, C. Franceschi, M. Passeri, Calcium metabolism and vitamin D in the extreme longevity, Exp. Gerontol. 43 (2008) 79–87. 30. L. Grimelius, G. Akerstrom, R. Bergstrom, Anatomy of the human parathyroid glands, Pathol. Ann. (1981) 1–20. 31. G.A. Ledger, M.F. Burritt, P.C. Kao, W.M. O’Fallon, B.L. Riggs, S. Khosla, Abnormalities of parathyroid hormone secretion in elderly women that are reversible by short term therapy with 1,25hydroxyvitamin D2, J. Clin. Endocrinol. Metab. 79 (1994) 211–216. 32. A.A. Portale, E.T. Lonergan, D.M. Tanney, B.P. Halloran, Aging alters calcium regulation of serum concentration of parathyroid hormone in healthy men, Am. J. Physiol. 272 (1997) E139–E146. 33. F. Cosman, V. Shen, B. Herrington, R. Lindsay, Response of the parathyroid gland to infusion of human parathyroid
192
34.
35. 36. 37.
38.
39.
40.
41.
42.
43.
44.
45.
46.
47.
48. 49.
Osteoporosis in Men
hormone (I-34), J. Clin. Endocrinol. Metab. 73 (1991) 1345–1351. G. Albrand, F. Munoz, E. Sornay-Rendu, F. DuBoeuf, P.D. Delmas, Independent predictors of all osteoporosis related fractures in healthy postmenousal women: the OFELY study, Bone 32 (2003) 78–85. E.S. Orwoll, Men, bone, and estrogen: unresolved issues, Osteoporos. Int. 14 (2003) 93–98. S. Lamberts, A. van den Beld, A. van der Levy, The endocrinology of aging, Science 278 (1997) 419–424. S. Khosla, L.J. Melton III, E.J. Atkinson, W.M. OFallon, G.G. Klee, B.L. Riggs, Relationship of serum sex steroid levels and bone turnover markers with bone mineral density in men and women: a key role for bioavailable estrogen, J. Clin. Endocrinol. Metab. 83 (1998) 2266–2274. G.A. Greendale, S. Edelstein, E. Barrett-Connor, Endogenous sex steroids and bone mineral density in older women and men: the Rancho Bernardo study, J. Bone Miner. Res. 11 (1997) 1833–1843. E. Orwoll, L.C. Lamber, L.M. Marshall, et al., Testosterone and estradiol among older men, J. Clin. Endocrinol. Metab. 91 (2006) 1336–1344. A. Falahati-Nini, B.L. Riggs, E.J. Atkinson, W.M. O’Fallon, R. Eastell, S. Khosla, Relative contributions of testosterone and estrogen in regulating bone resorption and formation in normal elderly men, J. Clin. Invest. 106 (2000) 1553–1560. S. Khosla, E.J. Atkinson, J. Melton, B.L. Riggs, Effects of age and estrogen status on serum PTH and biochemical markers of bone turnover in women, J. Clin. Endocrinol. Metab. 87 (1997) 1522–1527. B.Z. Leder, M.R. Smith, M.A. Fallon, M.T. Lee, J.S. Finkelstein, Effects of gonadal steroid suppression on skeletal sensitivity to parathyroid hormone in men, J. Clin. Endocrinol. Metab. 86 (2001) 511–516. H. Lee, J.S. Finkelstein, M. Miller, S.J. Comeaux, R.I. Cohen, B.Z. Leder, Effects of selective testosterone and estradiol withdrawal on skeletal sensitivity to parathyroid hormone in men, J. Clin. Endocrinol. Metab. 91 (2006) 1069–1075. J.E. Morley, H.M. Perry, F.E. Kaiser, H.M. Perry, Effects of testosterone replacement therapy in old hypogonadal males, J. Am. Geriatr. Soc. 41 (1993) 149–152. A.M. Isidori, E. Giannetta, E.A. Greco, et al., Effects of testosterone on body composition, bone metabolism and serum lipid profile in middle aged men: a meta analysis, Clin. Endocrinol. 63 (2005) 280–293. Y. Fujisawa, K. Kida, H. Matsuda, Role of change in vitamin D metabolism with age on calcium and phosphorus metabolism in normal human subjects and osteoporotic patients, J. Clin. Invest. 64 (1979) 729–736. N.E. Cooke, J.G. Haddad, Vitamin D binding protein, in: D. Feldman, F.H. Glorieux, J.W. Pike (Eds.) Vitamin D, Academic Press, San Diego, 2005, pp. 87–101. E. Corpas, M. Harman, M.R. Blackman, Human growth hormone and human aging, Endocrinol. Rev. 14 (1993) 20–39. F.C. Martin, Y. Ai-Lyn, P.H. Sonksen, Growth hormone secretion in the elderly: ageing and the somatopause, Baillière’s Clin. Endocrinol. Metab. 11 (1997) 223–250.
50. P. Szulc, M.O. Joly-Pharaboz, F. Marchand, P.D. Delmas, Insulin-like growth factor I is a determinant of hip bone mineral density in men less than 60 years of age: MINOS study, Calcif. Tissue Int. 74 (2004) 322–329. 51. K.Y. Ho, W.S. Evans, R.M. Blizzard, et al., Effects of sex and age on the 24 hour profile of growth hormone secretion in man: importance of endogenous estradiol concentrations, J. Clin. Endocrinol. Metab. 64 (1987) 51–58. 52. S. Boonen, J. Aerssens, P. Broos, W. Pelemans, J. Dequeker, Age-related bone loss and senile osteoporosis: evidence for both secondary hyperparathyroidism and skeletal growth factor deficiency in the elderly, Aging 7 (1995) 414–422. 53. S. Khosla, L.J. Melton III, S.J. Achenbach, A.L. Oberg, B.L. Riggs, Hormonal and biochemcial determinants of trabecular microstructure at the ultradistal radius in women and men, J. Clin. Endocrinol. 91 (2006) 885–891. 54. J.C. Crave, H. Lejeune, C. Brebant, C. Baret, M. Pugeat, Differntial effects of insulin and insulin like growth factor I on the production of plasma steroid-binding globulins by human hepatobastoma-dervied (Hep G2) cells, J. Clin. Endocrinol. Metab. 80 (1995) 1283–1289. 55. J. Pfeilschifter, C. Scheidt-Nave, G. Leidig-Bruckner, et al., Relationship between circulating insulin-like growth factor components and sex hormones in a population-based sample of 50-80 year old men and women, J. Clin. Endocrinol. Metab. 81 (1996) 2534–2540. 56. H.D. White, A.M. Ahmad, B.H. Durham, et al., PTH circadian rhythm and PTH target-organ sensitivity is altered in patients with adult growth hormone deficiency with low BMD, J. Bone Miner. Res. 22 (2007) 1798–1807. 57. F. Joseph, A.M. Ahmad, M. Ul-Haq, et al., Effects of growth hormone administration on bone mineral metabolism, PTH sensitivity and PTH secretory rhythm in postmenopausal women with established osteoporosis, J. Bone Miner. Res. 23 (2008) 721–729. 58. L. Condamine, F. Vztovsnik, M. Garabedian, Local action of phosphate depletion and IGF-1 on in vitro production of 1,25(OH)2 by kidney cells, J. Clin. Invest. 94 (1994) 1673–1679. 59. R. Marcus, G. Butterfield, L. Holloway, et al., Effects of short term administration of recombinant human growth hormone secretion in the elderly: ageing and the somatopause, Baillière’s Clin. Endocrinol. Metab. 11 (1997) 223–250. 60. J.Y. Reginster, R. Deroisy, A. Albert, D. Denis, et al., Relationship between whole plasma calcitonon levels, calcitonon secreatory capacity, and plasma levels of estrone in healthy women and postmenopausal osteoporotics, J. Clin. Invest. 83 (1989) 1073–1077. 61. A. Boucher, P. D’Amour, L. Hamel, P. Fugere, et al., Estrogen replacement decreases the set point of parathyroid hormone stimulation by calcium in normal postmenopausal women, J. Cin. Endocrinol. Metab. 68 (1989) 831–836. 62. R.D. Tiegs, J.J. Body, J.M. Barta, Secretion and metabolism of monomeric human calcitonin: effects of age, sex and thyroid damage, J. Bone Miner. Res. 1 (1986) 339. 63. C. Gennari, D. Agnusdei, Calcitonin, estrogens, and the bone, J. Steroid. Biochem. Mol. Biol. 37 (1990) 451–455.
Chapter
16
Changes in Bone Size and Geometry with Aging Pawel Szulc INSERM 831 Unit, University of Lyon, Hôpital Edouard Heriot, Lyon, France
Radial bone growth in children and adolescents
femoral shaft widens faster than humerus probably due to a greater stimulation during bipedal walking. In most studies, bone width and radial growth velocity at a given skeletal site are similar in prepubertal boys and girls [4]. However, in some studies, late prepubertal boys have a larger radius than age-matched girls [5], which may result from higher physical activity in boys than in girls. Bone widening accelerates again at the beginning of the pubertal spurt [6] (Figure 16.1). In boys, this acceleration starts later, thus, boys may enter the pubertal spurt with slightly longer and larger bones. Then, pubertal radial growth in boys is faster and lasts longer than in girls [7]. Consequently, mid- and late-pubertal boys have wider bones and, despite longer bones, higher width/length index.
In children and adolescents, radial growth is linked to longitudinal growth and follows a similar age-related pattern [1]. Radial growth is crucial for bone to maintain bending strength and an ability to withstand mechanical loads. In newborns and infants, average width of different bones is similar in both sexes [2, 3]. In infants, radial growth is rapid and similar in both sexes, but varies according to the skeletal site, e.g. widening of the humerus (in mm/year) is faster than that of the femoral shaft, probably due to a greater stimulation during walking on all fours [3] At the age of 3, radial growth slows by about 50%. At this age,
Girls
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Total area (mm2)
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0 5
10 11.27
0 15
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Figure 16.1 Age-dependency of the total cross-sectional area (CSA) of the radius of 177 boys and 185 girls aged 6–18 years. Results in adults aged 29–40 years are presented as vertical bars (mean SD). The age 11.27 years – age of the maximal velocity of the increase in total CSA in girls. In boys, the age-related increase in total CSA was linear. (Reproduced from Neu et al Osteoporos Int 2001;12:538-47 [6] with permission of the Springer Verlag). Osteoporosis in Men
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Radial bone growth during aging After completion of growth, young men have larger bones than women after adjustment for body height and weight [8]. Although men have proportionally longer lower limbs and shorter trunk (for the same height) than women, men also have wider long bones after adjustment for bone length (e.g. femoral shaft) and wider vertebral bodies (adjusted for body height or for the vertebral height). That men have larger (wider) bones means that men’s bones have greater external diameter, greater external perimeter and greater cross-sectional area (CSA) is obvious, but it is important to understand seemingly discordant data concerning the difference in age-related periosteal expansion in men and women. As men have larger bones, an increase in the external diameter by the same absolute value may correspond to a slightly higher increase in CSA in men (because bone is distributed around a larger perimeter) but to a slightly greater relative increase in external diameter and in CSA in women (because initial values used for calculation of the percentage are lower in women). Periosteal apposition continues during adult life at various skeletal sites, regardless of the age, ethnic group, study design and measurement method [9, 10]. Age-related changes in bone size assessed cross-sectionally were compared at various skeletal sites in the same cohort [11]. For most of the skeletal sites (except tibia shaft), the increase is higher in men than women both in the absolute (cm2) and relative terms (percentage of the young adult values), also when adjusted for body height [11]. It supports the idea of the higher periosteal expansion in men. However, the extent of periosteal expansion and sex difference varies according to the skeletal site and, partly, to the way of expression of the results, i.e. absolute or relative values [11].
4.5
(cm)
Women
Chinese r = 0.20p <0.01 Caucasians r = 0.13p <0.01
Age-related changes in bone size were also assessed separately in younger adult men and women (20 to 50 years, i.e. after the cessation of the longitudinal growth and until the age of menopause in the case of women) and after the age of 50 (Figure 16.2). Both cross-sectional and longitudinal studies indicate that periosteal bone expansion exists at various skeletal sites in men and in women, before and after the age of 50 (for women, before and after the menopause) [9–16]. Analyses carried out in various age groups of older persons show that the periosteal expansion continues late in age and in both sexes [14, 16–18]. However, despite the general trend found consistently in various cohorts, which shows the continuous periosteal expansion in the elderly, several discrepancies between the studies need to be discussed. First, trends in periosteal expansion seem to be sex specific. For instance, in a populationbased cohort recruited in one region and composed of 464 women and 345 men aged 21 to 102 (InCHIANTI study), periosteal expansion at the distal tibia accelerated after the menopause in women whereas it slowed in older men [16]. Also in a European cohort of 425 women and 414 men aged 65 years and older followed up prospectively for 2.7 years, the femoral shaft width increased significantly in women but not in men (width of the intertrochanteric region and of the femoral neck increased in both sexes) [18]. Secondly, in the same sex, trends in periosteal expansion seem to be site specific and cannot be extrapolated from one site to another. For instance, after the menopause, longitudinally assessed periosteal expansion accelerated at the distal tibia [16] but decreased at the distal radius in 463 premenopausal, perimenopausal and postmenopausal untreated women aged 30 to 89 years (OFELY cohort) who were followed up prospectively for 7 years [15]. In older men, rate of periosteal expansion assessed longitudinally decreased at
(cm)
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Figure 16.2 (A) Age-related trajectories of the total bone area during life span from the longitudinal data (thick line and Caucasians r = estimates 0.44 p < 0.01 2.0 their 95% CIs presented as dotted lines) and cross-sectional (thin line). (B) Longitudinal changes in total bone area during the 6-year 10 20 30 40 50 60 70 80 90 100 10 20 30 40 50 60 70 80 90 100 follow up according to baseline age decade, from 20 to 100 years, in 540 men and 633 women from the InCHIANTI study. (Reproduced Years B of the American Years from Lauretani et alAJ Bone Miner Res 2008; 23:400-8 [16] with permission Society for Bone and Mineral Research).
C h a p t e r 1 6 Changes in Bone Size and Geometry with Aging l
the distal tibia [16] but remained stable at the distal forearm in 725 men aged 50 and over who were followed up prospectively for 7.5 years (MINOS cohort) [14]. Thirdly, rate of periosteal apposition varies according to the skeletal site and even in different parts of the same bone. However, these results vary according to the study even for the same age range (65 years). For instance, in a cross-sectional analysis carried out in 3358 American men aged 65 to 100 (Mr OS cohort), periosteal expansion assessed by quantitative computed tomography was faster at the femoral shaft than at the femoral neck (both significant) [17]. By contrast, in a prospective analysis of 414 elderly European men aged 65 and over, external diameter assessed by dual energy xray absorptiometry (DXA) increased at the femoral neck but not at the femoral shaft [18]. Fourthly, rate of periosteal expansion may be age specific, but it can be assessed only in prospective studies in cohorts covering large age ranges. However, data are scanty and discordant. Cross-sectional studies calculate overall life-long increase in bone size which may be not homogeneous during the entire lifespan. Overall increase in bone size at the tibia assessed cross-sectionally was similar in both sexes [11], however, it was faster in men than women before the age of 50 and faster in women than men after the age of 70 [16]. At the distal radius, the trend was opposite: periosteal apposition slowed after menopause in women and was stable after the age of 50 in men [14, 15]. Thus, cross-sectional and prospective studies performed in large cohorts strongly suggest that periosteal expansion continues after the growth completion until late in age in various skeletal sites in both men and women. However, data on the differences in the age-related periosteal expansion between men and women, between younger and older persons and between the skeletal sites are discordant. These discrepancies depend partly on the scarcity of the longitudinal data. Moreover, available techniques do not allow for an accurate estimation of the periosteal expansion rate during the relatively short-term follow-up times (several years) in studies reported to date.
Determinants of the bone size and age-related changes in bone geometry Various factors influence bone size and shape in different periods of life.
Genetic Determinants Genetic control of bone size and shape has been shown in studies of various designs and from various populations. Linkage analyses identified chromosomal regions associated with the variability in bone size and shape [19, 20]. They harbor genes involved in the regulation of bone metabolism,
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e.g. aromatase or procollagen-lysine oxyglutamate dioxygenase 2. Studies of pedigrees and nuclear families show a significant heritability of bone size at the spine and proximal femur (width of femoral head, neck and shaft, femoral neck axis length) and of shape (neck shaft angle) [19, 21]. Single nucleotide polymorphisms of genes involved in the bone metabolism (vitamin D receptor, low density lipoprotein receptor-related protein 5) were associated with differences in bone size and shape [22, 23]. However, part of variability of bone size explained by the genetic determinants is small, about 2 %, i.e. less than 0.5 SD. Associations between genetic determinants and bone size may depend partly on the confounding effect of the overall body size and general robustness of the skeleton. Moreover, siblings share not only genes, but also common nutritional and lifestyle habits which may influence bone growth. However, associations that remain significant in multivariate models (adjusted for weight and/or height) suggest that some traits of bone morphology have genetic determinants. As bone geometry is an independent determinant of bone strength, these data improve our understanding of the heritability of the fracture risk.
Ethnic Factors Bone width and its age-related changes depend on ethnicity. However, ethnic differences may be spurious and disappear after adjustment for confounders. The term ‘ethnic group’ is broad and encompasses genetically different populations. For the same age group, differences in bone size depend on differences in stature, body segment length and bone length. The size of the radius in Caucasian women is larger than in South Asian women because they are taller and the difference disappears after adjustment for height [24]. By contrast, young Chinese men and women had shorter axis and lower external diameter of the femoral neck in comparison with sex- and age-matched Caucasians after adjustment for body weight, which partly reflects body size [25]. These data more convincingly prove the ethnic differences in bone size and shape. In the same ethnic group, the upper to lower segment ratio varies according to the sex and generation [26]. Thus, ethnic differences vary according to the bone (and are different for vertebral bodies and for long bones). Some ethnic differences vary according to the segment of the bone (e.g. femoral neck versus femoral shaft). For instance, in three groups of older women matched for age, weight and height, femoral neck was more slender in African American and in Nigerian women than in Caucasian women [27]. By contrast, femoral shaft width was similar African American and Caucasian women and greater than in Nigerian women. Four ethnic groups of older men (white, black, Asian, Hispanic) were investigated in the Mr OS study [28]. In comparison with white men, black men had lower femoral neck CSA, whereas Asian men had lower femoral shaft CSA (after adjustment for age, height and body mass index).
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Figure 16.3 Measured (unadjusted) femoral neck periosteal diameter plotted against age in 393 healthy Caucasian men and 788 women aged 18–93 years (open dots, dashed lines) and 291 Chinese men and 538 women aged 18–87 years (filled dots, solid lines). (Reproduced from Wang et al Bone 2005;36:978-86 [31] with permission of Elsevier).
Ethnic differences may partly depend on environmental factors. Two ethnic groups living in the same country may have different incomes, nutritional habits and physical activity, factors that can influence both longitudinal and radial skeletal growth. The effect of these factors may be site specific. For instance, no difference was found in the femoral neck width, respectively, between American white and American black women and between South African white and South African black women [29]. However, South African women (white and black) had narrower femoral neck than their American counterparts. By contrast, in both populations, black women had lower intertrochanter width than white women. The intertrochanter width did not differ between the groups of women of the same ethnic group living in different countries (e.g. American versus South African white women). Furthermore, differences in bone size may be greater in populations of the same ethnic groups living in different countries. Thus, the ethnic differences are not attributable only to the different genetic background. Few studies have assessed the ethnic differences in agerelated changes in bone size. CSA of the third lumbar vertebral body increased with age in Chinese and Caucasians of both sexes [30]. The relative increase (expressed in number of SD of young persons of the same sex and ethnicity) was similar in Chinese men and women (0.9 and 0.8 SD) whereas, in Caucasians, it was higher in men than women (1.1 versus 0.6 SD). The age-related relative increase in the femoral neck width was greatest in Caucasian men (7.9% between the age of 30–70 years), followed by Chinese women (3.8%), Caucasian women (2.0%) and no increase in Chinese men (0%) [31] (Figure 16.3). Thus, the ethnic differences in the age-related changes in bone size are site specific and sex specific, so the results cannot be extrapolated from one skeletal site onto another. However, these data need confirmation in prospective studies.
Nutrition Nutritional status plays a major role in formation of peak bone mass during growth and in maintenance of bone mass during aging. During growth, undernutrition is associated with slow longitudinal bone growth, accelerated bone turnover and slow bone mineral accrual which partly depends on low radial bone growth. Both clinical and experimental studies indicate that protein intake is the principal nutrient which determines radial bone growth [32]. In addition, experimental protein restriction is associated with lower periosteal bone formation [33]. By contrast, data concerning the impact of the deficiency of energy and other nutrients (including calcium) on radial bone growth are more limited.
Mechanical Load – Age Specificity and Site Specificity Mechanical load (body weight, physical effort) is a strong determinant of bone size and of the radial bone growth. It acts on the bone locally and its effect depends on the age of a subject. Comparable mechanical loads (tennis playing for similar periods and with similar intensity) stimulated periosteal expansion at the humerus shaft more strongly in peripubertal girls than in young women who started to play after the puberty [34] (Figure 16.4). Thus, the periosteum is more responsive to mechanical stimuli during rapid pubertal growth. This is in agreement with histomorphometric data that suggest that fraction of the periosteal perimeter occupied by active bone remodelling units is highest in young persons and decreases with age [35]. Bone size is also correlated positively with intensity and duration of the physical activity [36, 37]. The effect of the mechanical load, e.g. body weight, on bone geometry varies according to the skeletal site.
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Young starters
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Side-to-side difference: CoA: BSlt:
19.6% 26.1%
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Figure 16.4 Mean side-to-side differences (%) in the size of the humeral midshaft of the playing arm over the non-playing arm. The thickness of the gray area represents the playing-induced mean area change at the periosteal and endosteal sites. The outer gray area corresponds to the periosteal surface which encompasses total crosssectional area (CSA) of the humeral shaft. The inner gray area corresponds to the endocortical surface which encompasses the marrow cavity. In the young starters, total CSA is larger at the playing arm (thick outer gray area) and marrow cavities are similar in both arms (thin inner gray area). In the old starters, total CSA is slightly larger whereas marrow cavity is slightly narrower (not larger) in the playing arm. In the controls, total CSA and marrow cavity are marginally larger in the playing arm. CoA: cortical bone area; BSIt: densityweighted polar section modulus reflecting torsional and bending rigidity of the long bone shaft. (Reproduced from Kontulainen et al J Bone Miner Res 2003;18:352-59 [34] with permission of the American Society for Bone and Mineral Research).
Overweight children and adolescents had higher femoral neck width [38]. At the femoral neck, higher body weight exerts greater bending stress. As bone placed further from the neutral axis increases bending strength, it is metabolically ‘less expensive’ to add a smaller quantity of bone on the outer surface of bone. By contrast, bone mineral content (BMC) of the femoral shaft was higher in the obese than in the normal weight subjects but this increase was not accompanied by a higher width. At the femoral shaft, body weight exerts an axial stress and BMC is a strong determinant of compressive strength. In this growing population, it may be metabolically ‘less expensive’ to increase BMC by inhibiting endocortical expansion instead of forming new bone on the outer surface. Thus, the association between the mechanical load and bone morphology may depend on the type of the mechanical strain.
Mechanical Load – Direct Effect on Bone or Indirect Effect Via Muscle Mass Physical effort induces strains in bone and in muscles. Stimulatory effect of the mechanical load on bone may be direct and indirect through the effect of higher muscle mass on bone. In the in vivo model, four-point cycling bending applied to an immobilized rat tibia induced bone formation
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on the periosteal surface locally (most strongly at the level of the maximal strain) and in a dose-dependent manner [39]. By contrast, bone formation was not stimulated (or very weakly) on the endocortical surface. The effect of direct bending is greatest in the region of maximal bending and similar on the tensile and on the compressive sides [40]. These data point to the direct effect of the mechanical strain on bone. Several cross-sectional studies report a positive association between muscle mass and bone size [41]. However, this design does not allow cause and effect to be distinguished. Such studies do not assess previously acting factors that may have affected bone and muscle in parallel but independently such as genetic factors, nutrition, various mechanical loading or hormonal secretion, mainly androgens and somatotropic axis. Few situations permit an assessment of the intrinsic effect of muscular strain without the confounding effect of the mechanical load. In newborns with congenital neuromuscular disorders, width of long bones of the upper and lower limbs was 26–65% lower than in the control newborns, who had similar body length and similar lengths of bones [42]. Another model is bone geometry in myostatin-deficient mice. Myostatin is expressed in growing vertebrate skeletal muscle and decreases skeletal muscle growth. Myostatin-deficient mice have higher skeletal muscle mass and higher bone mass, mainly in the cortical compartment [43]. In particular, they have higher periosteal perimeter at the sites of muscular attachment (third trochanter, deltoid crest) which points to a local effect of muscular strain on periosteal bone formation [43, 44]. Jointly, the above data strongly suggest the double effect of mechanical load on the periosteal bone formation.
Somatotropic Axis – Growth Hormone, InsulinLike Growth Factor I Hormones of the somatotropic axis, i.e. growth hormone (GH) and insulin-like growth factor I (IGF-I) are strong stimulators not only of the longitudinal but also of radial bone growth. This is supported by clinical and experimental studies. Patients with childhood-onset GH deficiency (but not with the adult-onset GH deficit) and those with GH insensitivity (Laron syndrome) have narrower bones than age-matched controls [45, 46]. Also GH receptor deficient mice had narrower bones in comparison with wild type controls [47, 48]. Exogenous GH is presumed to stimulate periosteal bone formation. In hypophysectomized rats, GH treatment restored periosteal diameter [49] via an intermediary effect of IGF-I [48]. In GH-deficient adults, GH treatment increased bone width at some skeletal sites [50]. However, this increase may be spurious due to the higher subperiosteal mineralization.
Sex Steroid Hormones – Testosterone Sex steroid hormones are determinants of radial bone growth, especially during the pubertal spurt. However, their
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effects depend on the gender, hormone concentration and its mechanism of action. In young rats, gonadectomy resulted in a lower periosteal expansion in males but higher periosteal expansion in females [51]. Moreover, the effect of the sex steroid deficit on radial bone growth depends on the GH status in a site- and gender-specific way. The decrease in periosteal expansion is aggravated by GH deficiency in males (but not in females) at the femur (but not at the lumbar spine) [52]. Testosterone is presumed to stimulate periosteal apposition in boys because pubertal boys have faster radial growth and men have wider bones than age-matched girls and women. As clinical studies do not allow a distinction between the effect of testosterone and that of 17-estradiol on the periosteal apposition, we rely on the experimental studies in androgen-resistant male mice and in mice with androgen receptor knockout (ARKO). However, ARKO mice may have cryptorchism and lower testosterone and 17-estradiol levels. Thus, the lower CSA, lower periosteal perimeter and lower periosteal bone formation in ARKO mice are not sufficient proof of the direct effect of testosterone on the periosteal apposition [53]. Other data show more convincingly that androgens stimulate periosteal apposition through the androgen receptor. In the androgen-resistant (testicular feminized) male rats, femoral shaft width was lower than in control male rats [54]. Testosterone increased periosteal perimeter and periosteal bone formation in the wild-type orchidectomized mice but not in the androgen-resistant ones [55]. After orchidectomy, both dihydrotestosterone (DHT) and the combination of testosterone with an aromatase inhibitor stimulate periosteal bone formation in wild type pubertal male mice but not in ARKO mice [47, 53]. However, in the DHTtreated male mice, bone width was not greater than in the orchidectomized vehicle-treated mice which suggests that the stimulatory effect of androgens on the periosteal expansion is weak.
Sex Steroid Hormones – 17-Estradiol and Estrogen Receptor Alpha Data on the effect of 17-estradiol on periosteal apposition are discordant. It was suggested that 17-estradiol acts on bone through different mechanisms that attain highest intensity for different 17-estradiol levels [56]. During early puberty, slightly increasing 17-estradiol level activates the somatotropic axis, increases IGF-I secretion and accelerates longitudinal growth [57]. Clinical observations suggest that this effect may contribute to an acceleration of radial bone growth in early puberty in both sexes. Bone width is lower in girls and women with anorexia nervosa [58]. The earlier the onset of anorexia nervosa, the greater was the deficit in bone width at the lumbar spine and femoral neck [59]. In a boy with aromatase deficiency, low doses of 17-estradiol stimulated periosteal apposition [60].
The above mechanism probably involves estrogen receptor alpha (ER). In ER-deficient male mice, bones were narrower than in control mice [61]. After orchidectomy, exogenous 17-estradiol increased tibia CSA in wild type mice and in estradiol receptor beta (ER)-deficient but not in ER-deficient mice [62]. The ER-mediated mechanism is probably indirect and involves the stimulation of the secretion of IGF-I [61].
Sex Steroid Hormones – 17-Estradiol and Estrogen Receptor Beta Stimulation of ER may inhibit periosteal bone formation in an age- and site-specific way. This hypothesis is supported by the results of experimental and clinical studies. Inhibition of periosteal apposition may need higher levels of 17-estradiol, which is in agreement with lower affinity of 17-estradiol for ER than for ER [63]. High 17estradiol levels seem to slow, but do not completely block, periosteal apposition. For instance, ER-deficient adult female mice have wider bones than control females [64]. This difference was not found for ER-deficient male mice which have lower 17-estradiol level. Adult (6 months) ERdeficient female mice had wider femoral metaphysis (but not femoral shaft) than wild type age-matched mice [65]. By contrast, aged (13 months) ER-deficient female mice had wider femoral shaft, not distal femoral metaphysis. Growing ovariectomized female rats treated with 17estradiol for 6 weeks had higher 17-estradiol level and lower total CSA of tibia than control, intact, non-treated animals [66]. In growing male rats, short-term treatment with high dose estrogen (4 mg/kg s.c. daily) slowed periosteal bone formation and periosteal expansion [67]. Finally, growing male and female mice expressing human aromatase (AROM) had higher 17-estradiol levels and more slender tibias in comparison with wild type mice [68]. By contrast, no difference in tibia total CSA was found between aged AROM and wild type mice. Similar trends were also observed in clinical studies. In early pubertal girls, bone width increased most rapidly more than one year before menarche (when serum 17-estradiol levels were below the level in adult women), then slowed and stopped after menarche (when serum 17-estradiol has attained its adult levels) [69, 70]. In young men aged 18–20 years, highest concentration of free 17-estradiol was associated with slenderer tibia and radius [71]. The above results are consistent with the hypothesis that a higher 17-estradiol level may limit periosteal expansion. However, most studies did not assess ER type, so the involvement of ER in the observed phenomenon is speculative. Even if it is confirmed, it remains to be elucidated if this is a direct or an indirect effect. ER-deficient mice have higher serum IGFI level [72]. According to the ‘mechanostat’ theory, ER may interact with mechanical load and its activation would limit periosteal bone formation induced by mechanical strain [73].
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Furthermore, other mechanisms of action of 17-estradiol, independent of the above pathways, have also been suggested as potential regulators of the 17-estradiol-dependent periosteal bone formation and changes in bone size [74, 75].
Sex Steroid Hormones – Effect on the Periosteal Expansion in Older Subjects Data on the effect of sex steroids on periosteal bone remodeling in older subjects are limited. In aged male rats, endocortical bone turnover and medullary expansion increased significantly after orchidectomy [76]. By contrast, periosteal bone formation assessed by dynamic histomorphometric parameters decreased and rate of change of tibial CSA did not differ from the controls. It shows that periosteal bone formation fails to adapt to endosteal bone loss in rats and that the sex steroid deficit may contribute to this phenomenon. Clinical studies do not provide convincing data on the role of a sex steroid deficit in the regulation of periosteal apposition in older persons. After the menopause, the periosteal expansion rate decreased at the radius in the OFELY cohort but increased at the tibia in the InCHIANTI cohort [15, 16]. The 17-estradiol level was negatively correlated, albeit weakly, with the rate of periosteal expansion at the distal radius after the menopause [13]. By contrast, in postmenopausal women, serum sex steroids levels were not correlated with CSA of the vertebral body, femoral neck, distal radius and distal tibia [77]. In older men, CSA at the femoral neck, distal radius and distal tibia were weakly negatively correlated with the level of bioavailable testosterone [78]. Thus, the associations between sex steroid levels and bone size in older subjects are weak and inconsistent. In particular, it is not clear if these results reflect the lack of biological association or rather methodological problems concerning the measurements of low sex steroids levels (mainly of their free or bioavailable fractions) and the longitudinal assessment of periosteal expansion (discussed in detail below).
Age-related changes in bone shape Bone Shape – Introductory Remarks Relatively few studies have assessed the determinants and biological importance of bone shape. Bone shape depends partly on bone size, e.g. increase in the frontal width of the femoral neck is not matched by a proportional increase in the anteroposterior diameter [79]. Consequently, smaller femoral necks are more circular, whereas larger ones are more elliptical. Differences in bone shape related to sex or ethnic group have been observed for many bones, e.g. anterior wedging of the vertebral bodies at the thoracic kyphosis is more accentuated in men than in women [80].
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Anteroposterior flattening of the distal femur is more prominent in men than in women [81]. However, these analyses do not always take into account differences in body size and in the upper to lower segment ratio. Several studies have suggested that the shape of the femoral neck is a determinant of the risk of hip fracture and can account for differences in the risk of hip fracture between populations. However, results of the analyses of variability of the femoral neck axis length and of the neck-shaft angle according to sex and ethnic group are inconclusive. For instance, in some studies, men had slightly wider neckshaft angle (which could confer a slightly higher risk of hip fracture) but also greater size and BMC of the proximal femur which has a protective effect [82]. Comparisons of the shape of the proximal femur in elderly Asian, black and Caucasian women provided discordant results.
Bone Shape – Secular Trend and Age-Related Trend Some data also show secular trends in change in bone shape. In more recent populations, a secular trend towards more slender bones (lower width compared with the length) was found for femora and metacarpal bones [83, 84]. Secular changes were also observed in the shape of the proximal femur. A comparison of modern, historic and prehistoric human population samples shows that an increasingly sedentary existence is associated with a significant increase in the neck-shaft angle [85]. Comparison of the femora from the medieval and contemporary men and women shows that modern adults have a longer and more elliptical femoral neck and a greater neck-shaft angle than their medieval counterparts [86]. Interestingly, changes in the shape of bones may occur during much shorter periods of time. In women over 60 years old in the early 1990s, the femoral neck was 7% (P 0.0001) longer but not wider (1%, P 0.49) compared with their age-matched counterparts 40 years before, i.e. in the early 1950s [87]. Overall, these studies show a more fragile bone phenotype in more recent populations. However, in analyses of secular trends, it is difficult to take into account all the confounding factors (famine, lifestyle, etc.). Mechanical strains affect bone shape differently according to the skeletal site, part of the bone or axis of the bone. During walking and running, bending and tensile stresses operate in the sagittal plane stimulating periosteal apposition on the anterior and posterior surfaces. In early pubertal girls followed up for 2 years, periosteal apposition on the anterior and posterior surfaces was more than twice the amount added medially and laterally, which elongated the sagittal axis of the tibia CSA in comparison with the frontal one [88]. Similarly, in the upper limb, mechanical stresses are not uniform and act differently according to the bone axis. In older women, the ulna CSA was greater and more elliptical than in young women [89]. Deformation is greater
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and periosteal apposition increases more in the midshaft. For example, in a prehistoric sample of tibiae and femora of men and women, age-related increase in the external diameter was highest in the midshaft and greater at the tibia in men but at the femur in women [90].
Determinants of Bone Shape Few studies have assessed determinants of bone shape and their conclusions are partly based on speculations. The more rounded cross-sectional shape of bones in older generations was probably related to the vigorous life-long multidirectional mechanical strains [85, 91]. By contrast, current sedentary lifestyle would be associated with unidirectional activities such as walking which induce mechanical strains in a single plane. Their morphological consequence is the elliptical shape of CSA of bones of the lower limbs [79, 86, 88]. It suggests that the most active periosteal bone formation occurs in the plane of the greatest mechanical strain. Experimental data show that myostatin deficient mice have larger deltoid crest at the proximal humerus, an elongated third trochanter and a radius curved longitudinally and more expanded in the anteroposterior direction [44, 92, 93]. This is in agreement with the hypothesis that muscle force shapes bones by acting locally at the sites of tendinous insertions, where muscles ‘pull’ on bone and stimulate periosteal bone formation. By contrast, in the tarsometatarsus of adult roosters submitted to anteroposterior bending during high speed running, periosteal bone formation was greatest on the lateral surfaces, i.e. in the region of the highest strain gradient, and not in the anteroposterior axis, i.e. in the region of the highest strain [94]. These unexpected and counterintuitive results do not explain the clinical observations.
Bone Shape – Summary and Conclusions Overall, data on bone shape are rather limited and their biological and clinical significance is not always clear. Available studies help understand how periosteal expansion depends on the mechanical load and muscular force. Modern people have a more fragile bone phenotype, especially of the femoral neck, in comparison with our more distant ancestors. This trend may contribute to the higher age-specific incidence of hip fracture. However, the potential clinical impact of the studies concerning bone shape is not clear. Differences in the shape of proximal and distal femur in men and women may indicate that prostheses of the hip and knee should be slightly different according to gender. Difference in the anterior wedging of the vertebral bodies suggests that, in men, the diagnostic criteria for vertebral fractures should be more stringent than in women. Although bone shape is one of the determinants of the risk of the cervical hip fracture, the clinical utility of the morphological parameters of the femoral neck for the prediction of the cervical fracture at the individual level is doubtful.
Why do bones grow in width after cessation of the growth in length? Until now, mechanisms of the age-related increase in bone width have not been convincingly explained. However, several hypotheses have been put forward.
Cohort Effect The cohort effect refers to the situation where the observed trends do not reflect underlying biological reality but are artefacts due to sample composition. The cohort effect may be responsible for trends observed in cross-sectional rather than prospective studies. In the cross-sectional studies, true ontogenic change, secular trends and selective survival may provoke spurious results. True ontogenic change is not probable if similar trends are observed in different populations and different epochs. The age-related increase in bone width observed in cross-sectional studies could be explained by a secular trend if more recently born individuals tended to have more slender bones. Indeed, Trotter et al showed a negative partial correlation between the femoral shaft width and the birth year in white men and women after adjustment for age and femur length [84]. However, appropriate investigation of the secular trend of bone width would necessitate a long-term study carried out over several decades and based on a standardized protocol taking into account potential confounders (changes in body height, changes in bones length, physical activity, nutrition etc.). Selective survival refers to a higher mortality of individuals with a particular trait, in this context, narrower bones. In this case, older groups would consist of survivors having wider bones regardless of the periosteal apposition. For instance, bone width is correlated strongly with body height and low body height is an independent indicator of higher risk of death. Thus, selective survival may be a source of error in cross-sectional studies, in which the correlation between bone width and age was not adjusted for body height. Low bone width can reflect a poor robustness of the body, which could be associated with higher mortality. This can be a significant confounder especially in prehistoric populations.
Mechanical Compensation of the Endosteal Bone Loss Periosteal apposition may be a form of mechanical compensation of endosteal bone loss. According to this hypothesis, lower bone mass due to an age-related endosteal bone loss is exposed to higher mechanical strain, which is greater at the outer bone surface, mainly during bending and torsion. This hypothesis is supported by data that the further the mass is placed from the neutral axis, the more it increases the bending strength of a tubular structure. Thus, a smaller
C h a p t e r 1 6 Changes in Bone Size and Geometry with Aging l
quantity of bone deposited on the outer bone surface would offset loss of bending strength provoked by the loss of a greater quantity of bone on the endosteal surface. The hypothesis of mechanical compensation could be valid if periosteal apposition followed endosteal bone loss and were coupled in time with it, if it occurred predominantly in weight-bearing sites and, finally, if it correlated with the preceding endosteal bone loss. Lang et al studied changes in bone mass and geometry of the femoral neck and femoral shaft in the crew of an international space station before, after a long-duration (4–6 months) spaceflight and one year after the mission [95]. During the flight, loss of the cortical bone occurred by thinning of the cortex from the inner margin. During reloading after the flight, an increase in the total bone volume indicates that the increase in the cortical bone volume was determined by deposition of new bone on the outer surface. However, periosteal apposition is continuous from the adolescent–adult transition, i.e. it precedes endosteal bone loss. Postmenopausal acceleration of endosteal bone loss is not followed by a proportional acceleration of periosteal expansion. Endosteal bone loss is higher in women than men (at least in relation to peak BMC), whereas quantity of bone deposited on the outer surface is higher in men than women (at least, in absolute terms). Finally, periosteal apposition is observed in non-weight-bearing bones such as the skull and metacarpals.
Potential for Mechanical Protection and Response Periosteal apposition may represent a minimally expressed potential of bone to face unusual situations, such as fracture repair or altered mechanical loading, independent of prior endosteal bone loss. In the past, this mechanism may have played a selective role in men whose skeleton was exposed to greater mechanical loads and who sustained more fractures. Therefore, this mechanism may partly explain the difference in the bone size and in the rate of periosteal apposition between men and women. Moreover, periosteal apposition covers the outer surface of bone with an envelope which has a different orientation of lamellae than those of Haversian canals. This envelope can stop spreading of microcracks in the cortical bone. Thus, the higher periosteal apposition after unusually high physical load may not only increase bone mass and size and its mechanical resistance, but also inhibit spreading of microcracks that are probably more frequent in bone submitted to higher loads.
Lifelong Reaction to Everyday Mechanical Load Radial growth may result from lifelong periosteal apposition that occurs in reaction to everyday mechanical load and associated muscle function. If so, it should correlate with the magnitude of mechanical load and muscle force. Bone
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width and radial growth are greater in men who have larger muscle mass and are exposed higher everyday mechanical loads. Width of bones of the upper limbs was greatest in ocean rowing Alaskan Aleuts, medium in river rowing populations from Georgia and lowest in the New Mexico agricultural population [96]. The rate of radial growth in the non-weight-bearing sites decreases with age concurrently with a decrease in physical activity and muscle mass [15]. By contrast, an increase in bone size in the weight-bearing sites may reflect the adaptation of decreasing bone mass to the constant or higher body weight [16]. Periosteal apposition is greater in the sites of attachment of large muscles, e.g. in the Mr OS cohort, radial growth was higher at the femoral shaft (site of attachment of the quadriceps and the adductors muscles) than at the femoral neck (only loaded by body weight but no muscle attachment) [17]. The age-related enlargement of the human skull submitted to the strain of muscles participating in mastication is also in keeping with this hypothesis. Thus, this phenomenon may be a low intensity form of the adaptive capacity of bone which becomes significant if the low loads are repeated permanently for decades. A higher CSA of the humerus in the playing arm of tennis players would be a particular form of this mechanism: unusually high mechanical loads concentrated in the period of the highest responsiveness of the periosteum, i.e. during the pubertal spurt.
Neoteny Another hypothesis interprets continuous radial growth as a form of neoteny, i.e. delayed maturation linked to retarded differentiation which results in a retention of juvenile physical characteristics into maturity in adult individuals [97]. Thus, continuous periosteal apposition would represent prolonged (retarded?) maturation of the human skeleton. The concept of neoteny is a valuable tool in developmental biology and comparative studies. However, it does not explain the potential function of continuous radial growth, it rather suggests that this growth is without biological significance, although it does not exclude the possibility that individuals who have larger bones may benefit in some way from this characteristic. It is not clear, how to interpret the mechanical load-induced periosteal apposition from the point of view of neoteny. Local, mechanically induced radial growth may argue against neoteny. However, the age-related slowdown of periosteal apposition and, especially, attenuation of the responsiveness of bone to the mechanical stimulus is in keeping with this hypothesis. The above hypotheses are not mutually exclusive. An increase in periosteal apposition may occur after an unusually high mechanical load in normal bone and after a normal load a lowered bone mass and volume which remained after bone loss. In the early history of humanity, a low potential to adapt to mechanical load and to repair fractures may have led to disability and death in subjects with narrower bones and low capacity of radial growth, especially in men.
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Methodological limitations of the studies on the age-related changes in bone size Age-related changes in bone size and shape in humans have been assessed using several methods: measurements of bone specimens, measurements on radiographs, calculations from scans of single-photon absorptiometry, single X-ray absorptiometry and dual X-ray absorptiometry (DXA), quantitative computed tomography (QCT), high resolution peripheral QCT (HR-pQCT) and magnetic resonance imaging (MRI). Every method has its specific limitations and may explain why they provide slightly different (but perhaps complementary) data. They have various resolutions ranging from 80 m for HR-pQCT to about 1 mm for DXA. Bone diameter is measured on one line (e.g. on the radiographs) or is averaged from a various numbers of lines or slices (about 20 for DXA, 110 for HR-pQCT). Some methods assess bone diameter of the projected area of bone in a given presentation (radiographs, DXA) or the real CSA of bone (QCT, HR-pQCT, MRI). Every method has its threshold of mineral saturation which is used to detect the edges of cortical bone (subjective visual assessment on a radiograph, 0.350 g/cm2 on DXA, 0.7–1.2 g/cm3 for QCT). The principal limitation of these methods is that none of them has been established to assess accurately age-related changes in bone size and their accuracy and precision are poor in comparison with the real age-related changes in bone size observed in adults after growth completion. Results are also influenced by the effect of partial surface of a pixel (e.g. DXA) or partial volume of a voxel (e.g. QCT, HR-pQCT). From the methodological point of view, three study designs can be distinguished: retrospective, cross-sectional and prospective (longitudinal). The term ‘retrospective’ refers to studies based on measurements of archeological bone specimens or measurements carried out on radiographs made for diagnostic purpose and archived in departments of radiology. These analyses are relatively rapid, performed in homogeneous populations (archeological site, catchment area of a hospital) but data on the investigated subjects are scarce (especially in the prehistoric samples) and radiographs are not performed using standardized protocols. Thus, few analyses are feasible and conclusions should be drawn cautiously, especially conclusions concerning comparisons of different samples. Cross-sectional studies are performed in subjects of different ages recruited during a limited period of time in selected centers. These analyses are relatively rapid (limited by the duration of recruitment of the cohort) and may be performed in well-defined populations (geographical region, ethnicity). Measurements of bone size are performed using standardized protocols and other data are obtained using standard procedures (questionnaire, biological measurements). However, the principal point is definition of the region of interest (ROI) which should be ‘the same’ in all subjects. Different methods use different
a lgorithms to define ROI. Some algorithms use constant distances between the anatomical landmarks and the limit of ROI. With these methods, ROI covers different anatomical parts of bone in different persons. For instance, at the distal radius, ROI will be more distal, wider and more trabecular for taller persons but more proximal, narrower and more cortical for shorter (and most often older) persons. Consequently, the correlation of bone size with other parameters will be overestimated (e.g. with height) or underestimated (e.g. with age). In cross-sectional studies, data on bone size are obtained in subjects from different generations. More recent generations are taller and have better nutritional status. However, adjustment for body height does not take into account the variability of the length of different body segments (trunk versus lower limbs) and of individual bones (femur versus tibia). Furthermore, such adjustment overestimates agerelated increases in bone width because of the age-related loss in height. Older generations had higher physical activity, especially at work, and started working early, when the skeleton is very sensitive to mechanical load. Thus, in cross-sectional studies, the effect of early onset heavy physical activity at work is greater at the distal forearm, whereas age-related widening of bones of the lower limbs may depend on an increase in body mass index. In the elderly, the degree of mineralization of the subperiosteal layer may decrease and fall below the detection limit of the device, which underestimates the bone width in the elderly and, consequently, underestimates the age-related radial growth. Finally, the trend calculated in cross-sectional studies is an average trend over the investigated age range whereas, in fact, the rate of radial growth may vary according to the age group. Prospective studies have advantages similar to the crosssectional studies and, in addition, advantages over the cross-sectional studies because they obviate most of their limitations. However, the principal limitation of prospective studies is the poor resolution of the available methods in comparison with the real aging-related changes in bone size observed at the individual level. Therefore, prospective studies necessitate long follow up in large groups of subjects with several measurements per person obtained using methods where the instantaneous bone size is assessed as average width or CSA from several slices (20 for DXA, 110 for HR-pQCT). This approach can diminish the effect of the random error of measurement. However, a potential source of bias is that the oldest subjects and those who are sicker will be lost early to follow up and it is not known if they have the same rate of radial growth as the healthier and younger subjects who will be followed for a longer period. Finally, there are two limitations that are common for all types of studies regardless of the method of measurement and of the design. The first is the aforementioned limited extrapolation of the results from one skeletal site onto another. The second is the reproducibility of the region of interest. However, in cross-sectional studies, the principal point is to measure a comparable fragment of bone in all the individuals,
C h a p t e r 1 6 Changes in Bone Size and Geometry with Aging l
e.g. distal one-third of the radius. By contrast, a constant absolute distance from the extremity of the bone may correspond to morphologically different parts of the bone. For instance, the constant distance from the distal extremity of the radius corresponds to a more distal, wider and more trabecular site in a long bone and to a more proximal, narrower and more cortical site in a shorter bone. By contrast, in the longitudinal studies, the principal point is to measure the same fragment of bone in all the measurements in a given subject.
General conclusions Many studies carried out over recent years have assessed the age-related changes in bone size and shape. However, we have to recognize the methodological limitations of these studies. Therefore, better data are available concerning the rapid radial growth observed in children and adolescents, whereas data on the aging-related changes in bone size and shape are not conclusive. We need more studies concerning degree of the periosteal expansion according to the sex, age range and the skeletal site and, furthermore, studies on the determinants of the aging-related periosteal expansion and its clinical significance.
Acknowledgments I thank Professor Ego Seeman, University of Melbourne, for careful reading of the manuscript and helpful comments.
References 1. S.M. Garn, The course of bone gain and the phases of bone loss, Orthop. Clin. N. Am. 3 (1972) 503–520. 2. P.S. Venkatamaran, J.C. Duke, Bone mineral content of healthy, full-term neonates. Effect of race, gender and maternal cigarette smoking, Am. J. Dis. Child. 145 (1991) 1310–1312. 3. M.M. Maresh, Bone, muscle and fat measurements. Longitudinal measurements of the bone, muscle and fat widths from roentgenograms of the extremities during the first six years of life, Pediatrics 28 (1961) 971–984. 4. T. Sugimoto, M. Nishino, T. Tsunerari, et al., Radial bone mineral content of normal Japanese infants and prepubertal children: influence of age, sex and body size, Bone Miner. 24 (1994) 189–200. 5. C.M. Neu, F. Manz, F. Rauch, A. Merkel, E. Schoenau, Bone densities and bone size at the distal radius in healthy children and adolescents: a study using peripheral quantitative computed tomography, Bone 28 (2001) 227–232. 6. C.M. Neu, F. Rauch, F. Manz, E. Schoenau, Modeling of crosssectional bone size, mass and geometry at the proximal radius: a study of normal bone development using peripheral quantitative computed tomography, Osteoporos. Int. 12 (2001) 538–547. 7. S.A. Kontulainen, H.M. Macdonald, K.M. Khan, H.A. McKay, Examining bone surfaces across puberty: a 20-month pQCT trial, J. Bone Miner. Res. 20 (2005) 1202–1207.
203
8. J.W. Nieves, C. Formica, J. Ruffing, et al., Males have larger skeletal size and bone mass than females, despite comparable body size, J. Bone Miner. Res. 20 (2005) 529–535. 9. T.J. Beck, A.C. Looker, C.B. Ruff, H. Sievänen, H.W. Wahner, Structural trends in the aging femoral neck and femoral shaft: analysis of the Third National Health and Nutrition Examination Survey dual-energy X-ray absorptiometry data, J. Bone Miner. Res. 15 (2000) 2297–2304. 10. S.M. Garn, T.V. Sullivan, S.A. Decker, F.A. Larkin, V.M. Hawthorne, Continuing bone expansion and increasing bone loss over two-decade period in men and women from a total community sample, Am. J. Hum. Biol. 4 (1992) 57–67. 11. B.L. Riggs, L.J. Melton III, R.A. Robb, et al., Populationbased study of age and sex differences in bone volumetric density, size, geometry, and structure at different skeletal sites, J. Bone Miner. Res. 19 (2004) 945–954. 12. P. Szulc, F. Marchand, F. Duboeuf, P.D. Delmas, Crosssectional assessment of age-related bone loss in men: the MINOS study, Bone 26 (2000) 123–129. 13. H.G. Ahlborg, O. Johnell, C.H. Turner, G. Rannevik, M.K. Karlsson, Bone loss and bone size after menopause, N. Engl. J. Med. 349 (2003) 327–334. 14. P. Szulc, P.D. Delmas, Bone loss in elderly men: increased endosteal bone loss and stable periosteal apposition. The prospective MINOS study, Osteoporos. Int. 18 (2007) 495–503. 15. P. Szulc, E. Seeman, F. Duboeuf, E. Sornay-Rendu, P.D. Delmas, Bone fragility: failure of periosteal apposition to compensate for increased endocortical resorption in postmenopausal women, J. Bone Miner. Res. 21 (2006) 1856–1863. 16. F. Lauretani, S. Bandinelli, M.E. Griswold, et al., Longitudinal changes in BMD and bone geometry in a population-based study, J. Bone Miner. Res. 23 (2008) 400–408. 17. M.L. Marshall, T.F. Lang, L.C. Lambert, J.M. Zmuda, K.E. Ensrud, E.S. Orwoll, Dimensions and volumetric BMD of the proximal femur and their relation to age among older US men, J. Bone Miner. Res. 21 (2006) 1197–1206. 18. S. Kaptoge, N. Dalzell, N. Loveridge, T.J. Beck, K.T. Khaw, J. Reeve, Effects of gender, anthropometric variables, and aging on the evolution of the hip strength in men and women aged over 65, Bone 32 (2003) 561–570. 19. S. Demissie, J. Dupuis, L.A. Cupples, T.J. Beck, D.P. Kiel, D. Karasik, Proximal hip geometry is linked to several chromosomal regions: genome-wide linkage results from the Framingham Osteoporosis Study, Bone 40 (2007) 743–750. 20. D.P. Kiel, S. Demissie, J. Dupuis, K.L. Lunetta, J.M. Murabito, D. Karasik, Genome-wide association with bone mass and geometry in the Framingham Heart Study, BMC Med. Gen. 8 (Suppl. 1) (2007) S14. 21. W.X. Jian, J.R. Long, H.W. Deng, High heritability of bone size at the hip and spine in Chinese, J. Human. Genet. 49 (2004) 87–91. 22. Y. Fang, J.B. van Meurs, F. Rivadeneira, et al., Vitamin D receptor gene haplotype is associated with body height and bone size, J. Clin. Endocrinol. Metab. 92 (2007) 1491–1501. 23. S.L. Ferrari, S. Deutsch, U. Choudhury, et al., Polymorphisms in the low-density lipoprotein receptor-related protein 5 (LRP5) gene are associated with variation in vertebral bone mass, vertebral bone size, and stature in whites, Am. J. Hum. Genet. 74 (2004) 866–875. 24. K.A. Ward, D.K. Roy, S.R. Pye, et al., Forearm bone geometry and mineral content in UK women of European and South-Asian origin, Bone 41 (2007) 117–121.
204
Osteoporosis in Men
25. X.F. Wang, Y. Duan, T.J. Beck, E. Seeman, Varying contributions of growth and ageing to racial and sex differences in femoral neck structure and strength in old age, Bone 36 (2005) 978–986. 26. J.M. Tanner, T. Hayashi, M.A. Preece, N. Cameron, Increase in length of leg relative to trunk in Japanese children and adults from 1957 to 1977: comparison with British and with Japanese Americans, Ann. Hum. Biol. 9 (1982) 411–423. 27. T.M. Theobald, J.A. Cauley, C.C. Glüer, C.H. Bunker, F.A.M. Ukoli, H.K. Genant, Black-white differences in hip geometry, Osteoporos. Int. 8 (1998) 61–67. 28. L.M. Marshall, J.M. Zmuda, B.K.S. Chan, et al., Race and ethnic variation in proximal femur structure and BMD among older men, J. Bone Miner. Res. 23 (2008) 121–130. 29. D.A. Nelson, J.M. Pettifor, D.A. Barondess, D.D. Cody, K. Uusi-Rasi, T.J. Beck, Comparison of cross-sectional geometry of the proximal femur in white and black women from Detroit and Johannesburg, J. Bone Miner. Res. 19 (2004) 560–565. 30. Y. Duan, X.F. Wang, A. Evans, E. Seeman, Structural and biomechanical basis of racial and sex differences in vertebral fragility in Chinese and Caucasians, Bone 36 (2005) 987–998. 31. X.F. Wang, Y. Duan, T.J. Beck, E. Seeman, Varying contributions of growth and ageing to racial and sex differences in femoral neck structure and strength in old age, Bone 36 (2005) 978–986. 32. C. Hoppe, C. Molgaard, K. Fleischer Michaelsen, Bone size and bone mass in 10-year-old Danish children: effect of current diet, Osteporos. Int. 11 (2000) 1024–1030. 33. S. Bourrin, P. Ammann, J.P. Bonjour, R. Rizzoli, Dietary protein restriction lowers plasma insulin-like growth factor I (IGF-I), impairs cortical bone formation, and induces osteoblastic resistance to IGF-I in adult female rats, Endocirnology 141 (2000) 3149–3155. 34. S. Kontulainen, H. Sievänen, P. Kannus, M. Pasanen, I. Vuori, Effect of long-term impact-loading on mass, size, and estimated strength of humerus and radius of female racquet-sports players: a peripheral quantitative computed tomography study between young and old starters and controls, J. Bone Miner. Res. 18 (2003) 352–359. 35. B.N. Epker, H.M. Frost, Periosteal appositional bone growth from age two to age seventy in man. A tetracycline evaluation, Anat. Rec. 154 (1966) 573–577. 36. R.M. Daly, S.L. Bass, Lifetime sport and leisure activity participation is associated with greater bone size, quality and strength in older men, Osteoporos. Int. 17 (2006) 1258–1267. 37. M. Lorentzon, D. Mellström, C. Ohlsson, Association of amount of physical activity with cortical bone size and trabecular volumetric BMD in young adult men: the GOOD study, J. Bone Miner. Res. 20 (2005) 1936–1943. 38. M.A. Petit, T.J. Beck, J. Shults, B.S. Zemel, B.J. Foster, M.B. Leonard, Proximal femur bone geometry is appropriately adapted to lean mass in overweight children and adolescents, Bone 36 (2005) 568–576. 39. J.M. LaMothe, N.H. Hamilton, R.F. Zernicke, Strain rate influences periosteal adaptation in mature bone, Med. Eng. Phys. 27 (2005) 277–284. 40. D.M. Raab-Cullen, M.P. Akhter, D.B. Kimmel, R.R. Recker, Periosteal bone formation stimulated by externally induced bending strains, J. Bone Miner. Res. 9 (1994) 1143–1152. 41. P. Szulc, T.J. Beck, F. Marchand, P.D. Delmas, Low skeletal muscle mass is associated with poor structural parameters
42.
43.
44.
45.
46.
47.
48.
49.
50.
51.
52.
53.
54.
55.
56.
57.
of bone and impaired balance in elderly men – the MINOS study, J. Bone Miner. Res. 20 (2005) 721–729. J.I. Rodríguez, J. Palacios, A. García-Alix, I. Pastor, R. Paniagua, Effects of immobilization on fetal bone development. A morphometric study in newborns with congenital neuromuscular diseases with intrauterine onset, Calcif. Tissue Int. 43 (1988) 335–339. M.W. Hamrick, Increased bone mineral density in the femora of GDF8 knockout mice, Anat. Rec. A Discov. Mol. Cell Evol. Biol. 272 (2003) 388–391. M.W. Hamrick, A.C. McPherron, C.O. Lovejoy, Bone mineral content and density in the humerus of adult myostatindeficient mice, Calcif. Tissue Int. 71 (2002) 63–68. R.D. Murray, J.E. Adams, S.M. Shalet, A densitometric and morphometric analysis of the skeleton in adults with varying degrees of growth hormone deficiency, J. Clin. Endocrinol. Metab. 91 (2006) 432–438. L. Kornreich, O. Konen, M. Schwarz, et al., Abnormalities of the axial and proximal appendicular skeleton in adults with Laron syndrome, Skeletal. Radiol. 37 (2008) 153–160. K. Venken, S. Movérare-Skrtic, J.J. Kopchick, et al., Impact of androgens, growth hormone, and IGF-I on bone and muscle in male mice during puberty, J. Bone Miner. Res. 22 (2007) 72–82. N.A. Sims, P. Clément-Lacroix, F. Da Ponte, et al., Bone homeostasis in growth hormone receptor-null mice is restored by IGF-I but independent of Stat5, J. Clin. Invest. 106 (2000) 1095–1103. M.M. Chen, J.K. Yeh, J.F. Aloia, Histologic evidence: growth hormone completely prevents reduction in cortical bone gain and partially prevents cancellous osteopenia in the tibia of hypophysectomised rats, Anat. Rec. 249 (1997) 163–172. G. Johansson, T. Rosén, I. Bosaeus, L. Sjöström, B.A. Bengtsson, Two years of growth hormone (GH) treatment increases bone mineral content and density in hypopituitary patients with adult-onset GH deficiency, J. Clin. Endocrinol. Metab. 81 (1996) 2865–2873. B.T. Kim, L. Mosekilde, Y. Duan, et al., The structural and hormonal basis of sex differences in peak appendicular bone strength in rats, J. Bone Miner. Res. 18 (2003) 150–155. X.Z. Zhang, D.N. Kalu, B. Erbas, J.L. Hopper, E. Seeman, The effects of gonadectomy on bone size, mass, and volumetric density in growing rats are gender-, site-, and growth hormonespecific, J. Bone Miner. Res. 14 (1999) 802–809. K. Venken, K. De Gendt, S. Boonen, et al., Relative impact of androgen and estrogen receptor activation in the effects of androgens on trabecular and cortical bone in growing male mice: a study in the androgen receptor knockout mouse model, J. Bone Miner. Res. 21 (2006) 576–585. D. Vanderschueren, E. Van Herck, A.M. Suiker, et al., Bone and mineral metabolism in the androgen-resistant (testicular feminized) male rat, J. Bone Miner. Res. 8 (1993) 801–809. L. Vandenput, J.V. Swinnen, S. Boonen, et al., Role of the androgen receptor in skeletal homeostasis: the androgenresistant testicular feminized male mouse model, J Bone Miner Res 19 (2004) 1462–1470. D. Vanderschueren, K. Venken, J. Ophoff, R. Bouillon, S. Boonen, Sex steroids and the periosteum – reconsidering the roles of androgens and estrogens in periosteal expansion, J. Clin. Endocrinol. Metab. 91 (2006) 378–382. K.O. Klein, P.M. Martha Jr, R.M. Blizzard, T. Herbst, A.D. Rogol, A longitudinal assessment of hormonal and physical
C h a p t e r 1 6 Changes in Bone Size and Geometry with Aging l
58.
59.
60.
61.
62.
63.
64.
65.
66.
67.
68.
69.
70.
71.
72.
alterations during normal puberty in boys. II. Estrogen levels as determined by an ultrasensitive bioassay, J. Clin. Endocrinol. Metab. 81 (1996) 3203–3207. M.K. Karlsson, S.J. Weigall, Y. Duan, E. Seeman, Bone size and volumetric density in women with anorexia nervosa receiving estrogen replacement therapy and in women recovered from anorexia nervosa, J. Clin. Endocrinol. Metab. 85 (2000) 3177–3182. E. Seeman, M.K. Karlsson, Y. Duan, On exposure to anorexia nervosa, the temporal variation in axial and appendicular skeletal development predisposes to site-specific deficits in bone size and density: a cross-sectional study, J. Bone Miner. Res. 15 (2000) 2259–2265. R. Bouillon, M. Bex, D. Vanderschueren, S. Boonen, Estrogens are essential for male pubertal periosteal bone expansion, J. Clin. Endocrinol. Metab. 89 (2004) 6025–6029. O. Vidal, M.K. Lindberg, K. Hollberg, et al., Estrogen receptor specificity in the regulation of skeletal growth and maturation in male mice, Proc. Natl. Acad. Sci. USA 97 (2000) 5474–5479. M.K. Lindberg, S. Movérare, S. Skrtic, et al., Two different pathways for the maintenance of trabecular bone in adult male mice, J. Bone Miner. Res. 17 (2002) 555–562. G.G. Kuiper, B. Carlsson, K. Grandien, et al., Comparison of the ligand binding specificity and transcript tissue distribution of estrogen receptors alpha and beta, Endocrinology 138 (1997) 863–870. S.H. Windahl, O. Vidal, G. Andersson, J.A. Gustafsson, C. Ohlsson, Increased cortical bone mineral content but unchanged trabecular bone mineral density in female ERbeta(-/-) mice, J. Clin. Invest. 104 (1999) 895–901. H.Z. Ke, T.A. Brown, H. Qi, et al., The role of estrogen receptor-beta, in the early age-related bone gain and later agerelated bone loss in female mice, J. Musculoskelet Neuron. Interact. 2 (2002) 479–488. J.K. Yeh, M.M. Chen, J.F. Aloia, Effects of 17 beta-estradiol administration on cortical and cancellous bone of ovariectomized rats with and without hypophysectomy, Bone 20 (1997) 413–420. G.K. Wakley, G.L. Evans, R.T. Turner, Short-term effects of high dose estrogen on tibiae of growing male rats, Calcif. Tissue Int. 60 (1997) 37–42. Z. Peng, X. Li, S. Mäkelä, H.K. Väänänen, M. Poutanen, Skeletal changes in transgenic male mice expressing human cytochrome p450 aromatase, J. Bone Miner. Res. 19 (2004) 1320–1328. Q. Wang, M. Alén, P.H. Nicholson, et al., Differential effects of sex hormones on peri- and endocortical bone surfaces in pubertal girls, J. Clin. Endocrinol. Metab. 91 (2006) 277–282. Q. Wang, M. Alén, P. Nicholson, et al., Growth patterns at distal radius and tibial shaft in pubertal girls: a 2-year longitudinal study, J. Bone Miner. Res. 20 (2005) 954–961. M. Lorentzon, C. Swanson, N. Andersson, D. Mellström, C. Ohlsson, Free testosterone is a positive, whereas free estradiol is a negative, predictor of cortical bone size in young Swedish men: the GOOD study, J. Bone Miner. Res. 20 (2005) 1334–1341. M.K. Lindberg, S.L. Alatalo, J.M. Halleen, S. Mohan, J.A. Gustafsson, C. Ohlsson, Estrogen receptor specificity in the regulation of the skeleton in female mice, J. Endocrinol. 171 (2001) 229–236.
205
73. L.K. Saxon, C.H. Turner, Estrogen receptor beta: the antimechanostat?, Bone 36 (2005) 185–192. 74. F.A. Syed, U.I. Mödder, D.G. Fraser, et al., Skeletal effects of estrogen are mediated by opposing actions of classical and nonclassical estrogen receptor pathways, J. Bone Miner. Res. 20 (2005) 1992–2001. 75. M.K. Lindberg, Z. Weihua, N. Andersson, et al., Estrogen receptor specificity for the effects of estrogen in ovariectomized mice, J. Endocrinol. 174 (2002) 167–178. 76. N.S. Reim, B. Breig, K. Stahr, et al., Cortical bone loss in androgen-deficient aged male rats is mainly caused by increased endocortical bone remodeling, J. Bone Miner. Res. 23 (2008) 694–704. 77. S. Khosla, B.L. Riggs, R.A. Robb, et al., Relationship of volumetric bone density and structural parameters at different skeletal sites to sex steroid levels in women, J. Clin. Endocrinol. Metab. 90 (2005) 5096–5103. 78. S. Khosla, L.J. Melton 3rd, R.A. Robb, et al., Relationship of volumetric BMD and structural parameters at different skeletal sites to sex steroid levels in men, J. Bone Miner. Res. 20 (2005) 730–740. 79. R.M. Zebaze, A. Jones, F. Welsh, M. Knackstedt, E. Seeman, Femoral neck shape and the spatial distribution of its mineral mass varies with its size: clinical and biomechanical implications, Bone 37 (2005) 243–252. 80. T.W. O’Neill, J. Varlow, D. Felsenberg, et al., Variation in vertebral height ratios in population studies. European Vertebral Osteoporosis Study Group, J. Bone Miner. Res. 9 (1994) 1895–1907. 81. J.H. Lonner, J.G. Jasko, B.S. Thomas, Anthropometric differences between the distal femora of men and women, Clin. Orhtop. Rel. Res. 466 (2008) 2724–2729. 82. S.P. Tuck, M.S. Pearce, D.J. Rawlings, F.N. Birrell, L. Parker, R.M. Francis, Differences in bone mineral density and geometry in men and women: the Newcastle Thousand Families Study at 50 years old, Br. J. Radiol. 78 (2005) 493–498. 83. L. Kalichman, I. Malkin, M.J. Seibel, E. Kobyliansky, G. Livshits, Age-related changes and secular trends in hand bone size, Homo 59 (2008) 301–315. 84. M. Trotter, R.R. Peterson, R. Wette, The secular trend in the diameter of the femur of American whites and Negroes, Am. J. Phys. Anthrop. 28 (1968) 65–73. 85. J.Y. Anderson, E. Trinkaus, Patterns of sexual, bilateral and interpopulational variation in human femoral neck-shaft angles, J. Anat. 192 (1998) 279–285. 86. H. Sievänen, L. Jozsa, I. Pap, et al., Fragile external phenotype of modern human proximal femur in comparison with medieval bone, J. Bone Miner. Res. 22 (2007) 537–543. 87. I.R. Reid, K. Chin, M.C. Evans, J.G. Jones, Relation between increase in length of hip axis in older women between 1950s and 1990s and increase in age specific rates of hip fracture, Br. Med. J. 309 (1994) 508–509. 88. Q. Wang, S. Cheng, M. Alén, E. Seeman, Bone’s structural diversity in adult females is established before puberty, J. Clin. Endocrinol. Metab. (2009) 94 (2009) 1556–1561. 89. M.L. Bouxsein, K.H. Myburgh, M.C.H. van der Meulen, E. Lindenberger, R. Marcus, Age-related differences in crosssectional geometry of the forearm bones in healthy women, Calcif. Tissue Int. 54 (1994) 113–118.
206
Osteoporosis in Men
90. C.B. Ruff, WC. Hayes, Subperiosteal expansion and cortical remodelling of the human femur and tibia with aging, Science 217 (1982) 945–948. 91. D.J. Wescott, Effect of mobility on femur midshaft external shape and robusticity, Am. J. Phys. Anthropol. 130 (2006) 201–213. 92. M.W. Hamrick, T. Samaddar, C. Pennington, J. McCormick, Increased muscle mass with myostatin deficiency improves gains in bone strength with exercise, J. Bone Miner. Res. 21 (2006) 477–483. 93. M.W. Hamrick, A.C. McPherron, C.O. Lovejoy, J. Hudson, Femoral morphology and cross-sectional geometry of adult myostatin-deficient mice, Bone 27 (2000) 343–349.
94. S. Judex, T.S. Gross, RF. Zernicke, Strain gradients correlate with site of exercise-induced bone-forming surfaces in the adult skeleton, J. Bone Miner. Res. 12 (1997) 1737–1745. 95. T.F. Lang, A.D. Leblanc, H.J. Evans, Y. Liu, Adaptation of the proximal femur to skeletal reloading after long-duration spaceflight, J. Bone Miner. Res. 21 (2006) 1224–1230. 96. E. Weiss, Effects of rowing on humeral strength, Am. J. Phys. Anthropol. 121 (2003) 293–302. 97. L. Vinicius, M. Mirazon Lahr, Morphometric heterochrony and the evolution of growth, Evolution 57 (2003) 2459–2468.
Chapter
17
Aging and Bone Loss Steven Boonen1,2, Dirk Vanderschueren1, Filip Callewaert1 and Patrick Haentjens3 1
Center for Musculoskeletal Research, Leuven University Department of Experimental Medicine, Katholieke Universiteit Leuven, Leuven, Belgium 2 Division of Geriatric Medicine, Leuven University Hospital Department of Internal Medicine, Katholieke Universiteit Leuven, Leuven, Belgium 3 Center for Outcomes Research, University Hospital Brussels, Vrije Universiteit Brussel, Brussels, Belgium
Introduction
Large, population samples show a comparable change in bone health in men with aging. A comparison of two cohorts from North America (the Canadian Multicentre Osteoporosis Study [CaMos] and the United States National Health and Nutrition Examination Survey [NHANES] III study) showed similar decreases in BMD in men with aging, with an increased rate of decline occurring after age 40–50 years (Figure 17.2) [2]. Differences between the two cohorts were small and not significant.
While data on the effects of aging on bone loss in women are well known, many healthcare providers and patients are less familiar with the prevalence and impact of bone changes in older males. Understanding expected bone health changes and factors that predict accelerated bone loss is essential to designing preventive health maintenance strategies for men and women. This chapter will review the epidemiology of bone loss with aging in men, including definitions of abnormal bone density and other methods for assessing bone changes with aging. Factors affecting bone loss in men, including ethnic factors, weight and vitamin intake, will also be reviewed, as these may provide important markers when assessing male osteoporosis risk in the clinic. Practical approaches to maximize osteoporosis screening in men are also described.
Quantifying bone loss in men Fully understanding the effects of aging on bone health in men requires detailed knowledge of normal BMD and the effects of unique study populations on expected normative data. Normative data for many male groups are lacking from the literature. Thus, the selection of reference values against which data are compared to determine extent of bone loss is controversial. Consequently, recommendations for criteria of normal and abnormal BMD in men and selection of standards for use in research studies often vary. A broad understanding of the controversial nature of BMD values in men is essential to interpret effectively patient results in a clinical setting, as well as when interpreting clinical trial data. Supplemental measures of bone loss are important to quantify more fully important changes in bone occurring in men with aging.
Understanding bone loss with aging in men Bone density declines in aging men throughout their adult years. Studies consistently show a linear decline in many bone locations with age in male patients and population samples. A cross-sectional study evaluated 739 Portuguese primary care patients 20–82 years old without secondary causes of osteoporosis or concomitant use of medications known to affect bone metabolism [1]. Forearm bone mineral density (BMD) decreased linearly and significantly with age (P 0.001, Figure 17.1). The prevalence of osteoporosis, defined as forearm BMD 2.5 standard deviations below the young male reference, was 1.9% in men ages 40–49 years and 18.6% after age 70. Osteoporosis in Men
Defining Normal and Abnormal BMD in Men The World Health Organization (WHO) diagnostic criteria established for postmenopausal women is often used for the diagnosis of osteoporosis in men [3]. Recently, Kanis and colleagues reviewed available literature on the diagnosis of 207
Copyright 2009, 2010 Elsevier, Inc. All rights of reproduction in any form reserved.
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Osteoporosis in Men
Mean BMD (g/cm2)
0.6 0.56
0.54
0.5
0.53
0.52 0.49
0.4
20 to 39
40 to 49
50 to 59
60 to 69
70 and older
Years
Mean BMD (g/cm2)
Figure 17.1 Changes in forearm BMD with age. (Based on Lucas et al 2008 [1]).
1 0.9 0.8
0.93 0.91
0.89 0.89
0.7 0.6
20 to 29
30 to 39
0.84 0.83
40 to 49
0.81
0.79
0.81
0.81
50 to 59
60 to 69
0.75 0.77 70 to 79
0.7 0.72 80 and older
Years CaMos
NHANES III
Figure 17.2 Mean femoral neck BMD. (Based on Tenenhouse et al 2000 [2]).
osteoporosis in men and women and proposed using femoral neck BMD determined using dual-energy x-ray absorptiometry (DXA) as the standard, using the reference range from NHANES III for women ages 20–29 years [4]. A femoral neck 2.5 SD or more below the average for young adult women was recommended as the preferred reference for the diagnosis of abnormal BMD in men (Table 17.1). The International Osteoporosis Foundation has likewise recommended using a young healthy female reference for determining male osteoporosis, as this provides comparable vertebral and hip fracture risk to that seen in women using the same cut-off values [5]. Selecting an appropriate reference population is essential to defining osteoporosis in men. As expected, the prevalence of osteopenia and osteoporosis in men will vary, depending on the reference population utilized [6]. Table 17.2 shows the prevalence of BMD loss based on a comparison against female and male reference populations using data from a British study and the United States NHANES III data [6]. The number of men defined as having osteoporosis or osteopenia varied substantially, depending on the reference population used. Due to these types of differences, the International Society for Clinical Densitometry recommends using a male normative database for determining osteoporosis in men [7]. Studies evaluating BMD in men suggest that: using male versus female reference standards will result in differences in the identification of osteoporosis in men
l
Table 17.1 Proposed diagnostic criteria for bone health in men 50 years old Bone health category
T-score*
Normal
1 SD
Osteopenia Osteoporosis
1 to 2.5 SD 2.5 SD
* Based on young female reference from NHANES III; Data from Kanis et al 2008 [4]
comparable risk for fractures in men is achieved by using female reference standards for men most clinicians and researchers support using normal young female reference values for determining T-scores in men.
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Screening Men for Important Bone Loss The American College of Preventive Medicine recommends screening men 70 years old for bone loss [8]. Osteoporosis screening tools have typically been evaluated in women. The Osteoporosis Self-Assessment Screening Tool (OST) is a simple tool that has been validated in both men and women [8]. The OST is calculated by considering risk due to age and weight, with no requirement for BMD testing: OST scoring: 0.2 (body weight in kg age in years) scores 2 predict osteoporosis.
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209
l
Table 17.2 Comparison of prevalence of osteopenia and osteoporosis (%), based on female or male reference populations British cohort
NHANES III
Female reference Male reference Female reference Male reference Femoral neck Osteopenia Osteoporosis Trochanter Osteopenia Osteoporosis
30.1 1.2
47 2.7
35.6 4.4
52.7 7.3
9.7 0.3
21.0 0.4
16.2 1.6
27.7 2.5
Data from Holt et al 2002 [6]
Table 17.3 MOST scoring system
Prevalence of osteoporosis
80 70
Weight (kg)
60
106 95, 106 86, 95 77, 86 77
50 40 30 20 10 0
QUI
24/-1 to 3/≤-2 A Low risk
70
0
1
2
3
4
65, 70 60, 65 55, 60 55
1 2 3 4
2 3 4 5
3 4 5 6
4 5 6 7
5 6 7 8
From Lynn et al 2005 [10]
23/-2 to 2/≤-3 22/-3 to 1/≤-4 B C OST osteoporosis Moderate risk
High risk
Figure 17.3 Prevalence of osteoporosis based on OST risk score (from Adler et al 2003 [9]). (A) Score 3 denoted high-risk in a male population with a mean age of 64 years; (B) score 2 identified high risk in older men; (C) score 1 showed high risk in Caucasian women.
Recently, the performance of screening for bone loss in men using OST, MOST, QUI and body weight were evaluated using data from ambulatory men 65 years old participating in the Osteoporotic Fractures in Men (Mr OS) study (n 4658 Caucasian and 1914 Chinese men) [11]: MOST was calculated as (0.2 weight in kg) (0.1 QUI) suggested cut-off scores in Caucasian males were 2 for OST and 26 for MOST suggested cut-off scores for Chinese men were 1 for OST and 22 for MOST.
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Using a cut-off score of 2, the sensitivity and specificity for predicting osteoporosis in men (mean age 64 years), respectively, were 82% and 74%, with a negative predictive value of 97% [9]. Prevalence of osteoporosis using different OST cut-offs, based on patient sample age and gender, is shown in Figure 17.3. Another validated screening tool for bone loss in men is the Male Osteoporosis Screening Tool (MOST) [10]. MOST scores are calculated by using weight in kg and the quantitative ultrasound index (QUI) (Table 17.3). A cut-off score of 3 is used for screening, with a negative predictive value of 97.5%. DXA screening is recommended for men with a MOST score 7. MOST is scored by considering weight and QUI score 3 suggests no significant bone loss men scoring 7 should be screened with DXA.
l l l
l
OST and MOST were the most effective screening tools, with positive and negative predictive values each 90%. Among 1000 Caucasians screened, OST missed nine cases of osteoporosis and resulted in recommendations for 593 unnecessary DXA tests, while MOST missed four cases and recommended 577 unnecessary DXA tests. Among 1000 Chinese men screened, OST missed 12 cases and resulted in 550 unnecessary DXA tests, while MOST missed eight cases and resulted in 499 unnecessary DXA tests. Similarly, OST was shown to be a more cost-effective strategy for screening for important bone loss in men 70 years old compared with routine bone densitometry [12]. OST was likewise found to be an effective screening tool in a study of African–American men 35 years old [13]. In this
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sample, 87% of men identified with a high-risk OST score were diagnosed with osteopenia or osteoporosis based on World Health Organization criteria.
Measuring Bone Loss in Men Difficulty defining normal and abnormal BMD in men supports utilization of additional techniques to measure bone loss. Quantitative computed tomography (QCT) better defines age-associated changes in volumetric BMD, as well as bone geometry and microstructure. QCT offers a threedimensional measurement of BMD and provides separate volumetric density measurements of trabecular and cortical bone. Furthermore, QCT is not impacted by calcification and hyperostosis that can affect readings with DXA. QCT can also be used to predict fracture risk [14]. In the prospective Health, Aging and Body Composition study monitoring adults 70–79 years old (average follow up 6.4 years), vertebral trabecular volumetric BMD from QCT testing was shown to predict clinical non-spine fractures in black men [14]. The age-adjusted hazard ratio (HR) of fracture for each SD decrease in vertebral trabecular volumetric BMD was 3.00 (95% CI 1.29–7.00) in black men. QCT testing did not predict fractures in white men (HR 1.06, 95% CI 0.73–1.54). In another study using data from the Mr OS study, baseline QCT scans of the hip were obtained in 3347 men 65 years old, who were then followed prospectively for an average of 5.5 years [15]. HR per standard deviation decrease showed independent predictive value for lower percent cortical volume (HR 3.2, 95% CI 2.2–4.6), smaller minimal cross-sectional area (HR 1.6, 95% CI 1.2–2.1) and lower trabecular BMD (HR 1.7, 95% CI 1.2–2.4). Percent cortical volume and minimum cross-sectional area remained significant predictors of hip fracture risk after adjustment for areal BMD.
Bone loss with aging in men Age-related bone loss occurs in men, although the magnitude of change is smaller in men than women [16]. Data from the Network in Europe for Male Osteoporosis (NEMO) study showed an average BMD change in men ages 50–86 years old during the mean evaluation period of 3.5 years of 0.004 0.015 g/cm2 at the femoral neck, 0.001 0.013 g/cm2 at the trochanter and 0.001 0.019 g/cm2 in the lumbar spine. Means, however, varied by European country assessed. BMD loss was significantly greater in men with higher baseline BMD values (P 0.001). Higher baseline weight was associated with preserved BMD at all three sites (P 0.01), with weight gain associated with preserved BMD at the femoral neck and trochanter, but not the spine. Data from the MINOS study were also used to evaluate age-related bone loss in European men [17]. A total of
934 French men aged 19–50 years old without diseases or treatments known to affect bone metabolism were recruited from a large insurance company and advertisements. BMD was measured using DXA. Average BMD data are shown in Table 17.4. The single region with the greatest decrease between peak BMD and 80 years old was Ward’s triangle, which experienced a T-score loss of 2.5 and a BMD percentage loss of 43%. BMD loss continued across the full age range for all regions except the lumbar spine, which showed decreases of about 2.5% per decade from ages 30 to 55 years (for a total loss of about 6%), followed by non-significant increases after age 55. At all regions measured, variability in measurements increased significantly after the peak, with standard deviations about 20–35% higher in elderly men. Using WHO definitions for low BMD and osteoporosis in women, low BMD and osteoporosis were identified in men in the MINOS study in 31–46% and 4–17% of locations, respectively (Figure 17.4). Osteoporosis prevalence increased with age. For example, hip and distal forearm osteoporosis, respectively, occurred in 4% and 6% of men ages 51–60 years and 19% and 22% after age 70 years. This study concluded that: peak bone density occurs earlier in areas rich in trabecular bone and later in areas rich in cortical bone bone loss after peak varies according to skeletal site bone loss shows substantial inter-individual variability, which increases with aging.
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A linear decrease in BMD has similarly been identified with aging in Chinese men 65 years old [18]. Similar to previous studies, significant bone loss occurred at all three hip sites measured in Chinese men, with the greatest loss at Ward’s triangle (Figure 17.5).
Age-Related Changes in QCT Longitudinal bone loss, as measured by QCT, was assessed in the Osteoporotic Fractures in Men cohort of the Mr Table 17.4 BMD among men in the MINOS study Bone region
Lumbar spine Hip Total hip Femoral neck Trochanter Ward’s triangle Forearm Distal Ultradistal
Age at peak BMD (years)
BMD decrease after peak T-score loss
% decrease
29
0.2
2
25 25 25 25
1.3 1.2 1.1 2.5
16 13 14 43
40 30
1.8 1.6
16 18
Data from Szulc et al 2000 [17]
C h a p t e r 1 7 Aging and Bone Loss l
17
Ultradistal radius
Measurement location
38
14
Distal forearm
38
7
Intertrochanteric region Trochanter
4
Femoral neck
4
42 38 46 10
Total hip
45
6
Lumbar spine
211
31
0
10
20 30 Percentage Low BMD
40
50
Osteoporosis
1.40
1.40
1.20
1.20 Ward’s triangle BMD
Femoral neck BMD
Figure 17.4 Prevalence of low BMD and osteoporosis in men aged 51–85 in the MINOS study (Szulc et al 2000 [17]). Low BMD was defined as 1 T-score 2.5; osteoporosis was defined as T-score 2.5.
1.00 0.80 0.60
0.80 0.60 0.40
0.40 66 A
1.00
68
70
72 74 76 Age (yr)
78
66
80
68
70
B
72 74 Age (yr)
76
78
80
1.40
Greater trochanter BMD
1.20 1.00 0.80 0.60 0.40 66 C
68
70
72 74 Age (yr)
76
78
80
Figure 17.5 Distribution of BMD at different areas in 142 healthy Chinese men. (Reprinted from Chiu et al 2008 [18]).
212
Osteoporosis in Men A. Volume
50
Integral volume
Cortical volume
Medullary volume
Percent cortical volume
46.1
45.5*
44.6***
43.8***
42.3***
20.4
20.5
20.5
20.7*
20.9*
11
11.2
11.4**
11.7***
12.1***
9.1***
9.0***
8.8***
75 to 79
80 to 84
85 and older
Volume in cm3
40 30 20 10 9.3
0
65 to 69
9.3
70 to 74
Age in years B. Volumetric BMD Integral BMD
Cortical BMD
Trabecular BMD
0.75 0.526
0.526
0.524
0.301
0.297
0.086
0.08**
0.525
0.520
0.29***
0.283***
0.274***
0.075***
0.069***
0.067***
0.5
Percentage
Volume in g/cm3
1
0.25
0
65 to 69
70 to 74
75 to 79
80 to 84
85 and older
Age in years
Figure 17.6 Mean femoral neck QCT measures, adjusted for race/ethnicity, height and BMI (based on Marshall et al 2006 [19]). Significant difference compared with adjusted mean at ages 65–69: *P 0.05, **P 0.01, ***P 0.001.
OS study [19]. Changes in QCT measures are shown in Figure 17.6. Comparing the oldest to the youngest age groups of men, adjusted means increased 2% for integral volume, decreased 5% for cortical volume, increased 10% for medullary volume and decreased 8.2% for percent cortical volume. Adjusted mean volumetric BMD measures in the oldest compared with the youngest men decreased by 9% for integral and 22% for trabecular vBMDs. Cortical vBMD did not change significantly with age. Longitudinal changes in bone in men were also analyzed using data from the MINOS study [20]. Net bone loss increased with age in the body overall, as well as in the hip and distal forearm (Figure 17.7). Net bone was two to four times greater in men 70 years old compared with those 60 years old. A 6-year longitudinal study using tibia QCT measures from patients in the Italian Invecchiare in Chianti
was designed to understand better changes in bone loss in men and identify possible imbalances in bone apposition and resorption [21]. Follow-up data were available for 809 men and women. Decline in total volumetric BMD was less steep in men than women, with a lack in acceleration in loss in men compared with that seen in women after age 65 (Figure 17.8). In men, increase in total bone area occurred until around age 60. In addition, widening of the medullary area, which reflects endocortical resorption, was also less in men than women. Finally, cortical bone increased slightly in younger men, with a loss of change around age 50 and a slight decline in later years.
Bone Loss in Younger Men As noted in the MINOS study above, trabecular bone loss precedes cortical bone loss [17]. A recent study similarly
C h a p t e r 1 7 Aging and Bone Loss l
20
Femoral neck
213
0
10
–250
0
–500
–0.02 50–60 61–70 71–86
50–60 61–70 71–86
0
0
–10
–12 –0.02
–20
Whole body
–0.0001 –24
Distal radius
Figure 17.7 Net bone loss based on age. (Figures from Szulc et al 2007 [20]).
showed early trabecular bone loss in men, comparing bone loss at areas of trabecular and cortical bone in the distal radius and tibia and trabecular bone in the lumbar spine [22]. Cortical bone loss began in men after age 75 years, with only 15% of cortical bone loss occurring before age 50. Conversely, 42% of total lifetime trabecular bone loss occurred before age 50.
Factors contributing to bone loss A variety of factors has consistently been linked to low BMD in men, including ethnicity, low body weight, vitamin intake, older age, smoking, physical/functional limitations and previous fracture. Dietary factors, lipid markers and low testosterone have also been linked to low BMD.
Ethnicity In addition to geographical influences on bone health, ethnicity also significantly affects BMD and BMD loss. Evaluation of a random sample of men representing three ethnic groups (451 Caucasian, 367 black and 401 Hispanic) aged 30–79 years old living in the same city in the USA showed a higher BMD in black compared with Caucasian or Hispanic men (Table 17.5) [23]. Significant differences between Caucasians and Hispanics were restricted to the hip, where BMD was lower in Caucasians. Interestingly, with aging, BMD loss was most pronounced in Hispanics. Figure 17.9 shows a comparison of changes in BMD at the femoral neck. Similar and significantly greater reductions in BMD with aging were likewise seen with Hispanics compared with black and Caucasian men with BMD measurements of the whole body, hip, lumbar spine and forearm.
Data from the Baltimore Men’s Osteoporosis Study (MOST) likewise showed significant ethnic differences in BMD and bone loss [24]. Baseline BMD was significantly higher in blacks, with mean annual bone loss in the femoral neck of 2.1% in black males versus 1.1% in whites (Table 17.6). Change in hip BMD per year was a 0.05% increase in black men, versus a 0.8% loss in whites. Another analysis of data from MOST showed significantly more vertebral fractures in white compared with black men (7.3% versus 0.9%, P 0.01), for an age-adjusted odds ratio of 8.3 (95% CI: 1.1–62.5) [25]. Bone mass is Asian men also differs from Caucasians. A comparison of femoral neck evaluations in 3305 men 65 years old participating in the Osteoporotic Fractures in Men study showed features suggesting greater bone strength in both Asians and blacks, compared with Caucasians, including a 5% greater mean cortical thickness and 33–36% greater trabecular volumetric BMD [26]. The authors concluded that these features conferring greater bone strength to Asians and blacks may explain the reduced incidence of hip fractures typically seen in these two ethnic groups compared with Caucasians. Fewer studies have evaluated bone health in men living in the Middle East. Peak bone mass in a sample of 2340 Iranian men occurred between ages 20 and 24 years old, with mean values of 1.10 0.16 g/cm2 at the femoral neck and 1.18 0.15 g/cm2 in the lumbar spine [27]. These values were comparable to studies evaluating peak bone mass in Western countries and higher than recordings from other Middle Eastern countries. Ethnicity can also influence the likelihood of diagnosing osteoporosis and osteopenia. For example, using a sample of 98 consecutive elderly male patients, a retrospective review evaluated how many patients were receiving DXA screening
214
Osteoporosis in Men Table 17.5 Mean BMD (g/cm2) (SD), adjusted for age and height Location
Racial group Black
Whole body Total hip Femoral neck Lumbar spine Distal forearm Ultradistal forearm
Hispanic
1.28 (0.01)* † *†
1.09 (0.01) 0.94 (0.01)* † 1.11 (0.01)* † 0.80 (0.00)* † 0.56 (0.01)* †
Caucasian
1.21 (0.01) †
1.04 (0.01) 0.89 (0.01)† 1.03 (0.01) 0.76 (0.01) 0.53 (0.01)
1.20 (0.01) 0.99 (0.01) 0.83 (0.01) 1.02 (0.01) 0.75 (0.00) 0.52 (0.00)
*
Significantly different compared with Hispanics (P 0.05); Significantly different compared with Caucasians (P 0.05); Data from Araujo et al 2007 [23] †
in a rheumatology practice [28]. While 29% of Caucasians were evaluated with DXA, these same data were available for only 5% of African-Americans. Ethnicity was the only significant factor resulting in a higher likelihood of DXA testing, Caucasians being 7.7 times more likely to receive testing compared with African-American counterparts. Age and other potential risk factors were not significantly associated with the likelihood of DXA testing. Therefore, ethnic influences on ordering testing may result in some of the disparity in identification of osteoporosis, both in the clinic and in epidemiological surveys. This same research group showed that including a checklist of osteoporosis risk factors increased appropriate ordering of DXA testing, with DXA testing occurring before and after use of the checklist, respectively, in 6 versus 21% of African-Americans and 29 versus 42% of Caucasians [29]. These ethnic studies support that: femoral neck and shaft cortices are thicker and BMD and bone strength are greater in blacks and Asians, possibly explaining reduced fracture incidence in these ethnic groups bone loss with aging is more pronounced in Hispanics ethnicity is a strong predictor for receiving osteoporosis screening.
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Figure 17.8 (A) Longitudinal changes in total BMD (vBMD); (B) trabecular BMD (vBMDt); (C) total bone area (tCSA); (D) medullary bone area; (E) cortical bone area over 6 years. (Figures from Laurentani et al 2008 [21]).
In the Mr OS study, QCT scans were used to measure femoral neck and shaft bone dimensions and volume in men 65 years old [26]. Effect of race was evaluated by comparing measurements in blacks (n 170), Asian (n 121), Hispanic (n 90) and non-Hispanic white participants (n 2924). Compared with whites, blacks had a 3% smaller femoral neck cross-sectional area, 6% larger cortical volume and 3% smaller medullary volume, resulting in a 6% larger mean percent cortical volume (Table 17.7). Femoral neck dimensions were smaller among Asians, although these differences did not achieve statistical significance. Cortical volume was nearly 4% greater among Asians, which was
C h a p t e r 1 7 Aging and Bone Loss
Mean BMD (g/cm2)
l
Black
Hispanic
40 to 49
50 to 59 Age (years)
215
Caucasian
1 0.9 0.8 0.7
30 to 39
60 to 69
70 to 79
Figure 17.9 Mean BMD in the femoral neck. (Based on Araujo et al 2007 [23]).
Table 17.6 BMD in Black and Caucasian Americans in MOST Location
Black males
Caucasian males
P-value
Baseline mean BMD (g/cm2) (SD)
0.91 (0.15)
0.82 (0.12)
0.05
Femoral neck 1.05 (0.16) 0.96 (0.13) 0.05 Hip Annual change in BMD 0.010 (0.03) 0.017 (0.03) 0.05 (g/cm2 per year) (SD) Femoral neck 0.01 (0.03) 0.01(0.03) 0.007 Hip Data from Tracy et al 2005 [24]
significant. There were no significant differences between measurements for Hispanics and non-Hispanic whites. These data support thicker cortices in the femoral neck and shaft in black and Asian males compared with whites, which should translate to improved strength and may explain the reduced fracture risk in these racial groups.
Body Weight and Bone Loss Similar to risk in women, low weight and weight loss are associated with increased risk for osteoporosis in men. Weight loss has been consistently linked with increased rate of bone loss in the lumbar spine and hip in men [30]. Conversely, BMD increases at the lumbar spine and hip by about 3–7% for every 10 kg weight increase [30]. This relationship has been consistently identified across geographic regions, with a comparable change seen in China, Europe and the USA [30]. A recent survey of 1476 Norwegian men (mean age 45.1 years) showed that baseline body mass index (BMI) was positively correlated to BMD three decades later, with subsequent weight change also strongly related to BMD [31]. Osteoporosis occurred in 15.1% of men losing 10% of their weight, 14.1% losing 5 10%, 6.2% losing 5%, 2.6% gaining 5 10%, and 0.6% gaining 10%. Changing weight can also negatively affect bone health. Weight cycling during early adult years was linked to
increased forearm fracture risk in 4601 Norwegian men (mean age 71.6 years) participating in the Oslo Study [32]. Forearm fractures occurred in 35–43% of men reporting four or more episodes of weight loss between ages 25 and 50 years, compared with fractures in 17–18% of men without weight loss episodes. As obesity prevalence increases, it is essential to counsel male patients about healthy lifestyle habits to achieve and maintain a healthy weight rather than experiencing harmful repeated cycling of weight loss and gain.
Vitamins Evaluation of men and women participating in the Framingham Study showed greater bone loss in those with vitamin B6 deficiency (Figure 17.10) [33]. Lower concentrations of vitamins B6 and B12 were associated with increased risk for hip fracture, however, some of this risk was independent of BMD. A separate analysis for men was not provided. Increasing dietary intake of B vitamins may improve bone health and reduce fracture risk. Using data from 5304 men and women 55 years old participating in the Rotterdam study, B vitamin intake was significantly and independently linked to BMD at the lumbar spine and femoral neck, with riboflavin and pyridoxine the strongest contributors to increased BMD [34]. Separate analyses were not available to evaluate the effect in men alone. Overall, riboflavin and pyridoxine together predicted 1% of the variation in BMD at both sites. Dietary pyridoxine was associated with reduced risk of fractures, independent of femoral neck BMD. The incidence rate of fractures for patients in the top quartile for pyridoxine intake (mean 2.03 mg/day) was significantly reduced for non-vertebral (HR 0.77, 95% CI 0.65–0.92) and fragility fractures (HR 0.55, 95% CI 0.40–0.77) compared with the lower three quartiles (mean pyridoxine 1.30–1.67 mg/day). The percentage of vertebral fractures was not significantly reduced in patients in the top pyridoxine quartile (OR 0.86, 95% CI 0.65–1.13). Vitamin C has also been linked to bone health in men. Using data from the Framingham Osteoporosis Study,
Osteoporosis in Men
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Table 17.7 Mean femoral neck measurements (95% confidence intervals), adjusted for study site, age, height and BMI Measures
Race/ethnicity
Cross-sectional area (cm2) Integral volume (cm3) Cortical volume (cm3) Medullary volume (cm3) Percent cortical volume (%)
White n 2924
Black n 170
Asian n 121
Hispanic n 90
12.7 (12.6–12.7) 20.8 (20.7–20.9) 9.1 (9.0–9.1) 11.7 (11.6–11.8) 44.1 (43.9–44.3)
12.3 (12.1–12.5)** 21.0 (20.6–21.4) 9.6 (9.4–9.8)*** 11.4 (11.0-11.7) 46.7 (45.7–47.7)***
12.5 (12.2–12.8) 20.9 (20.5–21.4) 9.3 (9.1–9.5) 11.6 (11.2–12.1) 45.7 (44.5–46.9)*
12.5 (12.2–12.8) 20.1 (20.1–21.1) 9.2 (8.9–9.4) 11.4 (10.9–11.9) 45.2 (43.8–46.5)
Significantly different from whites: *P 0.009; **P 0.001; ***P 0.0001; based on Marshall 2008 [26]
Annual % Change in Femoral Neck BMD
Folate
Vitamin B12
Vitamin B6
0.00
economical and convenient screening tests are available adequately to screen men for significant bone loss.
Identifying Screening Candidates
–0.50
–1.00
–1.50 Normal
Low
Deficient
P for trend=0.01
–2.00
Figure 17.10 Least squares-adjusted mean annual percent change in femoral neck BMD. (Reprinted from McLean et al 2008 [33]).
vitamin C intake (through diet or supplements) was linked to BMD in men, but not women [35]. Higher dietary vitamin C intake was linked with less loss of BMD in men at the trochanter and lumbar spine (P 0.05), with a trend shown for loss of BMD at the femoral neck (P 0.09). Vitamin C intake was negatively associated with trochanter BMD for current smokers (P 0.01) and positively associated with femoral neck BMD in non-smokers (P 0.04). Furthermore, among men with a low calcium intake or low vitamin E intake, increased vitamin C intake was linked to a smaller loss of BMD at both the femoral neck and trochanter (P 0.05).
Practical screening for significant male bone loss and osteoporosis Due to the lower prevalence of osteoporosis in men compared with women, routine screening with DXA for all men is neither desirable nor cost effective. Candidates most likely to benefit from bone loss screening can be identified using readily available clinical data. Once candidates are identified,
Among an older male population, routinely employing validated screening tools, such as the OST and MOST (described above), can help identify those patients at higher risk for important bone loss who made need additional testing to diagnose osteoporosis. Clinical risk assessment can effectively identify those men for whom BMD testing is more likely to identify significant bone loss. Including a 10item osteoporosis risk factor checklist (Box 17.1) resulted in an increase in appropriate screening with DXA in males from 14% to 29% [29]. Zimering and colleagues proposed using an additive risk index to assess male osteoporosis risk, called the Mscore (male simple calculated osteoporosis risk estimation) [36]:
Mscore [2 (patient age in decades) (weight in pounds/10) 4 if gastrectomy, 4 if emphysema, 3 if 2 or more prior fractures 14].
Age and weight are truncated to integers, so the integer 7 would be used for a patient 75 years old and 18 would be used for a patient weighing 185 pounds. Higher Mscores denote greater risk, with Mscore values 9 defining low risk, 9–13 moderate risk and 13 high risk. These Mscore risk categories effectively predict abnormal BMD. In a group of 197 Caucasian males (mean age 69 years), osteoporosis was diagnosed using femoral neck BMD in 2% in the lowrisk category and 36% in the high-risk group, with an additional 55% in the high-risk group having osteopenia [36]. In this same study, a cut-off Mscore of 9 in both Caucasian and African-American men correlated with a cut-off of 4 using the previously validated osteoporosis self-assessment tool.
Utilizing Economical and Convenient Screening Screening may be more economically feasible by using less expensive and more convenient testing, such as ultrasound
C h a p t e r 1 7 Aging and Bone Loss l
Box 17.1 Osteoporosis risk factor checklist 1. Do you weigh less than 130 pounds? 2. Have you broken any bones after you became 50? 3. Have you been on any of the following medications: prednisone, inhaled steroids, thyroid or antiseizure medication? 4. Do you have rheumatoid arthritis? 5. Have you ever regularly had more than 3 alcoholic beverages a day? 6. Do you avoid dairy products? 7. Do you have relatives who have broken bones when they were elderly? 8. Have you ever been treated with hormonal therapy (Casadex, Zoladex, Lupron) for prostate cancer? 9. Are you shorter now than when you were 25 years old? 10. Have you ever smoked more than 10 cigarettes a day for more than 10 years? Reprinted from Richards et al 2008 [29]
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Factors influencing bone health in men were evaluated in the European Male Ageing Study (EMAS), which recruited men aged 40–79 from eight European countries. Quantitative heel ultrasound was performed in 3258 men in this study [43]. Significant differences were noted between countries for BUA, SOS and BMD heel ultrasound parameters. All parameters, however, decreased significantly with age. Factors associated with higher BUA, SOS and BMD values included: walking or cycling 1 hour daily demonstrating a faster time to walk 50 feet not smoking.
l l l
Alcohol consumption was not linked to ultrasound parameters. Effective screening for osteoporosis in men may be improved by: using clinical screening tools to identify high-risk patients, including OST and MOST screening for osteoporosis with heel quantitative ultrasound testing utilizing QCT to determine when to initiate treatment and monitor treatment efficacy.
l
l
l
testing in preference to the more expensive but widely accepted DXA. Both DXA and quantitative ultrasound can predict fragility fractures in men [37]. In 2007, the International Society for Clinical Densitometry (ISCD) issued position statements on the use of DXA and other technologies in osteoporosis [38]. The ISCD stated that spinal trabecular BMD, as measured by QCT, could be used to predict vertebral fractures in women, although sufficient data were not available to support use in men or for hip fractures in either gender. QCT could be used to determine when to initiate treatment, when considered in conjunction with clinical risk factors. Trabecular BMD was also recommended to monitor age-, disease- and treatmentrelated bone changes. The ISCD has also linked heel qualitative ultrasound measurements to global fracture risk and recommended heel ultrasound as an inexpensive and convenient method for identifying men and women at low or high risk for fracture [39]. Data, however, were not available to support using heel ultrasound as a measure to monitor treatment efficacy. Heel quantitative ultrasound has been shown to predict clinically significant bone abnormalities in men, with broadband ultrasound attenuation (BUA) more closely related to bone density and speed of sound (SOS) an effective predictor of vertebral fractures [40]. Heel quantitative ultrasound also predicts non-vertebral fractures nearly as well as predictions using hip BMD measurements [41]. Interestingly, both peripheral DXA and heel quantitative ultrasound produce significantly lower values on the dominant side, suggesting testing should be preferentially performed using the calcaneus on the dominant side for each patient [42].
Summary Despite the importance of bone loss in the aging male, men are generally unaware that bone loss and osteoporosis are potentially serious and prevalent for men, or that changes in lifestyle habits can significantly impact risk for bone loss [44]. QCT documents important longitudinal changes in male bone health, with trabecular bone loss preceding cortical loss. Bone loss is affected by ethnicity, body weight and vitamins. Screening for patients at high risk for bone loss using simple, easy-to-administer tools like the OST and MOST, as well as convenient and economical testing with qualitative ultrasound testing of at-risk patients may facilitate effectively identifying men with abnormal bone health.
References 1. R. Lucas, C. Silva, L. Costa, D. Arujo, H. Barros, Male ageing and bone mineral density in a sample of Portuguese men, Acta Reumatol. Port. 33 (3) (2008) 306–313. 2. A. Tenenhouse, L. Joseph, N. Kreiger, et al., Estimation of the prevalence of low bone density in Canadian women and men using a population-specific DXA reference standard: the Canadian Multicentre Osteoporosis Study (CaMos), Oseoporos. Int. 11 (10) (2000) 897–904. 3. World Health Organization (WHO). WHO scientific group on the assessment of osteoporosis at primary healthcare level, 2007. WHO. Available at: http://www.who.int/chp/topics/ Osteoporosis.pdf/ (accessed October 2008).
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4. J.A. Kanis, E.V. McCloskey, H. Johansson, A. Oden, L.J. Melton III, N. Khaltaev, A reference standard for the description of osteoporosis, Bone 42 (3) (2008) 467–475. 5. J.A. Kanis, C.C. Glüer, An update on the diagnosis and assessment of osteoporosis with densitometry. Committee of Scientific Advisors, International Osteoporosis Foundation, Osteoporos. Int. 11 (3) (2000) 192–202. 6. G. Holt, K.T. Khaw, D.M. Reid, et al., Prevalence of osteoporotic bone mineral density at the hip in Britain differs substantially from the US over 50 years of age: implications for clinical densitometry, Br. J. Radiol. 75 (897) (2002) 736–742. 7. E.M. Lewiecki, C.M. Gordon, S. Baim, et al., Special report on the 2007 adult and pediatric Position Development Conferences of the International Society for Clinical Densitometry, Osteoporos. Int. 19 (10) (2008) 1369–1378. 8. L.S. Lim, L.J. Hoeksema, K. Sherin, Screening for osteoporosis in the adult US population. ACPM position statement on preventive practice, Am. J. Prev. Med. 36 (4) (2009) 368–375. 9. R.A. Adler, M.T. Tran, V.I. Petrkov, Performance of the Osteoporosis Self-assessment Screening Tool for osteoporosis in American men, Mayo Clin. Proc. 78 (6) (2003) 723–727. 10. H.S. Lynn, M.C. Lan, S.S. Wong, A.L. Hong, An osteoporosis screening tool for Chinese men, Osteoporos. Int. 16 (7) (2005) 829–834. 11. H.S. Lynn, J. Woo, P.C. Leung, et al., An evaluation of osteoporosis screening tools for the osteoporotic fractures in men (MrOS) study, Osteoporos. Int. 19 (7) (2008) 1087–1092. 12. K. Ito, J.P. Hollenberg, M.E. Charlson, Using the osteoporosis self-assessment tool for referring older men for bone densitometry: a decision analysis, J. Am. Geriatr. Soc. 57 (2) (2009) 218–224. 13. B. Sinnott, S. Kukreja, E. Barengolts, Utility of screening tools for the prediction of low bone mass in African American men, Osteoporosis. Int. 17 (5) (2006) 684–692. 14. D.C. Mackey, J.G. Eby, F. Harris, et al., Prediction of clinical non-spine fractures in older black and white men and women with volumetric BMD of the spine and areal BMD of the hip: the Health, Aging, and Body Composition Study, J. Bone. Miner. Res. 22 (12) (2007) 1862–1868. 15. D.M. Black, M.L. Bouxsein, L.M. Marshall, et al., Proximal femoral structure and the prediction of hip fracture in men: a large prospective study using QCT, J. Bone Miner. Res. 23 (8) (2008) 1326–1333. 16. S. Kaptoge, D.M. Reid, C. Scheidt-Nave, et al., Geographic and other determinants of BMD change in European men and women at the hip and spine. a population-based study from the Network in Europe for Male Osteoporosis (NEMO), Bone 40 (3) (2007) 662–673. 17. P. Sculz, F. Marchand, F. Duboeuf, P.D. Delmas, Crosssectional assessment of age-related bone loss in men: the MINOS Study, Bone 26 (2) (2000) 123–129. 18. H.C. Chiu, C.H. Chen, M.L. Ho, H.W. Liu, S.F. Wu, J.K. Chang, Longitudinal changes in bone mineral density of healthy elderly men in southern Taiwan, J. Formos. Med. Assoc. 107 (8) (2008) 653–658. 19. L.M. Marshall, T.F. Lang, L.C. Lambert, J.M. Zmuda, K.E. Ensrud, E.S. Orwoll, Dimensions and volumetric BMD of the proximal femur and their relation to age among older U.S. men, J. Bone Miner. Res. 21 (8) (2006) 1197–1206.
20. P. Szulc, P.D. Delmas, Bone loss in elderly men: increased endosteal bone loss and stable periosteal apposition. The prospective MINOS study, Osteoporos. Int. 18 (4) (2007) 495–503. 21. F. Lauretani, S. Bandinelli, M.E. Griswold, et al., Longitudinal changes in BMD and bone geometry in a population-based study, J. Bone Miner. Res. 23 (3) (2008) 400–408. 22. B.L. Riggs, L.J. Melton, R.A. Robb, et al., A population-based assessment of rates of bone loss at multiple skeletal sites: evidence for substantial trabecular bone loss in young adult women and men, J. Bone Miner. Res. 23 (2) (2008) 205–214. 23. A.B. Araujo, T.G. Travison, S.S. Harris, M.F. Holick, A.K. Turner, JB. McKinlay, Race/ethnic differences in bone mineral density in men, Osteoporos. Int. 18 (7) (2007) 943–953. 24. J.K. Tracy, W.A. Meyer, R.H. Flores, P.D. Wilson, M.C. Hochberg, Racial differences in rate of decline in bone mass in older men: the Baltimore men’s osteoporosis study, J. Bone Miner. Res. 20 (7) (2005) 1228–1234. 25. J.K. Tracy, W.A. Meyer, M. Grigoryan, et al., Racial differences in the prevalence of vertebral fractures in older men: the Baltimore Men’s Osteoporosis Study, Osteoporos. Int. 17 (1) (2006) 99–104. 26. L.M. Marshall, J.M. Zmuda, B.K. Chan, et al., Race and ethnic variation in proximal femur structure and BMD among older men, J. Bone Miner. Res. 23 (1) (2008) 121–130. 27. B. Larijani, A. Moayyeri, A.A. Keshtkar, et al., Peak bone mass of Iranian population: the Iranian Multicenter Osteoporosis Study, J. Clin. Densitom. 9 (3) (2006) 367–374. 28. J.S. Richards, H.A. Young, R. DeSagun, G.S. Kerr, Elderly African-American and Caucasian men are infrequently screened for osteoporosis, J. Natl. Med. Assoc. 97 (5) (2005) 714–717. 29. J.S. Richards, R.L. Amdur, G.S. Kerr, Osteoporosis risk factor assessment increases the appropriate use of dual energy X-ray absorptiometry in men and reduces ethnic disparity, J. Clin. Rheumatol. 14 (1) (2008) 1–5. 30. A. Papaioannou, C.C. Kennedy, A. Cranney, et al., Risk factors for low BMD in healthy men age 50 years or older: a systematic review, Osteoporos. Int. 20 (4) (2009) 507–518. 31. H.E. Meyer, A.J. Søgaard, J.A. Falch, L. Jørgensen, N. Emaus, Weight change over three decades and the risk of osteoporosis in men: the Norwegian Epidemiological Osteoporosis Studies (NOREPOS), Am. J. Epidemiol. 168 (4) (2008) 454–460. 32. A.J. Søgaard, H.E. Meyer, S. Tonstad, L.L. Håheim, I. Holme, Weight cycling and risk of forearm fractures: a 28-year follow-up of men in the Oslo Study, Am. J. Epidemiol. 167 (8) (2008) 1005–1013. 33. R.R. McLean, P.F. Jacques, J. Selhub, et al., Plasma B vitamins, homocysteine, and their relation with bone loss and hip fracture in elderly men and women, J. Clin. Endocrinol. Metab. 93 (6) (2008) 2206–2212. 34. N. Yazdanpanah, M.C. Zillikens, F. Rivadeneira, et al., Effect of dietary B vitamins on BMD and risk of fracture in elderly men and women: the Rotterdam study, Bone 41 (6) (2007) 987–994. 35. S. Sahni, M.T. Hannan, D. Gagnon, et al., High vitamin C intake is associated with lower 4-year bone loss in elderly men, J. Nutr. 138 (10) (2008) 1931–1938. 36. M.B. Zimering, J.J. Shin, J. Shah, E. Wininger, C. Engelhart, Validation of a novel risk estimation tool for predicting low bone density in Caucasian and African American men veterans, J. Clin. Densitom. 10 (3) (2007) 289–297.
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37. S. Gonnelli, C. Cepollaro, L. Gennari, et al., Quantitative ultrasound and dual-energy X-ray absorptiometry in the prediction of fragility fracture in men, Osteoporos. Int. 16 (8) (2005) 963–968. 38. K. Engelke, J.E. Adams, G. Armbrecht, et al., Clinical use of quantitative computed tomography and peripheral quantitative computed tomography in the management of osteoporosis in adults: the 2007 ISCD Official Positions, J. Clin. Densitom. 11 (1) (2008) 123–162. 39. M.A. Krieg, R. Barkmann, S. Gonnelli, et al., Quantitative ultrasound in the management of osteoporosis: the 2007 ISCD Official Positions, J. Clin. Densitom. 11 (1) (2008) 163–187. 40. S. Mészáros, E. Tóth, V. Ferencz, E. Csupor, E. Hosszú, C. Horváth, Calcaneous quantitative ultrasound measurements predict vertebral fractures in idiopathic male osteoporosis, Joint Bone Spine 74 (1) (2007) 79–84.
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41. D.C. Bauer, S.K. Ewing, J.A. Cauley, K.E. Ensrud, S.R. Cummings, E.S. Orwoll, Quantitative ultrasound predicts hip and non-spine fracture in men: the MrOS study, Osteoporos. Int. 18 (6) (2007) 771–777. 42. S. Mészáros, V. Ferencz, E. Csupor, et al., Comparison of the femoral neck bone density, quantitative ultrasound and bone density of the heel between dominant and non-dominant side, Eur. J. Radiol. 60 (2) (2006) 293–298. 43. S.R. Pye, V. Devakumar, S. Boonen, et al., Quantitative heel ultrasound measurements in middle aged and elderly men: results from the European Male Ageing Study (EMAS), Osteoporos. Int. in press. 44. N.S. Ali, C. Shonk, M.S. El-Sayed, Bone health in men: influencing factors, Am. J. Health Behav. 33 (2) (2009) 213–222.
Chapter
18
The Effect of Age on Material Properties Matthew R. Allen1, David B. Burr 1,2,3 and Charles H. Turner2,3 1
Departments of Anatomy and Cell Biology, Indiana University School of Medicine, Indianapolis, USA Orthopaedic Surgery, Indiana University School of Medicine, Indianapolis, USA 3 Department of Biomedical Engineering, IUPUI, Indianapolis, USA 2
Introduction Aging leads to increased skeletal fragility in both men and women [1, 2], although the rapid changes in men begin about 20 years later than comparable changes in women. Increasing fragility with age is a multifactorial process, resulting from changes in both bone structure and the intrinsic properties of the bone material. The most easily measured age-related structural change is a loss of bone mass, which results in increased cortical bone porosity and loss of trabecular connectivity. In addition to the loss of bone mass, the bone that remains has altered material properties that contribute to increased bone fragility. The most prominent aging-related change to bone material is reduced toughness (increased brittleness) that results from changes to cross-linking of the collagen matrix and the accumulation of microdamage. These aging-related changes make the skeleton less able to withstand the impact forces that are generated when an individual falls, independent of how much bone there is and, therefore, increase the risk of fracture. As the changes to material properties – mineralization, collagen, microdamage (Figure 18.1) – each have differential effects on overall bone mechanics, it is important to explore the nature of these changes as a basis for assessing the reasons for the increased risk of fracture in older adults. It is important to note that the limited amount of data concerning these material properties, as well as biomechanical properties as a whole, make it unclear whether men and women experience similar age-related changes.
Material-Level Biomechanical Properties Collagen
Mineral
Figure 18.1 Collagen and mineral properties, as well as tissue microdamage accumulation, contribute to material-level biomechanical properties.
changes that occur at the whole bone level (structural biomechanical properties) and those that occur in the bone tissue itself (material biomechanical properties). Structurally, the mechanical properties of a bone are largely determined by the amount of bone present, but are also affected by the distribution or architecture of the bone mass. Thus, any aspect of a bone’s geometry/architecture that changes with age will affect the structural mechanical properties of a bone. The material biomechanical properties are those of the tissue itself, factoring out aspects of the structure. These material properties (sometimes called intrinsic biomechanical properties) can be determined by various methods, including whole bone tests, machined bone specimen tests or micro/nano-indentation tests (Table 18.1). The most common method for assessing material-level biomechanical properties is by conducting whole bone tests and then normalizing outcomes based on measures of bone mass and geometry/architecture. Whole bone tests,
Biomechanical material properties of the skeleton When considering the biomechanical changes that occur to the skeleton with age, it is necessary to distinguish between
Osteoporosis in Men
Microdamage
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Osteoporosis in Men Table 18.1 Methods for measuring material-level biomechanical properties Outcome variables
Specimens
Structural properties (ultimate force, stiffness and energy absorption) which are converted to material properties (ultimate stress, elastic modulus and toughness) by normalizing for bone mass and geometry
Whole bone
Ultimate stress, elastic modulus toughness
Machined cortical bone
Ultimate stress, elastic modulus toughness
Machined cortical bone or individual trabeculae Polished bone surface (trabecular or cortical bone) Machined specimens Machined cortical bone
Whole bone tests Bending Torsion Material tests Bending Tension Compression Torsion Shear Micromechanical Bending Tension Micro- and nano-indentation Ultrasound Fracture mechanics
Hardness, elastic modulus Elastic modulus Critical stress intensity factor and strain energy release rate; both measures of fracture toughness
Structural Biomechanical Properties
Material Biomechanical Properties Ultimate stress
Ultimate/Fracture Load
Energy
Displacement
mo stic Ela
Stress
s es ffn Sti
Load
du
lus
Yield load
Modulus of Toughness
Strain
Figure 18.2 Structural and material-level biomechanical properties obtained from mechanical tests.
conducted by applying a load to the bone and measuring its deformation, result in a load–deformation curve (Figure 18.2). The load-deformation curve can be divided into two portions that are separated by the yield point, the point on the curve after which the deformation of the bone is not fully recoverable if the load is released. Before the yield point, the bone deforms linearly as load increases and will return to its original shape when the load is removed; this is called elastic deformation (or pre-yield deformation). After the yield point, deformation is plastic (or post-yield deformation), meaning that damage to the structure is permanent and the structure will not recover its original shape.
The maximal load reached during the test is defined as the ultimate (or maximum) load (see Figure 18.2) and the load at fracture is called failure load. In bone, ultimate load and failure load are usually the same but, in other materials, particularly metals and plastics, failure load can be substantially less than ultimate load due to material deformation or microdamage. The slope of the linear part of the load–deformation curve is the structural stiffness of the bone and the area under the load–deformation curve is the work (or energy) to failure. The work to failure represents the amount of energy that can be absorbed by bone before it breaks. This is an important measurement of bone fragility
C h a p t e r 1 8 The Effect of Age on Material Properties l
because traumatic injury is mostly a transfer of energy into a tissue and the capacity of the tissue to absorb energy without breaking is a major index of its resistance to fracture. To determine material-level properties from these whole bone tests, it is necessary to adjust for aspects of bone size, mass and geometry/architecture. This is done by converting load values to stress (defined as load/area) and deformation values to strain (defined as a percent change in length) and creating a stress–strain curve (see Figure 18.2). The stress– strain curve defines the amount of strain required to generate a unit of stress in the bone tissue. For whole bone tests, most often three- or four-point bending, factors such as bone diameter and cross-sectional moment of inertia are used to derive stress from load and strain from displacement. However, material-level properties derived from whole bone tests are often inaccurate due to testing issues discussed below. For trabecular bone tests, either of isolated trabecular bone specimens or of sites where the majority of the tissue is trabecular bone (such as vertebra), factors such as specimen height, specimen cross-sectional area and bone volume are used to normalize for bone size and trabecular density. However, it is important to note that tests of trabecular bone specimens, even after normalizing for trabecular density and geometry, provide only an estimate of the material properties of bone. To assess the true material properties of trabecular bone, it is necessary to conduct either micro- or nano-indentation of trabecular bone or micro-mechanical testing of an individual trabecula [3]. As these latter tests are very difficult to do, the literature concerning trabecular material properties is limited. The same features defined on the load–displacement curve can be derived from the stress–strain curve (see Figure 18.2), but these features are related to the tissuelevel strength, stiffness or energy absorption capacity, independent of geometry. The stress achieved at yield, called yield stress, when permanent damage is sustained within the bone, is one measure of material strength. Another measure of strength is the maximum stress achieved before failure, called the ultimate stress, and for bone is generally the same as its breaking stress. The slope of the linear part of the stress–strain curve is material stiffness, often referred to as the elastic (or Young’s) modulus. The area under the stress–strain curve is referred to as the modulus of toughness (in units of N-m/m3 or Joules/m3), which is analogous to the work to failure measurement discussed above. As the units indicate, this is a volumetric measurement of toughness. Similar to the load–deformation curve, the stress–strain curve can be divided into pre-yield and postyield regions. This division can provide a lot of information about the propensity of the bone tissue towards damage and the nature of the mechanisms of its failure. A material that sustains little post-yield strain (and therefore has low post-yield toughness) before fracture is brittle, whereas one that sustains much post-yield strain (having high postyield toughness) is considered ductile. As bone tissue ages, it becomes more brittle and less tough, meaning that it can
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absorb less energy before it breaks. The underlying causes of these changes will be discussed in more detail later. Most whole bone tests are done in bending and, while this is a convenient way to conduct testing, the derived material properties can be inaccurate. The major problem is the short length compared to width of most bones. The aspect ratio (length:width) for a proper bending test specimen should be around 16:1 [4] yet, for most long bones is 5:1, resulting in substantial shear and bending deformation during testing. In addition whole bones are hollow cylinders and undergo ‘ring deformation’ when loaded and this contributes to experimental error [5]. These testing errors can be avoided by using standardized ‘material tests’ (see Table 18.1) with machined bone specimens, such that all are of equal dimensions and have proper aspect ratios. Such standardized test specimens are limited to cortical bone, as trabecular bone specimens of the same gross dimensions still have varying fractional bone volumes (i.e. bone volume/tissue volume), with an intrinsic component of architecture (e.g. trabecular thickness, number and connectivity, with some preferred orientation called anisotropy). In addition, micro- and nano-indentation mechanical testing provides direct measures of some material properties (see Table 18.1) and can be conducted on both cortical and trabecular bone. These tests provide measures of material hardness and modulus yet do not assess toughness. The lone method for measuring toughness of trabecular bone is to use micromechanical bending or tension of an individual trabecula; these tests can also be conducted on cortical machined specimens (see Table 18.1) [3]. Fracture mechanics testing utilizes machined cortical bone specimens to determine alternative measures of bone toughness, specifically characteristics of crack propagation and subsequent fracture mechanisms. While parameters of material strength (ultimate stress) and stiffness (elastic modulus) are relatively easy to define, the parameter of toughness can be obtained through various methods, each with a unique meaning. Toughness is important in bone biomechanics because a tough bone will be more resistant to fracture; it also is the biomechanical property most affected by aging as outlined in subsequent sections. The modulus of toughness, measured as the area under the stress–strain curve (in units of N-m/m3 or Joules/m3), is a volumetric measurement of toughness. The stress intensity factor KIc (in N/m or Joules/m2), measured by fracture mechanics tests, is a planar measure of fracture toughness that indicates how easily cracks initiate or grow in a tissue. Although these are measurements of different aspects of bone quality, they tend to follow similar trends with age.
Changes to biomechanical material properties with age There is ample literature showing that the biomechanical properties of bone decline with age in both men and
Osteoporosis in Men
women [6]. Both structural and material biomechanical properties of bone peak between the ages of 20 and 39 and decline thereafter (Figure 18.3) [2, 6]. Changes in tissue modulus are the slowest with age, declining only 0–2% per decade [2, 7, 8]. ultimate stress, or strength of the tissue, shows a greater age-related change, decreasing 2–5% per decade [2, 7, 8]. Ultimate strain, a measure of the tissue’s deformation prior to failure, declines nearly 6% per decade. Work to failure changes are the greatest, with declines of 7–12% per decade [2, 7, 8]. It is important to note, however, that variation in anatomical location as well as almost every parameter associated with biomechanical testing (loading mode, rate, direction) affect mechanical properties [8, 9]. This makes generalization among results difficult and leads to a fair amount of variability in the literature. Even so, age-related changes in material properties are clearly evident by the increased risk of fracture at the most common sites of age-related fracture (e.g. vertebra, radius, hip). Even at equivalent bone mass, a woman’s risk of fracturing her radius when she is in her 70s is four times her risk a decade earlier [10]. Similarly, there is a 2.5- to 3.0-fold increase in risk of hip fracture in women during the same period, at equivalent bone densities [11]. At lower bone densities, the effects of age-related declines in material properties on fracture risk are even greater [12]. The predominant age-associated biomechanical change is reduced material toughness, evident through the nearly 30% decline in ultimate strain and over 40% decline in toughness by the ninth decade of life relative to the maximal value during adulthood (see Figure 18.3). Both tissue strain and toughness are important biomechanically because their decline results in a tissue that is more brittle and thus more prone to fracture. This is particularly relevant in impact-related fractures, such
Age, yr
Elastic modulus, GPa
Ultimate stress, MN/m2
Ultimate strain, µε
20–29
17.0 (2.24)
140 (10)
34,000 (6700)
3.85 (1.10)
30–39
17.6 (0.28)
136 (3.5)
32,000 (9200)
3.55 (0.98)
40–49
17.7 (4.45)
139 (10.7)
30,000 (4000)
3.19 (0.53)
50–59
16.6 (1.74)
131 (12.6)
28,000 (5900)
2.84 (0.61)
60–69
17.1 (2.21)
129 (6.4)
25,000 (5500)
2.65 (0.78)
70–79
16.3 (1.78)
129 (5.5)
25,000 (6000)
2.57 (0.68)
80–89
15.6 (0.71)
120 (7.1)
24,000 (2100)
2.23 (0.12)
as those that occur at the hip with falling. The impact of a fall imparts energy into the bone and a bone that is tough can absorb substantial amounts of energy while one that is less tough (or more brittle) cannot. The strength and stiffness of a bone are less important in this situation. The classic example of the importance of toughness over stiffness is osteopetrotic bone. People with osteopetrosis are known to sustain fractures easily, despite having bone that is considerably stiffer than normal bone. As bone toughness is a clear determinant of fracture risk, its age-related decline appears mostly responsible for the age-related increase in bone tissue fragility.
Mineral effects in age-related material property alterations The principal material components of bone include mineral and collagen which together form a physiologically mineralized connective tissue matrix. The mineral component can be described at two levels, one at the nano-scale (comprised of small crystals of hydroxyapatite) and one at the microscale (the mean density of the tissue). Mineral crystals are not static, that is they can change with time both in size and purity. These changes are influenced by a number of factors, including properties of the collagen, diet, age, rate of turnover and various drugs [13]. Properties of the crystals form the foundation for tissuelevel mineralization, often referred to as bone mineral density distribution (BMDD) or the mean degree of mineralization of bone (MDMB). It is important to differentiate BMDD and MDMB from bone mineral density (BMD). BMD is often
Elastic modulus
Toughness, MN/m2 Percent change from 3rd decade to 9th decade
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0
Ultimate stress
Ultimate strain
Toughness
–10
–20
–30
–40
–50
Figure 18.3 Age-related changes in material-level biomechanical properties of human femora. Aging adversely affects ultimate strain and toughness, both indicators of increased tissue brittleness. Lesser effects of aging are seen for elastic modulus and ultimate stress. Data expressed as mean (SD). (Adapted from Burstein et al. Aging of bone tissue: mechanical properties. J Bone Joint Surg 1976;58A(1):82–86 [2]).
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Percent of bone area
measured clinically and provides a measure of density that is dependent on both the amount of bone and its mineralization. Conversely, BMDD (and MDMB), which can only be measured ex vivo, provides measures specific to tissue mineralization regardless of the amount of bone. Analysis of BMDD provides two key properties of the material mineralization, the average tissue mineralization and the degree of heterogeneity of the mineral throughout a section (Figure 18.4) [15, 16]. These parameters, dictated predominately by the rate of bone remodeling, are often considered indices of mean tissue age and have significant effects on biomechanical properties of the tissue. Because bone is constructed as a heterogeneous composite material, the tissue itself has areas that are more highly mineralized, interspersed with those that are less highly mineralized (Figure 18.5). This has an important mechanical effect that will delay a crack from propagating through and fracturing bone – just as it does other heterogeneous composite materials (indeed, this is why some composite materials are constructed in this way). Typically, materials that prevent the growth of cracks, even if they are not very effective at preventing the initiation of cracks, are tough – that is, they require a lot of energy to cause failure at the tissue level. Glass is not very tough; when cracks start, they grow easily, as anyone closely following a truck in their car has learned. Fiberglass, on the other hand is very tough; when cracks are initiated, their growth is stopped by the fibers that are embedded in the material. Bone is much closer to fiberglass than to glass and can be considered a relatively tough material.
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Biomechanically, the mineral component of the bone provides stiffness. Increases in mineral properties, either crystal size [17] or in average tissue-level mineralization [18, 19], are positively associated with stiffness of the tissue. Reductions in average mineralization result in bones that are more compliant (less stiff) [20]. Clinically, fractures occur both in those patients with the highest, and those in the lowest, mineralization quartiles [21]. Stiffness tends to be inversely correlated to toughness, so bone that is more highly mineralized and, consequently, stiffer, is also less tough [22]. This is a common trade-off among the biomechanical properties, where modifications which make the tissue stiffer make it more brittle and vice versa [23]. Indeed, Currey et al [24, 25] demonstrated that increasing amounts of mineralization – even mineralization within the normal physiological range – can reduce the energy required to fracture a bone either in impact (as in a fall on the hip), or in less traumatic overloading of the skeleton. In fact, Currey’s data suggest that a very small increase in mineralization – on the order of 2–3% – will lead to a 20% decrease in the energy required for fracture. Surprisingly, age-related changes to bone mineralization are not unequivocally defined but rather are highly variable. Although conventional wisdom is that aging results in more highly mineralized bone and reduced heterogeneity, there is no consensus in the existing literature. Tissue mineralization has been shown to increase, decrease or remain unchanged with age [15, 22, 26–35]. This variability likely has multiple sources including the experimental technique used for assessment of mineralization, the anatomical location of analysis and numerous factors associated with the individual from whom the tissue is obtained. Low bone turnover leads to increases in average tissue mineralization and reductions
Cawidth CaMean Calcium concentration (weight% or g/cm3)
Figure 18.4 Parameters of bone mineralization density distribution (BMDD). While several parameters can be obtained from these analyses, the two key outcome variables are: (1) the mean calcium concentration (CaMean), defined as the area under the curve, which is a measure of the average tissue mineralization; and (2) the width of the curve (CaWidth), defined as the full width of the curve at half of the maximum height (FWHM), which is a measure of mineralization heterogeneity across the tissue. (Adapted from Roschger P, Gupta HS, Berzlanovich A et al. Constant mineralization density distribution in cancellous human bone. Bone 2003;32(3):316-23 [14]).
Figure 18.5 Microradiograph depicting mineralization levels in bone. Gray values correspond to level of mineralization with lighter regions having higher mineral content. The average level of tissue mineralization and the heterogeneity of mineralization within a tissue each have significant effects on the biomechanical properties of bone, yet age-related changes to these parameters remain unclear. Image courtesy of Dr W. Eugene Roberts, Indiana University School of Dentistry.
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in mineralization heterogeneity; high bone turnover reduces average tissue mineralization and increases mineralization heterogeneity. Thus, any factor that modulates turnover has significant influence on the mineralization of the tissue [36]. Differences in dietary calcium and vitamin D can also directly affect mineralization [36, 37]. Thus, a significant proportion of the variability in mineralization data from studies using cadaver tissue are likely due to the presence of underlying conditions which affect turnover (e.g. hormonal status, time since menopause) or differences in dietary intake. Additionally, future studies using cadavers are likely to be influenced by the high proportion of individuals who have taken bisphosphonates, which increase average tissue mineralization and reduce heterogeneity [38, 39]. These challenges in controlling variables are likely to lead to continued lack of clarity concerning age-related changes to tissue mineralization. More consistent age-related changes have been shown with respect to mineral crystals. Age does not change average crystallinity, although crystallinity becomes more homogeneous with age [22, 26]. Mineral crystals do get larger with age [22, 26, 40, 41]. These crystal changes alter local stress distributions in the tissue, potentially permitting earlier crack initiation by decreasing the amount of plastic deformation that can occur before ultimate failure. These changes would be expected to contribute to the reduced toughness that occurs with age.
Collagen effects in age-related material property alterations The organic matrix is predominately comprised of type I collagen, complemented with a number of non-collagenous
proteins. Collagen undergoes various post-translational modifications including stabilization by both intra- and inter-molecular cross-links formed through enzymatic and non-enzymatic processes (Figure 18.6) [42]. Trivalent enzymatic cross-links, such as pyridinoline (PYD) and deoxypyridinoline (DPD), are generally used as a measure of mature collagen [42]. Advanced glycation end-products (AGEs) form non-enzymatic cross-links through a condensation process of arginine, lysine and ribose [43, 44]. AGEformation occurs over a period of years [43], so proteins with long half-lives, such as collagen, can accumulate substantial AGEs with age [45]. Several AGEs exist in bone including pentosidine, vesperlysine, imidazolone, N-carboxymethyllysine (CML) and furosine. Although pentosidine constitutes the smallest fraction of non-enzymatically-glycated (NEG) cross-links, it is routinely used as an index of NEG content. Alternatively, it is possible to measure total AGE content using a more technically advanced fluorescence method. Distinction between enzymatic and non-enzymatic cross-links is important as they exhibit different age-related changes and have distinct effects on mechanical properties. The amount, structure and organization of collagen all affect biomechanical properties of bone [42, 46, 47]. With aging, collagen content either remains stable [48–50] or declines [51–53]. In instances where collagen content is lower with age, these changes have been shown to be the single best predictor of age-related declines in failure energy [52]. Changes in the orientation of the collagen fibers [54], have a small, but detectable, influence on bone strength and stiffness [48, 55–57]. Collagen fibers are more frequently oriented in the transverse direction in older individuals, as compared to preferentially longitudinal in younger individuals [58]; longitudinal orientation of collagen is thought to be better able to withstand tensile forces [54]. There are also significant age-related changes to collagen integrity
Enzymatic collagen cross-links
Non-enzymatic collagen cross-links
Figure 18.6 Collagen cross-links are formed through enzymatic and non-enzymatic processes. These two classes of cross-links have unique and different effects on the bone’s biomechanical properties. Aging has minimal effects on the amount of enzymatic cross-linking in bone, yet there are significant age-related increases in non-enzymatic cross-links, which decrease the toughness of bone.
C h a p t e r 1 8 The Effect of Age on Material Properties l
[48, 59], such as denaturation of the collagen at the time of formation [60, 61] and this is associated more with declines in toughness [25, 61]. The most significant effect of collagen is on toughness because it dictates the post-yield properties of the tissue [46, 62–64]. The ratio of PYD to DPD is minimally changed with age, but has been shown to be affected by treatments that alter bone turnover. An increase in the PYD/DPD ratio has been related to increased compressive strength and stiffness in bone [65–69], but has minimal effects on toughness [48, 49, 62, 70]. Conversely, age-related increases in nonenzymatic cross-links (AGEs) are significant and have perhaps the most profound effects on biomechanical declines in toughness. AGEs are inversely correlated to bone toughness [71–74] and account for up to 35% of the variation in bone toughness in both cortical [62] and trabecular bone [74]. This is likely a consequence of increased brittleness: increased pentosidine concentration in bone reduces the ultimate strain [48] and post-yield deformation in bone [62, 72, 73] and is highly correlated (r2 0.60) to creep rate. The mechanism through which AGEs reduce toughness are not completely known, but it likely is related to their presence creating focal stress concentrations around existing cracks and permitting crack coalescence [75]. This is consistent with the findings that increased non-enzymatic cross-linking makes tissue more brittle by preventing the stress relaxation caused by crack initiation and/or by allowing cracks that are created to grow more easily [76, 77]. Additionally, NEGs have been shown to reduce collagen fibril diameter and alter collagen orientation and organization [78], changes that could also contribute to the adverse effects on toughness [79]. Several studies have documented a significantly higher concentration of pentosidine in serum [80] and bone [81, 82] of patients with fracture compared to non-fracture controls. Whereas in non-fracture subjects, AGEs accumulate more in the highly mineralized (and therefore older) fraction of bone, pentosidine content is greater in the newer, less mineralized bone in those subjects who sustained a fracture [82]. This suggests that there is a change in the glycation of new bone that promotes and accelerates the formation of non-enzymatic cross-links in the population of patients who fracture. The negative mechanical effects of AGE accumulation are supported in studies of diabetes. Because non-enzymatic cross-linking of collagen occurs in the presence of extracellular sugars, diabetic bone is known to have significant accumulation of AGEs [83, 84]. Given the known effects of AGE accumulation on bone toughness, the increased fracture risk in patients with adult-onset diabetes may be explained by the enhanced non-enzymatic cross-linking of collagen due to the accumulation of AGEs [78]. Although no data exist in human bone directly linking higher AGE levels and reduced toughness in patients with diabetes, animal models have
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clearly established such a relationship [85–88]. Reductions in bone toughness occur in an age-dependent manner and temporally match the onset of hyperglycemia in rat models of diabetes [87]. These negative changes in toughness are independent of BMD, but are significantly correlated to concentrations of pentosidine in the bone. Concentrations of enzymatic cross-links increase in human bone collagen up to the age of about 10–15 years [57] and thereafter remain constant [60–62] or decline slightly [50, 89]. AGE-formation occurs over a period of years [43], so proteins with long half-lives, such as bone collagen, can accumulate substantial AGEs with age [45]. AGEs accumulate in human blood [90] and bone [49, 53, 62, 77, 89] with age. Skeletal concentrations of pentosidine were found to have doubled in tissue from people aged 50–69 compared to those aged 19–49; bone from individuals aged 70–89 had levels that were more than threefold higher compared to the youngest cohort [60–62].
Microdamage effects in agerelated material property alterations Microdamage, small physiologically-formed cracks within the bone matrix, exists throughout the skeleton and plays an important role in skeletal physiology (Figure 18.7) [91, 92]. The physiological function of microdamage is to signal bone remodeling [93]. The mechanical function of microdamage is to dissipate energy [94, 95] and, therefore, the formation of microcracks is an important mechanism for preventing fracture. Yet microdamage, specifically its coalescence into a macrocrack, is the underlying foundation of fracture [8]. This results in the need for fine regulation and control of microdamage accumulation as a small amount is necessary, yet too much can be detrimental to the bone’s ability to resist fracture. All other things being equal, higher levels of microdamage compromise bone biomechanical properties [94, 95]. Damage in both biological and non-biological materials is often defined by a loss of stiffness [96, 97] with a common criterion for failure when the original stiffness of a material is reduced by 30% [98]. The initiation and growth of microscopic cracks reduces the overall strength [99] and stiffness of bone [95]. Yet microdamage is also known to serve as an outlet for energy dissipation by relieving stress [100]; the inability to form microcracks results in bone failure in a more brittle (less tough) fashion. These contrasting effects of microdamage on biomechanical properties, reduction of strength and stiffness but enhanced toughness, make it difficult to predict the specific biomechanical implications of microdamage. Numerous studies have shown clear evidence that microdamage increases with age [101–107]. In both trabecular
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Figure 18.7 Microdamage accumulation increases with age due predominately to an increase in crack nucleation resulting from increased tissue brittleness. The biomechanical effects of microdamage (white arrows) are two-fold: (1) to dissipate energy (a good thing) and (2) to reduce mechanical properties (a bad thing). (See color plate section).
and cortical bone, age can explain up to 70% of the variation in microdamage accumulation in males and up to 79% in females [103]. The very large increase in microdamage accumulation begins to occur at about the age of 70 years, but does not occur in all individuals and likely does not occur equally in all bones [108]. One hallmark of the accumulation of microdamage with age is its variability across the population. This may be related to individual variability in remodeling rates, given the influence of bone turnover rate on mineralization and alterations to the collagenous matrix, both of which influence the ability of tissue to form microdamage. Bone of aged individuals is more susceptible to the formation of microcracks compared to younger bone. This is partially explained by the inverse relationship between bone volume and microdamage [106, 108] suggesting age-related bone loss is permissive for damage formation. However, even if differences in structure are accounted for, aged bone accumulates significantly more microdamage than younger bone [53, 109] suggesting an inherent change in the material with age that promotes microdamage. As there is preferential accumulation of microdamage in the interstitial bone [103, 105, 110], it is likely that material changes associated with increased mean tissue age, such as higher mineralization or changes to the collagen matrix, are responsible for the age-related increase in microdamage. Not only does the amount of microdamage increase with age (on a population basis), but the morphology of the damage is also different in aged bone. Microdamage in younger individuals tends to exist in the form of many small cracks (often called diffuse damage) while in aged individuals the microcracks tend to be longer linear cracks [103, 104,
106, 110]. Consistent with these patterns, when bone is experimentally loaded, aged bone tends to form more and longer linear microcracks compared to young bone, which forms mostly diffuse microdamage [111]. These age-related changes in characteristics of microdamage morphology are significant as the formation of diffuse microdamage is consistent with the ability to dissipate energy and resist catastrophic fracture – something aged bone appears not to do efficiently. The increase in crack length with age, from lengths in younger bone of 30–50 m to some in aged bone reaching near or above 1 mm in length [104], is also consequential as increases in microcrack length are significantly associated with reductions in bone toughness [30, 104]. In addition to higher susceptibility of aged bone to form microdamage, there also appears to be a reduced capacity to remodel the microdamage that forms. Microdamage is usually targeted by remodeling, the mechanism for keeping the accumulation low in younger bone [112–115]. Reductions in remodeling are known to be associated with accumulation of microdamage, although these data predominately derive from laboratory experiments [116, 117]; human data regarding the effects of remodeling suppression on microdamage accumulation remain inconclusive [118–120]. In men, remodeling rates, judged by change in biochemical markers of bone turnover, are lowest when they are in their 50s and 60s and do not increase again until the eighth or ninth decade [121], about the time when microdamage accumulation is observed to increase rapidly. However, in women, turnover rates tend to remain high after menopause for the rest of their lives [122]. These patterns suggest that the inability to keep microdamage accumulation at levels of younger bone may be due to an age-related breakdown in the microdamage-remodeling feedback loop with age.
Conclusions 1. Aging results in reduction in the material-level biomechanical properties of bone – modulus, stress, strain and toughness. The most profound changes are reductions in toughness and this is likely responsible for the agerelated increase in bone tissue fragility. 2. Biomechanical properties of the bone material are dictated by intrinsic properties of the bone – mineral, the organic matrix, and microdamage. 3. The effects of aging on mineralization are variable and may not significantly contribute to the consistent agerelated decrements in bone toughness (Figure 18.8). It is likely that this inconsistency is due to individual variability which means that age-related trends that cannot be easily detected on a population basis could be significant determinants of intrinsic mechanical properties in individuals.
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Mineral changes are unclear
Increased non enzymatic collagen cross-links
Reduced ultimate stress
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microdamage – is unclear and necessitates more detailed study.
References Reduced modulus
Reduced toughness
Reduced ultimate stress
Increase in fracture risk
Figure 18.8 Summary of age-related changes to material properties of bone. Aging results in dramatic increases in nonenzymatic collagen cross-linking as well as increases in microdamage; changes to bone mineral content and quality with age are variable and their effects on bone biomechanical properties are unclear (see text). These changes in the material properties have the greatest age-related negative effect on bone toughness, which likely is the property most responsible for the increase in fracture risk with age. Aging reduces bone tissue modulus, although these changes are not large in magnitude and it is unclear whether changes in modulus increase fracture risk. Note: the magnitude of effect for a given parameter is noted by the thickness of the connecting arrow.
4. Enzymatic cross-links do not change significantly with age while non-enzymatically mediated cross-links, in the form of advanced glycation end-products (AGEs) increase significantly. This non-enzymatic cross-linking is significantly correlated to a reduction in bone toughness suggesting that it may be the principal factor responsible for reductions in bone toughness and increases in fracture with age (see Figure 18.8). 5. Microdamage increases exponentially with age, but also becomes highly variable, especially after the age of 70 years. These changes are associated with reductions in tissue strength, stiffness and toughness (see Figure 18.8). However, the ability to form some discrete amount of microdamage is beneficial and actually increases the innate toughness of the tissue; this is an important component of fracture resistance. Changes to the matrix that prevent microdamage from initiating, for example increased collagen cross-linking, will reduce its overall toughness. 6. Although the mechanical properties of bone decline overall as a consequence of normal aging processes, the most clinically important message from biomechanical measurements of bone properties is that the bone’s ability to absorb energy is significantly reduced (see Figure 18.8). This seriously impairs its ability to sustain impact loads of any great magnitude and emphasizes the importance of averting falls to prevent bone fracture. 7. Whether men and women differ in age-related changes to biomechanical material properties, or any of the intrinsic components – mineral, the organic matrix and
1. B. Martin, Aging and strength of bone as a structural material, Calcif. Tissue. Int. 53 (Suppl. 1) (1993) S34–S39 discussion S39-40. 2. A.H. Burstein, D.T. Reilly, M. Martens, Aging of bone tissue: mechanical properties, J. Bone. Joint. Surg. 58A (1) (1976) 82–86. 3. J.Y. Rho, R.B. Ashman, C.H. Turner, Young’s modulus of trabecular and cortical bone material: ultrasonic and microtensile measurements, J. Biomech. 26 (2) (1993) 111–119. 4. C.H. Turner, D.B. Burr, Basic biomechanical measurements of bone: a tutorial, Bone 14 (4) (1993) 595–608. 5. J.L. Schriefer, A.G. Robling, S.J. Warden, A.J. Fournier, J.J. Mason, C.H. Turner, A comparison of mechanical properties derived from multiple skeletal sites in mice, J. Biomech. 38 (3) (2005) 467–475. 6. F.G. Evans, Mechanical Properties of Bone, Charles C Thomas, Springfield, 1973. 7. P. Zioupos, J.D. Currey, Changes in the stiffness, strength, and toughness of human cortical bone with age. Bone 22 (1) (1998) 57–66. 8. K.J. Jepsen, The aging cortex: to crack or not to crack, Osteoporos. Int. 14 (Suppl. 5) (2003) 57–66. 9. C.H. Turner, J. Rho, Y. Takano, T.Y. Tsui, G.M. Pharr, The elastic properties of trabecular and cortical bone tissues are similar: results from two microscopic measurement techniques, J. Biomech. 32 (4) (1999) 437–441. 10. S.L. Hui, C.W. Slemenda, C.C. Johnston Jr., Age and bone mass as predictors of fracture in a prospective study, J. Clin. Invest. 81 (6) (1988) 1804–1809. 11. C. De Laet, A. Oden, H. Johansson, O. Johnell, B. Jonsson, J.A. Kanis, The impact of the use of multiple risk indicators for fracture on case-finding strategies: a mathematical approach, Osteoporos. Int. 16 (3) (2005) 313–318. 12. J.A. Kanis, O. Johnell, A. Oden, A. Dawson, C. De Laet, B. Jonsson, Ten year probabilities of osteoporotic fractures according to BMD and diagnostic thresholds, Osteoporos. Int. 12 (12) (2001) 989–995. 13. A. Boskey, Bone mineral crystal size, Osteoporos. Int. 14 (Suppl 5) (2003) S16–S20 discussion S-1. 14. P. Roschger, H.S. Gupta, A. Berzlanovich, et al., Constant mineralization density distribution in cancellous human bone, Bone 32 (3) (2003) 316–323. 15. G. Boivin, P.J. Meunier, The degree of mineralization of bone tissue measured by computerized quantitative contact microradiography, Calcif. Tissue. Int. 70 (6) (2002) 503–511. 16. G. Boivin, P.J. Meunier, Methodological considerations in measurement of bone mineral content, Osteoporos. Int. 14 (Suppl. 5) (2003) S22–S27 discussion S7-8. 17. I. Jager, P. Fratzl, Mineralized collagen fibrils: a mechanical model with a staggered arrangement of mineral particles, Biophys. J. 79 (4) (2000) 1737–1746. 18. H. Follet, G. Boivin, C. Rumelhart, P.J. Meunier, The degree of mineralization is a determinant of bone strength: a study on human calcanei, Bone 34 (5) (2004) 783–789.
230
Osteoporosis in Men
19. G. Boivin, Y. Bala, A. Doublier, et al., The role of mineralization and organic matrix in the microhardness of bone tissue from controls and osteoporotic patients, Bone 43 (3) (2008) 532–538. 20. C.J. Hernandez, G.S. Beaupre, T.S. Keller, D.R. Carter, The influence of bone volume fraction and ash fraction on bone strength and modulus., Bone 29 (1) (2001) 74–78. 21. T.E. Ciarelli, D.P. Fyhrie, A.M. Parfitt, Effects of vertebral bone fragility and bone formation rate on the mineralization levels of cancellous bone from white females, Bone 32 (3) (2003) 311–315. 22. O. Akkus, A. Polyakova-Akkus, F. Adar, M.B. Schaffler, Aging of microstructural compartments in human compact bone, J. Bone Miner. Res. 18 (6) (2003) 1012–1019. 23. J. Currey, Incompatible mechanical properties in compact bone, J. Theor. Biol. 231 (4) (2004) 569–580. 24. J.D. Currey, K. Brear, P. Zioupos, G.C. Reilly, Effect of formaldehyde fixation on some mechanical properties of bovine bone. Biomaterials 16 (16) (1995) 1267–1271. 25. J.D. Currey, J. Foreman, I. Laketic, J. Mitchell, D.E. Pegg, G.C. Reilly, Effects of ionizing radiation on the mechanical properties of human bone, J. Orthop. Res. 15 (1) (1997) 111–117. 26. J.S. Yerramshetty, C. Lind, O. Akkus, The compositional and physicochemical homogeneity of male femoral cortex increases after the sixth decade, Bone 39 (6) (2006) 1236–1243. 27. S.A. Reid, A. Boyde, Changes in the mineral density distribution in human bone with age: image analysis using backscattered electrons in the SEM, J. Bone Miner. Res. 2 (1) (1987) 13–22. 28. E.D. Simmons Jr., K.P.H. Pritzker, M.D. Grynpas, Agerelated changes in the human femoral cortex, J. Orthopaed. Res. 9 (2) (1991) 155–167. 29. P. Roschger, P. Fratzl, J. Eschberger, K. Klaushofer, Validation of quantitative backscattered electron imaging for the measurement of mineral density distribution in human bone biopsies, Bone 23 (4) (1998) 319–326. 30. T.L. Norman, Y.N. Yeni, C.U. Brown, Z. Wang, Influence of microdamage on fracture toughness of the human femur and tibia., Bone 23 (3) (1998) 303–306. 31. Y.N. Yeni, C.U. Brown, T.L. Norman, Influence of bone composition and apparent density on fracture toughness of the human femur and tibia. Bone 22 (1) (1998) 79–84. 32. J.D. Currey, Changes in the impact energy absorption of bone with age, J. Biomech. 12 (6) (1979) 459–469. 33. J.D. Currey, K. Brear, P. Zioupos, The effects of ageing and changes in mineral content in degrading the toughness of human femora, J. Biomech. 29 (2) (1996) 257–260. 34. H.M. Goldman, T.G. Bromage, A. Boyde, C.D. Thomas, J.G. Clement, Intrapopulation variability in mineralization density at the human femoral mid-shaft, J. Anat. 203 (2) (2003) 243–255. 35. P. Zioupos, Ageing human bone: factors affecting its biomechanical properties and the role of collagen, J. Biomater. Appl. 15 (3) (2001) 187–229. 36. P. Roschger, E.P. Paschalis, P. Fratzl, K. Klaushofer, Bone mineralization density distribution in health and disease, Bone 42 (3) (2008) 456–466. 37. G. Boivin, P. Lips, S.M. Ott, et al., Contribution of raloxifene and calcium and vitamin D3 supplementation to the increase
38.
39.
40.
41.
42. 43. 44.
45.
46. 47.
48.
49.
50.
51.
52.
53.
54.
of the degree of mineralization of bone in postmenopausal women, J. Clin. Endocrinol. Metab. 88 (9) (2003) 4199–4205. G.Y. Boivin, P.M. Chavassieux, A.C. Santora, J. Yates, P.J. Meunier, Alendronate increases bone strength by increasing the mean degree of mineralization of bone tissue in osteoporotic women, Bone 27 (5) (2000) 687–694. P. Roschger, S. Rinnerthaler, J. Yates, G.A. Rodan, P. Fratzl, K. Klaushofer, Alendronate increases degree and uniformity of mineralization in cancellous bone and decreases the porosity in cortical bone of osteoporotic women, Bone 29 (2) (2001) 185–191. L.M. Miller, V. Vairavamurthy, M.R. Chance, et al., In situ analysis of mineral content and crystallinity in bone using infrared micro-spectroscopy of the nu(4) PO(4)(3-) vibration, Biochim. Biophys. Acta. 1527 (1-2) (2001) 11–19. E.P. Paschalis, E. DiCarlo, F. Betts, P. Sherman, R. Mendelsohn, A.L. Boskey, FTIR microspectroscopic analysis of human osteonal bone, Calcif. Tissue. Int. 59 (6) (1996) 480–487. S. Viguet-Carrin, P. Garnero, P.D. Delmas, The role of collagen in bone strength, Osteoporos. Int. 17 (3) (2006) 319–336. V.M. Monnier, Toward a Maillard reaction theory of aging, Prog. Clin. Biol. Res. 304 (1989) 1–22. A.J. Bailey, R.G. Paul, L. Knott, Mechanisms of maturation and ageing of collagen, Mech. Ageing Dev. 106 (1–2) (1998) 1–56. P. Odetti, S. Rossi, F. Monacelli, et al., Advanced glycation end products and bone loss during aging, Ann. NY. Acad. Sci. 1043 (2005) 710–717. D. Burr, The contribution of the organic matrix to bone’s material properties, Bone 31 (1) (2002) 8–11. N.C. Avery, A.J. Bailey, Enzymic and non-enzymic crosslinking mechanisms in relation to turnover of collagen: relevance to aging and exercise, Scand. J. Med. Sci. Sports 15 (4) (2005) 231–240. P. Zioupos, J.D. Currey, A.J. Hamer, The role of collagen in the declining mechanical properties of aging human cortical bone, J. Biomed. Mater. Res. 45 (2) (1999) 108–116. C.J. Hernandez, S.Y. Tang, B.M. Baumbach, et al., Trabecular microfracture and the influence of pyridinium and nonenzymatic glycation-mediated collagen cross-links, Bone 37 (6) (2005) 825–832. D.R. Eyre, I.R. Dickson, K. Van Ness, Collagen cross-linking in human bone and articular cartilage. Age-related changes in the content of mature hydroxypyridinium residues, Biochem. J. 252 (2) (1988) 495–500. A.J. Bailey, T.J. Sims, E.N. Ebbesen, J.P. Mansell, J.S. Thomsen, L. Mosekilde, Age-related changes in the biochemical properties of human cancellous bone collagen: relationship to bone strength, Calcif. Tissue Int. 65 (3) (1999) 203–210. M. Ding, M. Dalstra, C.C. Danielsen, J. Kabel, I. Hvid, F. Linde, Age variations in the properties of human tibial trabecular bone, J. Bone Joint Surg. 79B (6) (1997) 995–1002. J.S. Nyman, A. Roy, J.H. Tyler, R.L. Acuna, H.J. Gayle, X. Wang, Age-related factors affecting the postyield energy dissipation of human cortical bone, J. Orthop. Res. 25 (5) (2007) 646–655. H.M. Goldman, C.D. Thomas, J.G. Clement, T.G. Bromage, Relationships among microstructural properties of bone at the human midshaft femur, J. Anat. 206 (2) (2005) 127–139.
C h a p t e r 1 8 The Effect of Age on Material Properties l
55. F.G. Evans, R. Vincentelli, Relation of collagen fiber orientation to some mechanical properties of human cortical bone, J. Biomech. 2 (1) (1969) 63–71. 56. D.T. Reilly, A.H. Burstein, V.H. Frankel, The elastic modulus for bone, J. Biomech. 7 (3) (1974) 271–275. 57. P. Garnero, O. Borel, E. Gineyts, et al., Extracellular posttranslational modifications of collagen are major determinants of biomechanical properties of fetal bovine cortical bone, Bone 38 (3) (2006) 300–309. 58. R. Vincentelli, Relation between collagen fiber orientation and age of osteon formation in human tibial compact bone, Acta Anat. (Basel) 100 (1) (1978) 120–128. 59. C.C. Danielsen, L. Mosekilde, J. Bollerslev, Thermal stability of cortical bone collagen in relation to age in normal individuals and in individuals with osteopetrosis, Bone 15 (1) (1994) 91–96. 60. X. Wang, R.A. Bank, J.M. TeKoppele, C.M. Agrawal, The role of collagen in determining bone mechanical properties, J. Orthop. Res. 19 (6) (2001) 1021–1026. 61. X. Wang, X. Li, X. Shen, C.M. Agrawal, Age-related changes of noncalcified collagen in human cortical bone, Ann. Biomed. Eng. 31 (11) (2003) 1365–1371. 62. X. Wang, X. Shen, X. Li, C.M. Agrawal, Age-related changes in the collagen network and toughness of bone, Bone 31 (1) (2002) 1–7. 63. K.J. Jepsen, M.B. Schaffler, J.L. Kuhn, R.W. Goulet, J. Bonadio, S.A. Goldstein, Type I, collagen mutation alters the strength and fatigue behavior of Mov13 cortical tissue, J. Biomech. 30 (11–12) (1997) 1141–1147. 64. K.J. Jepsen, S.A. Goldstein, J.L. Kuhn, M.B. Schaffler, J. Bonadio, Type-I collagen mutation compromises the postyield behavior of Mov13 long bone, J. Orthop. Res. 14 (3) (1996) 493–499. 65. H. Oxlund, M. Barckman, G. Ortoft, T.T. Andreassen, Reduced concentrations of collagen cross-links are associated with reduced strength of bone, Bone 17 (4 Suppl) (1995) 365S–371S. 66. H. Oxlund, L. Mosekilde, G. Ortoft, Reduced concentration of collagen reducible cross links in human trabecular bone with respect to age and osteoporosis, Bone 19 (5) (1996) 479–484. 67. A.J. Bailey, S.F. Wotton, T.J. Sims, P.W. Thompson, Posttranslational modifications in the collagen of human osteoporotic femoral head, Biochem. Biophys. Res. Commun. 185 (3) (1992) 801–805. 68. S. Lees, D.R. Eyre, S.M. Barnard, BAPN dose dependence of mature crosslinking in bone matrix collagen of rabbit compact bone: corresponding variation of sonic velocity and equatorial diffraction spacing, Connect Tissue Res. 24 (2) (1990) 95–105. 69. X. Banse, T.J. Sims, A.J. Bailey, Mechanical properties of adult vertebral cancellous bone: correlation with collagen intermolecular cross-links, J. Bone Miner. Res. 17 (9) (2002) 1621–1628. 70. T. Keaveny, G. Morris, E. Wong, et al., Collagen status and brittleness of human cortical bone in the elderly, J. Bone Miner. Res. 18 (Suppl. 2) (2003) S307. 71. D. Vashishth, P. Wu, G. Gibson, Age-related loss in bone toughness is explained by non-enzymatic glycation of collagen, Trans. Orthop. Res. Soc. (2004) 29.
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72. J. Boxberger, D. Vashishth, Nonenzymatic glycation affects bone fracture by modifying creep and inelastic properties of collagen, Trans. Orthop. Res. Soc. (2004) 29. 73. S. Tang, A. Sharan, E. Novak, T. Ford, D. Vashishth, Nonenzymatic glycation causes loss of toughening mechanisms in human cancellous bone, Trans. Orthop. Res. Soc. (2005) 30. 74. S. Viguet-Carrin, J.P. Roux, M.E. Arlot, et al., Contribution of the advanced glycation end product pentosidine and of maturation of type I collagen to compressive biomechanical properties of human lumbar vertebrae, Bone 39 (5) (2006) 1073–1079. 75. X. Wang, C. Qian, Prediction of microdamage formation using a mineral-collagen composite model of bone, J. Biomech. 39 (4) (2006) 595–602. 76. P. Wu, C. Koharski, H. Nonnenmann, D. Vashishth, Loading on non-enzymatically glycated and damaged bone results in an instantaneous fracture, Trans. Orthop. Res. Soc. 28 (2003) 404. 77. J. Catanese, R. Bank, J. Tekoppele, T. Keaveny, Increased cross-linking by non-enzymatic glycation reduces the ductility of bone and bone collagen, Proc. ASME 1999 Bioeng. Conf. 42 (1999) 267–268. 78. L.J. Dominguez, M. Barbagallo, L. Moro, Collagen overglycosylation: a biochemical feature that may contribute to bone quality, Biochem. Biophys. Res. Commun. 330 (1) (2005) 1–4. 79. J.D. Currey, Role of collagen and other organics in the mechanical properties of bone, Osteoporos. Int. 14 (Suppl. 5) (2003) S29–S36. 80. M. Yamamoto, T. Yamaguchi, M. Yamauchi, S. Yano, T. Sugimoto, Serum pentosidine levels are positively associated with the presence of vertebral fractures in postmenopausal women with type 2 diabetes, J. Clin. Endocrinol. Metab. 93 (3) (2008) 1013–1019. 81. M. Saito, K. Fujii, K. Marumo, Degree of mineralizationrelated collagen crosslinking in the femoral neck cancellous bone in cases of hip fracture and controls, Calcif. Tissue Int. 79 (3) (2006) 160–168. 82. M. Saito, K. Fujii, S. Soshi, T. Tanaka, Reductions in degree of mineralization and enzymatic collagen cross-links and increases in glycation-induced pentosidine in the femoral neck cortex in cases of femoral neck fracture, Osteoporos. Int. 17 (7) (2006) 986–995. 83. Y. Katayama, T. Akatsu, M. Yamamoto, N. Kugai, N. Nagata, Role of nonenzymatic glycosylation of type I collagen in diabetic osteopenia, J. Bone Miner. Res. 11 (7) (1996) 931–937. 84. S. Yamagishi, K. Nakamura, T. Imaizumi, Advanced glycation end products (AGEs) and diabetic vascular complications, Curr. Diabetes Rev. 1 (2005) 93–106. 85. G.K. Reddy, L. Stehno-Bittel, S. Hamade, C.S. Enwemeka, The biomechanical integrity of bone in experimental diabetes, Diabetes Res. Clin. Pract. 54 (1) (2001) 1–8. 86. J. Verhaeghe, A.M. Suiker, T.A. Einhorn, et al., Brittle bones in spontaneously diabetic female rats cannot be predicted by bone mineral measurements: studies in diabetic and ovariectomized rats, J. Bone Miner. Res. 9 (10) (1994) 1657–1667. 87. M. Saito, K. Fujii, Y. Mori, K. Marumo, Role of collagen enzymatic and glycation induced cross-links as a determinant of bone quality in spontaneously diabetic WBN/Kob rats, Osteoporos. Int. 17 (10) (2006) 1514–1523.
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88. R. Prisby, J. Swift, S. Bloomfield, H. Hogan, M. Delp, Altered bone mass, geometry and mechanical properties during the development and progression of type 2 diabetes in the Zucker diabetic fatty rat, J. Endocrinol. (2008) 199 (3) 379–388. 89. J.S. Nyman, A. Roy, R.L. Acuna, et al., Age-related effect on the concentration of collagen crosslinks in human osteonal and interstitial bone tissue, Bone 39 (6) (2006) 1210–1217. 90. M. Takahashi, M. Oikawa, A. Nagano, Effect of age and menopause on serum concentrations of pentosidine, an advanced glycation end product, J. Gerontol. A Biol. Sci. Med. Sci. 55 (3) (2000) M137–M140. 91. S.W. Donahue, S.A. Galley, Microdamage in bone: implications for fracture, repair, remodeling, and adaptation, Crit. Rev. Biomed. Eng. 34 (3) (2006) 215–271. 92. R.B. Martin, Fatigue microdamage as an essential element of bone mechanics and biology, Calcif. Tissue Int. 73 (2) (2003) 101–107. 93. D.B. Burr, R.B. Martin, M.B. Schaffler, E.L. Radin, Bone remodeling in response to in vivo fatigue microdamage, J. Biomech. 18 (3) (1985) 189–200. 94. D. Burr, Microdamage and bone strength, Osteoporos. Int. 14 (Suppl. 5) (2003) 67–72. 95. D.B. Burr, C.H. Turner, P. Naick, et al., Does microdamage accumulation affect the mechanical properties of bone? J. Biomech. 31 (4) (1998) 337–345. 96. K.L. Reifsnider, K. Schultz, J.C. Duke, Long-term fatigue behavior of composite materials. in: Long-term behavior of composites, (Ed.) ASTM, ASTM, Philadelphia, 1983, pp. 136–59. 97. M.J. Salkind, Fatigue in Composite Materials. Composite Materials Testing and Design, 2nd Conf., Philadelphia, 1972, pp. 143–169. 98. D.R. Carter, W.E. Caler, D.M. Spengler, V.H. Frankel, Uniaxial fatigue of human cortical bone. The influence of tissue physical characteristics, J. Biomech. 14 (7) (1981) 461–470. 99. D.R. Carter, W.C. Hayes, Compact bone fatigue damage I. Residual strength and stiffness, J. Biomech. 10 (5–6) (1977) 325–337. 100. D. Vashishth, J.C. Behiri, W. Bonfield, Crack growth resistance in cortical bone: concept of microcrack toughening, J. Biomech. 30 (8) (1997) 763–769. 101. N.L. Fazzalari, M.R. Forwood, K. Smith, B.A. Manthey, P. Herreen, Assessment of cancellous bone quality in severe osteoarthrosis: bone mineral density, mechanics, and microdamage, Bone 22 (4) (1998) 381–388. 102. S. Mori, R. Harruff, W. Ambrosius, D.B. Burr, Trabecular bone volume and microdamage accumulation in the femoral heads of women with and without femoral neck fractures, Bone 21 (6) (1997) 521–526. 103. M.B. Schaffler, K. Choi, C. Milgrom, Aging and matrix microdamage accumulation in human compact bone, Bone, 17 (6) (1995) 521–525. 104. P. Zioupos, Accumulation of in-vivo fatigue microdamage and its relation to biomechanical properties in ageing human cortical bone, J. Microsc. 201 (2) (2001) 270–278.
105. T.L. Norman, Z. Wang, Microdamage of human cortical bone: incidence and morphology in long bones, Bone 20 (4) (1997) 375–379. 106. M.E. Arlot, B. Burt-Pichat, J.-P. Roux, D. Vashishth, M.L. Bouxsein, P.D. Delmas, Microarchitecture influences microdamage accumulation in human vertebral trabecular bone, J. Bone Miner. Res. 23 (10) (2008) 1613–1618. 107. T.L. Norman, T.M. Little, Y.N. Yeni, Age-related changes in porosity and mineralization and in-service damage accumulation, J. Biomech. 41 (13) (2008) 2868–2873. 108. T.E. Wenzel, M.B. Schaffler, D.P. Fyhrie, In vivo trabecular microcracks in human vertebral bone, Bone 19 (2) (1996) 89–95. 109. A.C. Courtney, W.C. Hayes, L.J. Gibson, Age-related differences in post-yield damage in human cortical bone. Experiment and model, J. Biomech. 29 (11) (1996) 1463–1471. 110. T. Diab, D. Vashishth, Morphology, localization and accumulation of in vivo microdamage in human cortical bone., Bone 40 (3) (2007) 612–618. 111. T. Diab, K.W. Condon, D.B. Burr, D. Vashishth, Age-related change in the damage morphology of human cortical bone and its role in bone fragility, Bone 38 (3) (2006) 427–431. 112. D.B. Burr, Targeted and nontargeted remodeling, Bone 30 (1) (2002) 2–4. 113. V. Bentolila, T.M. Boyce, D.P. Fyhrie, R. Drumb, T.M. Skerry, M.B. Schaffler, Intracortical remodeling in adult rat long bones after fatigue loading, Bone 23 (3) (1998) 275–281. 114. R.B. Martin, Targeted bone remodeling involves BMU steering as well as activation, Bone 40 (6) (2007) 1574–1580. 115. S. Mori, D.B. Burr, Increased intracortical remodeling following fatigue damage, Bone 14 (2) (1993) 103–109. 116. M.R. Allen, D.B. Burr, Mineralization, microdamage, and matrix: how bisphosphonates influence material properties of bone, Bonekey 4 (2) (2007) 49–60 http://www.bonekeyibms.org/cgi/content/abstract/ibmske;4/2/49. 117. M. Allen, D. Burr, Skeletal microdamage: less about biomechanics and more about remodeling, Clin. Rev. Bone Miner. Metab. 6 (1) (2008) 24–30. 118. J.J. Stepan, D.B. Burr, I. Pavo, et al., Low bone mineral density is associated with bone microdamage accumulation in postmenopausal women with osteoporosis, Bone 41 (3) (2007) 378–385. 119. R.D. Chapurlat, M. Arlot, B. Burt-Pichat, et al., Microcrack frequency and bone remodeling in postmenopausal osteoporotic women on long-term bisphosphonates: a bone biopsy study, J. Bone Miner. Res. 22 (10) (2007) 1502–1509. 120. D.B. Burr, M.R. Allen, Low bone turnover and microdamage? How and where to assess it?, J. Bone Miner. Res. 23 (7) (2008) 1150–1151 author reply 2–3. 121. D. Fatayerji, R. Eastell, Age-related changes in bone turnover in men, J. Bone Miner. Res. 14 (7) (1999) 1203–1210. 122. P. Garnero, P.D. Delmas, New developments in biochemical markers for osteoporosis, Calcif. Tissue Int. 59 (Suppl. 1) (1996) S2–S9.
Chapter
19
Calcium, Bone Strength and Fractures Laura A.G. Armas, Joan M. Lappe and Robert P. Heaney Creighton University Osteoporosis Research Center, Omaha, NE, USA
Introduction
and best studied is active transcellular transport using the calcium binding protein, calbindin. Passive transport of calcium around the intestinal cells also occurs in the presence of a large calcium load. Parathyroid glands respond quickly to very small changes in blood calcium levels. In the face of lower calcium levels, PTH secretion is increased. PTH stimulates calcium absorption through the GI tract by increasing the renal synthesis of 1,25(OH)2D in the proximal tubule. This active form of vitamin D increases the expression of the epithelial calcium channel and calbindin for optimal absorption of calcium.
Calcium is an important building block for bone. It is necessary for bone acquisition in childhood and bone maintenance in adulthood. Calcium can only be obtained from the diet, so nutrition plays a large part in bone health. We will focus on calcium in this chapter, but other nutritional elements such as vitamin D, phosphorus and protein are just as important for overall bone health. These nutrients’ effects on skeletal health are complementary and likely additive. In nature, these nutrients are packaged and consumed together and their individual effects on bone cannot be separated from each other.
Renal Calcium Reabsorption In the kidney, almost all of the calcium in the glomerular filtrate is reabsorbed in the proximal convoluted and straight tubules by passive transport around the cells. Much of this reabsorption is determined by the rate of sodium reabsorption. Sodium chloride increases urinary calcium excretion [2]. PTH plays an important role in regulating the active transcellular reabsorption of calcium in the thick ascending limb and distal tubular segments.
Calcium Physiology In addition to making up the bone matrix, calcium is an important ion in all biological systems. Intracellular calcium is important in creating and maintaining action potentials, for contraction and motility, in cytoskeletal rearrangements, for cell division, in secretion and for modulation of enzyme activity. The extracellular concentration of calcium is essential for maintaining membrane potentials, neurotransmission, muscle contraction, exocytosis and blood clotting. The total extracellular pool of calcium is about 1 gram in adults. The blood concentration of calcium is maintained in a very narrow range through a complex system of checks and balances regulated primarily by parathyroid hormone (PTH) [1]. PTH controls gastrointestinal calcium absorption, renal calcium reabsorption and skeletal resorption to maintain blood calcium levels.
Skeletal Resorption With low dietary calcium intake, extracellular calcium cannot be maintained by intestinal absorption or renal reabsorption, so calcium from the skeleton will be used to maintain serum levels. The skeleton and teeth contain 1–1.2 kg calcium or about 99% of the body’s calcium. PTH stimulates bone resorption by increasing the activity and number of osteoclasts. Osteoclasts resorb the bone matrix, freeing the calcium for extracellular use. Through this complicated set of mechanisms, the blood levels of calcium can be maintained even in the presence of florid dietary calcium deficiency, but at the expense of bone. PTH’s efforts to raise calcium levels through bone resorption have a deleterious effect on bone strength distinct from
Gastrointestinal Calcium Absorption Calcium is absorbed in the gastrointestinal (GI) tract through several mechanisms [1]. The most important Osteoporosis in Men
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the effect of physically removing calcium from bone. The increased rate of bone resorption or ‘remodeling’ structurally weakens bone and is recognized as an independent risk for fracture [3]. Remodeling creates resorption bays on the sides of trabeculae, weakening the load bearing structure. With the increased rates of remodeling seen in aging, or calcium or vitamin D deficiency, the accumulation of resorption bays contributes to the fragility of the skeleton. Any medication or supplement that slows the remodeling process (bisphosphonates, estrogen, selective estrogen receptor modulators, calcium and vitamin D) decreases skeletal fragility. Oral calcium supplements decrease bone resorption and remodeling by providing an alternative to the skeleton as a source of calcium [4].
Calcium Sources The only exogenous sources of calcium are the diet and supplements. Some foods are naturally high in calcium, including dairy foods, some nuts and some water. Some foods are also fortified with calcium including breads, cereals and juices. Dairy products are the richest dietary sources of calcium. In fact, it is difficult to get enough calcium on a dairyfree diet. One serving of dairy has approximately 300 mg of calcium in addition to protein, phosphorus, vitamins and trace minerals. Not all food sources of calcium are equally bioavailable. For example, spinach contains 122 mg of calcium per 90 g serving, but very little (about 5%) is absorbed because the oxalate in the spinach interferes with calcium absorption [5]. This can be a source of clinical confusion to patients who may be told that certain foods (such as spinach) are calcium-rich. Supplements can also be used to reach recommended levels of calcium intake. Most calcium salts (citrate, carbonate, phosphate) exhibit similar bioavailability [6,7]. Brand name products have been shown to be the most reliable. Even relatively less soluble salts, such as carbonate, absorb well if taken with food. All calcium sources should be taken with meals and in small amounts throughout the day to ensure optimal absorption.
Sources of Calcium Loss Not all calcium that is ingested is absorbed. In adults, under ideal conditions, gross intestinal absorption is about 30% at meal loads of 300 mg. In addition to absorption, calcium is also lost through GI secretions entering the digestive tract, so net absorption is only about 10–15%. There are other sources of calcium loss, including sweat and urine. A substantial amount can be lost in sweat. A study in college basketball players found about 422 mg of calcium was lost in sweat during each training session. This was not inconsequential as the players also lost bone density throughout the basketball season (a decrease of 6.1% in total body bone mineral content (BMC) and a decrease of 10.5% in leg BMC) [8]. Calcium can also be lost through urine. Several
factors can interfere with the reabsorption of calcium in the kidney, including sodium and sulfate (derived in the metabolism of sulfur-containing amino acids). The net result of calcium output from GI secretions, sweat and urine in a sedentary adult is an obligatory calcium loss of 150–240 mg/d. In order just to maintain calcium balance, adults must absorb at least as much calcium from dietary intake. With a net absorption of 10–15%, this would require a dietary calcium intake of at least 1000–1500 mg/d in a typical adult. We know that many people fall short of meeting this intake.
Calcium Requirements Men tend to have slightly better calcium intakes than women but, even so, they also do not reach recommended intake levels. From the NHANES-III database, the median intake of calcium by men of all ages was 856 mg/d which is less than the recommended intake for adults or the elderly (Table 19.1). Men over age 60 were more likely to have low intakes with a median calcium intake of 716 mg/day from food. Only 29% of white, 9% of black and 14% of Mexican American adult males reported using calcium supplements [10] and, even with supplement use, only 42% of all males reached the recommended intake [11]. Male minorities were at especially high risk of low calcium intake [3].
Calcium’s Threshold Calcium is a threshold nutrient, i.e. there exists an intake level below which bone accretion varies with intake and above which bone accretion appears to be constant, regardless of intake. Above the threshold, the amount of bone accrued is dependent on genetic programming along with mechanical loading. However, below the threshold of intake, the skeleton does not retain enough calcium to build the amount of bone for which it was programmed [12]. Because of this threshold effect, we do need to be careful in interpreting studies of nutrients including calcium. Adding calcium to an already replete diet will not have additional effect and may be interpreted as having no effect. In many of the studies of calcium, the calcium effect was seen only in subjects who had a very low baseline intake. This effect can be assumed to be a result of increasing the subjects’ calcium intake closer to recommended levels. A good example of this was the Women’s Health Initiative Table 19.1 Dietary reference intakes for calcium [9] Childhood Adolescence Adult (19–50 yrs) Older adults (50years)
500–800 mg 1300 mg 1000 mg 1200 mg
C h a p t e r 1 9 Calcium, Bone Strength and Fractures l
(WHI) trial that added 1000 mg Ca2/d and 400 IU Vitamin D/d in the interventional group [13]. Overall, they did not see much of an effect on fractures, partly because the average baseline calcium intake was about 1150 mg/d, which is adequate for many people. The investigators noted in their report that the supplementation seemed to be more effective in those with low personal calcium supplementation which makes sense as calcium has a threshold effect and above a certain intake the excess would be excreted. Nutrient studies are particularly difficult to interpret because, unlike drug studies, there is never a placebo or control group that is completely free of the nutrient being evaluated. Everyone in the placebo group will be getting some, and perhaps a lot of, a particular nutrient from their normal dietary intake [14].
Calcium and Bone Strength Bone strength is the bone’s resistance to fracture. It is difficult to quantify exactly what makes up the ‘strength’ of bone. It is related to, but not equivalent with, bone mineral density (BMD). BMD is a strong predictor of fracture, but there are also other factors, such as bone structure, bone remodeling and the newly coined term ‘bone quality’ to consider. At this time, we can easily measure BMD clinically and new technologies such as peripheral quantitative computed tomography (pQCT) or micro-magnetic resonance imaging (MRI) are used in research to quantify bone structure. Remodeling can be assessed with bone markers in research studies, although their variability makes them less helpful in the individual patient. On the other hand, bone quality is an elusive term that encompasses the architecture/geometry and the material properties of bone and bone tissue. Investigators are still finding ways to define and measure bone quality. We have very few data on calcium’s effects on bone structure and quality so this section will focus mainly on bone mineral density as a surrogate marker for bone strength, albeit not a perfect one.
Evidence of calcium’s effect on BMD in adults In the mid-1990s, there were a series of trials that looked at calcium’s effect on BMD. Some trials also supplemented vitamin D, although vitamin D was obtained to some degree from sun and/or diet in all the trials. Vitamin D plays an important role by increasing active calcium absorption. In the face of vitamin D deficiency, a higher level of dietary calcium is needed to have adequate calcium absorption. If the levels of 25-hydroxyvitamin D were reported, it is helpful in interpreting the calcium effects but, unfortunately, in some studies, vitamin D status was not measured or reported. There are several studies showing that calcium supplementation alone does
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have an effect on bone mineral density. A meta-analysis of 15 of these trials in postmenopausal women using calcium supplements alone versus placebo found a small but significant effect on bone density [15]. They reported 2.05% increase in total body BMD, 1.66% increase in lumbar spine BMD and 1.64% increase in hip BMD. A study by Dawson-Hughes et al found that adding 500 mg calcium daily in postmenopausal women with very low calcium intakes (400 mg/d) maintained bone density in the femoral neck and radius and decreased the loss from the spine [16]. The majority of these women were vitamin D deficient (80 nmol/L) during the winter months and many were deficient during the summer months as well [17]. Another 4-year study of postmenopausal women with a mean baseline dietary calcium intake of 700 mg/d and 25-hydroxyvitamin D levels of 75 nmol/L showed reduced bone loss, as measured by dual energy x-ray absorptiometry (DXA), and decreased parathyroid hormone levels when supplemented with 1600 mg calcium citrate/d compared to women on placebo [18].
Bone Mineral Density in Men While some gender differences in calcium and bone accretion are known, such as hormonal influences, bone size, etc, not all differences are known. Many of the osteoporosis studies were done exclusively in postmenopausal females. A handful of studies of calcium’s effects on BMD have included men in their study design and calcium has been shown to have a beneficial effect on BMD in men as well. The Osteoporotic Fracture in Men Study was an observational multicenter study of osteoporosis risk factors in men [19]. This study found a positive relationship between dietary calcium intake and bone mineral density. The Rotterdam study, another large observational study of the elderly including men, found that the rate of age-related bone loss was slowed in men with higher dietary calcium intake [20]. Peacock et al showed maintenance of hip bone density measured by DXA, increased cortical thickness in the femoral shaft as measured by standard x-ray, decreased parathyroid hormone and decreased bone remodeling markers with the addition of 750 mg/d of additional calcium in a group of elderly men and women [21]. It is important to note that the subjects had a low baseline intake of about 546 mg Ca/d and 25-hydroxyvitamin D levels of 65 nmol/L. This additional calcium treatment had an observed effect by bringing most subjects into the recommended calcium intake ranges. Many of these studies were done in older subjects, but calcium also plays a role in maintaining bone mass in young healthy people. In a study of basketball players, aged 18–22, those who lost bone density during the playing season tended to have dietary calcium intakes 2000 mg/d [8]. Using additional calcium supplements in those with ‘low’ (2000 mg/d) dietary calcium intake reversed the bone loss. Few studies have been done in minorities, but what limited data we have point to differences in calcium accretion between
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races which are likely genetic. For example, African Americans have more efficient calcium retention than Caucasians, with lower urinary calcium loss and, at some ages, higher gastrointestinal calcium absorption [22]. African Americans also have higher bone mineral density than Caucasians and thus have lower propensity to fracture. The Osteoporotic Fracture in Men Study noted that African American men had 6–11% higher bone mineral density than Caucasian men [19]. This is despite evidence that African Americans have lower calcium intakes than whites. Their skeletons exhibit relative resistance to PTH [22,23] and hence to have better adaptation to a lower calcium diet. But calcium’s role in African American’s overall health cannot be disregarded since low calcium and the subsequent high parathyroid hormone response affects other body systems and may predispose them to hypertension and obesity [24]. In the last decade or so, the importance of vitamin D in improving calcium absorption has been recognized. The previous studies of bone health had focused on calcium without additional vitamin D supplementation. Since these nutrients work in conjunction with each other and are now often packaged together in supplements, we recognize that their effects should be examined together. All osteoporotic medications that are currently available were tested in conjunction with calcium. The more recent trials have used both calcium and vitamin D in efforts to increase bone mineral density and, consequently, decrease fracture. A study of elderly (65 years) men and women with low baseline calcium intakes (mean 748 mg/d) who were given additional 500 mg/ d calcium and 700 IU/d vitamin D improved bone density while the placebo group lost bone [25]. A similar study in middle-aged men used an additional 1000 mg calcium/d and 1000 IU vitamin D/d over three years and did not find an effect on bone density. This was likely because the baseline calcium intake was already adequate (mean 1159 mg/d) and above the threshold intake needed for optimal effect [26]. Adding additional calcium provided no additional benefit. An Australian study using 1000 mg of calcium and 800 IU of vitamin D3 from fortified milk for two years in men over the age of 50 showed that the rate of bone loss as measured by areal BMD by DXA was reduced [13]. The majority of these men had a baseline dietary calcium intake below 1000 mg/d and 50% had 25-hydroxyvitamin D levels 77 nmol/L. These are only a few of over 50 trials that have supported calcium’s role in lowering rates of bone loss in adults and the elderly [27]. As osteoporosis was originally recognized as a disease of primarily elderly women, many of these trials were done in women and many were postmenopausal women. There is need for more controlled trials in men of various ages and ethnicities.
Calcium and fractures Calcium decreases fractures, most likely through decreasing PTH’s resorption of the bone. There have been multiple trials
of calcium’s effect on fractures. These have been done with and without additional vitamin D. The results are somewhat confusing because of different trial designs, compliance with treatment and the subjects’ baseline dietary calcium intake. Trials that used only calcium to prevent fractures have had mixed results. Bischoff-Ferrari et al, in a meta-analysis of prospective cohort studies in men and women and randomized controlled trials of calcium’s effect on hip fractures in postmenopausal women, found a slight risk reduction for all non-vertebral fractures but an increased risk of hip fractures in trials that used calcium only. The authors speculated that other nutrients such as vitamin D or phosphorus may be needed in addition to calcium to prevent a hip fracture [28]. A more recent meta-analysis looked at 29 trials of calcium supplementation or calcium and vitamin D supplementation on fracture risk [29]. This meta-analysis included nearly 64 000 subjects, men and women over age 50. They found a 12% risk reduction in all fractures with calcium. This metaanalysis also pointed out several subtleties in the various trials that affected the outcome. They noted that trials with a higher compliance rate had greater fracture risk reduction. In fact, trials with compliance rates of 80% showed twice as much risk reduction as those trials with low compliance. The fracture risk reduction with calcium was seen in both men and women. Calcium also prevented fractures in those subjects with a previous fracture history. Those subjects with the lowest 25-hydroxyvitamin D levels at baseline had a greater risk reduction with treatment than those with adequate baseline 25-hydroxyvitamin D levels, pointing to a likely threshold effect of vitamin D. The same was true of calcium; those subjects with low baseline calcium intakes had a greater benefit from calcium supplements. The authors concluded that the greatest fracture risk reduction was with 1200 mg/d calcium and 800 IU vitamin D. They calculated that 63 people would need to be treated to prevent one fracture which, considering the low cost of calcium and vitamin D, has an excellent cost–benefit ratio [29]. Another meta-analysis compared five trials of calcium and vitamin D versus placebo to four trials of vitamin D versus placebo [30]. The authors found a protective effect against hip fracture (and other non-vertebral fractures) when both calcium and vitamin D were used (RR 0.82). The number needed to treat to prevent one hip fracture was 276 and the number needed to treat to prevent one nonvertebral fracture was 72. The authors also recommended supplementation (700–800 IU vitamin D and 1000–1200 mg calcium daily) at levels similar to the previous meta-analysis [29]. They concluded that both calcium and vitamin D were necessary to prevent fracture [30]. Since that meta-analysis was published, Bischoff-Ferrari published a secondary analysis of the Calcium Polyp Prevention Study, a 4-year controlled trial of 3 g calcium carbonate versus placebo [31]. This trial was originally undertaken to prevent colon cancer in patients with polyps. The subjects were predominantly male with a mean age of 61 years. They had a baseline calcium intake of 890 mg/d and 25-hydroxyvitamin D levels were
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73 nmol/L. The compliance with treatment was about 90% in over 75% of the subjects and, during the intervention, the fracture hazard ratio was 0.28 for the calcium group. The cohort was followed after the intervention was completed and the fracture reduction was not sustained, indicating that continuous calcium is needed to prevent fractures. This is likely because remodeling increases immediately when calcium intake drops, as the extracellular pool of calcium continues to lose calcium through sweat, urine and gastrointestinal secretions and needs a constant source of calcium. Calcium and vitamin D supplementation has been shown to reduce fractures in young adults as well. Lappe et al supplemented over 5000 female military recruits with 2000 mg/d of calcium and 800 IU/d of vitamin D or placebo [32]. There was a 20% lower incidence of stress fractures in the recruits on calcium and vitamin D. There have been some trials that have found no effect of calcium and/or vitamin D on fractures. These are a source of confusion for patients and physicians alike. In Britain, Porthouse et al did a randomized trial of 1000 mg Ca/d plus 800 IU vitamin D/d in elderly women [33]. They did not see an effect on fractures, but they had difficulties with compliance – only 55% were compliant at 2 years. The subjects also had a high baseline calcium intake (over 1000 mg/d). In fact, both the interventional and control groups had lower fracture rates than was predicted from previous studies. This was most likely because of the high baseline dietary calcium intake. The authors noted in their conclusion that the power of this study was reduced considerably because of the low fracture rate and high drop-out rate [33]. The Women’s Health Initiative trial is another source of potential confusion. The subjects had a high personal calcium intake (1150 mg/d) and many were on concurrent hormone replacement which would reduce fracture in and of itself. They also had difficulty with compliance in the subjects. Despite these limitations, there was a 29% reduction in hip fracture in patients who had a low baseline calcium intake and complied with the treatment [34]. The RECORD trial was another trial which did not observe a benefit from taking calcium 1000 mg/d and/or vitamin D 800 IU/d to prevent fractures [35]. Again, compliance was a problem – only 54% of the subjects were taking tablets at the end of 2 years. This trial also reported fewer fractures than was previously predicted in both the intervention and control groups. Based on the evidence that calcium increases bone density and reduces fracture rates, optimal calcium nutrition should be assured with the advent of newer osteoporosis medications. With many medications available for the prevention of fractures, calcium’s adjunctive role is sometimes forgotten. Drugs supply a stimulus for bone, but not the raw materials out of which bone is built. Calcium has an additive effect with other bone active medications [36]. All the randomized controlled trials (RCT) of osteoporosis medications including alendronate, risedronate, ibandronate, raloxifene, calcitonin and teriparatide were done with calcium- and most
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with vitamin D-treated subjects. Even the placebo-treated subjects in the control groups were treated with calcium and vitamin D. So patients treated with these medications must be treated with calcium and vitamin D in adequate quantities to expect the same results in increasing bone mineral density and decreasing fracture risk. In fact, the newer intravenous (I-V) forms of bisphosphonate treatment require calcium supplementation because they immediately lower bone resorption, limiting the skeletal availability of calcium. Blood levels of calcium can drop precipitously if there is not adequate dietary calcium intake [37].
Children and calcium The relationship between calcium and bone strength is found from childhood through adulthood. Although we have focused mainly on men and calcium in this chapter, the effect of childhood calcium intake on the adult skeleton bears mention. Optimum childhood skeletal development is critical for preventing osteoporosis in adulthood [38–41]. Growing children and adolescents are depositing large amounts of calcium in their skeletons. Thus, calcium deficiency during formation of the skeleton likely decreases the level of peak bone mass. Good calcium nutrition in childhood may positively affect peak bone mass by as much as 5–10% [42], an amount equal to about 0.5–1.0 standard deviation in peak skeletal mass. This difference is enough to decrease the risk of hip fractures later in life by 25–50% [43]. Unfortunately, many children and adolescents do not consume the recommended levels of dietary calcium. In a recent national survey, the mean calcium intake for girls aged 9–13 was 869 mg/day, while the mean intake for ages 14–18 was 777 mg/day [44]. The mean intake for boys was closer to the recommended level. For ages 9–13, it was 108 mg/day and for ages 14–18 it was 1172 mg/day. Evidence of the effect of calcium in children’s skeletons is provided by prospective studies that have found that high calcium intake in children and adolescents is associated with a more positive calcium balance [45] and greater BMD and/or BMC than in controls [46–49]. For example, Lee et al supplemented 7-year-old children with 300 mg/day of calcium [50]. Their typical baseline intake was very low (279 mg/day). After 18 months of intervention, the treatment group demonstrated significantly greater gains in radial BMC than the control group (16.5% versus 14.0%, P 0.02). In a subsequent study, Lee et al supplemented children in Hong Kong with 300 mg/day of calcium [51]. In this case, baseline calcium intake was 560 mg/day. After 18 months, the intervention group had a greater increase in spine BMC but not in radial BMD or BMC than the controls. This demonstrates that different skeletal sites may have different calcium thresholds. Wosje and Specker recently published a review of the role of calcium intake on bone mineralization [52]. They included
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a critical analysis of eight pediatric calcium supplementation trials and bone health. They found that increases in BMD in calcium-supplemented children occur primarily in cortical bone sites and are most pronounced in study populations with low baseline calcium intakes. They also found that increases in lumbar BMD are greater during puberty than before puberty. Review of studies conducted in infants indicated that a high mineral intake is positively associated with short-term gains in BMC. From this comprehensive review, the authors concluded that, in pediatric populations, the increases in BMD and BMC associated with high calcium intake do not persist after the supplementation has been stopped. (The same is true for most nutrients; intakes have to be sustained.) Other randomized controlled trials of calcium interventions in children show that high calcium diets increase bone mass, but that after completion of the intervention, the control group catches up [53,54]. Thus, the optimal approach to calcium nutrition in children is to encourage good dietary calcium intake early in childhood. The window of opportunity for encouraging calcium-rich diets is in the prepubertal stage since this is the age at which children are formulating their lifelong health behaviors [55]. Children who avoid dairy products in childhood are unlikely to change this behavior in adolescence or adulthood.
Conclusion Calcium is an important nutrient for building and maintaining bone. A vast majority of people do not have adequate calcium intakes and need encouragement to get more calcium from food or supplements. Observational studies and randomized controlled trials can cause more confusion for patients and their physicians and need to be interpreted very carefully. First, subjects’ baseline calcium intakes influence the outcome. Giving more calcium above a certain threshold will not improve outcomes substantially. Secondly, compliance plays an important role in trials and in treating patients. Common sense would indicate that calcium supplements, like any medication, do not work unless they are ingested. The scientific community needs to give consistent messages to the public, so patients will have confidence to comply with our recommendations.
References 1. F. Bringhurst, M. Demay, H. Kronenberg, Hormones and disorders of mineral metabolism, in: H.M. Kronenberg, S. Melmed, K.S. Polonsky, P.R. Larsen (Eds.), Williams Textbook of Endocrinology, eleventh ed., WB Saunders Company, Philadelphia, 2008, pp. 1155–1209. 2. L.K. Massey, S.J. Whiting, Dietary salt, urinary calcium, and bone loss, J. Bone Miner. Res. 11 (1996) 731–736. 3. R.P. Heaney, Is the paradigm shifting? Bone 33 (4) (2003) 457–465.
4. P.J. Elders, J.C. Netelenbos, P. Lips, et al., Calcium supplementation reduces vertebral bone loss in perimenopausal women: a controlled trial in 248 women between 46 and 55 years of age, J. Clin. Endocrinol. Metab. 73 (1991) 533–540. 5. R.P. Heaney, Calcium supplements: practical considerations, Osteoporos Int. 1 (1991) 65–71. 6. R.P. Heaney, M.S. Dowell, J. Bierman, C.A. Hale, A. Bendich, Absorbability and cost effectiveness in calcium supplementation, J. Am. Coll. Nutr. 20 (3) (2001) 239–246. 7. B.R. Martin, C.M. Weaver, R.P. Heaney, P.T. Packard, D.L. Smith, Calcium absorption from three salts and CaSO(4)-fortified bread in premenopausal women, J. Agric. Food Chem. 50 (13) (2002) 3874–3876. 8. R. Klesges, K. Ward, M. Shelton, et al., Changes in bone mineral content in male athletes: mechanisms of action and intervention effects, J. Am. Med. Assoc. 276 (1996) 226–230. 9. Dietary reference intakes for calcium, magnesium, phosphorus, vitamin d, and fluoride, Food and Nutrition Board, Institute of Medicine, National Academy Press, Washington, DC, 1997. 10. J. Ma, R.A. Johns, R.S. Stafford, Americans are not meeting current calcium recommendations, Am. J. Clin. Nutr. 85 (2007) 1361–1366. 11. K. Radimer, B. Bindewald, J. Hughes, B. Ervin, C. Swanson, M.F. Picciano, Dietary supplement use by US adults: data from the National Health and Nutrition Examination Survey, 1999–2002, Am. J. Epidemiol. 160 (2004) 339–349. 12. R. Heaney, S. Abrams, B. Dawson-Hughes, et al., Peak bone mass, Osteoporos Int. 11 (2000) 985–1009. 13. R.M. Daly, M. Brown, S. Bass, S. Kukuljan, C.A. Nowson, Calcium and vitamin D3 fortified milk reduces bone loss at clinically relevant skeletal sites in older men: a 2-year randomised controlled trial, J. Bone Miner. Res. 21 (2006) 397–405. 14. R.P. Heaney, Calcium, dairy products, and osteoporosis, J. Am. Coll. Nutr. 19 (1999) 83S–99S. 15. B. Shea, G. Wells, A. Cranney, et al., VII. Meta-analysis of calcium supplementation for the prevention of postmenopausal osteoporosis, Endocr. Rev. 23 (2002) 552–559. 16. B. Dawson-Hughes, G.E. Dallal, E.A. Krall, L. Sadowski, N. Sahyoun, S. Tannenbaum, A controlled trial of the effect of calcium supplementation on bone density in postmenopausal women, N. Engl. J. Med. 323 (1990) 878–883. 17. E.A. Krall, N. Sahyoun, S. Tannenbaum, G.E. Dallal, B. Dawson-Hughes, Effect of vitamin D intake on seasonal variations in parathyroid hormone secretion in postmenopausal women, N. Engl. J. Med. 321 (1989) 1777–1783. 18. B.L. Riggs, W.M. O’Fallon, J. Muhs, M.K. O’Connor, R. Kumar, L.J. Melton III, Long-term effects of calcium supplementation on serum parathyroid hormone level, bone turnover, and bone loss in elderly women, J. Bone Miner. Res. 13 (1998) 168–174. 19. J.A. Cauley, R.L. Fullman, K.L. Stone, et al., for the OS Research Group. Factors associated with the lumbar spine and proximal femur bone mineral density in older men, Osteoporos Int. 16 (2005) 1525–1537. 20. H. Burger, C.E.D.H. de Laet, P.L.A. van Daele, et al., Risk factors for increased bone loss in an elderly population. The Rotterdam Study, Am. J. Epidemiol. 147 (1998) 871–879. 21. M. Peacock, G. Liu, M. Carey, et al., Effect of calcium of 25OH vitamin D3 dietary supplementation on bone loss at the
C h a p t e r 1 9 Calcium, Bone Strength and Fractures l
22. 23.
24.
25.
26.
27. 28.
29.
30.
31.
32.
33.
34.
35.
36.
37.
hip in men and women over the age of 60, J. Clin. Endocrinol. Metab. 85 (2000) 3011–3019. J.F. Aloia, African Americans, 25-hydroxyvitamin D, and osteoporosis: a paradox, Am. J. Clin. Nutr. 88 (2) (2008) 545S–550S. F. Cosman, J. Nieves, D. Dempster, R. Lindsay, Vitamin D economy in blacks, J. Bone Miner. Res. 22 (Suppl. 2) (2007) V34–V38. R.P. Heaney, Low calcium intake among African Americans: effects on bones and body weight, J. Nutr. 136 (2006) 1095–1098. B. Dawson-Hughes, S.S. Harris, E.A. Krall, G.E. Dallal, Effect of calcium and vitamin D supplementation on bone density in men and women 65 years of age or older, N. Engl. J. Med. 337 (1997) 670–676. E.S. Orwoll, S.K. Oviatt, M.R. McClung, L.J. Deftos, G. Sexton, The rate of bone mineral loss in normal men and the effects of calcium and cholecalciferol supplementation, Ann. Intern. Med. 112 (1990) 29–34. R.P. Heaney, Calcium, dairy products, and osteoporosis, J. Am. Coll. Nutr. 19 (1999) 83S–99S. H.A. Bischoff-Ferrari, B. Dawson-Hughes, J.A. Baron, et al., Calcium intake and hip fracture risk in men and women: a meta-analysis of prospective cohort studies and randomized controlled trials, Am. J. Clin. Nutr. 86 (2007) 1780–1790. B.M.P. Tang, G.D. Eslick, C. Nowson, C. Smith, A. Bnsoussan, Use of calcium or calcium in combination with vitamin D supplementation to prevent fractures and bone loss in people aged 50 years and older: a meta-analysis, Lancet 370 (2007) 657–666. S. Boonen, P. Lips, R. Bouillon, H.A. Bischoff-Ferrari, D. Vanderschueren, P. Haentjens, Need for additional calcium to reduce the risk of hip fracture with vitamin D supplementation: evidence from a comparative metaanalysis of randomized controlled trials, J. Clin. Endocrinol. Metab. 92 (4) (2007) 1415–1423. H.A. Bischoff-Ferrari, J.R. Rees, M.V. Grau, E. Barry, J. Gui, J.A. Baron, Effect of calcium supplementation on fracture risk: a double-blind randomized controlled trial, Am. J. Clin. Nutr. 87 (2008) 1945–1951. J. Lappe, D. Cullen, G. Haynatzki, R. Recker, R. Ahlf, K. Thompson, Calcium and vitamin D supplementation decreases incidence of stress fractures in female navy recruits, J. Bone Mineral Res. 23 (2008) 741–749. J. Porthouse, S. Cockayne, C. King, et al., Randomised controlled trial of calcium and supplementation with cholecalciferol (vitamin D3) for prevention of fractures in primary care, Br. Med. J. 330 (2005) 1003–1006. R.D. Jackson, A.Z. LaCroix, M. Gass, et al., Calcium plus vitamin D supplementation and the risk of fractures, N. Engl. J. Med. 354 (2006) 669–683. A.M. Grant, for the RECORD Trial Group, Oral vitamin D3 and calcium for secondary prevention of low-trauma fractures in elderly people (randomised evaluation of calcium or vitamin D3, RECORD): a randomized placebo-controlled trial, Lancet 365 (2005) 1621–1628. J.W. Nieves, L. Komar, F. Cosman, R. Lindsay, Calcium potentiates the effect of estrogen and calcitonin on bone mass: review and analysis, Am. J. Clin. Nutr. 67 (1998) 18–24. E.S. Siris, K.W. Lyles, F.R. Singer, P.J. Meunier, Medical management of Paget’s disease of bone: indications for
38.
39.
40.
41.
42.
43. 44.
45.
46.
47.
48.
49.
50.
51.
52. 53.
54.
55.
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treatment and review of current therapies, J. Bone Miner. Res. 21 (2007) P94–P98. Consensus Development Conference, Diagnosis, prophylaxis, and treatment of osteoporosis, Am. J. Med. 94 (1993) 646–650. R. Bouillon, P. Burckhardt, C. Christiansen, et al., Consensus development conference: prophylaxis and treatment of osteoporosis, Osteoporos Int. 1 (1991) 114–117. S. Hui, C. Slemenda, C. Johnston, Age and bone mass as predictors of fracture in a prospective study, J. Clin. Invest. 81 (1988) 1804–1809. NIH Consensus Development Panel on Optimal Calcium Intake, Optimal calcium intake, J. Am. Med. Assoc. 272 (1994) 1942–1948. V. Matkovic, J. Ilich, M. Skugor, Calcium intake and skeletal formation, in: P. Burckhardt, R.P. Heaney (Eds.), Nutritional Aspects of Osteoporosis ’94, Ares-Serono Symposia Pub, Rome, 1995, pp. 129–145. R.P. Heaney, Calcium, dairy products and osteoporosis, J. Am. Coll. Nutr. 19 (2000) 83S–99S. G. Geller, J. Botkin, M.J. Green, et al., Genetic testing for susceptibility to adult-onset cancer, J. Am. Med. Assoc. 277 (1997) 1467–1474. V. Matkovic, D. Fontana, L. Tominac, G. Prem, C. Chesnut, Factors that influence peak bone mass formation: a study of calcium balance and the inheritance of bone mass in adolescent females, Am. J. Clin. Nutr. 52 (1990) 878–888. J. Cadogan, R. Eastell, N. Jones, M.E. Barker, Milk intake and bone mineral acquisition in adolescent girls: randomized, controlled intervention trial, Br. Med. J. 315 (1997) 1255–1260. G. Chan, K. Hoffman, M. McMurry, Effects of dairy products on bone and body composition in pubertal girls, J. Pediatr. 126 (1995) 551–556. N. Gilchrist, E. Smart, J. Turner, E. Hooke, R. March, C. Frampton, Dairy food supplementation in teenage girls: effects on bone density, biochemistry and dietary profile, Osteoporos Int. 6 (Supp. 1) (1996) 217. B. Specker, L. Mulligan, M. Ho, Longitudinal study of calcium intake, physical activity, and bone mineral content in infants 6–18 months of age, J. Bone Miner. Res. 14 (1999) 569–576. W. Lee, S. Leung, S. Wang, et al., Double-blind, controlled calcium supplementation and bone mineral accretion in children accustomed to a low-calcium diet, Am. J. Clin. Nutr. 60 (1994) 744–750. W. Lee, S. Leung, D. Leung, H. Tsang, J. Lau, J.A Cheng, randomized double-blind controlled calcium supplementation trial, and bone mineral accretion in children accustomed to a low-calcium diet, Br. J. Nutr. 74 (1995) 125–139. K. Wosje, B. Specker, Role of calcium in bone health during childhood, Nutr. Rev. 58 (2000) 253–268. C. Johnston, J. Miller, C. Slemenda, et al., Calcium supplementation and increases in bone mineral density in children, N. Engl. J. Med. 327 (1992) 82–87. T. Lloyd, N. Rollings, M. Andon, D. Eggli, D. Maugeri, V. Chinchilli, Enhanced bone gain in early adolescence due to calcium supplementation does not persist in late adolescence, J. Bone Miner. Res. 11 (1996) S154. D. Allensworth, Health education: State of the art, J. Sch. Health 63 (1993) 14–20.
Chapter
20
Vitamin D and Bone Roger Bouillon, Christa Maes, Lieve Verlinden, Geert Carmeliet and Annemieke Verstuyf Laboratory of Experimental Medicine and Endocrinology (LEGENDO), Katholieke Universiteit Leuven (KUL), Leuven, Belgium
Introduction
comes from this endogenous synthesis as nutritional or dietary sources of vitamin D are scarce. Indeed, apart from fatty fish and its liver (due to accumulation of vitamin D from plankton in the food chain), most natural sources (eggs, meat, mushroom and even milk or dairy products) have a low vitamin D content and will not provide an intake of vitamin D above 200 IU/d. Endogenous vitamin D3 is transported to the liver by a specific binding protein, DBP, an old member of the albumin family, whereas nutritional vitamin D2 or D3 is absorbed and bound to chylomicrons for uptake in fat and liver. Most tissues are able to metabolize vitamin D into 25-hydroxyvitamin D (25OHD) but the largest capacity is found in the liver. Probably four P450 enzymes are able to generate 25OHD from vitamin D. The microsomal P450 CYP2R1 is the most important one when the substrate concentration is low, whereas others, including the mitochondrial CYP27A1, are mostly functional at higher substrate concentrations. Mutation of CYP2R1 creates 25OHD-deficiency rickets [7]. 25OHD circulates in serum bound to DBP (at a surface cleft of the protein) and is the best marker for the nutritional vitamin D status, as vitamin D itself is rapidly removed from the circulation and thus only reflects recent access to the substrate. The serum concentration of 1,25-(OH)2D is by contrast not a good marker for the overall nutritional vitamin D status as it reflects the tightly regulated renal production by CYP27B1. This mitochondrial enzyme is present in many cells and tissues, with the highest concentrations in the kidney and the skin. The renal CYP27B1 (or 1-hydroxylase) activity is regulated by hormones (positively by parathyroid hormone (PTH), parathyroid hormone-related protein (PTHrP), calcitonin, growth hormone (GH) and insulinlike growth factor I (IGF-I); and negatively by FGF23 and klotho) or minerals (negative regulation by Ca and P). 1,25(OH)2D itself is also a negative regulator for CYP27B1 and a
The first extensive descriptions of rickets appeared in the 17th century as (PhD-like) monographs in Leiden (D. Whistler) and London (D. Glisson) [1]. The disease was clearly described by its effects on growth, bone weakness and general health. The etiology was unknown until the discovery of vitamins in general and of vitamin D in particular at the beginning of the 20th century. Before this discovery, a wide variety of treatment solutions were suggested including the use of fish liver oil as skin ointment and ‘exposure’ to country life. The dual origin of vitamin D certainly complicated its identification. Shortly thereafter cod liver oil supplements and/or enhanced exposure to sunshine rapidly eliminated endemic rickets in most Western countries. It then took about 80 years chemically to identify vitamin D as the causative agent and this was finally proven by its chemical synthesis, for which A. Windaus received the Noble prize in 1938 [1]; then to unravel its complex metabolic activation and inactivation to a very large number of natural metabolites (30); and to identify the role of the active metabolite 1,25-dihydroxyvitamin D (1,25-(OH)2D) as a ligand for a specific nuclear transcription factor [2–6].
Origin, metabolism, action and mode of action Exposure to solar UVB light (especially wavelength 290– 315 nm) converts 7-dehydro-cholesterol, the last step in the de novo synthesis of cholesterol, into previtamin D3 which is then rapidly converted into vitamin D3. Excess UVB destroys most of the previtamin D3 so that vitamin D intoxication by sunshine is avoided. Most of the vitamin D Osteoporosis in Men
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very potent stimulator of its catabolizing enzyme CYP24A1. Many other tissues apart from the kidney are able to produce locally 1,25-(OH)2D. The crucial role of 1-hydroxylase is best demonstrated by severe rickets in children and animals with genetic inactivating mutations of this enzyme. The catabolism of 25OHD and 1,25-(OH)2D is mainly dependent on a single multifunctional CYP24A1. Again this is best demonstrated by the severe hypercalcemia, frequently neonatally lethal, in CYP24A1 or 24-hydroxylase null mice [5, 8]. The active hormone, 1,25-(OH)2D, binds with high affinity to a single nuclear receptor, VDR, present in nearly all nucleated cells. This protein has a great structural similarity with other nuclear transcription factors (family of 48 genes in the human genome) with essentially a ligand binding domain (for hormone or ligand binding), a DNA binding domain (for binding to hormone responsive elements) and a region for protein–protein binding (such as dimerization and cofactor binding). Upon binding of 1,25-(OH)2D to the ligand-binding domain of VDR, a reconfiguration of the surface of VDR is induced generating a sequence of events (from heterodimerization with the retinoid X receptor (RXR) and binding to vitamin D response elements (VDREs) to recruitment of co-regulators and release of corepressors, together altering DNA accessibility) eventually leading to increased (or repressed) gene transcription. The essential role of VDR is obvious as deletion of crucial sequences of VDR causes severe vitamin D-resistant rickets in animals and patients. The nearly universal presence of vitamin D metabolizing enzymes, of the VDR and the large number of genes that are regulated (directly or indirectly) by 1,25-(OH)2D, all indicate that the vitamin D endocrine system has a wide spectrum of activities, much like many other steroid hormones or nuclear receptors (PPAR, AR, ER, GC, RAR). The actions of vitamin D beyond the calcium, phosphate and bone metabolism is beyond the scope of the present chapter and has been reviewed elsewhere [3, 5, 6, 9]. Indeed, vitamin D deficiency is associated with a series of immune diseases (infections, autoimmune diseases such as type 1 diabetes and multiple sclerosis), cancer, cardiovascular and metabolic diseases and increased mortality. For each of these associations, animal or cellular data have provided molecular mechanisms but the formal proof of causality is yet missing. The vitamin D endocrine system also influences muscle function and, together with its action on calcium and bone metabolism, this can explain the important role of vitamin D in osteoporosis. Moreover, several intervention studies support a causal role of vitamin D in bone diseases in general and osteoporosis in particular.
Vitamin D and bone: basic mechanisms Calcium and bone homeostasis requires the coordinated actions of cells located in different tissues capable of
active calcium and phosphate transport, such as the intestine, kidney and bone and, at certain times during life, in the growth plate, mammary gland and placenta. All these tissues are therefore real or potential targets for vitamin D action. Moreover, the parathyroid glands are key regulators of extracellular calcium homeostasis and are also a direct vitamin D target. The intestine is the key target for vitamin D’s effect on calcium homeostasis. This has been amply demonstrated by normalization of the severe bone and growth plate phenotype of mice and children with inactivating VDR mutations. Indeed, older observations already clearly demonstrated that intravenous infusion of calcium or a very high oral intake of calcium can largely correct severe rickets of children with vitamin D resistant rickets type II [10]. Similarly, calcium infusion also corrected the bone histology of severely vitamin D deficient rats [11]. In fact, after calcium infusion, the bone volume was even higher than in control animals due to the rapid mineralization of excessive osteoid that was built up during prolonged vitamin D deficiency. The detailed analysis of bone and growth plate of VDR or CYP27B1 null mice raised on a rescue diet (high calcium diet or high calcium with lactose diet) provided convincing evidence for a perfect correction of bone volume, bone histology and bone strength by a high calcium diet [12, 13] even in the absence of vitamin D action. This correction of bone structure and mass was also observed in the growth plate. These observations allow two conclusions: 1. the intestinal absorption of calcium and phosphate is a crucial target for vitamin D action. However the bone rescue is only possible with truly massive increase in calcium intake (5 g/d for children with VDR resistance) and also depends on the calcium:phosphate ratio of the diet [14] and is, therefore, not a true option for physiologic replacement therapy 2. the presence of VDR in bone and growth plate seems not to be absolutely vital for their normal development and function in basal circumstances. Of course this does not imply that vitamin D is totally redundant, not in normal and certainly not in pathological circumstances (e.g. fracture repair, aging).
Intestinal Calcium Absorption Intestinal calcium absorption and especially active calcium absorption is poor in the absence of vitamin D or VDR [13], whereas phosphate absorption is modestly impaired. The molecular mechanisms involved in this active calcium and phosphate absorption have been explored by a candidate gene and by whole genome search (-array). Several calcium transporters are under the control of the vitamin D endocrine system, as well for luminal calcium entry (TRPV5 and especially TRPV6), calcium transport across the cell (especially CaBP-9 k) and uphill transport from the cell
C h a p t e r 2 0 Vitamin D and Bone l
into the bloodstream (especially PMCA1b or Ca-ATPase) [5, 13, 15]. CaBP-9 k was for a long time considered to be the essential step in calcium transport, but CaBP-9 k null mice have normal active calcium absorption on a normal and even low calcium diet [16]. PMCA is regulated by vitamin D, as shown by gene expression following 1,25-(OH)2D administration, but its basal expression is hardly affected in VDR null mice. No intestine-specific PMCA null mice exist and total deletion is lethal. TRPV6 is very extensively regulated by 1,25-(OH)2D from virtually totally absent in VDR null mice to extremely upregulated by a low calcium diet or 1,25-(OH)2D therapy. This is confirmed by the presence of multiple cooperative VDREs in the promoter of TRPV6 [17]. Nevertheless, deletion of TRPV6 does not cause rickets and only minimally impairs active calcium absorption [18]. Even combined deficiency of CaBP-9 k and TRPV6 does not seriously impair basal calcium absorption and such animals are still capable of increasing their intestinal calcium absorption when challenged with a low calcium diet [18]. The paracellular calcium absorption was long considered to be responsible for passive vitamin D independent calcium absorption but several genes involved in tight junction are vitamin D dependent and the expression of claudin-2 and claudin-12 is impaired in VDR null mice [5]. Therefore, although there is little doubt that the intestine is the key and non-redundant target for vitamin D action, the precise molecular details of vitamin D mediated calcium and phosphate absorption are still incompletely identified. The essential role of intestinal VDR is further strengthened by the correction of the bone and growth plate phenotypes by partial rescue of the intestinal VDR in VDR null mice [19] and by the very severe bone demineralization (even more than in total VDR null mice) in mice with selective deletion of VDR in the intestine [20].
Renal Handling of Calcium The renal handling of calcium is fairly similar to the active intestinal absorption but uses TRPV5 instead of TRPV6. The urinary calcium excretion of VDR null mice is higher than expected on the basis of filtered calcium load and indicate impaired renal calcium reabsorption. This is confirmed by the marked hypercalciuria of TRPV5 null mice, leading to secondary hyperparathyroidism and bone loss and compensatory increase in intestinal TRPV6 expression and calcium absorption [21]. Vitamin D, however, seems to decrease the urinary loss of calcium and phosphate and thereby indirectly improves the mineral balance. The role of vitamin D in renal and intestinal phosphate handling is incompletely understood.
Parathyroid Hormone The production and secretion of parathyroid hormone is enhanced by vitamin D deficiency or resistance. The presence of VDR, 1-hydroxylase and the negative regulation
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of PTH expression by 1,25-(OH)2D confirms a negative feedback loop either mediated by extracellular calcium, 1,25-(OH)2D itself or both. Loss of 1,25-(OH)2D and VDR expression in the parathyroid gland and resistance to vitamin D action in case of chronic renal failure are all together cooperative mechanisms in the rapid progression of severe secondary hyperparathyroidism in case of chronic renal failure. A direct role for VDR in PTH secretion was recently demonstrated by a doubling of serum PTH levels in mice with genetically engineered selective VDR deficiency in the parathyroid glands [22].
Osteoblasts and Osteoclasts Most genes that are typically expressed in osteoblasts and osteoclasts (and thus are essential for their cellular differentiation and function) are under control of 1,25-(OH)2D. Indeed, genes that are essential for the early commitment of mesenchymal cells towards osteoblast lineage (runx2, osx) as well as more mature markers of osteoblast function (alkaline phosphatase, osteocalcin, osteopontin) and matrix synthesis are all under the control of vitamin D action. Also osteoclastogenesis as well as genes that are essential for osteoclast function (RANK, OPG, cathepsin K) are markedly regulated by 1,25-(OH)2D. Nevertheless, VDR null mice have a normal prenatal bone development and their postnatal bone phenotype can be rescued by a very high calcium intake [5]. To understand fully the role of VDR on osteoblast, osteocyte and osteoclast function, cell-specific VDR deletion or overexpression will be needed. Overexpression of VDR in osteoblasts driven by an osteocalcin promoter (and thus resulting in VDR overexpression at a later stage of osteoblast function) resulted in increased bone formation, size and strength [5]. However, selective VDR deletion in osteoblasts by a Cre-Lox system also increased bone size and mass [23]. Therefore, the intrinsic effects of the vitamin D endocrine system on bone cells and bone tissue is far from solved.
Chondrocytes VDR is expressed in chondrocytes which also respond to 1,25-(OH)2D exposure by changing gene expression and cell phenotype. The growth plate abnormalities, especially the hypertrophy of the hypertrophic growth plate and its impaired or delayed mineralization and vascular invasion, are hallmarks of vitamin D deficient or resistant rickets. Nevertheless, the growth plate phenotype of VDR or CYP27B1 null mice is rescued by a high calcium diet. In accordance with these data, the growth plate was normal in mice with chondrocytespecific deletion of VDR [24]. However, such mice display increased trabecular bone mass as long as the growth plate remains fully active. This rather paradoxical phenotype is probably related to delayed vascular invasion, decreased
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osteoclast number and may be linked to decreased FGF23 expression in bone and the enhanced renal expression of 1hydroxylase and NaP transporters [24].
Vitamin D and bone: clinical aspects The causal link between vitamin D and rickets has been amply demonstrated by the ‘Lazarus’ type of rescue of endemic rickets by empirical cod liver oil administration early in the 20th century. In fact, only one genuine randomized controlled trial has demonstrated that vitamin D (400 IU/d) can prevent the occurrence of rickets in a (Turkish) population with high background risk of rickets [25]. Based on careful small scale clinical observations in the first half of the 20th century, doses as low as 100–200 IU of vitamin D3 per day can cure or prevent rickets. Most regulatory agencies throughout the world recommend that newborn infants receive a minimum of 200 IU/d (5 g vitamin D3), but this recommendation has recently been adjusted to 400 IU D3 per day by the American Pediatric Academy. Rickets can, of course, also be due to inborn errors of metabolism, especially of 1-hydroxylase (vitamin D pseudodeficiency) that can be perfectly treated by physiological doses of 1-hydroxyvitamin D or 1,25-(OH)2D. Vitamin D resistance rickets (type II) is due to inactivating VDR receptors (or rarely by another mechanism) and can be corrected by calcium infusions or high oral calcium intake. Chronic renal failure also causes severe bone dystrophy due to a combination of deficiency of 1,25-(OH)2D, phosphate retention, secondary hyperparathyroidism and FGF23 excess, and can be largely prevented or corrected by optimal calcium intake, 1-hydroxylated vitamin D metabolites or analogs and correction of phosphate excess. Whereas vitamin D-related bone disorders were largely identified and corrected in the beginning of the 20th century, its role in the initially silent epidemic of osteoporosis was only gradually identified at the end of the 20th century. Osteoporosis is a complex disease, probably including multiple pathogenic mechanisms and thus representing rather a syndrome than a single disease, leading to decreased bone mass, impaired quality of structural bone elements and increased risk of a variety of fractures. The role of vitamin D in these diseases is probably not uniform. The most common types of osteoporosis (postmenopausal osteoporosis and especially osteoporosis of the elderly) were linked to vitamin D because of its frequent association with increased PTH secretion, lower 25OHD and sometimes lower 1,25(OH)2D levels and impaired intestinal calcium absorption [26]. Indeed, there is consistent evidence that patients with vertebral and especially hip fractures have lower 25OHD levels and, for hip fractures, also frequently lower 1,25(OH)2D levels than healthy controls [27–32].
Table 20.1 Defining optimal vitamin D status for bone Hard endpoints 1 Placebo controlled intervention studies → vitamin D/25OHD and fractures 2 Prospective/cross-sectional studies → 25OHD and fractures Surrogate endpoints 3 Prospective/cross-sectional studies → 25OHD and BMC/BMD → 25OHD and bone turnover markers 4 Prospective/cross-sectional or intervention studies → 25OHD and calcium absorption 5 Cross-sectional/intervention studies → 25OHD and PTH 6 Cross-sectional/intervention studies → 25OHD and 1,25(OH)2D
To demonstrate the causality between vitamin D status, metabolism or action and common types of osteoporosis, as well as to define the optimal vitamin D status, a series of surrogate markers and hard endpoints can be used (Table 20.1). There is little doubt that serum 25OHD is the best marker for nutritional vitamin D status. The list of possible causes of vitamin D deficiency or insufficiency (definition see below) is long, but all causes require a combined deficiency of endogenous synthesis and insufficient intake, absorption or metabolism of exogenous vitamin D (Table 20.2). To define the optimal, or at least the minimally required, supply of vitamin D, several studies have addressed the question of which level of 25OHD is needed to optimize 1,25-(OH)2D or PTH levels, or to optimize intestinal calcium absorption or bone mass. In addition, these surrogate markers can be studied before or after vitamin D supplementation (see Table 20.1).
Surrogate endpoints 1 25-(OH)2D concentration Most studies could not find a correlation between 25OHD and 1,25-(OH)2D concentration in healthy adults with sufficient access to vitamin D. However, in more vitamin D insufficient patients, a positive correlation has been observed, indicating that 25OHD can be the rate limiting step for the synthesis of the active hormone until a threshold level (about 20 ng/ml) is obtained [28].
PTH level The optimal intake of vitamin D, and especially the concentration of 25OHD needed to reach an optimal PTH level, have been extensively used as surrogate markers for defining the minimal or best vitamin D nutritional status. Most studies used simple cross-sectional 25OHD and PTH status
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Table 20.2 Causes of vitamin D deficiency Low exposure to UVB or sunlight climatologic reason (latitude) occupational, social, religious or cultural reasons (submarine personnel, extensive clothing and use of veil) discordance between skin pigmentation and exposure to sunshine low mobility (elderly, institutionalized persons) avoidance of direct sunlight (e.g. newborns, infants) excessive use of sunscreen Low vitamin D intake (especially fatty fish) Decreased intestinal absorption biliary cirrhosis fat malabsorption celiac disease bariatric surgery pancreatitis Impaired metabolism impaired 25-hydroxylase (inborn error) impaired 1-hydroxylase (inborn error, chronic renal failure, FGF23 excess) Increased catabolism or loss nephrotic syndrome anticonvulsant therapy low calcium intake or absorption Miscellaneous obesity
[28, 33, 34], but these studies have generated a wide variety of cut-off values (varying from 12 to 40 ng/ml) below which mean PTH levels start to rise. Moreover, about half of the subjects with even (very) low 25OHD levels still have PTH levels within the normal range. In addition, calcium intake and renal function have a major influence on the relationship between 25OHD and PTH levels. These confusing results also complicate the diagnosis of primary hyperparathyroidism based on serum PTH-calcium levels [35]. A better strategy is therefore to use vitamin D intervention therapy to define the PTH–25OHD relation. Holick’s study revealed that vitamin D supplementation indeed increased 25OHD and decreased PTH levels, however, the PTH decrease was greatest in subjects with low basal 25OHD levels and PTH concentrations did not change after vitamin D supplementation of subjects with baseline 25OHD levels above 20 ng/ml [36]. Therefore, using PTH as a surrogate marker for optimal 25OHD level does not clarify a generally accepted threshold, but there is unanimity that 25OHD concentration should be 20 ng/ml (50 nmol/l) [30].
Intestinal Calcium Absorption In view of the essential role of vitamin D for intestinal calcium absorption, optimal intestinal active calcium absorption (at the
247
plateau level) could be a very useful marker for defining the best 25OHD level. Based on a series of studies, Heaney concluded that maximal intestinal calcium absorption requires 25OHD levels well above 32 ng/ml [37, 38]. However, these studies used minor changes in serum calcium after an oral calcium load to estimate calcium absorption and such methodology is not a reliable method for true calcium absorption. Methods using calcium isotopes (single or preferably dual oral/iv calcium load) could not clearly demonstrate a correlation between serum 25OHD and true calcium absorption, neither in children nor in adults, whereas serum 1,25-(OH)2D levels showed a good correlation with calcium absorption [39]. Two recent intervention studies demonstrated that vitamin D supplementation of subjects with baseline 25OHD levels of 20 ng/ml did not [40] or only minimally [41] increased correctly measured intestinal calcium absorption. Therefore, if calcium absorption is used as a surrogate marker for optimal vitamin D status, levels above 20 ng/ml 25OHD do not further improve the external calcium balance.
Bone Mineral Density and Bone Turnover Markers Bone mineral density is widely used as the most reliable method to diagnose osteopenia and osteoporosis and subsequent fracture risk. Cross-sectional studies have been largely unable to define a correlation between bone mineral density (BMD) and 25OHD and this may be due to the long latency of vitamin D effects on bone mass or the multifactorial origin of osteoporosis. A few studies reveal a slight decrease in BMD when 25OHD falls below 12 or 20 ng/ml [29, 42–44], whereas the NHANES data showed that lower BMD is linked to lower 25OHD without a clear threshold (but very small benefits from 25OHD levels 20 ng/ml). Intervention studies with vitamin D, however, could not demonstrate a significant increase in BMD [45, 46], whereas combined high calcium and vitamin D supplementation had a small effect on hip BMD (2.2% after 5 years of supplementation) [40]. Bone turnover markers are also used as predictors for osteoporosis and fractures and could therefore be used as surrogate markers to define the optimal vitamin D status. However, both cross-sectional and vitamin D intervention studies have not provided clear evidence for a 25OHD threshold [47].
Hard endpoints Cross-sectional or prospective observational studies relating 25OHD levels with fracture occurrence could provide a good guideline for optimal vitamin D status. A nested control study using the WHI data revealed that baseline 25OHD levels below 19 ng/ml conveyed a 1.77 increased subsequent risk for hip fracture whereas levels 20 ng/ml did not change such fracture risk [48].
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Table 20.3 Hip fracture risk versus calcium and/or vitamin D supplements Study
Hip fracture (RR, Treatment 95% CI, statistics)
Trivedi et al 2003 [49] Meyer et al 2002 [50] Grant et al 2005 [51] Lips et al 1996 [52] Dawson-Hughes et al 1997 [53] Chapuy et al 2002 [54] Porthouse et al 2005 [55] Chapuy et al 1994 [33]
D D D D CaD
0.87 1.08 1.14 1.21 0.20
(0.49–1.49), NS (0.73–1.57), NS (0.75–1.72), NS (0.83–1.75), NS (0.02–8.78), NS
CaD CaD CaD
0.62 0.71 0.74
Jackson et al 2006 [56] Grant et al 2005 [51]
CaD CaD
0.88 1.14
(0.36–1.07), NS (0.31–1.64), NS (0.60–0.91), p 0.05 (0.72–1.07), NS (0.76–1.73), NS
Table 20.4 Meta-analysis of calcium and/or vitamin D supplementation and fracture risks: ‘meta-analysis of meta-analysis’ Metaanalysis
No of studies evaluated Conclusions
Averrell et al 2005 [57]
n 45
Combined calcium and vitamin D but not vitamin D therapy alone reduces hip fracture risk especially in frail elderly people
Bischoffn 12 Ferrari et al 2005 [58]
Vitamin D supplementation (800 IU/d) decreases fracture risks (hip …) whereas 400 IU/d is not protective Calcium supplements do not reduce the risk of hip or vertebral fractures and may even increase hip fracture risk Combined calcium and vitamin D supplements are needed to reduce fracture risk (hip; non-vertebral, vertebral) Vitamin D monotherapy reduces the incidences of falls and there is a trend for reduction of fractures Calcium or calciumvitamin D supplementation reduces all types of fracture risk. No additional benefits of vitamin D 1-hydroxyvitamin D reduces vertebral and non-vertebral fracture risk but risk of hypercalcemia is also increased Combined calcium and vitamin D supplement reduces hip fracture risk but calcium supplements only may increase this fracture risk
Bischoffn 17 Ferrari et al 2007 [59] Boonen et al n 9 2007 [60]
The real evaluation of possible benefits of vitamin D and the optimal 25OHD level for bone is of course to be found in a meta-analysis of intervention studies, preferably randomized controlled trials. A large number of small and large studies have been published (Table 20.3) and have resulted in a multitude of meta-analyses (Table 20.4) using slightly different techniques and especially different inclusion criteria. The interpretation of these results is further complicated by the variable study design including the use of calcium or vitamin D alone or in combination, variable dosages, to variable baseline difference in vitamin D status or calcium intake and, especially, the high rate of loss of follow up so that sometimes great differences are observed between intention-to-treat and per protocol analysis. A summary of the size and odd ratio for hip fractures in different randomized trials is shown in Table 20.3. Hip fracture was selected here as it represents a hard to miss endpoint and also because this type of fracture has major health consequences (mortality, morbidity, quality of life and costs). Most of the studies did not reach significant odd ratios except for the original Chapuy study. Moreover, the studies using vitamin D alone generated an odd ratio 1 in three out of four studies, whereas the calcium vitamin D studies resulted in an odds ratio 1 in five of the six studies (see Table 20.3). Calcium alone had no significant effect on non-vertebral fractures (RR 0.92; CL 0.81–1.05) or hip fractures (RR 1.64; CL 1.02–2.64) in a meta-analysis of randomized controlled trials and prospective cohort studies on calcium supplementation [59]. Another metaanalysis (see Table 20.4), however, concluded that calcium supplementation alone reduced the overall fracture risk, but this analysis included a much larger number of studies, whereas Bischoff-Ferrari et al [59] included only well validated studies. Several meta-analyses, however, concluded that combined vitamin D and calcium supplementation decreased the subsequent fracture risks (see Table 20.4)
Jackson et al n 9 2007 [61] Tang et al 2007 [62]
n 17
O’Donnell et al 2008 [63]
n 16
Reid et al 2008 [64]
n 17
especially with a vitamin D intake 700 IU/d and a total calcium intake 1 g/d. The relative risk reduction for hip and non-vertebral fractures amounts to about 20% [60]. The compliance of this therapy is, however, cumbersome, especially with regard to the high calcium intake [65]. In view of the potential cardiovascular risks of very high calcium intake [64], a more conservative approach with regard to massive calcium intake is desirable. Unfortunately, most intervention and cohort studies did not systematically include serum 25OHD levels before and during supplementation or used outdated 25OHD assays that are now known to have a serious accuracy problem (both high blank value and systematic overestimation of true concentration). Therefore, the 25OHD levels recorded in some subgroups of some of these studies are unreliable for defining the optimal 25OHD level. However, the dosage of vitamin D intake and the compliance are much more reliable and should guide us for optimal therapy (Figure 20.1).
C h a p t e r 2 0 Vitamin D and Bone l
2 1.8
249
Lips
1.6 RR (95% Cl)
1.4
Record
1.2
WHI*
1
Trivedi
Chapuy
WHI**
608 IU –
623 IU +
760 IU +
0.8 0.6 0.4 0.2 0 340 IU –
376 IU +
448 IU +
Calcium supplement
Figure 20.1 Hip fracture efficacy by total estimated vitamin D intake. Estimated mean daily vitamin D intake is expressed as: (trial intake baseline intake) percent compliance. Presence () or absence () of additional calcium supplements is also expressed. (Adapted from Bischoff-Ferrari et al Osteoporos Int 2007;18:401–7, with permission).
These data clearly suggest that a vitamin D3 supplement of 700–800 IU/d with a daily calcium intake of 1 g/d should be the baseline therapy for all subjects at risk for osteoporotic fractures. Of course, this treatment should, in addition, include more potent pharmacologic agents with proven anti-vertebral and preferably anti-hip fracture efficacy [66, 67].
Choice of vitamin D product and treatment regimen Vitamin D3 has been used in nearly all randomized controlled trials (RCT) on fracture risk and other endpoints, whereas in many countries vitamin D2 is widely used. Therefore, the question arises whether vitamin D2 is equipotent to D3. For rickets, older German studies claimed that D3 is more potent (several fold) than D2 but as 200– 400 IU/d is usually recommended and 100 IU/d is able to prevent most cases of rickets, no clinical efficacy difference between D2 and D3 is observed. 1,25-(OH)2D2 is equipotent to 1,25-(OH)2D3 in vitro but 25OHD2 is less tightly bound to DBP and, therefore, has a more rapid clearance than 25OHD3. Daily dosing of vitamin D2 or D3 produces similar plasma concentrations of 25OHD2 and 25OHD3 [68] but, when intermittent pulse doses are given, then plasma 25OHD levels remain higher after vitamin D3 than after oral vitamin D2 [69]. Daily dosing of vitamin D3 results in similar 25OHD3 levels as when given weekly, whereas monthly dosing is either equivalent [70] or slightly less potent [71] than the equivalent daily dose. Natural metabolites or analogs of vitamin D may have therapeutic benefits over plain vitamin D just as for other
ligands of nuclear receptors. A meta-analysis revealed that 1-hydroxyvitamin D had similar effects on fracture risk as vitamin D itself but at a higher risk of hypercalcemia [63]. Newer analogs have shown promising results in rats or mice [72, 73] and one Chugai compound, ED71, increased BMD in Japanese postmenopausal women [74] and fracture data are expected in 2009.
Optimal vitamin D status versus present world reality Based on a variety of surrogate and hard endpoints, it remains difficult to define the optimal vitamin D status. There is unanimity that serum levels of 25OHD should exceed 20 ng/ml (Table 20.5) [6, 30, 66, 75–78]. Higher 25OHD levels may even bring additional benefits. Despite the detection of widespread occurrence of mild to severe vitamin D deficiency as early as the 1980s [30, 79], the situation is not much better in the 21st century (Table 20.6). Indeed, several large scale epidemiologic studies or overviews of studies clearly show that mean 25OHD levels around the world are hardly above 20 ng/ml indicating that one-quarter to one-half of apparently healthy adults are vitamin D insufficient or worse. In elderly subjects and in many Arabian countries, the vitamin D status is in the truly deficient range. The strategy to improve the vitamin D status is not simple. Higher exposure to UVB is efficient for the vitamin D status but probably not safe with regard to photo aging or skin cancer of fair skin type persons. Increasing the usage of vitamin D rich food is not a real option either. Vitamin D supplementation, either on an individual scale (vitamin D supplements) or by increasing
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Table 20.5 Definition of vitamin D status 25OHD concentration (ng/ml)
(nmol/l)
10
25
vitamin D deficiency
10–20 20* or 32* (100) 150
25–50 50*
vitamin D insufficiency normal vitamin D status
80* (400) 600
risk of vitamin D toxicity
*
Different opinions and interpretation of existing data [6, 30, 64, 66].
Table 20.6 Serum 25OHD in healthy subjects (selected overview) Study
Serum 25OHD Comments
NHANES III n 12644 [79] World meta-analysis n 494 studies [81] MORE Study n 7564 [29]
30 ng/ml 20 ng/ml 21 ng/ml
Overall Non-Hispanic blacks Little effect of latitude
28 ng/ml
German Nutritional Survey n 4030 [82] Australian Study n 1669 [83] Queensland Geelong Tasmania MrOS Study n 1606 [84]
1 ng/ml
Postmenopausal osteoporotic women 5 continents 18–79 years
27 ng/ml 30 ng/ml 20 ng/ml 25 ng/ml
3 regions women only 60 years
26% below 20 ng/ml Cross-sectional study of healthy, older US men
the usage of vitamin D-enriched food, is probably necessary and requires detailed understanding of the local food habits and traditions to reach the groups most in need of these supplements. The amount of vitamin D supplementation (whether on a daily or intermittent base) should aim at achieving serum 25OHD levels above 20 ng/ml in 95% of adults without causing vitamin D toxicity in even a minority who combine sun exposure, natural vitamin D rich food and vitamin D supplements. As 1000 IU/d increases 25OHD levels by about 10 ng/ml, a daily dose of 600–1000 IU of vitamin D3 should be able to obtain this minimal 25OHD target. If future prospective trials would indicate that higher 25OHD levels (30–40 ng/ml) are conveying additional benefits without new risks, then a thorough revision of guidelines and strategies for vitamin D supplementation worldwide would be needed.
References 1. R. Bouillon, Vitamin D: from photosynthesis, metabolism and action, to clinical applications (in press), in: L.J. De Groot, J.L. Jameson (Eds.) Endocrinology, sixth ed., Elsevier Saunders, Philadelphia, 2009. 2. M.R. Haussler, C.A. Haussler, L. Bartik, et al., Vitamin D receptor: molecular signaling and actions of nutritional ligands in disease prevention, Nutr. Rev. 66 (10 Suppl 2) (2008) S98–S112. 3. M.F. Holick, Vitamin D deficiency, N. Engl. J. Med. 357 (3) (2007) 266–281. 4. A.W. Norman, Minireview: vitamin D receptor: new assignments for an already busy receptor., Endocrinology 147 (12) (2006) 5542–5548. 5. R. Bouillon, G. Carmeliet, L. Verlinden, et al., Vitamin D and human health: lessons from vitamin D receptor null mice, Endocr. Rev. 29 (6) (2008) 726–776. 6. R. Bouillon, H. Bischoff-Ferrari, W. Willett, Vitamin D and health: perspectives from mice and man, J. Bone Miner Res. 23 (7) (2008) 974–979. 7. J.B. Cheng, M.A. Levine, N.H. Bell, D.J. Mangelsdorf, D.W. Russell, Genetic evidence that the human CYP2R1 enzyme is a key vitamin D 25-hydroxylase., Proc. Natl. Acad. Sci. USA 101 (20) (2004) 7711–7715. 8. St R. Arnaud, A. Arabian, R. Travers, et al., Deficient mineralization of intramembranous bone in vitamin D-24-hydroxylaseablated mice is due to elevated 1,25-dihydroxyvitamin D and not to the absence of 24,25-dihydroxyvitamin D, Endocrinology 141 (7) (2000) 2658–2666. 9. G. Eelen, C. Gysemans, L. Verlinden, et al., Mechanism and potential of the growth-inhibitory actions of vitamin D and analogs, Curr. Med. Chem. 14 (17) (2007) 1893–1910. 10. S. Balsan, M. Garabedian, M. Larchet, et al., Long-term nocturnal calcium infusions can cure rickets and promote normal mineralization in hereditary resistance to 1,25-dihydroxyvitamin D, J. Clin. Invest. 77 (5) (1986) 1661–1667. 11. J.L. Underwood, H.F. DeLuca, Vitamin D is not directly necessary for bone growth and mineralization, Am. J. Physiol. 246 (6 Pt 1) (1984) E493–E498. 12. Y.C. Li, M. Amling, A.E. Pirro, et al., Normalization of mineral ion homeostasis by dietary means prevents hyperparathyroidism, rickets, and osteomalacia, but not alopecia in vitamin D receptor-ablated mice., Endocrinology 139 (10) (1998) 4391–4396. 13. S.J. Van Cromphaut, M. Dewerchin, J.G. Hoenderop, et al., Duodenal calcium absorption in vitamin D receptor-knockout mice: functional and molecular aspects, Proc. Natl. Acad. Sci. USA 98 (23) (2001) 13324–13329. 14. R. Masuyama, Y. Nakaya, S. Tanaka, et al., Dietary phosphorus restriction reverses the impaired bone mineralization in vitamin D receptor knockout mice, Endocrinology 142 (1) (2001) 494–497. 15. S.J. Van Cromphaut, K. Rummens, I. Stockmans, et al., Intestinal calcium transporter genes are upregulated by estrogens and the reproductive cycle through vitamin D receptorindependent mechanisms, J. Bone Miner Res. 18 (10) (2003) 1725–1736. 16. S. Akhter, G.D. Kutuzova, S. Christakos, H.F. DeLuca, Calbindin D9 k is not required for 1,25-dihydroxyvitamin
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17.
18.
19.
20.
21.
22.
23.
24.
25.
26.
27.
28.
29.
30.
D3-mediated Ca2 absorption in small intestine, Arch. Biochem. Biophys. 460 (2) (2007) 227–232. M.B. Meyer, M. Watanuki, S. Kim, N.K. Shevde, J.W. Pike, The human transient receptor potential vanilloid type 6 distal promoter contains multiple vitamin D receptor binding sites that mediate activation by 1,25-dihydroxyvitamin D3 in intestinal cells, Mol. Endocrinol. 20 (6) (2006) 1447–1461. B.S. Benn, D. Ajibade, A. Porta, et al., Active intestinal calcium transport in the absence of transient receptor potential vanilloid type 6 and calbindin-D9 k, Endocrinology 149 (6) (2008) 3196–3205. R. Masuyama, I. Stockmans, R. Van Looveren, et al., Partial VDR rescue in intestine reverses impaired bone mineralization of VDR null mice. Conference abstract of the 13th Workshop on Vitamin D, 08-12/04/2006, Victoria, Canada, p. 69, 2006. L. Lieben, R. Masuyama, I. Stockmans, K. Moermans, R. Bouillon, G. Carmeliet, Deletion of the vitamin D receptor in the intestine induces severe bone loss to preserve normal calcemia, Bone 42 (2008) S58. J.G. Hoenderop, J.P. van Leeuwen, B.C. van der Eerden, et al., Renal Ca2 wasting, hyperabsorption, and reduced bone thickness in mice lacking TRPV5, J. Clin. Invest. 112 (12) (2003) 1906–1914. J. Silver, T. Meier, R. Levi, et al., Parathyroid-specific knockout of the vitamin D receptor leads to a phenotype resembling hyperparathyroidism, Conference abstract of the Renal Week of the American Society of Nephrology (2008) 4-9/11/2008, Philadelphia, 2008. Y. Yamamoto, T. Yoshizawa, T. Fukuda, et al., A genetic evidence of direct VDR function in osteoblasts – Generation and analysis of osteoblast-specific VDR KO mice, J. Bone Miner Res. 19 (Suppl. 1) (2004) S26. R. Masuyama, I. Stockmans, S. Torrekens, et al., Vitamin D receptor in chondrocytes promotes osteoclastogenesis and regulates FGF23 production in osteoblasts, J. Clin. Invest. 116 (12) (2006) 3150–3159. E. Beser, T. Cakmakci, Factors affecting the morbidity of vitamin D deficiency rickets and primary protection, East Afr. Med. J. 71 (6) (1994) 358–362. S. Khosla, B.L. Riggs, Pathophysiology of age-related bone loss and osteoporosis, Endocrinol. Metab. Clin. North Am. 34 (4) (2005) 1015–1030 xi. J.C. Gallagher, B.L. Riggs, J. Eisman, A. Hamstra, S.B. Arnaud, H.F. DeLuca, Intestinal calcium absorption and serum vitamin D metabolites in normal subjects and osteoporotic patients: effect of age and dietary calcium, J. Clin. Invest. 64 (3) (1979) 729–736. J.M. Quesada, W. Coopmans, B. Ruiz, P. Aljama, I. Jans, R. Bouillon, Influence of vitamin D on parathyroid function in the elderly, J. Clin. Endocrinol. Metab. 75 (2) (1992) 494–501. P. Lips, T. Duong, A. Oleksik, et al., A global study of vitamin D status and parathyroid function in postmenopausal women with osteoporosis: baseline data from the multiple outcomes of raloxifene evaluation clinical trial, J. Clin. Endocrinol. Metab. 86 (3) (2001) 1212–1221. P. Lips, Vitamin D deficiency and secondary hyperparathyroidism in the elderly: consequences for bone loss and fractures and therapeutic implications, Endocr. Rev. 22 (4) (2001) 477–501.
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31. K.S. Tsai, H. Heath III, R. Kumar, B.L. Riggs, Impaired vitamin D metabolism with aging in women. Possible role in pathogenesis of senile osteoporosis, J. Clin. Invest. 73 (6) (1984) 1668–1672. 32. D.M. Slovik, J.S. Adams, R.M. Neer, M.F. Holick, J.T. Potts Jr., Deficient production of 1,25-dihydroxyvitamin D in elderly osteoporotic patients, N. Engl. J. Med. 305 (7) (1981) 372–374. 33. M.C. Chapuy, M.E. Arlot, F. Duboeuf, et al., Vitamin D3 and calcium to prevent hip fractures in the elderly women, N. Engl. J. Med. 327 (23) (1992) 1637–1642. 34. M.K. Thomas, D.M. Lloyd-Jones, R.I. Thadhani, et al., Hypovitaminosis D in medical inpatients, N. Engl. J. Med. 338 (12) (1998) 777–783. 35. R. Eastell, A. Arnold, M.L. Brandi, et al., Diagnosis of asymptomatic primary hyperparathyroidism: proceedings of the third international workshop, J. Clin. Endocrinol. Metab. 94 (2) (2009) 340–350. 36. A. Malabanan, I.E. Veronikis, M.F. Holick, Redefining vitamin D insufficiency., Lancet 351 (9105) (1998) 805–806. 37. R.P. Heaney, M.S. Dowell, C.A. Hale, A. Bendich, Calcium absorption varies within the reference range for serum 25hydroxyvitamin D, J. Am. Coll. Nutr. 22 (2) (2003) 142–146. 38. R.P. Heaney, Vitamin D and calcium interactions: functional outcomes, Am. J. Clin. Nutr. 88 (2) (2008) 541S–544S. 39. A.G. Need, B.E. Nordin, Misconceptions – vitamin D insufficiency causes malabsorption of calcium., Bone 42 (6) (2008) 1021–1024. 40. K. Zhu, A. Devine, I.M. Dick, S.G. Wilson, R.L. Prince, Effects of calcium and vitamin D supplementation on hip bone mineral density and calcium-related analytes in elderly ambulatory Australian women: a five-year randomized controlled trial, J. Clin. Endocrinol. Metab. 93 (3) (2008) 743–749. 41. K.E. Hansen, A.N. Jones, M.J. Lindstrom, L.A. Davis, J.A. Engelke, M.M. Shafer, Vitamin D insufficiency: disease or no disease?, J. Bone Miner Res. 23 (7) (2008) 1052–1060. 42. M.E. Ooms, P. Lips, J.C. Roos, et al., Vitamin D status and sex hormone binding globulin: determinants of bone turnover and bone mineral density in elderly women, J. Bone Miner Res. 10 (8) (1995) 1177–1184. 43. H.A. Bischoff-Ferrari, T. Dietrich, E.J. Orav, B. wson-Hughes, Positive association between 25-hydroxy vitamin D levels and bone mineral density: a population-based study of younger and older adults, Am. J. Med. 116 (9) (2004) 634–639. 44. N.O. Kuchuk, N.M. van Schoor, S.M. Pluijm, A. Chines, P. Lips, Vitamin D status, parathyroid function, bone turnover and bone mineral density in postmenopausal women with osteoporosis in global perspective, J. Bone Miner Res. 24 (4) (2008) 693–701. 45. M. Peacock, G. Liu, M. Carey, et al., Effect of calcium or 25OH vitamin D3 dietary supplementation on bone loss at the hip in men and women over the age of 60, J. Clin. Endocrinol. Metab. 85 (9) (2000) 3011–3019. 46. J.F. Aloia, S.A. Talwar, S. Pollack, J. Yeh, A randomized controlled trial of vitamin D3 supplementation in African American women, Arch. Intern. Med. 165 (14) (2005) 1618–1623. 47. M.S. Barnes, P.J. Robson, M.P. Bonham, J.J. Strain, J.M. Wallace, Effect of vitamin D supplementation on vitamin D status and bone turnover markers in young adults, Eur. J. Clin. Nutr. 60 (6) (2006) 727–733.
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48. J.A. Cauley, A.Z. Lacroix, L. Wu, et al., Serum 25-hydroxyvitamin D concentrations and risk for hip fractures, Ann. Intern. Med. 194 (4) (2008) 242–250. 49. D.P. Trivedi, R. Doll, K.T. Khaw, Effect of four monthly oral vitamin D3 (cholecalciferol) supplementation on fractures and mortality in men and women living in the community: randomised double blind controlled trial, Br. Med. J. 326 (7387) (2003) 469. 50. H.E. Meyer, G.B. Smedshaug, E. Kvaavik, J.A. Falch, A. Tverdal, J.I. Pedersen, Can vitamin D supplementation reduce the risk of fracture in the elderly? A randomized controlled trial, J. Bone Miner Res. 17 (4) (2002) 709–715. 51. A.M. Grant, A. Avenell, M.K. Campbell, et al., Oral vitamin D3 and calcium for secondary prevention of low-trauma fractures in elderly people (randomised evaluation of calcium or vitamin D, RECORD): a randomised placebo-controlled trial, Lancet 365 (9471) (2005) 1621–1628. 52. P. Lips, W.C. Graafmans, M.E. Ooms, P.D. Bezemer, L.M. Bouter, Vitamin D supplementation and fracture incidence in elderly persons. A randomized, placebo-controlled clinical trial, Ann. Intern. Med. 124 (4) (1996) 400–406. 53. B. Dawson-Hughes, S.S. Harris, E.A. Krall, G.E. Dallal, Effect of calcium and vitamin D supplementation on bone density in men and women 65 years of age or older, N. Engl. J. Med. 337 (10) (1997) 670–776. 54. M.C. Chapuy, R. Pamphile, E. Paris, et al., Combined calcium and vitamin D3 supplementation in elderly women: confirmation of reversal of secondary hyperparathyroidism and hip fracture risk: the Decalyos II study, Osteoporos. Int. 13 (3) (2002) 257–264. 55. J. Porthouse, S. Cockayne, C. King, et al., Randomised controlled trial of calcium and supplementation with cholecalciferol (vitamin D3) for prevention of fractures in primary care., Br. Med. J. 330 (7498) (2005) 1003. 56. R.D. Jackson, A.Z. Lacroix, M. Gass, et al., Calcium plus vitamin D supplementation and the risk of fractures, N. Engl. J. Med. 354 (7) (2006) 669–683. 57. A. Avenell, W.J. Gillespie, L.D. Gillespie, D.L. O’Connell, Vitamin D and vitamin D analogues for preventing fractures associated with involutional and post-menopausal osteoporosis, Cochrane Database Syst. Rev. 3 (2005) CD000227. 58. H.A. Bischoff-Ferrari, W.C. Willett, J.B. Wong, E. Giovannucci, T. Dietrich, B. wson-Hughes, Fracture prevention with vitamin D supplementation: a meta-analysis of randomized controlled trials, J. Am. Med. Assoc. 293 (18) (2005) 2257–2264. 59. H.A. Bischoff-Ferrari, B. wson-Hughes, J.A. Baron, et al., Calcium intake and hip fracture risk in men and women: a meta-analysis of prospective cohort studies and randomized controlled trials, Am. J. Clin. Nutr. 86 (6) (2007) 1780–1790. 60. S. Boonen, P. Lips, R. Bouillon, H.A. Bischoff-Ferrari, D. Vanderschueren, P. Haentjens, Need for additional calcium to reduce the risk of hip fracture with vitamin D supplementation: evidence from a comparative metaanalysis of randomized controlled trials, J. Clin. Endocrinol. Metab. 92 (4) (2007) 1415–1423. 61. C. Jackson, S. Gaugris, S.S. Sen, D. Hosking, The effect of cholecalciferol (vitamin D3) on the risk of fall and fracture: a meta-analysis, Q. J. Med. 100 (4) (2007) 185–192.
62. B.M. Tang, G.D. Eslick, C. Nowson, C. Smith, A. Bensoussan, Use of calcium or calcium in combination with vitamin D supplementation to prevent fractures and bone loss in people aged 50 years and older: a meta-analysis, Lancet 370 (9588) (2007) 657–666. 63. S. O’Donnell, D. Moher, K. Thomas, D.A. Hanley, A. Cranney, Systematic review of the benefits and harms of calcitriol and alfacalcidol for fractures and falls, J. Bone Miner Metab. 26 (6) (2008) 531–542. 64. M.J. Bolland, P.A. Barber, R.N. Doughty, et al., Vascular events in healthy older women receiving calcium supplementation: randomised controlled trial, Br. Med. J. 336 (7638) (2008) 262–266. 65. M.F. Holick, E.S. Siris, N. Binkley, et al., Prevalence of Vitamin D inadequacy among postmenopausal North American women receiving osteoporosis therapy, J. Clin. Endocrinol. Metab. 90 (6) (2005) 3215–3224. 66. C. Roux, H.A. Bischoff-Ferrari, S.E. Papapoulos, A.E. de Papp, J.A. West, R. Bouillon, New insights into the role of vitamin D and calcium in osteoporosis management: an expert roundtable discussion, Curr. Med. Res. Opin. 24 (5) (2008) 1363–1370. 67. S.R. Cummings, A 55-year-old woman with osteopenia, J. Am. Med. Assoc. 296 (21) (2006) 2601–2610. 68. M.F. Holick, R.M. Biancuzzo, T.C. Chen, et al., Vitamin D2 is as effective as vitamin D3 in maintaining circulating concentrations of 25-hydroxyvitamin D, J. Clin. Endocrinol. Metab. 93 (3) (2008) 677–681. 69. L.A. Armas, B.W. Hollis, R.P. Heaney, Vitamin D2 is much less effective than vitamin D3 in humans, J. Clin. Endocrinol. Metab. 89 (11) (2004) 5387–5391. 70. S. Ish-Shalom, E. Segal, T. Salganik, B. Raz, I.L. Bromberg, R. Vieth, Comparison of daily, weekly, and monthly vitamin D3 in ethanol dosing protocols for two months in elderly hip fracture patients, J. Clin. Endocrinol. Metab. 93 (9) (2008) 3430–3435. 71. V. Chel, H.A. Wijnhoven, J.H. Smit, M. Ooms, P. Lips, Efficacy of different doses and time intervals of oral vitamin D supplementation with or without calcium in elderly nursing home residents, Osteoporos. Int. 19 (5) (2008) 663–671. 72. H.Z. Ke, H. Qi, D.T. Crawford, et al., A new vitamin D analog, 2MD, restores trabecular and cortical bone mass and strength in ovariectomized rats with established osteopenia, J. Bone Miner Res. 20 (10) (2005) 1742–1755. 73. Bouillon, R. Use of vitamin D analogs for the treatment of osteoporosis. Conference abstract of the 4th International symposium on Paget’s disease, 12-13/07/2007, Oxford, p. 13, 2007. 74. T. Matsumoto, N. Kubodera, ED-71, a new active vitamin D3, increases bone mineral density regardless of serum 25(OH)D levels in osteoporotic subjects, J. Steroid Biochem. Mol. Biol. 103 (3-5) (2007) 584–586. 75. C. Munns, M.R. Zacharin, C.P. Rodda, et al., Prevention and treatment of infant and childhood vitamin D deficiency in Australia and New Zealand: a consensus statement, Med. J. Aust. 185 (5) (2006) 268–272. 76. B. Dawson-Hughes, R.P. Heaney, M.F. Holick, P. Lips, P.J. Meunier, R. Vieth, Estimates of optimal vitamin D status, Osteoporos. Int. 16 (7) (2005) 713–716.
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77. P. Lips, Which circulating level of 25-hydroxyvitamin D is appropriate?, J. Steroid Biochem. Mol. Biol. 89–90 (1–5) (2004) 611–614. 78. A.W. Norman, R. Bouillon, S.J. Whiting, R. Vieth, P. Lips, 13th Workshop consensus for vitamin D nutritional guidelines, J. Steroid Biochem. Mol. Biol. 103 (3–5) (2007) 204–205. 79. R.A. Auwerx, J.H. Lissens, W.D. Pelemans, W.K. Vitamin D status in the elderly: seasonal substrate deficiency causes 1,25-dihydroxycholecalciferol deficiency, Am. J. Clin. Nutr. 45 (4) (1987) 755–763. 80. R. Scragg, M. Sowers, C. Bell, Serum 25-hydroxyvitamin D, ethnicity, and blood pressure in the Third National Health and Nutrition Examination Survey, Am. J. Hypertens. 20 (7) (2007) 713–719.
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81. T. Hagenau, R. Vest, T.N. Gissel, et al., Global vitamin D levels in relation to age, gender, skin pigmentation and latitude: an ecologic meta-regression analysis, Osteoporos. Int. 20 (1) (2009) 133–140. 82. B. Hintzpeter, G.B. Mensink, W. Thierfelder, M.J. Muller, C. Scheidt-Nave, Vitamin D status and health correlates among German adults, Eur. J. Clin. Nutr. 62 (9) (2008) 1079–1089. 83. I. van der Mei, A.L. Ponsonby, O. Engelsen, et al., The high prevalence of vitamin D insufficiency across Australian populations is only partly explained by season and latitude, Environ. Health Perspect. 115 (8) (2007) 1132–1139. 84. E. Orwoll, C.M. Nielson, L.M. Marshall, et al., Vitamin D deficiency in older men, J. Clin. Endocrinol. Metab. 94 (4) (2009) 1214–1222 Epub 2009 Jan 27.
Chapter
21
Role of Dietary Protein in Bone Growth and Bone Loss René Rizzoli Division of Bone Diseases [WHO Collaborating Center for Osteoporosis Prevention], Department of Rehabilitation and Geriatrics, Geneva University Hospitals and Faculty of Medicine, Geneva, Switzerland
Introduction
the various tools to assess dietary intakes, such as diary, last 24-hour recall, food frequency questionnaire or nutritional intake history, contributes to the discrepant findings regarding the relationship between bone health and nutrition.
At a given age, bone mass and bone fragility are determined by the amount of bone accumulated and the structure built at the end of skeletal growth, the so-called peak bone mass, and by the amount of bone lost and the structural degradation occurring subsequently [1]. There is a large body of evidence linking nutritional intakes, particularly protein, to bone growth and to bone loss later in life, both influencing fracture risk (Figure 21.1) [2, 3]. Sufficient dietary protein is necessary for bone homeostasis during growth as well as in the elderly. Several mechanisms, among them the growth hormone-insulin-like growth factor I target organ axis, are likely to be implicated. However, a clear relationship between bone variables and nutritional intakes is generally difficult to be firmly established. Indeed, most dietary intake evaluation tools have a poor accuracy, relying on the subject’s memory, which could be particularly unreliable in the oldest old. Furthermore, low reproducibility of
Low peak bone mass
Nutrition (protein)
Nonskeletal factors (propensity to fall)
Postmenopausal bone loss
Age-related bone loss
Low bone mass
Other risk factors
Fracture
Dietary protein and bone growth Peak bone mass is achieved for most parts of the skeleton by the end of the second decade of life [4–6]. In males, some bone consolidation, particularly in the peripheral cortical bone compartment, could take place during the third decade [4]. Puberty is the period during which the sex difference in bone mass observed in adult subjects becomes fully expressed. The important gender difference in bone mass that develops during pubertal maturation appears to result from a greater increase in bone size, a characteristic associated with a larger increment in the cortical shell in males as compared to females [7]. There is no sex difference in the volumetric trabecular density at the end of the period of maturation, i.e. in young healthy adults in their third decade. During puberty, a small increase in cancellous bone volumetric density is ascribed to a thickening of the trabeculae [8]. Thus, puberty appears to be the critical period during which gender differences in bone mass become expressed. The significantly greater mean areal bone mineral density (BMD) values observed in young healthy adult males as compared to females in the lumbar spine and at the level of the midfemoral or midradial diaphysis appear to be essentially due to a more prolonged period of pubertal maturation rather than a greater maximal rate of bone accretion [9]. Protein intakes in children and adolescents are susceptible to influence bone growth and bone mass accumulation [10]. In ‘well’-nourished children and adolescents, it may
Poor bone quality (architecture)
Figure 21.1 Potential influence of protein intake on various components of bone fragility. Osteoporosis in Men
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be that variations in the protein intake within the ‘normal’ range can have a significant effect on skeletal growth and thereby modulate the genetic potential in peak bone mass attainment. Prospective observational studies suggest that both calcium and protein intakes are independent variables of bone mineral mass acquisition, particularly before the onset of pubertal maturation. In a recent study, we found that bone mineral density/bone mineral content (BMD/ BMC) changes in prepubertal boys were positively associated with spontaneous protein intake [11]. In addition, this study has also suggested that protein intake modulates the effect of calcium supplementation on bone mineral mass gain in prepubertal boys [12]. Hence, in prepubertal boys, the favorable effects of calcium supplements were mostly detectable in those with a lower protein intake. At higher protein intake, the effect of calcium was not significant, suggesting possibly that calcium requirements for optimal bone growth could be lower with high levels of dietary protein. Furthermore, in healthy prepubertal boys, the impact of increased physical activity on bone mineral content appears to be higher at protein intake within a range above the usual recommended allowance [11]. Current recommendations for daily protein intakes in children of that age, however, still remain speculative [13]. Recommended dietary allowances are estimates derived from interpolation of requirements determined in infants and young adults [13, 14]. The spontaneous consumption of protein by healthy prepubertal children 7–11 years of age is well above the recommended dietary allowances. Concern has been frequently expressed about the putative adverse effect of high protein intakes. In our cohort of healthy, quite active physically prepubertal boys, a consumption of 1.7 g/kg body weight of animal protein as compared to the recommended allowance of 0.9– 1.0 g/kg body weight/day for total protein was not associated with any apparent detrimental effect. Even protein intakes above the median were associated with a greater bone mass gain [11]. This observation can by no means be taken as a scientific basis to reconsider the nowadays widely accepted recommendation of protein intakes for children. It should at least not promote public health initiatives aimed at reducing the spontaneous intakes of protein to the level of the recommended allowances by national and international agencies. Nutritional environmental factors seem to affect bone accumulation at specific periods during infancy and adolescence. In a prospective survey carried out in a cohort of female and male subjects aged 9–19 years, food intake was assessed twice, at a one-year interval, using a 5-day dietary diary method with a weighing of all consumed foods. In this cohort of adolescents, we found a positive correlation between yearly lumbar and femoral bone mass gain and calcium or protein intake. This correlation appeared to be significant mainly in prepubertal children, but not in those having reached a peri- or postpubertal stage [9]. It remained statistically significant after adjustment for spontaneous calcium intake.
In a prospective longitudinal study performed in healthy children and adolescents of both genders, between the ages of 6 and 18, dietary intakes were recorded over 4 years, using a yearly administered 3-day diary [15]. Bone mass and size were measured at the radius diaphysis by peripheral computerized tomography. A significant positive association was found between long-term protein intakes on the one hand and periosteal circumferences, cortical area, bone mineral content and with a calculated strength strain index on the other hand. The relatively high mean protein intakes in this cohort with a Western style diet should be highlighted. Indeed, protein intakes were around 2 g/kg body weight/day in prepubertal children, whereas they were around 1.5 g/kg body weight/day in pubertal individuals. The minimal requirements for protein intakes in the corresponding age groups are 0.99 and 0.95, respectively. There was no association between bone variables and intakes of nutrients with high sulfur-containing amino acids or intake of calcium. Overall, protein intakes accounted for 3–4% of the bone parameters’ variance. However, even when they are prospective and longitudinal, observational studies do not allow one to draw conclusions on a causal relationship. Indeed, it is quite possible that protein intake could be, to a large extent, related to growth requirement during childhood and adolescence. Altogether, the results indicate that moderate-to-high dietary protein intake is associated with a higher peak bone mass. However, only intervention studies with bone mass, mineralization and geometry as endpoints could reliably address this question. To our knowledge, there is no large randomized controlled trial having tested the effects of dietary protein supplements on bone mass accumulation, except milk or dairy products.
Dairy products and bone growth One liter of milk provides 32–35 g of protein, mostly casein, but also whey-protein which contains numerous growthpromoting elements in addition to calcium, phosphorus, calories and vitamins [16–18]. The correlation between bone health and dairy products intake has been investigated in both cross-sectional and longitudinal observational studies and in intervention trials. In growing children, long-term milk avoidance is associated with smaller stature and lower bone mineral mass, either at specific sites or at the whole body levels [19–29]. Low milk intake during childhood and/ or adolescence increases the risk of fracture before puberty (2.6-fold) and, possibly, later in life [30–32]. In a 7-year observational study, there was a positive influence of dairy product consumption on bone mineral density at the spine, hip and forearm in adolescents, leading thereby to a higher peak bone mass [33]. Of interest, calcium supplements did not affect spine BMD in this study. In addition, higher dairy products intakes were associated with greater total and cortical proximal radius cross-sectional area. Based on these
C h a p t e r 2 1 Role of Dietary Protein in Bone Growth and Bone Loss l
observations, it was suggested that, whereas calcium supplements could influence volumetric BMD and thus the remodeling process, dairy products may have an additional effect on bone growth and periosteal bone expansion, i.e. a modeling influence. In agreement with this observation, milk consumption frequency and milk intake at age 5–12 and 13–17 years were significant predictors of the height of 12–18 yearold adolescents studied in the NHANES 1999–2002 [34]. Leighton and Clark, and Orr probably ran the first controlled milk intervention studies [35, 36]. In British schoolchildren, 400–600 ml/day of milk had a positive effect on height gain over a 7-month period. Subsequently, a variety of intervention trials have confirmed a favorable influence of dairy products on bone health during childhood and adolescence [37–46]. In a randomized open intervention trial, Cadogan et al studied the effects of 568 ml/day milk supplement for 18 months in 12-year-old girls [38]. With this milk supplement, the differences between the treated and control groups in calcium and protein intakes at the end of the study were around 420 mg/day and 14 g/day, respectively, taking into consideration the spontaneous consumption of either nutrient. In the milk-supplemented group, serum insulin-like growth factor I (IGF-I) levels were significantly higher (17%). Compared to the control group, the intervention group had greater increases of whole body bone mineral density and bone mineral content. Among the various skeletal sites measured, pelvis and lower limbs showed the highest response to milk supplements. In another randomized controlled study, cheese supplements appeared to be more beneficial for cortical bone accrual than a similar amount of calcium supplied in the form of tablets [39]. This could also be compatible with a favorable effect of dairy products-provided protein. The positive influence of milk on cortical bone thickness may be related to an effect on the modeling process, since metacarpal periosteal diameter was significantly increased in Chinese children receiving milk supplements.
Dietary protein and bone mineral mass In numerous studies, a positive association between bone mass at various skeletal sites and spontaneous protein intake has been detected in pre- or postmenopausal women [47–63] as well as in men [64–66]. Unadjusted BMD was greater in the group with the higher protein intake in a large series of data collected in the frame of the Study of Osteoporotic Fracture [59]. There was a positive correlation between radial bone mineral content and protein intake in Japanese or American women. Besides numerous crosssectional studies showing a positive association between bone mass and protein intake, a longitudinal follow-up in the frame of the Framingham study has demonstrated that the rate of bone mineral loss was inversely correlated to
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dietary protein intake. This inverse relationship between longitudinal femoral neck areal BMD changes and dietary protein was observed in both men and women [67]. Recently, spontaneous higher protein intake was associated with an increase in BMD in a group of patients receiving calcium supplements and followed longitudinally [68, 69]. In contrast, there are very few surveys in which high protein intake was accompanied with lower bone mass. In a cross-sectional study, a protein intake close to 2 g/kg body weight was associated with reduced bone mineral density only at one out of the two forearm sites measured in young college women [70].
Dietary protein and fracture risk An indirect argument in favor of a deleterious effect of high protein intake on bone is that hip fracture appears to be more frequent in countries with high protein intake of animal origin [71, 72]. But, as expected, the countries with the highest incidence are those with the longest life expectancy, accounting for an elevated fracture incidence. In the large Nurse Health Study, a trend for a hip fracture incidence inversely related to protein intake has been reported [73, 74]. Similarly, hip fracture was higher with low energy intake, low serum albumin levels and low muscle strength in the NHANES I study. In a prospective study carried out in more than 40 000 women in Iowa, higher protein intake was associated with a reduced risk of hip fracture [75] (Figure 21.2). The protective effect was observed with dietary protein of animal origin. These findings were confirmed in a prospective longitudinal study, but mostly in the subjects in the 60–69 years age range [76]. In another survey, no association between hip fracture and non-dairy animal protein intake could be detected [77]. However, in this study, fracture risk was increased when a high protein diet was accompanied by a low calcium intake, in agreement with the requirement of sufficient calcium intake to detect Falls
Osteoporosis
Mechanical overload
Mechanical incompetence Fracture
Protein deficiency Rehabilitation To restore independence To reduce disabilities Prevention subsequent fracture
Figure 21.2 Role of protein deficiency in the pathogenesis of fragility fracture.
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a favorable influence of dietary protein on bone. In a longitudinal study, hip fracture incidence was positively related to a higher ratio animal-to-vegetal protein intake, whereas protein of vegetable origin was rather protective [59].
Dietary protein and bone metabolism High protein intake has been claimed to be a risk factor for osteoporosis. The proposed underlying mechanism implies that higher protein intake increases acid production and renal acid excretion, because of protons released during the oxidation of sulfur-containing amino acids such as methionine, cysteine and cystine. Since urinary calcium excretion directly varies with acid excretion, urinary calcium is positively correlated with protein intake [78–81]. These associations would thus suggest that high protein intake will, in turn, induce a negative calcium balance and, consequently, would favor bone loss [82]. Furthermore, nutrition-generated acid load would lead to an increased bone dissolution in healthy individuals, this by analogy to the classical physicochemical in vitro observation indicating that lowering pH favors the dissolution of calcium phosphate crystals, including those of hydroxyapatite. However, further studies indicate that a reduction in dietary protein may lead to a decline in calcium absorption and to secondary hyperparathyroidism. A low (0.7 g/kg body weight/day), but not a high protein intake (2.1 g/kg body weight/day) was associated with an increase in biochemical markers of bone turnover as compared with a diet containing 1.0 g/kg of protein [83–87]. High meat diets (1.6 g/kg body weight/day of protein) compared to 0.9 g/kg for 8 weeks did not affect calcium retention nor indices of bone metabolism [88]. This would suggest that the protein intake would be potentially harmful for the skeleton; it is not clearly determined yet. The question whether the source of protein, animal versus vegetal, would differently affect calcium metabolism has been the object of emotional belief [82]. This belief relies on the hypothesis that animal protein would generate more sulfuric acid from sulfurcontaining amino acids than a vegetarian diet. That animal protein in contrast to vegetal protein would be consistently detrimental for bone health is not supported by chemical and experimental evidence. Indeed, a vegetarian diet with protein derived from grains and legumes would deliver as many millimoles of sulfur per gram protein as would a purely meatbased diet [82, 89]. On the other hand, it is true that meats contain other than sulfur acid-producing substances. High protein intakes are not associated with significant changes in blood pH [90]. However, in favor of this endogenous acid production in bone metabolism, it appears that neutralization of this endogenous acid production with potassium bicarbonate is associated with positive calcium balance [91]. In a cross-sectional survey, bone mineral density was higher in subjects with diets rich in fruit and vegetables, presumably
rich in alkali [89, 92]. This issue is further complicated by the fact that the vegetable intake-induced decrease in bone resorption [93] has been shown to be independent from acidbase changes [94] and that potassium, but not sodium bicarbonate (i.e. the same anion) or citrate administration, reduces urinary calcium excretion [81, 95]. Finally, if high protein intake was really harmful for the skeleton, some consistent inverse relationship should be detected between bone mineral density and dietary protein, which is not the case. Experimental and clinical studies suggest that dietary protein, by influencing both the production and action of IGF-I, particularly the growth hormone (GH)-IGF system, could control bone anabolism (Figure 21.3) [3, 96]. The hepatic production and plasma level of IGF-I are under the influence of dietary protein [97]. Protein restriction has been shown to reduce IGF-I plasma levels by inducing a resistance to the action of GH at the hepatic level [96] and by an increase of IGF-I metabolic clearance rate [98]. Decreased levels of IGF-I have been found in states of undernutrition such as marasmus, anorexia nervosa, celiac disease, or in human immunodeficiency virus- (HIV-) infected patients [96]. Elevated protein intake is able to prevent the decrease in IGF-I usually observed in hypocaloric states [99, 100]. When IGF-I was given to growing rats maintained under a low protein diet at doses normalizing its plasma levels, it failed to restore skeletal longitudinal growth [96]. The administration of pharmacological doses of IGF-I, producing a 5-fold increase in IGF-I circulating levels in adult rats, in an attempt to correct the negative influence of protein deficiency, was without effects on bone if the protein intake was insufficient [101]. IGF-I is an essential factor for longitudinal bone growth and also exerts anabolic effects on bone mass during adulthood [102, 103]. Furthermore, by its renal action on tubular reabsorption of phosphate and on the synthesis of calcitriol, through a direct action on renal cells [104], IGF-I can be considered as an important controller of the intestinal absorption and of the extracellular concentration of both calcium and phosphate, the main elements of bone mineral (see Figure 21.3). On the other hand, IGF-I can selectively stimulate the transport of inorganic phosphate across the plasma membrane in kidney and osteoblastic cell lines [105, 106]. Since undernutrition can concern all kinds of nutrients in the elderly, and not only protein, we developed an experimental model of selective protein deprivation in adult male rats, with isocaloric low protein diets supplemented with identical amounts of minerals in order to study the specific influence of protein deficiency in the pathogenesis of osteoporosis [107]. This model enables the study of bone mineral mass, bone strength and bone remodeling. Eight-month-old male rats were pair-fed a control (15% casein) or isocaloric low protein (2.5% casein) diet for 1 or 7 months. In proximal tibia, isocaloric low protein diet significantly decreases BMD (12%), cancellous bone mass
C h a p t e r 2 1 Role of Dietary Protein in Bone Growth and Bone Loss l
Protein intake
IGF-I
Bone growth
1,25-(OH)2D3
Intestinal absorption of calcium and Pi
TmPi/GFR
Serum Pi
Figure 21.3 Effects of IGF-I on bone formation, intestinal calcium and phosphorus absorption and renal tubular reabsorption of phosphorus.
(71%) and trabecular thickness (30%), resulting in a significant reduction in ultimate strength (27%). In cortical middiaphysis, low protein diet decreases BMD (9%), enlarges the medullary cavity (36%), leading to cortical thinning and lower mechanical strength (20%). In cancellous bone, protein deficiency transiently depresses bone formation rate (60%), osteoid seam thickness (15%) and mineral apposition rate (20%), indicating a decrease in osteoblast recruitment and activity. Cortical loss (15%) results from an imbalance between endosteal modeling drifts with impaired bone formation rate (70%). From the first week of protein deficiency, osteocalcin and IGF-I (32%) levels drop significantly. Bone resorption activity and urinary deoxypyridinoline remain unchanged throughout the experiment. Protein deficiency in aged male rats induced cortical and trabecular thinning and decreased bone strength, in association with a remodeling imbalance with a bone formation impairment and a decrease in IGF-I levels. Isocaloric dietary protein deficiency is associated with decreased BMD and bone strength, as a consequence of increased bone resorption and decreased bone formation. To evaluate the role of bone resorption in this process, we tested the effect of the bisphosphonate pamidronate in 5.5-month-old female or 6-month-old male rats pair-fed a control (15% casein) or an isocaloric low protein (2.5% casein) diet for 19 and 26 weeks, respectively [108]. Pamidronate (0.6 mg/kg) was given subcutaneously 5 days/month for 4 months in female rats or for 5 months in male rats. The increase in bone resorption in female rats (100%) and in male rats (33%) fed a low protein diet was prevented by pamidronate treatment. The reduced osteocalcin levels observed in rats fed a low protein diet were further decreased in both female (34%) and male (30%) rats treated with pamidronate. The bone turnover decrease induced by pamidronate prevented bone strength reduction, trabecular bone loss, microarchitecture and BMD alterations induced by the isocaloric low protein diet. Similar effects were observed at the level of the midshaft tibia. Significant decrease of plasma IGF-I was observed in
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rats fed a low protein diet independently of the pamidronate treatment. Thus, inhibition of increased bone resorption in rats fed an isocaloric low protein diet fully prevents bone loss and alteration of bone strength. Thus, the decrease in bone mass and bone strength is related to an early inhibition of bone formation and a later acceleration of bone resorption. Whereas a rapid decrease in circulating IGF-I could account for the former, the latter might be related to testosterone deficiency caused by protein undernutrition. Indeed, some state of hypogonadism was associated with long-term isocaloric low protein diet. At an early time-point (1 month), histomorphometry analysis shows that bone loss process is mainly related to a depressed bone formation [107]. Adult male and female rats differed by the kinetics of the response to the isocaloric low protein diet, with changes occurring more slowly in males than in females [107, 109]. Since there was an alteration of the growth hormoneIGF-I bone axis in protein undernutrition, with altered production of both hormones, decreased bone formation and increased bone resorption and a marked increase in bone fragility, we investigated whether the administration of growth hormone or IGF-I could reverse this process. Under an isocaloric low protein diet, the IGF-I response to GH appeared to be blunted, but the most striking finding was that growth hormone was rather catabolic on bone, instead of anabolic, since there was a dose-dependent decrease of bone strength after 4 weeks of growth hormone treatment in animals fed the isocaloric low protein diet [110]. We then tested the effects of protein replenishment by administering essential amino acid supplements in the same relative proportion as in casein [111]. These supplements caused an increase of IGF-I up to a level higher than in rats fed the control diet, increased biochemical bone formation and decreased markers of bone resorption and improved bone strength more than bone mineral mass, probably in relation to an increase in cortical thickness, as demonstrated by micro-quantitative computerized tomography. Closing the loop, locally produced IGF-I appears of major importance in the bone damage caused by protein undernutrition. Indeed, transgenic mice with osteoblast-targeted overexpression of IGF-I do not display the decrease in bone mass and bone strength induced by an isocaloric low protein diet [111]. In addition to alterations in the control and action of the growth hormone-IGF-I system, protein undernutrition can be associated with alterations of cytokine secretion, such as interferon gamma, tumor necrosis factor alpha (TNF) or transforming growth factor beta [112]. TNF and interleukin-6 generally increase with aging. In a situation of cachexia, such as in chronic heart failure, an inverse correlation between bone mineral density and TNF levels has been found, further implicating a possible role of uncontrolled cytokines production in bone loss. Increased TNF can be a crucial factor in the sex hormone deficiencyinduced bone loss, but it also plays a role in the target organ
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resistance to insulin and possibly to IGF-I. Along the same line, certain amino acids given to rats fed a low protein diet can increase the liver protein synthesis response to TNF. However, an increase in bone resorption under a low protein diet was also detected in ovariectomized animals, indicating the presence of a low protein diet-dependent and sex hormone-independent component [109]. Histomorphometry analysis and biochemical markers of bone remodeling results indicate that the low protein intake-induced decrease in bone mineral mass and bone strength is related to an uncoupling between bone formation and resorption [107]. The prevalence of bone resorption over formation could be partially explained by the altered sex hormone status. However, other mechanisms, including the effects of circulating or locally released cytokines, are likely. Production and action of TNF play a central role in the accelerated bone loss caused by sex hormone deficiency, as indicated by experiments carried out in transgenic mice overexpressing TNF receptor 1 protein, which blocks the effects of this factor. Indeed, in these animals, the influence of ovariectomy [113] or orchidectomy is prevented in transgenic animals overexpressing the TNF receptor 1. To address the issue of the accelerated bone loss occurring under a low protein diet, we used the model of transgenic mice, which overexpresses the soluble TNF receptor. Blocking TNF activity prevented the component of increased bone resorption induced by the isocaloric low protein diet, without modifying the alterations in bone formation [114]. Similarly, we also assessed whether interleukin-1 (IL-1) could be involved in this process. The effects of an isocaloric low protein diet were studied in transgenic mice overexpressing an IL-1 receptor antagonist, a situation in which IL-1 is prevented from exerting its biological action. In this model, low protein diet-induced bone loss in the IL-1 receptor-antagonist overexpressing mice and their negative littermates was identical [115]. In humans too, the amino acid oxidation rate was lower in children with kwashiorkor repleted with milk as compared with egg white and protein breakdown and synthesis correlated inversely with TNF levels [116]. Amino acids as constituents of protein can influence calcium homeostasis controling systems [117]. In addition to calcium, magnesium and other multivalent cations, calcium-sensing receptor is influenced by amino acids, specifically L-amino acids. As shown in cellular assays, aromatic amino acids, such as L-Phe, L-Trp, L-His or L-Ala are much more potent in their interaction with the calcium sensing receptor than others like L-Leu or L-Val [117–119]. Elevated levels of the former amino acids do indeed suppress parathyroid hormone (PTH) from normal human parathyroid cells in vitro. High protein diet increases urinary calcium excretion. This could be related to amino acids activating calcium-sensing receptor in both parathyroid cells and kidney cortical thick ascending loop leading to decreased PTH release and lower renal tubular calcium reabsorption, respectively. In humans, increased
intake of aromatic, but not of branched-chain amino acids is associated with increases in serum IGF-I, intestinal calcium absorption and 24-h urinary calcium excretion, without any change in biochemical markers of bone turnover [120]. Under these conditions, more than 90% of the dietary protein-induced increase in urinary calcium excretion would arise from enhanced intestinal calcium absorption.
Effects of protein insufficiency correction As suggested above, a restoration of the altered G-IGF-I system in the elderly by protein replenishment is likely to influence favorably not only bone mineral density, but also muscle mass and strength, since these two variables are important determinants of the risk of falling. Intervention studies using a simple oral dietary preparation that normalizes protein intake [121] can improve the clinical outcome after hip fracture. It should be emphasized that a 20 g protein supplement brought the intake from low to a level still below RDA (0.8 g/kg body weight), thus avoiding the risk of an excess of dietary protein [3]. Follow up showed a significant difference in the clinical course in the rehabilitation hospitals, with the supplemented patients doing better. The significantly lower rate of complications (bedsore, severe anemia, intercurrent lung or renal infections, 44% versus 87%) and deaths was still observed at six months (40% versus 74%) [122]. In this study, the total length of stay in the orthopedic ward and rehabilitation hospital was significantly shorter in supplemented patients than in controls (median: 24 versus 40 days). Normalization of protein intake, independently of that of energy, calcium and vitamin D, is in fact responsible for this more favorable outcome, as shown in a randomized controlled trial, in which protein intake was the primary variable accounting for the better outcome which was recorded. In undernourished elderly patients with a recent hip fracture, an increase in the protein intake, from low to normal, can also be beneficial for bone integrity. Indeed, in a double-blind, placebo-controlled study, protein repletion with 20 g protein supplement daily for 6 months as compared to an isocaloric placebo, produced greater gains in serum prealbumin, IGF-I and IgM and an attenuated proximal femur BMD decrease [123] (Table 21.1). In this trial, all 82 patients (women and men, mean age 80.7 1.2 yrs) were given 200 000 IU vitamin D once at baseline and 550 mg/day of calcium, starting within one week after an osteoporotic hip fracture. In a multiple regression analysis, baseline IGF-I concentrations, biceps muscle strength, together with protein supplements accounted for more than 30% of the variance of the length of stay in rehabilitation hopitals (r2 0.312, P 0.0005), which was reduced by 25% in the protein supplemented group. Thus, the lower incidence of medical complications observed after a protein supplement [121, 122] is also compatible with the hypothesis
C h a p t e r 2 1 Role of Dietary Protein in Bone Growth and Bone Loss l
Table 21.1 Effects of protein supplements in elderly with hip fracturea,b Prealbumin IGF-I IgM Proximal femur BMD Stay in rehabilitation hospital
Increased Increased Increased Decreased Decreased
a
As compared with placebo controls. Tkatch et al 1992 [122]; Schürch et al 1998 [123].
b
of IGF-I improving the immune status, as this growth factor can stimulate the proliferation of immunocompetent cells and modulate immunoglobulin secretion [124]. We recently completed short-term studies on the kinetics and determinants of the IGF-I response to protein supplements in a situation associated with low baseline IGF-I levels. In elderly patients with a recent hip fracture, we found that a 20 g/day protein supplement increased serum IGF-I and IGF-binding protein-3 as soon as one week. The increase in bone turnover, as assessed by biochemical markers, was slightly delayed (Chevalley et al, unpublished observations). In another short-term study on the kinetics and determinants of the IGF-I response to protein supplements in a situation associated with low baseline IGF-I levels, such as the frail elderly, we found that a 20 g/day protein supplement increased serum IGF-I and IGF-binding protein-3 as soon as 1 week, with a maximal response by 2 weeks [125]. By one week, this response appeared to be of higher magnitude with zinc supplements. An animal model was designed to mimic the situation observed in elderly women in whom estrogen deficiency and/or low protein intake (but also calcium and vitamin D deficiency) are known to contribute to the pathogenesis of osteoporosis [111]. We then investigated whether the administration of dietary essential amino acid supplements in adult rats made osteoporotic by estrogen deficiency and reduced protein intake could reverse the deleterious effects caused by these maneuvers. Six-month-old rats were ovariectomized (OVX) and fed an isocaloric 2.5% casein diet for 10 weeks or sham-operated (SHAM) and fed an isocaloric 15% casein diet. The animals fed the 2.5% casein diet were given isocaloric supplements of essential amino acids in similar relative proportion to that of casein at doses of 2.5% or 5% of total diet for an additional 16 weeks. Essential amino acid supplements increased vertebrae, femur and tibia bone strength in OVX rats fed a low protein diet. The mechanical changes induced by this dietary isocaloric supplement were associated with the prevention of a further BMD decrease or even with some increases and changes in microarchitecture, such as from a rod to a plate trabecular spatial configuration and increased cortical thickness. Higher IGF-I levels, as well as greater bone formation and reduced bone resorption as assessed by biochemical markers of bone remodeling, were found in rats receiving essential amino acid supplements.
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Thus, in this animal model, dietary essential amino acid supplements increased bone strength through modifications of BMD, trabecular architecture and cortical thickness possibly by an IGF-I-mediated process. The role of protein depletion–repletion has been evaluated in animal models of specific gene invalidation or overexpression, mimicking human diseases [126]. For instance, neurofibromatosis results from a deficiency in neurofibromin, Nf1 protein product, a tumor-suppressor protein. Mice with a specifically osteoblast ablated Nf1 gene displayed an increased bone mass phenotype, with increased bone formation and resorption. This bone phenotype can be rescued by nutritional restriction of protein intake [127]. In contrast, an opposite phenotype was found in mice with ablation of the transcription factor ATF-4, a situation analogous to the Coffin-Lowry syndrome [128]. In vitro, the marked decrease in collagen synthesis in ATF-4 null osteoblast can be corrected by the addition of non-essential amino acids, in agreement with the regulatory role of ATF-4 in amino acid transport [129]. Finally, the low bone mass phenotype of ATF-4 nul mice can be rescued by high protein feeding [127].
Acknowledgment Mrs. Marianne Perez is thanked for her invaluable help in preparing the manuscript.
References 1. C.J. Hernandez, G.S. Beaupre, D.R. Carter, A theoretical analysis of the relative influences of peak BMD, age-related bone loss and menopause on the development of osteoporosis, Osteoporos. Int. 14 (10) (2003) 843–847. 2. R. Rizzoli, P. Ammann, T. Chevalley, J.P. Bonjour, Protein intake and bone disorders in the elderly, Joint Bone Spine 68 (5) (2001) 383–392. 3. R. Rizzoli, J. Bonjour, Dietary protein and bone health, J. Bone Miner. Res. 19 (2004) 527–531. 4. J.P. Bonjour, R. Rizzoli, Bone acquisition in adolescence, in: R. Marcus, D. Feldman, J. Kelsey (Eds.), Osteoporosis, Academic Press, San Diego, 2001, pp. 621–638. 5. J.P. Bonjour, G. Theintz, B. Buchs, D. Slosman, R. Rizzoli, Critical years and stages of puberty for spinal and femoral bone mass accumulation during adolescence, J. Clin. Endocrinol. Metab. 73 (3) (1991) 555–563. 6. R. Rizzoli, J.P. Bonjour, S.L. Ferrari, Osteoporosis, genetics and hormones, J. Mol. Endocrinol. 26 (2) (2001) 79–94. 7. E. Seeman, The structural and biomechanical basis of the gain and loss of bone strength in women and men, Endocrinol. Metab. Clin. North. Am. 32 (1) (2003) 25–38. 8. A.M. Parfitt, R. Travers, F. Rauch, F.H. Glorieux, Structural and cellular changes during bone growth in healthy children, Bone 27 (4) (2000) 487–494. 9. G. Theintz, B. Buchs, R. Rizzoli, et al., Longitudinal monitoring of bone mass accumulation in healthy adolescents: evidence for a marked reduction after 16 years of age at the
262
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
21.
22.
23.
24.
25.
26.
Osteoporosis in Men
levels of lumbar spine and femoral neck in female subjects, J. Clin. Endocrinol. Metab. 75 (4) (1992) 1060–1065. J.P. Bonjour, P. Ammann, T. Chevalley, R. Rizzoli, Protein intake and bone growth, Can. J. Appl. Physiol. 26 (Suppl.) (2001) S153–S166. T. Chevalley, J.P. Bonjour, S. Ferrari, R. Rizzoli, High-protein intake enhances the positive impact of physical activity on BMC in prepubertal boys, J. Bone Miner. Res. 23 (1) (2008) 131–142. T. Chevalley, S. Ferrari, D. Hans, et al., Protein intake modulates the effet of calcium supplementation on bone mass gain in prepubertal boys, J. Bone Miner. Res. 17 (Suppl. 1) (2002) S172. N.R. Rodriguez, Optimal quantity and composition of protein for growing children, J. Am. Coll. Nutr. 24 (2) (2005) 150S–154S. K.G. Dewey, G. Beaton, C. Fjeld, B. Lonnerdal, P. Reeds, Protein requirements of infants and children, Eur. J. Clin. Nutr. 50 (Suppl. 1) (1996) S119–S147 discussion S14750. U. Alexy, T. Remer, F. Manz, C.M. Neu, E. Schoenau, Longterm protein intake and dietary potential renal acid load are associated with bone modeling and remodeling at the proximal radius in healthy children, Am. J. Clin. Nutr. 82 (5) (2005) 1107–1114. O. Kelly, S. Cusack, K.D. Cashman, The effect of bovine whey protein on ectopic bone formation in young growing rats, Br. J. Nutr. 90 (3) (2003) 557–564. M.C. Kruger, G.G. Plimmer, L.M. Schollum, N. Haggarty, S. Ram, K. Palmano, The effect of whey acidic protein fractions on bone loss in the ovariectomised rat, Br. J. Nutr. 94 (2) (2005) 244–252. K.E. Scholz-Ahrens, J. Schrezenmeir, Effects of bioactive substances in milk on mineral and trace element metabolism with special reference to casein phosphopeptides, Br. J. Nutr. 84 (2000) S147–S153. R.E. Black, S.M. Williams, I.E. Jones, A. Goulding, Children who avoid drinking cow milk have low dietary calcium intakes and poor bone health, Am. J. Clin. Nutr. 76 (3) (2002) 675–680. W. Bounds, J. Skinner, B.R. Carruth, P. Ziegler, The relationship of dietary and lifestyle factors to bone mineral indexes in children, J. Am. Diet. Assoc. 105 (5) (2005) 735–741. G.M. Chan, K. Hoffman, M. McMurry, Effects of dairy products on bone and body composition in pubertal girls, J. Pediatr. 126 (4) (1995) 551–556. E. Hidvegi, A. Arato, E. Cserhati, C. Horvath, A. Szabo, Slight decrease in bone mineralization in cow milk-sensitive children, J. Pediatr. Gastroenterol. Nutr. 36 (1) (2003) 44–49. D. Infante, R. Tormo, Risk of inadequate bone mineralization in diseases involving long-term suppression of dairy products, J. Pediatr. Gastroenterol. Nutr. 30 (3) (2000) 310–313. V.B. Jensen, I.M. Jorgensen, K.B. Rasmussen, C. Molgaard, P. Prahl, Bone mineral status in children with cow milk allergy, Pediatr. Allergy Immunol. 15 (6) (2004) 562–565. A.R. Opotowsky, J.P. Bilezikian, Racial differences in the effect of early milk consumption on peak and postmenopausal bone mineral density, J. Bone Miner. Res. 18 (11) (2003) 1978–1988. J.E. Rockell, S.M. Williams, R.W. Taylor, A.M. Grant, I.E. Jones, A. Goulding, Two-year changes in bone and body composition in young children with a history of prolonged milk avoidance, Osteoporos. Int. 16 (9) (2005) 1016–1023.
27. A.Z. Budek, C. Hoppe, H. Ingstrup, K.F. Michaelsen, S. Bugel, C. Molgaard, Dietary protein intake and bone mineral content in adolescents – The Copenhagen Cohort Study, Osteoporos. Int. 18 (12) (2007) 1661–1667. 28. C. Hoppe, C. Molgaard, K.F. Michaelsen, Bone size and bone mass in 10-year-old Danish children: effect of current diet, Osteoporos. Int. 11 (12) (2000) 1024–1030. 29. C. Hoppe, C. Molgaard, A. Juul, K.F. Michaelsen, High intakes of skimmed milk, but not meat, increase serum IGF-I and IGFBP-3 in eight-year-old boys, Eur. J. Clin. Nutr. 58 (9) (2004) 1211–1216. 30. A. Goulding, J.E. Rockell, R.E. Black, A.M. Grant, I.E. Jones, S.M. Williams, Children who avoid drinking cow’s milk are at increased risk for prepubertal bone fractures, J. Am. Diet. Assoc. 104 (2) (2004) 250–253. 31. H.J. Kalkwarf, J.C. Khoury, B.P. Lanphear, Milk intake during childhood and adolescence, adult bone density, and osteoporotic fractures in US women, Am. J. Clin. Nutr. 77 (1) (2003) 257–265. 32. D. Teegarden, R.M. Lyle, W.R. Proulx, C.C. Johnston, C.M. Weaver, Previous milk consumption is associated with greater bone density in young women, Am. J. Clin. Nutr. 69 (5) (1999) 1014–1017. 33. V. Matkovic, J.D. Landoll, N.E. Badenhop-Stevens, et al., Nutrition influences skeletal development from childhood to adulthood: a study of hip, spine, and forearm in adolescent females, J. Nutr. 134 (3) (2004) 701S–705S. 34. A.S. Wiley, Does milk make children grow? Relationships between milk consumption and height in NHANES 1999– 2002, Am. J. Hum. Biol. 17 (4) (2005) 425–441. 35. G. Leighton, M. Clark, Milk consumption and the growth of school-children, BMJ (1929) 40–43. 36. J. Orr, Milk consumption and the growth of school-children, BMJ (1928) 202–203. 37. I.A. Baker, P.C. Elwood, J. Hughes, M. Jones, F. Moore, P.M. Sweetnam, A randomised controlled trial of the effect of the provision of free school milk on the growth of children, J. Epidemiol. Commun. Hlth. 34 (1) (1980) 31–34. 38. J. Cadogan, R. Eastell, N. Jones, M.E. Barker, Milk intake and bone mineral acquisition in adolescent girls: randomised, controlled intervention trial, Br. Med. J. 315 (7118) (1997) 1255–1260. 39. S. Cheng, A. Lyytikainen, H. Kroger, C. Lamberg-Allardt, et al., Effects of calcium, dairy product, and vitamin D supplementation on bone mass accrual and body composition in 10–12-y-old girls: a 2-y randomized trial, Am. J. Clin. Nutr. 82 (5) (2005) 1115–1126 quiz 11471148. 40. X. Du, K. Zhu, A. Trube, et al., Effects of school-milk intervention on growth and bone mineral accretion in Chinese girls aged 10–12 years: accounting for cluster randomisation, Br. J. Nutr. 94 (6) (2005) 1038–1039. 41. X. Du, K. Zhu, A. Trube, et al., School-milk intervention trial enhances growth and bone mineral accretion in Chinese girls aged 10–12 years in Beijing, Br. J. Nutr. 92 (1) (2004) 159–168. 42. E.M. Lau, H. Lynn, Y.H. Chan, W. Lau, J. Woo, Benefits of milk powder supplementation on bone accretion in Chinese children, Osteoporos. Int. 15 (8) (2004) 654–658. 43. M.J. Merrilees, E.J. Smart, N.L. Gilchrist, et al., Effects of diary food supplements on bone mineral density in teenage girls, Eur. J. Nutr. 39 (6) (2000) 256–262.
C h a p t e r 2 1 Role of Dietary Protein in Bone Growth and Bone Loss l
44. J.S. Volek, A.L. Gomez, T.P. Scheett, et al., Increasing fluid milk favorably affects bone mineral density responses to resistance training in adolescent boys, J. Am. Diet. Assoc. 103 (10) (2003) 1353–1356. 45. K. Zhu, X. Du, C.T. Cowell, et al., Effects of school milk intervention on cortical bone accretion and indicators relevant to bone metabolism in Chinese girls aged 10–12 y in Beijing, Am. J. Clin. Nutr. 81 (5) (2005) 1168–1175. 46. K. Zhu, H. Greenfield, X. Du, Q. Zhang, D.R. Fraser, Effects of milk supplementation on cortical bone gain in Chinese girls aged 10–12 years, Asia Pac. J. Clin. Nutr. 12 (Suppl) (2003) S47. 47. J.F. Chiu, S.J. Lan, C.Y. Yang, et al., Long-term vegetarian diet and bone mineral density in postmenopausal Taiwanese women, Calcif. Tissue Int. 60 (3) (1997) 245–249. 48. C. Cooper, E.J. Atkinson, D.D. Hensrud, et al., Dietary protein intake and bone mass in women, Calcif. Tissue Int. 58 (5) (1996) 320–325. 49. A. Devine, I.M. Dick, A.F. Islam, S.S. Dhaliwal, R.L. Prince, Protein consumption is an important predictor of lower limb bone mass in elderly women, Am. J. Clin. Nutr. 81 (6) (2005) 1423–1428. 50. G. Geinoz, C.H. Rapin, R. Rizzoli, et al., Relationship between bone mineral density and dietary intakes in the elderly, Osteoporos. Int. 3 (5) (1993) 242–248. 51. T. Hirota, M. Nara, M. Ohguri, E. Manago, K. Hirota, Effect of diet and lifestyle on bone mass in Asian young women, Am. J. Clin. Nutr. 55 (6) (1992) 1168–1173. 52. S.C. Ho, J. Woo, S. Lam, Y. Chen, A. Sham, J. Lau, Soy protein consumption and bone mass in early postmenopausal Chinese women, Osteoporos. Int. 14 (2003) 835–842. 53. J.Z. Ilich, R.A. Brownbill, L. Tamborini, Bone and nutrition in elderly women: protein, energy, and calcium as main determinants of bone mineral density, Eur. J. Clin. Nutr. 57 (4) (2003) 554–565. 54. J.E. Kerstetter, A.C. Looker, K.L. Insogna, Low dietary protein and low bone density, Calcif. Tissue Int. 66 (4) (2000) 313. 55. E.M. Lau, T. Kwok, J. Woo, S.C. Ho, Bone mineral density in Chinese elderly female vegetarians, vegans, lacto-vegetarians and omnivores, Eur. J. Clin. Nutr. 52 (1) (1998) 60–64. 56. K. Michaelsson, L. Holmberg, H. Mallmin, A. Wolk, R. Bergstrom, S. Ljunghall, Diet, bone mass, and osteocalcin: a cross-sectional study, Calcif. Tissue Int. 57 (2) (1995) 86–93. 57. J.H. Promislow, D. Goodman-Gruen, D.J. Slymen, E. BarrettConnor, Protein consumption and bone mineral density in the elderly: the Rancho Bernardo Study, Am. J. Epidemiol. 155 (7) (2002) 636–644. 58. P.B. Rapuri, J.C. Gallagher, V. Haynatzka, Protein intake: effects on bone mineral density and the rate of bone loss in elderly women, Am. J. Clin. Nutr. 77 (6) (2003) 1517–1525. 59. D.E. Sellmeyer, K.L. Stone, A. Sebastian, S.R. Cummings, A high ratio of dietary animal to vegetable protein increases the rate of bone loss and the risk of fracture in postmenopausal women. Study of Osteoporotic Fractures Research Group, Am. J. Clin. Nutr. 73 (1) (2001) 118–122. 60. D. Teegarden, R.M. Lyle, G.P. McCabe, et al., Dietary calcium, protein, and phosphorus are related to bone mineral density and content in young women, Am. J. Clin. Nutr. 68 (3) (1998) 749–754.
263
61. D.L. Thorpe, S.F. Knutsen, W. Lawrence Beeson, S. Rajaram, G.E. Fraser, Effects of meat consumption and vegetarian diet on risk of wrist fracture over 25 years in a cohort of peri- and postmenopausal women, Publ. Hlth. Nutr. (2007) 1–9. 62. M. Thorpe, M.C. Mojtahedi, K. Chapman-Novakofski, E. McAuley, E.M. Evans, A positive association of lumbar spine bone mineral density with dietary protein is suppressed by a negative association with protein sulfur, J. Nutr. 138 (1) (2008) 80–85. 63. F.A. Tylavsky, J.J. Anderson, Dietary factors in bone health of elderly lactoovovegetarian and omnivorous women, Am. J. Clin. Nutr. 48 (Suppl. 3) (1988) 84249. 64. A. Coin, E. Perissinotto, G. Enzi, et al., Predictors of low bone mineral density in the elderly: the role of dietary intake, nutritional status and sarcopenia, Eur. J. Clin. Nutr. (18 July 2007). 65. E. Orwoll, M. Ware, L. Stribrska, et al., Effects of dietary protein deficiency on mineral metabolism and bone mineral density, Am. J. Clin. Nutr. 56 (2) (1992) 314–319. 66. S.J. Whiting, J.L. Boyle, A. Thompson, R.L. Mirwald, R.A. Faulkner, Dietary protein, phosphorus and potassium are beneficial to bone mineral density in adult men consuming adequate dietary calcium, J. Am. Coll. Nutr. 21 (5) (2002) 402–409. 67. M.T. Hannan, K.L. Tucker, B. Dawson-Hughes, L.A. Cupples, D.T. Felson, D.P. Kiel, Effect of dietary protein on bone loss in elderly men and women: the Framingham Osteoporosis Study, J. Bone Miner. Res. 15 (12) (2000) 2504–2512. 68. B. Dawson-Hughes, Interaction of dietary calcium and protein in bone health in humans, J. Nutr. 133 (3) (2003) 852S–854S. 69. B. Dawson-Hughes, S.S. Harris, Calcium intake influences the association of protein intake with rates of bone loss in elderly men and women, Am. J. Clin. Nutr. 75 (4) (2002) 773–779. 70. J.A. Metz, J.J. Anderson, P.N. Gallagher Jr., Intakes of calcium, phosphorus, and protein, and physical-activity level are related to radial bone mass in young adult women, Am. J. Clin. Nutr. 58 (4) (1993) 537–542. 71. B.J. Abelow, T.R. Holford, K.L. Insogna, Cross-cultural association between dietary animal protein and hip fracture: a hypothesis, Calcif. Tissue Int. 50 (1) (1992) 14–18. 72. L.A. Frassetto, K.M. Todd, R.C. Morris Jr., A. Sebastian, Worldwide incidence of hip fracture in elderly women: relation to consumption of animal and vegetable foods, J. Gerontol. A. Biol. Sci. Med. Sci. 55 (10) (2000) M585–M592. 73. D. Feskanich, W.C. Willett, M.J. Stampfer, G.A. Colditz, Protein consumption and bone fractures in women, Am. J. Epidemiol. 143 (5) (1996) 472–479. 74. D. Feskanich, W.C. Willett, M.J. Stampfer, G.A. Colditz, Milk, dietary calcium, and bone fractures in women: a 12-year prospective study, Am. J. Publ. Hlth. 87 (6) (1997) 992–997. 75. R.G. Munger, J.R. Cerhan, B.C. Chiu, Prospective study of dietary protein intake and risk of hip fracture in postmenopausal women, Am. J. Clin. Nutr. 69 (1) (1999) 147–152. 76. H.J. Wengreen, R.G. Munger, N.A. West, et al., Dietary protein intake and risk of osteoporotic hip fracture in elderly residents of Utah, J. Bone Miner. Res. 19 (4) (2004) 537–545. 77. H.E. Meyer, J.I. Pedersen, E.B. Loken, A. Tverdal, Dietary factors and the incidence of hip fracture in middle-aged Norwegians. A prospective study, Am. J. Epidemiol. 145 (2) (1997) 117–123.
264
Osteoporosis in Men
78. R. Itoh, N. Nishiyama, Y. Suyama, Dietary protein intake and urinary excretion of calcium: a cross-sectional study in a healthy Japanese population, Am. J. Clin. Nutr. 67 (1998) 438–444. 79. N.E. Johnson, E.N. Alcantara, H. Linkswiler, Effect of level of protein intake on urinary and fecal calcium and calcium retention of young adult males, J. Nutr. 100 (1970) 1425–1430. 80. J.E. Kerstetter, L.H. Allen, Dietary protein increases urinary calcium, J. Nutr. 120 (1) (1990) 134–136. 81. J. Lemann Jr., Relationship between urinary calcium and net acid excretion as determined by dietary protein and potassium: a review, Nephron 81 (Suppl. 1) (1999) 18–25. 82. R.P. Heaney, Protein intake and bone health: the influence of belief systems on the conduct of nutritional science, Am. J. Clin. Nutr. 73 (1) (2001) 5–6. 83. J.E. Kerstetter, D.M. Caseria, M.E. Mitnick, et al., Increased circulating concentrations of parathyroid hormone in healthy, young women consuming a protein-restricted diet, Am. J. Clin. Nutr. 66 (5) (1997) 1188–1196. 84. J.E. Kerstetter, M.E. Mitnick, C.M. Gundberg, et al., Changes in bone turnover in young women consuming different levels of dietary protein, J. Clin. Endocrinol. Metab. 84 (3) (1999) 1052–1055. 85. J.E. Kerstetter, K.O. O’Brien, D.M. Caseria, D.E. Wall, K.L. Insogna, The impact of dietary protein on calcium absorption and kinetic measures of bone turnover in women, J. Clin. Endocrinol. Metab. 90 (1) (2005) 26–31. 86. J.E. Kerstetter, K.O. O’Brien, K.L. Insogna, Dietary protein affects intestinal calcium absorption, Am. J. Clin. Nutr. 68 (4) (1998) 859–865. 87. J.E. Kerstetter, K.O. O’Brien, K.L. Insogna, Dietary protein, calcium metabolism, and skeletal homeostasis revisited, Am. J. Clin. Nutr. 78 (Suppl. 3) (2003) 584S–592S. 88. Z.K. Roughead, L.K. Johnson, G.I. Lykken, J.R. Hunt, Controlled high meat diets do not affect calcium retention or indices of bone status in healthy postmenopausal women, J. Nutr. 133 (4) (2003) 1020–1026. 89. S.A. New, Nutrition Society Medal lecture. The role of the skeleton in acid-base homeostasis, Proc. Nutr. Soc. 61 (2) (2002) 151–164. 90. J. Lutz, Calcium balance and acid-base status of women as affected by increased protein intake and by sodium bicarbonate ingestion, Am. J. Clin. Nutr. 39 (2) (1984) 281–288. 91. A. Sebastian, S.T. Harris, J.H. Ottaway, K.M. Todd, R.C. Morris Jr., Improved mineral balance and skeletal metabolism in postmenopausal women treated with potassium bicarbonate, N. Engl. J. Med. 330 (25) (1994) 1776–1781. 92. S.A. New, C. Bolton-Smith, D.A. Grubb, D.M. Reid, Nutritional influences on bone mineral density: a crosssectional study in premenopausal women, Am. J. Clin. Nutr. 65 (6) (1997) 1831–1839. 93. R.C. Muhlbauer, F. Li, Effect of vegetables on bone metabolism, Nature 401 (6751) (1999) 343–344. 94. R.C. Muhlbauer, A. Lozano, A. Reinli, Onion and a mixture of vegetables, salads, and herbs affect bone resorption in the rat by a mechanism independent of their base excess, J. Bone Miner. Res. 17 (7) (2002) 1230–1236. 95. K. Sakhaee, M. Nicar, K. Hill, C.Y. Pak, Contrasting effects of potassium citrate and sodium citrate therapies on urinary chemistries and crystallization of stone-forming salts, Kidney Int. 24 (3) (1983) 348–352.
96. J.P. Thissen, J.M. Ketelslegers, L.E. Underwood, Nutritional regulation of the insulin-like growth factors, Endocr. Rev. 15 (1) (1994) 80–101. 97. W.L. Isley, L.E. Underwood, D.R. Clemmons, Dietary components that regulate serum somatomedin-C concentrations in humans, J. Clin. Invest. 71 (2) (1983) 175–182. 98. J.P. Thissen, M.L. Davenport, J.B. Pucilowska, M.V. Miles, L.E. Underwood, Increased serum clearance and degradation of 125I-labeled IGF-I in protein-restricted rats, Am. J. Physiol. 262 (4 Pt 1) (1992) E406–E411. 99. J.E. Jensen, T.G. Jensen, T.K. Smith, D.A. Johnston, S.J. Dudrick, Nutrition in orthopaedic surgery, J. Bone Joint Surg. 64A (9) (1982) 1263–1272. 100. V.C. Musey, S. Goldstein, P.K. Farmer, P.B. Moore, L.S. Phillips, Differential regulation of IGF-1 and IGF-binding protein-1 by dietary composition in humans, Am. J. Med. Sci. 305 (3) (1993) 131–138. 101. S. Bourrin, P. Ammann, J.P. Bonjour, R. Rizzoli, Dietary protein restriction lowers plasma insulin-like growth factor I (IGF-I), impairs cortical bone formation, and induces osteoblastic resistance to IGF-I in adult female rats, Endocrinology 141 (9) (2000) 3149–3155. 102. E.R. Froesch, C. Schmid, J. Schwander, J. Zapf, Actions of insulin-like growth factors, Annu. Rev. Physiol. 47 (1985) 443–467. 103. T. Niu, C.J. Rosen, The insulin-like growth factor-I gene and osteoporosis: a critical appraisal, Gene 361 (2005) 38–56. 104. J. Caverzasio, C. Montessuit, J.P. Bonjour, Stimulatory effect of insulin-like growth factor-1 on renal Pi transport and plasma 1,25-dihydroxyvitamin D3, Endocrinology 127 (1) (1990) 453–459. 105. G. Palmer, J.P. Bonjour, J. Caverzasio, Stimulation of inorganic phosphate transport by insulin-like growth factor I and vanadate in opossum kidney cells is mediated by distinct protein tyrosine phosphorylation processes, Endocrinology 137 (11) (1996) 4699–4705. 106. G. Palmer, J.P. Bonjour, J. Caverzasio, Expression of a newly identified phosphate transporter/retrovirus receptor in human SaOS-2 osteoblast-like cells and its regulation by insulin-like growth factor I, Endocrinology 138 (12) (1997) 5202–5209. 107. S. Bourrin, A. Toromanoff, P. Ammann, J.P. Bonjour, R. Rizzoli, Dietary protein deficiency induces osteoporosis in aged male rats, J. Bone Miner. Res. 15 (8) (2000) 1555–1563. 108. S. Mekraldi, A. Toromanoff, R. Rizzoli, P. Ammann, Pamidronate prevents bone loss and decreased bone strength in adult female and male rats fed an isocaloric low-protein diet, J. Bone Miner. Res. 20 (8) (2005) 1365–1371. 109. P. Ammann, S. Bourrin, J.P. Bonjour, J.M. Meyer, R. Rizzoli, Protein undernutrition-induced bone loss is associated with decreased IGF-I levels and estrogen deficiency, J. Bone Miner. Res. 15 (4) (2000) 683–690. 110. P. Ammann, M.L. Aubert, J.M. Meyer, R. Rizzoli, Catabolic effects of growth hormone on bone under low protein intake, Osteoporos. Int. 13 (Suppl. 1) (2002) S12–S13. 111. P. Ammann, A. Laib, J.P. Bonjour, J.M. Meyer, P. Ruegsegger, R. Rizzoli, Dietary essential amino acid supplements increase bone strength by influencing bone mass and bone microarchitecture in ovariectomized adult rats fed an isocaloric low-protein diet, J. Bone Miner. Res. 17 (7) (2002) 1264–1272.
C h a p t e r 2 1 Role of Dietary Protein in Bone Growth and Bone Loss l
112. G. Dai, D.N. McMurray, Altered cytokine production and impaired antimycobacterial immunity in protein-malnourished guinea pigs, Infect. Immun. 66 (8) (1998) 3562–3568. 113. P. Ammann, R. Rizzoli, J.P. Bonjour, et al., Transgenic mice expressing soluble tumor necrosis factor-receptor are protected against bone loss caused by estrogen deficiency, J. Clin. Invest. 99 (7) (1997) 1699–1703. 114. P. Ammann, I. Garcia, J.P. Bonjour, R. Rizzoli, Tumor necrosis factor- (TNF-) plays a prominent role in protein undernutrition-induced bone resorption, J. Bone Miner. Res. 16 (Suppl. 1) (2001) S147. 115. P. Ammann, C. Gabay, G. Palmer, I. Garcia, R. Rizzoli, Tumor necrosis factor alpha but not interleukine-1 is involved in protein undernutrition-induced bone resorption, J. Bone Miner. Res. 17 (Suppl. 1) (2002) S205. 116. M.J. Manary, D.R. Brewster, R. Broadhead, et al., Wholebody protein kinetics in children with kwashiorkor and infection: a comparison of egg white and milk as dietary sources of protein, Am. J. Clin. Nutr. 66 (3) (1997) 643–648. 117. A.D. Conigrave, E.M. Brown, R. Rizzoli, Dietary protein and bone health: roles of amino acid-sensing receptors in the control of calcium metabolism and bone homeostasis, Annu. Rev. Nutr. 28 (2008) 131–155. 118. A.D. Conigrave, E.M. Brown, L-amino acid-sensing by calcium-sensing receptors: implications for GI physiology, Am. J. Physiol. 291 (2006) G753–G761. 119. A.D. Conigrave, H.C. Mun, L. Delbridge, S.J. Quinn, M. Wilkinson, E.M. Brown, L-amino acids regulate parathyroid hormone secretion, J. Biol. Chem. 279 (37) (2004) 38151–38159.
265
120. B. Dawson-Hughes, S.S. Harris, H.M. Rasmussen, G.E. Dallal, Comparative effects of oral aromatic and branched-chain amino acids on urine calcium excretion in humans, Osteoporos. Int. 18 (7) (2007) 955–961. 121. M. Delmi, C.H. Rapin, J.M. Bengoa, P.D. Delmas, H. Vasey, J.P. Bonjour, Dietary supplementation in elderly patients with fractured neck of the femur., Lancet 335 (8696) (1990) 1013–1016. 122. L. Tkatch, C.H. Rapin, R. Rizzoli, et al., Benefits of oral protein supplementation in elderly patients with fracture of the proximal femur, J. Am. Coll. Nutr. 11 (5) (1992) 519–525. 123. M.A. Schürch, R. Rizzoli, D. Slosman, L. Vadas, P. Vergnaud, J.P. Bonjour, Protein supplements increase serum insulin-like growth factor-I levels and attenuate proximal femur bone loss in patients with recent hip fracture. A randomized, doubleblind, placebo-controlled trial, Ann. Intern. Med. 128 (10) (1998) 801–809. 124. C.J. Auernhammer, C.J. Strasburger, Effects of growth hormone and insulin-like growth factor I on the immune system, Eur. J. Endocrinol. 133 (6) (1995) 635–645. 125. A. Rodondi, P. Ammann, R. Rizzoli, Zinc increases the effects of essential amino acids-whey protein supplements in frail elderly, J. Nutr. Hlth. Aging. 13 (6) (2009) 491–494. 126. T.J. Martin, Protein nutrition as therapy for a genetic disorder of bone? Cell Metab. 4 (6) (2006) 419–420. 127. F. Elefteriou, M.D. Benson, H. Sowa, et al., ATF4 mediation of NF1 functions in osteoblast reveals a nutritional basis for congenital skeletal dysplasiae, Cell Metab. 4 (6) (2006) 441–451. 129. H.P. Harding, Y. Zhang, H. Zeng, et al., An integrated stress response regulates amino acid metabolism and resistance to oxidative stress, Mol. Cell. 11 (3) (2003) 619–633.
Chapter
22
The Molecular Biology of Sex Steroids in Bone: Similarities and Differences among the Sexes Stavroula Kousteni Division of Endocrinology, Department of Medicine, College of Physicians and Surgeons, Columbia University, New York, NY, USA
Introduction
or differentiation. Direct effects on osteoblast differentiation and osteoclast lifespan may also be involved. In parallel, estrogen and androgens regulate the lifespan of osteoclasts, osteoblasts and osteocytes. Indeed, maintenance of the balance between bone formation and resorption depends on two parallel actions: prolongation of osteoblast lifespan and induction of osteoclast apoptosis [11–14]. In addition, the estrogen receptor (ER) controls the survival of osteocytes, former osteoblasts that are entombed in the mineralized matrix. Osteocytes communicate through gap junctions with neighboring osteocytes, osteoblasts and osteoclasts on the bone surface and endothelial cells of the bone marrow vasculature and serve as sensors and responders to mechanical strains [15, 16]. The ER confers pro-survival signals to osteocytes by an action that occurs either in the presence or in the absence of stimulation by estrogen. In the latter case, unliganded ER is required [11, 17]. The pro-survival effects of sex steroids on osteoblasts and osteocytes as well as their pro-apoptotic action on osteoclasts stem from an extranuclear function of the sex steroid receptors that involves activation of kinases within preassembled scaffolds called caveolae. Appreciation of the adverse effects of estrogen and androgen deficiency on the skeleton has launched a quest for the elucidation of the mechanism of the skeletal actions of sex steroids and the pathogenesis of the bone loss resulting from sex steroid deficiency. The purpose of this chapter is to provide a perspective on the advances that have been made in our understanding of the cellular and molecular mechanisms by which estrogens and androgens influence adult bone homeostasis. By extension, the pathogenetic mechanisms responsible for the development of osteoporosis following sex steroid deficiency have become clearer.
In adult vertebrates, bones are constantly renewed by the process of remodeling, which includes two cellular events occurring in a time ordered process. The first event is resorption, or destruction of the mineralized bone matrix, by osteoclasts. The second event, occurring later, is bone formation by osteoblasts [1, 2]. Bone remodeling is affected in the most frequent degenerative disease of bones, osteoporosis, a low bone mass disease due to an unbalanced increase in bone resorption [3, 4]. Starting in their mid-40s, in women, and at least a decade later in men, progressive declines in bone mass and strength occur [5, 6]. In women, the process is accelerated at menopause because of the rather abrupt decline of estrogens. Estrogen deficiency in women, whether from ovariectomy or from natural menopause, is associated with an increase in bone remodeling, increased bone resorption and a coupled increase in bone formation [7, 8]. However, resorption outstrips formation, resulting in a net loss of bone. Similarly, loss of androgens in males from disease, chemical or surgical castration, or the slow age-associated decline of androgen levels has the same adverse effect on the skeleton. These well established clinical observations underscore the fundamental, protective effects of sex steroids on the skeleton: the suppression of the rate of bone remodeling and the maintenance of a balance between bone formation and bone resorption [7, 9, 10]. Control of bone remodeling by estrogen results from attenuating effects on the birth rate of osteoblast and osteoclast progenitors as well as from suppressing the production and action of cytokines that are responsible for osteoclastogenesis and osteoblastogenesis [7]. These effects result, in part, from the transcriptional regulation of genes responsible for osteoclastogenesis and mesenchymal cell replication and/ Osteoporosis in Men
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General aspects of the mechanisms of sex steroid action in bone cells Similar to many well-described nuclear receptors, estrogen and androgen receptors are activated mainly by binding to their ligands. Binding of estrogen or androgen to their cognate receptor causes homo- or heterodimerization of the protein and results in conformational changes that allow for interaction with several coactivator proteins. The receptor–coactivator(s) complex attaches to specific DNA response elements (estrogen response elements, EREs, or androgen response elements, AREs) and the basal transcription machinery, causing histone acetylation, decondensation of the chromatin and initiation of transcription. Estrogen and androgens also regulate the transcription of genes that do not contain EREs or AREs by forming protein–protein complexes with other transcription factors, thus preventing them from interacting with their target gene promoters [18]. In the last 10 years, numerous effects of estrogen and androgens that are independent of classical transcriptional actions of the receptors have been established. These result from extranuclear activities of the receptors that involve rapid activation of various kinases. Eventually, these events lead to activation of kinase-regulated transcription factors and, thus, transcription, thereby integrating extranuclear with nuclear actions. One of the best documented extanuclear actions of estrogen in a variety of cell types, including bone, endothelial and neuronal cells, is the activation of the mitogen-activated protein kinases (MAPKs). MAPKs are serine–threonine kinases that transduce chemical and physical signals from the cell surface to the nucleus, thereby controlling proliferation, differentiation and survival [19]. In general, direct effects of estrogen and androgens that affect the lifespan of osteoblasts, osteocytes and osteoclasts are initiated by and require extranuclear activity of the ER or androgen receptor (AR). Similarly, part of the effects of estrogen on osteoblast differentiation involves the activation of signaling cascades that cross-talk with kinases. Using molecular and genetic tools as well as synthetic ligands, it has been possible to dissociate and specifically retain the kinase-initiated from the classical transcriptional actions of estrogen. This endeavor has revealed impressive results as it has uncovered novel biological outcomes of estrogen action on the osteoblast.
Estrogen and androgens control osteoblastogenesis and osteoclastogenesis Effects on Osteoclastogenesis Estrogens and androgens suppress osteoclastogenesis by both direct and indirect, stromal cell-mediated action. The direct actions have been observed in stromal cell free
cultures of bone marrow derived hematopoietic cells that are stimulated to become osteoclasts with the addition of receptor activator of NF-kappaB ligand (RANKL) and macrophage colony stimulating factor (MCSF) [13, 20, 21]. Indirect effects have been documented in vitro and, in the case of androgens, also in vivo. Overexpression of the AR in stromal cells of the osteoblastic lineage suppresses bone resorption and increases the levels of serum osteoprotegerin (OPG), the decoy ligand for the RANKL receptor, in male mice [22]. Similarly, targeted deletion of AR in osteoblasts leads to trabecular bone loss in the vertebrae through increased osteoclast activity [23]. Suppression of RANKLstimulated osteoclast formation by a stromal cell independent mechanism involves repression of c-Jun. Estrogen or androgen blocks RANKL/MCSF-induced activator protein1-dependent transcription, through suppressing both c-Jun expression and its phosphorylation by c-Jun N-terminal kinase [20, 21]. Osteoclasts are derived from hematopoietic progenitors of the myeloid lineage and their development depends on a network of autocrine and paracrine factors produced by stromal and osteoblastic cells. Thus, mechanistically, osteoblast-mediated effects of sex steroids on osteoclastogenesis involve actions to regulate the production of osteoclastogenic cytokines by bone marrow stromal cells and osteoblasts [24]. Interleukin-6 (IL-6) is a paradigm of a cytokine important for osteoclastogenesis [25]. Estrogens and androgens suppress the production of IL-6, as well the expression of the two subunits of the IL-6 receptor, IL-6R and gp130 in cells of the bone marrow stromal/osteoblastic lineage, in rats and in humans [26–31]. Neutralization of IL-6 with antibodies or knockout of the IL-6 gene in mice prevents the upregulation of CFU-GM in the marrow and the expected increase of osteoclast numbers in trabecular bone sections and also protects the loss of bone following loss of sex steroids [27, 32, 33]. The suppressive effects of estrogen or androgens on IL-6 production result from an indirect effect of the receptor protein on the transcriptional activity on the proximal 225 bp sequence of the human IL-6 gene promoter [27, 34]. They also involve protein–protein interactions between the ER and transcription factors such as NF-B and C/EBP [35]. Nonetheless, IL-6 does not seem to be required for osteoclastogenesis in vivo under normal physiologic conditions since osteoclast formation is unaffected in sex steroid replete mice treated with a neutralizing anti-IL-6 antibody or in IL-6 deficient mice [32, 33]. This situation probably reflects the fact that the expression of the gp80 subunit of the IL-6 receptor in bone is a limiting factor for the effects of the cytokine. The paradigm of IL-6 as a target gene for sex steroid action in bone and, in particular, the suppressive effects of these hormones on osteoclastogenesis, has been extended to include tumor necrosis factor (TNF), a cytokine that enhances osteoclast formation by upregulating the production of RANKL by stromal cells and MCSF [36]. In addition, there has been evidence that estrogens stimulate the
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production of the potent anti-osteoclastogenic factor osteoprotegerin (OPG). Estrogen loss may also increase the sensitivity of osteoclasts to IL-1 (another osteoclastogenic cytokine) by increasing the ratio of the IL-1RI over the IL-1 decoy receptor (IL-RII) [37] or increase the number of TNF-synthesizing lymphocytes [38]. As in the case of IL-6, the effects of estrogen on TNF and MCSF are mediated via protein–protein interactions between the ER and other transcription factors. Because of the interdependent nature of the production of IL-1, IL-6 and TNF, a significant increase in one of them may amplify the effect of the others [39].
Effects on osteoblastogenesis Replication of Osteoblast Progenitors Loss of sex steroids increases not only bone resorption but also bone formation. A result of the increased bone resorption after loss of sex steroids, which increases the number of osteoclast progenitors in the murine bone marrow, is the stimulation of osteoblastogenesis. In the case of androgens, there are conflicting studies suggesting both stimulatory and repressing effects on osteoblast differentiation and proliferation using a variety of different cell culture systems [40–42]. However, genetic experiments support the notion that androgens are inhibitory to osteoblast differentiation. Indeed, osteoblast-specific inactivation of the AR in osteoblasts resulted in greatly increased levels of serum osteocalcin [23]. Although osteoblast numbers were not quantified in this report, the biochemical analysis suggests increased bone formation in the absence of AR. The number of osteoblast progenitors (CFU-OB) is increased after gonadectomy, in parallel with an increase in the circulating levels of the bone formation marker osteocalcin [43]. The temporal pattern of these changes is similar to the increase in osteoclastogenesis and the rate of bone loss. The general view was that increased osteoblastogenesis that ensues with sex steroid deficiency is the result of increased osteoclastogenesis. However, experiments using a mouse model of osteopenia due to defective osteoblastogenesis (SAMP6 mouse) suggest that osteoblastogenesis may also be affected directly by the loss of sex steroids and independently from the fate of osteoclasts. In SAMP6 mice, defective osteoclastogenesis is secondary to impaired osteoblast formation as evidenced by the fact that osteoclastogenesis in ex-vivo cultures of the bone marrow of SAMP6 mice can be restored by addition of osteoblastic cells from wild type mice [44]. Moreover, unlike wild type animals, ovariectomy or orchidectomy in SAMP6 mice failed to increase osteoclastogenesis. Thus, stimulation of mesenchymal cell differentiation towards the osteoblastic lineage following sex steroid deficiency may precede the increased osteoclastogenesis. In support of this view, the rate of remodeling and the expected bone loss following gonadectomy is attenuated in mice with defective osteoblastogenesis [45].
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In line with these observations, the production of CFUOB, most of which were found to be dividing early transit amplifying cells, is regulated by estrogen. The hormone suppresses CFU-OB self-renewal acting through ER [46]. A similar inhibitory effect of androgens has been described. The inhibitory effect of estrogen on CFU-OB self-renewal may be critical for their bone protective effects. Thus, the mouse model of osteopenia displays blunted osteoblastogenic and osteoclastogenic response, blunted bone loss following loss of estrogens, as well as low CFU-OB selfrenewal, as compared to control mice [46]. The JAK/STAT pathway IL-6-type cytokines, besides their osteoclastogenic properties, promote differentiation of committed osteoblastic cells toward a more mature phenotype through their receptors that are expressed in stromal/osteoblastic cells. Indeed, IL-6type cytokines induce osteoblastic lineage commitment of murine embryonic fibroblasts, primarily via gp130-mediated activation of the Janus family (JAKs). JAK activation leads to the recruitment and phosphorylation of signal transducers and activators of transcription (STATs) which, in turn, upregulate the expression of p21 via binding of STAT3 to the p21 promoter [47–50]. Estrogen and non-aromatizable androgens interact with this pathway by downregulating the expression of both IL-6 [34] and the gp130 signal transducing subunit of the IL-6 receptor [28]. Interactions with BMP (Smad and Runx2) and TGF signaling
In addition to its ability to attenuate the self-renewal of transit-amplifying osteoblast progenitors in the bone marrow [46], estrogen has been shown to attenuate osteoblast differentiation induced by osteogenic agents such as bone morphogenetic protein 2 (BMP-2) or parathyroid hormone (PTH) in bone marrow stromal cells, calvaria cells, osteoblastic cell lines and primary periosteal osteoblast progenitors [51, 52]. Thus, another means by which estrogen may affect osteoblastogenesis is by regulating the differentiation of early committed or uncommitted osteoblast progenitors. At the molecular level, such effects of estrogen may be mediated by its ability to interact with targets of the BMP signaling cascade. In general, estrogen suppresses BMP functions by repressing the activity of BMP reporters, BMP-dependent gene expression and BMP-2-induced Smad activation [51, 53, 54]. Additionally, estradiol-bound ER interacts with the transcription factor Runx2 directly through its DNA binding domain or indirectly through its N-terminal and ligand binding domain [55]. Estrogen enhances Runx2 activity independent of changes in Runx2 levels or its DNA binding potential [56]. Androgens, however, fail to increase Runx2 activity, whereas Runx2 potently suppresses gene expression induced by estrogen or androgens. Downstream of Runx2, the upregulating effect
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of estrogen on Runx2 activity appears to result in increases in the transcription of genes induced by the transforming growth factor- (TGF) type I receptor gene promoter, which contains several Runx binding sites. This series of events further potentiate the enhancing effect of TGF on Smad-mediated transcription. Although not specifically examined in these studies, since TGF stimulates activation of Smad proteins that inhibit osteoblast differentiation, it is possible that the effects of estrogen on Runx2 contribute to its anti-osteoblastogenic actions. In support of this notion, osteoblast-specific inactivation of Runx2 in mice, by means of expressing a dominant negative Runx2 construct in osteoblasts, blunted the loss of bone mass that follows ovariectomy [57]. In fact, estrogen loss failed to affect both osteoblastogenesis and osteoclastogenesis in these mice, thus indicating that Runx2 may be involved in bone loss due to estrogen deficiency. Alternatively, estrogen may have anti-osteoblastogenic effects when acting on early or uncommitted osteoblast progenitors but may favor terminal differentiation in situations when osteoblasts have already been induced to their lineage by osteogenic agents. Tob (transducer of erB2) is an anti-proliferative protein that acts as an inhibitor of BMPs. Ovariectomized Tobdeficient mice demonstrated higher levels of bone formation and mineral apposition rates as compared to ovariectomized wild type animals [58]. In contrast, resorption parameters were similar in between estrogen deficient Tob knockout and wild type mice. These in vivo observations along with ex vivo studies suggested that estrogen and Tob signaling converge and both repress BMP-induced Smad activity and BMP-dependent gene expression. Another pathway that interacts with estrogen and androgen signaling is that elicited by TGF, a growth factor that can influence osteoblast differentiation. Androgens upregulate TGF protein levels and activity – as well as insulin growth factors – which, in turn, regulate bone formation [41, 59, 60]. It has been shown that estrogen and TGF cross-talk by means of TGF-dependent activation of the ERs and their co-regulators, primarily via the MAPK pathway. It is speculated that the estrogen-activated MAPK pathway would enhance the TGF–MAPK pathway which, in turn, phosphorylates the ER [61]. This response leads to suppression of Smad activity. Therefore, it appears that the ER can elicit a wide range of responses that may vary depending on the contribution of and synergy with different signaling cascades. Alternatively, it has been proposed that the specific type of estrogen receptor (ER or ER) may be responsible for different responses of osteoblastic cells to estrogen. An example of this is the regulation of the TGF-inducible early response gene 1 (TIEG1) expression by estrogen in osteoblasts [62]. TIEG1 is rapidly induced by ER but not by ER through recruitment of the steroid receptor co-activators SRC1 and SRC2 to the activation function 1 (AF1) domain of ER. The importance of this observation is further highlighted by the fact that
SRC1 is involved in the regulation of bone mass [63, 64]. Inactivation of SRC1 leads to osteopenia in the trabeculae of both female and male mice without affecting cortical bone mass. However, although loss of SRC1 function in females impairs their response to estrogen administration, the hormone is sufficient to prevent trabecular bone loss in the male gonadecomized SRC1-deficient mice.
Osteoblast Differentiation is Differentially Affected by Kinase-Initiated and Classical Nuclear Actions of the ER Estrogen is a suppressor of osteoblast differentiation. Extensive experimental and clinical evidence suggests that estrogen deficiency increases osteoblastogenesis and osteoclastogenesis and, thereby, the rate of bone turnover. The anti-osteoblastogenic effects involve attenuation of the self-renewal of transit-amplifying osteoblast progenitors in the bone marrow [46] as well as suppression of osteoblast differentiation induced by potent osteogenic agents such as BMP-2 [51] or PTH [52]. In general, suppression of osteoblast differentiation is thought to result from classical transcriptional actions of the ER. Remarkably, selective activation of kinase-mediated actions of the ER has a profound effect. It reveals a novel biological property of estrogen that can only be elicited in the absence of genotropic actions of the receptor and leads to an opposite effect, namely induction of osteoblast differentiation [51]. Selective activation of kinase-mediated actions of the ER induces osteoblastic differentiation in established cell lines of uncommitted osteoblast precursors and primary cultures of osteoblast progenitors. In these studies, selective activation of kinase-mediated actions of the ER was achieved by three different means: forced extranuclear localization of the ligand binding domain of the ER; use of the synthetic ER ligand 4-Estren-3, 17-diol (estren) [11, 65]; and use of a cell-impermeable estrogen dendrimer conjugate (EDC) comprising abiotic non-degradable poly(amido)amine macromolecules and multiple estrogen molecules, that binds to ER and prevents its entry to the nucleus [66]. Both estren and EDC were found to stimulate kinase-mediated ER actions 1000–10 000 times more potently than direct DNA actions [65–67]. Thus, they promote the expression of ERKregulated transcriptional targets but have no effect on several ERE or AP-1-containing genes. Specifically, estrogen acting via membrane localized ER, but not nuclear ER, promotes activation of a signaling pathway that is recognized for its pro-differentiating actions on osteoblast progenitors: the Wnt/-catenin signaling cascade. Selective activation of extranuclear actions of the ER upregulates the expression of Wnt members and their Frizzled receptors. It also stimulates Wnt/-catenin-mediated transcription in a transgenic ‘reporter’ mouse expressing ubiquitously a TCF--galactosidase reporter construct
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in which three TCF sites upstream of the minimal c-fos promoter drive the expression of -galactosidase. Similar to Wnt/-catenin-mediated transcription, extranuclear actions of ER stimulate BMP-2 signaling as demonstrated by the phosphorylation of the BMP-2-activated Smads, Smad1, Smad5 and Smad8. The BMP-2 target Runx2, a transcription factor that is absolutely required for osteoblast differentiation [68] is also upregulated. In parallel, the expression or activity of alkaline phosphatase and osteocalcin which, together with Runx2, are markers of osteogenic potential, are also increased. Thus, the pro-differentiating effects result from an extranuclear function of the ER causing activation of ERKs and downstream potentiation of both the BMP and Wnt signaling cascades. The Src, PI3K and JNK kinases may also be involved. The striking dichotomy of the effects of selective activation of kinases versus activation of both kinases and genomic actions of the ER suggests that at least some responses of target cells to estrogen may be the result of a balance between extranuclear and nuclear actions of the receptor. Removal of genotropic counter-regulatory actions on Wnts, Wnt receptors or antagonists, BMPs and/or regulators of BMP signaling may ‘unleash’ the differentiation process. In support of this hypothesis, estradiol administration to mice in which the ER lacks DNA binding activity and classical ERE-mediated transcription (ERNERKI/) induced Smad1/5/8 phosphorylation within 1 h, but this effect could not be seen in wild type controls in which the ER is capable of both ERE-dependent and independent actions. Collectively, this evidence revealed for the first time the existence of a large signalosome, in which inputs from the ER, kinases, BMPs and Wnt-signaling converge to induce differentiation of osteoblast precursors [51]. ER can either induce it or repress it, depending on whether the activating ligand precludes or accommodates ERE-mediated transcription. In support of the idea that extranuclear ER signaling is required for the bone homeostasis, loss of ERE-dependent functions of the ER in ERNERKI/ mice has no effect on trabecular bone, although it does lead to some deficits in the cortical compartment. Moreover, observations with the ERNERKI/ mice further support the hypothesis stated above, that there exists a balance between classical and non-classical ER signaling pathways which, when altered, can result in a markedly aberrant response to estrogen. ERNERKI/ mice show paradoxical and opposite responses in trabecular and cortical bone in response to estrogen deprivation or estrogen replacement [69]. Loss of ERE signaling compromises cortical but does not affect trabecular bone mass and, as opposed to normal mice, estrogen suppresses cortical bone in ERNERKI/ animals. However, classical ERE signaling is required for the effects of estrogen on the growing male skeleton as evidenced by the observed axial and appendicular osteopenia in male ERNERKI/ mice [70].
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Estrogen and androgens control bone cell survival Pro-Survival Actions on Osteoblasts and Osteocytes The role of osteoblast and osteoclast apoptosis as a determinant of bone mass has been documented by several in vivo observations, many of which reflect at least part of the bone protective effects of hormones such as sex steroids, PTH or the adverse effect of glucocorticoids [71–77]. Estrogen and non-aromatizable androgens, in particular, have been shown to prolong the lifespan of osteoblasts or osteocytes in cell culture systems as well as in murine models of estrogen or androgen deficiency [7, 10]. The anti-apoptotic effect of estrogen and androgens on osteoblasts has been documented in response to various pro-apoptotic stimuli and can be mediated by either ER or ER or by the AR [11]. It results from a mechanism that is distinct from that requiring direct interaction of the receptors with DNA, or protein–protein interaction between the receptors and other transcription factors [11, 12]. Indeed, elimination of every domain that is required for classical transcriptional actions of the ER (AF-1 function, DNA binding and dimerization domains) and retention of only the ligand binding domain of the ER is sufficient to confer the pro-survival actions of estrogen. Moreover, unlike the classical genotropic action of the receptor protein, extranuclear localization of the ER is necessary since the anti-apoptotic effect is eliminated by nuclear targeting of the receptor. Specifically, anti-apoptosis is due to activation of a signaling pathway that involves rapid (within 5 min) and sequential phosphorylation of the Src, Shc and ERK1/2 kinases. The kinase domain of Src as well as the Src homology 2 domain, with which ER probably interacts [78], are necessary for the anti-apoptotic effect. Activated ERKs translocate to the nucleus and activate the transcription factor Elk-1 which, in turn, binds to the serum response element (SRE), present in the promoter of many genes and rapidly induces their transcription. The ERK-activated transcription factors CREB and C/EBP are also rapidly phosphorylated in response to estrogen and are indispensable for the anti-apoptosis signaling mechanism in osteoblasts. Phosphorylation of Elk-1 and C/EBP is transient, whereas phosphorylation of CREB is sustained. Phosphorylation and activation of the Src/Shc/ERK signaling cascade, along with its downstream transcriptional targets Elk-1, and C/EBP and CREB are retained when the receptor is localized outside the nucleus. In contrast, restriction of the ER in the nucleus eliminates those effects. Consistent with reports in other tissues [79, 80], ERKs were found to be responsible for the upregulation of basal AP-1 activity in osteoblasts and osteocytes. In parallel to its action on the Src/Shc/ERK kinases and their target transcription factors, estrogen rapidly downregulates ERKinduced AP-1-dependent transcription through repression
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of a JNKK1/MEKK1/JNK1 pathway, originally described to be activated by cytokines or cellular stress [12, 81]. It appears that, in the presence of estrogen, JNK signaling is suppressed and this effect overrides the stimulatory action of ERKs on AP-1. Similar to the stimulatory effects of estrogen on Src/Shc/ERK signaling, downeregulation of JNK1/AP-1- mediated transcription is also mediated by extranuclear localization of the ER. Elucidation of the stimulatory effect of estrogen and androgens on Elk-1, CREB and C/EBP activity through Src/Shc/ERK, as well as the suppressive affect on AP-1 through JNK1, suggests that these are only few of several other transcription factors regulated by the kinase-mediated mechanism of gene transcription. Furthermore, in contrast to the evidence that rapid activation of MAP kinases by membrane-associated ER suppresses AP-1 activity, estrogen-activated nuclear ER stimulates AP-1 activity directly [82]. The demonstration of a diametrically opposite effect of kinase-mediated versus classical effects of estrogens on the activity of AP-1, indicates that kinase modulation by sex steroids leads to both stimulatory and inhibitory effects on transcription. Therefore, the response of a target cell to estrogen may be determined by the balance between membrane- and nucleus-associated receptor actions. In addition to the evidence that the anti-apoptotic effect of estrogen and androgens involves modulation of transcription factors downstream of at least two kinase-initiated signaling transduction cascades (ERKs and JNK), it also requires kinase-mediated modification of the functional activity of proteins, independent of any transcriptional changes. Specifically, estrogen-induced activation of PI3K and ERKs leads to phosphorylation and inactivation of the pro-apoptotic protein Bad, most likely via an effect of the ribosomal S6 kinase, Rsk2 [12]. This finding is in line with studies in neuronal and hematopoietic cells, highlighting the requirement of both transcription-dependent and -independent mechanisms in the survival signals transduced by ERKs [83, 84].
Pro-apoptotic Actions on Osteoclasts Estrogen and non-aromatizable androgens control bone cell survival not only by anti-apoptotic actions on osteoblasts and osteocytes but also by exerting an opposite, proapoptotic effect on osteoclasts [11, 13]. The pro-apoptotic effects of sex steroids on osteoclasts also involve rapid ERK activation. However, in contrast to their transient effect on ERK phosphorylation in osteoblasts and osteocytic cells (return to base line by 30 minutes), estrogeninduced ERK phosphorylation in osteoclasts is sustained for at least 24 hours following exposure to the hormone. Conversion of sustained ERK phosphorylation to transient, by activation of the adenylate cyclase/cAMP/protein kinase A pathway, abrogates the pro-apoptotic effect of estrogen on osteoclasts. Likewise, prolongation of ERK activation in
osteocytes, by means of leptomycin B-induced inhibition of ERK export from the nucleus, or forced nuclear localization of ERK2, converts the anti-apoptotic effect of estrogen to a pro-apoptotic one. Thus, the mechanistic basis of the divergence of the biologic outcome on the survival of the two cell types depends on the kinetics of ERK phosphorylation and the length of time that phospho-ERKs are retained in the nucleus, perhaps by determining the activation of a distinct set of transcription factors [13]. Recently, selective ablation of ER in differentiated osteoclasts [85] or cells of the monocyte/macrophage lineage [86] resulted in trabecular bone loss and increased osteoclastogenesis and osteoclast apoptosis. In one study, these events were associated with upregulation of Fas ligand (FasL) expression in osteoclasts, indicating that estrogen regulates the life span of mature osteoclasts, in part, via the induction of the Fas/FasL system [85]. In the second study, deletion of ER abrogated the pro-apoptotic action of estrogen in osteoclasts [86]. In contrast, anti-osteoclastogenic and pro-apoptotic actions of estrogen in osteoclasts were retained in the ERNERKI/ mouse indicating that classical signaling through ERE sites is dispensable for these effects. It has been demonstrated that estrogen and nonaromatizable androgens suppress osteoclastogenesis by attenuating the production of osteoclastogenic cytokines by stromal/osteoblastic cells and that this effect results from a classical transcriptional action of the ER [7]. However, in agreement with the observations that sex steroids directly affect osteoclast survival in an ERK-dependent manner, cytokines like interleukin-1 (IL-1), IL-6, TNF or RANKL exert potent anti-apoptotic effects on osteoclast progenitors and mature osteoclasts [87], by inducing transient activation of ERKs [88–91]. Additionally, estrogen and androgens suppress RANKL-induced osteoclast differentiation by blocking RANKL/MCSF-induced AP-1-dependent transcription through reduction of c-jun activity. The latter is due to both reduced c-jun expression and decreased c-jun phosphorylation [21, 92]. In contrast, selective c-Src inhibitors stimulate osteoclast apoptosis, both in vitro and in vivo, by inducing sustained ERK phosphorylation [93]. Hence, in line with their pro-apoptotic action on mature osteoclasts, the suppressive effect of estrogen and androgens on osteoclastogenesis may also result, at least in part, from indirect kinase-mediated attenuation of the production of cytokines and also from direct pro-apoptotic effects on osteoclast progenitors [94, 95].
Oxidative stress and the control of bone mass A novel mechanism of estrogen action in bone has been elucidated during the last 5 years. Estrogen regulates bone cell fate by modulating the production or signaling of
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reactive oxygen species (ROS). Indeed, ovariectomy (or orchidectomy) leads to an increase in ROS production in the bone marrow as well as the phosphorylation of p66shc, in bone [96]. Phosphorylation of p66shc is the result of increased intracellular ROS and is required for transduction of oxidant stress signals leading to apoptosis [97]. In agreement with these observations, administration of the antioxidants N-acetyl cysteine (NAC) or ascorbate to ovariectomized mice increases tissue glutathione levels and abolishes ovariectomy-induced bone loss. Similarly, l-buthionine-(S,R)-sulfoximine (BSO), a specific inhibitor of glutathione synthesis, causes substantial bone loss when administered to intact mice [96, 98]. Part of the bone protective affects of NAC in ovariectomized mice can be explained by actions of estrogen to reduce thiol antioxidants in osteoclasts. Specifically, using cultures of osteoclasts as well as bone marrow cells from ovariectomized mice, it has been shown that estrogen suppresses osteoclastogenesis by increasing glutathione and thioredoxin reductases, the main enzymes responsible for maintaining thiol antioxidants in a reduced state and, thus, by increasing the levels of ROS [96, 98]. Upregulation of glutathione and thioredoxin reductases by estrogen depends on an extranuclear action of the ER because it requires activation of Src and ERK signaling [96]. Additionally, estrogen-induced increase in ROS levels may favor osteoclastogenesis by means of ROS-enhanced expression of osteoclastogenic transcription factors (NF-B) and cytokines (TNF) [98, 99]. Interestingly, the kinase-mediated pro-apoptotic effects of estrogen on osteoclasts are attenuated following inhibition of glutathione synthesis by BSO [96]. This seemingly paradoxical observation can be explained by an intriguing mechanism which is universal to all different types of cells and serves to stimulate antioxidant responses. Certain levels of oxidative stress serve as a pro-survival signal by means of their ability to trigger antioxidant response signaling cascades that not only rescue cells from apoptosis but, ultimately, prolong their lifespan. Similar to the pro-apoptotic effect of estrogen on osteoclasts, its anti-apoptotic actions on osteoblasts also require glutathione [96]. However in osteoblasts, estrogen rescues the cells from the deleterious consequences of ROS by counteracting ROS-activated apoptotic signals. Proapoptotic stimuli as well as oxidative stress (H2O2) stimulate the phosphorylation of p66shc in osteoblastic cells within 2 min. Estrogen attenuates the phosphorylation of p66shc and this effect is also mediated by ERKs. Importantly, p66shc phosphorylation increases following ovariectomy of mice in which one endogenous ER allele has been replaced by a mutated form of ER that lacks DNA binding activity (ERNERKI/). ERNERKI/ mice lack classical ER signaling through ERE sites but retain signaling through protein– protein interactions of the ER with other proteins [100] as well as kinase-mediated signaling of the receptor [51]. Thus, p66shc phosphorylation is negatively regulated by
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estrogen in vivo and this effect is conferred by a kinasemediated mechanism of ER action.
Estrogen receptor signaling and mechanotransduction Estrogen-Independent Action of the ER in Osteoblasts and Osteocytes Mechanical loading acts as an anabolic stimulus for the skeleton because it promotes bone formation. Similar to the anti-apoptotic effects of estrogen, mechanical stimulation promotes osteocyte and osteoblast survival [101–103]. Integrin signaling as well as intact caveolae and the kinase activities of Src and focal adhesion kinase and downstream phosphorylation and nuclear translocation of ERKs are required [103]. Implicating a role of ER in the adaptive response of bone to mechanical forces, mice lacking ER or ER exhibit a poor osteogenic response to bone loading [104, 105]. Osteocytes or osteoblasts lacking ER and ER are unresponsive to mechanical stimulation and both ER as well as ER rescue ERK activation in response to stretching [17]. ERK activation in response to stretching is also recovered by transfecting the ligand-binding domain of either receptor or an ER mutant that does not bind estrogen. Both plasma membrane localization of ER and its interaction with caveolin-1 are required for stretchinginduced ERK activation and anti-apoptosis. Thus, in addition to their role as ligand-dependent mediators of the effects of estrogens, the membrane-associated ERs serve a novel function that is ligand independent and essential for the transduction of mechanical forces into pro-survival signals in osteocytes and osteoblasts.
Osteoblasts, ER Level and Wnt Signaling Mice lacking ER show a compromised response of their skeletons to the bone-forming effect of mechanical loading. Estrogen deficiency has been associated with a marked decline in ER protein levels in osteocytes [106]. This is paralleled by a reduction in the strain-related stimulus in these cells. Based on these observations and because strain does not by itself stimulate an increase in ER levels, it has been proposed that a decline in ER levels following menopause may render cells less responsive to mechanical stimulation. Thus, it may contribute to the increased fragility seen in postmenopausal women. Additionally, ER supports mechanical stress-activated Wnt signaling as evidenced by studies showing that ER depletion in cultured osteoblasts abolishes activation of Wnt signaling induced by mechanical stress [107]. Moreover, mechanical loading failed to stimulate the expression of several Wnt target genes in ER deficient mice. Although the molecular mechanism of the interaction between Wnt and ER in mechanical loading
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has not yet been elucidated, it is not surprising, considering the reported association of the ER and other nuclear receptors with -catenin [51, 108].
Effects on the Periosteum In sharp contrast to their similar actions on cancellous bone, estrogens and androgens differentially regulate periosteal bone formation in the growing skeleton as well as periosteal expansion in adult and aging men and women. In general, estrogens suppress whereas androgens promote periosteal expansion in rodents, primates and humans [109–114]. In both genders, gonadectomy affects cancellous bone in an identical manner by increasing bone turnover, but differentially affects cortical bone primarily because estrogen deficiency increases periosteal expansion whereas androgen deficiency reduces periosteal apposition rates [115]. The cellular targets of sex steroid actions on the periosteum and the molecular mechanisms and signaling events that confer their differential effects have recently begun to be elucidated. Androgens promote both the proliferation and osteoblast differentiation from periosteumderived mesenchymal progenitors in vitro and in vivo [52]. Accordingly, overexpression of the AR in cells of the osteoblastic lineage promotes periosteal expansion [22]. In contrast, estrogens promote the expansion of early osteoblast progenitors but inhibit their differentiation by osteogenic agents such as PTH or BMP-2. The molecular mechanisms that underlie the pro-differentiating effects of androgens as well as the anti-osteoblastogenic effects of estrogens on periosteal osteoblast precursors involve modulation of BMP and Wnt signaling. This was shown by the induction by androgen, or suppression by estrogen, of Smad1/5/8 activity and Wnt/-catenin-mediated transcription in periosteal cells in vitro and in vivo. Inhibitors of Wnt or BMP signaling abrogated the pro-differentiating actions of dihydrotestosterone (DHT). These findings indicate that interactions between each hormone and components of BMP or Wnt signaling are a prerequisite for the development and maturation of periosteal osteoblasts from their precursors. Moreover, they suggest that the different effects of estrogens and androgens on the periosteum result from opposing actions on the recruitment of early periosteal osteoblast progenitors. The property of estrogen to increase periosteal osteoblast precursor number, yet maintain them in an undifferentiated state may reflect actions of the hormone on a cell population distinct from that affected by androgens or PTH. It has also been proposed that both estrogen and androgens are required for periosteal expansion in puberty and that, in both sexes, estrogen induces a dose-dependent biphasic response at the periosteal surface [116–118]. Androgens enlarge periosteal bone by means of increasing
muscle size and, in turn, increasing the mechanical load on the periosteum. Low estrogen levels may permit the anabolic affects of androgens on the periosteum by lowering the threshold of mechanical sensitivity. High estrogen levels suppress periosteal expansion also by interfering with mechanical loading. Similar to the proposed stimulatory effect of low doses of estrogens, unliganded ER has been found to be required for the pro-differentiating actions of BMP-2 in periosteal osteoblasts. Thus, ER may be a major switch which can either stimulate (in the presence of estrogen) or suppress (in the absence of estrogen) periosteal bone formation. It is therefore tempting to speculate the dual action of ER in periosteal osteoblast differentiation may explain the seeming paradox of the dose-dependent biphasic response of the periosteum to estrogens. Low doses of estrogen may recapitulate the stimulatory actions of unliganded ER on periosteal expansion.
T cells and the regulation of bone resorption Evidence suggests that pro-osteoclastogenic immunological perturbations are not uncommon in estrogen-treated humans and that T cells play a role in the anti-resorptive effects of estrogen in humans and mouse models. Recently, RANKL expression on lymphocytes and marrow stromal cells was shown to be elevated during estrogen deficiency in humans and correlates directly with increases in bone resorption markers and inversely with serum estrogen levels [119]. In the same study, production of cytokines representative of TH1 lymphocytes increased in postmenopausal women and this effect was reversed by estrogen administration. A series of studies in ovariectomized growing mice and in a strain of mice which are unable to induce T-cell activation, have been used to dissect the role of T cells in the effects of estrogen in bone. Those studies have shown that estrogen deficiency leads to an increase in IL-7 production by organs such as bone, thymus and spleen, in part due to decreases in TGF [120]. This event activates T cells which, in turn, release interferon (IFN) to stimulate antigen presentation by dendritic cells and macrophages, amplifying T-cell activation and release of the osteoclastogenic factors RANKL and TNF [121]. Both estrogen and androgens are reported to suppress thymic function. Accordingly, castration reverses thymic atrophy and increases export of thymic emigrants to the periphery [122], whereas sex steroids inhibit thymus regeneration by promoting thymocyte apoptosis and an arrest of differentiation [123]. Thus, ovariectomy expands thymic T cells and lead to the thymic export of naïve T cells [124]. In fact, another mechanism by which estrogen suppresses T-cell-dependent TNF production is by regulating T-cell differentiation in the thymus [121, 125]. This process is
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due to the ability of estrogen to upregulate the expression of major histocompatibility complex II (MHCII) and CD80 in macrophages and dendritic cells, respectively. T-cell precursors originate in the marrow and migrate to the thymus where T-cell differentiation, selection and expansion takes place, mainly under the control of IL-7. Following release from the thymus these new T cells home to peripheral lymphoid organs including the bone marrow itself. Estrogen decreases thymic output through an IL-7-dependent mechanism, blunting the size of the pool of bone marrow T cells available for activation and expansion.
ER and AR knockout models Mouse models deficient for ER (ERKO), ER (ERKO), both ER and ER (DERKO) or the AR (ARKO), have been generated by several investigative groups (reviewed in Chapters 23 and 25). In general, although informative with regard to the effects of estrogen on bone development and growth, these models have produced little understanding of the role of ERs in the maintenance of the adult skeleton. Briefly, in the case of the ERs, the models show a less dramatic phenotype than that expected from humans with an inactivating mutation in the ER gene. Initial studies reported a reduction in bone mineral density (BMD) in male ERKO, no effect in male ERKO and an increase in cortical bone and periosteal apposition in female ERKO mice. Male DERKO mice showed a reduction in BMD that was similar to that of ERKO animals suggesting that perhaps ER is the main receptor that confers the protective actions of estrogen to bone. However, some of these ERKO and ERKO mice do not appear to be complete knockout models because they express truncated but still functional ER transcripts. More recent studies with complete knockout ER models show differing and contrasting skeletal phenotypes. Such discrepancies and the lack of expected skeletal changes may be due to the increased serum levels of estradiol and testosterone. The use of genetics tools for cell-specific inactivation of the receptors should eliminate problems stemming from the systemic effects of ER deletion, such as the dramatically elevated sex steroid levels in the serum due to inactivation of the receptor in the gonads. Moving towards that direction, ER deletion in osteoclasts resulted in osteopenia due to increased turnover [85, 86] and AR inactivation in osteoblasts caused increased bone resorption, leading to a reduction in trabecular bone volume [23]. Such models along with models which dissect specific functions of the receptors [126] should discriminate direct effects of the receptors in osteoblasts, osteocytes or osteoclasts from effects that are the consequences of receptor deletion in other cell types. Hence, they should help to clarify the mechanisms of estrogen and androgen action on bone cells.
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References 1. S. Harada, G.A. Rodan, Control of osteoblast function and regulation of bone mass, Nature 423 (6937) (2003) 349–355. 2. S.L. Teitelbaum, F.P. Ross, Genetic regulation of osteoclast development and function, Nat. Rev. Genet. 4 (8) (2003) 638–649. 3. G.A. Rodan, T.J. Martin, Therapeutic approaches to bone diseases., Science 289 (5484) (2000) 1508–1514. 4. LG. Raisz, Clinical practice. Screening for osteoporosis, N. Engl. J. Med. 353 (2) (2005) 164–171. 5. B.L. Riggs, L.J. Melton III, R.A. Robb, et al., Populationbased analysis of the relationship of whole bone strength indices and fall-related loads to age- and sex-specific patterns of hip and wrist fractures, J. Bone. Miner. Res. 21 (2) (2006) 315–323. 6. M.L. Bouxsein, L.J. Melton III, B.L. Riggs, et al., Age- and sex-specific differences in the factor of risk for vertebral fracture: a population-based study using QCT, J. Bone. Miner. Res. 21 (9) (2006) 1475–1482. 7. S.C. Manolagas, S. Kousteni, R.L. Jilka, Sex steroids and bone, Recent Prog. Horm. Res. 57 (2002) 385–409. 8. B.L. Riggs, S. Khosla, L.J. Melton III, Sex steroids and the construction and conservation of the adult skeleton, Endocr. Rev. 23 (3) (2002) 279–302. 9. S.C. Manolagas, Birth and death of bone cells: basic regulatory mechanisms and implications for the pathogenesis and treatment of osteoporosis, Endocr Rev. 21 (2) (2000) 115–137. 10. S.C. Manolagas, S. Kousteni, J.R. Chen, M. Schuller, L. Plotkin, T. Bellido, Kinase-mediated transcription, activators of nongenotropic estrogen-like signaling (ANGELS), and osteoporosis: a different perspective on the HRT dilemma, Kidney. Int. Suppl. 91 (2004) S41–S49. 11. S. Kousteni, T. Bellido, L.I. Plotkin, et al., Nongenotropic, sex-nonspecific signaling through the estrogen or androgen receptors: dissociation from transcriptional activity, Cell 104 (2001) 719–730. 12. S. Kousteni, L. Han, J.-R. Chen, et al., Kinase-mediated regulation of common transcription factors accounts for the boneprotective effects of sex steroids, J. Clin. Invest. 111 (2003) 1651–1664. 13. J.R. Chen, L.I. Plotkin, J.I. Aguirre, et al., Transient versus sustained phosphorylation and nuclear accumulation of ERKs underlie anti-versus pro-apoptotic effects of estrogens, J. Biol. Chem. 280 (6) (2005) 4632–4638. 14. S.C. Manolagas, Birth and death of bone cells: basic regulatory mechanisms and implications for the pathogenesis and treatment of osteoporosis, Endocr. Rev. 21 (2) (2000) 115–137. 15. G. Marotti, V. Cane, S. Palazzini, C. Palumbo, Structurefunction relationships in the osteocyte., Ital. J. Min. Electro. Metab. 4 (2) (1990) 93–106. 16. E.M. Aarden, E.H. Burger, PJ. Nijweide, Function of osteocytes in bone, J. Cell. Biochem. 55 (1994) 287–299. 17. J.I. Aguirre, L.I. Plotkin, A.R. Gortazar, et al., A novel ligand-independent function of the estrogen receptor is essential for osteocyte and osteoblast mechanotransduction, J. Biol. Chem. 282 (35) (2007) 25501–25508.
278
Osteoporosis in Men
18. D.P. McDonnell, The molecular pharmacology of SERMs, Trends Endocrinol. Metab. 10 (8) (1999) 301–311. 19. L. Chang, M. Karin, Mammalian MAP kinase signalling cascades, Nature 410 (6824) (2001) 37–40. 20. D.M. Huber, A.C. Bendixen, P. Pathrose, et al., Androgens suppress osteoclast formation induced by RANKL and macrophage-colony stimulating factor., Endocrinology 142 (9) (2001) 3800–3808. 21. N.K. Shevde, A.C. Bendixen, K.M. Dienger, J.W. Pike, Estrogens suppress RANK ligand-induced osteoclast differentiation via a stromal cell independent mechanism involving c-Jun repression., Proc. Natl. Acad. Sci. USA 97 (14) (2000) 7829–7834. 22. K.M. Wiren, X.W. Zhang, A.R. Toombs, et al., Targeted overexpression of androgen receptor in osteoblasts: unexpected complex bone phenotype in growing animals., Endocrinology 145 (7) (2004) 3507–3522. 23. A.J. Notini, J.F. McManus, A. Moore, et al., Osteoblast deletion of exon 3 of the androgen receptor gene results in trabecular bone loss in adult male mice, J. Bone. Miner. Res. 22 (3) (2007) 347–356. 24. S.C. Manolagas, R.L. Jilka, Cytokines, hematopoiesis, osteoclastogenesis, and estrogens, Calcif. Tissue. Int. 50 (1992) 199–202. 25. S.C. Manolagas, R.L. Jilka, T. Bellido, C.A. O’Brien, A.M. Parfitt, Interleukin-6-type cytokines and their receptors, in: J.P. Bilezikian, L.G. Raisz, G.A. Rodan (Eds.) Principles of bone biology, Academic Press, San Diego, 1996, pp. 131–701. 26. G. Girasole, R.L. Jilka, G. Passeri, et al., 17b-estradiol inhibits interleukin-6 production by bone marrow-derived stromal cells and osteoblasts in-vitro: a potential mechanism for the antiosteoporotic effect of estrogens, J. Clin. Invest. 89 (1992) 883–891. 27. T. Bellido, R.L. Jilka, B.F. Boyce, et al., Regulation of interleukin-6, osteoclastogenesis and bone mass by androgens: the role of the androgen receptor, J. Clin. Invest. 95 (1995) 2886–2895. 28. S.C. Lin, T. Yamate, Y. Taguchi, et al., Regulation of the gp80 and gp130 subunits of the IL-6 receptor by sex steroids in the murine bone marrow, J. Clin. Invest. 100 (8) (1997) 1980–1990. 29. S.C. Manolagas, R.L. Jilka, Bone marrow, cytokines, and bone remodeling – emerging insights into the pathophysiology of osteoporosis, N. Engl. J. Med. 332 (1995) 305–311. 30. G. Passeri, G. Girasole, R.L. Jilka, S.C. Manolagas, Increased interleukin-6 production by murine bone marrow and bone cells after estrogen withdrawal, Endocrinology 133 (1993) 822–828. 31. C. Scheidt-Nave, H. Bismar, G. Leidig-Bruckner, et al., Serum interleukin 6 is a major predictor of bone loss in women specific to the first decade past menopause, J. Clin. Endocrinol. Metab. 86 (5) (2001) 2032–2042. 32. R.L. Jilka, G. Hangoc, G. Girasole, et al., Increased osteoclast development after estrogen loss: mediation by interleukin-6, Science 257 (1992) 88–91. 33. V. Poli, R. Balena, E. Fattori, et al., Interleukin-6 deficient mice are protected from bone loss caused by estrogen depletion, EMBO J. 13 (1994) 1189–1196.
34. S.T. Pottratz, T. Bellido, H. Mocharla, D. Crabb, SC. Manolagas, 17b-estradiol inhibits expression of human interleukin-6 promoter-reporter constructs by a receptor-dependent mechanism, J. Clin. Invest. 93 (1994) 944–950. 35. D.P. McDonnell, J.D. Norris, Analysis of the molecular pharmacology of estrogen receptor agonists and antagonists provides insights into the mechanism of action of estrogen in bone., Osteoporos. Int. 7 (Suppl. 1) (1997) S29–S34. 36. S. Srivastava, W.M. Neale, R.B. Kimble, et al., Estrogen blocks M-CSF gene expression and osteoclast formation by regulating phosphorylation of egr-1 and its interaction with Sp-1, J. Clin. Invest. 102 (10) (1998) 1850–1859. 37. T. Sunyer, J. Lewis, P. Collin-Osdoby, P. Osdoby, Estrogen’s bone-protective effects may involve differential IL-1 receptor regulation in human osteoclast-like cells, J. Clin. Invest. 103 (10) (1999) 1409–1418. 38. S. Cenci, M.N. Weitzmann, C. Roggia, et al., Estrogen deficiency induces bone loss by enhancing T-cell production of TNF-alpha, J. Clin. Invest. 106 (10) (2000) 1229–1237. 39. RL. Jilka, Cytokines, bone remodeling, and estrogen deficiency: a 1998 update, Bone 23 (1998) 75–81. 40. C.H. Kasperk, J.E. Wergedal, J.R. Farley, T.A. Linkhart, R.T. Turner, DJ. Baylink, Androgens directly stimulate proliferation of bone cells in vitro, Endocrinology 124 (1989) 1576–1578. 41. C. Kasperk, A. Helmboldt, I. Borcsok, et al., Skeletal sitedependent expression of the androgen receptor in human osteoblastic cell populations, Calcif. Tissue. Int. 61 (6) (1997) 464–473. 42. L.C. Hofbauer, K.C. Hicok, S. Khosla, Effects of gonadal and adrenal androgens in a novel androgen-responsive human osteoblastic cell line, J. Cell. Biochem. 71 (1) (1998) 96–108. 43. R.L. Jilka, K. Takahashi, M. Munshi, D.C. Williams, P.K. Roberson, SC. Manolagas, Loss of estrogen upregulates osteoblastogenesis in the murine bone marrow: evidence for autonomy from factors released during bone resorption, J. Clin. Invest. 101 (1998) 1942–1950. 44. R.L. Jilka, R.S. Weinstein, K. Takahashi, A.M. Parfitt, S.C. Manolagas, Linkage of decreased bone mass with impaired osteoblastogenesis in a murine model of accelerated senescence, J. Clin. Invest. 97 (7) (1996) 1732–1740. 45. R.S. Weinstein, R.L. Jilka, A.M. Parfitt, SC. Manolagas. The effects of androgen deficiency on murine bone remodeling and bone mineral density are mediated via cells of the osteoblastic lineage, Endocrinology 138 (1997) 4013–4021. 46. G. DiGregorio, M. Yamamoto, A. Ali, et al., Attenuation of the self-renewal of transit amplifying osteoblast progenitors in the murine bone marrow by 17b-estradiol, J. Clin. Invest. 107 (2001) 803–812. 47. T. Bellido, V.Z. Borba, P. Roberson, S.C. Manolagas, Activation of the Janus kinase/STAT (signal transducer and activator of transcription) signal transduction pathway by interleukin-6-type cytokines promotes osteoblast differentiation, Endocrinology 138 (9) (1997) 3666–3676. 48. T. Bellido, C.A. O’Brien, P.K. Roberson, S.C. Manolagas, Transcriptional activation of the p21WAF1,CIP1,SDI1gene by interleukin-6 type cytokines – a prerequisite for their prodifferentiating and anti-apoptotic effects on human osteoblastic cells, J. Biol. Chem. 273 (33) (1998) 21137–21144.
C h a p t e r 2 2 The Molecular Biology of Sex Steroids in Bone: Similarities and Differences among the Sexes l
49. Y. Taguchi, M. Yamamoto, T. Yamate, et al., Interleukin-6-type cytokines stimulate mesenchymal progenitor differentiation toward the osteoblastic lineage, Proc. Assoc. Am. Phys. 110 (6) (1998) 559–574. 50. C.A. Brien, I. Gubrij, S.-C. Lin, R.L. Saylors, S.C. Manolagas, STAT3 activation in stromal/osteoblastic cells is required for induction of the receptor activator of NF-kB ligand and stimulation of osteoclastogenesis by gp130-utilizing cytokines or interleukin-1 but not 1,25-dihydroxyvitamin D3 or parathyroid hormone, J. Biol. Chem. 274 (1999) 19301–19308. 51. S. Kousteni, M. Almeida, L. Han, T. Bellido, R.L. Jilka, S.C. Manolagas, Induction of osteoblast differentiation by selective activation of kinase-mediated actions of the estrogen receptor, Mol. Cell. Biol. 27 (4) (2007) 1516–1530. 52. M. Ogita, M.T. Rached, E. Dworakowski, J.P. Bilezikian, S. Kousteni, Differentiation and proliferation of periosteal osteoblast progenitors are differentially regulated by estrogens and intermittent parathyroid hormone administration, Endocrinology 149 (11) (2008) 5713–5723. 53. D.B. Ong, S.M. Colley, M.R. Norman, S. Kitazawa, J.H. Tobias, Transcriptional regulation of a BMP-6 promoter by estrogen receptor alpha, J. Bone. Miner. Res. 19 (3) (2004) 447–454. 54. T. Yamamoto, F. Saatcioglu, T. Matsuda, Cross-talk between bone morphogenic proteins and estrogen receptor signaling, Endocrinology 143 (7) (2002) 2635. 55. O. Khalid, S.K. Baniwal, D.J. Purcell, et al., Modulation of Runx2 activity by estrogen receptor-alpha: implications for osteoporosis and breast cancer, Endocrinology 149 (12) (2008) 5984–5995. 56. T.L. McCarthy, W.Z. Chang, Y. Liu, M. Centrella, Runx2 integrates estrogen activity in osteoblasts, J. Biol. Chem. 278 (44) (2003) 43121–43129. 57. Z. Maruyama, C.A. Yoshida, T. Furuichi, et al., Runx2 determines bone maturity and turnover rate in postnatal bone development and is involved in bone loss in estrogen deficiency, Dev. Dyn. 236 (7) (2007) 1876–1890. 58. M. Usui, Y. Yoshida, K. Tsuji, et al., Tob deficiency superenhances osteoblastic activity after ovariectomy to block estrogen deficiency-induced osteoporosis, Proc. Natl. Acad. Sci. USA. 101 (17) (2004) 6653–6658. 59. C. Kasperk, S.M. Watt, D. Strong, et al., Studies of the mechanism by which androgens enhance mitogenesis and differentiation in bone cells, J. Clin. Endocrinol. Metab. 71 (1990) 1322–1329. 60. P.V. Bodine, B.L. Riggs, TC. Spelsberg, Regulation of c-fos expression and TGF-beta production by gonadal and adrenal androgens in normal human osteoblastic cells, J. Steroid. Biochem. Mol. Biol. 52 (2) (1995) 149–158. 61. P.H. Driggers, J.H. Segars, Estrogen action and cytoplasmic signaling pathways. Part II: the role of growth factors and phosphorylation in estrogen signaling, Trends Endocrinol. Metab. 13 (10) (2002) 422–427. 62. J.R. Hawse, M. Subramaniam, D.G. Monroe, et al., Estrogen receptor beta isoform-specific induction of transforming growth factor beta-inducible early gene-1 in human osteoblast cells: an essential role for the activation function 1 domain, Mol. Endocrinol. 22 (7) (2008) 1579–1595.
279
63. U.I. Modder, A. Sanyal, A.E. Kearns, et al., Effects of loss of steroid receptor coactivator-1 on the skeletal response to estrogen in mice, Endocrinology 145 (2) (2004) 913–921. 64. U.I. Modder, A. Sanyal, J. Xu, B.W. O’Malley, T.C. Spelsberg, S. Khosla, The skeletal response to estrogen is impaired in female but not in male steroid receptor coactivator (SRC)-1 knock out mice, Bone 42 (2) (2008) 414–421. 65. S. Kousteni, J.-R. Chen, T. Bellido, et al., Reversal of bone loss in mice by nongenotropic signaling of sex steroids, Science 298 (2002) 843–846. 66. W.R. Harrington, S.H. Kim, C.C. Funk, et al., Estrogen dendrimer conjugates that preferentially activate extranuclear, nongenomic versus genomic pathways of estrogen action, Mol. Endocrinol. 20 (3) (2006) 491–502. 67. M. Almeida, L. Han, C.A. O’Brien, S. Kousteni, S.C. Manolagas, Classical genotropic versus kinase-initiated regulation of gene transcription by the estrogen receptor alpha, Endocrinology 147 (4) (2006) 1986–1996. 68. D. Chen, M. Zhao, G.R. Mundy, Bone morphogenetic proteins, Growth Factors 22 (4) (2004) 233–241. 69. F. Syed, U. Modder, D. Fraser, et al., Skeletal effects of estrogen are mediated by opposing actions of classical and nonclassical estrogen receptor pathways, J. Bone. Miner. Res. 20 (2005) 1992–2001. 70. F.A. Syed, D.G. Fraser, T.C. Spelsberg, et al., Effects of loss of classical estrogen response element signaling on bone in male mice, Endocrinology 148 (4) (2007) 1902–1910. 71. R.S. Weinstein, R.L. Jilka, A.M. Parfitt, SC. Manolagas, Inhibition of osteoblastogenesis and promotion of apoptosis of osteoblasts and osteocytes by glucocorticoids: potential mechanisms of their deleterious effects on bone, J. Clin. Invest. 102 (1998) 274–282. 72. T. Bellido, L.I. Plotkin, C.A. O’Brien, S.C. Manolagas, R.L. Jilka, PTH-mediated control of proteasome-mediated degradation of Runx2/Cbfa1: a pivotal determinant of the longevity of PTH-initiated anti-apoptosis signaling in osteoblastic cells, J. Bone. Miner. Res. 17 (2002) S128. 73. L.I. Plotkin, R.S. Weinstein, A.M. Parfitt, P.K. Roberson, S.C. Manolagas, T. Bellido, Prevention of osteocyte and osteoblast apoptosis by bisphosphonates and calcitonin, J. Clin. Invest. 104 (10) (1999) 1363–1374. 74. R.L. Jilka, R.S. Weinstein, T. Bellido, P. Roberson, A.M. Parfitt, SC. Manolagas, Increased bone formation by prevention of osteoblast apoptosis with parathyroid hormone, J. Clin. Invest. 104 (4) (1999) 439–446. 75. A.M. Vertino, C.M. Bula, J.R. Chen, et al., Nongenotropic, anti-apoptotic signaling of 1alpha,25(OH)2-vitamin D3 and analogs through the ligand binding domain of the vitamin D receptor in osteoblasts and osteocytes. Mediation by Src, phosphatidylinositol 3-, and JNK kinases, J. Biol. Chem. 280 (14) (2005) 14130–14137. 76. M. Almeida, L. Han, T. Bellido, S.C. Manolagas, S. Kousteni, Wnt proteins prevent apoptosis of both uncommitted osteoblast progenitors and differentiated osteoblasts by beta-catenindependent and -independent signaling cascades involving Src/ERK and phosphatidylinositol 3-kinase/AKT, J. Biol. Chem. 280 (50) (2005) 41342–41351. 77. P. Bodine, W. Zhao, Y. Kharode, et al. Targeted disruption of secreted frizzled-related protein (SFRP)-1 in mice leads to
280
78.
79.
80.
81.
82.
83.
84.
85.
86.
87.
88.
89.
90.
91.
92.
Osteoporosis in Men
decreased osteoblast and osteocyte apoptosis and increased trabecular bone formation, J. Bone. Miner. Res. 17 (2002) S126. A. Migliaccio, G. Castoria, M. Di Domenico, et al., Steroidinduced androgen receptor-oestradiol receptor beta-Src complex triggers prostate cancer cell proliferation, EMBO J. 19 (20) (2000) 5406–5417. A. Minden, A. Lin, M. McMahon, et al., Differential activation of ERK and JNK mitogen-activated protein kinases by Raf-1 and MEKK, Science 266 (5191) (1994) 1719–1723. R. Paumelle, D. Tulasne, C. Leroy, J. Coll, B. Vandenbunder, V. Fafeur, Sequential activation of ERK and repression of JNK by scatter factor/hepatocyte growth factor in madindarby canine kidney epithelial cells, Mol. Biol. Cell. 11 (11) (2000) 3751–3763. B. Su, M. Karin, Mitogen-activated protein kinase cascades and regulation of gene expression, Curr. Opin. Immunol. 8 (3) (1996) 402–411. P.J. Kushner, D.A. Agard, G.L. Greene, et al., Estrogen receptor pathways to AP-1, J. Steroid. Biochem. Mol. Biol. 74 (5) (2000) 311–317. A. Bonni, A. Brunet, A.E. West, S.R. Datta, M.A. Takasu, M.E. Greenberg, Cell survival promoted by the Ras-MAPK signaling pathway by transcription-dependent and -independent mechanisms, Science 286 (5443) (1999) 1358–1362. M.P. Scheid, V. Duronio, Dissociation of cytokine-induced phosphorylation of Bad and activation of PKB/akt: involvement of MEK upstream of Bad phosphorylation., Proc. Natl. Acad. Sci. USA. 95 (13) (1998) 7439–7444. T. Nakamura, Y. Imai, T. Matsumoto, et al., Estrogen prevents bone loss via estrogen receptor alpha and induction of Fas ligand in osteoclasts., Cell 130 (5) (2007) 811–823. M. Martin-Millan, M. Almeida, E. Ambrogini, et al., ERa deletion in cells of the monocyte/macrophage lineage increases osteoclastogenesis and abrogates the pro-apoptotic effect of E2 on osteoclasts, J Bone Miner Metab 23 (Suppl. 1) (2008) S28. B.F. Boyce, L. Xing, R.L. Jilka, et al., Apoptosis and bone cells, in: J.P. Bilezikian, L.G. Raisz, G.A. Rodan (Eds.) Principles of bone biology, 2nd edn., Academic Press, Orlando, 2002, pp. 151–168. A. Gingery, E. Bradley, A. Shaw, MJ. Oursler, Phosphatidylinositol 3-kinase coordinately activates the MEK/ ERK and AKT/NFkappaB pathways to maintain osteoclast survival, J. Cell. Biochem. 89 (1) (2003) 165–179. Z.H. Lee, S.E. Lee, C.W. Kim, et al., IL-1alpha stimulation of osteoclast survival through the PI 3-kinase/Akt and ERK pathways, J. Biochem. (Tokyo) 131 (1) (2002) 161. S.E. Lee, W.J. Chung, H.B. Kwak, et al., Tumor necrosis factor-alpha supports the survival of osteoclasts through the activation of Akt and ERK, J. Biol. Chem. 276 (52) (2001) 49343–49349. H. Nakamura, A. Hirata, T. Tsuji, T. Yamamoto, Role of osteoclast extracellular signal-regulated kinase (ERK) in cell survival and maintenance of cell polarity, J. Bone. Miner. Res. 18 (7) (2003) 1198–11205. S. Srivastava, G. Toraldo, M.N. Weitzmann, S. Cenci, F.P. Ross, R. Pacifici, Estrogen decreases osteoclast formation by down-regulating receptor activator of NF-kappa B ligand (RANKL)-induced JNK activation, J. Biol. Chem. 276 (12) (2001) 8836–8840.
93. I. Recchia, N. Rucci, A. Funari, et al., Reduction of c-Src activity by substituted 5,7-diphenyl-pyrrolo[2,3-d]-pyrimidines induces osteoclast apoptosis in vivo and in vitro. Involvement of ERK1/2 pathway, Bone 34 (1) (2004) 65–79. 94. Y. Gao, W.P. Qian, K. Dark, et al., Estrogen prevents bone loss through transforming growth factor beta signaling in T cells., Proc. Natl. Acad. Sci. USA. 101 (47) (2004) 16618–16623. 95. D.E. Hughes, A. Dai, J.C. Tiffee, H.H. Li, G.R. Mundy, B.F. Boyce, Estrogen promotes apoptosis of murine osteoclasts mediated by TGF-b., Nat. Med. 2 (1996) 1132–1336. 96. M. Almeida, L. Han, M. Martin-Millan, et al., Skeletal involution by age-associated oxidative stress and its acceleration by loss of sex steroids, J. Biol. Chem. 282 (37) (2007) 27285–27297. 97. E. Migliaccio, M. Giorgio, S. Mele, et al., The p66shc adaptor protein controls oxidative stress response and life span in mammals, Nature 402 (6759) (1999) 309–313. 98. J.M. Lean, J.T. Davies, K. Fuller, et al., A crucial role for thiol antioxidants in estrogen-deficiency bone loss, J. Clin. Invest. 112 (6) (2003) 915–923. 99. J.M. Lean, Jagger C.J, Kirstein B, Fuller K, Chambers T.J. Hydrogen peroxide is essential for estrogen-deficiency bone loss and osteoclast formation, Endocrinology 146 (2) (2005) 728–735. 100. M. Jakacka, M. Ito, F. Martinson, T. Ishikawa, E.J. Lee, J.L. Jameson, An estrogen receptor (ER)alpha deoxyribonucleic acid-binding domain knock-in mutation provides evidence for nonclassical ER pathway signaling in vivo, Mol. Endocrinol. 16 (10) (2002) 2188–2201. 101. J.I. Aguirre, L.I. Plotkin, S.A. Stewart, et al., Osteocyte apoptosis is induced by weightlessness in mice and precedes osteoclast recruitment and bone loss, J. Bone. Miner. Res. (2006). 102. C. Dufour, X. Holy, P.J. Marie, Skeletal unloading induces osteoblast apoptosis and targets alpha5beta1-PI3K-Bcl-2 signaling in rat bone, Exp. Cell. Res. 313 (2) (2007) 394–403. 103. L.I. Plotkin, I. Mathov, J.I. Aguirre, A.M. Parfitt, S.C. Manolagas, T. Bellido, Mechanical stimulation prevents osteocyte apoptosis: requirement of integrins, Src kinases, and ERKs, Am. J. Physiol. Cell. Physiol. 289 (3) (2005) C633–C643. 104. K. Lee, H. Jessop, R. Suswillo, G. Zaman, L. Lanyon, Endocrinology: bone adaptation requires oestrogen receptoralpha, Nature 424 (6947) (2003) 389. 105. K.C. Lee, H. Jessop, R. Suswillo, G. Zaman, L.E. Lanyon, The adaptive response of bone to mechanical loading in female transgenic mice is deficient in the absence of oestrogen receptor-alpha and -beta, J. Endocrinol. 182 (2) (2004) 193–201. 106. G. Zaman, H.L. Jessop, M. Muzylak, et al., Osteocytes use estrogen receptor alpha to respond to strain but their ERalpha content is regulated by estrogen, J. Bone. Miner. Res. 21 (8) (2006) 1297–1306. 107. V.J. Armstrong, M. Muzylak, A. Sunters, et al., Wnt/betacatenin signaling is a component of osteoblastic bone cell early responses to load-bearing and requires estrogen receptor alpha, J. Biol. Chem. 282 (28) (2007) 20715–20727. 108. A.P. Kouzmenko, K. Takeyama, S. Ito, et al., Wnt/beta-catenin and estrogen signaling converge in vivo, J. Biol. Chem. 279 (39) (2004) 40255–40258.
C h a p t e r 2 2 The Molecular Biology of Sex Steroids in Bone: Similarities and Differences among the Sexes l
109. R.T. Turner, B.L. Riggs, TC. Spelsberg, Skeletal effects of estrogen, Endocr. Rev. 15 (1994) 275–300. 110. R.T. Turner, K.S. Hannon, L.M. Demers, J. Buchanan, NH. Bell, Differential effects of gonadal function on bone histomorphometry in male and female rats, J. Bone. Miner. Res. 4 (1989) 557–563. 111. G.K. Wakley, G.L. Evans, RT. Turner, Short-term effects of high dose estrogen on tibiae of growing male rats, Calcif. Tissue. Int. 60 (1) (1997) 37–42. 112. V. Coxam, B.M. Bowman, M. Mecham, C.M. Roth, M.A. Miller, S.C. Miller, Effects of dihydrotestosterone alone and combined with estrogen on bone mineral density, bone growth, and formation rates in ovariectomized rats, Bone 19 (1996) 107–114. 113. M. Gunness, E. Orwoll, Early induction of alterations in cancellous and cortical bone histology after orchiectomy in mature rats, J. Bone. Miner. Res. 10 (11) (1995) 1734–1735. 114. C. Lea, N. Kendall, AM. Flanagan, Casodex (a nonsteroidal antiandrogen) reduces cancellous, endosteal, and periosteal bone formation in estrogen-replete female rats, Calcif. Tissue. Int. 58 (4) (1996) 268–272. 115. B.T. Kim, L. Mosekilde, Y. Duan, et al., The structural and hormonal basis of sex differences in peak appendicular bone strength in rats, J. Bone. Miner. Res. 18 (1) (2003) 150–155. 116. D. Vanderschueren, K. Venken, J. Ophoff, R. Bouillon, S. Boonen, Sex steroids and the periosteum: reconsidering the role of androgens and estrogens in periosteal expansion, J. Clin. Endocrinol. Metab. 91 (2006) 378–382. 117. K. Venken, G.K. De, S. Boonen, et al., Relative impact of androgen and estrogen receptor activation in the effects of androgens on trabecular and cortical bone in growing male mice: a study in the androgen receptor knockout mouse model, J. Bone. Miner. Res. 21 (4) (2006) 576–585. 118. O.V. Leppanen, J. Jokihaara, I. Pajamaki, H. Sievänen, P. Kannus, Estrogen and regulation of bone periosteum – a
119.
120.
121.
122.
123.
124.
125.
126.
281
misperceived interaction., J. Bone. Miner. Res. 21 (Suppl. 1) (2006) S376. G. Eghbali-Fatourechi, S. Khosla, A. Sanyal, W.J. Boyle, D.L. Lacey, BL. Riggs, Role of RANK ligand in mediating increased bone resorption in early postmenopausal women, J. Clin. Invest. 111 (8) (2003) 1221–1230. C. Roggia, Y. Gao, S. Cenci, et al., Up-regulation of TNFproducing T cells in the bone marrow: a key mechanism by which estrogen deficiency induces bone loss in vivo, Proc. Natl. Acad. Sci. USA. 98 (24) (2001) 13960–13965. S. Cenci, G. Toraldo, M.N. Weitzmann, et al., Estrogen deficiency induces bone loss by increasing T cell proliferation and lifespan through IFN-gamma-induced class II transactivator, Proc. Natl. Acad. Sci. USA. 100 (18) (2003) 10405–10410. M. Utsuyama, K. Hirokawa, Hypertrophy of the thymus and restoration of immune functions in mice and rats by gonadectomy, Mech. Ageing. Dev. 47 (1989) 175–185. S.A. Okasha, S. Ryu, Y. Do, R.J. McKallip, M. Nagarkatti, P.S. Nagarkatti, Evidence for estradiol-induced apoptosis and dysregulated T cell maturation in the thymus., Toxicology 163 (1) (2001) 49–62. M.R. Ryan, R. Shepherd, J.K. Leavey, et al., An IL-7dependent rebound in thymic T cell output contributes to the bone loss induced by estrogen deficiency, Proc. Natl. Acad. Sci. USA. 102 (46) (2005) 16735–16740. J. Adamski, Z. Ma, S. Nozell, E.N. Benveniste, 17betaEstradiol inhibits class II major histocompatibility complex (MHC) expression: influence on histone modifications and cbp recruitment to the class II MHC promoter, Mol. Endocrinol. 18 (8) (2004) 1963–1964. F.A. Syed, A. Sanyal, D. Fraser, et al., Loss of signaling through classical EREs leads to osteopenia and paradoxical responses to estrogen in cortical bone, J. Bone. Miner. Res. 19 (Suppl. 1) (2004) S339.
Chapter
23
Estrogen and the Skeleton – Rodents Filip Callewaert, Katrien Venken, Steven Boonen and Dirk Vanderschueren Center for Musculoskeletal Research, Leuven University Department of Experimental Medicine and Leuven University Center for Metabolic Bone Diseases, Katholieke Universiteit Leuven, Leuven, Belgium
Introduction
a larger bone size in men compared with women [10]. This larger male cortical bone mass is maintained throughout life and is accompanied by increased bone strength and reduced fracture risk [10, 11]. Therefore, the mechanism that determines the acquisition of a greater bone size is very important for the understanding of the pathophysiology of osteoporosis. The gender dimorphism in bone size has traditionally been attributed to opposing actions of sex steroids on periosteal bone formation, with androgen-driven stimulation in males and estrogen-mediated inhibition in females. This assumption originates from findings of a decreased versus increased periosteal apposition following gonadectomy in male versus female growing rats, respectively [12]. The hypothesis that estrogens decrease bone size was, however, challenged by a number of clinical observations in men, but also by experiments in male rodents. In fact, estrogens appear essential for skeletal maturation and adequate acquisition of bone mass, since men with a disruptive mutation in the ER gene or with aromatase deficiency have a reduced bone mass and still open epiphyses [2–8]. Moreover, estrogen treatment of an adolescent aromatase-deficient boy results in an increase of bone size [7]. Likewise, administration of an aromatase inhibitor to growing male rats reduces serum estradiol levels as well as periosteal bone formation [13]. This reduction of periosteal bone expansion is similar to the decrease of bone mass observed in orchidectomized rodents, despite normal to elevated testosterone concentrations [13]. Also, in mice in which the aromatase gene is disrupted, cortical bone size and thickness are significantly lower compared with corresponding control mice [14]. Therefore, aromatization of testosterone into estrogens appears to be essential for periosteal bone expansion during puberty, at least in males. Even though the above-mentioned observations in men and rodents provided strong evidence for an important role of estrogens in bone metabolism, the relative importance of ER and ER for the stimulation of periosteal bone
Androgens may regulate the male skeleton directly through stimulation of the androgen receptor (AR) or indirectly through aromatization of androgens (testosterone, T) into estrogens (17-estradiol, E2) and, thereafter, stimulation of the estrogen receptor alpha (ER) or beta (ER). In men, only about 20% of E2 is directly secreted by the testes, the other 80% is derived from aromatization of testosterone and androstenedione in peripheral tissues, mainly in adipose tissue (including bone) [1]. Observations in men with a mutation in the ER gene [2, 3] or in the gene encoding the aromatase enzyme [4–8] have demonstrated the essential role of estrogens for male bone metabolism as these men presented with severe osteoporosis, increased bone turnover and unfused epiphyses. Aromatase deficient men benefit from estrogen therapy as bone density increased and growth plates closed following initiation of treatment [6]. Furthermore, the importance of estrogen in agerelated bone loss and fracture risk in men has been well established [9]. However, the relative important role of the estrogen pathway in men is still not fully resolved. Several questions remain unanswered. First, to what extent is estrogen needed for male skeletal development and maintenance? Second, what is the relative role of the estrogen pathway versus the androgen pathway? Finally, what is the role of estrogen in the homeostasis of trabecular and cortical bone compartments, respectively? As some of these questions were investigated in rodent models, the aim of this chapter is to give an overview of the most important findings in these animal studies and to discuss their potential relevance for humans.
Estrogens and bone growth in males The amount of bone accrued during growth is a major determinant of fracture risk in later life. Growth produces Osteoporosis in Men
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ER disruption causes severe osteopenia, similar to AR disruption alone (Figure 23.2) [19]. Therefore, ER activation is not involved in trabecular bone modeling in male rodents during growth, which is in contrast with the well established role of ER in female mice [25] (see Figure 23.2).
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acquisition in males remained unresolved. In order further to elucidate the role of the estrogen receptors, the skeletal phenotype of transgenic mouse models in which the genes for ER or ER have been knocked out singly (ERKO or ERKO) or together (ER/KO) have been investigated extensively. Cortical bone mass as well as cortical thickness is decreased in male ERKO and ER/KO mice due to a reduced periosteal bone apposition [15]. In contrast, cortical bone parameters are unaffected in male ERKO mice [16]. Thus, ER – not ER – is involved in the regulation of cortical radial bone expansion in male mice. This is consistent with human data which show a highly increased expression of ER versus ER in cortical bone [17]. However, sex steroid levels are also dramatically increased in ERKO and ER/KO [16], probably due to estrogen insensitivity of the hypothalamus – pituitary axis [18]. The finding that these estrogen resistant animals have a reduced cortical bone mass despite elevated testosterone concentrations further supports the concept that testosterone alone is not sufficient for an optimal periosteal expansion of the male skeleton. Furthermore, little is known about the differential action of AR and ER pathways on bone. To this end, AR-ER double knockout (KO) mice have been characterized more recently, comparing their bone phenotype with single AR and ER knockout mice [19]. Combined AR and ER inactivation additionally reduces cortical bone mass and strength compared to either AR or ER disruption alone (Figure 23.1). These results unequivocally demonstrate that both AR and ER activation are needed for periosteal bone growth and to optimize cortical bone acquisition in males. Although ER and AR are clearly involved in male periosteal expansion, the underlying mechanism is still not resolved. ER activation appears to interfere with the secretion of growth hormone (GH) and insulin-like growth factor-I (IGF-I) in growing rodents [20, 21]. In addition, estrogen deficiency by means of ER disruption in male mice has been reported to be associated with reduced serum IGF-I concentrations [19, 22]. Since the GH-IGF-I axis is the major regulator of postnatal growth [23], a decrease in serum IGF-I may therefore explain the impaired periosteal growth in estrogen deficient or resistant rodents. In contrast with the clear impact of ER activation on cortical bone, the role of ER signaling on male trabecular bone development appears much less important. Similar to cortical bone, ER has no role for trabecular bone development as male ERKO mice, in contrast with female ERKO mice, have no trabecular bone phenotype [16, 24]. Moreover, the trabecular bone number in male ERKO is even increased compared with male wild type mice during puberty [19, 24]. This increase of cancellous bone mass in estrogen resistant mice is, however, entirely related to higher biological androgen activity and AR signaling, since administration of an anti-androgen normalized trabecular bone volume to wild type level [24]. In line with this concept, combined AR and
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Figure 23.1 (A) Cortical bone mineral content (BMC) and (B) cortical strength strain index (SSI) in male WT, ERKO, ARKO and ARERKO mice. Cortical BMC and SSI were assessed in vivo by peripheral quantitative computed tomography (pQCT) and were expressed as a percentage of WT control mice. Values are expressed as means SE. aP 0.05 versus WT; b P 0.05 versus WT, ERKO and ARKO.
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Figure 23.2 Trabecular bone structure in male WT, ERKO, ARKO and ARERKO mice, as measured by microcomputed tomography.
C h a p t e r 2 3 Estrogen and the Skeleton – Rodents l
Estrogens and bone maintenance in males Sex steroids are important not only for the maintenance of the female skeleton, but also for the male skeleton. As in men, sex steroid deficiency in rats as induced by orchidectomy (orx) results in dramatic bone loss reminiscent of osteoporosis in hypogonadal men, allowing the rat to be used as a model for male hypogonadism. Bone turnover is substantially increased following orx resulting in significant trabecular bone loss [26]. In addition, orx in the aged male rat decreases the cortical area mainly resulting from an increased endocortical bone resorption [26, 27]. Also intracortical bone remodeling is upregulated as demonstrated by the enhanced cortical porosity [27]. Earlier studies in orx rats have provided evidence for bone-sparing activity of both androgens and estrogens [28, 29]. The aromatizable androgen testosterone (T) has been shown to prevent orx-induced trabecular and cortical bone loss in the aged male rat [29]. However, in order to assess the relative contribution of AR versus ER modulation on male adult bone, different doses of the non-aromatizable androgen dihydrotestosterone (DHT) and 17-estradiol (E2) have been administered to this rat model [30]. DHT and E2 both inhibit the orx-induced rise of bone turnover markers to a similar extent, indicating that both the AR and ER pathway may be activated in the hypogonadal rodent skeleton. However, the bone-protective effect of E2 involves the prevention of trabecular and cortical bone loss, while only high-dose DHT prevents trabecular but not cortical bone loss [30]. Interestingly, estrogen administration may even increase trabecular bone mass above intact control level as a result of an important reduction of bone turnover [30]. A similar experiment as in rats has been also performed in mice in order to compare directly the effects of ER versus AR activation on trabecular and cortical bone structure [22]. In these adult mice, AR and ER activation are equally effective in the maintenance of trabecular bone mass, but the mechanism of action differs. While estrogens maintain trabecular bone mass by increased number and thickness of trabeculae, androgens only preserve trabecular number. This notion is further supported by the different effects of DHT and E2 on serum osteocalcin. E2 action may be explained not only by a suppression of the orchidectomy-induced increase in bone turnover, as is the case for DHT, but also by an increased bone formation. This finding is in line with earlier observations demonstrating high serum osteocalcin levels in orchidectomized mice treated with E2 [31, 32]. Accordingly, other studies in E2-treated mice describe marked increases in osteoblast numbers along with significant effects on trabecular bone formation in E2-treated mice [33, 34]. A stimulatory effect of estrogens on bone formation in adult mice is further supported by a decrease of the endocortical perimeter most likely due to enhanced endocortical apposition, which ultimately resulted in a thicker
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cortex. The periosteal perimeter, on the other hand, is not affected by either E2 or DHT treatment, indicating that the periosteum appears to be rather unresponsive to sex steroid stimulation in aged rodents. However, the cortical volumetric bone mineral density (BMD) is maintained by E2 but not DHT, which corresponds well with the observation that estrogens, rather than androgens, are associated with cortical volumetric BMD at different skeletal sites in elderly men [9, 35–37]. Interestingly, ER activation increases serum levels of insulin-like growth factor-I, which is positively correlated with all the cortical and trabecular bone parameters that are specifically preserved by ER activation but not AR activation, suggesting that insulin-like growth factor-I might mediate these effects of ER activation. Thus, the in vivo bone-sparing effect of ER activation is clearly distinct from the bone-sparing effect of AR activation also in adult male mice. Although the above mentioned studies demonstrate that estrogens are clearly able to prevent sex steroid-related bone loss in male rodents and thus provide major insight into the mechanism of action of estrogens, the doses administered are supraphysiological for males. Therefore, these preclinical observations are not directly applicable to hypogonadal men because of expected estrogen related side effects such as feminization. However, the selective ER modulator (SERM) lasofoxifene appears to prevent not only orx-induced bone loss but also the age-related changes in bone mass, bone structure and bone turnover in aging male rats [38, 39]. This important preclinical, however still limited, data therefore open interesting perspectives for the treatment of hypogonadal or elderly men. In conclusion, estrogen and androgen signaling have distinct roles in the development and maintenance of the male rodent skeleton. With regard to cortical bone, not only androgen signaling but also estrogen signaling is essential for periosteal bone expansion and optimal cortical bone mass acquisition in male rats and mice. Estrogen signaling on cortical bone may be indirectly related to its interaction with the growth hormone – insulin-like growth factor-I axis. Androgen signaling is the dominant pathway in the development and maintenance of trabecular bone mass in male rodents, while estrogen signaling is of minor importance. The use of rodent models has significantly contributed to the understanding of the regulation of bone growth and maintenance by sex steroids.
References 1. J.M. Kaufman, A. Vermeulen, The decline of androgen levels in elderly men and its clinical and therapeutic implications, Endocr. Rev. 26 (2005) 833–876. 2. E.P. Smith, J. Boyd, G.R. Frank, et al., Estrogen resistance caused by a mutation in the estrogen-receptor gene in a man, N. Engl. J. Med. 331 (1994) 1056–1061.
286
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3. E.P. Smith, B. Specker, B.E. Bachrach, et al., Impact on bone of an estrogen receptor-alpha gene loss of function mutation, J. Clin. Endocrinol. Metab. 93 (2008) 3088–3096. 4. C. Carani, K. Qin, M. Simoni, et al., Effect of testosterone and estradiol in a man with aromatase deficiency, N. Engl. J. Med. 337 (1997) 91–95. 5. V. Rochira, M. Faustini-Fustini, A. Balestrieri, C. Carani, Estrogen replacement therapy in a man with congenital aromatase deficiency: effects of different doses of transdermal estradiol on bone mineral density and hormonal parameters, J. Clin. Endocrinol. Metab. 85 (2000) 1841–1845. 6. J.P. Bilezikian, A. Morishima, J. Bell, M.M. Grumbach, Increased bone mass as a result of estrogen therapy in a man with aromatase deficiency, N. Engl. J. Med. 339 (1998) 599–603. 7. R. Bouillon, M. Bex, D. Vanderschueren, S. Boonen, Estrogens are essential for male pubertal periosteal bone expansion, J. Clin. Endocrinol. Metab. 89 (2004) 6025–6029. 8. B.L. Herrmann, B. Saller, O.E. Janssen, et al., Impact of estrogen replacement therapy in a male with congenital aromatase deficiency caused by a novel mutation in the CYP19 gene, J. Clin. Endocrinol. Metab. 87 (2002) 5476–5484. 9. S. Khosla, L.J. Melton III., E.J. Atkinson, W.M. O’Fallon, G.G. Klee, B.L. Riggs, Relationship of serum sex steroid levels and bone turnover markers with bone mineral density in men and women: a key role for bioavailable estrogen, J. Clin. Endocrinol. Metab. 83 (1998) 2266–2274. 10. E. Seeman, Clinical review 137: sexual dimorphism in skeletal size, density, and strength, J. Clin. Endocrinol. Metab. 86 (2001) 4576–4584. 11. E. Seeman, Pathogenesis of bone fragility in women and men, Lancet 359 (2002) 1841–1850. 12. R.T. Turner, G.K. Wakley, K.S. Hannon, Differential effects of androgens on cortical bone histomorphometry in gonadectomized male and female rats, J. Orthop. Res. 8 (1990) 612–617. 13. D. Vanderschueren, E. van Herck, J. Nijs, A.G. Ederveen, R. De Coster, R. Bouillon, Aromatase inhibition impairs skeletal modeling and decreases bone mineral density in growing male rats, Endocrinology 138 (1997) 2301–2307. 14. C. Miyaura, K. Toda, M. Inada, et al., Sex- and age-related response to aromatase deficiency in bone, Biochem. Biophys. Res. Commun. 280 (2001) 1062–1068. 15. O. Vidal, M.K. Lindberg, K. Hollberg, et al., Estrogen receptor specificity in the regulation of skeletal growth and maturation in male mice, Proc. Natl. Acad. Sci. USA 97 (2000) 5474–5479. 16. N.A. Sims, S. Dupont, A. Krust, et al., Deletion of estrogen receptors reveals a regulatory role for estrogen receptorsbeta in bone remodeling in females but not in males, Bone 30 (2002) 18–25. 17. S. Bord, A. Horner, S. Beavan, J. Compston, Estrogen receptors alpha and beta are differentially expressed in developing human bone, J. Clin. Endocrinol. Metab. 86 (2001) 2309–2314. 18. B.T. Akingbemi, R. Ge, C.S. Rosenfeld, et al., Estrogen receptor-alpha gene deficiency enhances androgen biosynthesis in the mouse Leydig cell, Endocrinology 144 (2003) 84–93. 19. F. Callewaert, K. Venken, J. Ophoff, et al., Differential regulation of bone and body composition in male mice with combined inactivation of androgen and estrogen receptor-, Faseb J. 23 (2009) 232–240.
20. K. Venken, F. Schuit, L. Van Lommel, et al., Growth without growth hormone receptor: estradiol is a major growth hormone-independent regulator of hepatic insulin-like growth factor-I synthesis, J. Bone Miner. Res. 20 (2005) 2138–2149. 21. A. Juul, The effects of oestrogens on linear bone growth, Hum. Reprod. Update 7 (2001) 303–313. 22. S. Moverare, K. Venken, A.L. Eriksson, et al., Differential effects on bone of estrogen receptor alpha and androgen receptor activation in orchidectomized adult male mice, Proc. Natl. Acad. Sci. USA 100 (2003) 13573–13578. 23. F. Lupu, J.D. Terwilliger, K. Lee, G.V. Segre, A. Efstratiadis, Roles of growth hormone and insulin-like growth factor 1 in mouse postnatal growth, Dev. Biol. 229 (2001) 141–162. 24. N.A. Sims, P. Clement-Lacroix, D. Minet, et al., A functional androgen receptor is not sufficient to allow estradiol to protect bone after gonadectomy in estradiol receptor-deficient mice, J. Clin. Invest. 111 (2003) 1319–1327. 25. M.K. Lindberg, S.L. Alatalo, J.M. Halleen, S. Mohan, J.A. Gustafsson, C. Ohlsson, Estrogen receptor specificity in the regulation of the skeleton in female mice, J. Endocrinol. 171 (2001) 229–236. 26. D. Vanderschueren, L. Vandenput, S. Boonen, M.K. Lindberg, R. Bouillon, C. Ohlsson, Androgens and bone, Endocr. Rev. 25 (2004) 389–425. 27. N.S. Reim, B. Breig, K. Stahr, et al., Cortical bone loss in androgen-deficient aged male rats is mainly caused by increased endocortical bone remodeling, J. Bone Miner. Res. 23 (2008) 694–704. 28. G.K. Wakley, H.D. Schutte Jr., K.S. Hannon, R.T. Turner, Androgen treatment prevents loss of cancellous bone in the orchidectomized rat, J. Bone Miner. Res. 6 (1991) 325–330. 29. D. Vanderschueren, E. Van Herck, A.M. Suiker, W.J. Visser, L.P. Schot, R. Bouillon, Bone and mineral metabolism in aged male rats: short and long term effects of androgen deficiency, Endocrinology 130 (1992) 2906–2916. 30. L. Vandenput, S. Boonen, E. Van Herck, J.V. Swinnen, R. Bouillon, D. Vanderschueren, Evidence from the aged orchidectomized male rat model that 17beta-estradiol is a more effective bone-sparing and anabolic agent than 5alphadihydrotestosterone, J. Bone Miner. Res. 17 (2002) 2080–2086. 31. M.K. Lindberg, S. Moverare, S. Skrtic, et al., Two different pathways for the maintenance of trabecular bone in adult male mice, J. Bone Miner. Res. 17 (2002) 555–562. 32. L. Vandenput, A.G. Ederveen, R.G. Erben, et al., Testosterone prevents orchidectomy-induced bone loss in estrogen receptor-alpha knockout mice, Biochem. Biophys. Res. Commun. 285 (2001) 70–76. 33. A. Samuels, M.J. Perry, A.E. Goodship, W.D. Fraser, J.H. Tobias, Is high-dose estrogen-induced osteogenesis in the mouse mediated by an estrogen receptor?, Bone 27 (2000) 41–46. 34. A. Plant, A. Samuels, M.J. Perry, S. Colley, R. Gibson, J.H. Tobias, Estrogen-induced osteogenesis in mice is associated with the appearance of Cbfa1-expressing bone marrow cells, J. Cell Biochem. 84 (2002) 285–294. 35. C.W. Slemenda, C. Longcope, L. Zhou, S.L. Hui, M. Peacock, C.C. Johnston, Sex steroids and bone mass in older men. Positive associations with serum estrogens and negative associations with androgens, J. Clin. Invest. 100 (1997) 1755–1759. 36. S. Khosla, L.J. Melton III., R.A. Robb, et al., Relationship of volumetric BMD and structural parameters at different
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skeletal sites to sex steroid levels in men, J. Bone Miner. Res. 20 (2005) 730–740. 37. I. Van Pottelbergh, S. Goemaere, J.M. Kaufman, Bioavailable estradiol and an aromatase gene polymorphism are determinants of bone mineral density changes in men over 70 years of age, J. Clin. Endocrinol. Metab. 88 (2003) 3075–3081. 3 8. H.Z. Ke, H. Qi, D.T. Crawford, K.L. Chidsey-Frink, H.A. Simmons, D.D. Thompson, Lasofoxifene (CP-336,156), a selective estrogen receptor modulator, prevents bone
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loss induced by aging and orchidectomy in the adult rat, Endocrinology 141 (2000) 1338–1344. 39. H.Z. Ke, H. Qi, K.L. Chidsey-Frink, D.T. Crawford, D.D. Thompson, Lasofoxifene (CP-336,156) protects against the age-related changes in bone mass, bone strength, and total serum cholesterol in intact aged male rats, J. Bone Miner. Res. 16 (2001) 765–773.
Chapter
24
Estrogen and the Skeleton – Humans Liesbeth Vandenput and Claes Ohlsson Center for Bone Research, Department of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
Introduction
unfused epiphyses and a markedly delayed bone age of 15 years. He was tall and had experienced no pubertal growth spurt, suggesting continued linear growth into adulthood. Moreover, despite normal serum T levels and elevated E2 levels, he had severe osteopenia associated with elevated markers of bone remodeling. A follow-up examination of the same propositus revealed decreased cortical and trabecular volumetric bone mineral density (BMD) and a reduced cortical area due to increased endocortical circumference with normal periosteal circumference, as measured by peripheral quantitative computed tomography (pQCT) at the distal radius [10]. Histomorphometric analysis of the iliac crest bone biopsy showed osteopenia with normal trabecular number but reduced thickness and a markedly low activation frequency. Soon thereafter, two men with estrogen deficiency, due to mutations in the aromatase gene, were described [11,12]. These individuals had undetectable E2 levels and almost identical skeletal phenotypes as the estrogen-resistant man, regardless of normal or elevated T levels. But, contrary to the estrogen-resistant male who had no response to estrogen therapy, these aromatase-deficient men responded to estrogen treatment with a significantly increased bone mass, suppression of bone resorption and growth plate closure [12,13]. Since then, several new cases of aromatase deficiency have been reported, all with similar baseline skeletal phenotypes as the landmark case report by Smith et al. Efforts have been made to find the optimal dosage of estrogen replacement therapy for maintaining bone mass and E2 levels in these men. Rochira et al suggested that the adequate substitutive dose of transdermal E2 therapy in adult men with aromatase deficiency may be 25 g twice weekly, corresponding to serum E2 levels of 24 pg/ml (88 pmol/l). A lower dose of 12.5 g twice weekly, providing serum E2 levels of 15 pg/ml (55 pmol/l), was associated with a decrease in BMD [14]. The substitutive
Sex steroids are important for the skeletal growth and maintenance of both the female and the male skeleton [1]. However, the relative contribution of androgens versus estrogens in the regulation of the male skeleton remains unclear. The effects of testosterone (T) can be exerted either directly through the androgen receptor or indirectly via aromatization to estradiol (E2) and activation of estrogen receptor- and/or -. All three of these sex steroid receptors are expressed in bone [2] and experimental animal studies have indicated that each of these three receptors mediates site-specific skeletal effects of sex steroids [3–6].
Estrogen and bone growth in men It is well established that estrogens play an important role in regulating bone metabolism in women. Following natural menopause, cancellous bone mass decreases considerably and this can be prevented by estrogen replacement [7]. In accordance, androgens have a major influence on skeletal metabolism in men, as evidenced by the effects of sex steroid deficiency on the male skeleton [8]. Based on these data, the traditional view was that estrogens and androgens were the main sex steroids influencing bone maturation and maintenance in women and men, respectively. This concept was however challenged in the 1990s by the description of several ‘experiments of nature’. In 1994, Smith et al described a 28-year-old man with a naturally occurring mutation in the estrogen receptor- gene, making him resistant to estrogen [9]. This patient had undergone normal early growth and developed normal male secondary sexual characteristics but had eunuchoid skeletal proportions, Osteoporosis in Men
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dose of 50 g per week was later confirmed in another case report by Hermann et al [15,16]. In a fourth case of aromatase deficiency of an adult man [17], it was shown that high-dose T treatment did not improve bone maturation and only slightly increased bone density at the lumbar spine. Transdermal E2 treatment, on the other hand, closed the epiphyses and increased BMD in this aromatase and mildly hypogonadal male [17], reinforcing the principal role of estrogen in the final phase of skeletal maturation and mineralization in men. Bouillon et al described a propositus with aromatase deficiency, which was detected during puberty [18]. Estrogen treatment resulted in an accelerated growth phase followed by epiphyseal fusion and an increase in bone size at the cortical site as measured by pQCT, suggesting that the observed increased BMD as measured by dual energy x-ray absorptiometry (DXA) is actually an increase in bone size. Most recently, Lanfranco et al used the noncompliance of their aromatase-deficient patient to try to find the physiological E2 levels needed to complete bone maturation and mineralization [19]. Epiphyseal closure and the normalization of BMD and bone turnover markers only occurred with serum E2 levels above 20 pg/ml (73 pmol/l). This study thus confirms the threshold E2 level proposed by Rochira et al [14] needed for adequate skeletal maturation.
Estrogen and bone maintenance in men While all these studies clearly demonstrated the importance of estrogen in male skeletal growth and development, the role of estrogen in regulating bone remodeling and maintenance in adult men remained unresolved. To this end, several human cross-sectional observational studies related BMD in adult and elderly men to sex steroid levels. In general, these observational studies reported that serum E2,
and especially bioavailable E2, correlated better with BMD at various sites than total or bioavailable T [20–28], even across different racial and ethnic groups [29]. Moreover, prospective studies have shown that serum E2 was the best predictor of both the increase in bone mass in young men [30] and the decrease of bone density in elderly men [30–32]. In fact, Khosla et al suggested that, in elderly men, a threshold exists for bioavailable E2 of 11 pg/ml (40 pmol/l), corresponding to a total E2 level of 31 pg/ml (114 pmol/ l), below which the rate of bone loss at the radius and the ulna was clearly associated with bioavailable E2 levels (Figure 24.1) [30]. Above this level, no apparent association between the rate of bone loss and bioavailable E2 levels was found. Similar thresholds for serum E2 were reported in elderly men by Gennari et al [32] for bone loss at the femoral neck and lumbar spine and by Szulc et al [27] for changes in biochemical markers of bone turnover. Direct evidence for the relative contributions of T versus E2 on bone metabolism in men was provided by an interventional study by Falahati-Nini et al, using E2- or T-treatment in aging men with eliminated endogenous E2 and T [33]. This study attributed most of the effects of sex steroids on bone resorption to E2, whereas both T and E2 were important in maintaining bone formation in aging men. In a rather similar study of young men, Leder et al suggested that both androgens and estrogens contribute to regulating bone resorption whereas androgens regulate bone formation [34]. All together, these clinical studies indicate that estrogen plays a major role in regulating the male skeleton. An important role of T is, however, not excluded, since it is responsible for the sexual dimorphism of the skeleton and it may contribute to the inhibition of bone resorption and maintenance of bone formation [2,35]. Furthermore, it provides the necessary substrate for aromatization. This pivotal role of estrogen with respect to male skeletal metabolism has since been confirmed in several other
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Figure 24.1 Rate of change in mid-radius BMD (A) and mid-ulna BMD (B) as a function of bioavailable E2 levels in elderly men from Rochester, Minnesota. Model r2 values were 0.20 and 0.25 for the radius and ulna, respectively (both P 0.001 for comparison with a oneslope model). •, Subjects with bioavailable E2 levels below 40 pmol/l (11 pg/ml); °, those with values above 40 pmol/l. (Reproduced from Khosla et al J Clin Endocrinol Metab 2001;86:3555-61 [30] with permission of the Endocrine Society).
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studies. Treatment of elderly men with an aromatase inhibitor resulted in significant increases in bone resorption, together with decreases in bone formation markers [36]. In addition, the selective estrogen receptor modulator (SERM) raloxifene increased hip BMD and tended to increase lumbar spine BMD in men treated with a gonadotropin-releasing hormone agonist for prostate cancer [37]. On the other hand, this SERM did not have any significant beneficial bone-sparing effect in elderly men after 6 months of treatment; a conclusion based only on bone turnover markers and not density measurements [38]. Gennari et al demonstrated that elderly men with a high number of repeats in the aromatase (CYP19) gene, encoding the enzyme necessary for the conversion of T into E2, had higher E2 levels, decreased rates of bone loss and tended to have fewer fractures compared to men with a low number of repeats [39]. A study by Van Pottelbergh et al [31] in elderly community-dwelling men confirmed these findings, suggesting that differences in E2 levels due to a polymorphism in the aromatase gene may predispose men to increased age-related bone loss and fracture risk.
both serum E2 levels and T levels were inversely associated with fracture risk when analyzed separately. However, in multivariate analyses, serum free E2, but not free T, was an independent predictor of all fractures in these elderly men. Moreover, when analyzing the effect of having low E2 and/or low T levels, subjects with low serum E2 levels had an increased risk of fractures, independent of T status. In contrast, subjects with low T levels but normal E2 levels were not at higher risk for fracture. In addition, the inverse relationship between serum E2 levels and fracture risk was nonlinear, with a strong relationship at E2 levels below 16 pg/ml (59 pmol/l), corresponding to 0.3 pg/ml (1 pmol/l) for free E2 (Figure 24.2). This observation further confirms the concept of a threshold E2 level for skeletal health in men [46]. The threshold E2 level for fracture risk described in the MrOS Sweden Study [45] is slightly lower than those previously described for bone maturation, BMD and markers of bone resorption [14,27,30,32]. This difference could be due to the fact that, in the latter studies, serum E2 was analyzed using immunoassay-based techniques, while it was analyzed by mass spectrometry in the Swedish cohort. However, a similar threshold for serum E2 of 18 pg/ml (66 pmol/l), below which
Incidence/1000 person-years
Even though the above-mentioned studies provide strong evidence for an important role of estrogens for bone metabolism in men, little is known about the relative role of androgens and estrogens on fracture risk in men. In cross-sectional studies, inverse associations between both serum E2 [28,40] and T [28] and prevalent fractures have been shown. Still, the roles of serum E2 and T as predictors of fracture risk in men analyzed in prospective studies remain unresolved. A subset analysis from the Rotterdam Study failed to show any association between either serum T or serum E2 and vertebral fracture risk [41]. Similarly, neither serum E2 nor serum T predicted risk of fracture in the Tromsö Study, including 105 men with non-vertebral fractures [42]. Data from the Framingham study, including 39 men with hip fractures during an 18-year follow-up, indicated that serum E2, but not T, was a significant predictor of fracture risk [43]. In contrast, the Dubbo Osteoporosis study, including 113 men with fractures, reported that serum T but not E2 predicted risk of fractures [44]. These conflicting results might be due to the fact that these previous prospective studies have been underpowered, including few incident fractures and most of them [41–43] have analyzed the baseline sex steroid levels using immunoassay-based techniques, which have been shown to have a questionable specificity, especially at lower concentrations. Most recently, Mellström et al analyzed the predictive role of serum E2 and T levels for incident fracture risk in the MrOS Sweden Study, the largest populationbased cohort so far (n 3014, 3.3 years follow up), with sex steroid levels measured at baseline with the mass spectrometry technique [45]. These investigators found that
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Figure 24.2 Yearly incidence of fractures in relation to total E2 and free E2 (fE2) in elderly men from the Swedish MrOS Study. Poisson regression models were used to determine the relationship between serum hormone levels and fracture risk (all validated fractures were included). (Reproduced from Mellström et al J Bone Miner Res 2008;23:1552-60 [45], with permission of the American Society for Bone and Mineral Research).
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ip fracture risk increased, was described previously in the Framingham Study [43]. Alternatively, the mechanisms involved in the impact of E2 on BMD and bone resorption may differ from those conferring the impact of E2 on fracture risk. A BMD-independent impact of E2 on fracture risk is supported by the findings of Mellström et al, since the association between free E2 levels and fractures was only slightly attenuated by adjustment for BMD [45]. In a similar manner, the association between E2 and fracture risk was independent of BMD in older postmenopausal women included in the Study of Osteoporosis Fractures (SOF) cohort [47]. In conclusion, these human studies have gathered substantial evidence for the existence of a threshold E2 level below 20–25 pg/ml (73–92 pmol/l) in men for bone maturation, bone loss as well as fracture risk. Even though these findings do not exclude an important role for T in male skeletal homeostasis, they do provide proof of an important role for estrogen in bone metabolism in men.
References 1. B.L. Riggs, S. Khosla, L.J. Melton, Sex steroids and the construction and conservation of the adult skeleton, Endocr. Rev. 23 (2002) 279–302. 2. D. Vanderschueren, L. Vandenput, S. Boonen, M.K. Lindberg, R. Bouillon, C. Ohlsson, Androgens and bone, Endocr. Rev. 25 (2004) 389–425. 3. S.H. Windahl, O. Vidal, G. Andersson, J.A. Gustafsson, C. Ohlsson, Increased cortical bone mineral content but unchanged trabecular bone mineral density in female ERbeta(/) mice, J. Clin. Invest. 104 (1999) 895–901. 4. O. Vidal, M.K. Lindberg, K. Hollberg, et al., Estrogen receptor specificity in the regulation of skeletal growth and maturation in male mice, Proc. Natl. Acad. Sci. USA 97 (2000) 5474–5479. 5. S. Moverare, K. Venken, A.L. Eriksson, et al., Differential effects on bone of estrogen receptor and androgen receptor activation in orchidectomized adult male mice, Proc. Natl. Acad. Sci. USA 100 (2003) 13573–13578. 6. N.A. Sims, P. Clement-Lacroix, D. Minet, et al., A functional androgen receptor is not sufficient to allow estradiol to protect bone after gonadectomy in estradiol receptor-deficient mice, J. Clin. Invest. 111 (2003) 1319–1327. 7. B.L. Riggs, S. Khosla, L.J. Melton III., A unitary model for involutional osteoporosis: estrogen deficiency causes both type I and type II osteoporosis in postmenopausal women and contributes to bone loss in aging men, J. Bone Miner. Res. 13 (1998) 763–773. 8. J.J. Stepan, M. Lachman, J. Zverina, V. Pacovsky, D.J. Baylink, Castrated men exhibit bone loss: effect of calcitonin treatment on biochemical indices of bone remodeling, J. Clin. Endocrinol. Metab. 69 (1989) 523–527. 9. E.P. Smith, J. Boyd, G.R. Frank, et al., Estrogen resistance caused by a mutation in the estrogen-receptor gene in a man, N. Engl. J. Med. 331 (1994) 1056–1061. 10. E.P. Smith, B. Specker, B.E. Bachrach, et al., Impact on bone of an estrogen receptor- gene loss of function mutation, J. Clin. Endocrinol. Metab. 93 (2008) 3088–3096.
11. A. Morishima, M.M. Grumbach, E.R. Simpson, C. Fisher, K. Qin, Aromatase deficiency in male and female siblings caused by a novel mutation and the physiological role of estrogens, J. Clin. Endocrinol. Metab. 80 (1995) 3689–3698. 12. C. Carani, K. Qin, M. Simoni, et al., Effect of testosterone and estradiol in a man with aromatase deficiency, N. Engl. J. Med. 337 (1997) 91–95. 13. J.P. Bilezikian, A. Morishima, J. Bell, M.M. Grumbach, Increased bone mass as a result of estrogen therapy in a man with aromatase deficiency, N. Engl. J. Med. 339 (1998) 599–603. 14. V. Rochira, M. Faustini-Fustini, A. Balestrieri, C. Carani, Estrogen replacement therapy in a man with congenital aromatase deficiency: effects of different doses of transdermal estradiol on bone mineral density and hormonal parameters, J. Clin. Endocrinol. Metab. 85 (2000) 1841–1845. 15. B.L. Herrmann, B. Saller, O.E. Janssen, et al., Impact of estrogen replacement therapy in a male with congenital aromatase deficiency caused by a novel mutation in the CYP19 gene, J. Clin. Endocrinol. Metab. 87 (2002) 5476–5484. 16. B.L. Herrmann, O.E. Janssen, S. Hahn, M. Broecker-Preuss, K. Mann, Effects of estrogen replacement therapy on bone and glucose metabolism in a male with congenital aromatase deficiency, Horm. Metab. Res. 37 (2005) 178–183. 17. L. Maffei, Y. Murata, V. Rochira, et al., Dysmetabolic syndrome in a man with a novel mutation of the aromatase gene: effects of testosterone, alendronate, and estradiol treatment, J. Clin. Endocrinol. Metab. 89 (2004) 61–70. 18. R. Bouillon, M. Bex, D. Vanderschueren, S. Boonen, Estrogens are essential for male pubertal periosteal bone expansion, J. Clin. Endocrinol. Metab. 89 (2004) 6025–6029. 19. F. Lanfranco, L. Zirilli, M. Baldi, et al., A novel mutation in the human aromatase gene: insights on the relationship among serum estradiol, longitudinal growth and bone mineral density in an adult man under estrogen replacement treatment, Bone 43 (2008) 628–635. 20. G.A. Greendale, S. Edelstein, E. Barrett-Connor, Endogenous sex steroids and bone mineral density in older women and men: the Rancho Bernardo study, J. Bone Miner. Res. 12 (1997) 1833–1843. 21. C.W. Slemenda, C. Longcope, L. Zhou, S.L. Hui, M. Peacock, C.C. Johnston, Sex steroids and bone mass in older men. Positive associations with serum estrogens and negative associations with androgens, J. Clin. Invest. 100 (1997) 1755–1759. 22. S. Khosla, L.J. Melton III., E.J. Atkinson, W.M. O’Fallon, G.G. Klee, B.L. Riggs, Relationship of serum sex steroid levels and bone turnover markers with bone mineral density in men and women: a key role for bioavailable estrogen, J. Clin. Endocrinol. Metab. 83 (1998) 2266–2274. 23. B. Ongphiphadhanakul, R. Rajatanavin, S. Chanprasertyothin, N. Piaseu, L. Chailurkit, Serum oestradiol and oestrogenreceptor gene polymorphism are associated with bone mineral density independently of serum testosterone in normal males, Clin. Endocrinol. 49 (1998) 803–809. 24. J.R. Center, T.V. Nguyen, P.N. Sambrook, J.A. Eisman, Hormonal and biochemical parameters in the determination of osteoporosis in elderly men, J. Clin. Endocrinol. Metab. 84 (1999) 3626–3635. 25. S. Amin, Y. Zhang, C.T. Sawin, et al., Association of hypogonadism and estradiol levels with bone mineral density in elderly
C h a p t e r 2 4 Estrogen and the Skeleton – Humans l
26.
27.
28.
29.
30.
31.
32.
33.
34.
35.
36.
men from the Framingham study, Ann. Intern. Med. 133 (2000) 951–963. A.W. van den Beld, F.H. de Jong, D.E. Grobbee, H.A. Pols, S.W. Lamberts, Measures of bioavailable serum testosterone and estradiol and their relationships with muscle strength, bone density, and body composition in elderly men, J. Clin. Endocrinol. Metab. 85 (2000) 3276–3282. P. Szulc, F. Munoz, B. Claustrat, et al., Bioavailable estradiol may be an important determinant of osteoporosis in men: the MINOS study, J. Clin. Endocrinol. Metab. 86 (2001) 192–199. D. Mellstrom, O. Johnell, O. Ljunggren, et al., Free testosterone is an independent predictor of BMD and prevalent fractures in elderly men: MrOS Sweden, J. Bone Miner. Res. 21 (2006) 529–535. A.B. Araujo, T.G. Travison, B.Z. Leder, J.B. McKinlay, Correlations between serum testosterone, estradiol, and sex hormone-binding globulin and bone mineral density in a diverse sample of men, J. Clin. Endocrinol. Metab. 93 (2008) 2135–2141. S. Khosla, L.J. Melton III., E.J. Atkinson, W.M. O’Fallon, Relationship of serum sex steroid levels to longitudinal changes in bone density in young versus elderly men, J. Clin. Endocrinol. Metab. 86 (2001) 3555–3561. I. Van Pottelbergh, S. Goemaere, J.M. Kaufman, Bioavailable estradiol and an aromatase gene polymorphism are determinants of bone mineral density changes in men over 70 years of age, J. Clin. Endocrinol. Metab. 88 (2003) 3075–3081. L. Gennari, D. Merlotti, G. Martini, et al., Longitudinal association between sex hormone levels, bone loss, and bone turnover in elderly men, J. Clin. Endocrinol. Metab. 88 (2003) 5327–5333. A. Falahati-Nini, B.L. Riggs, E.J. Atkinson, W.M. O’Fallon, R. Eastell, S. Khosla, Relative contributions of testosterone and estrogen in regulating bone resorption and formation in normal elderly men, J. Clin. Invest. 106 (2000) 1553–1560. B.Z. Leder, K.M. LeBlanc, D.A. Schoenfeld, R. Eastell, J.S. Finkelstein, Differential effects of androgens and estrogens on bone turnover in normal men, J. Clin. Endocrinol. Metab. 88 (2003) 204–210. K. Venken, F. Callewaert, S. Boonen, D. Vanderschueren, Sex hormones, their receptors and bone health, Osteoporos. Int. 19 (2008) 1517–1525. P. Taxel, D.G. Kennedy, P.M. Fall, A.K. Willard, J.M. Clive, L.G. Raisz, The effect of aromatase inhibition on sex steroids,
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gonadotropins, and markers of bone turnover in older men, J. Clin. Endocrinol. Metab. 86 (2001) 2869–2874. M.R. Smith, M.A. Fallon, H. Lee, J.S. Finkelstein, Raloxifene to prevent gonadotropin-releasing hormone agonist-induced bone loss in men with prostate cancer: a randomized controlled trial, J. Clin. Endocrinol. Metab. 89 (2004) 3841–3846. P.M. Doran, B.L. Riggs, E.J. Atkinson, S. Khosla, Effects of raloxifene, a selective estrogen receptor modulator, on bone turnover markers and serum sex steroid and lipid levels in elderly men, J. Bone. Miner. Res. 16 (2001) 2118–2125. L. Gennari, L. Masi, D. Merlotti, et al., A polymorphic CYP19 TTTA repeat influences aromatase activity and estrogen levels in elderly men: effects on bone metabolism, J. Clin. Endocrinol. Metab. 89 (2004) 2803–2810. E. Barrett-Connor, J.E. Mueller, D.G. von Muhlen, G.A. Laughlin, D.L. Schneider, D.J. Sartoris, Low levels of estradiol are associated with vertebral fractures in older men, but not women: the Rancho Bernardo Study, J. Clin. Endocrinol. Metab. 85 (2000) 219–223. H.W. Goderie-Plomp, M. van der Klift, W. de Ronde, A. Hofman, F.H. de Jong, H.A. Pols, Endogenous sex hormones, sex hormone-binding globulin, and the risk of incident vertebral fractures in elderly men and women: the Rotterdam Study, J. Clin. Endocrinol. Metab. 89 (2004) 3261–3269. A. Bjornerem, L.A. Ahmed, R.M. Joakimsen, et al., A prospective study of sex steroids, sex hormone-binding globulin, and non-vertebral fractures in women and men: the Tromsö Study, Eur. J. Endocrinol. 157 (2007) 119–125. S. Amin, Y. Zhang, D.T. Felson, et al., Estradiol, testosterone, and the risk for hip fractures in elderly men from the Framingham Study, Am. J. Med. 119 (2006) 426–433. C. Meier, T.V. Nguyen, D.J. Handelsman, et al., Endogenous sex hormones and incident fracture risk in older men: the Dubbo Osteoporosis Epidemiology Study, Arch. Intern. Med. 168 (2008) 47–54. D. Mellström, L. Vandenput, H. Mallmin, et al., Older men with low serum estradiol and high serum SHBG have an increased risk of fractures, J. Bone Miner. Res. 23 (2008) 1552–1560. S. Khosla, L.J. Melton III., B.L. Riggs, Estrogen and the male skeleton, J. Clin. Endocrinol. Metab. 87 (2002) 1443–1450. S.R. Cummings, W.S. Browner, D. Bauer, et al., Endogenous hormones and the risk of hip and vertebral fractures among older women. Study of Osteoporotic Fractures Research Group, N. Engl. J. Med. 339 (1998) 733–738.
Chapter
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Androgens and Bone: Basic Aspects Kristine M. Wiren,1,2 and Eric S. Orwoll1 1
Bone and Mineral Unit, Oregon Health & Science University Portland VA Medical Center, Portland, Oregon, USA
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Introduction
Androgens and the role of androgen metabolism in bone
Most research in gonadal steroid action on bone has focused on the effects of estrogen because of the obvious importance of the menopause in the development of osteoporosis. However, it is clear that androgens also have important effects on both skeletal development and the maintenance of bone mass and the mechanisms by which androgens affect skeletal homeostasis are becoming increasingly clear. Thus, it has been demonstrated that androgens:
All steroid hormones, including sex steroids, are derived from cholesterol. Sex steroids are synthesized as a consequence of enzymatic conversion, predominantly in gonadal tissue, the adrenal gland and placenta. After such peripheral metabolism, androgenic activity is represented in a variety of steroid molecules that include testosterone (Figure 25.1). There is evidence in a range of tissues that the eventual cellular effects of testosterone may not be the result (or not only the result) of direct action of testosterone, but may also reflect the effects of sex steroid metabolites formed as a consequence of local enzyme activities.
1 influence growth plate maturation helping to determine longitudinal bone growth during development 2 mediate regulation of trabecular (cancellous) and cortical bone mass in a fashion distinct from estrogen, leading to the development of a sexually dimorphic skeleton 3 modulate peak bone mass acquisition 4 inhibit bone loss (for review see [1–3]).
DHT The most important testosterone metabolites active in bone are 5-DHT (the result of 5 reduction of testosterone) and estradiol (formed by the aromatization of testosterone). Testosterone and DHT are the major and most potent androgens, with androstenedione (the major circulating androgen in women) and dehydroepiandrosterone (DHEA) as immediate androgen precursors that exhibit weak androgen activity [11]. In men, the most abundant circulating androgen metabolite is testosterone, while concentrations of other weaker androgens like androstenedione and DHEA-sulfate are similar between males and females. Downstream metabolites of androstenedione and DHT include 5-androstanedione and 5-androstane-3 or 3,17-diol (3- or -diol) respectively. Although these steroids are considered inactive at the AR, the DHT metabolites 3-diol can function as an allosteric modulator to influence gamma-aminobutyric acid A (GABAA) receptor function, while 3-diol demonstrates estrogenic activity at estrogen receptor (ER)- receptors [12]. 3/-Hydroxysteroid dehydrogenase activity has been shown in osteoblasts [13]. In sum, data suggest that aromatase cytochrome P450 (the
A specific role for androgen in skeletal health is clear, at least in animal models. For example, in castrate animals, replacement with non-aromatizable androgens (e.g. 5-dihydrotestosterone, DHT) yields beneficial effects that are clearly distinct from those observed with estrogen replacement [4,5]. In intact females, blockade of the androgen receptor (AR) with the specific AR antagonist hydroxyflutamide results in osteopenia [6]. Consistent with this finding, treatment of females with non-aromatizable androgen alone results in improvements in bone mineral density [7]. Finally, combination therapy with estrogen and androgen in postmenopausal women is more beneficial than either steroid alone [8–10]. Combined, these reports suggest the possibility of both distinct and overlapping actions of androgens and estrogens on the skeleton in both sexes. A growing awareness of the importance of the effects of androgen on bone and the potential to make use of this information for the treatment of bone disorders, has fuelled an increase in research. Osteoporosis in Men
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product of the CYP19 gene), 17-hydroxysteroid dehydrogenase (17-HSD), 3/-HSD and 5-reductase activities are all present in bone tissue, at least to some measurable extent in some compartments, but the biological relevance of each remains somewhat controversial. 5-Reductase is an important activity with regard to androgen metabolism, since testosterone is converted to the more potent androgen metabolite DHT via 5-reductase action. 5-Reductase activity was first described in crushed rat mandibular bone [14] with similar findings reported in crushed human spongiosa [15]. Two different 5-reductase genes encode type 1 and type 2 isozymes in many mammalian species; osteoblastic cells predominantly express the type 1 isozyme [13,16]. Essentially the same metabolic activities were reported in experiments with human epiphyseal cartilage and chondrocytes [17]. In general, the Km values for bone 5-reductase activity are similar to those in other androgen responsive tissues [15,18]. However, given that the cellular populations in most studies were mixed, the specific cell type responsible for the activity is unknown. Interestingly, Turner et al found that periosteal cells do not have detectable 5-reductase activity [19], raising the possibilities that the enzyme may be functional in only selected skeletal compartments and that testosterone may be the active androgen metabolite at this clinically important site in bone as it is in muscle. From a clinical perspective, the general importance of this enzymatic activity is uncertain, as patients with 5-reductase type 2 deficiency have normal bone mineral
density [20] and Bruch et al found no significant correlation between enzyme activities and bone volume [21]. In mutant null mice lacking 5-reductase type 1 (mice express very little type 2 isozyme), the effect on the skeleton has not been analyzed due to mid-gestational fetal death as a consequence of estrogen excess [22]. In addition, analysis of the importance of 5-reductase activity has been approached with the use of finasteride, an inhibitor of 5-reductase activity (type 1 in humans; both types in rodents). Treatment of male animals does not recapitulate the effects of castration [23], strongly suggesting that reduction of testosterone to DHT is not a major determinant in the effects of gonadal hormones on bone. Consistent with this finding, testosterone therapy in hypogonadal older men, either when administered alone or when combined with finasteride, increases bone mineral density, again suggesting that DHT is not essential for the beneficial effects of testosterone on bone [24]. Combined, the available data do not support the general importance of this metabolic pathway. Thus, the impact of this enzyme, which isozyme may be involved, whether it is uniformly present in all cell types involved in bone modeling/remodeling, or whether local activity is important at all, remain unresolved issues.
Aromatase A second primary enzymatic arm of testosterone metabolism involves the biosynthesis of estrogens from androgen
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precursors, catalyzed by aromatase. Of note, this enzyme is well known to be both expressed and regulated in a very pronounced tissue-specific manner from a variety of promoters [25]. Aromatase also demonstrates pronounced species differences, given the low peripheral levels found in rodents [26], including in cortical bone in mice [27]. Modest levels of aromatase activity have been reported in human bone from mixed cell populations derived from both sexes [28–30] and from osteoblastic cell lines [31,32]. Aromatase expression in intact bone has also been documented by in situ hybridization and immunohistochemical analysis [30]. Aromatase mRNA is expressed predominantly in lining cells, chondrocytes and some adipocytes, however, there is no detectable expression in osteoclasts. The enzyme kinetics in bone cells appears similar to those in other tissues, although the Vmax may be increased by glucocorticoids [32]. Whether the level of aromatase activity in bone is high enough to produce physiologically relevant concentrations of steroids remains an open question; nevertheless, in the male, only 15% of circulating estrogen is produced in the testes, with the remaining 85% produced by peripheral metabolism that, in addition to fat, could include bone as one site of conversion [33]. Aromatase catalyzes the metabolism of adrenal and testicular C19 androgens, such as androstenedione and testosterone, to the C18 estrogens estrone and estradiol. Aromatase thus produces the potent estrogen estradiol (E2) from testosterone and the weaker estrogen estrone (E1) from its adrenal precursors androstenedione and DHEA [28]. Typically in the circulation, E2 will make up to 40% of total estrogen, E1 will make up an additional 40%, with estriol (E3) comprising the remaining 20% of total estrogen [34]. In addition to aromatase itself, osteoblasts contain enzymes that are able to interconvert estradiol and estrone (17-HSD) and to hydrolyze estrone sulfate, the most abundant estrogen in the circulation, to estrone through steroid sulfatase. Synergistic enhancement of aromatase activity and aromatase mRNA expression is seen after treatment with dexamethasone and 1,25(OH)2D3 [28], dexamethasone and forskolin [35] and dexamethasone and prostaglandin E(2) [36], in human osteoblast-like cells. In addition, both leptin and 1,25(OH)2D3 treatment increased aromatase activity in human mesenchymal stem cells during osteogenesis, but not during adipogenesis [37]. Additional studies are needed better to define expression, given the potential importance of the enzyme, and its regulation by a variety of mechanisms (including androgens and estrogens) in other tissues. The clinical impact of aromatase activity and an indication of the importance of conversion of circulating androgen into estrogen is shown in reports of women and men with aromatase deficiencies, who present with a skeletal phenotype [38]. Interestingly, natural mutation is remarkably rare with only seven males and ten females reported to date [39]. The presentation of men with aromatase deficiency
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is very similar to that observed with a man with estrogen receptor- (ER) deficiency, namely an obvious delay in bone age, lack of epiphyseal closure and tall stature, with high bone turnover and osteopenia [33]. These findings suggest that aromatase (and likely estrogen action) has a substantial role to play during skeletal development in the male as well as the female. In addition, estrogen therapy of males with aromatase deficiency has been associated with an increase in bone mass and size [33,40], particularly in the growing skeleton. Pharmacological inhibition of aromatization using non-steroidal inhibitors, such as vorozole or letrozole, results in modest decreases in bone mineral density and changes in skeletal modeling in young growing orchidectomized males [41] and less dramatically so in boys with constitutional delay of puberty after treatment for one year [42], suggesting short-term treatment during growth has limited negative consequences in males. Inhibition of aromatization in older orchidectomized males resembles castration with similar increases in bone resorption and bone loss, suggesting that aromatase activity likely plays an important role in skeletal maintenance in males [43]. These studies speak to the importance of aromatase activity, and estrogen itself, in the mediation of some androgen action in bone in both males and females, although the importance in rodents may be reduced because of the low levels of aromatase expression in the periphery. The presence of these enzymes in the periphery, including to some extent in bone, clearly raises the difficult issue of the origin of androgenic effects in the skeleton; do they arise solely from direct androgen effects (as is suggested by the actions of non-aromatizable androgens such as DHT) and/or from the local or other site production of estrogenic intermediates? The results described above would indicate that both steroids appear to be important to both male and female skeletal health.
Androgen Precursors and Metabolites The 17-HSDs (most of which are dehyrogenase-reductases, except type 5 that is an aldo-keto reductase) have been shown either to catalyze the last step of sex steroid synthesis or the first step of their degradation (to produce weak or potent sex steroids via oxidation or reduction, respectively) and can thus also play a critical role in peripheral steroid metabolism. The oxidative pathway forms 17-ketosteroids while the reductive pathway forms 17-hydroxysteroids. The enzyme reversibly catalyzes the formation of androstenediol (an estrogen) from DHEA, in addition to the biosynthesis of estradiol from estrone, the synthesis of testosterone from androstenedione and the production of DHT from 5-androstanedione all via the reductive activity of 17-HSD. Of the 13 enzyme isotypes of 17-HSD activity, types 1–4 have been demonstrated in human osteoblastic cells [44]. Interestingly, ubiquitous overexpression of human 17-HSD (HSD17B1) in female mice results in
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masculinization, but specific characterization of the consequences in bone has not yet been reported [45]. Ubiquitous overexpression of human 17-HSD type 2 delays skeletal development in male prepubertal mice, but has no effect on adults [46]. There are few data describing possible sex differences for the expression or activity for any of these metabolic enzymes in bone.
Synthetic Androgens In addition to the endogenous steroid metabolites highlighted in Figure 25.1, there are also a variety of drugs with androgenic activity. These include the anabolic steroids, such as non-aromatizable nandrolone, that bind and activate AR (albeit with lower affinity than testosterone [47]). In addition, a class of drugs referred to as selective AR modulators (SARMs) are under extensive development and demonstrate tissue-specific agonist or antagonist activities with respect to AR transactivation. These orally active nonsteroidal non-aromatizable SARMS are being developed to target positive androgen action in tissues such as bone, muscle, fat and to influence libido but, at the same time, not to exacerbate prostate growth, hirsutism and acne. Several have recently been identified with beneficial effects on bone mass in males and females, exclusively in a hypogonadal setting [48–53]. SARMS may thus provide a new alternative to androgen replacement therapy and potentially for age-related fragility.
maintenance. It thus seems likely that further elucidation of the regulation steroid metabolism and the potential mechanisms by which androgenic and estrogenic effects are coordinated, will have physiological, pathophysiological and therapeutic implications.
Mechanisms of androgen action in bone: the androgen receptor The specific mechanisms by which androgens affect skeletal homeostasis, and whether these effects are directly mediated in bone, are areas of intensified research. As a classic steroid hormone, the biological cellular signaling responses to androgen are mediated through the AR, a ligand-inducible transcription factor. ARs have been identified in a variety of cells found in bone [55] and the characterization of AR expression in these cells thus clearly identifies bone as a target tissue for androgen action. The direct effects of androgen that influence the complex processes of proliferation, differentiation, mineralization and gene expression in the osteoblast are being characterized, but much remains to be established. Androgen effects on bone may also be indirectly modulated and/or mediated by other autocrine and paracrine factors in the bone microenvironment. The rest of this chapter will review recent progress on the characterization of androgen action in bone.
Androgen versus Estrogen action Thus, androgen effects in bone may occur through multiple complex mechanisms that involve testosterone, DHT, weaker androgens and androgen metabolites and the estrogens that are derived from the conversion of androgen precursors. Both androgen and estrogen receptor-mediated processes may mediate these effects in distinct skeletal compartments. Although estrogens exert a major influence on bone, there is compelling evidence that many of the biological actions of androgens in the skeleton are mediated via AR activation in males. Both in vivo and in vitro systems reveal the effects of the non-aromatizable androgen DHT to be essentially the same as those of testosterone (see below). In addition, blockade of the AR with the receptor antagonist flutamide results in osteopenia as a result of reduced bone formation [6]. In addition, complete androgen insensitivity results in a significant decrease in bone mineral density in spine and hip sites [20] even in the setting of strong compliance with estrogen treatment [54]. These reports clearly indicate that androgens, independent of estrogenic metabolites, have primary effects on osteoblast function. However, the clinical reports of subjects with aromatase deficiency also highlight the relevance of metabolism of androgen to bio-potent estrogens at least in the circulation, to influence bone development and/or
Molecular mechanisms of androgen action in bone cells: The AR Direct characterization of AR expression in a variety of tissues, including bone, was made possible by the cloning of the AR cDNA. The AR is a member of the class I (so-called classical or steroid) nuclear receptor superfamily, as are the ER and ER isoforms, the progesterone receptor, the mineralocorticoid and glucocorticoid receptor. Steroid receptors are transcription factors with a highlyconserved modular design characterized by three functional domains: the transactivation, DNA binding and ligand binding domains. In the absence of ligand, the AR protein is generally localized in the cytoplasmic compartment of target cells in a large complex of molecular chaperones, consisting of loosely bound heat-shock, cyclophilin and other accessory proteins. As lipids, androgens can freely diffuse through the plasma membrane to bind the AR and induce a conformational change. Once bound by ligand, the AR dissociates from the multiprotein complex, translocates to the nucleus and recruits co-activators or co-repressors, some of which are cell type specific [56], allowing the formation
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of homodimers (or potentially heterodimers) that activate a cascade of events in the nucleus. Once bound to DNA, the AR influences transcription and/or translation of a specific network of genes, leading to cell-specific responses to the steroid. A steroid hormone target tissue can be defined as one that possesses the steroid receptor, at a functional level, with a measurable response in the presence of hormone. In addition to other organ systems including muscle, brain, liver, kidney, fat and prostate, bone tissue clearly meets this standard with respect to androgen. Colvard et al first reported the presence of AR mRNA and specific androgen binding sites in normal human osteoblastic cells [57]. The abundance of both AR and ER proteins was similar, suggesting that androgens and estrogens each play important roles in skeletal physiology. Subsequent reports have confirmed AR mRNA expression and/or the presence of androgen binding sites in both normal and clonal, transformed osteoblastic cells derived from a variety of species. The size of the AR mRNA transcript in osteoblasts (about 10 kb) is similar to that described in prostate and other tissues, as is the size of the AR protein analyzed by Western blotting (110 kDa) [18]. There are reports of two isoforms of AR protein in human osteoblast-like cells (110 and 97 kDa) [58] as first described in human prostatic tissue. It appears these isoforms do not possess similar functional activities in bone, particularly with respect to effects on proliferation [59]. The number of specific androgen binding sites in osteoblasts varies, depending on methodology and the cell source, from 1000 to 14 000 sites/cell, but is in a range seen in other androgen target tissues. Furthermore, the binding affinity of the AR found in osteoblastic cells (Kd 0.5–2 109) is typical of that found in other tissues. Androgen binding is specific, without significant competition by estrogen, progesterone or dexamethasone [18, 57, 60]. Finally, testosterone and DHT appear to have relatively similar binding affinities [18, 61]. All these data are consistent with the notion that the direct biologic effects of androgenic steroids in osteoblasts are mediated at least in part via classic mechanisms associated with the AR as a member of the steroid hormone receptor superfamily described above. In addition to the classical AR present in bone cells, several other androgen-dependent signaling pathways have been reported. Specific binding sites for weaker adrenal androgens (such as DHEA) have been described [62]; DHEA does transactivate AR [11], thus raising the possibility that DHEA or similar androgenic compounds may also have direct effects in bone. DHEA and its metabolites may also bind and activate additional receptors, including ER, peroxisome proliferator activated receptor- and pregnane X receptor. Bodine et al [63] showed that DHEA caused a rapid inhibition of c-fos expression in human osteoblastic cells that was more robust than seen with the classical androgens (DHT, testosterone, androstenedione).
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In addition, DHEA may inhibit bone resorption by osteoclasts when in the presence of osteoblasts, likely through changes in osteoprotgerin (OPG) and receptor activator of NFB ligand (RANKL) concentrations [64]. Alternatively, androgens may be specifically bound in osteoblastic cells by a novel 63-kDa cytosolic protein [65]. In addition, there are reports of distinct AR polymorphisms identified in different races that may have biological impact on androgen responses [66]. These different isoforms have the potential to interact in distinct fashions with other signaling molecules, such as c-Jun [67], but to date none has been shown to affect bone tissue. Finally, androgens may regulate osteoblast activity via rapid non-genomic mechanisms [68] through membrane receptors displayed at the bone cell surface [69]. The role and biologic significance of these non-classical signaling pathways in androgenmediated responses in bone in vivo remains highly controversial and most data support the contention that genomic signaling is the more significant regulator in bone and other tissues [70–74].
Localization of AR expression in osteoblastic populations Ultimately, bone mass is determined by two biological processes: formation and resorption. Distinct cell types mediate these processes. The bone-forming cell, the osteoblast, synthesizes bone matrix, regulates mineralization and is responsive to most calciotropic hormones. The osteoclast is responsible for bone resorption. Clues about the potential sequelae of AR signaling in bone will likely be derived from a better understanding of the cell types in which expression is documented. In vivo analysis has demonstrated significant expression of AR in all cells of the osteoblast lineage including osteoblasts, osteocytes and osteoclasts [75]. Interestingly, ARs are also expressed in bone marrow stromal [76] and mesenchymal precursor cells [77], pluripotent cells that can differentiate into muscle, bone and fat. Androgen action may modulate precursor differentiation toward the osteoblast and/or myoblast lineage, while inhibiting differentiation toward the adipocyte lineage. These effects on stromal differentiation could underlie some of the well-described consequences of androgen administration on body composition including increased muscle mass. To date, it has not been established how significant the contribution is of the increased muscle mass associated with androgen administration positively to influence bone quality. However, anabolic steroid therapy to severely burned children results in significantly increased lean mass months before an effect can be demonstrated in bone [78], suggesting the importance of muscle in biomechanical linkage as a mechanism to increase bone mineral density.
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In the bone microenvironment, the localization of AR expression has been described in intact human bone by Abu et al using immunocytochemical methods [55]. In developing bone from young adults, ARs were predominantly expressed in active osteoblasts at sites of bone formation (Figure 25.2). ARs were also observed in osteocytes embedded in the bone matrix. Importantly, both the pattern of AR distribution and the level of expression were similar in males and in females. Furthermore, AR is observed in bone marrow and stromal/osteoblast precursor cells [76]. In addition, expression of the AR has been characterized
in cultured osteoblastic cell populations isolated from bone biopsy specimens, determined at both the mRNA level and by binding analysis [58]. Expression varied according to the skeletal site of origin and age of the donor of the cultured osteoblastic cells: AR expression was higher at cortical and intramembranous bone sites and lower in trabecular bone. This distribution pattern correlates with androgen responsiveness in the bone compartment. AR expression was highest in osteoblastic cultures generated from young adults and somewhat lower in samples from either prepubertal or senescent bone. Data indicate preferential nuclear staining
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Figure 25.2 The localization of AR in normal tibial growth plate and adult osteophytic human bone. (A) Morphologically, sections of the growth plate consist of areas of endochondral ossification with undifferentiated (small arrow head), proliferating (large arrow heads), mature (small arrow) and hypertrophic (large arrow) chondrocytes. Bar 80 m. An inset of an area of the primary spongiosa is shown in (B). (B) Numerous osteoblasts (small arrow heads) and multinucleated osteoclasts (large arrow heads) on the bone surface. Mononuclear cells within the bone marrow are also present (arrows). Bar 60 m. (C) In the growth plate, AR is predominantly expressed by hypertrophic chondrocytes (large arrow heads). Minimal expression is observed in the mature chondrocytes (small arrow heads). The receptors are rarely observed in the proliferating chondrocytes (arrow). (D) In the primary spongiosa, the AR is predominantly and highly expressed by osteoblasts at modeling sites (arrow heads). Bar 20 m. (E) In the osteophytes, AR is also observed at sites of endochondral ossification in undifferentiated (small arrow heads), proliferating (large arrow heads), mature (small arrows) and hypertrophic-like (large arrow) chondrocytes. Bar 80 m. (F) A higher magnification of (E) showing proliferating, mature and hypertrophic-like chondrocytes (large arrows, small arrows, and very large arrows respectively) Bar 40 m. (G) At sites of bone remodeling, the receptors are highly expressed in the osteoblasts (small arrow heads) and also in mononuclear cells in the bone marrow (large arrow heads). Bar 40 m. (H) AR is not detected in osteoclasts (small arrow heads) Bar 40 m. B, Bone: C, Cartilage; BM, Bone marrow [55].
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or indirectly after aromatization into estrogens with subsequent activation of ER.
of AR in males at sexual maturity, suggesting activation and translocation of the receptor in bone when androgenic steroid levels are elevated, consistent with androgen regulation of AR levels [79,80]. Again, no differences were found between male and female samples, suggesting that differences in receptor number per se do not underlie development of a sexually dimorphic skeleton. Since androgens are so important in bone development at the time of puberty, it is not surprising that ARs are also present in epiphyseal chondrocytes [55]. The expression of ARs in such a wide variety of cell types known to be important for bone modeling during development and remodeling in the adult, provides evidence for direct actions of androgens in bone and cartilage tissue. These results illuminate the complexity of androgen action on bone. Thus, although bone is a target tissue with respect to androgen action, the mechanisms and cell types by which androgens exert their effects on bone biology remain incompletely characterized. In terms of mechanism of action, an additional complexity is that testosterone may influence bone directly by activation of the AR
Regulation of AR expression The regulation of AR expression in osteoblasts is also incompletely characterized. Autologous regulation of AR mRNA by androgen has been well described and appears to be tissue specific; upregulation by androgen exposure is seen in a variety of mesenchymal cells including osteoblasts [79–81], whereas in prostate and smooth muscle tissue, downregulation is observed after androgen exposure [79] (Figure 25.3). The androgen mediated upregulation observed in osteoblasts can occur through changes in AR gene transcription [79,80]. Interestingly, a novel property of the AR is that binding of androgen can increase AR protein levels, as shown in osteoblastic cells [80]. This property distinguishes AR from most other steroid receptor molecules that are
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Figure 25.3 Dichotomous regulation of AR mRNA levels in osteoblast-like and prostatic carcinoma cell lines after exposure to androgen. (A) Time course of changes in AR mRNA abundance after DHT exposure in human SaOS-2 osteoblastic cells and human LNCaP prostatic carcinoma cells. To determine the effect of androgen exposure on hAR mRNA abundance, confluent cultures of either osteoblast-like cells (SaOS-S) or prostatic carcinoma cells (LNCaP) were treated with 108 M DHT for 0, 24, 48, or 72 h. Total RNA was then isolated and subjected to RNase protection analysis with 50 g total cellular RNA from SaOS-2 osteoblastic cells and 10 g total RNA from LNCaP cultures. (B) Densitometic analysis of AR mRNA steady-state levels. The AR mRNA to -actin ratio is expressed as the mean SEM compared to the control value from three to five independent assessments [79].
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downregulated by ligand binding. At least in part, the elevated AR protein levels may be a consequence of increased stability mediated by androgen binding [82], but the stability of AR in osteoblastic cells has not been determined. The mechanism(s) that underlie tissue specificity in autologous AR regulation and the possible biological significance of distinct autologous regulation of AR, is not yet understood. It is possible that AR upregulation by androgen in bone may result in an enhancement of androgen responsiveness at times when androgen levels are rising or elevated. Ligandindependent activation of AR has also been described in other tissues, but has not been explored in bone. Quantitative determination of AR expression during osteoblast differentiation is difficult to achieve in bone slices. However, analysis of AR, ER and ER mRNA and protein expression during osteoblast differentiation in vitro demonstrates that each receptor displays distinct differentiation stage patterns in osteoblasts (Figure 25.4) [83], indicating that osteoblast differentiation and steroid receptor regulation are intimately associated. The levels of AR expression increase throughout osteoblast differentiation with the highest AR levels seen in mature osteoblast or osteocyte cultures. Given the high level of AR expression, this finding suggests that an important compartment for androgen action in bone may be mature, mineralizing osteoblasts. Given that the osteocyte is the most abundant cell type in bone and a likely mediator of both focal bone deposition and the response to mechanical strain [84], it is not surprising that androgens may also augment the osteoanabolic effects of mechanical strain in osteoblasts [85]. However, an analysis of the consequences of AR action on loading in vivo has yet to be performed. AR expression in osteoblasts can be upregulated by exposure to other steroid hormones, including glucocorticoids, estrogen or 1,25-dihydroxyvitamin D3 [60]. Whether additional hormones, growth factors or agents influence AR expression in bone is not known. Further, whether the AR in osteoblasts undergoes post-translational processing that might influence receptor signaling (stabilization, phosphorylation, etc.) as described in other tissues [86,87] and the potential functional implications [88] are also unknown. Steroid receptor transcriptional activity, including that of the AR, is strongly influenced by transcriptional regulators such as co-activators or co-repressors. These co-activators/ co-repressors can influence the downstream signaling of nuclear receptors; their levels are influenced by the cellular context and these co-regualtors can differentially affect specific promoters. AR specific co-activators have been identified [89], many of which interact with the ligand binding domain of the receptor. Expression and regulation of these modulators may thus influence the ability of steroid receptors to regulate gene expression in bone, but this remains underexplored with respect to androgen receptor action. Furthermore, phosphorylation of specific co-activators, for
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Figure 25.4 Expression analyses of ER, ER and AR during in vitro differentiation in normal rat osteoblastic (rOB) cultures. (A) Normal rOB cells were cultured for the indicated number of days during proliferation, matrix maturation, mineralization and post-mineralization stages. Total RNA was isolated and subjected to relative RT-PCR analysis using primers specific for rat ER, ER and AR or rat GAPDH. Reverse transcription was conducted with PCR carried out for 40 cycles for the steroid receptors, with parallel reactions performed using GAPDH primers for 25 cycles (all in the linear range). Bands for rat ER at the predicted 240 bp, rat ER at 262 bp, rat AR at 276 bp and GAPDH at 609 bp are shown. (B) Analyses of ER, ER and AR mRNA relative abundance. Semiquantitative analysis of mRNA steady-state expression by relative RT-PCR was performed after scanning the negative image of the photographed gels. Data are expressed in arbitrary units as the ratio of receptor abundance to GAPDH expression, then normalized to expression values at day 4 in pre-confluent cultures. Data represent mean SEM [83].
example by mitogen-activated (MAP) kinase, may influence AR activity at specific target genes [90]. The specific co-activator/co-repressor profile present in cells representing different bone compartments (i.e. periosteal fibroblasts, proliferating or mineralizing osteoblasts) may help
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determine the activity of the selective receptor modulators such as SARMS described above.
Evidence suggests that androgens act directly on the osteoblast to influence expression and function. However, and likely as a consequence of the complexity of osteoblast differentiation, data supporting an effect of androgen to influence bone cells are inconsistent. There are reports, some in clonal osteoblastic cell lines, of modulatory effects of gonadal androgen treatment on proliferation, differentiation, matrix production and on mineral accumulation [91], but the effect of androgen on osteoblast proliferation has been shown to be biphasic in nature, with enhancement following short or transient treatment but significant inhibition following longer treatment. As a case in point, Kasperk et al [92] demonstrated in osteoblast-like cells in primary culture (murine, passaged human) that a variety of androgens in serum-free medium increase DNA synthesis ([3H]thymidine incorporation) and cell counts. Testosterone and non-aromatizable androgens (DHT and fluoxymesterone) were nearly equally effective regulators. Yet the same group [60] reported that prolonged DHT treatment inhibited normal human osteoblastic cell proliferation (cell counts) in cultures pretreated with DHT. In addition, Benz et al have shown that prolonged androgen exposure in the presence of serum inhibited proliferation (cell counts) by 15–25% in a transformed human osteoblastic line (TE-85) [61]. Testosterone and DHT again were nearly equally effective regulators. Hofbauer et al [93] examined the effect of DHT exposure on proliferation in hFOB/AR-6, an immortalized human osteoblastic cell line stably transfected with an AR expression construct (with 4000 receptors/cell). In this line, DHT treatment inhibited cell proliferation by 20–35%. Although various studies employed different model systems (transformed osteoblastic cells versus second to fourth passage normal human cells) and culture conditions (including differences in the state of osteoblast differentiation, receptor number, phenol red-containing versus phenol red-free or serum containing versus serum-free), it appears exposure time may be the significant variable. Time dependence for the response to androgen was clearly shown by Wiren et al [94], where osteoblast proliferation was stimulated with brief treatment times, but with prolonged DHT treatment that is more consistent with an in vivo exposure, osteoblast viability decreased (Figure 25.5). This result was AR dependent (i.e. inhibitable by co-incubation with flutamide) and was observed in both normal rat calvarial osteoblasts and in AR stably transfected MC-3T3 cells. In mechanistic terms, reduced viability was associated with overall
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Figure 25.5 Complex effect of androgen on DNA accumulation in osteoblastic cultures. Kinetics of DHT response in proliferating colAR-MC3T3 cultures measured with colorimetric (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) (MTT) assay. Cultures of stably transfected colAR-MC3T3 continuously with 108 M DHT for 2 days led to increased MTT accumulation, but longer treatment for 3 or 5 days resulted in inhibition. Data are mean SEM of six to eight dishes with six wells/dish. *P < 0.05; **P < 0.01 (versus control) [94].
reduction in MAP kinase signaling and with downstream inhibition of elk-1 gene expression, protein abundance and extent of phosphorylation. The inhibition of MAP kinase activity after chronic androgen treatment again contrasts with the response seen after brief androgen exposure, where stimulation of MAP kinase signaling and AP-1 transactivation is observed [94]. This rapid in vitro response may be mediated through non-genomic mechanisms [95,96]. Combined, most data suggest that the in vivo response to androgen treatment on osteoblast proliferation is generally inhibitory. It is also important to consider the process of programmed cell death, or apoptosis, as a component of control of osteoblast survival. In particular, as the osteoblast population differentiates in vitro, the mature bone cell phenotype undergoes apoptosis [97]. With respect to the effects of androgen exposure, chronic DHT treatment has been shown to result in enhanced osteoblast apoptosis in vitro in both proliferating osteoblastic (at day 5) and in mature osteocytic cultures (day 29) (Figure 25.6) [98]. In the same study, the inhibition observed with DHT treatment was opposite to inhibitory effects on apoptosis seen with E2 treatment. An androgen-mediated increase in the Bax/Bcl-2 ratio was also observed, predominantly through
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Figure 25.6 Characterization of osteoblast apoptosis: results of androgen and estrogen treatment during proliferation (day 5) and during differentiation into mature osteoblast/osteocytes cultures (day 29). Apoptosis was assessed at day 5 or day 29 after continuous DHT and E2 treatment (both at 108 M). Apoptosis was induced by etoposide treatment in proliferating cultures and by serum starvation for 48 h in confluent cultures before isolation, replaced with 0.1% BSA. (A) Analysis of apoptosis after evaluating DNA fragmentation by cytoplasmic nucleosome enrichment at day 5. The data are expressed as mean SEM (n 6) from two independent experiments. **P < 0.01, ***P < 0.001 (versus control). (B) Analysis of apoptosis by cytoplasmic nucleosome enrichment analysis at day 29. The data are expressed as mean SEM (n 6) from two independent experiments. **P < 0.01 versus control [98].
inhibition of Bcl-2 and was dependent on functional AR. Overexpression of bcl-2 or RNAi knockdown of bax abrogated the effects of DHT, indicating that increased Bax/ Bcl-2 was necessary and sufficient for androgen-enhanced apoptosis. The increase in the Bax/Bcl-2 ratio was at least in part a consequence of reductions in Bcl-2 phosphorylation and protein stability, consistent with inhibition of MAP kinase pathway activation after DHT treatment as noted above. Supporting in vivo analysis of calvaria in AR-transgenic male mice also demonstrated enhanced apoptosis with elevated TUNEL staining in both osteoblasts and osteocytes and was observed even in areas of new bone growth [98]. This may not be surprising, given an association between new bone growth and apoptosis [99], as has been observed in other remodeling tissues and/or associated with development and tissue homeostasis. Apoptotic cell death could thus be important in making room for new bone formation and matrix deposition, which may have clinical significance by influencing bone homeostasis and bone mineral density [100]. Thus, mounting evidence suggests that chronic androgen treatment does not increase osteoblast number or viability in the mature bone compartment and this evidence does not support a suggestion for strong anabolic responses directly in bone as a consequence of androgen therapy. Osteoblast differentiation can be characterized by changes in alkaline phosphatase activity and/or alterations in the expression of important extracellular matrix proteins, such as type I collagen, osteocalcin and osteonectin. As noted with other responses, the effects of androgens on expression of these marker activities/proteins are poorly described and inconsistent. For example, enhanced osteoblast differentiation, as measured by increased matrix
production, has been shown to result from androgen exposure in both normal osteoblasts and transformed clonal human osteoblastic cells (TE-89). Androgen treatment appeared to increase the proportion of cells expressing alkaline phosphatase activity, thus representing a shift toward a more differentiated phenotype [101]. Kasperk et al subsequently reported dose-dependent increases in alkaline phosphatase activity in both high and low-alkaline phosphatase subclones of SaOS2 cells [102] and human osteoblastic cells [60]. However, there are also reports, in a variety of model systems, of androgens either inhibiting [93] or having no effect on alkaline phosphatase activity [81], which may reflect both the complexity and dynamics of osteoblastic differentiation. Androgen-mediated increases in type I -1 collagen protein and mRNA levels [61, 102] and increased osteocalcin secretion [60], have also been described. Consistent with increased collagen production, androgen treatment has also been shown to stimulate mineral accumulation in a time- and dose-dependent manner [60, 81, 103]. However, in vivo models with bone-targeted overexpression of AR in transgenic mice, employing two distinct promoters, showed decreased levels of bone markers in total RNA extracts derived from long bone samples [27, 104]. Both lines demonstrate decreased levels of most osteoblastic and most osteoclastic genes that include reduced levels of the major matrix proteins collagen, osterix and osteocalcin. Combined, these results suggest that, under certain conditions, androgens may enhance osteoblast differentiation. However, it is becoming increasingly clear that the direct effects of androgens on osteoblasts are generally negative and thus likely play an inhibitory role in the regulation of bone matrix production and/or organization.
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Positive anabolic effects of androgen in bone may thus be limited to distinct lineages, for example cells in the periosteal compartment [27,104].
Androgen effects on osteoclasts and other cells Androgens also influence other cell types in bone that are important in determining bone balance. Potential modulation of osteoclast action by DHT is incompletely characterized, although there are reports of AR expression in the osteoclast [75]. Androgen treatment reduces bone resorption of isolated osteoclasts, inhibits osteoclast formation [105] and that stimulated by parathyroid hormone (PTH) [106] and may play a direct role regulating aspects of osteoclast activity in both AR null mice [107]. Indirect effects of androgen to modulate osteoclasts are indicated by the increase in OPG following testosterone treatment in osteoblasts [108] and in skeletally-targeted AR-transgenic mice [27]. In addition, DHEA treatment has been shown to increase the OPG/ RANKL ratio in osteoblastic cells and inhibit osteoclast activity in coculture [64]. Androgen may be a less significant determinant of bone resorption in vivo than estrogen [109], although this remains controversial [110]. As with effects noted in osteoblastic populations, androgens regulate chondrocyte proliferation and expression. Although some of the consequences of androgen action are mediated after metabolic conversion to estrogen, which limits long bone growth, non-aromatizable androgen stimulates longitudinal bone growth [111]. AR expression has been demonstrated in cartilage and androgen exposure promotes chondrogenesis. Increased [35S]sulfate incorporation into newly synthesized cartilage [112] is androgen mediated. Regulation of these effects is obviously complex, as they were dependent on the age of the animals and the site from which chondrocytes were derived. Thus, in addition to effects on osteoblasts, multiple cell types in the skeletal milieu are regulated by androgen exposure. The effects of androgens on osteoblast activity must certainly also be considered in the context of the very complex endocrine, paracrine and autocrine milieu in the bone microenvironment. Systemic and/or local factors can act in concert, or can antagonize, to influence bone cell function. This has been well described with regard to modulation of the effects of estrogen on bone. Androgens have also been shown to regulate well-known modulators of osteoblast proliferation or function. The most extensively characterized growth factor influenced by androgen exposure is transforming growth factor- (TGF-). TGF- is stored in bone (the largest reservoir for TGF-) in a latent form and has been show to be a mitogen for osteoblasts [113]. Androgen treatment has been shown to increase TGF- activity in human osteoblast primary cultures. The expression of some TGF-
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mRNA transcripts (apparently TGF-2) was increased, but no effect on TGF-1 mRNA abundance was observed [63,92]. At the protein level, specific immunoprecipitation analysis reveals DHT mediated increases in TGF- activity to be predominantly TGF-2 [60,63]. DHT has also been shown to inhibit both TGF- gene expression and TGF--induced early gene expression that correlates with growth inhibition in this cell line [93]. The TGF--induced early gene has been shown to be a transcription factor that may mediate some TGF- effects. These results are consistent with the notion that TGF- may mediate androgen effects on osteoblast proliferation. On the other hand, TGF1 mRNA levels are increased by androgen treatment in human clonal osteoblastic cells (TE-89), under conditions where osteoblast proliferation is slowed [61]. Thus, the specific TGF- isoform may determine osteoblast responses. It is interesting to note that, in vivo, orchiectomy (ORX) drastically reduces bone content of TGF- levels and testosterone replacement prevents this reduction [114]. These data support the findings that androgens influence cellular expression of TGF- and suggest that the bone loss associated with castration is related to a reduction in growth factor abundance induced by androgen deficiency. Other growth factor systems may also be influenced by androgens. Conditioned media from DHT treated normal osteoblast cultures are mitogenic and DHT pretreatment increases the mitogenic response to fibroblast growth factor and to insulin-like growth factor II (IGF-II) [92]. In part, this may be due to slight increases in IGF-II binding in DHT treated cells [92], as IGF-I and IGF-II levels in osteoblast conditioned media are not affected by androgen [92]. Although most studies have not found regulation of IGF-I or IGF-II abundance by androgen exposure [18,92], there is a report in an androgen-responsive human osteoblastic cell line that androgens can increase IGF-I, IGF binding protein (IGFBP)-2 and IGFBP-3 expression and, at the same time, decrease levels of the inhibitory IGFBP-4 [115]. Androgens may also modulate expression of components of the AP-1 transcription factor [63] and/or transiently increase AP-1 transcriptional activation [94]. Thus, androgens may modulate osteoblast differentiation via a mechanism whereby growth factors or other mediators of differentiation are regulated by androgen exposure. Androgens may also modulate responses to additional important osteotropic hormones/regulators. Testosterone and DHT specifically inhibit the cAMP response elicited by PTH or parathyroid hormone-related protein (PTHrP) in the human clonal osteoblast-like cell line SaOS-2 while the inactive or weakly active androgen 17-epitestosterone had no effect. This inhibition may be mediated via an effect on the PTH receptor-Gs-adenylyl cyclase [116]. The production of prostaglandin E2 (PGE2), another important regulator of bone metabolism, is also affected by androgens. Pilbeam and Raisz showed that androgens (both DHT and testosterone) were potent inhibitors of both parathyroid
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hormone and interleukin-1 stimulated PGE2 production in cultured neonatal mouse calvaria [117]. The effects of androgens on PTH action and PGE2 production suggest that androgens could act to modulate (reduce) bone turnover in response to long-term treatment with these agents. Finally, both estrogen and androgen [118] can inhibit production of interleukin-6 by osteoblastic cells. In stromal cells of the bone marrow, androgens have been shown to have potent inhibitory effects on the production of interleukin6 and the subsequent stimulation of osteoclastogenesis by marrow osteoclast precursors [119]. Interestingly, adrenal androgens (androstenediol, androstenedione, DHEA) have similar inhibitory activities on interleukin-6 gene expression and protein production by stromal cells [119]. The loss of inhibition of interleukin-6 (IL-6) production by androgen may also contribute to the marked increase in bone remodeling and resorption that follows orchiectomy, in addition to modulation of osteoclast activity through changes in the OPG/RANKL ratio as noted above. Moreover, androgens inhibit the expression of the genes encoding the two subunits of the IL-6 receptor (gp80 and gp130) in the murine bone marrow, another mechanism which may blunt the effects of this osteoclastogenic cytokine in intact animals [120]. In these aspects, the effects of androgens seem to be very similar to those of estrogen, which may also inhibit osteoclastogenesis via mechanisms that involve IL-6 inhibition and/or OPG/RANKL ratio changes.
Androgen effects on bone: animal studies The effects of androgens on bone remodeling have been examined fairly extensively in animal models. Much of this work has been in species not perfectly suited to reflect human bone metabolism (rodents) and, certainly, the field remains incompletely explored. Nevertheless, animal models do provide valuable insights into the effects of androgens at organ and cellular levels. Many of the studies of androgen action have been performed in male rodents, in which rapid skeletal growth occurs until about 4 months of age, at which time epiphyseal growth slows markedly (although never completely ceases at some sites). Because the effects of androgen may be different in growing and more mature animals [121], it is appropriate to consider the two situations independently.
Effects on bone growth during skeletal development In most mammals, there is a marked gender difference in bone morphology. The mechanisms responsible for these
differences are complex and presumably involve both androgenic and estrogenic actions. During early development and adolescence, skeletal development is characterized by marked expansion of cortical proportions and increasing trabecular density. During this process, the skeleton develops distinctly in males and females, with the most significant differences at the periosteal and endocortical surfaces. As sex differences in skeletal morphology and physiology occur at or around puberty, it is hypothesized that gender differences, particularly with respect to ‘bone quality’ and architecture, i.e. predominantly bone width, are modulated at least in part by estrogens and androgens. Consistent with this, a distinct response to estrogen and androgen has been described in vivo especially in cortical bone. At the periosteum, estrogen suppresses while androgen stimulates new bone formation yet, conversely, at the endocortical surface, estrogen stimulates but androgen strongly suppresses formation, at least in males [27, 104]. Thus, estrogen tends to decrease while androgen increases radial growth in cortical bone through periosteal apposition. At the endocortical surface, in contrast, estrogen increases while androgen suppresses bone formation [27, 104]. These distinct responses to estrogen and androgen during growth likely play an important role in determining sexual dimorphism of the skeleton, i.e. that male bones are wider but not thicker than females [122]. Young men do have larger bone areas than women with increased whole bone cross-sectional area, particularly at peripheral sites [123]. Interestingly aromatase gene polymorphisms that variably influence sex steroid concentrations also suggest a positive role for androgen action at the periosteal surface, given findings that testosterone concentrations were associated with larger bones and larger medullary space while, in contrast, estradiol levels were shown to be associated with smaller medullary space [124]. Androgens are also essential for the production of peak total-body bone mass in males [125]. Low levels of estrogen (with increased levels of androgen) may also be important for stimulation of periosteal bone formation during development [40]. Yet, in sum, these two sex steroids may act in opposition at distinct bone sites/compartments.
Effects on epiphyseal function during development Estrogens are particularly important for the regulation of epiphyseal function and act to reduce the rate of longitudinal growth via influences on chondrocyte proliferation and action, as well as on the timing of epiphyseal closure [126]. Androgens appear to have opposite effects and tend to promote long bone growth, chondrocyte maturation and metaphyseal ossification. Androgen deficiency retards those processes [127]. Nevertheless, excess concentrations
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of androgen will accelerate aging of the growth plate and reduces growth potential, possibly via conversion to estrogens. Although the specific roles of sex steroids in the regulation of epiphyseal growth and maturation remain somewhat unresolved, there is evidence that androgens do have direct effects independent of those of estrogen. For instance, testosterone injected directly into the growth plates of rats increases plate width [128]. In a model of endochondral bone development based on the subcutaneous implantation of demineralized bone matrix in castrate rats, both testosterone and DHT increase the incorporation of calcium during osteoid formation [103]. Interestingly, in this model, androgens reduced the incorporation of [35S]sulfate into glycosaminoglycans early in the developing cartilage. In sum, these data support the contention that androgens play a direct role in chondrocyte physiology.
Effects on bone mass in growing male animals: animal models of altered androgen responsiveness The most dramatic effect of androgens during growth is on bone size. Male animals have larger bones and, particularly, thicker cortices than females [126]. The contribution of AR signaling in vivo has been approached in genetic animal models with global AR modulation, including global (i.e. non-targeted) AR knockout mice [129] and the testicular feminization (Tfm) model of androgen insensitivity syndrome (AIS) [130,131]. In all of these models, the effect of the genetic manipulation is present from before birth. The bone phenotype that develops in a global AR null (ARKO) male mouse model is a high-turnover osteopenia, with reduced trabecular bone volume and a significant stimulatory effect on osteoclast function with little effect in females [129,132,133]. In the Tfm (AR deficient), androgens are presumed to be incapable of action, but estrogen and androstenedione concentrations are considerably higher than in normal males [134,135]. Clear increases also exist in Tfm male rats in serum concentrations of calcium, phosphorus and osteocalcin, whereas IGF-I concentrations are decreased. Estimates of bone mass suggest that Tfm rats have reduced longitudinal and radial growth rates, but that trabecular volume and density are similar to those of normal rats. In selected sites, measures of bone mass and remodeling were intermediate between normal male and female values. This model indicates that androgens have an independent role to play in normal bone growth and metabolism, but the model is complex and not easily dissected. In Tfm mice, meticulous analysis by Vanderschueren et al [130] has shown that the positive effects of testosterone on cortical bone are generally mediated by stimulation of periosteal bone formation, which was absent in Tfm mice. The analysis
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shows that AR-mediated testosterone action is essential for periosteal bone formation (in male mice) and also contributes to trabecular bone maintenance. This is very similar to the study of humans with the androgen insensitivity syndrome. Marcus et al [54] reported that there is a deficit in bone mineral density in women with androgen insensitivity even when compliance with estrogen replacement is excellent. However, inadequate estrogen replacement appeared to worsen the deficit and other environmental factors are difficult to quantitate. Thus, Tfm models demonstrate the importance of AR in mediating the positive effects of androgen to contribute to trabecular bone maintenance and in cortical bone, particularly at the periosteal surface [130]. Finally, a useful model for characterization of androgen signaling during development is represented by animals with tissue-selective modulation of AR expression, in which the effects of both overexpression and targeted deletion of AR have been characterized. Knockdown of genomic AR signaling in mature osteoblasts results in cancellous osteopenia, with increased bone resorption, a reduction in trabecular bone volume and a decrease in trabecular number, indicating the importance of AR signaling to maintain trabecular bone [136]. AR overexpression also results in a bone phenotype. Two distinct lines have been characterized with bone-targeted AR overexpression; one constructed with full-length AR under the control of the 3.6 kb type I collagen promoter and a second model employing the 2.3 kb type I collagen promoter to control AR overexpression. AR3.6-transgenic mice demonstrate overexpression in osteoblast stromal precursors and throughout the osteoblast lineage [27]. A major advantage of this model is overexpression of AR in the periosteal compartment, a known target for androgen anabolic action in the skeleton. The AR2.3-transgenic mice have overexpression of AR that is restricted to mature osteoblasts and osteocytes [104]. Since osteocytes are the most abundant cell type in bone [84] and also have the highest concentration of AR [83], these cells are likely an important target cell for androgen action and may represent a central mediator for skeletal responses to testosterone therapy in vivo. In general, AR overexpression in vivo results in a low turnover state in males with a significant reduction in cortical bone area due to inhibition of bone formation at the endosteal surface and a lack of marrow infilling. AR signaling also plays an important role in the trabecular bone, with increased trabecular bone volume via an increase in trabecular number but not width and reduced osteoclast number and/or activity. Finally, results indicate that enhanced androgen signaling in bone results in changes that are detrimental to biomechanical competence and whole bone strength, likely via reductions in osteoblast vigor and matrix quality. Again, there is little phenotype in female animals [133], so that the role of AR in normal female bone physiology is unclear. It is instructive to compare and contrast the skeletal phenotypes that develop in the two distinct AR-transgenic lines.
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In common between the two models, a phenotype with reduced bone turnover, reduced formation at endosteal surfaces, increased trabecular bone volume but compromised femoral strength in all biomechanical parameters tested is observed. With the exception of enhanced periosteal activity in AR3.6-transgenic males (Figure 25.7), neither model exhibits anabolic responses in the cortical bone compartment and, instead, both show inhibition of bone formation at the endocortical surface with compromised biomechanical properties and increased bone fragility. Thus, based on overlap in promoter activity, bone properties likely to be mediated at least in part by enhanced androgen signaling in mature osteoblasts/osteocytes include increased trabecular bone volume, reduced bone turnover, reduced formation with decreased osteoblast vigor at endosteal surfaces and compromised biomechanical strength with increased bone fragility. These results are observed in both models. The most striking contrast between the two AR-transgenic models is observed at periosteal surfaces in AR3.6-transgenic males, which show increased cortical bone formation in the periosteum and dramatic intramembranous calvarial thickening, likely
mediated by periosteal fibroblasts and/or immature osteoblasts. The specificity of the periosteal anabolic effect in AR3.6-transgenic males is consistent with previous reports documenting the importance of androgen signaling in periosteal expansion [137]. Periosteal bone formation defines the cross-sectional area of bone or bone width, whereas endosteal formation or resorption determines cortical thickness. Thus, androgen inhibition of medullary bone formation at the endosteal surface in males may subserve an important physiological adaptive function, being key for appropriate spatial distribution and maintenance of the total amount/weight of bone in the cortical envelope [104]. A reasonable hypothesis is that androgens strongly promote the addition of cortical width through periosteal growth, but balance that growth with inhibition in the marrow cavity so that the skeleton does not become too heavy [138]. Based on these findings, a model for the consequences of androgen signaling has been proposed, where the effects of AR activation are distinct in different skeletal compartments (Figure 25.8). Bone is also positively influenced by androgens at intramembranous
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Figure 25.8 Model for androgen action in the skeleton mediated by AR transactivation. Androgen activation of AR influences a variety of target organs and skeletal sites, including marrow stromal cells and trabecular, cortical and intramembranous bone compartments. Arrows indicate the changes associated with androgen action. In trabecular bone, androgen action preserves or increases trabecular number, has little effect on trabecular thickness and, thus, reduces trabecular spacing. In cortical bone, AR activation results in reduced bone formation at the endosteal surface but stimulation of bone formation at the periosteal surface; correspondingly decreased periosteal but increased endosteal resorption results in no change in cortical area. In the transgenic models reviewed here, AR activation in mature bone cells in vivo results in a low turnover phenotype, with inhibition of bone formation and inhibition of gene expression in both osteoblasts and osteoclasts. In the absence of compensatory changes at the periosteal surface, these changes are detrimental to overall matrix quality, biomechanics and whole bone strength [104].
sites [27]. In addition, androgen administration increases muscle mass, partially mediated by effects on mesenchymal stem cell lineage commitment [77], likely to influence indirectly bone density through biomechanical linkage.
Effects on the periosteum: the role of AR versus aromatization of testosterone As noted, androgen-mediated AR transactivation is likely a key determinant of the sexually dimorphic pattern of periosteal apposition that is most clearly demonstrated in male AR-transgenic mice in the absence of hormone administration [27]. Androgens are also unable to stimulate periosteal growth and radial bone expansion in the AR knockout model [139]. Essentially, all of the alterations induced by ORX (in both growing and mature animals) can be prevented, at least in part, by replacement with either testosterone or non-aromatizable androgens [5,140]. These results strongly suggest that aromatization of androgens to
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estrogens cannot fully explain the actions of androgens on bone metabolism. However, estrogens also seem to play a role in the effects of androgen on periosteal apposition. Although AR activity is essential, low levels of estrogens are likely required for optimal stimulation of periosteal growth [139], as observed in aromatase deficiency in males [40]. Estrogens may also help prevent bone loss following castration in male animals. Vanderschueren et al. [141] reported that estradiol (and nandrolone) was capable of not only preventing the increase in biochemical indices stimulated by ORX, but also preventing cortical and trabecular bone loss. In fact, estradiol resulted in an absolute increase in trabecular bone volume not achieved with androgen replacement. Similarly, estrogen was reported to antagonize the increase in blood flow resulting from castration and to increase bone ash weight more consistently than testosterone. Although data thus far available are incomplete, these studies raise obvious questions of the overlap between the actions of androgens and estrogens in bone and/or the consequences of skeletal adaptation. Although androgen and AR signaling is the likely mediator of periosteal expansion that results in larger bones in males, other hormones can influence periosteal growth and radial bone expansion, including growth hormone and PTH. While both testosterone and DHT stimulate periosteal bone formation in growth hormone receptor knockout male mice and do so without an effect on serum IGF-I or skeletal IGF-I expression, loss of growth hormone signaling dramatically reduced periosteal growth [137]. The ability of intermittent PTH to promote periosteal expansion may be mediated via enhanced differentiation of periosteal precursors [142]. Osteoblasts and periosteal fibroblasts frequently respond in a distinct fashion to hormonal, pharmacological or mechanical stimuli [143]. Interestingly, periosteal cell differentiation is much slower than osteoblasts derived from cancellous bone [144]. These results may not be surprising given that osteoblasts and periosteal cells reside in different bone niches and the source of periosteal fibroblasts remains an open question.
Effects on bone mass in adults: effects of castration in young and adult animals The effects of androgens on bone mass remodeling can be inferred by observing the results of androgen withdrawal after gonadectomy. In most studies, orchiectomy in young rats results in a reduction in cortical bone mass within 2–4 weeks. Calcium content of the femur or tibia [145], whole femoral, tibial or body bone mineral density [146,147] and tibial diaphyseal cortical area [5] have been shown to be lower in castrated than in sham operated controls. Similar
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trends have been reported in young, castrate male mice [148]. In animals followed for longer periods after castration (90 days), the density of cortical bone was slightly (but not significantly) reduced, but bone area was clearly lessened in the diaphysis of the femur [145]. At least in part, the reduction in cortical bone mass appears to result from a reduction in periosteal bone formation rate induced by gonadectomy in males [4, 5]. This response is distinctly different than that induced by oophorectomy, which results in an increase in periosteal apposition in the period immediately after surgery. This divergent trend in the periosteal response to castration in male and female animals abolishes the sexual dimorphism usually present in radial bone growth. Endosteal bone formation does not seem to be affected by orchiectomy [4]. As another indication that the cortical skeleton is affected by androgens, the characteristic acute increase in creatine kinase activity induced from diaphyseal bone by androgen treatment is abolished by orchiectomy [140]. For unclear reasons, it remains intact in epiphyseal specimens. Although castration in the male tends to slow growth and weight gain, the effects on cortical bone histomorphometry are present in pair-fed rats and in groups in which there was no difference in growth rates [4, 5] indicating that the skeletal effects are not merely the indirect result of changes in body size or composition. Certainly, androgens are known to interact with the growth hormone-IGF system in the coordination of skeletal growth. Growth hormone deficiency in males has no net effect on endosteal growth but reduced by half expansion at the periosteal surface [149], underscoring the co-dependence of these two hormonal systems in the control of pubertal skeletal change. Cancellous bone mass is also reduced in castrate young male rats. Tibial metaphyseal bone volume and vertebral bone mineral density are clearly reduced [4, 145, 147], an effect which is seen rapidly following castration [4]. The reduction in bone volume is dramatic, with differences between control and castrate of 40–50% appearing in 4–10 weeks [147, 150]. Rosen et al showed that measures of trabecular bone volume and mineral density diverged much more than did areal measures of the proximal tibia or distal femur (by dual energy X-ray absorptiometry) and speculated that this difference reflected a more intense bone deficit from trabecular than from cortical compartments [147]. An important issue that remains unresolved is whether the bone deficit is a result of actual loss of bone mass following castration, or whether the differences between castrate and control animals results from a failure of castrate animals to accrue bone normally. Nevertheless, bone changes following orchiectomy occur in the presence of an increase in skeletal blood flow, osteoclast numbers and surface [4], serum and urine calcium levels [4] and increased serum tartrate resistant acid phosphatase activity [146]. All these findings strongly suggest an increase in bone remodeling and bone resorption. On the other hand, in one report, distal
femoral bone loss following castration is accompanied by a reduction in bone remodeling [151]. Parathyroid hormone concentrations have not been measured in these experiments, but vitamin D concentrations do not appear to be altered by orchiectomy [4]. In sum, trabecular bone mass, as well as cortical mass, is clearly dependent on adequate androgen action in the growing male animal. Results from animal studies also support an effect of androgen on bone formation in the mature animal. In mature rats, castration has been used to evaluate the consequences of loss of sex steroids (both estrogen and androgen). It is well established that castration eventually results in osteopenia and both cortical and trabecular compartments are affected. At a time when longitudinal growth has slowed markedly, pronounced differences as a consequence of castration appear in cortical bone ash weight per unit length, cross-sectional area, cortical thickness and bone mineral density [141,152]. Castration results in changes in both trabecular and cortical bone compartments and dramatic bone loss in trabecular bone is noted in both males and females, but sex-specific responses are most dimorphic in cortical bone. For example, distinct effects of androgen are seen with gonadectomy when comparing the effects of ORX in male versus ovariectomy (OVX) in female rats. OVX and the associated loss of sex steroids in the female generally result in decreased trabecular area with increased osteoclast number. In cortical bone, an increase at the periosteal surface is seen with circumferential enlargement but a decrease in endosteal labeling. These results demonstrate that estrogen protects trabecular bone predominantly through inhibition of osteoclast activity/recruitment, but has an inhibitory action at the periosteal surface as noted above [130]. In the male, ORX with the attendant loss of sex steroids also result in decreased trabecular area with increased osteoclast number but, in contrast with the female, periosteal formation in cortical bone is reduced with the loss of androgen. Androgen treatment is effective in suppressing the acceleration of bone remodeling normally seen after ORX [153]. This divergent trend in the periosteal response to castration in male and female animals abolishes the sexual dimorphism usually present in radial bone growth. In the intact animal, the stimulation of endosteal formation by estrogen compensates for the lack of periosteal formation, thus leading to no difference in cortical width or biomechanical strength between the sexes. Nevertheless, factors that influence periosteal apposition may constitute an important therapeutic class since periosteal bone formation is often a neglected determinant of bone strength [154]. ORX shows little net effect on the endosteal surface in males [149] or slight reductions likely due to increased resorption. Consistent with this, increased intracortical resorption cavities are reported to result from ORX [155]. As might be expected in light of these changes, breaking strength (N) is decreased in cortical bone [149]. In addition, it appears that ORX affects cranial development more than
C h a p t e r 2 5 Androgens and Bone: Basic Aspects l
OVX [156], suggesting that androgen action is also important in intramembraneous bone. In addition to changes in bone size at the periosteal surface, trabecular bone volume is reduced rapidly after castration as well [157,158] and osteopenia becomes pronounced with time [159]. This bone loss appears to result in part from increased bone resorption, as it is associated with increased resorption cavities, osteoclasts and blood flow [160]. Dynamic histomorphometric and biochemical measures of bone remodeling increase quickly [145,158], with evidence of increased osteoclast numbers only 1 week after castration [158]. These changes include an increase in osteoblastic activity as well as increased bone resorption, reflecting an initial high turnover state that is followed by a reduction in remodeling rates and low turnover osteopenia. In the SAMP6 mouse, a model of accelerated senescence in which osteoblastic function is impaired, the rise in remodeling following ORX is blunted, which has been interpreted as evidence that the early changes after gonadectomy are dependent on osteoblast-derived signals [161]. As noted above, androgens reduce osteoclast formation and activity [105], which may be partially mediated by increased OPG levels [27,108]. The initial phase of increased bone remodeling activity subsides with time [145,160] and, by 4 months, there is evidence of a depression in bone turnover rates in some skeletal areas [160]. As in younger animals, indices of mineral metabolism are not altered by these changes in skeletal metabolism [141]. Careful histomorphometric analysis by Ohlsson and workers of androgen action in ORX mice has shown that the bone sparing effect of AR activation in trabecular bone is distinct from the bone-sparing effect of ER at that site [162]. The analysis demonstrated that AR activation does preserve the number of trabeculae, but does not preserve thickness or volumetric density, nor mechanical strength in cortical bone. As a potential model for the effects of hypogonadism in humans, animal models therefore suggest an early phase of high bone turnover and bone loss after ORX, followed by a reduction in remodeling rates and osteopenia. The remodeling imbalance responsible for loss of bone mass appears complex, as there are changes in rates of both bone formation and resorption and patterns that vary from one skeletal compartment to another. These overall changes are similar in overall pattern to those noted in female animals after castration, in which a loss of estrogen signaling has been associated with a stimulation of osteoblast progenitor differentiation, an increase in osteoclast numbers, bone resorption and bone loss [163].
Androgens in the female animal Of course androgens are present in females as well as males and may affect bone metabolism. In castrate female rats,
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DHT (a non-aromatizable androgen) administration suppresses elevated concentrations of bone resorption markers, as well as those of increased osteocalcin [164]. However, alkaline phosphatase activity increases further. Additional evidence to support the contention that androgens play a role in females includes the fact that antiandrogens (e.g. flutamide) are capable of evoking osteopenia in intact (i.e. fully estrogenized) female rats [6]. This obviously suggests that androgens provide crucial support to bone mass independent of estrogens in the adult. Of interest, the character of the bone loss induced by flutamide suggested that estrogen prevents bone resorption, whereas androgens may stimulate bone formation. In periosteal bone, DHT and testosterone appear to stimulate bone formation after ORX in young male rats, whereas in castrate females they suppress bone formation [5], perhaps reflecting an interaction or synergism between sex steroids and their effects on bone. As noted above, combination therapy with estrogen and androgen in postmenopausal women is more beneficial than either steroid alone [8–10], which has been confirmed in an animal model [165]. There is also some information concerning androgens in additional animal models, including primates. For instance, in adult female cynomolgus monkeys, testosterone treatment increased cortical and trabecular bone density as well as biomechanical strength [166].
Effects of replacement sex steroids after castration Essentially, all of the alterations induced by orchiectomy (in both growing and mature animals) can be prevented by replacement with either testosterone or non-aromatizable androgens [5,140,150,167,168]. These results strongly suggest that aromatization of androgens to estrogens cannot fully explain the actions of androgens on bone metabolism. On the other hand, estrogens also seem to prevent bone loss following castration in male animals. Vanderscheuren et al reported that estradiol (plus nandrolone) was capable of not only preventing the increase in biochemical indices stimulated by orchiectomy, but was also able to prevent cortical and cancellous bone loss [141]. In fact, estradiol resulted in an absolute increase in trabecular bone volume not achieved with androgen replacement. Similarly, estrogen was reported to antagonize the increase in blood flow resulting from castration and to increase bone ash weight more consistently than testosterone. Although the data thus far available are incomplete, these studies raise obvious questions of the overlap between the actions of androgens and estrogens in bone. The gender reverse condition of employing androgen replacement in female animals is also instructive. Nonaromatizable androgens are capable of preventing or reversing osteopenia and abnormalities in bone remodeling in
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oophorectomized females [5]. These actions apparently result from the suppression of trabecular bone resorption as well as stimulation of periosteal bone formation [169]. Very similar results have been reported following the treatment of oophorectomized animals with DHEA [170]. Moreover, blockage of androgen action with an AR antagonist in female rats already treated with an estrogen antagonist increases bone loss and indices of osteoclast activity more than treatment with an estrogen antagonist alone [171], again indicating that ovarian androgens (apart from estrogens) exert a protective effect on bone in females. Analogously, androstenedione reduces (although does not abrogate) trabecular bone loss (and remodeling alterations) in oophorectomized animals treated with an aromatase inhibitor [172]. This protective effect was blocked by the addition of an AR antagonist [173]. Finally, whereas aromatase inhibition in male rats reduces bone mass, the large increase in remodeling induced by ORX does not occur in these animals [41]. Also, ORX in ERKO mice further reduces bone mass [73]. The latter observation implicates a role for androgens in the maintenance of bone mass in ERKO mice.
Summary The effects of androgens on bone health are obviously pervasive and complex. Androgens are important in the maintenance of a healthy skeleton and influence skeletal modeling and remolding by multiple mechanisms through effects on osteoblasts, osteocytes, osteoclasts and even perhaps an influence on the differentiation of pluripotent stem cells toward distinct lineages. The specific effects of androgens on bone cells are mediated directly through an androgen receptor- (AR-) signaling pathway, but there are also indirect contributions to overall skeletal health through aromatization and estrogen receptor (ER) signaling. The effects of androgens are particularly dramatic during growth in boys and may play a role during this period in girls as well. Androgens strongly promote the addition of cortical width through periosteal growth but balance that growth with inhibition of formation in the marrow cavity so that the skeleton does not become too heavy during development and, thus, may subserve an important physiological adaptive function. Throughout the rest of life, androgens can affect skeletal function in both sexes. Since the effects of androgens are still poorly characterized, more needs to be done to unravel the mechanisms by which androgens influence the physiology and pathophysiology of bone and there remains much to be learned about the roles of androgens at all levels in both males and in females. The interaction of androgens and estrogens and how their respective actions can be utilized for specific diagnostic and therapeutic benefit are important but unanswered issues. With an increase in the understanding of the nature of androgen effects will come greater
opportunities to use their positive actions in the prevention and treatment of a wide variety of skeletal disorders.
References 1. K.M. Wiren, Androgens and bone growth: it’s location, location, location, Curr. Opin. Pharmacol. 5 (6) (2005) 626–632. 2. B. Clarke, S. Khosla, Androgens and bone, Steroids 74 (3) (2009) 296–305. 3. D. Vanderschueren, J. Gaytant, S. Boonen, K. Venken, Androgens and bone, Curr. Opin. Endocrinol. Diabetes. Obes. 15 (3) (2008) 250–254. 4. R. Turner, K. Hannon, L. Demers, J. Buchanan, N. Bell, Differential effects of gonadal function on bone histomorphometry in male and female rats, J. Bone Miner. Res. 4 (4) (1989) 557–563. 5. R. Turner, G. Wakley, K. Hannon, Differential effects of androgens on cortical bone histomorphometry in gonadectomized male and female rats, J. Orthopaedic Res. 8 (1990) 612–617. 6. A. Goulding, E. Gold, Flutamide-mediated androgen blockade evokes osteopenia in the female rat, J. Bone Miner. Res. 8 (6) (1993) 763–769. 7. V. Coxam, B. Bowman, M. Mecham, C. Roth, M. Miller, S. Miller, Effects of dihydrotestosterone alone and combined with estrogen on bone mineral density, bone growth, and formation rates in ovariectomized rats, Bone 19 (1996) 107–114. 8. B. Miller, M. De Souza, K. Slade, A. Luciano, Sublingual administration of micronized estradiol and progesterone, with and without micronized testosterone: effect on biochemical markers of bone metabolism and bone mineral density, Menopause 7 (2000) 318–326. 9. C. Castelo-Branco, J. Vicente, F. Figueras, et al., Comparative effects of estrogens plus androgens and tibolone on bone, lipid pattern and sexuality in postmenopausal women, Maturitas 34 (2000) 161–168. 10. L.G. Raisz, B. Wiita, A. Artis, et al., Comparison of the effects of estrogen alone and estrogen plus androgen on biochemical markers of bone formation and resorption in postmenopausal women, J. Clin. Endocrinol. Metab. 81 (1) (1996) 37–43. 11. Q. Mo, S. Lu, N. Simon, Dehydroepiandrosterone and its metabolites: differential effects on androgen receptor trafficking and transcriptional activity, J. Steroid Biochem. Mol. Biol. 99 (2006) 50–58. 12. G. Kuiper, P. Shughrue, I. Merchenthaler, J. Gustafsson, The estrogen receptor beta subtype: a novel mediator of estrogen action in neuroendocrine systems, Front. Neuroendocrinol. 19 (4) (1998) 253–286. 13. A. Lemus, J. Enriquez, A. Hernandez, R. Santillan, G. PerezPalacios, Bioconversion of norethisterone, a progesterone receptor agonist into estrogen receptor agonists in osteoblastic cells, J. Endocrinol. 200 (2) (2009) 199–206. 14. J. Vittek, K. Altman, G. Gordon, A. Southren, The metabolism of 7alpha-3H-testosterone by rat mandibular bone, Endocrinology 94 (2) (1974) 325–329. 15. H. Schweikert, W. Rulf, N. Niederle, H. Schafer, E. Keck, F. Kruck, Testosterone metabolism in human bone, Acta Endocrinol. 95 (1980) 258–264.
C h a p t e r 2 5 Androgens and Bone: Basic Aspects l
16. S. Issa, D. Schnabel, M. Feix, et al., Human osteoblast-like cells express predominantly steroid 5alpha-reductase type 1, J. Clin. Endocrinol. Metab. 87 (2002) 5401–5407. 17. L. Audi, A. Carrascosa, A. Ballabriga, Androgen metabolism by human fetal epiphyseal cartilage and its condrocytes in primary culture, J. Clin. Endocrinol. Metab. 58 (1984) 819–825. 18. Y. Nakano, I. Morimoto, O. Ishida, et al., The receptor, metabolism and effects of androgen in osteoblastic MC3T3E1 cells, Bone Miner. 26 (1994) 245–259. 19. R. Turner, B. Bleiberg, D. Colvard, P. Keeting, G. Evans, T. Spelsberg, Failure of isolated rat tibial periosteal cells to 5 reduce testosterone to 5-dihydroxytestosterone, J. Bone Miner. Res. 5 (1990) 775–779. 20. V. Sobel, B. Schwartz, Y. Zhu, J. Cordero, J. ImperatoMcGinley, Bone mineral density in the complete androgen insensitivity and 5-reductase-2 deficiency syndromes, J. Clin. Endocrinol. Metab. 91 (2006) 3017–3023. 21. H. Bruch, L. Wolf, R. Budde, G. Romalo, H. Scheikert, Androstenedione metabolism in cultured human osteoblastlike cells, J. Clin. Endocrinol. Metab. 75 (1) (1992) 101–105. 22. M. Mahendroo, K. Cala, C. Landrum, D. Russell, Fetal death in mice lacking 5-reductase type 1 caused by estrogen excess, Mol. Endocrinol. 11 (1997) 917–927. 23. H. Rosen, S. Tollin, R. Balena, et al., Bone density is normal in male rats treated with finasteride, Endocrinology 136 (1995) 1381–1387. 24. J. Amory, N. Watts, K. Easley, et al., Exogenous testosterone or testosterone with finasteride increases bone mineral density in older men with low serum testosterone, J. Clin. Endocrinol. Metab. 89 (2004) 503–510. 25. E. Simpson, M. Mahendroo, G. Means, et al., Aromatase cytochrome P450, the enzyme responsible for estrogen biosynthesis, Endocr. Rev. 15 (1994) 342–355. 26. E. Simpson, C. Clyne, G. Rubin, et al., Aromatase – a brief overview, Annu. Rev. Physiol. 64 (2002) 93–127. 27. K.M. Wiren, X.W. Zhang, A.R. Toombs, et al., Targeted overexpression of androgen receptor in osteoblasts: unexpected complex bone phenotype in growing animals, Endocrinology 145 (7) (2004) 3507–3522. 28. H. Nawata, S. Tanaka, S. Tanaka, et al., Aromatase in bone cell: association with osteoporosis in postmenopausal women, J. Steroid Biochem. Mol. Biol. 53 (1995) 165–174. 29. H. Schweikert, L. Wolf, G. Romalo, Oestrogen formation from androstenedione in human bone, Clin. Endocr. 43 (1995) 37–42. 30. H. Sasano, M. Uzuki, T. Sawai, et al., Aromatase in human bone tissue, J. Bone Miner. Res. 12 (1997) 1416–1423. 31. A. Purohit, A. Flanagan, M. Reed, Estrogen synthesis by osteoblast cell lines, Endocrinology 131 (4) (1992) 2027–2029. 32. S. Tanaka, Y. Haji, T. Yanase, R. Takayanagi, H. Nawata, Aromatase activity in human osteoblast-like osteosarcoma cell, Calcif. Tissue Int. 52 (1993) 107–109. 33. L. Gennari, R. Nuti, J. Bilezikian, Aromatase activity and bone homeostasis in men, J. Clin. Endocrinol. Metab. 89 (2004) 5898–5907. 34. S. Lin, R. Shi, W. Qiu, et al., Structural basis of the multispecificity demonstrated by 17beta-hydroxysteroid dehydrogenase types 1 and 5, Mol. Cell Endocrinol. 248 (2006) 38–46. 35. M. Watanabe, S. Ohno, S. Nakajin, Forskolin and dexamethasone synergistically induce aromatase (CYP19) expression in
36.
37.
38.
39.
40.
41.
42.
43.
44.
45.
46.
47.
48.
49.
50.
313
the human osteoblastic cell line SV-HFO, Eur. J. Endocrinol. 152 (4) (2005) 619–624. M. Watanabe, M. Noda, S. Nakajin, Aromatase expression in a human osteoblastic cell line increases in response to prostaglandin E(2) in a dexamethasone-dependent fashion, Steroids 72 (9-10) (2007) 686–692. A. Pino, J. Rodriguez, S. Rios, et al., Aromatase activity of human mesenchymal stem cells is stimulated by early differentiation, vitamin D and leptin, J. Endocrinol. 191 (2006) 715–725. M. Jones, W. Boon, J. Proietto, E. Simpson, Of mice and men: the evolving phenotype of aromatase deficiency, Trends Endocrinol. Metab. 17 (2006) 55–64. L. Zirilli, V. Rochira, C. Diazzi, G. Caffagni, C. Carani, Human models of aromatase deficiency, J. Steroid Biochem. Mol. Biol. 109 (3-5) (2008) 212–218. R. Bouillon, M. Bex, D. Vanderschueren, S. Boonen, Estrogens are essential for male pubertal periosteal bone expansion, J. Clin. Endocrinol. Metab. 89 (2004) 6025–6029. D. Vanderschueren, E. Van Herck, J. Nijs, A. Ederveen, Aromatase inhibition impairs skeletal modeling and decreases bone mineral density in growing male rats, Endocrinology 138 (1997) 2301–2307. S. Wickman, E. Kajantie, L. Dunkel, Effects of suppression of estrogen action by the p450 aromatase inhibitor letrozole on bone mineral density and bone turnover in pubertal boys, J. Clin. Endocrinol. Metab. 88 (2003) 3785–3789. D. Vanderschueren, E. Van Herck, R. De Coster, R. Bouillon, Aromatization of androgens is important for skeletal maintenance of aged male rats, Calcif. Tissue Int. 59 (1996) 179–183. M. Feix, L. Wolf, H. Schweikert, Distribution of 17betahydroxysteroid dehydrogenases in human osteoblast-like cells, Mol. Cell Endocrinol. 171 (2001) 163–164. T. Saloniemi, T. Lamminen, K. Huhtinen, et al., Activation of androgens by hydroxysteroid (17beta) dehydrogenase 1 in vivo as a cause of prenatal masculinization and ovarian benign serous cystadenomas, Mol. Endocrinol. 21 (11) (2007) 2627–2636. Z. Shen, Z. Peng, Y. Sun, H. Vaananen, M. Poutanen, Overexpression of human hydroxysteroid (17beta) dehydrogenase 2 induces disturbance in skeletal development in young male mice, J. Bone Miner. Res. 23 (8) (2008) 1217–1226. J. Kemppainen, E. Langley, C. Wong, K. Bobseine, W. Kelce, E. Wilson, Distinguishing androgen receptor agonists and antagonists: distinct mechanisms of activation by medroxyprogesterone acetate and dihydrotestosterone, Mol. Endocrinol. 13 (1999) 440–454. J. Miner, W. Chang, M. Chapman, et al., An orally active selective androgen receptor modulator is efficacious on bone, muscle, and sex function with reduced impact on prostate, Endocrinology 148 (2007) 363–373. G. Allan, M. Lai, T. Sbriscia, et al., A selective androgen receptor modulator that reduces prostate tumor size and prevents orchidectomy-induced bone loss in rats, J. Steroid Biochem. Mol. Biol. 103 (2007) 76–83. J. Kearbey, W. Gao, R. Narayanan, et al., Selective androgen receptor modulator (SARM) treatment prevents bone loss and reduces body fat in ovariectomized rats, Pharm. Res. 24 (2) (2007) 328–335.
314
Osteoporosis in Men
51. W. Gao, P. Reiser, C. Coss, et al., Selective androgen receptor modulator treatment improves muscle strength and body composition and prevents bone loss in orchidectomized rats, Endocrinology 146 (2005) 4887–4897. 52. S. Page, B. Marck, J. Tolliver, A. Matsumoto, Tissue selectivity of the anabolic steroid, 19-nor-4-androstenediol3beta,17beta-diol in male Sprague Dawley rats: selective stimulation of muscle mass and bone mineral density relative to prostate mass, Endocrinology 149 (4) (2008) 1987–1993. 53. E. Vajda, A. Hogue, K. Griffiths, et al., Combination treatment with a selective androgen receptor modulator (SARM) and a bisphosphonate has additive effects in osteopenic female rats, J. Bone Miner. Res. 24 (2009) 231–240. 54. R. Marcus, D. Leary, D. Schneider, E. Shane, M. Favus, C. Quigley, The contribution of testosterone to skeletal development and maintenance: lessons from the androgen insensitivity syndrome, J. Clin. Endocrinol. Metab. 85 (2000) 1032–1037. 55. E. Abu, A. Horner, V. Kusec, J. Triffitt, J. Compston, The localization of androgen receptors in human bone, J. Clin. Endocrinol. Metab. 82 (1997) 3493–3497. 56. S. Kumar, M. Saradhi, N. Chaturvedi, R. Tyagi, Intracellular localization and nucleocytoplasmic trafficking of steroid receptors: an overview, Mol. Cell Endocrinol. 246 (2006) 147–156. 57. D. Colvard, E. Eriksen, P. Keeting, et al., Identification of androgen receptors in normal human osteoblast-like cells, Proc. Natl. Acad. Sci. USA 86 (1989) 854–857. 58. C. Kasperk, A. Helmboldt, I. Borcsok, et al., Skeletal sitedependent expression of the androgen receptor in human osteoblastic cell populations, Calcif. Tissue Int. 61 (1997) 464–473. 59. U. Liegibel, U. Sommer, I. Boercsoek, et al., Androgen receptor isoforms AR-A and AR-B display functional differences in cultured human bone cells and genital skin fibroblasts, Steroids 68 (2003) 1179–1187. 60. C. Kasperk, G. Wakley, T. Hierl, R. Ziegler, Gonadal and adrenal androgens are potent regulators of human bone cell metabolism in vitro, J. Bone Miner. Res. 12 (1997) 464–471. 61. D. Benz, M. Haussler, M. Thomas, B. Speelman, B. Komm, High-affinity androgen binding and androgenic regulation of a1(I)-procollagen and transforming growth factor- steady state messenger ribonucleic acid levels in human osteoblast-like osteosarcoma cells, Endocrinology 128 (1991) 2723–2730. 62. A. Meikle, R. Dorchuck, B. Araneo, et al., The presence of a dehydroepiandrosterone-specific receptor binding complex in murine T cells, J. Steroid Biochem. Molec. Biol. 42 (1992) 293–304. 63. P. Bodine, B. Riggs, T. Spelsberg, Regulation of c-fos expression and TGF- production by gonadal and adrenal androgens in normal human osteoblastic cells, J. Steroid Biochem. Molec. Biol. 52 (2) (1995) 149–158. 64. Y. Wang, L. Wang, J. Li da, W. Wang, Dehydroepiandrosterone inhibited the bone resorption through the upregulation of OPG/RANKL, Cell Mol. Immunol. 3 (2006) 41–45. 65. K. Wrogemann, G. Podolsky, J. Gu, E. Rosenmann, A. 63-kDa protein with androgen-binding activity is not from the androgen receptor, Biochem. Cell Biol. 69 (1991) 695–701. 66. C. Pettaway, Racial differences in the androgen/androgen receptor pathway in prostate cancer, J. Natl. Med. Assoc. 91 (1999) 653–660.
67. A. Grierson, R. Mootoosamy, C. Miller, Polyglutamine repeat length influences human androgen receptor/c-Jun mediated transcription, Neurosci. Lett. 277 (1999) 9–12. 68. S. Kousteni, J. Chen, T. Bellido, et al., Reversal of bone loss in mice by nongenotropic signaling of sex steroids, Science 298 (2002) 843–846. 69. M. Lieberherr, B. Grosse, Androgens increase intracellular calcium concentration and inositol 1,4,5-triphosphate and diacylglycerol formation via a pertussis toxin-sensitive G-protein, J. Biol. Chem. 269 (1994) 7217–7223. 70. S. Windahl, R. Galien, R. Chiusaroli, et al., Bone protection by estrens occurs through non-tissue-selective activation of the androgen receptor, J. Clin. Invest. 116 (2006) 2500–2509. 71. M. Centrella, T. McCarthy, W. Chang, D. Labaree, R. Hochberg, Estren (4-estren-3alpha,17beta-diol) is a prohormone that regulates both androgenic and estrogenic transcriptional effects through the androgen receptor, Mol. Endocrinol. 18 (2004) 1120–1130. 72. B. van der Eerden, J. Emons, S. Ahmed, et al., Evidence for genomic and nongenomic actions of estrogen in growth plate regulation in female and male rats at the onset of sexual maturation, J. Endocrinol. 175 (2002) 277–288. 73. N. Sims, P. Clement-Lacroix, D. Minet, et al., A functional androgen receptor is not sufficient to allow estradiol to protect bone after gonadectomy in estradiol receptor-deficient mice, J. Clin. Invest. 111 (2003) 1319–1327. 74. S. Hewitt, J. Collins, S. Grissom, K. Hamilton, K. Korach, Estren behaves as a weak estrogen rather than a nongenomic selective activator in the mouse uterus, Endocrinology 147 (2006) 2203–2214. 75. B. van der Eerden, N. van Til, A. Brinkmann, C. Lowik, J. Wit, M. Karperien, Gender differences in expression of androgen receptor in tibial growth plate and metaphyseal bone of the rat, Bone 30 (2002) 891–896. 76. R. Gruber, K. Czerwenka, F. Wolf, G. Ho, M. Willheim, M. Peterlik, Expression of the vitamin D receptor, of estrogen and thyroid hormone receptor alpha- and beta-isoforms, and of the androgen receptor in cultures of native mouse bone marrow and of stromal/osteoblastic cells, Bone 24 (1999) 465–473. 77. I. Sinha-Hikim, W. Taylor, N. Gonzalez-Cadavid, W. Zheng, S. Bhasin, Androgen receptor in human skeletal muscle and cultured muscle satellite cells: up-regulation by androgen treatment, J. Clin. Endocrinol. Metab. 89 (2004) 5245–5255. 78. K. Murphy, S. Thomas, R. Mlcak, D. Chinkes, G. Klein, D. Herndon, Effects of long-term oxandrolone administration in severely burned children, Surgery 136 (2004) 219–224. 79. K. Wiren, X.-W. Zhang, C. Chang, E. Keenan, E. Orwoll, Transcriptional up-regulation of the human androgen receptor by androgen in bone cells, Endocrinology 138 (1997) 2291–2300. 80. K. Wiren, E. Keenan, X. Zhang, B. Ramsey, E. Orwoll, Homologous androgen receptor up-regulation in osteoblastic cells may be associated with enhanced functional androgen responsiveness, Endocrinology 140 (7) (1999) 3114–3124. 81. M. Takeuchi, H. Kakushi, M. Tohkin, Androgens directly stimulate mineralization and increase androgen receptors in human osteoblast-like osteosarcoma cells, Biochem. Biophys. Res. Commun. 204 (2) (1994) 905–911.
C h a p t e r 2 5 Androgens and Bone: Basic Aspects l
82. E. Langley, J. Kemppainen, E. Wilson, Intermolecular NH2-/ carboxyl-terminal interactions in androgen receptor dimerization revealed by mutations that cause androgen insensitivity, J. Biol. Chem. 273 (1998) 92–101. 83. K.M. Wiren, A. Chapman Evans, X.W. Zhang, Osteoblast differentiation influences androgen and estrogen receptoralpha and -beta expression, J. Endocrinol. 175 (3) (2002) 683–694. 84. E. Seeman, Osteocytes – martyrs for integrity of bone strength, Osteoporos. Int. 17 (10) (2006) 1443–1448. 85. U. Liegibel, U. Sommer, P. Tomakidi, et al., Concerted action of androgens and mechanical strain shifts bone metabolism from high turnover into an osteoanabolic mode, J. Exp. Med. 196 (2002) 1387–1392. 86. J. Kemppainen, M. Lane, M. Sar, E. Wilson, Androgen receptor phosphorylation, turnover, nuclear transport, and transcriptional activities, J. Biol. Chem. 267 (1992) 968–974. 87. T. Ikonen, J. Palvimo, P. Kallio, P. Reinikainen, O. Janne, Stimulation of androgen-regulated transactivation by modulators of protein phosphorylation, Endocrinology 135 (1994) 1359–1366. 88. L. Wang, X. Liu, W. Kreis, D. Budman, Phosphorylation/ dephosphorylation of androgen receptor as a determinant of androgen agonistic or antagonistic activity, Biochem. Biophys. Res. Commun. 259 (1999) 21–28. 89. H. MacLean, G. Warne, J. Zajac, Localization of functional domains in the androgen receptor, J. Steroid Biochem. Molec. Biol. 62 (4) (1997) 233–242. 90. I. Agoulnik, W. Bingman III., M. Nakka, et al., Target genespecific regulation of androgen receptor activity by p42/p44 mitogen-activated protein kinase, Mol. Endocrinol. 22 (11) (2008) 2420–2432. 91. M. Notelovitz, Androgen effects on bone and muscle, Fertil. Steril. 77 (Suppl 4) (2002) S34–S41. 92. C. Kasperk, R. Fitzsimmons, D. Strong, et al., Studies of the mechanism by which androgens enhance mitogenesis and differentiation in bone cells, J. Clin. Endocrinol. Metab. 71 (1990) 1322–1329. 93. L. Hofbauer, K. Hicok, S. Khosla, Effects of gonadal and adrenal androgens in a novel androgen-responsive human osteoblastic cell line, J. Cell Biochem. 71 (1) (1998) 96–108. 94. K.M. Wiren, A.R. Toombs, X.W. Zhang, Androgen inhibition of MAP kinase pathway and Elk-1 activation in proliferating osteoblasts, J. Mol. Endocrinol. 32 (1) (2004) 209–226. 95. H. Kang, C. Cho, K. Huang, et al., Nongenomic androgen activation of phosphatidylinositol 3-kinase/Akt signaling pathway in MC3T3-E1 osteoblasts, J. Bone Miner. Res. 19 (2004) 1181–1190. 96. Y. Zagar, G. Chaumaz, M. Lieberherr, Signaling cross-talk from Gbeta4 subunit to Elk-1 in the rapid action of androgens, J. Biol. Chem. 279 (2004) 2403–2413. 97. M. Lynch, C. Capparelli, J. Stein, G. Stein, J. Lian, Apoptosis during bone-like tissue development in vitro, J. Cell Biochem. 68 (1998) 31–49. 98. K.M. Wiren, A.R. Toombs, A.A. Semirale, X. Zhang, Osteoblast and osteocyte apoptosis associated with androgen action in bone: requirement of increased Bax/Bcl-2 ratio, Bone 38 (5) (2006) 637–651. 99. C. Palumbo, M. Ferretti, A. De Pol, Apoptosis during intramembranous ossification, J. Anat. 203 (2003) 589–598.
315
100. M. Miura, X. Chen, M. Allen, et al., A crucial role of caspase-3 in osteogenic differentiation of bone marrow stromal stem cells, J. Clin. Invest. 114 (2004) 704–713. 101. C. Kasperk, J. Wergedal, J. Farley, T. Linkart, R. Turner, D. Baylink, Androgens directly stimulate proliferation of bone cells in vitro, Endocrinology 124 (1989) 1576–1578. 102. C. Kasperk, K. Faehling, I. Borcsok, R. Ziegle, Effects of androgens on subpopulations of the human osteosarcoma cell line SaOS2, Calcif. Tissue Int. 58 (1996) 376–382. 103. S. Kapur, A. Reddi, Influence of testosterone and dihydrotestosterone on bone-matrix induced endochondral bone formation, Calcif. Tissue Int. 44 (1989) 108–113. 104. K.M. Wiren, A.A. Semirale, X.W. Zhang, et al., Targeting of androgen receptor in bone reveals a lack of androgen anabolic action and inhibition of osteogenesis A model for compartment-specific androgen action in the skeleton, Bone 43 (2008) 440–451. 105. D. Huber, A. Bendixen, P. Pathrose, et al., Androgens suppress osteoclast formation induced by RANKL and macrophagecolony stimulating factor, Endocrinology 142 (2001) 3800–3808. 106. Q. Chen, H. Kaji, T. Sugimoto, K. Chihara, Testosterone inhibits osteoclast formation stimulated by parathyroid hormone through androgen receptor, FEBS Lett. 491 (2001) 91–93. 107. H. Kawano, T. Sato, T. Yamada, et al., Suppressive function of androgen receptor in bone resorption, Proc. Natl. Acad. Sci. USA 100 (2003) 9416–9421. 108. Q. Chen, H. Kaji, M. Kanatani, T. Sugimoto, K. Chihara, Testosterone increases osteoprotegerin mRNA expression in mouse osteoblast cells, Horm. Metab. Res. 36 (2004) 674–678. 109. A. Falahati-Nini, B. Riggs, E. Atkinson, W. O’Fallon, R. Eastell, S. Khosla, Relative contributions of testosterone and estrogen in regulating bone resorption and formation in normal elderly men, J. Clin. Invest. 106 (2000) 1553–1560. 110. B. Leder, K. LeBlanc, D. Schoenfeld, R. Eastell, J. Finkelstein, Differential effects of androgens and estrogens on bone turnover in normal men, J. Clin. Endocrinol. Metab. 88 (2003) 204–210. 111. O. Nilsson, R. Marino, F. De Luca, M. Phillip, J. Baron, Endocrine regulation of the growth plate, Horm. Res. 64 (2005) 157–165. 112. M. Corvol, A. Carrascosa, L. Tsagris, O. Blanchard, R. Rappaport, Evidence for a direct in vitro action of sex steroids on rabbit cartilage cells during skeletal growth: influence of age and sex, Endocrinology 120 (1987) 1422–1429. 113. M. Centrella, M. Horowitz, J. Wozney, T. McCarthy, Transforming growth factor- gene family members and bone, Endoc. Rev. 15 (1994) 27–39. 114. R. Gill, R. Turner, T. Wronski, N. Bell, Orchiectomy markedly reduces the concentration of the three isoforms of transforming growth factor beta in rat bone, and reduction is prevented by testosterone, Endocrinology 139 (2) (1998) 546–550. 115. F. Gori, L. Haufbauer, C. Conover, S. Khosla, Effects of androgens on the insulin-like growth factor system in an androgenresponsive human osteoblastic cell line, Endocrinology 140 (1999) 5579–5586. 116. S. Fukayama, H. Tashjian, Direct modulation by androgens of the response of human bone cells (SaOS-2) to human parathyroid hormone (PTH) and PTH-related protein, Endocrinology 125 (1989) 1789–1794.
316
Osteoporosis in Men
117. C. Pilbeam, L. Raisz, Effects of androgens on parathyroid hormone and interleukin-1-stimulated prostaglandin production in cultured neonatal mouse calvariae, J. Bone Miner. Res. 5 (11) (1990) 1183–1188. 118. L. Hofbauer, S. Khosla, Androgen effects on bone metabolism: recent progress and controversies, Eur. J. Endocrinol. 140 (4) (1999) 271–286. 119. T. Bellido, R. Jilka, B. Boyce, et al., Regulation of interleukin-6, osteoclastogenesis, and bone mass by androgens, J. Clin. Invest. 95 (1995) 2886–2895. 120. S. Lin, T. Yamate, Y. Taguchi, et al., Regulation of the gp80 and gp130 subunits of the IL-6 receptor by sex steroids in the murine bone marrow, J. Clin. Invest. 100 (8) (1997) 1980–1990. 121. K. Venken, F. Callewaert, S. Boonen, D. Vanderschueren, Sex hormones, their receptors and bone health, Osteoporos. Int. 19 (11) (2008) 1517–1525. 122. E. Seeman, The structural and biomechanical basis of the gain and loss of bone strength in women and men, Endocrinol. Metab. Clin. North Am. 32 (2003) 25–38. 123. B. Riggs, L. Melton III., R. Robb, et al., Population-based study of age and sex differences in bone volumetric density, size, geometry, and structure at different skeletal sites, J. Bone Miner. Res. 19 (2004) 1945–1954. 124. M. Lorentzon, C. Swanson, A. Eriksson, D. Mellstrom, C. Ohlsson, Polymorphisms in the aromatase gene predict areal BMD as a result of affected cortical bone size: the GOOD study, J. Bone Miner. Res. 21 (2) (2006) 332–339. 125. D. Vanderschueren, L. Vandenput, S. Boonen, Reversing sex steroid deficiency and optimizing skeletal development in the adolescent with gonadal failure, Endocr. Dev. 8 (2005) 150–165. 126. R. Turner, B. Riggs, T. Spelsberg, Skeletal effects of estrogen, Endocrine Rev. 15 (1994) 275–300. 127. H. Lebovitz, G. Eisenbarth, Hormonal regulation of cartilage growth and metabolism, Vitam. Horm. (NY) 33 (1975) 575–648. 128. S. Ren, S. Malozowski, P. Sanchez, D. Sweet, D. Loriaux, F. Cassorla, Direct administration of testosterone increases rat tibial epiphyseal growth plate width, Acta Endocr. (Copenh) 21 (1989) 401–405. 129. S. Yeh, M. Tsai, Q. Xu, et al., Generation and characterization of androgen receptor knockout (ARKO) mice: an in vivo model for the study of androgen functions in selective tissues, Proc. Natl. Acad. Sci. USA 99 (2002) 13498–13503. 130. L. Vandenput, J. Swinnen, S. Boonen, et al., Role of the androgen receptor in skeletal homeostasis: the androgenresistant testicular feminized male mouse model, J. Bone Miner. Res. 19 (2004) 1462–1470. 131. T. Tozum, M. Oppenlander, A. Koh-Paige, D. Robins, L. McCauley, Effects of sex steroid receptor specificity in the regulation of skeletal metabolism, Calcif. Tissue Int. 75 (2004) 60–70. 132. S. Kato, T. Matsumoto, H. Kawano, T. Sato, K. Takeyama, Function of androgen receptor in gene regulations, Steroid Biochem. Mol. Biol. 89-90 (1-5) (2004) 627–633. 133. T. Matsumoto, H. Shiina, H. Kawano, T. Sato, S. Kato, Androgen receptor functions in male and female physiology, J. Steroid Biochem. Mol. Biol. 109 (3-5) (2008) 236–241. 134. D. Vanderschueren, E. Van Herck, A. Suiker, et al., Bone and mineral metabolism in the androgen-resistant (testicular feminized) male rat, J. Bone Miner. Res. 8 (7) (1993) 801–809.
135. D. Vanderschueren, E. Van Herck, P. Geusens, et al., Androgen resistance and deficiency have difference effects on the growing skeleton of the rat, Calcif. Tissue Int. 55 (1994) 198–203. 136. A. Notini, J. McManus, A. Moore, et al., Osteoblast deletion of exon 3 of the androgen receptor gene results in trabecular bone loss in adult male mice, J. Bone Miner. Res. 22 (2007) 347–356. 137. K. Venken, S. Moverare-Skrtic, J. Kopchick, et al., Impact of androgens, growth hormone, and IGF-I on bone and muscle in male mice during puberty, J. Bone Miner. Res. 22 (2007) 72–82. 138. P. Chavassieux, E. Seeman, P. Delmas, Insights into material and structural basis of bone fragility from diseases associated with fractures: how determinants of the biomechanical properties of bone are compromised by disease, Endocr. Rev. 28 (2) (2007) 151–164. 139. K. Venken, K. De Gendt, S. Boonen, et al., Relative impact of androgen and estrogen receptor activation in the effects of androgens on trabecular and cortical bone in growing male mice: a study in the androgen receptor knockout mouse model, J. Bone Miner. Res. 21 (2006) 576–585. 140. D. Somjen, Z. Mor, A. Kaye, Age dependence and modulation by gonadectomy of the sex-specific response of rat diaphyseal bone to gonadal steroids, Endocrinology 134 (1994) 809–814. 141. D. Vanderschueren, E. Van Herck, A. Suiker, W. Visser, L. Schot, R. Bouillon, Bone and mineral metabolism in aged male rats: Short and long term effects of androgen deficiency, Endocrinology 130 (1992) 2906–2916. 142. M. Ogita, M. Rached, E. Dworakowski, J. Bilezikian, S. Kousteni, Differentiation and proliferation of periosteal osteoblast progenitors are differentially regulated by estrogens and intermittent parathyroid hormone administration, Endocrinology 149 (11) (2008) 5713–5723. 143. M. Allen, J. Hock, D. Burr, Periosteum: biology, regulation, and response to osteoporosis therapies, Bone 35 (2004) 1003–1012. 144. E. Tonna, E. Cronkite, Skeletal cell labeling following continuous infusion with tritiated thymidine, Lab. Invest. 19 (5) (1968) 510–515. 145. D. Vanderschueren, I. Jans, E. van Herck, K. Moermans, J. Verhaeghe, R. Bouillon, Time-related increase of biochemical markers of bone turnover in androgen-deficient male rats, J. Bone Miner. Res. 26 (1994) 123–131. 146. B. Ongphiphadhanakul, S. Alex, L. Braverman, D. Baran, Excessive L-thyroxine therapy decreases femoral bone mineral densities in the male rat: effect of hypogonadism and calcitonin, Bone Miner. Res. 7 (1992) 1227–1231. 147. H. Rosen, S. Tollin, R. Balena, et al., Differentiating between orchiectomized rats and controls using measurements of trabecular bone density: a comparison among DXA, histomorphometry, and peripheral quantitative computerized tomography, Calcif. Tissue Int. 57 (1995) 35–39. 148. A. Ornoy, S. Giron, R. Aner, M. Goldstein, B. Boyan, Z. Schwartz, Gender dependent effects of testosterone and 17b-estradiol on bone growth and modelling in young mice, Bone Miner. 24 (1994) 43–58. 149. B.T. Kim, L. Mosekilde, Y. Duan, et al., The structural and hormonal basis of sex differences in peak appendicular bone strength in rats, J. Bone Miner. Res. 18 (1) (2003) 150–155.
C h a p t e r 2 5 Androgens and Bone: Basic Aspects l
150. G. Wakley, H. Schutte, K. Hannon, R. Turner, Androgen treatment prevents loss of cancellous bone in the orchidectomized rat, J. Bone Miner. Res. 6 (4) (1991) 325–330. 151. J. Tuukkanen, Z. Peng, H. Vaananen, Effect of running exercise on the bone loss induced by orchidectomy in the rat, Calcif. Tissue Int. 55 (1994) 33–37. 152. C. Danielsen, Long-term effect of orchidectomy on cortical bone from rat femur: bone mass and mechanical properties, Calcif. Tissue Int. 50 (1992) 169–174. 153. K. Venken, S. Boonen, E. Van Herck, et al., Bone and muscle protective potential of the prostate-sparing synthetic androgen 7alpha-methyl-19-nortestosterone: Evidence from the aged orchidectomized male rat model, Bone 36 (2005) 663–670. 154. E. Seeman, Periosteal bone formation – a neglected determinant of bone strength, N. Engl. J. Med. 349 (2003) 320–323. 155. G. Prakasam, J. Yeh, M. Chen, M. Castro-Magana, C. Liang, J. Aloia, Effects of growth hormone and testosterone on cortical bone formation and bone density in aged orchiectomized rats, Bone 24 (1999) 491–497. 156. T. Fujita, J. Ohtani, M. Shigekawa, et al., Effects of sex hormone disturbances on craniofacial growth in newborn mice, J. Dent. Res. 83 (3) (2004) 250–254. 157. C. Wink, W.L. Felts, Effects of castration on the bone structure of male rats: a model of osteoporosis, Calcif. Tissue Int. 32 (1980) 77–82. 158. M. Gunness, E. Orwoll, Early induction of alterations in cancellous and cortical bone histology after orchiectomy in mature rats, J. Bone Miner. Res. 10 (1995) 1735–1744. 159. D. Vanderschueren, L. Vandenput, S. Boonen, M. Lindberg, R. Bouillon, C. Ohlsson, Androgens and bone, Endocr. Rev. 25 (2004) 389–425. 160. M. Verhas, A. Schoutens, M. L’hermite-Baleriaux, et al., The effect of orchidectomy on bone metabolism in aging rats, Calcif. Tissue Int. 39 (1986) 74–77. 161. R. Weinstein, R. Jilka, A. Parfitt, S. Manolagas, The effects of androgen deficiency on murine bone remodeling and bone mineral density are mediated via cells of the osteoblastic lineage, Endocrinology 138 (1997) 4013–4021. 162. S. Moverare, K. Venken, A. Eriksson, et al., Differential effects on bone of estrogen receptor alpha and androgen receptor activation in orchidectomized adult male mice, Proc. Natl. Acad. Sci. USA 100 (2003) 13573–13578.
317
163. R. Jilka, K. Takahashi, M. Munshi, D. Williams, P. Roberson, S. Manolagas, Loss of estrogen upregulates osteoblastogenesis in the murine bone marrow. Evidence for autonomy from factors released during bone resorption, J. Clin. Invest. 101 (1998) 1942–1950. 164. R. Mason, H. Morris, Effects of dihydrotestosterone on bone biochemical markers in sham and oophorectomized rats, J. Bone Miner. Res. 12 (1997) 1431–1437. 165. A. Tivesten, S. Moverare-Skrtic, A. Chagin, et al., Additive protective effects of estrogen and androgen treatment on trabecular bone in ovariectomized rats, J. Bone Miner. Res. 19 (2004) 1833–1839. 166. M. Kasra, M. Grynpas, The effects of androgens on the mechanical properties of primate bone, Bone 17 (1995) 265–270. 167. A. Schoutens, M. Verhas, M. L’Hermite-Baleriaux, et al., Growth and bone haemodynamic responses to castration in male rats. Reversibility by testosterone, Acta Endocrinol. 107 (1984) 428–432. 168. D. Vanderschueren, E. Van Herck, P. Schot, et al., The aged male rat as a model for human osteoporosis: evaluation by nondestructive measurements and biomechanical testing, Calcif. Tissue Int. 53 (1993) 342–347. 169. J. Tobias, A. Gallagher, T. Chambers, 5-dihydrotestosterone partially restores cancellous bone volume in osteopenic ovariectomized rats, Am. J. Physiol. 267 (1994) E853–E859. 170. R. Turner, E. Lifrak, M. Beckner, G. Wakley, K. Hannon, L. Parker, Dehydroepiandrosterone reduces cancellous bone osteopenia in ovariectomized rats, Am. J. Physiol. 258 (1990) E673–E677. 171. C. Lea, A. Flanagan, Ovarian androgens protect against bone loss in rats made oestrogen deficient by treatment with ICI 182,780, J. Endocrinol. 160 (1999) 111–117. 172. C. Lea, A. Flanagan, Physiological plasma levels of androgens reduce bone loss in the ovariectomized rat, Am. J. Physiol. 274 (1998) E328–E335. 173. C. Lea, V. Moxham, M. Reed, A. Flanagan, Androstenedione treatment reduces loss of cancellous bone volume in ovariectomised rats in a dose-responsive manner and the effect is not mediated by oestrogen, J. Endocrinol. 156 (1998) 331–339.
Chapter
26
Androgens and the Skeleton – Humans Benjamin Z. Leder Endocrine Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
Introduction
be discussed, though the role estrogens play in male bone metabolism is discussed in greater detail in Chapter 24.
In 1940, Fuller Albright proposed that estrogen deficiency was the causative factor in postmenopausal osteoporosis, the first suggestion that gonadal steroids play an essential role in human bone metabolism [1]. Albright and colleagues then went on to demonstrate that both exogenous estrogens and androgens induce positive calcium balance in both estrogen deficient women and in eugonadal men [2]. Since these early observations, the centrality of gonadal steroid action in maintaining bone health has become well accepted and an area of intense interest in both the laboratory and the clinic. In men specifically, the role of androgens and their estrogenic metabolites in regulating the skeleton throughout life has become increasingly apparent through a large number of important observational and interventional studies. Furthermore, our understanding has moved beyond general clinical observations that relate the pubertal rise in testosterone (and estradiol) to increases in bone mineral content and the age-associated decline in androgen production to bone loss. We have now begun to characterize the molecular mechanisms by which gonadal steroids influence osteoblast and osteoclast function. Despite this increased understanding, however, much is yet to be learned concerning the relative roles gonadal steroids play in skeletal development, skeletal maintenance and in the pathophysiology of osteoporosis in men. Furthermore, the clinical potential and safety of androgen administration or other hormonal manipulations in the prevention and treatment of bone fragility in men at various stages of life remains unclear. In this chapter, we will review the role that androgens play in male skeletal metabolism, the skeletal consequences of disorders of gonadal steroid production or action and the therapeutic effects of androgen administration and manipulation in men. The relative roles of androgens and estrogens will also Osteoporosis in Men
Androgens and bone metabolism in normal men Adult bone mineral density (BMD) is determined by two factors: 1 the peak bone mass achieved during development 2 the amount of bone lost after accrual of peak bone mass. In men, gonadal steroids are among the key regulators affecting both of these processes and hence modulate bone metabolism throughout life.
Androgens and Skeletal Changes at Puberty Puberty is associated with an acceleration in linear growth and a corresponding increase in cortical and trabecular bone mass in both boys and girls [3,4]. In males, these skeletal changes are dramatic as almost 50% of adult skeleton is added between the start of puberty and the achievement of peak bone mass in the early twenties (Figure 26.1) [5–7]. While the central role of the growth hormone-insulin-like growth factor I (GH-IGF-I) axis in the stimulation of growth velocity is well demonstrated, it is also clear that gonadal steroids are crucial regulators of all phases of pubertal growth (initiation, maintenance and conclusion) and the corresponding maturation of the skeleton. The importance of androgens in the accrual of bone mass is suggested by several observations. First, the increase in bone formation rates and the accrual of bone mass in boys is associated with both pubertal stage and testosterone 319
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Osteoporosis in Men
320 1.1
Lumbar spine (L2–L4) BMD Female Male
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Femoral neck BMD Female Male
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2.0
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2 3 Pubertal stage
*
1.8
1.6
5
*
Femoral shaft BMD Female Male
g/cm2
4
*
1.4
0.2 0
1
2 3 Pubertal stage
4
5
Figure 26.1 Relation between BMD of the lumbar spine, femoral neck and femoral shaft and pubertal stage in female and male subjects. *P 0.05 for comparison between male and female subjects [5].
level [5,7,8]. Second, the absence of androgen secretion at the time of puberty results in low bone mineral content (BMC) and density even in the setting of a normal GHIGF-I axis, whereas male precocious puberty is associated with increased bone accrual [9,10]. Furthermore, androgen therapy reliably stimulates bone formation and increases BMD in males with either a delay or absence of pubertal development [11–14]. Finally, the pubertal pattern of bone accrual in genetic males with complete androgen insensitivity (CAI) caused by mutations in the androgen receptor (AR) is more similar to genetic females than genetic males despite high levels of circulating estrogens [15–18]. The extent to which differences in the adult male and female skeletal development are due to differences in pubertal gonadal steroid secretion or other genetic or environmental factors remains ill-defined. The most striking difference observed in the skeletons of men and women is in bone size and BMC [19]. For example, vertebral body size is significantly larger in males than in females throughout development [20,21]. Despite this increase in bone size (and hence BMC), however, trabecular BMD is not higher in males than in females after corrections are made for height, weight and stage of puberty [20–22]. Similarly, bone size and BMC in the appendicular skeleton, which is dominated by cortical bone, is also greater in males than in females [23–25]. These gender differences appear to extend to measures of BMD but are lessened when corrected for differences in bone size [22,26,27]. The mechanisms by which androgens may be mediating gender differences in bone size and content are currently an area of significant interest. Animal models and some human observational studies have suggested that the higher levels of androgens in males may stimulate periosteal bone formation and cortical thickening during pubertal development, whereas the higher estrogen levels in females may preferentially decrease periosteal bone formation [28]. These issues are discussed in more detail in Chapters 7–9. In the final stages of puberty, there is fusion of the epiphyses and termination of linear growth. While the process has long been known to be under the control of gonadal steroids, more recent studies have unequivocally shown that estrogens are the key hormonal regulator of this process. Specifically, several men with inactivating mutations of the aromatase genes as well as a single man with a loss of function mutation of the estrogen receptor- gene all have a phenotype characterized by severe osteopenia and prolonged linear growth without epiphyseal closure [29–33]. In the case of the men with aromatase mutations, estradiol administration dramatically increased bone mass and stimulated fusion of the epiphyses [29–31,34,35]. Additionally, recent clinical trials have demonstrated that pharmacological aromatase inhibition can delay skeletal maturation and hence increase linear growth in diverse clinical settings [36–40]. Taken together, these observations demonstrate that while gonadal steroids are important modulators of
C h a p t e r 2 6 Androgens and the Skeleton – Humans l
the pubertal increase in bone mass in males, some of the actions previously ascribed to androgens are mediated through their metabolism to estrogens.
Androgens and Skeletal Changes in Aging Just as puberty is associated with increased gonadal steroid production and rapid skeletal accrual, aging in men is associated with decreased gonadal steroid production and bone loss. While this decline in androgen production with aging in men is not completely analogous to the termination of ovarian estradiol production (and accompanied accelerated bone loss) experienced by women during the menopausal transition, the more modest reduction of gonadal steroid production is associated with diverse physiological consequences that include effects on skeletal integrity. The issue of hormonal changes in the aging male is clinically important. As life expectancy has increased over the past several generations, the population of the USA has aged dramatically. Whereas in 2000 the proportion of persons over the age of 65 in the USA was 12.4%, it is expected to rise to 19.6% by 2030 with over 19.5 million individuals being over the age of 85 [41]. Numerous studies have shown that aging in men is associated with a slow, steady decline in gonadal androgen production [42–51]. Most studies also report that circulating levels of estrogens also decrease as men age, although the decrease in estradiol is less dramatic than the decrease in testosterone (Figures 26.2A and B, respectively) [52]. This decline in gonadal steroid function leads to an incidence of classically defined hypogonadism of greater than 20% and a more global general reduction in androgen production as compared to the peak levels achieved in early adulthood [48,51]. Moreover, a recent report has suggested that this age-related decline in androgen production is superimposed upon an ageindependent population-level decrease in androgen production, at least in American men [53]. Numerous skeletal changes occur in men as they age, only some of which may be related to changes in gonadal steroid physiology (discussed in detail in Chapters 13–18). Clearly, fracture rates in men increase dramatically in the eighth and ninth decades of life [54], though changes in BMD and bone geometry likely occur earlier [54,55]. The exact pattern of age-related bone loss in men is controversial and the differences between reported rates in various studies are likely related to differences in skeletal imaging techniques (dual x-ray absorptiometry (DXA) versus quantitative computerized tomography (QCT)) and differences in the site of interest (trabecular versus cortical bone). Generally, it appears that trabecular bone loss begins early in adulthood whereas cortical bone loss does not begin until middle life [56,57]. This loss in trabecular bone is well illustrated in Figure 26.3. More recently, a longitudinal population-based study utilizing high-resolution peripheral quantitative computerized tomography (pQCT) seems to
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confirm these findings [58]. The extent to which declining androgen levels are associated with fracture, bone mineral density or bone loss in men is discussed below.
Relationship Between Androgens and Skeletal Parameters in Men Many observational studies have explored the relationship between variables related to skeletal health (fracture rates, BMD, biochemical markers of bone turnover, rates of bone loss) and gonadal steroid indices (serum total, bioavailable and free gonadal steroid levels, gene polymorphisms related to steroid metabolism). The results of these investigations have yielded conflicting results, a fact that is likely attributable to differences in study methodology (small sample sizes, homogeneous study populations, gonadal steroid assay performance, varying statistical methodologies) [58– 77]. Additionally, there are limitations in trying to associate a single serum hormone level to variables related to skeletal health that represents a lifetime of bone metabolism. Nonetheless, important themes have emerged from these studies, including the observation that there are associations between bone-health related variables and gonadal steroids, with sometimes stronger associations observed between estradiol and BMD than between testosterone and BMD. Recently, important studies have emerged from larger cohorts of men that provide some of the most definitive data in this area. The Boston Area Community Health Bone Survey (BACH/Bone) is a cross-sectional study of skeletal health in 1219 ethnically diverse men between the ages of 30 and 79. In this cohort, BMD at various sites did not correlate with either total or calculated free testosterone whereas femoral neck and total hip BMD were associated with total and calculated free estradiol levels even after multivariate adjustment. Additionally, these patterns of association were unaffected by ethnic or racial background [78]. While the BACH/Bone reported associations among men of diverse ages, the larger Osteoporotic Fractures in Men Study (MrOS) studied men over the age of 65 (n 2447) recruited from six distinct cities in the USA. In this cohort, the relationship between gonadal steroid level and skeletal parameters was assessed in a manner to maximize clinical relevance. Specifically, the relationship between each subject’s gonadal steroid status (eugonadal, borderline hypogonadal or hypogonadal) and incident osteoporosis or rapid bone loss was assessed in a combined cross-sectional and longitudinal approach [79]. Men were categorized as being either osteoporotic or osteopenic based on comparisons with a male specific database and established World Health Organization criteria (T 2.5 and T between 2.5 and 1, respectively) while their gonadal steroid status is shown in Table 26.1. The prevalence of osteoporosis in the hip was higher in the testosterone deficient group (12.2%) than the possibly deficient and normal groups (4.1% and 6.0%, respectively). Similarly, the prevalence of osteoporosis in the hip
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Plasma hormone concentration (pg/ml)
25
20
15
10
5
Estradiol Bioavailable estradiol
0 <50 (n = 27)
50–54 (n = 27)
55–59 (n = 81)
60–64 65–69 70–74 75–79 80–84 >84 (n = 84) (n = 109) (n = 98) (n = 219) (n = 102) (n = 34)
(A)
Age group
Plasma hormone concentration (pg/ml)
3500 3000 2500 2000
Testosterone Bioavailable testosterone
1500 1000 500 0
<50 50–54 55–59 60–64 65–69 70–74 75–79 80–84 >84 (n = 27) (n = 27) (n = 81) (n = 84) (n = 109) (n = 98) (n = 219) (n = 102) (n = 34)
(B)
Age group
Figure 26.2 (A) Levels of endogenous total and bioavailable estradiol in 810 men aged 24–90 years, by 5-year age group, Rancho Bernardo,California, 1984–1993. Data were adjusted for multiple covariates, including body mass index, waist:hip ratio, alcohol intake (g/week), smoking (cigarettes/day), sample storage time (months) and caffeine intake (g/month) [52]. (B) Levels of endogenous total and bioavailable testosterone in 810 men aged 24–90 years, by 5-year age group, Rancho Bernardo, California, 1984–1993. Data were adjusted for multiple covariates, including body mass index, waist:hip ratio, alcohol intake (g/week), smoking (cigarettes/day), sample storage time (months) and caffeine intake (g/month) [52].
was higher in the estradiol deficient group (15.4%) than the possibly deficient and normal groups (5.9% and 2.8%, respectively). The prevalence of testosterone and estradiol deficiency was also higher in the groups with osteoporosis compared with men with bone density in the osteopenic or normal range (6.9% versus 2.4% and 3.2% for testosterone deficiency and 9.2% versus 3.3% and 2.4% for estradiol). Furthermore, rapid bone loss, defined as annualized rate of bone density loss 3% at the femoral neck or total hip, was also associated with lower levels of testosterone
and estradiol levels. After adjustment for age, weight and baseline BMD, however, the relationship between rapid bone loss and estradiol was not statistically significant. Additionally, while no threshold level of estradiol was associated with either the prevalence of osteoporosis or bone loss, a testosterone level of less than 200 ng/dl did appear to be a threshold for rapid bone loss. Finally, subsequent analyses revealed that lower levels of both bioavailable testosterone and estradiol exacerbated the decline in hip BMD that is associated with weight loss in older men [80].
C h a p t e r 2 6 Androgens and the Skeleton – Humans
Vertebral total vBMD mg/cm3
l
300
200
100 0 20
40
60
80
100
Age years
Figure 26.3 Values for vBMD (g/cm3) of the total vertebral body (80% trabecular bone) of the population sample between 20 and 97 years of age. Individual values and smoother lines are given for premenopausal women in circles, for postmenopausal women in triangles and for men in crosses [57].
Table 26.1 Gonadal steroid status in the Osteoporotic Fractures in Men Study Deficient
Possible deficient
Normal
Testosterone (ng/dl)
200
200–400
400
Estradiol (pg/ml)
10
10–20
20
The Mr OS study is complemented by an analogous study of 3000 men between the ages of 69 and 80 that is currently underway in Sweden (MrOS Sweden). In this study, total and free levels of both testosterone and estradiol predicted BMD at each measured site, even after correction for multiple confounding variables [81]. Furthermore, when free testosterone and estradiol were simultaneously included in the regression model (to assess the independent predictive value of each hormone separately), free testosterone remained a predictor of BMD at all sites except the lumbar spine and free estradiol remained a predictor at all skeletal sites. Several differences in the relationship between skeletal parameters, testosterone and estradiol were found, however. Specifically, free estradiol below the median did not predict any fracture-related endpoint (fracture after the age of 50, osteoporosis related fracture, x-rayverified fracture or height loss) whereas estradiol levels in the lowest 10th percentile did. Conversely, free testosterone below the median predicted most fracture indices in men. Notably, the predictive value of free testosterone was not affected by adjustment for BMD, suggesting that the relationship between androgen levels and fracture is not mediated solely by the relationship between androgens and bone mineral density. It is thus likely that testosterone may be influencing other factors related to fracture risk, such as
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bone geometry, bone quality (including microarchitecture) or risk of falls (coordination, neuromuscular function). This latter possibility is supported by data from the MrOS cohort which separately reported that the risk of falling was higher in men with lower bioavailable testosterone levels [82]. Finally, in a follow-up analysis from MrOS Sweden, serum levels of biologically inactive conjugated androgen metabolites were shown to be even stronger predictors of BMD in older men than their corresponding non-conjugated bioactive hormones, perhaps due to the comparatively lower dayto-day variability in the metabolites when compared to the circulating active hormones [83]. While the relationships between bone and gonadal steroids levels have been evaluated in some depth, the independent influence of sex-hormone binding globulin (SHBG) in male bone metabolism has also received attention. For example, in MrOS Sweden, it was reported that after multivariate regression, lower serum free estradiol levels and higher serum SHGB levels, but not testosterone, were independently associated with increased fracture risk [84]. Indeed, the independent influence of SHBG is illustrated by the fact that the hazard ratio for fracture incidence remains elevated in subjects with higher SHBG levels even if their estradiol levels are normal or high. In further support for a role of SHBG, the MrOS cohort was combined with a cohort of younger men (age 18–20) enrolled in the Gothenburg Osteoporosis and Obesity Determinants (GOOD) study and polymorphisms in the SHBG promoter, serum SHBG levels, gonadal steroid levels and BMD were assessed. In this analysis, variants in the SHBG promoter gene that are associated with higher serum levels of SHBG were positively related to BMD [85]. Furthermore, the level of serum testosterone did not affect the association between SHBG and BMD, suggesting a direct effect of SHBG on the skeleton and challenging orthodoxy of the long-held ‘free hormone hypothesis’. Indeed, while the possibility that SHBG may directly affect bone metabolism had been suggested in a mouse model demonstrating that megalin, an endocytic receptor, can act as a pathway for cellular uptake of biologically active androgens and estrogens bound to SHBG [86], the GOOD findings remain somewhat in contrast to the majority of studies that report a negative relationship between serum SHBG and bone density [84, 87–89]. Taken together, these observational studies have moved the field forward significantly. Specifically, the scope of the MrOS studies has allowed us to confirm much of what has been observed in smaller studies about the integral role of both estradiol and testosterone in male metabolism, particularly in aging. Moreover, the results from these more recent studies challenge some hypotheses (such as a threshold estradiol serum level necessary for maintaining skeletal integrity in men) while supporting others (such as a potential independent role for SHBG in modulating bone metabolism in men).
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Bone mineral density in men with hypogonadism or other disorders of androgen action Depending on the definition used, hypogonadism is present in up to a third of men with documented osteoporosis and men with hypogonadism are 6.5 times more likely to have a minimal trauma hip fracture than are eugonadal men [90–92]. The skeletal phenotype of hypogonadal males depends on multiple factors including the age of onset, the degree of decreased gonadal steroid production and the absence or presence of concurrent hormonal disorders. Nonetheless, conditions of gonadal steroid deficiency, though diverse, underscore the integral importance of normal gonadal function in male bone integrity. Furthermore, the study of these conditions provides a fertile area to increase our understanding of the effects of gonadal steroids on the skeleton.
Skeletal Health in Men with Primary Hypogonadism and Klinefelter’s Syndrome Men who have undergone castration frequently develop osteoporosis and fracture (the effects of gonadotropin-releasing hormone (GnRH) analogs are discussed below) [93,94]. Osteopenia is also observed in hypogonadal patients with hemochromatosis, although these patients may have either primary or secondary hypogonadism [95]. Klinefelter’s syndrome (XXY male syndrome), the most common congenital cause of male hypogonadism, also appears to be associated with low bone mass, although studies have produced mixed results. Several reports have concluded that patients with Klinefelter’s syndrome (KS) have reduced BMD [96–99], although others found normal bone mass [100]. Reports of BMD in these men may be confounded by the heterogeneity in the degree of hypogonadism, the relatively higher estrogen/androgen ratio in patients with KS and the possible effects of the underlying genetic abnormality.
Skeletal Health in Men with Secondary Hypogonadism Men with pituitary tumors often display varying degrees of gonadal steroid deficiency and thus provide a model of potentially reversible adult onset hypogonadism. For example, both cortical and trabecular bone mineral density are reduced in men with hyperprolactinemic hypogonadism and the degree of cortical BMD reduction is associated with the duration of hyperprolactinemia [101]. Furthermore, when these men are treated medically, surgically or with radiation therapy, those in whom testosterone levels normalize experience significant increases in BMD [102]. Idiopathic hypogonadotropic hypogonadism (IHH) provides a purer model of secondary hypogonadism. IHH is a congenital abnormality characterized by the inability to secrete gonadotropin-releasing hormone (GnRH). Men with
this disorder are hypogonadal, do not have other hormonal abnormalities and have marked reduction in both cortical and trabecular bone density [9]. Moreover, when men with IHH are rendered eugonadal for 2 years (using pulsatile GnRH, human chorionic gonadotropin (hCG) or testosterone), cortical BMD increases slightly in those with closed epiphyses whereas both trabecular and cortical BMD increase in men with open epiphyses [11]. Importantly, BMD remains lower in men with IHH even after treatment and the severity of the osteopenia in IHH appears to be negatively associated with the age of initial therapy [103].
Skeletal Health in Men Receiving GnRH Analogs Androgen deprivation therapy (ADT) via GnRH analogs (or less commonly orchiectomy) has become the mainstay of treatment in men with advanced prostate cancer and the use of these drugs represents a new challenge in the maintenance of skeletal health in older men. GnRH analogs cause reversible and near-complete inhibition of gonadal steroid production. This inhibition, in turn, leads to an acute increase in bone resorption (and later formation) that is partially prevented by the administration of either pure androgen or estrogen and completely prevented by the administration of both (Figure 26.4) [104–106]. Numerous studies have demonstrated that long-term exposure to these drugs causes significant bone loss at both trabecular and cortical sites [107,108]. As shown in Figure 26.5, the pattern of GnRH-associated bone loss is somewhat analogous to the bone loss that occurs in postmenopausal women in that the rate of bone loss is greatest in patients newly treated but continues at a slower rate even after long-term therapy, especially at cortical sites such as the radius [109]. Moreover, this bone loss has significant clinical consequences. In large medical claims databases (which likely under-represent the actual risk), fracture rates at most anatomic sites are significantly higher in men with prostate cancer receiving ADT than in controls [110,111]. As shown in Figure 26.6, this risk only increases with sustained therapy. Given that men with locally advanced prostate cancer have significant long-term survival and may be treated with lifelong ADT, it is likely that the clinical impact of GnRH analog therapy will continue to grow in the coming decades. Fortunately, ADT-associated bone loss appears to respond well to standard anti-resorptive therapy, despite the castrate circulating levels of gonadal androgens and estrogens that these patients experience [107,112].
Skeletal Health in Genetic Males with Androgen Insensitivity Patients with complete androgen insensitivity syndrome (AIS) are genetic males who lack androgen receptor activity. These patients are phenotypically female but have male
C h a p t e r 2 6 Androgens and the Skeleton – Humans
325
l
N-telopetide levels before and after 6 weeks of GnRH analog therapy 26
*
nmol/L
24
*
*
22
* 20 18 16
Group 1 (–T–E)
Group 2 (+T–E)
Group 3 (–T+E)
Week 0
Group 4 (+T+E)
Week 6
Figure 26.4 58 healthy men between the ages of 20 and 45 were randomized to receive a GnRH analog, an aromatase inhibitor and hormone add-back therapy to produce the following treatment groups: (1) estradiol and testosterone deficient group (T E); (2) estradiol deficient but testosterone sufficient group (T E); (3) estradiol sufficient and testosterone deficient group (T E); (4) estradiol and testosterone sufficient group (T E). Mean (SEM) serum NTX levels baseline and after 6 weeks of therapy are shown. *P 0.001 compared with wk 0 [106]. Control PCA no ADT 2
PA spine
e
1
PCA chronic ADT PCA acute ADT
0
0 Change in bone mineral density (%)
a
–4
d
0
2
6 Trochanter d
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–3 12
–4 2
e
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–1
–1 b
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be
–4
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6 Femoral neck d
1
12
e
0 a
–1
0
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be
–2
ce
–3 12
e
–3
–2 ce
–3
6
1
bd
–2 ce
0
e
–1
cd
–2 be
Total radius
0
–1 –2
–6
1
Total body
12
–3
0
6 Months
12
Figure 26.5 Percent change in BMD at the PA spine, total body, total radius, trochanter, total hip and femoral neck in men with prostate cancer (PCA) and healthy controls. Results are shown as mean SE. (a) P 0.05, acute androgen deprivation therapy (ADT) versus no ADT; (b) P 0.05, acute ADT versus no ADT and healthy controls; (c) P 0.05, acute ADT versus no ADT, healthy controls, and chronic ADT; (d) P 0.05, percent change from baseline to 6 months; (e) P 0.05, percent change from baseline to 12 months [109].
internal reproductive organs. Circulating levels of testosterone and estradiol in women with AIS are generally elevated compared to normal males. Because they are completely unresponsive to androgens, however, these patients provide
a valuable model to assess the specific effects of lifelong androgen deficiency on the accrual of peak bone mass. The model is far from perfect, however, as their elevated estradiol levels prior to gonadectomy, the differences in the
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Osteoporosis in Men No androgen deprivation (N = 32,931)
Unadjusted fracture-free survival (%)
100
GnRH agonist, 1–4 doses (N = 3763)
90 80 70 GnRH agonist, 5–8 doses (N = 2171)
60 50
GnRH agonist, ≥9 doses (N = 5061)
40 30
Orchiectomy (N = 3399)
20 10 0 1
2
3
7 4 5 6 Years after diagnosis
8
9
10
Figure 26.6 Unadjusted fracture-free survival among patients with prostate cancer, according to androgen deprivation therapy. The curves start at 12 months after diagnosis and androgen deprivation was initiated within 6 months after diagnosis. GnRH denotes gonadotropinreleasing hormone. The number of doses is the number administered within 12 months after diagnosis [110].
timing of gonadectomy in these patients and differences in the age of onset and duration in the prescribed treatment with pharmacological doses of estrogens, may confound clinical observations. Case reports of women with AIS have generally reported varying degrees of osteopenia [113]. In a more systematic review, BMD was measured in 28 women with AIS (22 complete and 6 high-grade partial), aged 11– 65 [16]. In subjects with complete AIS, the mean lumbar BMD was reduced when compared with age-matched controls, although hip BMD was similar. BMD was normal in subjects with partial AIS. Women who reported good compliance with estrogen therapy had higher BMD than those who had been less compliant. When ‘bone mineral apparent density’ (a calculated measure that adjusts for differences in bone size) was used as the primary variable, however, even estrogen compliant women had lower spine and hip BMD compared to age-matched women. Furthermore, when BMD in these patients was compared to male standards, the reductions were even more profound. Together, these findings suggest that the osteopenia in women with complete AIS may be due to a specific role of androgen action in skeletal accrual.
Skeletal Health in Men with Histories of Delayed Puberty Delayed puberty is defined by the absence or incomplete development of secondary sexual characteristics by an age at least 2 standard deviations below the mean of gender and culture-matched children. Men with histories of constitutionally-delayed puberty (CDP) meet this definition but do not have a permanent defect in gonadal steroid function or sensitivity. As such, they provide a useful model to test
the hypothesis that the timing of puberty can affect skeletal integrity even in men who later develop into eugonadal adults. Bone accrual is clearly delayed in these patients [114]. More importantly, some studies, but not all, suggest that these skeletal defects persist into adulthood [115,116]. For example, in a study of 23 men with CDP and 21 healthy controls, radial BMD, spinal BMD and femoral BMD were lower in the men with histories of CDP (all of whom eventually underwent pubertal development without having received hormone therapy) compared to controls. The magnitude of the effect and the individual subject variability in radial BMD are illustrated in Figure 26.7 [115]. Moreover, these differences between men with CDP and controls persist even after adjustment for bone size [117]. Thus, it appears that the normal timing of gonadal steroid secretion at puberty may be necessary to achieve peak bone, although larger samples of similar subjects are needed.
Skeletal Health in Men Taking 5-Reductase Inhibitors In many target tissues, such as skin and prostate, the actions of testosterone are substantially mediated by its conversion to dihydrotestosterone (DHT) via the enzymes 5-reductase types I and II. In vitro studies have shown that testosterone can also be converted to DHT within human bone and that DHT potently stimulates osteoblast proliferation [118,119]. Conversely, BMD is normal in men with 5-reductase deficiency [17]. Nonetheless, given the increased therapeutic use of 5-reductase inhibitors for the treatment of benign prostatic hyperplasia, potential skeletal effects have been an area of interest. Reassuringly, data from clinical trials have shown that finasteride, a 5-reductase inhibitor that predominantly
C h a p t e r 2 6 Androgens and the Skeleton – Humans l
techniques aimed at assessing skeletal fragility. Moreover, these studies have sometimes reported conflicting results, likely due to differences in the degree of underlying hypogonadism (if any) in the study populations, differences in the previous treatment status of the subjects and differences in the prescribed androgen regimen (dose, mode of delivery, aromatizable versus non-aromatizable).
1.0
Radial bone density (g/cm2)
0.9
0.8
Effects of Androgen Replacement in Hypogonadal Men
0.7
0.6
0.5
327
Men with delayed puberty
Normal men
Figure 26.7 Radial BMD in 23 men with constitutional delay of puberty (CDP) and 21 normal men. The horizontal lines indicate the group means and the shaded areas the mean 1 SD and 2 SD for the normal men. The mean values in the two groups were significantly different (P 0.0002) [115].
inhibits the type II isoenzyme, does not affect bone turnover or BMD [120–122]. Additionally, a recent populationbased case control study reported that hip fracture rates were actually decreased in finasteride users [123]. Whether this decreased hip fracture rate is a true phenomenon (possibly mediated through increased estrogen production in the setting of finasteride), however, remains unclear. Nonetheless, current data suggest that DHT does not play a crucial role in male bone homeostasis, although it remains possible that selective inhibition of 5-reductase type I (the predominant isoenzyme in bone) would uncover skeletal abnormalities that have thus far not been identified.
Effects of androgen therapy on skeletal integrity in men Pharmacological and physiological androgen administration can have profound effects on various aspects of body composition in men including the skeleton. Thus, the therapeutic potential of exogenous androgen administration in treating or preventing skeletal fragility is an area of great interest in both hypogonadal men and in elderly men with declining androgen production. Nonetheless, while the antifracture efficacy of estrogen replacement in postmenopausal women is well established, studies of androgen administration in men have been limited to smaller clinical trials utilizing intermediate endpoints such as changes in biochemical markers of bone turnover, BMD or other imaging
While several randomized controlled trials have assessed the skeletal effects of testosterone treatment in unequivocally hypogonadal men, the interpretation of these studies has been limited by their small sample sizes, heterogeneous study populations, differing modes of androgen therapy and reliance on surrogate markers of fracture risk reduction. Nonetheless, most studies of androgen administration in hypogonadal men have reported decreases in biochemical markers of bone turnover and beneficial effects on both cortical and trabecular BMD, regardless of the underlying etiology of the hypogonadism [11,124–127]. For example, androgen replacement increases BMD in men with IHH, (particularly in those with open epiphyses) [11], in hypogonadal men with hemochromatosis [126] and in men with acquired primary or secondary hypogonadism of various causes [124,125]. Additionally, it appears that men who had never been treated with androgens had greater increases in BMD compared to those who had been previously exposed [125]. Recently, however, a meta-analysis evaluated the cumulative results in this area by combining data from eight studies that utilized randomized placebo-controlled methodology and reported that, compared with placebo, intramuscular testosterone was associated with an 8% gain in lumbar bone mineral density whereas transdermal testosterone, with more physiologic dosing, had no significant effect [128]. Furthermore, the study reported that testosterone use (through either route) was not associated with a significant gain in femoral neck bone mineral density. These somewhat surprising results are likely related to the fact that the authors chose to include studies from diverse populations, including some who were not clearly hypogonadal or subjects with significant co-morbid illnesses known to affect bone metabolism. Nonetheless, the lack of robust placebo-controlled data in younger unequivocally hypogonadal men remains an issue, albeit one that may not be soon addressed given that testosterone replacement in this population has become established therapy for reasons which extend beyond effects on bone health. Recently, newer imaging techniques have attempted to go beyond BMD in the assessment of androgen effects in hypogonadal men. In the first study of its kind, 10 untreated severely hypogonadal men underwent an assessment by magnetic resonance micro-imaging (microMRI) of the distal tibia and by DXA of the spine and hip before and after two years of testosterone therapy [129]. Unlike standard DXA,
Osteoporosis in Men
microMRI’s increased resolution allows for an assessment of trabecular architecture that previously was available only through bone biopsy. After 24 months of testosterone treatment, BMD of the spine increased 7.4%, BMD of the total hip increased by 3.8% and architectural parameters assessed by microMRI also improved significantly. It is likely that microMRI as well as other techniques, such as pQCT, will continue to define the effects of testosterone therapy more thoroughly in a variety of clinical settings.
Effects of Androgen Replacement in Elderly Men with Declining Androgen Production The effects of androgen administration on the skeleton and other organs systems in elderly men with borderline or modest hypogonadism (i.e. men over 55–60 with serum testosterone levels below the lower limit of normal in young healthy men) is currently an area of great interest and subject of numerous controlled and uncontrolled studies [130]. Placebo controlled studies have been limited, however, and report conflicting results [131–135]. Contrasting two of the larger studies demonstrates how study design likely contributes to these conflicting outcomes. In one study, 108 men over 65 were randomized to receive a testosterone patch or a placebo patch for 36 months [133]. The majority of these subjects did not have osteoporosis by current WHO criteria nor were they hypogonadal (mean testosterone level 367 ng/dL). In the study’s primary analysis related to bone health, BMD of the lumbar spine did not increase more in the treated group than it did in the placebo group (Figure 26.8). In a post-hoc secondary linear regression analysis, however, the authors reported that there was a significant relationship between a subject’s pretreatment serum testosterone concentration and the effect of testosterone treatment on lumbar spine bone density. In a subsequent study, 70 men over age 65 were randomly assigned to receive either intramuscular testosterone, intramuscular testosterone plus finasteride or placebo injections and pills for 36 months [136]. These subjects were more clearly hypogonadal (mean testosterone levels between 286 and 303 ng/dL) and the administered testosterone dose (200 mg testosterone enanthate IM every 2 weeks) was likely supraphysiologic. In contrast to the study described above, BMD at a variety of sites (including the PA spine) increased more in the testosterone-treated groups versus the placebo group (Figure 26.9). These increases in BMD were associated with decreases in biochemical markers of bone resorption and were not affected by concomitant finasteride treatment. Importantly, however, the magnitude of the increases in BMD observed even with this supraphysiological testosterone regimen, were not substantially different than the increases observed with bisphosphonate or teriparatide therapy in men with osteoporosis even in the setting of hypogonadism [92,137]. Recently, the skeletal effects of a novel method of increasing endogenous androgen production were studied
105 Bone mineral density, L2–L4 (% basal)
328
104 Testosterone 103 102 101 Placebo 100 99 0
6
12
18
24
30
36
Time (months)
Figure 26.8 Mean (SE) bone mineral density of the lumbar spine (L2–L4) as a percentage of the basal value in 108 men over 65 years of age who were treated with either testosterone or placebo (54 men each). Bone mineral density increased significantly (P 0.001) from 0 to 36 months in both groups, but the increase was not significantly different between the two groups at 36 months [133].
in older men with mild hypogonadism. Specifically, the aromatase inhibitor, anastrozole, was administered to men over age 60. Because estradiol is the major negative regulator of hypothalamic and pituitary stimulation of the gonads in men, administration of this drug in older men increases serum bioavailable and total testosterone levels to the youthful normal range while reducing estradiol levels only modestly (and within the normal range) [138]. Despite this increase in androgen production, however, no effect on bone turnover was observed [139]. Taken together, it seems clear that the role of exogenous testosterone administration in improving skeletal parameters in older men with declining androgen production remains unproven. Furthermore, there remains theoretical safety concerns regarding testosterone therapy in an older population along with still unproven efficacy in other organ systems and in subjective measures such as health-related quality of life. As suggested by the Institute of Medicine [140], larger clinical trials are now needed to define the role of androgens more clearly in this growing population of men.
Effects of Dehydroepiandrosterone (DHEA) in Men DHEA and its sulfate DHEAS are derived from the adrenal glands in both sexes. These steroids circulate in the serum and are believed to exert their physiological effects by their conversion to more potent androgens and estrogens in peripheral tissues. Similar to, but to an even greater degree than gonadal androgens, the production of DHEA decreases with aging in men, a fact that has led to hypotheses regarding a potential
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Figure 26.9 Mean percentage increase ( SEM) in BMD of the lumbar spine (A), trochanteric (B), total hip (C) and intertrochanteric (D) regions in older men with low testosterone (T) who were treated with either T (T-only), testosterone plus finasteride (T F) or placebo for 36 months. *, P 0.05 compared with baseline and placebo [136].
role for DHEA in the physiological deterioration of aging, including the development of skeletal fragility. Nonetheless, observational studies have failed to find an association between circulating DHEA or DHEAS levels and BMD or fracture in men [61,141]. Furthermore, several randomized controlled trials have investigated the effects of DHEA on bone metabolism and BMD in older men and have generally been disappointing. Despite the administration of doses of DHEA that increased serum DHEAS levels by several fold (and well within the youthful normal range), the effects on biochemical markers of bone turnover and BMD have generally been either statistically or clinically insignificant [135,142–144].
Effects of Supraphysiological Androgen Administration in Normal Men While pharmacologic doses of testosterone have been administered to men in a variety of clinical settings, the effects of these large doses of androgens on the skeleton have not been well defined. In a small prospective study, testosterone enanthate (200 mg/week) was administered to 13 healthy men and their skeletal responses were compared to eight healthy controls [145]. BMD at most skeletal sites increased in the treated men. Moreover, this increase in BMD occurred in the
setting of increases in serum osteocalcin but no change in urinary hydroxyproline, suggesting that high-dose testosterone may stimulate osteoblast function, although this remains unproven. In a separate uncontrolled prospective clinical trial, 23 men aged 34–73, all of whom had vertebral fractures, were treated with relatively high dose parenteral testosterone every two weeks for 6 months [146]. Mean bone mineral density at the lumbar spine increased by about 5% whereas hip BMD did not change. Biochemical markers of bone turnover were reduced slightly but these changes were not significant. In a more recent study, 237 healthy men were first treated with a GnRH analog to inhibit endogenous gonadal steroid production and then randomized to receive either placebo or one of four doses of topical testosterone for 16 weeks [147]. The range of doses of testosterone administered to the subjects resulted in serum testosterone levels that ranged from profoundly hypogonadal to modestly supraphysiological. Biochemical markers of bone formation and resorption increased in men receiving either no testosterone or subphysiological doses of testosterone (resulting in serum levels below approximately 200 ng/dL), but remained stable in the men who received higher doses of testosterone, including the group who received as much as twice the normal replacement dose. No effects on BMD were observed though this may have been related to the short duration of treatment.
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Summary and future directions While our understanding of the role androgens play in male skeletal biology has grown dramatically in the past decade, much is still unknown, both in terms of the mechanisms by which androgens affect bone as well as the true therapeutic potential of androgens in diverse clinical settings. Nonetheless, while conflicting study results make many definitive conclusions impossible, several conclusions are clearly supported. First among these conclusions is that gonadal steroids (both androgens and estrogens) play an integral role in male skeletal development. Boys who lack gonadal steroids at puberty do not accrue bone normally and boys who do not produce or respond to estrogens cannot complete skeletal maturation. Also clear is that men who become hypogonadal in adulthood experience increased bone turnover, lose bone and, in the setting of severe gonadal steroid deprivation, will experience increased fracture risk. Moreover, this hypogonadism-associated increase in bone turnover can be partially inhibited by androgens or estrogens but the combination is required for complete normalization. Therapeutically, it is clear that androgen administration increases bone mineral density in unequivocally hypogonadal men but its ability to increase bone mineral density in older men with mild hypogonadism remains unproven. Also unproven is whether androgen administration can safely be given to older men for prolonged periods or whether androgen administration will reduce the risk of osteoporotic fracture in any clinical setting. It is hoped that future research in this area will focus not only on the mechanisms by which androgens exert their influence on the skeleton, but also in the larger clinical questions that will undoubtedly require investment in large clinical trials and other human studies.
References 1. F. Albright, E. Bloomberg, P.H. Smith, Post-menopausal osteoporosis, Trans. Assoc. Am. Phys. 55 (1940) 298–305. 2. E.C. Reifenstein, F. Albright, The metabolic effects of steroid hormones in osteoporosis, J. Clin. Invest. 26 (1947) 24–56. 3. V. Gilsanz, Accumulation of bone mass during childhood and adolescence, in: E. Orwoll (Ed.), Osteoporosis in Men, Academic Press, San Diego, 1999, pp. 65–85. 4. R.J. Perry, C. Farquharson, S.F. Ahmed, The role of sex steroids in controlling pubertal growth, Clin. Endocrinol. (Oxf) 68 (1) (2008) 4–15. 5. J.P. Bonjour, G. Theintz, B. Buchs, D. Slosman, R. Rizzoli, Critical years and stages of puberty for spinal and femoral bone mass accumulation during adolescence, J. Clin. Endocrinol. Metab. 73 (3) (1991) 555–563. 6. V. Gilsanz, D.T. Gibbens, T.F. Roe, et al., Vertebral bone density in children: effect of puberty, Radiology 166 (3) (1988) 847–850. 7. B.J. Riis, S. Krabbe, C. Christiansen, B.D. Catherwood, L.J. Deftos, Bone turnover in male puberty: a longitudinal study, Calcif. Tissue Int. 37 (3) (1985) 213–217.
8. S. Krabbe, C. Christiansen, Longitudinal study of calcium metabolism in male puberty. I. Bone mineral content, and serum levels of alkaline phosphatase, phosphate and calcium, Acta Paediatr. Scand. 73 (6) (1984) 745–749. 9. J.S. Finkelstein, A. Klibanski, R.M. Neer, S.L. Greenspan, D.I. Rosenthal, W.F. Crowley Jr., Osteoporosis in men with idiopathic hypogonadotropic hypogonadism, Ann. Intern. Med. 106 (3) (1987) 354–361. 10. G. Saggese, S. Bertelloni, G.I. Baroncelli, Sex steroids and the acquisition of bone mass, Horm. Res. 48 (Suppl 5) (1997) 65–71. 11. J.S. Finkelstein, A. Klibanski, R.M. Neer, et al., Increases in bone density during treatment of men with idiopathic hypogonadotropic hypogonadism, J. Clin. Endocrinol. Metab. 69 (4) (1989) 776–783. 12. O. Arisaka, M. Arisaka, A. Hosaka, N. Shimura, K. Yabuta, Effect of testosterone on radial bone mineral density in adolescent male hypogonadism, Acta Paediatr. Scand. 80 (3) (1991) 378–380. 13. E.J. Richmond, A.D. Rogol, Male pubertal development and the role of androgen therapy, Nat. Clin. Pract. Endocrinol. Metab. 3 (4) (2007) 338–344. 14. A.D. Rogol, Pubertal androgen therapy in boys, Pediatr. Endocrinol. Rev. 2 (3) (2005) 383–390. 15. S. Bertelloni, G.I. Baroncelli, G. Federico, M. Cappa, R. Lala, G. Saggese, Altered bone mineral density in patients with complete androgen insensitivity syndrome, Horm. Res. 50 (6) (1998) 309–314. 16. R. Marcus, D. Leary, D.L. Schneider, E. Shane, M. Favus, C.A. Quigley, The contribution of testosterone to skeletal development and maintenance: lessons from the androgen insensitivity syndrome, J. Clin. Endocrinol. Metab. 85 (3) (2000) 1032–1037. 17. V. Sobel, B. Schwartz, Y.S. Zhu, J.J. Cordero, J. ImperatoMcGinley, Bone mineral density in the complete androgen insensitivity and 5alpha-reductase-2 deficiency syndromes, J. Clin. Endocrinol. Metab. 91 (8) (2006) 3017–3023. 18. G.R. Frank, Role of estrogen and androgen in pubertal skeletal physiology, Med. Pediatr. Oncol. 41 (3) (2003) 217–221. 19. H. Rico, M. Revilla, E.R. Hernandez, L.F. Villa, M. Alvarez del Buergo, Sex differences in the acquisition of total bone mineral mass peak assessed through dual-energy X-ray absorptiometry, Calcif. Tissue Int. 51 (4) (1992) 251–254. 20. V. Gilsanz, M.I. Boechat, R. Gilsanz, M.L. Loro, T.F. Roe, W.G. Goodman, Gender differences in vertebral sizes in adults: biomechanical implications, Radiology 190 (3) (1994) 678–682. 21. V. Gilsanz, M.I. Boechat, T.F. Roe, M.L. Loro, J.W. Sayre, W.G. Goodman, Gender differences in vertebral body sizes in children and adolescents, Radiology 190 (3) (1994) 673–677. 22. Y.M. Henry, R. Eastell, Ethnic and gender differences in bone mineral density and bone turnover in young adults: effect of bone size, Osteoporos. Int. 11 (6) (2000) 512–517. 23. V. Gilsanz, A. Kovanlikaya, G. Costin, T.F. Roe, J. Sayre, F. Kaufman, Differential effect of gender on the sizes of the bones in the axial and appendicular skeletons, J. Clin. Endocrinol. Metab. 82 (5) (1997) 1603–1607. 24. A.M. Fehily, R.J. Coles, W.D. Evans, P.C. Elwood, Factors affecting bone density in young adults, Am. J. Clin. Nutr. 56 (3) (1992) 579–586.
C h a p t e r 2 6 Androgens and the Skeleton – Humans l
25. P.J. Kelly, L. Twomey, P.N. Sambrook, J.A. Eisman, Sex differences in peak adult bone mineral density, J. Bone Miner. Res. 5 (11) (1990) 1169–1175. 26. P.W. Lu, C.T. Cowell, S.A. Lloyd-Jones, J.N. Briody, R. Howman-Giles, Volumetric bone mineral density in normal subjects, aged 5–27 years, J. Clin. Endocrinol. Metab. 81 (4) (1996) 1586–1590. 27. N. Zamberlan, G. Radetti, C. Paganini, et al., Evaluation of cortical thickness and bone density by roentgen microdensitometry in growing males and females, Eur. J. Pediatr. 155 (5) (1996) 377–382. 28. E. Seeman, Periosteal bone formation – a neglected determinant of bone strength, N. Engl. J. Med. 349 (4) (2003) 320–323. 29. J.P. Bilezikian, A. Morishima, J. Bell, M.M. Grumbach, Increased bone mass as a result of estrogen therapy in a man with aromatase deficiency, N. Engl. J. Med. 339 (9) (1998) 599–603. 30. C. Carani, K. Qin, M. Simoni, et al., Effect of testosterone and estradiol in a man with aromatase deficiency, N. Engl. J. Med. 337 (2) (1997) 91–95. 31. V. Rochira, M. Faustini-Fustini, A. Balestrieri, C. Carani, Estrogen replacement therapy in a man with congenital aromatase deficiency: effects of different doses of transdermal estradiol on bone mineral density and hormonal parameters, J. Clin. Endocrinol. Metab. 85 (5) (2000) 1841–1845. 32. A. Morishima, M.M. Grumbach, E.R. Simpson, C. Fisher, K. Qin, Aromatase deficiency in male and female siblings caused by a novel mutation and the physiological role of estrogens, J. Clin. Endocrinol. Metab. 80 (12) (1995) 3689–3698. 33. E.P. Smith, J. Boyd, G.R. Frank, et al., Estrogen resistance caused by a mutation in the estrogen-receptor gene in a man, N. Engl. J. Med. 331 (16) (1994) 1056–1061. 34. B.L. Herrmann, O.E. Janssen, S. Hahn, M. Broecker-Preuss, K. Mann, Effects of estrogen replacement therapy on bone and glucose metabolism in a male with congenital aromatase deficiency, Horm. Metab. Res. 37 (3) (2005) 178–183. 35. L. Maffei, Y. Murata, V. Rochira, et al., Dysmetabolic syndrome in a man with a novel mutation of the aromatase gene: effects of testosterone, alendronate, and estradiol treatment, J. Clin. Endocrinol. Metab. 89 (1) (2004) 61–70. 36. M. Hero, E. Norjavaara, L. Dunkel, Inhibition of estrogen biosynthesis with a potent aromatase inhibitor increases predicted adult height in boys with idiopathic short stature: a randomized controlled trial, J. Clin. Endocrinol. Metab. 90 (12) (2005) 6396–6402. 37. M. Hero, S. Wickman, L. Dunkel, Treatment with the aromatase inhibitor letrozole during adolescence increases near-final height in boys with constitutional delay of puberty, Clin. Endocrinol. (Oxf) 64 (5) (2006) 510–513. 38. A. Karmazin, W.V. Moore, J. Popovic, J.D. Jacobson, The effect of letrozole on bone age progression, predicted adult height, and adrenal gland function, J. Pediatr. Endocrinol. Metab. 18 (3) (2005) 285–293. 39. N.C. Kreher, O.H. Pescovitz, P. Delameter, A. Tiulpakov, Z. Hochberg, Treatment of familial male-limited precocious puberty with bicalutamide and anastrozole, J. Pediatr. 149 (3) (2006) 416–420. 40. N. Mauras, L. Gonzalez de Pijem, H.Y. Hsiang, et al., Anastrozole increases predicted adult height of short adolescent males treated
41.
42.
43.
44.
45.
46.
47. 48.
49.
50.
51.
52.
53.
54.
55. 56.
331
with growth hormone: a randomized, placebo-controlled, multicenter trial for one to three years, J. Clin. Endocrinol. Metab. 93 (3) (2008) 823–831. CDC, Public Helath and Aging: Trends in Aging: United States and Worldwide, Center for Disease Control and Prevention, 2003 available online http://www.cdc.gov/mmwr/ preview/mmwrhtml/mm5206a2.htm. A. Gray, J.A. Berlin, J.B. McKinlay, C. Longcope, An examination of research design effects on the association of testosterone and male aging: results of a meta-analysis, J. Clin. Epidemiol. 44 (7) (1991) 671–684. A. Gray, H.A. Feldman, J.B. McKinlay, C. Longcope, Age, disease, and changing sex hormone levels in middle-aged men: results of the Massachusetts Male Aging Study, J. Clin. Endocrinol. Metab. 73 (5) (1991) 1016–1025. F.E. Kaiser, S.P. Viosca, J.E. Morley, A.D. Mooradian, S.S. Davis, S.G. Korenman, Impotence and aging: clinical and hormonal factors, J. Am. Geriatr. Soc. 36 (6) (1988) 511–519. J.P. Deslypere, A. Vermeulen, Leydig cell function in normal men: effect of age, life-style, residence, diet, and activity, J. Clin. Endocrinol. Metab. 59 (5) (1984) 955–962. H.W. Baker, H.G. Burger, D.M. de Kretser, et al., Changes in the pituitary-testicular system with age, Clin. Endocrinol. (Oxf) 5 (4) (1976) 349–372. A. Vermeulen, J.P. Deslypere, Testicular endocrine function in the ageing male, Maturitas 7 (3) (1985) 273–279. S.M. Harman, E.J. Metter, J.D. Tobin, J. Pearson, M.R. Blackman, Longitudinal effects of aging on serum total and free testosterone levels in healthy men. Baltimore Longitudinal Study of Aging, J. Clin. Endocrinol. Metab. 86 (2) (2001) 724–731. J.E. Morley, F.E. Kaiser, H.M. Perry III., et al., Longitudinal changes in testosterone, luteinizing hormone, and folliclestimulating hormone in healthy older men, Metabolism 46 (4) (1997) 410–413. K. Nahoul, M. Roger, Age-related decline of plasma bioavailable testosterone in adult men, J. Steroid Biochem. 35 (2) (1990) 293–299. H.A. Feldman, C. Longcope, C.A. Derby, et al., Age trends in the level of serum testosterone and other hormones in middle-aged men: longitudinal results from the Massachusetts male aging study, J. Clin. Endocrinol. Metab. 87 (2) (2002) 589–598. R.L. Ferrini, E. Barrett-Connor, Sex hormones and age: a crosssectional study of testosterone and estradiol and their bioavailable fractions in community-dwelling men, Am. J. Epidemiol. 147 (8) (1998) 750–754. T.G. Travison, A.B. Araujo, A.B. O’Donnell, V. Kupelian, J.B. McKinlay, A population-level decline in serum testosterone levels in American men, J. Clin. Endocrinol. Metab. 92 (1) (2007) 196–202. W.M. Garraway, R.N. Stauffer, L.T. Kurland, W.M. O’Fallon, Limb fractures in a defined population. I. Frequency and distribution, Mayo Clin. Proc. 54 (11) (1979) 701–707. E. Seeman, Pathogenesis of bone fragility in women and men, Lancet 359 (9320) (2002) 1841–1850. D.E. Meier, E.S. Orwoll, J.M. Jones, Marked disparity between trabecular and cortical bone loss with age in healthy men. Measurement by vertebral computed tomography and radial photon absorptiometry, Ann. Intern. Med. 101 (5) (1984) 605–612.
332
Osteoporosis in Men
57. B.L. Riggs, L.J. Melton III., R.A. Robb, et al., Populationbased study of age and sex differences in bone volumetric density, size, geometry, and structure at different skeletal sites, J. Bone Miner. Res. 19 (12) (2004) 1945–1954. 58. B.L. Riggs, L.J. Melton, R.A. Robb, et al., A populationbased assessment of rates of bone loss at multiple skeletal sites: evidence for substantial trabecular bone loss in young adult women and men, J. Bone Miner. Res. 23 (2) (2008) 205–214. 59. A.W. van den Beld, F.H. de Jong, D.E. Grobbee, H.A. Pols, S.W. Lamberts, Measures of bioavailable serum testosterone and estradiol and their relationships with muscle strength, bone density, and body composition in elderly men, J. Clin. Endocrinol. Metab. 85 (9) (2000) 3276–3282. 60. P.J. Drinka, J. Olson, S. Bauwens, S.K. Voeks, I. Carlson, M. Wilson, Lack of association between free testosterone and bone density separate from age in elderly males, Calcif. Tissue Int. 52 (1) (1993) 67–69. 61. G.A. Greendale, S. Edelstein, E. Barrett-Connor, Endogenous sex steroids and bone mineral density in older women and men: the Rancho Bernardo Study, J. Bone Miner. Res. 12 (11) (1997) 1833–1843. 62. S. Khosla, L.J. Melton III., E.J. Atkinson, W.M. O’Fallon, Relationship of serum sex steroid levels to longitudinal changes in bone density in young versus elderly men, J. Clin. Endocrinol. Metab. 86 (8) (2001) 3555–3561. 63. S. Khosla, L.J. Melton III., E.J. Atkinson, W.M. O’Fallon, G.G. Klee, B.L. Riggs, Relationship of serum sex steroid levels and bone turnover markers with bone mineral density in men and women: a key role for bioavailable estrogen, J. Clin. Endocrinol. Metab. 83 (7) (1998) 2266–2274. 64. D.E. Meier, E.S. Orwoll, E.J. Keenan, R.M. Fagerstrom, Marked decline in trabecular bone mineral content in healthy men with age: lack of association with sex steroid levels, J. Am. Geriatr. Soc. 35 (3) (1987) 189–197. 65. S. Murphy, K.T. Khaw, A. Cassidy, J.E. Compston, Sex hormones and bone mineral density in elderly men, Bone Miner. 20 (2) (1993) 133–140. 66. D. Rudman, P.J. Drinka, C.R. Wilson, et al., Relations of endogenous anabolic hormones and physical activity to bone mineral density and lean body mass in elderly men, Clin. Endocrinol. (Oxf) 40 (5) (1994) 653–661. 67. S. Amin, Y. Zhang, C.T. Sawin, et al., Association of hypogonadism and estradiol levels with bone mineral density in elderly men from the Framingham study, Ann. Intern. Med. 133 (12) (2000) 951–963. 68. J.R. Center, T.V. Nguyen, P.N. Sambrook, J.A. Eisman, Hormonal and biochemical parameters in the determination of osteoporosis in elderly men, J. Clin. Endocrinol. Metab. 84 (10) (1999) 3626–3635. 69. B. Ongphiphadhanakul, R. Rajatanavin, S. Chanprasertyothin, N. Piaseu, L. Chailurkit, Serum oestradiol and oestrogenreceptor gene polymorphism are associated with bone mineral density independently of serum testosterone in normal males, Clin. Endocrinol. (Oxf) 49 (6) (1998) 803–809. 70. C.W. Slemenda, C. Longcope, L. Zhou, S.L. Hui, M. Peacock, C.C. Johnston, Sex steroids and bone mass in older men. Positive associations with serum estrogens and negative associations with androgens, J. Clin. Invest. 100 (7) (1997) 1755–1759.
71. S. Goemaere, I. Van Pottelbergh, H. Zmierczak, et al., Inverse association between bone turnover rate and bone mineral density in community-dwelling men 70 years of age: no major role of sex steroid status, Bone 29 (3) (2001) 286–291. 72. A.M. Kenny, J.C. Gallagher, K.M. Prestwood, C.A. Gruman, L.G. Raisz, Bone density, bone turnover, and hormone levels in men over age 75, J. Gerontol. A Biol. Sci. Med. Sci. 53 (6) (1998) M419–M425. 73. P. Szulc, B. Claustrat, F. Marchand, P.D. Delmas, Increased risk of falls and increased bone resorption in elderly men with partial androgen deficiency: the MINOS study, J. Clin. Endocrinol. Metab. 88 (11) (2003) 5240–5247. 74. E. Barrett-Connor, J.E. Mueller, D.G. von Muhlen, G.A. Laughlin, D.L. Schneider, D.J. Sartoris, Low levels of estradiol are associated with vertebral fractures in older men, but not women: the Rancho Bernardo Study, J. Clin. Endocrinol. Metab. 85 (1) (2000) 219–223. 75. S. Boonen, D. Vanderschueren, X.G. Cheng, et al., Agerelated (type II) femoral neck osteoporosis in men: biochemical evidence for both hypovitaminosis D- and androgen deficiency-induced bone resorption, J. Bone Miner. Res. 12 (12) (1997) 2119–2126. 76. L. Gennari, D. Merlotti, G. Martini, et al., Longitudinal association between sex hormone levels, bone loss, and bone turnover in elderly men, J. Clin. Endocrinol. Metab. 88 (11) (2003) 5327–5333. 77. H.W. Goderie-Plomp, M. van der Klift, W. de Ronde, A. Hofman, F.H. de Jong, H.A. Pols, Endogenous sex hormones, sex hormone-binding globulin, and the risk of incident vertebral fractures in elderly men and women: the Rotterdam Study, J. Clin. Endocrinol. Metab. 89 (7) (2004) 3261–3269. 78. A.B. Araujo, T.G. Travison, S.S. Harris, M.F. Holick, A.K. Turner, J.B. McKinlay, Race/ethnic differences in bone mineral density in men, Osteoporos. Int. (2007). 79. H.A. Fink, S.K. Ewing, K.E. Ensrud, et al., Association of testosterone and estradiol deficiency with osteoporosis and rapid bone loss in older men, J. Clin. Endocrinol. Metab. 91 (10) (2006) 3908–3915. 80. K.E. Ensrud, C.E. Lewis, L.C. Lambert, et al., Endogenous sex steroids, weight change and rates of hip bone loss in older men: the MrOS study, Osteoporos. Int. 17 (9) (2006) 1329–1336. 81. D. Mellstrom, O. Johnell, O. Ljunggren, et al., Free testosterone is an independent predictor of BMD and prevalent fractures in elderly men: MrOS Sweden, J. Bone Miner. Res. 21 (4) (2006) 529–535. 82. E. Orwoll, L.C. Lambert, L.M. Marshall, et al., Endogenous testosterone levels, physical performance, and fall risk in older men, Arch. Intern. Med. 166 (19) (2006) 2124–2131. 83. L. Vandenput, F. Labrie, D. Mellstrom, et al., Serum levels of specific glucuronidated androgen metabolites predict BMD and prostate volume in elderly men, J. Bone Miner. Res. (2006). 84. D. Mellstrom, L. Vandenput, H. Mallmin, et al., Older men with low serum estradiol and high serum SHBG have an increased risk of fractures, J. Bone Miner. Res. 23 (10) (2008) 1552–1560. 85. A.L. Eriksson, M. Lorentzon, D. Mellstrom, et al., SHBG gene promoter polymorphisms in men are associated with serum sex hormone-binding globulin, androgen and androgen metabolite
C h a p t e r 2 6 Androgens and the Skeleton – Humans l
levels, and hip bone mineral density, J. Clin. Endocrinol. Metab. 91 (12) (2006) 5029–5037. 86. A. Hammes, T.K. Andreassen, R. Spoelgen, et al., Role of endocytosis in cellular uptake of sex steroids, Cell 122 (5) (2005) 751–762. 87. S.F. Evans, M.W. Davie, Low body size and elevated sexhormone binding globulin distinguish men with idiopathic vertebral fracture, Calcif. Tissue Int. 70 (1) (2002) 9–15. 88. E. Legrand, C. Hedde, Y. Gallois, et al., Osteoporosis in men: a potential role for the sex hormone binding globulin, Bone 29 (1) (2001) 90–95. 89. G. Martinez Diaz-Guerra, F. Hawkins, A. Rapado, M.A. Ruiz Diaz, M. Diaz-Curiel, Hormonal and anthropometric predictors of bone mass in healthy elderly men: major effect of sex hormone binding globulin, parathyroid hormone and body weight, Osteoporos. Int. 12 (3) (2001) 178–184. 90. N. Kelepouris, K.D. Harper, F. Gannon, F.S. Kaplan, J.G. Haddad, Severe osteoporosis in men, Ann. Intern. Med. 123 (6) (1995) 452–460. 91. H.L. Stanley, B.P. Schmitt, R.M. Poses, W.P. Deiss, Does hypogonadism contribute to the occurrence of a minimal trauma hip fracture in elderly men? (see comments), J. Am. Geriatr. Soc. 39 (8) (1991) 766–771. 92. E. Orwoll, M. Ettinger, S. Weiss, et al., Alendronate for the treatment of osteoporosis in men, N. Engl. J. Med. 343 (9) (2000) 604–610. 93. H.W. Daniell, Osteoporosis after orchiectomy for prostate cancer (see comments), J. Urol. 157 (2) (1997) 439–444. 94. J.J. Stepan, M. Lachman, J. Zverina, V. Pacovsky, D.J. Baylink, Castrated men exhibit bone loss: effect of calcitonin treatment on biochemical indices of bone remodeling, J. Clin. Endocrinol. Metab. 69 (3) (1989) 523–527. 95. T. Diamond, D. Stiel, S. Posen, Osteoporosis in hemochromatosis: iron excess, gonadal deficiency, or other factors? Ann. Intern. Med. 110 (6) (1989) 430–436. 96. D.A. Smith, M.S. Walker, Changes in plasma steroids and bone density in Klinefelter’s syndrome, Calcif. Tissue Res. 22 (Suppl) (1977) 225–228. 97. C. Foresta, G. Ruzza, R. Mioni, A. Meneghello, C. Baccichetti, Testosterone and bone loss in Klinefelter syndrome, Horm. Metab. Res. 15 (1) (1983) 56–57. 98. M. Horowitz, J.M. Wishart, P.D. O’Loughlin, H.A. Morris, A.G. Need, B.E. Nordin, Osteoporosis and Klinefelter’s syndrome, Clin. Endocrinol. (Oxf) 36 (1) (1992) 113–118. 99. J.P. van den Bergh, A.R. Hermus, A.I. Spruyt, C.G. Sweep, F.H. Corstens, A.G. Smals, Bone mineral density and quantitative ultrasound parameters in patients with Klinefelter’s syndrome after long-term testosterone substitution, Osteoporos. Int. 12 (1) (2001) 55–62. 100. G. Luisetto, I. Mastrogiacomo, G. Bonanni, et al., Bone mass and mineral metabolism in Klinefelter’s syndrome, Osteoporos. Int. 5 (6) (1995) 455–461. 101. S.L. Greenspan, R.M. Neer, E.C. Ridgway, A. Klibanski, Osteoporosis in men with hyperprolactinemic hypogonadism, Ann. Intern. Med. 104 (6) (1986) 777–782. 102. S.L. Greenspan, D.S. Oppenheim, A. Klibanski, Importance of gonadal steroids to bone mass in men with hyperprolactinemic hypogonadism, Ann. Intern. Med. 110 (7) (1989) 526–531. 103. C.Y. Guo, T.H. Jones, R. Eastell, Treatment of isolated hypogonadotropic hypogonadism effect on bone mineral
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density and bone turnover, J. Clin. Endocrinol. Metab. 82 (2) (1997) 658–665. 104. A. Falahati-Nini, B.L. Riggs, E.J. Atkinson, W.M. O’Fallon, R. Eastell, S. Khosla, Relative contributions of testosterone and estrogen in regulating bone resorption and formation in normal elderly men, J. Clin. Invest. 106 (12) (2000) 1553–1560. 105. B.Z. Leder, K.M. LeBlanc, D.A. Schoenfeld, R. Eastell, J.S. Finkelstein, Differential effects of androgens and estrogens on bone turnover in normal men, J. Clin. Endocrinol. Metab. 88 (1) (2003) 204–210. 106. H. Lee, J.S. Finkelstein, M. Miller, S.J. Comeaux, R.I. Cohen, B.Z. Leder, Effects of selective testosterone and estradiol withdrawal on skeletal sensitivity to parathyroid hormone in men, J. Clin. Endocrinol. Metab. 91 (3) (2006) 1069–1075. 107. S.L. Greenspan, Approach to the prostate cancer patient with bone disease, J. Clin. Endocrinol. Metab. 93 (1) (2008) 2–7. 108. M.R. Smith, Treatment-related osteoporosis in men with prostate cancer, Clin. Cancer Res. 12 (20 Pt 2) (2006) 6315s–6319s. 109. S.L. Greenspan, P. Coates, S.M. Sereika, J.B. Nelson, D.L. Trump, N.M. Resnick, Bone loss after initiation of androgen deprivation therapy in patients with prostate cancer, J. Clin. Endocrinol. Metab. 90 (12) (2005) 6410–6417. 110. V.B. Shahinian, Y.F. Kuo, J.L. Freeman, J.S. Goodwin, Risk of fracture after androgen deprivation for prostate cancer, N. Engl. J. Med. 352 (2) (2005) 154–164. 111. M.R. Smith, S.P. Boyce, E. Moyneur, M.S. Duh, M.K. Raut, J. Brandman, Risk of clinical fractures after gonadotropin-releasing hormone agonist therapy for prostate cancer, J. Urol. 175 (1) (2006) 136–139 discussion 139. 112. M.R. Smith, F.J. McGovern, A.L. Zietman, et al., Pamidronate to prevent bone loss during androgen-deprivation therapy for prostate cancer, N. Engl. J. Med. 345 (13) (2001) 948–955. 113. S.G. Soule, G. Conway, G.M. Prelevic, M. Prentice, J. Ginsburg, H.S. Jacobs, Osteopenia as a feature of the androgen insensitivity syndrome, Clin. Endocrinol. (Oxf) 43 (6) (1995) 671–675. 114. B. Krupa, T. Miazgowski, Bone mineral density and markers of bone turnover in boys with constitutional delay of growth and puberty, J. Clin. Endocrinol. Metab. 90 (5) (2005) 2828–2830. 115. J.S. Finkelstein, R.M. Neer, B.M. Biller, J.D. Crawford, A. Klibanski, Osteopenia in men with a history of delayed puberty, N. Engl. J. Med. 326 (9) (1992) 600–604. 116. S. Bertelloni, G.I. Baroncelli, M. Ferdeghini, G. Perri, G. Saggese, Normal volumetric bone mineral density and bone turnover in young men with histories of constitutional delay of puberty (see comments), J. Clin. Endocrinol. Metab. 83 (12) (1998) 4280–4283. 117. J.S. Finkelstein, A. Klibanski, R.M. Neer, Evaluation of lumber spine bone mineral density (BMD) using dual energy x-ray absorptiometry (DXA) in 21 young men with histories of constitutionally-delayed puberty (letter; comment), J. Clin. Endocrinol. Metab. 84 (9) (1999) 3400–3401 discussion 3403-4. 118. H.U. Schweikert, W. Rulf, N. Niederle, H.E. Schafer, E. Keck, F. Kruck, Testosterone metabolism in human bone, Acta Endocrinol. (Copenh) 95 (2) (1980) 258–264.
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119. C.H. Kasperk, J.E. Wergedal, J.R. Farley, T.A. Linkhart, R.T. Turner, D.J. Baylink, Androgens directly stimulate proliferation of bone cells in vitro, Endocrinology 124 (3) (1989) 1576–1578. 120. H. Matzkin, J. Chen, Y. Weisman, et al., Prolonged treatment with finasteride (a 5 alpha-reductase inhibitor) does not affect bone density and metabolism, Clin. Endocrinol. (Oxf) 37 (5) (1992) 432–436. 121. A.M. Matsumoto, L. Tenover, M. McClung, et al., The long-term effect of specific type II 5alpha-reductase inhibition with finasteride on bone mineral density in men: results of a 4-year placebo controlled trial, J. Urol. 167 (5) (2002) 2105–2108. 122. S.R. Tollin, H.N. Rosen, K. Zurowski, et al., Finasteride therapy does not alter bone turnover in men with benign prostatic hyperplasia – a Clinical Research Center study, J. Clin. Endocrinol. Metab. 81 (3) (1996) 1031–1034. 123. S.J. Jacobsen, T.C. Cheetham, R. Haque, J.M. Shi, R.K. Loo, Association between 5-alpha reductase inhibition and risk of hip fracture, J. Am. Med. Assoc. 300 (14) (2008) 1660–1664. 124. L. Katznelson, J.S. Finkelstein, D.A. Schoenfeld, D.I. Rosenthal, E.J. Anderson, A. Klibanski, Increase in bone density and lean body mass during testosterone administration in men with acquired hypogonadism, J. Clin. Endocrinol. Metab. 81 (12) (1996) 4358–4365. 125. H.M. Behre, S. Kliesch, E. Leifke, T.M. Link, E. Nieschlag, Long-term effect of testosterone therapy on bone mineral density in hypogonadal men, J. Clin. Endocrinol. Metab. 82 (8) (1997) 2386–2390. 126. T. Diamond, D. Stiel, S. Posen, Effects of testosterone and venesection on spinal and peripheral bone mineral in six hypogonadal men with hemochromatosis, J. Bone Miner. Res. 6 (1) (1991) 39–43. 127. S.J. Howell, J.A. Radford, J.E. Adams, E.M. Smets, R. Warburton, S.M. Shalet, Randomized placebo-controlled trial of testosterone replacement in men with mild Leydig cell insufficiency following cytotoxic chemotherapy, Clin. Endocrinol. (Oxf) 55 (3) (2001) 315–324. 128. M.J. Tracz, K. Sideras, E.R. Bolona, et al., Testosterone use in men and its effects on bone health. A systematic review and meta-analysis of randomized placebo-controlled trials, J. Clin. Endocrinol. Metab. 91 (6) (2006) 2011–2016. 129. M. Benito, B. Vasilic, F.W. Wehrli, et al., Effect of testosterone replacement on trabecular architecture in hypogonadal men, J. Bone Miner. Res. 20 (10) (2005) 1785–1791. 130. S. Bhasin, G.R. Cunningham, F.J. Hayes, et al., Testosterone therapy in adult men with androgen deficiency syndromes: an endocrine society clinical practice guideline, J. Clin. Endocrinol. Metab. 91 (6) (2006) 1995–2010. 131. C. Christmas, K.G. O’Connor, S.M. Harman, et al., Growth hormone and sex steroid effects on bone metabolism and bone mineral density in healthy aged women and men, J. Gerontol. A Biol. Sci. Med. Sci. 57 (1) (2002) M12–M18. 132. A.M. Kenny, K.M. Prestwood, C.A. Gruman, K.M. Marcello, L.G. Raisz, Effects of transdermal testosterone on bone and muscle in older men with low bioavailable testosterone levels, J. Gerontol. A Biol. Sci. Med. Sci. 56 (5) (2001) M266–M272.
133. P.J. Snyder, H. Peachey, P. Hannoush, et al., Effect of testosterone treatment on bone mineral density in men over 65 years of age, J. Clin. Endocrinol. Metab. 84 (6) (1999) 1966–1972. 134. J.S. Tenover, Effects of testosterone supplementation in the aging male, J. Clin. Endocrinol. Metab. 75 (4) (1992) 1092–1098. 135. K.S. Nair, R.A. Rizza, P. O’Brien, et al., DHEA in elderly women and DHEA or testosterone in elderly men, N. Engl. J. Med. 355 (16) (2006) 1647–1659. 136. J.K. Amory, N.B. Watts, K.A. Easley, et al., Exogenous testosterone or testosterone with finasteride increases bone mineral density in older men with low serum testosterone, J. Clin. Endocrinol. Metab. 89 (2) (2004) 503–510. 137. E.S. Orwoll, W.H. Scheele, S. Paul, et al., The effect of teriparatide [human parathyroid hormone (1-34)] therapy on bone density in men with osteoporosis, J. Bone Miner. Res. 18 (1) (2003) 9–17. 138. B.Z. Leder, J.L. Rohrer, S.D. Rubin, J. Gallo, C. Longcope, Effects of aromatase inhibition in elderly men with low or borderline-low serum testosterone levels, J. Clin. Endocrinol. Metab. 89 (3) (2004) 1174–1180. 139. B.Z. Leder, J.S. Finkelstein, Effect of aromatase inhibition on bone metabolism in elderly hypogonadal men, Osteoporos. Int. 16 (12) (2005) 1487–1494. 140. Committee on Assessing the Need for Clinical Trials of Testosterone Replacement Therapy. Testosterone and Health Outcomes. Testosterone and Aging, pp 32-111, 2004. National Academies Press,Washington, DC. 141. E. Barrett-Connor, D. Kritz-Silverstein, S.L. Edelstein, A prospective study of dehydroepiandrosterone sulfate (DHEAS) and bone mineral density in older men and women, Am. J. Epidemiol. 137 (2) (1993) 201–206. 142. C.M. Jankowski, W.S. Gozansky, R.S. Schwartz, et al., Effects of dehydroepiandrosterone replacement therapy on bone mineral density in older adults: a randomized, controlled trial, J. Clin. Endocrinol. Metab. 91 (8) (2006) 2986–2993. 143. M. Muller, A.W. van den Beld, Y.T. van der Schouw, D.E. Grobbee, S.W. Lamberts, Effects of dehydroepiandrosterone and atamestane supplementation on frailty in elderly men, J. Clin. Endocrinol. Metab. 91 (10) (2006) 3988–3991. 144. D. von Muhlen, G.A. Laughlin, D. Kritz-Silverstein, J. Bergstrom, R. Bettencourt, Effect of dehydroepiandrosterone supplementation on bone mineral density, bone markers, and body composition in older adults: the DAWN trial, Osteoporos. Int. 19 (5) (2008) 699–707. 145. N.R. Young, H.W. Baker, G. Liu, E. Seeman, Body composition and muscle strength in healthy men receiving testosterone enanthate for contraception, J. Clin. Endocrinol. Metab. 77 (4) (1993) 1028–1032. 146. F.H. Anderson, R.M. Francis, K. Faulkner, Androgen supplementation in eugonadal men with osteoporosis – effects of 6 months of treatment on bone mineral density and cardiovascular risk factors, Bone 18 (2) (1996) 171–177. 147. J.S. Finkelstein, S.M. Burnett-Bowie, A.F. Moore, et al., Toward a physiologically-based definition of hypogonadism in men: dose-response relationship between testosterone and and bone resorption (abstract), J. Bone Miner. Res. 23 (Suppl) (2008) 30.
Chapter
27
Androgen Effects on the Skeletal Muscle Shalender Bhasin, Rajan Singh, Ravi Jasuja and Thomas W. Storer Section of Endocrinology, Diabetes and Nutrition Boston University School of Medicine and Boston Medical Center, Boston, USA
Introduction
not standardized, as many participants continued to train ad lib. Thus, these earlier studies failed to separate the effects of resistance exercise training from those of androgens. However, the publication of a randomized placebocontrolled trial of a supraphysiological dose of testosterone in healthy young men with or without a standardized program of resistance exercise training in 1996 dramatically changed academic opinion [13]. This study provided conclusive evidence that supraphysiologic doses of testosterone increase skeletal muscle mass and maximal voluntary strength and that these anabolic effects of testosterone are augmented by resistance exercise training [13]. It unleashed an enormous pharmaceutical and academic investment into the discovery of non-steroidal selective androgen receptor modulators (SARMs) that are preferentially anabolic [5]. This chapter will review the epidemiological and clinical trials data on the effects of testosterone on skeletal muscle mass, muscle performance and physical function, the potential applications of testosterone and other androgens as function promoting anabolic therapies and the current hurdles in drug development efforts.
After being submerged in controversy for much of the latter half of the twentieth century [1–4], androgens have witnessed a remarkable resurrection during the past decade because of their potential as function promoting anabolic therapies that might also reduce fracture risk [5, 6]. Shortly after the discovery and chemical synthesis of testosterone, pioneering research of Kochakian [7–9] and Kenyon [10] revealed the nitrogen retaining actions of androgens. The recognition of the anabolic effects of androgens paved the way for the development of many testosterone derivatives in the 1940s and 1950s because of their anabolic potential. However, the controversy surrounding the abuse of androgens by athletes and recreational body builders restrained serious scientific investigation of their application as function promoting anabolic therapies for the prevention and treatment of functional limitations associated with aging and chronic diseases. Although androgen doping in competitive sports continued to grow since its initial use among the Russian power lifters in early 1950s [11, 12], the academic community remained remarkably skeptical about the anabolic effects of androgens. This skepticism was reflected in the Endocrine Society’s position statement in 1984 which essentially declared that when diet and exercise levels are controlled, androgens do not increase muscle mass or strength [1]. The earlier studies to investigate the anabolic effects of androgen administration on skeletal muscle mass and muscle strength in humans were indeed inconclusive for several reasons [1, 4]. The doses of androgens used in earlier studies were substantially lower than those used by athletes, who use progressively increasing doses of multiple androgens in a practice known as stacking. Many earlier studies were neither randomized nor blinded. Energy and protein intake were not controlled or standardized; the participants in some of the studies were allowed to take protein supplements. Some of the studies included competitive athletes. The exercise stimulus was Osteoporosis in Men
Epidemiological studies demonstrating the relationship of serum testosterone concentrations and muscle mass and physical function Androgen deficient men have lower fat free mass [14] and higher fat mass than age-matched eugonadal men [15, 16]. The age-associated decline in bioavailable testosterone levels is associated with decreased appendicular muscle mass [17–20] and reduced muscle strength in older men [21–23]. In population-based studies of older men, lower testosterone concentrations are associated with decreased physical 335
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function, using self-reported as well as performance-based measures of physical function [23–25]. In the Longitudinal Aging Study of Amsterdam, serum testosterone concentrations were positively associated with muscle strength and physical performance in cross-sectional analyses [23]. However, in the longitudinal analysis of data from the LASA and Health ABC studies, neither total nor free testosterone levels were predictive of decline in grip strength or physical performance measures over a three-year followup period [25]. In the Massachusetts Male Aging Study, self-reported physical function, as assessed by the physical function domain of SF-36, was associated with total and bioavailable testosterone levels [26]. In the MrOS Study, low bioavailable testosterone levels were associated with a lower level of physical performance and increased risk of falls [25]. However, the association of bioavailable testosterone level with fall risk persisted even after adjusting for physical performance, suggesting that testosterone levels may reduce fall propensity through other mechanisms [25]. Low testosterone levels have also been associated with increased risk of mobility limitations in older men [27]. Epidemiological studies have demonstrated an inverse relationship between serum testosterone levels and measures of obesity, including waist-to-hip ratio and visceral fat mass [28, 29]. In a cohort of 511 men aged 30–79 years, testosterone levels at baseline were inversely related to subsequent development of central adiposity, estimated 12 years later [29]. In this study, total and free testosterone concentrations were negatively correlated with waist/hip circumference ratio, visceral fat area, glucose, insulin and C-peptide concentrations [28].
The effects of experimental lowering of endogenous testosterone concentrations on body composition Experimental suppression of serum testosterone levels by administration of a long-acting gonadotropin-releasing hormone (GnRH) agonist analog in healthy young men is associated with a significant reduction in fat-free mass, an increase in fat mass and a decrease in fractional muscle protein synthesis [30]. In this study, gonadal suppression was also associated with a decrease in whole body leucine oxidation as well as non-oxidative leucine disappearance rates [30].
The effects of physiologic testosterone replacement in models of androgen deficiency In all models of androgen deficiency that have been examined, testosterone replacement has been consistently shown
to exert anabolic effects. For example, in pioneering studies conducted by Kochakian et al [7–9], administration of testosterone propionate promoted nitrogen retention in orchidectomized rats and dogs [7–9]. Other studies reported nitrogen retention with testosterone therapy of androgen deficient men, prepubertal boys and women [10]. Several recent studies [15, 31–34] have re-examined the effects of testosterone on body composition and muscle mass in hypogonadal men using stable isotopes [15, 31–33, 35–37]. These studies are in agreement that replace ment doses of testosterone, when administered to healthy, androgen-deficient men, increase fat-free mass, muscle size and maximal voluntary strength [15, 31–33, 35–37]. The muscle accretion during testosterone administration is associated with an increase in fractional muscle protein synthesis [30, 31] and a decrease in muscle protein degradation.
Testosterone dose-response relationships in young and older men The magnitude of the gains in fat-free mass, muscle size and muscle strength during testosterone supplementation is related to the administered dose of testosterone and the circulating testosterone concentrations [38, 39]. In a randomized, masked study of testosterone dose-response relationships, healthy young and older men were treated with a long-acting GnRH agonist to suppress endogenous testosterone production and concomitantly given one of several graded doses of testosterone enanthate ranging from 25 mg intramuscularly weekly to 600 mg intramuscularly weekly [38, 39]. Testosterone administration was associated with dose-dependent increments in fat-free mass, appendicular muscle mass and maximal voluntary strength in the leg press exercise in healthy young as well as older men (Figure 27.1) [38, 39]. In multivariate models, the gains in lean body mass and muscle size during testosterone administration could largely be explained by testosterone dose and the circulating testosterone concentrations [40]. Changes in whole body, appendicular and truncal fat mass were inversely associated with testosterone dose and circulating testosterone concentrations [41]. Different androgen-dependent outcomes differ in their testosterone dose-response relationships [38, 39]. Thus, several measures of sexual function and prostate specific antigen (PSA) levels in young men are normalized at serum testosterone concentrations that are at or near the lower end of the normal male range [42, 43], while changes in skeletal muscle mass and strength are linearly related to testosterone dose and concentrations even in the supraphysiologic range.
C h a p t e r 2 7 Androgen Effects on the Skeletal Muscle
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Figure 27.1 Testosterone dose-response relationships in healthy young and older men. Healthy young (19–34 years of age) and older (60–75 years of age) were treated with a long-acting GnRH agonist to suppress endogenous testosterone production in conjunction with graded doses of testosterone enanthate ranging from 25 mg weekly to 600 mg intramuscularly weekly. The treatment duration was 20 weeks. The mean (SEM) change in fat-free mass, skeletal muscle mass, fat mass and leg press strength are shown in young (black bars) and older (gray bars) men. (Adapted with permission from Bhasin et al, J Clin Endocrinol Metab 2005;90:678-88 [39]).
The increments in serum testosterone concentrations are higher in older men than young men, presumably due to decreased testosterone plasma clearance rates in older men [44]. Older men also experience greater increments in hemoglobin and hematocrit in response to testosterone administration, even after adjusting for the higher testosterone levels [45]; these age-related differences in hematocrit response to testosterone cannot be explained easily on the basis of changes in erythropoietin or transferring receptor levels [45].
Interactive effects of testosterone and resistance exercise training Testosterone administration and resistance exercise training, each increases muscle mass and maximal voluntary strength and the effects of the two interventions administered together are greater than that of each intervention alone [13]. Thus, resistance exercise training augments the anabolic effects of androgen on the muscle. The mechanisms by which testosterone and resistance exercise training improve muscle mass and strength are not fully understood.
Randomized clinical trials of testosterone in older men with low or low normal testosterone levels Several studies [37, 46–58] have established that testosterone replacement of middle-aged and older men with low testosterone levels is associated with a significant increase in lean body mass and a reduction in fat mass. Meta-analyses of randomized clinical trials in middle-aged and older men have confirmed that testosterone therapy is associated with greater increments in fat-free mass than those associated with placebo administration alone (Figure 27.2A) [5]. Although testosterone supplementation significantly increased grip strength to a greater extent than placebo (Figure 27.2B) [5], the changes in muscle strength and physical function were inconsistent across trials. In a study by Snyder et al [46] testosterone treatment of older men did not increase muscle strength or improve physical function, but these men were not uniformly hypogonadal and were unusually fit for their age [46]. In addition, their muscle strength was measured by a method (Biodex dynamometer) which did not demonstrate a response even in younger men with classical hypogonadism after testosterone administration [36]. In contrast, Urban et al [55] used higher doses of testosterone than those used by Snyder [46] and reported significant
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Ly, 2001 Kenny, 2001 Harman, 2003
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Wittert, 2003 Snyder, 1999 Tenover, 1992 Page, 2005 Ferrando, 2003 Combined
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gains in maximal voluntary strength. In our dose-response study, testosterone administration was associated with very substantial dose-dependent increases in leg press strength and leg power [38]. Testosterone effects on muscle performance are domain-specific; testosterone improves maximal voluntary strength and power, but it does not affect either muscle fatigability or specific force [59]. The increments in maximal voluntary strength during testosterone administration are proportional to the gains in skeletal muscle mass [59]. Unlike resistance exercise training, testosterone administration does not improve the contractile properties of skeletal muscle. Testosterone therapy improves self-reported physical function, as assessed by physical function domain of MOS SF-36 [46]. However, the changes in performance-based measures of physical function have been inconsistent across trials [60–62]. Most randomized trials of testosterone have failed to demonstrate clear improvements in physical function measures [61, 62].
Combined
Individual
Figure 27.2 (A) Forest plot of contrast in fat-free mass change between testosterone and placebo groups in randomized, placebo-controlled clinical trials of testosterone administration in healthy men, 45 years of age or older. These eight trials included middle-aged and older men 45 years of age with low or low normal testosterone levels, and were double-blind, randomized trials of 90 days or more which used testosterone or its esters in replacement doses and which reported body composition data. Odds ratios were pooled using a random effects model after weighting for sample size. Clopper-Pearson method was used to compute 95% confidence intervals. (Adapted with permission from Bhasin et al, Nat Clin Pract Endocrinol Metab 2006;2:14659 [5]). (B) Meta-analysis plot of difference in right hand grip
Many chronic illnesses, such as end-stage renal disease, HIV-infection, chronic obstructive lung disease (COPD), congestive heart failure and many types of cancers, are associated with high prevalence of low testosterone levels, changes in body composition, including the loss of lean body mass and strength, and increased risk of functional limitations and disability [63–67]. A substantial fraction of HIV-infected men, including those receiving highly effective anti-retroviral therapy, has low total and/or free testosterone levels [65, 67–70]. Low testosterone levels in HIV-infected men are associated with weight loss, loss of lean body mass and exercise capacity and greater risk of disease progression [65, 67, 68, 71]. Several randomized trials have examined the effects of androgen supplementation in men with chronic illness [72–79]. Two separate meta-analyses of placebo-controlled randomized trials of testosterone replacement in HIVinfected men with weight loss concluded that testosterone therapy is associated with greater gains in body weight and fat-free mass than those associated with placebo therapy [5, 80]. However, these inferences were weakened by the heterogeneity of the patient populations that were included in strength change between testosterone and placebo groups in randomized, placebo-controlled clinical trials of testosterone administration in healthy men 45 years of age or older. (Adapted with permission from Bhasin et al, Nat Clin Pract Endocrinol Metab 2006;2:146-59).
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these trials and differences in testosterone regimens. The three studies [72, 73, 75] that showed gains in fat-free mass included patients with low testosterone levels. In two placebo-controlled, randomized trials, we have demonstrated that testosterone replacement in HIV-infected men with low testosterone levels is associated with significant gains in fatfree mass [72–79]. In one study [72)], we determined the effects of testosterone replacement, with or without a program of resistance exercise, on muscle strength and body composition in HIV-infected men with weight loss. HIVinfected men with serum testosterone levels less than 350 ng/ dl, and weight loss of 5% or more were randomized to one of four groups: placebo, no exercise; testosterone enanthate 100 mg weekly, no exercise; placebo plus exercise; or testosterone plus exercise [72]. In the placebo-only group, muscle strength did not change in any of the five exercises. Men treated with testosterone alone, exercise alone, or combined testosterone and exercise, experienced significant increases in maximum voluntary muscle strength in the leg press, leg curls, bench press, and latissimus dorsi pull downs. Thus, when the confounding influence of the learning effect is minimized and appropriate androgen-responsive measures of muscle strength are selected, testosterone replacement is associated with demonstrable increase in maximal voluntary strength in HIV-infected men with low testosterone levels. We do not know whether androgen replacement improves sense of well-being, physical function or other health-related outcomes in HIV-infected men. Fat-free mass is decreased and physical function is markedly impaired in men with end-stage renal disease who are on maintenance hemodialysis [81–83]. Nandrolone decanoate has been reported to increase hemoglobin levels and fat-free mass in men with end-stage renal disease [81, 84, 85]. Testosterone replacement is associated with a greater increase in fat-free mass, bone density, muscle strength and quality of life than placebo in men receiving glucocorticoids [86, 87]. Schols et al [88] have reported modest increases in lean body mass and respiratory muscle strength with a low dose of nandrolone in 217 men and women with COPD. Casaburi et al [89] have demonstrated that testosterone therapy increases fat-free mass, muscle size and maximal muscle strength in men with COPD who have low testosterone levels to a greater extent than placebo. The effects of testosterone and resistance exercise training on muscle strength were greater than those of testosterone alone [89].
Possible Reasons for the Failure of the Previous Studies of Testosterone Replacement in Older Men and in Men With Chronic Illness to Demonstrate Significant Improvements in Physical Function In spite of unequivocal evidence that testosterone therapy in androgen-deficient men increases fat-free mass and
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maximal voluntary strength, we do not know if testosterone improves physical function. Many previous studies of testosterone replacement in older men did not examine changes in physical function. The few studies that did examine this issue suffered from methodological problems in the measurements of physical function. The doses of testosterone used in some trials were relatively low and were associated with either small or no significant increments in testosterone levels [61, 62]. As testosterone effects on the skeletal muscle are related to testosterone dose and circulating concentrations, it is possible that these doses were insufficient to produce clinically meaningful changes in muscle mass and strength. A major reason for the failure to demonstrate improvements in physical function is that the first generation testosterone trials were conducted in healthy older men and used measures of physical function that had a relatively low ceiling [90]. The widely used measures such as standing up from a chair and 4-meter walk are tasks that require only a small fraction of an individual’s maximal voluntary strength. In most healthy, older men, the baseline maximal voluntary strength is far higher than the threshold below which these measures would detect impairment. Given the low intensity of the tasks used, it is not surprising that relatively healthy older individuals recruited in these initial testosterone trials showed neither impairment in these threshold-dependent [90] measures of physical function at baseline, nor an improvement in performance on these tasks during testosterone administration. Because testosterone improves maximal voluntary leg strength, we posit that it would improve measures of physical function that are threshold-independent and require near-maximal strength of critical muscle groups such as the quadriceps. Another confounder in the measurement of muscle function is the learning effect. For instance, subjects who are unfamiliar with weight lifting exercises often demonstrate improvements in measures of muscle performance simply because of increased familiarity with the exercise equipment and technique. Therefore, in efficacy trials of anabolic interventions, it is important to incorporate strategies to minimize the confounding influence of the learning effect. Because of the considerable test-to-test variability in tests of physical function, it is possible that previous studies did not have adequate power to detect meaningful differences in measures of physical function between the placebo and testosterone-treated groups. It is possible that translation of muscle mass and strength gains into functional improvements may require functional training or behavioral intervention. We do not know whether task-specific training is necessary to induce the types of neuromuscular adaptations that are necessary for improvements in physical function. The subjects recruited in the first generation trials of testosterone were healthy community-dwelling men who did not have any functional limitations. Several ongoing
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testosterone trials aim to determine whether testosterone therapy can improve physical function in older men with mobility limitations or frailty [91].
Testosterone effects on fatigue/ energy, sense of well-being and quality of life In epidemiological studies, testosterone levels have been inconsistently associated with mood indices [92–94]. Low bioavailable testosterone has been reported to be associated with depression in men [94]. In one cross-sectional study of healthy, older men, the men who were depressed had the lowest testosterone levels [95]. Testosterone appears to be associated more with dysthymic mood than with major depressive disorder [92]. In open label trials, androgen administration in androgen-deficient men has been reported to improve positive aspects of mood and to reduce negative aspects of mood [96]. Similar improvements in mood and sense of wellbeing have been reported with testosterone replacement in surgically menopausal women [97] and women with adrenal insufficiency [98, 99]. In uncontrolled studies of depressed men with low testosterone levels, testosterone was effective in alleviating depression [100]. A recent, placebo-controlled, trial demonstrated that testosterone replacement of men with refractory depression and low testosterone levels was associated with greater improvements in depression indices than placebo [101]. In HIV-infected men with low testosterone levels, testosterone supplementation was more effective than placebo in restoring libido and energy and alleviating depressed mood [66, 102]. There is additional evidence that androgens improve energy and reduce sense of fatigue in HIV-infected men [102–105]. In focus groups, patients and physicians consider agerelated changes in energy levels, sexual performance and physical function and fatigue as important contributors to the impaired quality of life [106, 107]. However, there is a paucity of data on androgen effects on quality of life in older men. Short-term studies of testosterone supplementation have not shown significant improvements in overall quality of life (QoL) scores using generic QoL questionnaires [46, 102, 108–110]. However, these studies did not have sufficient power. Also, the QoL questionnaires used (e.g. SF-36) in previous studies are multidimensional and include several domains that are not androgen responsive. Indeed, some studies have reported improvements in the physical function domain of SF-36. Studies in hypogonadal men and in HIV-infected men with weight loss suggest that testosterone improves sense of energy, lessens fatigue and improves positive affect and attenuates negative affect [96, 102–105, 111, 112].
Reaction time Testosterone has been shown to affect neuromuscular transmission and reaction time in a frog hind leg model [113, 114]. It is possible that testosterone may influence fall propensity by reducing reaction time.
Mechanisms of testosterone effects on skeletal muscle The mechanisms by which testosterone increases skeletal muscle mass are poorly understood. Histomorphometric analyses of biopsies of vastus lateralis muscle obtained from young and older men participating in testosterone doseresponse studies have revealed that testosterone administration induces hypertrophy of both type I and type II skeletal muscle fibers [115]. However, testosterone does not affect the absolute number or the relative proportion of type I and II muscle fibers [115]. Testosterone-induced increase in muscle size is associated with an increase in the number of satellite cells [116, 117]. Three general hypotheses have been proposed to explain the anabolic effects of testosterone on the skeletal muscle and they are not mutually exclusive; it is possible that all three pathways – in addition to other known and unknown pathways – may contribute to the skeletal muscle mass gains observed during testosterone therapy. These hypotheses include stimulation of muscle protein synthesis [31, 48, 49, 55, 118–120], stimulation of growth hormone/insulin-like growth factor I axis and the regulation of mesenchymal stem cell differentiation [121–123]. The protein synthesis hypothesis has dominated the field since the 1940s when testosterone and other androgens were shown to increase nitrogen retention in androgen deficient men [7, 9]. These observations led to the hypothesis that testosterone stimulates muscle protein synthesis. Several investigators using stable isotopes have shown that testosterone therapy improves fractional muscle protein synthesis and reutilization of amino acids [48, 49, 55, 119, 120]. The effects of testosterone on muscle protein degradation are less clear. The muscle protein synthesis hypothesis does not easily explain the reciprocal change in fat mass [41] and the increased number of satellite cells in testosterone-treated men [124]. These observations led us to consider the alternate hypothesis that testosterone might regulate the differentiation of mesenchymal multipotent cells, promoting their differentiation into the myogenic lineage and inhibiting adipogenic differentiation. To test this hypothesis, we first asked whether androgen receptor protein was expressed in mesenchymal progenitor cells in the skeletal muscle. We found that the AR protein was expressed predominantly in satellite cells, identified by their location outside the sarcolemma
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but inside the lamina, and by C-met and CD34 staining [125]. AR protein expression was also observed in many myonuclei and in CD34 cells outside the lamina, vascular endothelial cells and myofibroblasts [125]. Thus, a number of mesenchymal, multipotent precursor cells, resident in the skeletal muscle, express AR and could be targets of androgen action [125]. We determined the effects of testosterone and DHT on the differentiation of multipotent, mesenchymal C3H10T1/2 cells [122]. Although untreated cells express low levels of AR protein, DHT and testosterone upregulate AR expression in these cells. Androgen stimulation of AR expression was blocked by the AR-antagonist, flutamide, suggesting that AR is involved in this autoregulation. Incubation with testosterone and DHT increases the number of MyoD myogenic cells and MHC myotubes and MyoD and MHC mRNA and protein levels increased dose dependently [126]. Both testosterone and DHT also decrease the number of Oil Red O positive adipocytes and downregulate the expression of PPAR2 mRNA and PPAR2 and C/EBP proteins that are markers of adipogenic differentiation [126]. The effects of testosterone and DHT on myogenesis and adipogenesis are blocked by bicalutamide, an androgen receptor antagonist. Hence, testosterone and DHT regulate the differentiation of mesenchymal multipotent cells by promoting their differentiation into the myogenic lineage and inhibiting their differentiation into adipocytes through an AR-mediated pathway (Figure 27.3) [126, 127]. The observation that differentiation of mesenchymal multipotent cells is androgen-regulated provides a unifying explanation for the reciprocal effects of androgens on muscle and fat mass and for the observed increase in satellite cell number. Our data do not exclude the possibility that androgens might also affect additional steps in myogenic and adipogenic differentiation pathways. Pluripotent stem cells Mesenchymal stem Fat cell lineage
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Cells
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+ Satellite cell
+
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Bhasin et al, J Gerontol Med Sci 2003
Figure 27.3 This model of androgen action hypothesizes that androgens promote the differentiation of mesenchymal stem cells into the myogenic lineage and inhibit their differentiation into adipogenic lineage. Additionally, testosterone and DHT have been shown to inhibit the differentiation of preadipocytes into adipocytes [121]. Others have shown that testosterone increases fractional muscle protein synthesis [31,49].
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In separate studies, we have shown that DHT also regulates the differentiation of human marrow-derived, mesenchymal stem cells from adult men [128]. DHT upregulates AR expression and inhibits lipid accumulation in adipocytes differentiated from hMSCs and downregulates the expression of aP2, PPAR, leptin and C/EBP [128]. Bicalutamide attenuates DHT’s inhibitory effects on adipogenic differentiation of hMSCs. Adipocytes differentiated in the presence of DHT accumulate smaller oil droplets suggesting a reduced extent of maturation. DHT decreases the incorporation of labeled fatty acid into triglyceride and downregulates acetyl CoA carboxylase and DGAT2 expression in adipocytes derived from hMSCs [128]. Thus, DHT inhibits adipogenic differentiation of hMSCs through an AR-mediated pathway, but it does not affect the proliferation of either hMSCs [128]. Emerging evidence suggests that Wnt signaling plays an important role in regulating the differentiation of mesenchymal progenitor cells [129, 130] and that testosterone and DHT promote the association of liganded androgen receptor with -catenin, stabilizing the latter and causing the androgen receptor–-catenin complex to translocate into the nucleus and activate a number of Wnt target genes [121–123]. Double immunofluorescence and immunoprecipitation studies have revealed that AR, -catenin and TCF-4 are co-localized in the nucleus in both testosterone-treated (100 nM) and DHTtreated (10 nM) cells [123], suggesting that they interact to form a complex. Both -catenin and TCF-4 play an essential role in mediating androgen effects on the differentiation of C3H10T1/2 cells [123]. Testosterone regulates the expression of several Wnt target genes, including follistatin, which plays an essential role in mediating testosterone’s effects on myogenesis [123]. The androgen signal is cross-communicated to the TGF-/ SMAD pathway through follistatin [123], which blocks TGF-/SMAD signaling in vivo and in vitro (Figure 27.4). It has been widely recognized that testosterone therapy augments pulsatile growth hormone (GH) secretion and increases serum insulin-like growth factor I (IGF-I) concentrations in peripubertal boys and in boys with constitutional delay of puberty [131–135]. The testosterone-associated increase in GH secretion is the result of a higher mass of GH secreted per burst and a higher maximal rate of GH secretion within each burst [136]. Additionally, androgens increase the magnitude of the nyctohemeral rhythm in the mass of GH secretory pulses [136]. This increase in GH secretion may contribute to the growth promoting effects of testosterone in boys with constitutional delay of puberty [137]. Androgen administration has also been shown to increase circulating IGF-I levels [38] and upregulate intramuscular IGF-I mRNA expression in men [49, 138]. However, anecdotally, we have observed that testosterone therapy increases lean body mass even in hypogonadal men who have had hypophysectomy and are GH deficient [32]. These data suggest that, although testosterone therapy may
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Wnt LRP-5/6
LiCl
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AR AR β-catenin
β-catenin
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Integrin-linked kinases
GSK-3 APC
Axin
β-catenin β-catenin
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Target genes Myogenesis Cell fate
Adipogenesis
Figure 27.4 The role of Wnt signaling pathway in mediating androgen effects on the skeletal muscle. Androgens regulate differentiation of mesenchymal multipotent cells into myogenic lineage by promoting the association of liganded AR with betacatenin, stabilizing the latter, and causing translocation of the AR-beta-catenin complex into the nucleus where it associates with TCF-4 and regulates the expression of a number of Wnt target genes, including follistatin. These Wnt target genes, especially follistatin, regulate myogenic and adipogenic differentiation [121–123]. Other components of the canonical Wnt pathway are also shown. AR; androgen receptor; TCF-4: T cell factor-4; APC: adenoma polyposis colon; Dsh: disheveled; GSK3: glycogen synthase kinase 3 beta; LiCl: lithium chloride.
augment GH secretion and circulating IGF-I levels, it may not be essential for mediating the anabolic effects of testosterone on the muscle. The role of the intramuscular IGF-I system in mediating androgen effects on the muscle also needs further investigation.
How testosterone effects on the skeletal muscle–bone unit may affect fracture risk No randomized trials have determined the effects of testosterone on bone fracture rates. In a recent study, using large groups of men and women, it has been reported that there is a more significant relationship with bone cross-sectional, sub-periosteal dimensions and the thickness of the corticalis and muscle mass than with weight [139]. According to the mechanostatic theory, muscle contractions induce tension in the bone and activate bone modeling via osteocyte mechanoreceptors [140]. During embryogenesis, the muscle– bone system is functionally unified via Wnt signaling and is controlled by the same hormones and genes [141]. The role of muscle in skeletal development during childhood and its integrity in adulthood has been suggested to be dependent on sexual differences. The relationship of bone mass to
muscle mass in young boys and girls is comparable, however, bone mass levels in boys are greater by 4.5% compared to the girls by age seven and by 6–15% in early puberty [142]. In adults, the sexual difference in the relationship between bone and muscle mass is also apparent. In a study measuring the ratio of bone density to muscle cross-section (pQCT) in pre- and postmenopausal women and men, it was shown that bone mass in adult men has a closer relationship to muscle than in women [143]. IGF-I is an important regulator of the muscle–bone system that not only regulates the development of the childhood skeleton but also is important in maintaining its stability during adulthood. Other chapters in this book describe the effects of testosterone therapy on bone mass and quality in men in detail. Androgens are especially attractive as therapeutic agents for fracture prevention because, in addition to their potential effects on bone mass and quality, androgens may also affect fracture risk by reducing fall propensity. As most fractures are associated with a fall, measures that can reduce fall risk may independently reduce fracture risk without affecting the bone [144]. The risk factors for falls in older individuals include reduced muscle strength and balance, decreased reaction time, visual impairment, dementia and psychotropic medications [144, 145]. According to the 2006 Behavioral Risk Factor Surveillance System (BRFSS) survey [146], approximately 5.8 million (15.9%) persons 65 years of age or older reported falling at least once in the preceding three months and 31% of those who fell sustained an injury that resulted in a doctor visit or restricted activity for at least one day [146]. Multifactorial assessment and targeted intervention for preventing falls and injuries among older people have had limited success. Testosterone may reduce fall risk by several mechanisms. First, testosterone administration has been shown to improve lower extremity strength in a dose dependent manner. Muscle strength is an important factor in postural control, which affects fall propensity [147, 148]. Lower extremity strength is a particularly important determinant of fall risk [148–150]. It is possible that testosterone therapy, by improving lower extremity strength, may improve postural control and reduce fall risk. Time-critical obstacle avoidance mechanisms are impaired in older individuals for a variety of factors including a slow reaction time. Testosterone may reduce reaction time through its effects on neuromuscular transmission [113, 114].
Achieving tissue selectivity of testosterone effects Our testosterone dose-response studies demonstrated unequivocally that very substantial skeletal muscle remodeling is possible with testosterone administration even in older men [38, 39]. However, there is a trade-off between the anabolic
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effects and the potential adverse effects. The higher the testosterone dose, the greater is the magnitude of skeletal muscle mass and muscle strength gains as well as the potential for adverse effects. These data provide a compelling rationale for the development of molecules that selectively increase skeletal muscle mass and physical function without the dose limiting side effects. Historically two general approaches have been used to achieve tissue selectivity of androgen action. The first approach is to develop SARMs with the desired activity profile and tissue selectivity. The second approach is to elucidate the mechanisms of androgen action on the skeletal muscle and the prostate and to identify signaling molecules that are downstream of androgen receptor and which activate pathways involved in skeletal muscle hypertrophy, but not the prostate. SARMs are androgen receptor ligands that bind androgen receptor, but which activate androgenic signaling selectively in a tissue-specific manner [5, 6]. Steroidal SARMs are based on modification of the testosterone structure and have been available since the 1940s. The discovery of non-steroidal SARMs emerged in the late 1990s from the pioneering efforts of James Dalton and Duane Miller at the University of Memphis, Tennessee, and the scientists at Ligand Pharmaceuticals. Since then, many different structural classes of molecules have been explored by different pharmaceutical companies [6]: aryl-propionamide (GTX, Inc.), bicyclic hydantoin (BMS), quinolinones (Ligand Pharmaceuticals), tetrahydroquinoline analogs (Kaken Pharmaceuticals, Inc.), benzimidazole, imidazolopyrazole, indole and pyrazoline derivatives (Johnson and Johnson), azasteroidal derivatives (Merck) and aniline, diaryl aniline and bezoxazepinones derivatives (GSK). The mechanistic basis of the tissue selective actions of SARMs is not fully understood. The first generation nonsteroidal SARMs are neither aromatized nor 5--reduced; the failure of these compounds to undergo 5--reduction may contribute to relative prostate sparing. It has been hypothesized that binding of SARMs to androgen receptor leads to recruitment of a unique repertoire of co-activators and corepressors which, in turn, determines the profile of gene activation and tissue selectivity [151]. Indeed, SARM binding has been shown to recruit liganded AR to a different set of androgen-responsive promoters [151]. Others have postulated that ligand binding to AR confers a unique conformation to AR, leading to subsequent binding of a unique set of co-regulator proteins [5, 152]. These hypotheses are not mutually exclusive and it is possible that all of these mechanisms may contribute to the tissue selective actions of SARMs. Because many of the data in this discovery field have been generated by pharmaceutical companies and remain unpublished, it is difficult to gauge the relative potency and selectivity of different SARMs. In the Hirschberger assay, the first generation non-steroidal SARMs have shown some degree of tissue selectivity with respect to the prostate and anabolic effects on the levator ani muscle and bone [153–156]. Several
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SARMs have undergone early phase I and II trials in humans; these studies have revealed modest increments in lean body mass and relative safety at the doses that have been tested, but have not approached the substantially greater gains reported with supraphysiologic doses of testosterone [13, 38, 39]. SARMs hold considerable promise as tissue selective function promoting anabolic therapies, but a number of regulatory uncertainties have hindered drug development efforts [157, 158]. There has been a lack of consensus on how to operationalize functional limitations within the context of these clinical trials. What outcomes should serve as measures of efficacy? What are the minimal clinically important differences in the primary outcome that should guide sample size estimates? A substantial current effort by an academic group of investigators to forge a consensus around these vexing issues should facilitate progress in the field [157, 158].
Conclusion A large body of evidence supports the conclusion that androgen administration increases skeletal muscle mass, maximal voluntary strength and leg power. However, neither the clinical benefits of androgen therapy on physical function and patient-important health outcomes nor the long-term safety of androgen administration in older men has been demonstrated to date. Strategies to translate the anabolic effects of androgens on skeletal muscle mass and strength into functional improvements are needed.
References 1. J. Wilson, Androgen abuse by athletes, Endocr. Rev. 9 (1988) 181–191. 2. M.R. Graham, B. Davies, F.M. Grace, A. Kicman, J.S. Baker, Anabolic steroid use: patterns of use and detection of doping, Sports Med. 38 (2008) 505–525. 3. D.J. Handelsman, Heather A. Androgen abuse in sports, Asian J. Androl. 10 (2008) 403–415. 4. S. Bhasin, L. Woodhouse, T.W. Storer, Proof of the effect of testosterone on skeletal muscle, J. Endocrinol. 170 (2001) 27–38. 5. S. Bhasin, O.M. Calof, T.W. Storer, et al., Drug insight: testosterone and selective androgen receptor modulators as anabolic therapies for chronic illness and aging, Nat. Clin. Pract. Endocrinol. Metab. 2 (2006) 146–159. 6. R. Narayanan, M.L. Mohler, C.E. Bohl, D.D. Miller, J.T. Dalton, Selective androgen receptor modulators in preclinical and clinical development, Nucl. Recept. Signal 6 (2008) e010. 7. C. Kochakian, J. Murlin, The effect of male hormone on the protein and energy metabolism of castrate dogs, J. Nutrition 10 (1935) 437–459. 8. C. Kochakian, Testosterone and testosterone acetate and the protein and energy metabolism of castrate dogs, Endocrinology 21 (1937) 750–755.
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Osteoporosis in Men
9. C. Kochakian, Comparison of protein anabolic property of various androgens in the castrated rat, Am. J. Physiol. 60 (1950) 53–58. 10. A. Kenyon, K. Knowlton, I. Sandiford, F.C. Koch, G. Lotwin, A comparative study of the metabolic effects of testosterone propionate in normal men and women and in eunuchoidism, Endocrinology 26 (1940) 26–45. 11. H. Kopera, The history of anabolic steroids and a review of clinical experience with anabolic steroids, Acta Endocrinol. Suppl. (Copenh) 271 (1985) 11–18. 12. D.H. Catlin, K.D. Fitch, A. Ljungqvist, Medicine and science in the fight against doping in sport, J. Intern. Med. 264 (2008) 99–114. 13. S. Bhasin, T.W. Storer, N. Berman, et al., The effects of supraphysiologic doses of testosterone on muscle size and strength in normal men, N. Engl. J. Med. 335 (1996) 1–7. 14. M.A. Hoffman, W.C. DeWolf, A. Morgentaler, Is low serum free testosterone a marker for high grade prostate cancer? J. Urol. 163 (2000) 824–827. 15. L. Katznelson, J.S. Finkelstein, D.A. Schoenfeld, D.I. Rosenthal, E.J. Anderson, A. Klibanski, Increase in bone density and lean body mass during testosterone administration in men with acquired hypogonadism, J. Clin. Endocrinol. Metab. 81 (1996) 4358–4365. 16. L. Katznelson, D.I. Rosenthal, M.S. Rosol, et al., Using quantitative CT to assess adipose distribution in adult men with acquired hypogonadism, Am. J. Roentgenol. 170 (1998) 423–427. 17. L.J. Melton III., S. Khosla, C.S. Crowson, M.K. O’Connor, W.M. O’Fallon, B.L. Riggs, Epidemiology of sarcopenia, J. Am. Geriatr. Soc. 48 (2000) 625–630. 18. L.J. Melton III., S. Khosla, B.L. Riggs, Epidemiology of sarcopenia, Mayo Clin. Proc. 75 (Suppl) (2000) S10–S12 discussion S12-13. 19. R.N. Baumgartner, Body composition in healthy aging, Ann. N.Y. Acad. Sci. 904 (2000) 437–448. 20. R.N. Baumgartner, K.M. Koehler, D. Gallagher, et al., Epidemiology of sarcopenia among the elderly in New Mexico, Am. J. Epidemiol. 147 (1998) 755–763. 21. T.A. Roy, M.R. Blackman, S.M. Harman, J.D. Tobin, M. Schrager, E.J. Metter, Interrelationships of serum testosterone and free testosterone index with FFM and strength in aging men, Am. J. Physiol. Endocrinol. Metab. 283 (2002) E284–E294. 22. J.E. Morley, F.E. Kaiser, H.M. Perry III., et al., Longitudinal changes in testosterone, luteinizing hormone, and folliclestimulating hormone in healthy older men, Metabolism 46 (1997) 410–413. 23. L.A. Schaap, S.M. Pluijm, J.H. Smit, et al., The association of sex hormone levels with poor mobility, low muscle strength and incidence of falls among older men and women, Clin. Endocrinol. (Oxf) 63 (2005) 152–160. 24. A.B. O’Donnell, T.G. Travison, S.S. Harris, J.L. Tenover, J.B. McKinlay, Testosterone, dehydroepiandrosterone and physical performance in older men: results from the Massachusetts male aging study, J. Clin. Endocrinol. Metab. 91 (2006) 425–431. 25. E. Orwoll, L.C. Lambert, L.M. Marshall, et al., Endogenous testosterone levels, physical performance, and fall risk in older men, Arch. Intern. Med. 166 (2006) 2124–2131. 26. K. Dacal, S. Sereika, S. Greenspan, Quality of life in prostate cancer patients taking androgen deprivation therapy, J. Am. Geriatr. Soc. 54 (2006) 85–90.
27. J. Krasnoff, S. Basaria, M. Pencina, et al., Free Testosterone Levels are Associated With Mobility Limitation and Physical Performance in Community-Dwelling Men: The Framingham Offspring Study, The Endocrine Society Meeting, Washington, DC, 2009. 28. J.C. Seidell, P. Bjorntorp, L. Sjostrom, H. Kvist, R. Sannerstedt, Visceral fat accumulation in men is positively associated with insulin, glucose, and C-peptide levels, but negatively with testosterone levels., Metabolism 39 (1990) 897–901. 29. K.T. Khaw, E. Barrett-Connor, Lower endogenous androgens predict central adiposity in men, Ann. Epidemiol. 2 (1992) 675–682. 30. N. Mauras, V. Hayes, S. Welch, et al., Testosterone deficiency in young men: marked alterations in whole body protein kinetics, strength, and adiposity, J. Clin. Endocrinol. Metab. 83 (1998) 1886–1892. 31. I.G. Brodsky, P. Balagopal, K.S. Nair, Effects of testosterone replacement on muscle mass and muscle protein synthesis in hypogonadal men – a clinical research center study, J. Clin. Endocrinol. Metab. 81 (1996) 3469–3475. 32. S. Bhasin, T.W. Storer, N. Berman, et al., Testosterone replacement increases fat-free mass and muscle size in hypogonadal men, J. Clin. Endocrinol. Metab. 82 (1997) 407–413. 33. C. Wang, R.S. Swedloff, A. Iranmanesh, et al., Transdermal testosterone gel improves sexual function, mood, muscle strength, and body composition parameters in hypogonadal men. Testosterone Gel Study Group, J. Clin. Endocrinol. Metab. 85 (2000) 2839–2853. 34. P.J. Snyder, D.A. Lawrence, Treatment of male hypogonadism with testosterone enanthate, J. Clin. Endocrinol. Metab. 51 (1980) 1335–1339. 35. C. Wang, D.R. Eyre, R. Clark, et al., Sublingual testosterone replacement improves muscle mass and strength, decreases bone resorption, and increases bone formation markers in hypogonadal men – a clinical research center study, J. Clin. Endocrinol. Metab. 81 (1996) 3654–3662. 36. P.J. Snyder, H. Peachey, J.A. Berlin, et al., Effects of testosterone replacement in hypogonadal men, J. Clin. Endocrinol. Metab. 85 (2000) 2670–2677. 37. C. Steidle, S. Schwartz, K. Jacoby, T. Sebree, T. Smith, R. Bachand, AA2500 testosterone gel normalizes androgen levels in aging males with improvements in body composition and sexual function, J. Clin. Endocrinol. Metab. 88 (2003) 2673–2681. 38. S. Bhasin, L. Woodhouse, R. Casaburi, et al., Testosterone dose-response relationships in healthy young men, Am. J. Physiol. Endocrinol. Metab. 281 (2001) E1172–E1181. 39. S. Bhasin, L. Woodhouse, R. Casaburi, et al., Older men are as responsive as young men to the anabolic effects of graded doses of testosterone on the skeletal muscle, J. Clin. Endocrinol. Metab. 90 (2005) 678–688. 40. L.J. Woodhouse, S. Reisz-Porszasz, M. Javanbakht, et al., Development of models to predict anabolic response to testosterone administration in healthy young men, Am. J. Physiol. Endocrinol. Metab. 284 (2003) E1009–E1017. 41. L.J. Woodhouse, N. Gupta, M. Bhasin, et al., Dose-dependent effects of testosterone on regional adipose tissue distribution in healthy young men, J. Clin. Endocrinol. Metab. 89 (2004) 718–726. 42. F. Buena, R.S. Swerdloff, B.S. Steiner, et al., Sexual function does not change when serum testosterone levels are
C h a p t e r 2 7 Androgen Effects on the Skeletal Muscle l
43.
44.
45.
46.
47.
48.
49.
50.
51.
52. 53.
54.
55.
56.
57. 58.
pharmacologically varied within the normal male range, Fertil. Steril. 59 (1993) 1118–1123. P.B. Gray, A.B. Singh, L.J. Woodhouse, et al., Dose-dependent effects of testosterone on sexual function, mood, and visuospatial cognition in older men, J. Clin. Endocrinol. Metab. 90 (2005) 3838–3846. A.D. Coviello, K. Lakshman, N.A. Mazer, S. Bhasin, Differences in the apparent metabolic clearance rate of testosterone in young and older men with gonadotropin suppression receiving graded doses of testosterone, J. Clin. Endocrinol. Metab. 91 (2006) 4669–4675. A.D. Coviello, B. Kaplan, K.M. Lakshman, T. Chen, A.B. Singh, S. Bhasin, Effects of graded doses of testosterone on erythropoiesis in healthy young and older men, J. Clin. Endocrinol. Metab. 93 (2008) 914–919. P.J. Snyder, H. Peachey, P. Hannoush, et al., Effect of testosterone treatment on body composition and muscle strength in men over 65 years of age, J. Clin. Endocrinol. Metab. 84 (1999) 2647–2653. M.R. Blackman, J.D. Sorkin, T. Munzer, et al., Growth hormone and sex steroid administration in healthy aged women and men: a randomized controlled trial, J. Am. Med. Assoc. 288 (2002) 2282–2292. A.A. Ferrando, K.D. Tipton, D. Doyle, S.M. Phillips, J. Cortiella, R.R. Wolfe, Testosterone injection stimulates net protein synthesis but not tissue amino acid transport, Am. J. Physiol. 275 (1998) E864–E871. A.A. Ferrando, M. Sheffield-Moore, C.W. Yeckel, et al., Testosterone administration to older men improves muscle function: molecular and physiological mechanisms, Am. J. Physiol. Endocrinol. Metab. 282 (2002) E601–E607. A.M. Kenny, K.M. Prestwood, C.A. Gruman, K.M. Marcello, L.G. Raisz, Effects of transdermal testosterone on bone and muscle in older men with low bioavailable testosterone levels, J. Gerontol. A Biol. Sci. Med. Sci. 56 (2001) M266–M272. J.E. Morley, H.M. Perry III., F.E. Kaiser, et al., Effects of testosterone replacement therapy in old hypogonadal males: a preliminary study, J. Am. Geriatr. Soc. 41 (1993) 149–152. J.S. Tenover, Effects of testosterone supplementation in the aging male, J. Clin. Endocrinol. Metab. 75 (1992) 1092–1098. J.L. Tenover, Experience with testosterone replacement in the elderly, Mayo Clin. Proc. 75 (Suppl) (2000) S77–S81 discussion S82. R. Sih, J.E. Morley, F.E. Kaiser, H.M. Perry III., P. Patrick, C. Ross, Testosterone replacement in older hypogonadal men: a 12-month randomized controlled trial, J. Clin. Endocrinol. Metab. 82 (1997) 1661–1667. R.J. Urban, Y.H. Bodenburg, C. Gilkison, et al., Testosterone administration to elderly men increases skeletal muscle strength and protein synthesis, Am. J. Physiol. 269 (1995) E820–E826. J.E. Clague, F.C. Wu, M.A. Horan, Difficulties in measuring the effect of testosterone replacement therapy on muscle function in older men, Int. J. Androl. 22 (1999) 261–265. J.L. Tenover, Testosterone replacement therapy in older adult men, Int. J. Androl. 22 (1999) 300–306. P.J. Snyder, H. Peachey, P. Hannoush, et al., Effect of testosterone treatment on bone mineral density in men over 65 years of age, J. Clin. Endocrinol. Metab. 84 (1999) 1966–1972.
345
59. T.W. Storer, L. Magliano, L. Woodhouse, et al., Testosterone dose-dependently increases maximal voluntary strength and leg power, but does not affect fatigability or specific tension, J. Clin. Endocrinol. Metab. 88 (2003) 1478–1485. 60. S.T. Page, J.K. Amory, F.D. Bowman, et al., Exogenous testosterone (T) alone or with finasteride increases physical performance, grip strength, and lean body mass in older men with low serum T, J. Clin. Endocrinol. Metab. 90 (2005) 1502–1510. 61. K.S. Nair, R.A. Rizza, P. O’Brien, et al., DHEA in elderly women and DHEA or testosterone in elderly men, N. Engl. J. Med. 355 (2006) 1647–1659. 62. M.H. Emmelot-Vonk, H.J. Verhaar, H.R. Nakhai Pour, et al., Effect of testosterone supplementation on functional mobility, cognition, and other parameters in older men: a randomized controlled trial, J. Am. Med. Assoc. 299 (2008) 39–52. 63. I.R. Reid, Serum testosterone levels during chronic glucocorticoid therapy, Ann. Intern. Med. 106 (1987) 639–640. 64. M.R. MacAdams, R.H. White, B.E. Chipps, Reduction of serum testosterone levels during chronic glucocorticoid therapy, Ann. Intern. Med. 104 (1986) 648–651. 65. S. Arver, I. Sinha-Hikim, G. Beall, M. Guerrero, R. Shen, S. Bhasin, Serum dihydrotestosterone and testosterone concentrations in human immunodeficiency virus-infected men with and without weight loss, J. Androl. 20 (1999) 611–618. 66. S. Grinspoon, C. Corcoran, T. Stanley, A. Baaj, N. Basgoz, A. Klibanski, Effects of hypogonadism and testosterone administration on depression indices in HIV-infected men, J. Clin. Endocrinol. Metab. 85 (2000) 60–65. 67. S. Grinspoon, C. Corcoran, K. Lee, et al., Loss of lean body and muscle mass correlates with androgen levels in hypogonadal men with acquired immunodeficiency syndrome and wasting, J. Clin. Endocrinol. Metab. 81 (1996) 4051–4058. 68. A.S. Dobs, W.L. Few III., M.R. Blackman, S.M. Harman, D.R. Hoover, N.M. Graham, Serum hormones in men with human immunodeficiency virus-associated wasting, J. Clin. Endocrinol. Metab. 81 (1996) 4108–4112. 69. G.O. Coodley, M.O. Loveless, H.D. Nelson, M.K. Coodley, Endocrine function in the HIV wasting syndrome, J. Acquir. Immune. Defic. Syndr. 7 (1994) 46–51. 70. P. Rietschel, C. Corcoran, T. Stanley, N. Basgoz, A. Klibanski, S. Grinspoon, Prevalence of hypogonadism among men with weight loss related to human immunodeficiency virus infection who were receiving highly active antiretroviral therapy, Clin. Infect. Dis. 31 (2000) 1240–1244. 71. B. Salehian, D. Jacobson, R.S. Swerdloff, M.R. Grafe, I. Sinha-Hikim, J.A. McCutchan, Testicular pathologic changes and the pituitary-testicular axis during human immunodeficiency virus infection, Endocr. Pract. 5 (1999) 1–9. 72. S. Bhasin, T.W. Storer, M. Javanbakht, et al., Testosterone replacement and resistance exercise in HIV-infected men with weight loss and low testosterone levels, J. Am. Med. Assoc. 283 (2000) 763–770. 73. S. Bhasin, T.W. Storer, N. Asbel-Sethi, et al., Effects of testosterone replacement with a nongenital, transdermal system, Androderm, in human immunodeficiency virus-infected men with low testosterone levels, J. Clin. Endocrinol. Metab. 83 (1998) 3155–3162. 74. G.O. Coodley, M.K. Coodley, A trial of testosterone therapy for HIV-associated weight loss, Aids 11 (1997) 1347–1352.
346
Osteoporosis in Men
75. S. Grinspoon, C. Corcoran, H. Askari, et al., Effects of androgen administration in men with the AIDS wasting syndrome. A randomized, double-blind, placebo-controlled trial, Ann. Intern. Med. 129 (1998) 18–26. 76. A.S. Dobs, J. Cofrancesco, W.E. Nolten, et al., The use of a transscrotal testosterone delivery system in the treatment of patients with weight loss related to human immunodeficiency virus infection, Am. J. Med. 107 (1999) 126–132. 77. F.R. Sattler, S.V. Jaque, E.T. Schroeder, et al., Effects of pharmacological doses of nandrolone decanoate and progressive resistance training in immunodeficient patients infected with human immunodeficiency virus, J. Clin. Endocrinol. Metab. 84 (1999) 1268–1276. 78. A. Strawford, T. Barbieri, M. Van Loan, et al., Resistance exercise and supraphysiologic androgen therapy in eugonadal men with HIV-related weight loss: a randomized controlled trial, J. Am. Med. Assoc. 281 (1999) 1282–1290. 79. A. Strawford, T. Barbieri, R. Neese, et al., Effects of nandrolone decanoate therapy in borderline hypogonadal men with HIV-associated weight loss, J. Acquir. Immune. Defic. Syndr. Hum. Retrovirol. 20 (1999) 137–146. 80. A. Kong, P. Edmonds, Testosterone therapy in HIV wasting syndrome: systematic review and meta-analysis, Lancet Infect. Dis. 2 (2002) 692–699. 81. K.L. Johansen, K. Mulligan, M. Schambelan, Anabolic effects of nandrolone decanoate in patients receiving dialysis: a randomized controlled trial, J. Am. Med. Assoc. 281 (1999) 1275–1281. 82. K.L. Johansen, Physical functioning and exercise capacity in patients on dialysis, Adv. Ren. Replace Ther. 6 (1999) 141–148. 83. P. Painter, K. Johansen, Physical functioning in end-stage renal disease. Introduction: a call to activity, Adv. Ren. Replace Ther. 6 (1999) 107–109. 84. D. Buchwald, S. Argyres, R.E. Easterling, et al., Effect of nandrolone decanoate on the anemia of chronic hemodialysis patients, Nephron 18 (1977) 232–238. 85. J.S. Berns, M.R. Rudnick, R.M. Cohen, A controlled trial of recombinant human erythropoietin and nandrolone decanoate in the treatment of anemia in patients on chronic hemodialysis, Clin. Nephrol. 37 (1992) 264–267. 86. I.R. Reid, D.J. Wattie, M.C. Evans, J.P. Stapleton, Testosterone therapy in glucocorticoid-treated men, Arch. Intern. Med. 156 (1996) 1173–1177. 87. B.A. Crawford, P.Y. Liu, M.T. Kean, J.F. Bleasel, D.J. Handelsman, Randomized placebo-controlled trial of androgen effects on muscle and bone in men requiring long-term systemic glucocorticoid treatment, J. Clin. Endocrinol. Metab. 88 (2003) 3167–3176. 88. A.M. Schols, P.B. Soeters, R. Mostert, R.J. Pluymers, E.F. Wouters, Physiologic effects of nutritional support and anabolic steroids in patients with chronic obstructive pulmonary disease. A placebo-controlled randomized trial, Am. J. Respir. Crit. Care. Med. 152 (1995) 1268–1274. 89. R. Casaburi, S. Bhasin, L. Cosentino, et al., Effects of testosterone and resistance training in men with chronic obstructive pulmonary disease, Am. J. Respir. Crit. Care. Med. 170 (2004) 870–878. 90. N.K. LeBrasseur, S. Bhasin, R. Miciek, T.W. Storer, Tests of muscle strength and physical function: reliability and discrimination of performance in younger and older men and older men with mobility limitations, J. Am. Geriatr. Soc. 56 (2008) 2118–2123.
91. N.K. LeBrasseur, N. Lajevardi, R. Miciek, N. Mazer, T.W. Storer, S. Bhasin, Effects of testosterone therapy on muscle performance and physical function in older men with mobility limitations (The TOM Trial): design and methods, Contemp. Clin. Trials 30 (2009) 133–140. 92. S.N. Seidman, A.B. Araujo, S.P. Roose, et al., Low testosterone levels in elderly men with dysthymic disorder, Am. J. Psychiatr. 159 (2002) 456–459. 93. S.N. Seidman, A.B. Araujo, S.P. Roose, J.B. McKinlay, Testosterone level, androgen receptor polymorphism, and depressive symptoms in middle-aged men, Biol. Psychiatr. 50 (2001) 371–376. 94. E. Barrett-Connor, D.G. Von Muhlen, D. Kritz-Silverstein, Bioavailable testosterone and depressed mood in older men: the Rancho Bernardo Study, J. Clin. Endocrinol. Metab. 84 (1999) 573–577. 95. H.C. Margolese, The male menopause and mood: testosterone decline and depression in the aging male – is there a link? J. Geriatr. Psychiatr. Neurol. 13 (2000) 93–101. 96. C. Wang, G. Alexander, N. Berman, et al., Testosterone replacement therapy improves mood in hypogonadal men – a clinical research center study, J. Clin. Endocrinol. Metab. 81 (1996) 3578–3583. 97. J.L. Shifren, G.D. Braunstein, J.A. Simon, et al., Trans dermal testosterone treatment in women with impaired sexual function after oophorectomy, N. Engl. J. Med. 343 (2000) 682–688. 98. W. Arlt, F. Callies, J.C. van Vlijmen, I. Koehler, et al., Dehydroepiandrosterone replacement in women with adrenal insufficiency, N. Engl. J. Med. 341 (1999) 1013–1020. 99. W. Arlt, F. Callies, B. Allolio, DHEA replacement in women with adrenal insufficiency – pharmacokinetics, bioconversion and clinical effects on well-being, sexuality and cognition, Endocr. Res. 26 (2000) 505–511. 100. S.N. Seidman, J.G. Rabkin, Testosterone replacement therapy for hypogonadal men with SSRI-refractory depression, J. Affect. Disord. 48 (1998) 157–161. 101. H.G. Pope Jr., G.H. Cohane, G. Kanayama, A.J. Siegel, J.I. Hudson, Testosterone gel supplementation for men with refractory depression: a randomized, placebo-controlled trial, Am. J. Psychiatry. 160 (2003) 105–111. 102. J.G. Rabkin, S.J. Ferrando, G.J. Wagner, R. Rabkin, DHEA treatment for HIV patients: effects on mood, androgenic and anabolic parameters, Psychoneuroendocrinology 25 (2000) 53–68. 103. J.G. Rabkin, G.J. Wagner, R. Rabkin, A double-blind, placebocontrolled trial of testosterone therapy for HIV-positive men with hypogonadal symptoms, Arch. Gen. Psychiatr. 57 (2000) 141–147 discussion 155–56. 104. J.G. Rabkin, R. Rabkin, G. Wagner, Testosterone replacement therapy in HIV illness, Gen. Hosp. Psychiatr. 17 (1995) 37–42. 105. G.J. Wagner, J.G. Rabkin, R. Rabkin, Testosterone as a treatment for fatigue in HIV men, Gen. Hosp. Psychiatr. 20 (1998) 209–213. 106. A. Novak, M. Brod, J. Elbers, Andropause and quality of life: findings from patient focus groups and clinical experts, Maturitas 43 (2002) 231–237. 107. J.E. Morley, Andropause, testosterone therapy, and quality of life in aging men, Cleve. Clin. J. Med. 67 (2000) 880–882. 108. P. Reddy, C.M. White, A.B. Dunn, N.M. Moyna, P.D. Thompson, The effect of testosterone on health-related quality
C h a p t e r 2 7 Androgen Effects on the Skeletal Muscle l
109.
110.
111.
112.
113.
114.
115.
116.
117.
118.
119.
120.
121.
122.
of life in elderly males – a pilot study, J. Clin. Pharm. Ther. 25 (2000) 421–426. A.M. Kenny, S. Bellantonio, C.A. Gruman, R.D. Acosta, K.M. Prestwood, Effects of transdermal testosterone on cognitive function and health perception in older men with low bioavailable testosterone levels, J. Gerontol. A Biol. Sci. Med. Sci. 57 (2002) M321–M325. S.N. Seidman, Testosterone deficiency and depression in aging men: pathogenic and therapeutic implications, J. Gend. Specif. Med. 4 (2001) 44–48. G.M. Alexander, R.S. Swerdloff, C. Wang, et al., Androgenbehavior correlations in hypogonadal men and eugonadal men. I. Mood and response to auditory sexual stimuli, Horm. Behav. 31 (1997) 110–119. P.E. Knapp, T.W. Storer, K.L. Herbst, et al., Effects of a supraphysiological dose of testosterone on physical function, muscle performance, mood, and fatigue in men with HIVassociated weight loss, Am. J. Physiol. Endocrinol. Metab. 294 (2008) E1135–E1143. C.E. Blanco, P. Popper, P. Micevych, Anabolic-androgenic steroid induced alterations in choline acetyltransferase messenger RNA levels of spinal cord motoneurons in the male rat, Neuroscience 78 (1997) 873–882. M. Leslie, Forger N.G, Breedlove S.M. Sexual dimorphism and androgen effects on spinal motoneurons innervating the rat flexor digitorum brevis, Brain Res. 561 (1991) 269–273. I. Sinha-Hikim, J. Artaza, L. Woodhouse, et al., Testosteroneinduced increase in muscle size in healthy young men is associated with muscle fiber hypertrophy, Am. J. Physiol. Endocrinol. Metab. 283 (2002) E154–E164. I. Sinha-Hikim, S.M. Roth, M.I. Lee, S. Bhasin, Testosterone-induced muscle hypertrophy is associated with an increase in satellite cell number in healthy, young men, Am. J. Physiol. Endocrinol. Metab. 285 (2003) E197–E205. I. Sinha-Hikim, M. Cornford, H. Gaytan, M.L. Lee, S. Bhasin, Effects of testosterone supplementation on skeletal muscle fiber hypertrophy and satellite cells in community-dwelling older men, J. Clin. Endocrinol. Metab. 91 (2006) 3024–3033. E.L. Dillon, M. Sheffield-Moore, D. Paddon-Jones, et al., Amino acid supplementation increases lean body mass, basal muscle protein synthesis, and IGF-1 expression in older women, J. Clin. Endocrinol. Metab. 94 (2009) 1630–1637. M. Sheffield-Moore, D. Paddon-Jones, S.L. Casperson, et al., Androgen therapy induces muscle protein anabolism in older women, J. Clin. Endocrinol. Metab. 91 (2006) 3844–3849. M. Sheffield-Moore, R.J. Urban, S.E. Wolf, et al., Shortterm oxandrolone administration stimulates net muscle protein synthesis in young men, J. Clin. Endocrinol. Metab. 84 (1999) 2705–2711. R. Singh, J.N. Artaza, W.E. Taylor, et al., Testosterone inhibits adipogenic differentiation in 3T3-L1 cells: nuclear translocation of androgen receptor complex with beta-catenin and T-cell factor 4 may bypass canonical Wnt signaling to down-regulate adipogenic transcription factors, Endo crinology 147 (2006) 141–154. R. Singh, J.N. Artaza, W.E. Taylor, N.F. Gonzalez-Cadavid, S. Bhasin, Androgens stimulate myogenic differentiation and inhibit adipogenesis in C3H 10T1/2 pluripotent cells through an androgen receptor-mediated pathway, Endocrinology 144 (2003) 5081–5088.
347
123. R. Singh, S. Bhasin, M. Braga, et al., Regulation of myogenic differentiation by androgens: cross talk between androgen receptor/beta-catenin and follistatin/transforming growth factor-beta signaling pathways, Endocrinology 150 (2009) 1259–1268. 124. S. Bhasin, W.E. Taylor, R. Singh, et al., The mechanisms of androgen effects on body composition: mesenchymal pluripotent cell as the target of androgen action, J. Gerontol. A Biol. Sci. Med. Sci. 58 (2003) M1103–M1110. 125. I. Sinha-Hikim, W.E. Taylor, N.F. Gonzalez-Cadavid, W. Zheng, S. Bhasin, Androgen receptor in human skeletal muscle and cultured muscle satellite cells: up-regulation by androgen treatment, J. Clin. Endocrinol. Metab. 89 (2004) 5245–5255. 126. R. Singh, J.N. Artaza, W.E. Taylor, N.F. Gonzalez-Cadavid, S. Bhasin, Androgens stimulate myogenic differentiation and inhibit adipogenesis in C3H 10T1/2 pluripotent cells through an androgen receptor-mediated pathway, Endocrinology 144 (2003) 5081–5088. 127. R. Singh, S. Bhasin, M. Braga, et al., Regulation of myogenic differentiation by androgens: cross-talk between androgen receptor/{beta}-catenin and follistatin/TGF-{beta} signaling pathways, Endocrinology (2008). 128. V. Gupta, S. Bhasin, W. Guo, et al., Effects of dihydrotestosterone on differentiation and proliferation of human mesenchymal stem cells and preadipocytes, Mol. Cell Endocrinol. 296 (2008) 32–40. 129. C.N. Bennett, S.E. Ross, K.A. Longo, et al., Regulation of Wnt signaling during adipogenesis, J. Biol. Chem. 277 (2002) 30998–31004. 130. S.E. Ross, N. Hemati, K.A. Longo, et al., Inhibition of adipogenesis by Wnt signaling, Science 289 (2000) 950–953. 131. M. Bondanelli, M.R. Ambrosio, A. Margutti, P. Franceschetti, M.C. Zatelli, degli Uberti E.C. Activation of the somatotropic axis by testosterone in adult men: evidence for a role of hypothalamic growth hormone-releasing hormone, Neuroendocrinology 77 (2003) 380–387. 132. G.D. Eakman, J.S. Dallas, S.W. Ponder, B.S. Keenan, The effects of testosterone and dihydrotestosterone on hypothalamic regulation of growth hormone secretion, J. Clin. Endocrinol. Metab. 81 (1996) 1217–1223. 133. A. Giustina, T. Scalvini, C. Tassi, et al., Maturation of the regulation of growth hormone secretion in young males with hypogonadotropic hypogonadism pharmacologically exposed to progressive increments in serum testosterone, J. Clin. Endocrinol. Metab. 82 (1997) 1210–1219. 134. B.S. Keenan, G.E. Richards, S.W. Ponder, J.S. Dallas, M. Nagamani, E.R. Smith, Androgen-stimulated pubertal growth: the effects of testosterone and dihydrotestosterone on growth hormone and insulin-like growth factor-I in the treatment of short stature and delayed puberty, J. Clin. Endocrinol. Metab. 76 (1993) 996–1001. 135. L. Liu, G.R. Merriam, R.J. Sherins, Chronic sex steroid exposure increases mean plasma growth hormone concentration and pulse amplitude in men with isolated hypogonadotropic hypogonadism, J. Clin. Endocrinol. Metab. 64 (1987) 651–656. 136. A. Ulloa-Aguirre, R.M. Blizzard, E. Garcia-Rubi, et al., Testosterone and oxandrolone, a nonaromatizable androgen, specifically amplify the mass and rate of growth hormone
348
137.
138.
139.
140. 141. 142.
143.
144.
145.
146.
147.
148.
149.
Osteoporosis in Men (GH) secreted per burst without altering GH secretory burst duration or frequency or the GH half-life, J. Clin. Endocrinol. Metab. 71 (1990) 846–854. K. Link, R.M. Blizzard, W.S. Evans, D.L. Kaiser, M.W. Parker, A.D. Rogol, The effect of androgens on the pulsatile release and the twenty-four-hour mean concentration of growth hormone in peripubertal males, J. Clin. Endocrinol. Metab. 62 (1986) 159–164. M.I. Lewis, M. Fournier, T.W. Storer, et al., Skeletal muscle adaptations to testosterone and resistance training in men with COPD, J. Appl. Physiol. 103 (2007) 1299–1310. X. Sun, S.F. Lei, F.Y. Deng, et al., Genetic and environmental correlations between bone geometric parameters and body compositions, Calcif. Tissue Int. 79 (2006) 43–49. H.M. Frost, Bone’s mechanostat: a 2003 update, Anat. Rec. A Discov. Mol. Cell Evol. Biol. 275 (2003) 1081–1101. T. Matsuoka, P.E. Ahlberg, N. Kessaris, et al., Neural crest origins of the neck and shoulder, Nature 436 (2005) 347–355. H. Macdonald, S. Kontulainen, M. Petit, P. Janssen, H. McKay, Bone strength and its determinants in pre- and early pubertal boys and girls, Bone 39 (2006) 598–608. S. Khosla, E.J. Atkinson, B.L. Riggs, L.J. Melton III., Relationship between body composition and bone mass in women, J. Bone Miner. Res. 11 (1996) 857–863. J.A. Stevens, S. Olson, Reducing falls and resulting hip fractures among older women, MMWR Recomm. Rep. 49 (2000) 3–12. S.D. Berry, R.R. Miller, Falls: epidemiology, pathophysiology, and relationship to fracture, Curr. Osteoporos. Rep. 6 (2008) 149–154. J.A. Stevens, K.A. Mack, L.J. Paulozzi, M.F. Ballesteros, Self-reported falls and fall-related injuries among persons aged or 65 years – United States, 2006, J. Safety Res. 39 (2008) 345–349. C.G. Horlings, B.G. van Engelen, J.H. Allum, B.R. Bloem, A weak balance: the contribution of muscle weakness to postural instability and falls, Nat. Clin. Pract. Neurol. 4 (2008) 504–515. S.R. Lord, P.N. Sambrook, C. Gilbert, et al., Postural stability, falls and fractures in the elderly: results from the Dubbo Osteoporosis Epidemiology Study, Med. J. Aust. 160 (684-85) (1994) 688–691. J.D. Moreland, J.A. Richardson, C.H. Goldsmith, C.M. Clase, Muscle weakness and falls in older adults: a systematic
150.
151.
152.
153.
154.
155.
156.
157.
158.
review and meta-analysis, J. Am. Geriatr. Soc. 52 (2004) 1121–1129. B.D. Lloyd, D.A. Williamson, N.A. Singh, et al., Recurrent and injurious falls in the year following hip fracture: a prospective study of incidence and risk factors from the sarcopenia and hip fracture study, J. Gerontol. A Biol. Sci. Med. Sci. (2009). R. Narayanan, C.C. Coss, M. Yepuru, J.D. Kearbey, D.D. Miller, J.T. Dalton, Steroidal androgens and nonsteroidal, tissue-selective androgen receptor modulator, S-22, regulate androgen receptor function through distinct genomic and nongenomic signaling pathways, Mol. Endocrinol. 22 (2008) 2448–2465. G. Sathya, C.Y. Chang, D. Kazmin, C.E. Cook, D.P. McDonnell, Pharmacological uncoupling of androgen receptor-mediated prostate cancer cell proliferation and prostate-specific antigen secretion, Cancer Res. 63 (2003) 8029–8036. D. Yin, Y. He, M.A. Perera, et al., Key structural features of nonsteroidal ligands for binding and activation of the androgen receptor, Mol. Pharmacol. 63 (2003) 211–223. W. Gao, P.J. Reiser, C.C. Coss, et al., Selective androgen receptor modulator treatment improves muscle strength and body composition and prevents bone loss in orchidectomized rats, Endocrinology 146 (2005) 4887–4897. J. Ostrowski, J.E. Kuhns, J.A. Lupisella, et al., Pharmaco logical and x-ray structural characterization of a novel selective androgen receptor modulator: potent hyperanabolic stimulation of skeletal muscle with hypostimulation of prostate in rats, Endocrinology 148 (2007) 4–12. K. Hanada, K. Furuya, N. Yamamoto, et al., Bone anabolic effects of S-40503, a novel nonsteroidal selective androgen receptor modulator (SARM), in rat models of osteoporosis, Biol. Pharm. Bull. 26 (2003) 1563–1569. Functional outcomes for clinical trials in frail older persons: time to be moving, J. Gerontol. A Biol. Sci. Med. Sci. 63 (2008) 160–164. S. Bhasin, M.A. Espeland, W.J. Evans, et al., Indications, labeling, and outcomes assessment for drugs aimed at improving functional status in older persons: a conversation between aging researchers and FDA regulators, J. Gerontol. A Biol. Sci. Med. Sci. 64 (2009) 487–491.
Chapter
28
Epidemiology of Fractures Shreyasee Amin Division of Rheumatology, College of Medicine, Mayo Clinic, Rochester, MN, USA
Introduction Incidence per 10 000 population
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There is increasing awareness that osteoporosis in men is an important public health issue. The main clinical consequence of osteoporosis, be it in men or women, is a fracture. Osteoporotic fractures in general, but particularly of the hip, are associated with considerable morbidity and mortality, which appear to be worse for men than women [1–3]. It is estimated that one in eight men over the age of 50 years will suffer an osteoporotic fracture at the hip, spine or distal forearm in their lifetime [4]. Of the 9.0 million new osteoporotic fractures reported to have occurred worldwide in the year 2000, 39% were in men [5]. Nevertheless, it is important to note that not all fractures in men are related to osteoporosis. Fractures at certain bone sites appear to be more likely to be secondary to bone fragility than others. Furthermore, fracture incidence in men relates not only to diminished bone strength as seen in osteoporosis, but also to frequency of exposure to trauma of sufficient force which can result in fracture, irrespective of bone strength. In fact, the differences in fracture incidence observed between men and women, as well as between men from various racial/ ethnic backgrounds or geographic locations, may relate not only to bone strength but also to trauma exposure. This chapter will review the epidemiology of fractures in men with particular distinction between overall and osteoporotic fractures, as well as differences, where applicable, between men and women, races/ethnicity and geographic locations which, together, may provide additional insights into the pathogenesis of osteoporotic fractures in men.
Females
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Figure 28.1 Average annual fracture incidence rate per 10 000 population, by age group and sex. (From Donaldson et al. J Epidemiol Communy Hlth 1990;44(3):241-45 [7]).
now several studies demonstrating that, before the age of 50 years, men are more likely to sustain a fracture than women [6–12]. Indeed, in a prospective study of fracture incidence among 15 000 adults in Scotland, there was a higher incidence of overall fractures in men than women in all age groups from 15 to 49 years, with males in this age range 2.9 times more likely to sustain a fracture than females (95% CI 2.7–3.1) [9]. In contrast, after the age of 50 years, it is well recognized that women have a higher incidence of overall fractures than men [5–15], although there are some geographic differences. In men, similar to women, there tends to be an exponential rise in fracture incidence after age 75 years, particularly for hip fractures, however, the absolute incidence of overall fractures still tends to be lower in men than in women [6–15] (see Figure 28.1).
Overall fracture incidence in men
Differences in fracture incidence patterns between men and women
The observed pattern of overall fracture incidence in men follows a bimodal distribution, with a peak in adolescence and then again with advanced age (Figure 28.1). There are Osteoporosis in Men
Males 400
The difference in fracture incidence observed between men and women across ages provides additional insight into the 351
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understanding of risks for fracture in men, as well as for women. The pattern observed appears to be due not only to a difference in their bone strength but also to the type and frequency of trauma experienced by men compared with women at different ages. It is essential to recall that bone strength is only one of two main factors contributing to fracture occurrence in an individual. The second is the amount of force applied to the bone. If bone strength is diminished, as seen in osteoporosis, small to moderate forces (e.g. a fall from a standing height or less) may be sufficient to cause a fracture. On the other hand, if a force is large enough in magnitude (e.g. motor vehicle accidents, falls from a substantial height), a fracture may occur regardless of the strength of bone although those with low BMD remain at greater risk [152]. Although fracture incidence in men is higher than women below the age of 50 years, the cause of the fractures, in general, appear to be related to high-energy trauma events and, therefore, for most situations, have not been previously considered to be associated with pathologically lower bone strength. That being said, recent findings suggest that deficits in bone strength may play a contributing factor to fractures in adolescence [16]. But exposure to trauma remains an important risk factor. Sports activities were found to be a major source of limb fractures in young males [6,17,18]. One study found that fights accounted for a number of fractures in younger men, in marked contrast to women [6]. Another study, from the USA, identified that the incidence rate for a work-related fracture for male employees was more than twice that for female employees (76.3 versus 30.7 per 10 000 workers) [19]. This higher rate for fractures in men was noted across all industrial sectors [19]. Fractures in the workplace for men most commonly involved the hands and feet [19]. In contrast, part of the explanation for the higher fracture incidence among women over the age of 50 years is that women have an increased risk of falls with aging relative to men [20,21]. Thus, in this age range, the observed lower absolute incidence of osteoporotic fractures in older men compared with women appears to be due not only to better bone strength in men, but also a relatively lower frequency of trauma. Indeed, among US adults aged 65 years and older, non-fatal, unintentional fall related injuries disproportionately affected women [22]. Based on 22 560 cases from a nationally representative sample of emergency room visits during January–December 2001, the investigators estimated that 1.64 million older adults were treated in emergency departments for unintentional fall-related injuries and, of these, 70.5% were women [22]. Of fall-related injuries, fractures were the most frequent and accounted for 38% of injuries in women and 28% for men. Fractures following a fall were 2.2 times higher in women than men [22]. Some speculate that the reason for this difference between men and women in frequency of falls relates to better muscle strength or balance in men but, overall, the reasons remain unclear.
Osteoporotic fractures in men Osteoporosis is defined as an asymptomatic systemic bone disease characterized by low bone mass and microarchitectural deterioration of bone tissue, with a consequent increase in bone fragility and susceptibility to fracture [23]. Clinically, certain fractures are more likely to occur following minimal trauma in aging men. Based on observations of the different patterns of site-specific fracture incidence across ages, some have suggested that those which increase with age may be more likely to be related to osteoporosis, since bone strength, in general, tends to decrease with age (Figure 28.2) [10]. On the other hand, it could also reflect, in part, an age-related pattern of falls. In a study examining the fracture incidence between 1988 and 1998 in 5 million men and women registered in the UK’s General Practice Research Database, the ageand sex-specific fracture incidence at the femur, vertebrae, radius/ulna, humerus, clavicle, scapula, ribs and pelvis appeared to increase with aging in men [10]. Fractures involving the distal lower extremity and the skull did not increase with age and were thus considered to be less likely to be associated with osteoporosis in men (see Figure 28.2). Similarly, in an incidence study of all fractures that occurred during the year 2000 at the Royal Infirmary of Edinburgh, which serves a population of over 500 000 men and women, fractures of the proximal femur, humerus and clavicle were among those typically seen in elderly men [11]. In the Rotterdam study, fractures of the proximal femur, forearm and humerus were also found to be among the most frequent sites of incident non-vertebral fractures in both older men and women [15]. In general, similar findings were also noted in older men from a population based study of fracture incidence from the USA [24]. In a study from Reykjavik, Iceland, among 4137 men, age 42–69 years at baseline, followed for a mean of 18.5 years, 53% of fractures were caused by low-energy trauma, with fractures of the hip (proximal femur), forearm and humerus resulting from low-energy trauma in 75%, 77% and 72% of cases, respectively [25]. Fractures of the verterbrae and pelvis were caused by low-energy trauma in 35% and 36% of cases, respectively [25]. However, among a cohert in the USA of 5995 men over the age of 65 years followed for a mean of 4.7 years, 74% of incidental clinical vertebral fractures were attributable to low-energy trauma, suggesting that in elderly men most vertebral fractures are the result of low trauma [25a]. Overall, osteoporotic fractures in men appear to involve, most consistently, fractures of the hip vertebrae, forearm and humerus, although fragility fractures at other sites, including the pelvis, ribs and clavicle, also occur in aging men. Based on data from published sources around the world, it was estimated that 9.0 million new osteoporotic fractures occurred worldwide in the year 2000, of which 39% were in men [5]. Of all the hip, forearm, clinical vertebral and humerus
C h a p t e r 2 8 Epidemiology of Fractures l
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Figure 28.2 Age- and gender-specific incidence of fractures at selected sites among 5 million men and women registered in the General Practice Research Database, 1988–1998. (A) Fractures showing pronounced increase in incidence with age. (B) Fractures showing no apparent increase in incidence with advancing age. (From van Staa et al. Bone 2001;29(6):517–22 [10]).
fractures, approximately 30%, 20%, 42% and 25% were in men, respectively [5].
Fractures at specific bone sites The epidemiology of fractures in men at specific bone sites, particularly the hip, spine, distal forearm and proximal humerus will be reviewed separately. Fractures at the hip and spine are the best characterized for men and also are associated with significant morbidity and mortality in men.
Nevertheless, it is increasingly recognized that non-hip and non-spine fractures combined also account for considerable morbidity and health care costs [3]. Furthermore, low trauma fractures involving not only the hip and spine, but also other sites of the upper and lower limbs, increase the risk of subsequent fracture in men [26–28].
Hip Fractures Hip fractures in aging men are a worldwide problem and are the fractures most associated with morbidity and
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mortality. As a result, it remains the best studied of all fractures in men. Over the past several decades, there were several reports observing a secular increase in the age-adjusted incidence of hip fractures worldwide [29–36], particularly in men [29–31, 33, 37]. More recently, however, this increase has started to level off in some areas [38–42], although not everywhere [43, 44]. Given the increasing size of the global population and improving longevity of men, the number of men with hip fractures is estimated to reach 1.8 million worldwide by 2050 [45]. If modest assumptions regarding future secular trends are considered, some have suggested that it could even reach 6.8 million [46]. The incidence of hip fractures in men exponentially increases after the age of 75 years, while prior to this age, hip fractures are relatively uncommon. This sharp increase in agespecific hip fracture incidence in elderly men is documented worldwide in population-based studies from North America [24, 34, 47–49], South America [50, 51], Europe [9–11, 13, 15, 25, 29, 35–37, 39, 41, 50, 52–54], Australia [14, 55, 56], Asia [32, 43, 50, 57–60], the Middle East [61] and Africa [62, 63]. However, the absolute incidence of hip fracture in men does vary around the globe [64]. The highest incidence for hip fracture in men was observed in Scandinavian and other northern European countries, as well as in whites from North America [61, 65]. In contrast, some of the lowest incidence rates for hip fracture in men have been reported among blacks and Asians [61, 65]. Hip fracture incidence has also been observed to be low in some parts of South America and other equatorial areas [51, 64]. Interestingly, the 10-year probability of hip fracture risk is reported to increase by 0.3% in men per 10° latitude increment and by 0.8% in women [66]. These findings were similar following adjustment for economic prosperity, which was also found to be associated with increased hip fracture risk [66]. In a study from Sweden, which has one of the highest prevalences of hip fracture in the world, it was observed that foreign-born elderly in Sweden had a significantly lower risk for hip fracture than native Swedes, in both men and women [67]. This study would suggest that climate and seasonal differences alone cannot account for the geographic variability in hip fracture incidence observed. The risk of hip fracture in men relative to women also appears to vary geographically. The age-adjusted female-tomale ratio for hip fractures appears to be highest for whites, with a ratio up to 3–4:1 [65]. In contrast, the female-to-male ratio may be closer to 1:1 in parts of Asia and among blacks from South Africa, with men even having a higher absolute incidence of hip fractures than women in some reports [57, 65, 68]. On the other hand, in some parts of Asia, others have reported a female-to-male ratio of 2.5, which is only slightly lower than the 2.9 ratio observed in the USA [60]. Again, differences not just in bone strength, but also in trauma exposure between men and women and among men from different parts of the world, may explain some of the geographic variability in observed hip fracture rates. Indeed, in a study from China, where the incidence of fracture
in men and women was almost equal, hip fractures in older Chinese men were more likely to be due to accidents compared with women, especially falls from bicycles (28% versus 10%) [58]. Although the reasons for the variability in hip fracture incidence observed worldwide remain unclear, genetic, environmental and lifestyle factors are likely all important contributing factors. Of all fractures, the morbidity and mortality following a hip fracture are among the greatest and appear to be worse for men than women [1, 2, 69–74]. Men are twice as likely to die in hospital following a hip fracture than women [69, 71]. The reported 1-year mortality rates after hip fracture have ranged from 31 to 35% in men compared with 17–22% in women [70, 73, 74]. The number of co-morbid conditions at the time of fracture contributes to mortality risk [2, 69, 75] and may also account for the differences observed between men and women. Furthermore, the consequence of a hip fracture remains serious for men who fracture even at relatively younger ages [72]. The decrease in life-expectancy following a hip fracture is greatest for younger men than older men, estimated at 11.5 years in men age 60–69 years who fracture, compared with 5 and 1.5 years for men age 70–79 years and age 80 years who fracture, respectively [72]. Some studies indicate that up to 50% of men may need institutionalized care after hip fracture [71, 75]. Even among those who do return home, many men do not regain the level of function they enjoyed prior to fracture [75]. Compared with their female counterparts, men remain undertreated for osteoporosis following hip fracture [74]. At the time of hospital discharge following a hip fracture, 7% of men, compared with 31% of women, were given osteoporosis therapy of any kind [74]. Even at 1 to 5 years of follow up, only 27% of men were receiving any osteoporosis treatment, in contrast to 71% of women [74], while twothirds of these men were being treated with only calcium and vitamin D [74].
Vertebral Fractures The epidemiology of vertebral (spine) fractures is not as well studied as hip fractures, due to a variety of factors. For one, not all vertebral fractures come to clinical attention, so their true incidence is more difficult to ascertain and thereby often underestimated. Many vertebral fractures are noted incidentally as a vertebral deformity on radiographs. Nonetheless, vertebral fractures, even if asymptomatic, are predictive of subsequent fracture incidence in both men and women [76–79]. Several studies have attempted to estimate the prevalence and incidence of vertebral fractures, however, these estimates do vary, in part, due to different criteria used to define a vertebral deformity and to whether clinically symptomatic and/or asymptomatic vertebral fractures are considered. Differences in the epidemiology of vertebral fractures between men and women have been described, although racial/ethnic or geographic comparisons are more limited.
C h a p t e r 2 8 Epidemiology of Fractures l
The prevalence of a radiographically defined vertebral deformity was determined in 15 570 men and women (46% men), aged 50–79 years, from 19 European countries in the European Vertebral Osteoporosis Study (EVOS) [80]. The age-standardized prevalence of vertebral deformity was estimated to be similar for both men and women, either 12% or 20%, depending on the criteria used to define vertebral deformity [80]. However, below age 65 years, men had a higher prevalence of vertebral deformity than women, while after this age women had a higher prevalence [80]. In both men and women, the prevalence of vertebral deformity increased with older age, although the increase was greater in women than men after age 65 years [80]. Similar observations were noted in a study from the USA involving 899 women and 529 men over age 50 years [81], as well as in a study of thoracic spine fractures in 27 000 women and 30 000 men in Finland [82]. There was also an age-related increase in prevalence of vertebral deformity in men from the MINOS cohort, regardless of the definition used for vertebral deformity [83]. The incidence of vertebral fractures in men and women was estimated in the European Prospective Osteoporosis Study (EPOS) [84]. From a total of 14 011 men and women age 50 years and older recruited from population-based registers in 29 European centers, 6788 (3174 men) had baseline and follow-up spinal radiographs after a mean follow up of 3.8 years [84]. Vertebral fractures were defined by both morphometric criteria and qualitative assessment [84]. Regardless of the criteria used, the incidence of vertebral fractures in men was roughly half the rate of women. The age-standardized incidence of morphometric vertebral fractures was 5.7 per 1000 person years at risk (pyr) in men versus 10.7/1000 pyr in women [84]. Using the qualitative assessment, the incidence of vertebral fracture was 6.8/1000 pyr and 12.1/1000 pyr for men and women, respectively [84]. Others have also shown that the age-adjusted incidence for radiographically defined vertebral fractures in men is half the rate of women [48,85]. The distribution of incident vertebral fractures within the spine appears to be highest at the mid-thoracic and the thoracolumbar spine [85], with incident fractures at T12 and L1 being the most frequent, in both men and women [85]. Similar to hip fractures, the incidence of vertebral fractures increases markedly with aging [10, 14, 24, 55, 84]. As has also been observed with hip fracture incidence, there is also a geographic variation in fracture distribution, with the highest rates reported in Sweden than elsewhere in Europe [84]. The presence of vertebral deformity in men is associated with lower energy, poorer sleep, pain, immobility and social isolation when compared with controls [86]. Severe vertebral deformity is related to functional impairment, particularly in men [87]. In a 10-year study from the Swedish cohort of EVOS, prevalent vertebral deformity was a predictor of mortality in men during the forthcoming decade (age-adjusted hazard ratio: 2.4, 95% CI: 1.6–3.9) [79]. The
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association between vertebral deformity and negative health outcomes is reported to be worse for men than women [88].
Distal Forearm Fractures The incidence of distal forearm fractures follows a bimodal distribution with respect to age, being highest below the age of 15 years before falling to a plateau and then rising again after the age of 50 years [89]. When males and females are considered separately, males have the highest incidence of fractures relative to females in youth [9, 18, 89] and peaks between 10 and 14 years of age [18, 89]. In men, the incidence of distal radius fractures then falls and remains relatively stable with age, with perhaps a slight increase in the very elderly [7, 9, 89–92], in contrast to women, where the increase occurs around the time of the menopause [7, 9, 89, 90, 92]. More importantly, men with a distal forearm fracture are at an increased risk for a subsequent hip fracture (hazard ratio: 2.27, 95% CI: 1.15, 4.5 in men age 40 years) [93]. Self-reported disability was high for both men and women following a distal forearm fracture, particularly if the dominant hand was affected [94].
Proximal Humerus Fractures Considered an osteoporotic fracture in both men and women, proximal humerus fractures tend to occur in fit elderly persons of advanced age, particularly over the age of 80 years [95–97]. Fractures of the humerus, particularly the proximal humerus, are frequently noted in older men [9, 24, 55, 95–99] and the incidence may be increasing [98, 100]. Fractures of the proximal humerus have also been associated with increased mortality within the first 5 years after fracture and this risk appears to be higher in men than women [78]. Low trauma fractures of the upper limb, in general, appear to increase the risk for subsequent fracture in men [26].
Other Fractures The epidemiology of other fractures in men remains more limited. Similar to what has been observed at the distal forearm, lower limb fractures, in general, are more common in males than females below age 40 years while, after age 50 years, the incidence is higher in women than men, with the difference increasing with age [10]. Similarly, a bimodal peak has been described for the incidence rates specifically of femoral and tibial shaft fractures in men, being greatest in both young (age 15–34 years) and elderly (over age 70 years) men [9]. While ankle fractures have not traditionally been considered osteoporotic fractures, they do appear to predict subsequent fracture risk in men (relative risk: 4.59, 95% CI: 2.45–8.61), however, not in women [26]. Although there were initial reports of low trauma fractures at the ankle increasing in incidence [102], it now appears to be stabilizing [103]. Clavicular fractures occur more frequently in young men than women [10, 104]. However, the location of clavicular
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fractures differs with aging. Fractures of the proximal clavicle appear to occur in the elderly, while fractures of the midclavicle occur predominantly in children [104]. Fractures of the pelvis in men increase with aging and are also associated with osteoporosis [105, 106].
size. Fracture risk at other non-hip sites also appears to be lower for black men compared with white men [116, 117]. Interestingly, while Asian men do tend to have similar or slightly lower bone density values when compared with white men [118], hip fracture incidence among Asian men in the USA is actually lower than white men [109, 111]. Whether the difference in fracture risk can be explained by other structural factors which contribute to bone strength is unclear but is suggested by results from the USA Osteoporotic Fractures in Men (MrOS) Study [119]. They reported that femoral neck bone density, measured by dualenergy x-ray absorptiometry, was similar between white and Asian men, but Asian men had greater cortical thickness and higher trabecular volumetric bone mineral density, measured by quantitative computed tomography [119]. These structural features may confer advantages for bone strength and help explain the lower hip fracture rate in Asian men compared with white men [119]. Similar findings were noted in black men [119]. Fracture risk at other bone sites and comparisons between different races/ethnic groups is limited. It should be noted that there remains no clear consensus on how osteoporosis or osteopenia in men should be defined, with some recommending the use of male-specific T-scores, while others suggest using female-specific T-scores. While female-specific T-scores may provide more conservative estimates, it should be noted that even if male-specific Tscores are used to define osteoporosis and osteopenia, a much
Bone density and fracture risk in men Similar to women, low bone density is an important predictor of fracture risk in older men [107,108]. Racial/ ethnic differences in fracture incidence in men do appear to be partly explained by differences in bone strength as assessed by bone density. When studies of hip fracture incidence among different ethnic groups within the USA are reviewed, white men have higher fracture rates than Hispanic, Asian or black men [109–112]. Therefore, prevalence estimates for low bone density among men from other races and ethnicity groups would be expected to be lower than white men. Indeed, using NHANES III data, investigators estimated the prevalence of osteopenia and osteoporosis in men to be highest for non-Hispanic whites, compared to Mexican-American and non-Hispanic black men [113]. Furthermore, white men have lower bone mineral density than black men at the radius [114], lumbar spine [114, 115] and femoral neck [114, 115], even after adjustment for body Men
Women All non-vetebral fractures
17.93% normal BMD
12.63% normal BMD 44.09% Osteoporosis
20.69% Osteoporosis
43.29% Osteopenia
61.38% Osteopenia
Hip fractures 2.78% normal BMD 38.89% Osteoporosis
5.17% normal BMD 66.79% Osteoporosis
58.33% Osteopenia
31.33% Osteopenia
Figure 28.3 Percentage of non-vertebral or hip fractures that occurred in men and women with osteoporosis, osteopenia or normal BMD using gender-specific T-scores. (From Schuit et al. Bone 2004;34(1):195-202 [15]).
C h a p t e r 2 8 Epidemiology of Fractures l
lower proportion of non-vertebral and hip fractures occur in men characterized as having osteoporosis when compared with women (Figure 28.3) [15]. While low bone density is a well-recognized predictor of fracture risk in men, we clearly need a better way of establishing which men are at greatest risk of fracture than the current use of T-scores, regardless of how it is defined.
Summary In summary, fracture incidence in men follows a bimodal distribution, peaking in adolescence and again with advanced age. Fractures are more frequent in men than women at younger ages and appear more likely to be related to trauma exposure, whereas with advanced age, fractures are more common in women than men. There are differences in fractures incidence in men observed worldwide and this may be due to a combination of genetic, environmental and lifestyle factors. Osteoporotic fractures in older men most frequently involve the hip, vertebrae, distal forearm and proximal humerus. There is an increased mortality and disability following osteoporotic fractures in men, particularly of the hip, spine and proximal humerus, and which are greater for men than for women. Low trauma fractures in men are strong predictors of subsequent fracture risk. Despite the significant public health burden of osteoporotic fractures in men, men at high risk for fracture still appear to be undertreated, especially when compared with women.
References 1. D. Bliuc, N.D. Nguyen, V.E. Milch, T.V. Nguyen, J.A. Eisman, J.R. Center, Mortality risk associated with low-trauma osteoporotic fracture and subsequent fracture in men and women, J. Am. Med. Assoc. 301 (5) (2009) 513–521. 2. G. Holt, R. Smith, K. Duncan, J.D. Hutchison, A. Gregori, Gender differences in epidemiology and outcome after hip fracture: evidence from the Scottish Hip Fracture Audit, J. Bone Joint Surg. 90B (4) (2008) 480–483. 3. P.D. Delmas, F. Marin, R. Marcus, D.A. Misurski, B.H. Mitlak, Beyond hip: importance of other nonspinal fractures, Am. J. Med. 120 (5) (2007) 381–387. 4. L.J. Melton III, E.A. Chrischilles, C. Cooper, A.W. Lane, B.L. Riggs, Perspective. How many women have osteoporosis?, J. Bone Miner. Res. 7 (9) (1992) 1005–1010. 5. O. Johnell, J.A. Kanis, An estimate of the worldwide prevalence and disability associated with osteoporotic fractures, Osteoporos. Int. 17 (12) (2006) 1726–1733. 6. W.M. Garraway, R.N. Stauffer, L.T. Kurland, W.M. O’Fallon, Limb fractures in a defined population. I. Frequency and distribution, Mayo Clin. Proc. 54 (11) (1979) 701–707. 7. L.J. Donaldson, A. Cook, R.G. Thomson, Incidence of fractures in a geographically defined population, J. Epidemiol. Communy. Hlth. 44 (3) (1990) 241–245. 8. J.A. Kanis, F.A. Pitt, Epidemiology of osteoporosis, Bone 13 (Suppl 1) (1992) S7–S15.
357
9. B.R. Singer, G.J. McLauchlan, C.M. Robinson, J. Christie, Epidemiology of fractures in 15,000 adults: the influence of age and gender, J. Bone Joint Surg. 80B (2) (1998) 243–248. 10. T.P. van Staa, E.M. Dennison, H.G. Leufkens, C. Cooper, Epidemiology of fractures in England and Wales, Bone 29 (6) (2001) 517–522. 11. C.M. Court-Brown, Caesar B. Epidemiology of adult fractures: A review, Injury 37 (8) (2006) 691–697. 12. L.J. Donaldson, I.P. Reckless, S. Scholes, J.S. Mindell, N. J. Shelton, The epidemiology of fractures in England, J. Epidemiol. Commun. Hlth. 62 (2) (2008) 174–180. 13. J.A. Kanis, O. Johnell, A. Oden, et al., Long-term risk of osteoporotic fracture in Malmo, Osteoporos. Int. 11 (8) (2000) 669–674. 14. H. Cooley, G. Jones, A population-based study of fracture incidence in southern Tasmania: lifetime fracture risk and evidence for geographic variations within the same country, Osteoporos. Int. 12 (2) (2001) 124–130. 15. S.C.E. Schuit, M. van der Klift, A.E.A.M. Weel, et al., Fracture incidence and association with bone mineral density in elderly men and women: the Rotterdam Study, Bone 34 (1) (2004) 195–202 [erratum appears in Bone 2006;38(4):603]. 15a. D.C. MacKay, L.Y. Lui, P.M. Cawthon, et al., High-trauma fractures and low bone mineral density in older women and men. J. Am. Med. Assoc. 298 (20) (2007) 2381–2388. 16. S, Kirmani, D. Christen, G.H. van Lenthe, et al., Bone structure at the distal radius during adolescent growth, J. Bone Miner Res. 24(6) (2009) 1033–1042. 17. E.C. Powell, R.R. Tanz, In-line skate and rollerskate injuries in childhood, Pediatr. Emerg. Care 12 (1996) 259–262. 18. S. Khosla, L.J Melton III., M.B. Dekutoski, S.J. Achenbach, A.L. Oberg, B.L. Riggs, Incidence of childhood distal forearm fractures over 30 years. A population-based study, J. Am. Med. Assoc. 290 (2003) 1479–1485. 19. S.S. Islam, R.S. Biswas, A.M. Nambiar, et al., Incidence and risk of work-related fracture injuries: experience of a statemanaged workers’ compensation system, J. Occup. Environ. Med. 43 (2) (2001) 140–146. 20. R.W. Sattin, D.A. Lambert Huber, C.A. DeVito, et al., The incidence of fall injury events among the elderly in a defined population, Am. J. Epidemiol. 131 (6) (1990) 1028–1037. 21. S.J. Winner, C.A. Morgan, J.G. Evans, Perimenopausal risk of falling and incidence of distal forearm fracture, Br. Med. J. 298 (6686) (1989) 1486–1488. 22. J.A. Stevens, E.D. Sogolow, Gender differences for non-fatal unintentional fall related injuries among older adults, Injury. Prev. 11 (2) (2005) 115–119. 23. Anonymous, Consensus development conference: diagnosis, prophylaxis, and treatment of osteoporosis, Am. J. Med. 94 (6) (1993) 646–650. 24. L.J. Melton III., C.S. Crowson. W.M. O’Fallon, Fracture incidence in Olmsted County, Minnesota: comparison of urban with rural rates and changes in urban rates over time, Osteoporos. Int. 9 (1) (1999) 29–37. 25. B.Y. Jonsson, K. Siggeirsdottir, B. Mogensen, H. Sigvaldason, G. Sigursson, Fracture rate in a population-based sample of men in Reykjavik, Acta Ortho. Scand. 75 (2) (2004) 195–200. 25a. S.S. Freitas, E. Barrett-Connor, K.E. Ensrud, et al., Rate and circumstances of clinical vertebral fractures in older men, Osteoporos. Int. 19 (5) (2008) 615–623.
358
Osteoporosis in Men
26. J.R. Center, D. Bliuc, T.V. Nguyen, J.A. Eisman, Risk of subsequent fracture after low-trauma fracture in men and women.[see comment], J. Am. Med. Assoc. 297 (4) (2007 24) 387–394. 27. J.A. Kanis, O. Johnell, C. De Laet, et al., A meta-analysis of previous fracture and subsequent fracture risk, Bone 35 (2) (2004) 375–382. 28. T.P. van Staa, H.G. Leufkens, C. Cooper, Does a fracture at one site predict later fractures at other sites? A British cohort study, Osteoporos. Int. 13 (8) (2002) 624–629. 29. D. Agnusdei, A. Camporeale, D. Gerardi, S. Rossi, L. Bocchi, C. Gennari, Trends in the incidence of hip fracture in Siena, Italy, from 1980 to 1991, Bone 14 (Suppl 1) (1993) S31–S34. 30. B. Gullberg, H. Duppe, B. Nilsson, et al., Incidence of hip fractures in Malmo, Sweden (1950–1991), Bone 14 (Suppl 1) (1993) S23–S29. 31. R. Hedlund, A. Ahlbom, U. Lindgren, Hip fracture incidence in Stockholm 1972–1981, Acta Orthop. Scand. 57 (1) (1986) 30–34. 32. T. Hashimoto, K. Sakata, N. Yoshimura, Epidemiology of osteoporosis in Japan, Osteoporos. Int. 7 (Suppl 3) (1997) S99–S102. 33. L.J. Melton III., W.M. O’Fallon, B.L. Riggs, Secular trends in the incidence of hip fractures, Calcif. Tissue Int. 41 (2) (1987) 57–64. 34. A.D. Martin, K.G. Silverthorn, C.S. Houston, S. Bernhardson, A. Wajda, L.L. Roos, The incidence of fracture of the proximal femur in two million Canadians from 1972 to 1984. Projections for Canada in the year 2006, Clin. Orthop. Relat. Res. 266 (1991) 111–118. 35. I. Paspati, A. Galanos, G.P. Lyritis, Hip fracture epidemiology in Greece during 1977–1992, Calcif. Tissue Int. 62 (6) (1998) 542–547. 36. M. Wildner, W. Casper, K.E. Bergmann, A secular trend in hip fracture incidence in East Germany, Osteoporos. Int. 9 (2) (1999) 144–150. 37. P. Kannus, S. Niemi, J. Parkkari, M. Palvanen, I. Vuori, M. Jarvinen, Hip fractures in Finland between 1970 and 1997 and predictions for the future [see comments], Lancet 353 (9155) (1999) 802–805. 38. T.D. Spector, C. Cooper, A.F. Lewis, Trends in admissions for hip fracture in England and Wales, 1968–85, Br. Med. J. 300 (6733) (1990) 1173–1174. 39. C. Rogmark, I. Sernbo, O. Johnell, J.A. Nilsson, Incidence of hip fractures in Malmo, Sweden, 1992–1995. A trend-break, Acta Orthop. Scand. 70 (1) (1999) 19–22. 40. L.J. Melton III., T.M. Therneau, D.R. Larson, Long-term trends in hip fracture prevalence: the influence of hip fracture incidence and survival, Osteoporos. Int. 8 (1) (1998) 68–74. 41. T.M. Huusko, P. Karppi, V. Avikainen, H. Kautiainen, R. Sulkava, The changing picture of hip fractures: dramatic change in age distribution and no change in age-adjusted incidence within 10 years in Central Finland, Bone 24 (3) (1999) 257–259. 42. P. Kannus, S. Niemi, J. Parkkari, M. Palvanen, I. Vuori, M. Jarvinen, Nationwide decline in incidence of hip fracture, J. Bone Miner. Res. 21 (12) (2006) 1836–1838. 43. H. Hagino, H. Katagiri, T. Okano, K. Yamamoto, R. Teshima, Increasing incidence of hip fracture in Tottori Prefecture, Japan: trend from 1986 to 2001, Osteoporos. Int. 16 (12) (2005) 1963–1968. 44. D.S. Zingmond, L.J. Melton III, S.L. Silverman, Increasing hip fracture incidence in California Hispanics, 1983 to 2000, Osteoporos. Int. 15 (8) (2004) 603–610.
45. C. Cooper, G. Campion, L.J. Melton III, Hip fractures in the elderly: a world-wide projection, Osteoporos. Int. 2 (6) (1992) 285–289. 46. B. Gullberg, O. Johnell, J.A. Kanis, World-wide projections for hip fracture, Osteoporos. Int. 7 (5) (1997) 407–413. 47. S.J. Jacobsen, J. Goldberg, T.P. Miles, J.A. Brody, W. Stiers, A.A. Rimm, Hip fracture incidence among the old and very old: a population-based study of 745,435 cases, Am. J. Pub. Hlth. 80 (7) (1990) 871–873. 48. C. Cooper, E.J. Atkinson, W.M. O’Fallon, L.J. Melton III., Incidence of clinically diagnosed vertebral fractures: a population-based study in Rochester, Minnesota, 1985–1989, J. Bone Mineral. Res. 7 (2) (1992) 221–227. 49. P. Clark, P. Lavielle, F. Franco-Marina, et al., Incidence rates and life-time risk of hip fractures in Mexicans over 50 years of age: a population-based study, Osteoporos. Int. 16 (12) (2005) 2025–2030. 50. A.V. Schwartz, J.L. Kelsey, S. Maggi, et al., International variation in the incidence of hip fractures: cross-national project on osteoporosis for the World Health Organization Program for Research on Aging, Osteoporos. Int. 9 (3) (1999) 242–253. 51. F.A. Castro da Rocha, A.R. Ribeiro, Low incidence of hip fractures in an equatorial area, Osteoporos. Int. 14 (6) (2003) 496–499. 52. A.A. Ismail, S.R. Pye, W.C. Cockerill, et al., Incidence of limb fracture across Europe: results from the European Prospective Osteoporosis Study (EPOS), Osteoporos. Int. 13 (7) (2002) 565–571. 53. I.M. Giversen, Time trends of age-adjusted incidence rates of first hip fractures: a register-based study among older people in Viborg County, Denmark, 1987–1997, Osteoporos. Int. 17 (4) (2006) 552–564. 54. M.L. Alvarez-Nebreda, A.B. Jimenez, P. Rodriguez, J.A. Serra, Epidemiology of hip fracture in the elderly in Spain, Bone 42 (2) (2008) 278–285. 55. K.M. Sanders, G.C. Nicholson, A.M. Ugoni, J.A. Pasco, E. Seeman, M.A. Kotowicz, Health burden of hip and other fractures in Australia beyond 2000. Projections based on the Geelong Osteoporosis Study [see comments], Med. J. Aust. 170 (10) (1999) 467–470. 56. K.P. Chang, J.R. Center, T.V. Nguyen, J.A. Eisman, Incidence of hip and other osteoporotic fractures in elderly men and women: Dubbo Osteoporosis Epidemiology Study, J. Bone Miner. Res. 19 (4) (2004) 532–536. 57. X. Ling, A. Lu, X. Zhao, X. Chen, S.R. Cummings, Very low rates of hip fracture in Beijing, People’s Republic of China: the Beijing Osteoporosis Project, Am. J. Epidemiol. 144 (9) (1996) 901–907. 58. L. Yan, B. Zhou, A. Prentice, X. Wang, M.H. Golden, Epidemiological study of hip fracture in Shenyang, People’s Republic of China, Bone 24 (2) (1999) 151–155. 59. E.M. Lau, C. Cooper, H. Fung, D. Lam, K.K. Tsang, Hip fracture in Hong Kong over the last decade – a comparison with the UK., J. Pub. Hlth. Med. 21 (3) (1999) 249–250. 60. E.M. Lau, J.K. Lee, P. Suriwongpaisal, S.M. Saw, S. Das De, A. Khir, P. Sambrook, The incidence of hip fracture in four Asian countries: the Asian Osteoporosis Study (AOS), Osteoporos. Int. 12 (3) (2001) 239–243. 61. A. Memon, W.M. Pospula, A.Y. Tantawy, S. Abdul-Ghafar, A. Suresh, A. Al-Rowaih, Incidence of hip fracture in Kuwait, Int. J. Epidemiol. 27 (5) (1998) 860–865.
C h a p t e r 2 8 Epidemiology of Fractures l
62. R.M.D. Zebaze, E. Seeman, Epidemiology of hip and wrist fractures in Cameroon, Africa, Osteoporos. Int. 14 (4) (2003) 301–305. 63. A. El Maghraoui, B.A. Koumba, I. Jroundi, L. Achemlal, A. Bezza, M.A. Tazi, Epidemiology of hip fractures in 2002 in Rabat, Morocco, Osteoporos. Int. 16 (6) (2005) 597–602. 64. J.A. Kanis, O. Johnell, C. De Laet, B. Jonsson, A. Oden, A.K. Ogelsby, International variations in hip fracture probabilities: implications for risk assessment, J. Bone Miner. Res. 17 (7) (2002) 1237–1244. 65. S. Maggi, J.L. Kelsey, J. Litvak, S.P. Heyse, Incidence of hip fractures in the elderly: a cross-national analysis [see comments], Osteoporos. Int. 1 (4) (1991) 232–241. 66. O. Johnell, F. Borgstrom, B. Jonsson, J. Kanis, Latitude, socioeconomic prosperity, mobile phones and hip fracture risk, Osteoporos. Int. 18 (3) (2007) 333–337. 67. L. Furugren, L. Laflamme, Hip fractures among the elderly in a Swedish urban setting: different perspectives on the significance of country of birth, Scand. J. Pub. Hlth. 35 (1) (2007) 11–16. 68. L. Solomon, Osteoporosis and fracture of the femoral neck in the South African Bantu, J. Bone Joint. Surg. 50B (1) (1968) 2–13. 69. A.H. Myers, E.G. Robinson, M.L. Van Natta, J.D. Michelson, K. Collins, S.P. Baker, Hip fractures among the elderly: factors associated with in-hospital mortality, Am. J. Epidemiol. 134 (10) (1991) 1128–1137. 70. L. Forsen, A.J. Sogaard, H.E. Meyer, T. Edna, B. Kopjar, Survival after hip fracture: short- and long-term excess mortality according to age and gender, Osteoporos. Int. 10 (1) (1999) 73–78. 71. T.H. Diamond, S.W. Thornley, R. Sekel, P. Smerdely, Hip fracture in elderly men: prognostic factors and outcomes [see comments], Med. J. Aust. 167 (8) (1997) 412–415. 72. J.R. Center, T.V. Nguyen, D. Schneider, P.N. Sambrook, J.A. Eisman, Mortality after all major types of osteoporotic fracture in men and women: an observational study, Lancet 353 (9156) (1999) 878–882. 73. M.A. Schurch, R. Rizzoli, B. Mermillod, H. Vasey, J.P. Michel, J.P. Bonjour, A prospective study on socioeconomic aspects of fracture of the proximal femur, J. Bone Miner. Res. 11 (12) (1996) 1935–1942. 74. G.M. Kiebzak, G.A. Beinart, K. Perser, C.G. Ambrose, S.J. Siff, M.H. Heggeness, Undertreatment of osteoporosis in men with hip fracture, Arch. Int. Med. 162 (19) (2002) 2217–2222. 75. G. Poor, E.J. Atkinson, W.M. O’Fallon, L.J. Melton III, Determinants of reduced survival following hip fractures in men, Clin. Orthop. Relat. Res. 319 (1995) 260–265. 76. A.A. Ismail, W. Cockerill, C. Cooper, et al., Prevalent vertebral deformity predicts incident hip though not distal forearm fracture: results from the European Prospective Osteoporosis Study, Osteoporos. Int. 12 (2) (2001) 85–90. 77. L.J. Melton III, E.J. Atkinson, C. Cooper, B.L. Riggs, Vertebral fractures predict subsequent fractures, Osteoporos. Int. 10 (3) (1999) 214–221. 78. O. Johnell, J.A. Kanis, A. Oden, et al., Mortality after osteoporotic fractures, Osteoporos. Int. 15 (1) (2004) 38–42. 79. R. Hasserius, M.K. Karlsson, B.E. Nilsson, I. RedlundJohnell, O. Johnell, European Vertebral Osteoporosis Study.
80.
81.
82.
83.
84.
85.
86.
87.
88.
89.
90.
91.
92.
93.
94.
359
Prevalent vertebral deformities predict increased mortality and increased fracture rate in both men and women: a 10-year population-based study of 598 individuals from the Swedish cohort in the European Vertebral Osteoporosis Study, Osteoporos. Int. 14 (1) (2003) 61–68. T.W. O’Neill, D. Felsenberg, J. Varlow, C. Cooper, J.A. Kanis, A.J. Silman, The prevalence of vertebral deformity in European men and women: the European Vertebral Osteoporosis Study, J. Bone Miner. Res. 11 (7) (1996) 1010–1018. K.M. Davies, M.R. Stegman, R.P. Heaney, R.R. Recker, Prevalence and severity of vertebral fracture: the Saunders County Bone Quality Study, Osteoporos. Int. 6 (2) (1996) 160–165. S. Santavirta, Y.T. Konttinen, M. Heliovaara, P. Knekt, P. Luthje, A. Aromaa, Determinants of osteoporotic thoracic vertebral fracture. Screening of 57,000 Finnish women and men, Acta Orthop. Scand. 63 (2) (1992) 198–202. P. Szulc, F. Munoz, F. Marchand, P.D. Delmas, Semiquantitative evaluation of prevalent vertebral deformities in men and their relationship with osteoporosis: the MINOS study, Osteoporos. Int. 12 (4) (2001) 302–310. D. Felsenberg, A.J. Silman, M. Lunt, et al., Incidence of vertebral fracture in Europe: results from the European Prospective Osteoporosis Study (EPOS), J. Bone Miner. Res. 17 (4) (2002) 716–724. M. Van der Klift, C.E.D.H. De Laet, E.V. McCloskey, A. Hofman, H.A.P. Pols, The incidence of vertebral fractures in men and women: the Rotterdam Study, J. Bone Miner. Res. 17 (6) (2002) 1051–1056. A.C. Scane, R.M. Francis, A.M. Sutcliffe, M.J. Francis, D.J. Rawlings, C.L. Chapple, Case-control study of the pathogenesis and sequelae of symptomatic vertebral fractures in men, Osteoporos. Int. 9 (1) (1999) 91–97. H. Burger, P.L. Van Daele, K. Grashuis, et al., Vertebral deformities and functional impairment in men and women, J. Bone Miner. Res. 12 (1) (1997) 152–157. C. Matthis, U. Weber, T.W. O’Neill, H. Raspe, Health impact associated with vertebral deformities: results from the European Vertebral Osteoporosis Study (EVOS), Osteoporos. Int. 8 (4) (1998) 364–372. A.E.R. Wigg, T.C. Hearn, K.A. McCaul, S.M. Anderton, V.M. Wells, J. Krishnan, Number, incidence, and projections of distal forearm fractures admitted to hospital in Australia., J. Trauma Injury Infect. Crit. Care 55 (1) (2003) 87–93. L.J. Melton III, P.C. Amadio, C.S. Crowson, W.M. O’Fallon. Long-term trends in the incidence of distal forearm fractures, Osteoporos Int 8 (4) (1998) 341–348. T.W. O’Neill, C. Cooper, J.D. Finn, et al. Incidence of distal forearm fracture in British men and women, Osteoporos. Int. 12 (7) (2001) 555-558. P.W. Thompson, J. Taylor, A. Dawson, The annual incidence and seasonal variation of fractures of the distal radius in men and women over 25 years in Dorset, UK, Injury 35 (5) (2004) 462–466. H. Mallmin, S. Ljunghall, I. Persson, T. Naessen, U.B. Krusemo, R. Bergstrom, Fracture of the distal forearm as a forecaster of subsequent hip fracture: a population-based cohort study with 24 years of follow-up, Calcif. Tissue Int. 52 (4) (1993) 269–272. P.E. Beaule, G.F. Dervin, A.A. Giachino, K. Rody, J. Grabowski, A. Fazekas, Self-reported disability following
360
Osteoporosis in Men
distal radius fractures: the influence of hand dominance, J. Hand Surg. 25A (3) (2000) 476–482. 95. C.M. Court-Brown, A. Garg, M.M. McQueen, The epidemiology of proximal humeral fractures, Acta Orthop. Scand. 72 (4) (2001) 365–371. 96. S.P. Chu, J.L. Kelsey, T.H.M. Keegan, et al., Risk factors for proximal humerus fracture, Am. J. Epidemiol. 15 (160 (4)) (2004) 360–367. 97. R. Ekholm, J. Adami, J. Tidermark, K. Hansson, H. Tornkvist, S. Ponzer, Fractures of the shaft of the humerus. An epidemiological study of 401 fractures, J. Bone Joint. Surg. 88B (11) (2006) 1469–1473. 98. P. Kannus, M. Palvanen, S. Niemi, J. Parkkari, M. Jarvinen, I. Vuori, Osteoporotic fractures of the proximal humerus in elderly Finnish persons: sharp increase in 1970–1998 and alarming projections for the new millennium, Acta Orthop. Scand. 71 (5) (2000) 465–470. 99. T.V. Nguyen, J.R. Center, P.N. Sambrook, J.A. Eisman, Risk factors for proximal humerus, forearm, and wrist fractures in elderly men and women: the Dubbo Osteoporosis Epidemiology Study, Am. J. Epidemiol. 153 (6) (2001) 587–595. 100. M. Palvanen, P. Kannus, S. Niemi, J. Parkkari, Update in the epidemiology of proximal humeral fractures, Clin. Orthop. Relat. Res. 442 (2006) 87–92. 101. J.A. Kaye, H. Jick, Epidemiology of lower limb fractures in general practice in the United Kingdom, Injury Prevent. 10 (6) (2004) 368–374. 102. P. Kannus, M. Palvanen, S. Niemi, J. Parkkari, M. Jarvinen, Increasing number and incidence of low-trauma ankle fractures in elderly people: Finnish statistics during 1970–2000 and projections for the future, Bone 31 (3) (2002) 430–433. 103. P. Kannus, M. Palvanen, S. Niemi, J. Parkkari, M. Jarvinen, Stabilizing incidence of low-trauma ankle fractures in elderly people Finnish statistics in 1970–2006 and prediction for the future, Bone 43 (2) (2008) 340–342. 104. A. Nordqvist, C. Petersson, The incidence of fractures of the clavicle, Clin. Orthop. Relat. Res. 300 (1994) 127–132. 105. L.J. Melton III., J.M. Sampson, B.F. Morrey, D.M. Ilstrup, Epidemiologic features of pelvic fractures, Clin. Orthop. Relat. Res. 155 (1981) 43–47. 106. P. Kannus, M. Palvanen, S. Niemi, J. Parkkari, M. Jarvinen, Epidemiology of osteoporotic pelvic fractures in elderly people in Finland: sharp increase in 1970–1997 and alarming projections for the new millennium, Osteoporos. Int. 11 (5) (2000) 443–448. 107. S.R. Cummings, P.M. Cawthon, K.E. Ensrud, J.A. Cauley, H.A. Fink, E.S. Orwoll, Osteoporotic Fractures in Men
108.
109.
110.
111.
112.
113.
114.
115.
116. 117.
118.
119.
Research, Study of Osteoporotic Fractures Research. BMD and risk of hip and nonvertebral fractures in older men: a prospective study and comparison with older women, J. Bone Miner. Res. 21 (10) (2006) 1550–1556. N.D. Nguyen, J.A. Eisman, J.R. Center, T.V. Nguyen, Risk factors for fracture in nonosteoporotic men and women, J. Clin. Endocrinol. Metab. 92 (3) (2007) 955–962. S.L. Silverman, R.E. Madison, Decreased incidence of hip fracture in Hispanics, Asians, and blacks: California Hospital Discharge Data, Am. J. Publ. Hlth. 78 (11) (1988) 1482–1483. D.S. Lauderdale, S.J. Jacobsen, S.E. Furner, P.S. Levy, J.A. Brody, J. Goldberg, Hip fracture incidence among elderly Hispanics, Am. J. Publ. Hlth. 88 (8) (1998) 1245–1247. D.S. Lauderdale, S.J. Jacobsen, S.E. Furner, P.S. Levy, J.A. Brody, J. Goldberg, Hip fracture incidence among elderly Asian-American populations, Am. J. Epidemiol. 146 (6) (1997) 502–509. R.L. Bauer, Ethnic differences in hip fracture: a reduced incidence in Mexican Americans, Am. J. Epidemiol. 127 (1) (1988) 145–149. A.C. Looker, E.S. Orwoll, C.C. Johnston Jr., et al., Prevalence of low femoral bone density in older US adults from NHANES III [see comments], J. Bone Miner. Res. 12 (11) (1997) 1761–1768. D.A. Nelson, G. Jacobsen, D.A. Barondess, A.M. Parfitt, Ethnic differences in regional bone density, hip axis length, and lifestyle variables among healthy black and white men, J. Bone Miner. Res. 10 (5) (1995) 782–787. N.H. Bell, L. Gordon, J. Stevens, J.R. Shary, Demonstration that bone mineral density of the lumbar spine, trochanter, and femoral neck is higher in black than in white young men, Calcif. Tissue Int. 56 (1) (1995) 11–13. J.A. Baron, J. Barrett, D. Malenka, et al., Racial differences in fracture risk, Epidemiology 5 (1) (1994) 42–47. J.K. Tracy, W.A. Meyer, M. Grigoryan, et al., Racial differences in the prevalence of vertebral fractures in older men: the Baltimore Men’s Osteoporosis Study. Osteoporos. Int. 17 (1) (2006) 99–104. E. Dennison, N. Yoshimura, T. Hashimoto, C. Cooper, Bone loss in Great Britain and Japan: a comparative longitudinal study, Bone 23 (4) (1998) 379–382. L.M. Marshall, J.M. Zmuda, B.K.S. Chan, et al., Race and ethnic variation in proximal femur structure and BMD among older men. J. Bone Miner. Res. 23 (1) (2008) 121–130.
Chapter
29
Individualized Prognosis of Fracture in Men Tuan V Nguyen and John A Eisman Osteoporosis and Bone Biology Program, Garvan Institute of Medical Research, Sydney, NSW, Australia University of New South Wales, Sydney, NSW, Australia St Vincent’s Hospital, Sydney, NSW, Australia
Magnitude of the problem
aged 60 or over is 1.4-fold greater than that in men less than 60 years of age [11]. The age-related increase in the incidence of fracture provides a convenient way to quantify the residual lifetime risk of fracture in the general population. There have been few estimates of longitudinal lifetime risk of fracture in the world. However, using data from the Dubbo Osteoporosis Epidemiology Study [12], it has been estimated that the residual lifetime risk of any fracture for men from the age 60 was 25%, which is lower than for women (44%). One way to appreciate the magnitude of fracture risk in the general population is to consider these estimates within the context of other chronic diseases. The lifetime risk of fragility fracture in men is lower than the 1-in-2 lifetime risk of getting coronary heart disease (CHD) [13] or 45% chance of being diagnosed with some type of cancer [14] but comparable with lifetime risk of developing diabetes mellitus [15]. These comparisons re-emphasize that osteoporotic fracture is a public health burden and that, with the aging of the population, the societal burden is likely to increase further unless overall risk is reduced by public health interventions. Because fragility or osteoporotic fracture is defined as a fracture related to minimal trauma (i.e. a fall from standing height or less) [16, 17] in the research setting, fractures clearly due to major trauma (such as motor vehicle accidents) or due to underlying diseases (such as cancer or bone-related diseases) were excluded from most analyses [1, 5, 12, 18–22]. However, results from a recent population-based study [23] have shown that the prevalence of osteoporosis in high trauma fracture (i.e. falling from higher than standing height or due to a motor vehicle accident) was comparable to that of the low trauma fracture population counterparts. Therefore, some ‘high trauma’ fractures could also be fragility fractures.
Osteoporosis and its consequence of fracture in men are increasingly recognized as a major men’s health issue with public health significance. Among those aged 60 years or above, approximately one-third of all fractures in the general population occur in men [1–3]. Men with an initial fracture are at increased risk of subsequent fracture [1]. Although the risk of an initial fracture in men is lower than that in women, the absolute risk of subsequent fracture in men is comparable to that in women [4]. It is well known that men with a fracture have a greater risk of premature mortality than women [5–8]. For instance, the relative risk of one-year mortality in men with a hip fracture was 4.2, which was higher than that in women (relative risk 3.3) [8] and it appears that most of the excess death occurs within 6 months after the fracture [9, 10]. These facts collectively suggest that fracture in men is a serious medical condition and novel thinking about prevention should be high on the agenda of research and development. One important component of fracture prevention is the development of effective prognostic models for identifying men at high-risk of fragility fracture. This chapter contends that the prognosis of fracture should be individualized by making use of multiple risk factors to which an individual is uniquely exposed. Overall, the incidence of any fracture in men is lower than in women. Among those aged 60 years, the annual incidence of any new fracture in men ranged between 70 and 200 per 10 000 person-years, whereas in women, the rate is typically between 200 and 550 per 10 000 person-years. In both sexes, the risk of fracture increases with advancing age, but the gradient was greater in women than in men. For example, fracture rates in women aged 60 or over are six times higher than that in women 35–59 years of age; in men, the magnitude of difference is smaller; fracture rates in men Osteoporosis in Men
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Theoretically, any fracture related to low bone density (BMD) may be considered an osteoporotic fracture. Fractures of the spine, hip and wrist (distal forearm) have long been regarded as typical osteoporotic fractures [3, 12, 24–26]. This view is now challenged with new data showing that almost all types of fracture occurred more often in patients with low BMD [20, 27], therefore, the majority of all types of agedrelated fractures could be osteoporotic in nature. According to this definition, the following fracture types are considered osteoporotic: vertebrae, hip and other femoral, wrist–forearm, humeral, rib, pelvic, clavicle, scapula, sternum, tibia and fibula. Fractures of the skull and face, hands and fingers, feet and toes and patella are usually classified as not due to osteoporosis [28].
Hip Fracture Hip fractures include femoral neck, intertrochanteric or subtrochanteric fractures and the classification is based on their location. In risk parlance, the term ‘hip fracture’ refers to all these types of hip fracture. From the age of 60, it is estimated that 17 out of 100 men will sustain a hip fracture during their remaining lifetime. This risk is actually comparable with the risk of being diagnosed with prostate cancer [14]. Hip fracture is long recognized as the most serious consequence of osteoporosis, because it incurs many subsequent complications, including premature mortality, pain and disability [5, 29]. Men with a hip fracture have a higher risk of mortality than women. Indeed, recent data have shown that 30% of men compared with 17% of women who have sustained a hip fracture will die within 12 months after the event [30]. However, the causes of death among these individuals are not clear. Among those who survive the fracture, over 20% patients require long-term care, with a significantly reduced quality of life [31].
Vertebral Fracture Osteoporosis has sometimes been referred to as a ‘silent disease’ because individuals often do not have apparent symptoms and pain until a fracture occurs. Asymptomatic vertebral fracture is considered silent, because most patients (75%) do not realize that they have had a fracture and do not seek medical attention [32]. Currently, there is no ‘gold standard’ for the identification of vertebral fracture [33, 34], therefore, estimates of the overall vertebral fracture prevalence and incidence rate in elderly men depends in part on the definition used [35]. Asymptomatic vertebral fracture can be detected by conventional radiology, but it is not an attractive means for large scale screening on the grounds of cost and radiation exposure. Recent data suggest that the prevalence of asymptomatic vertebral fracture in men is comparable to that in women. In an early study [36], it was observed that the prevalence of vertebral fracture in men was similar to that in women.
In a large scale study on 15 570 men and women aged 50–79 years, lateral spinal radiographs evaluated by the McCloskey and Eastell method [37] found that vertebral fracture was present in 12% of the women and men. As expected, the prevalence of vertebral fracture increased with age with the gradient being steeper in women than in men [38]. The use of corticosteroid therapy tends to increase the risk of asymptomatic vertebral fracture. In a comparative cross-sectional study, vertebral fracture was found in 25% of patients on corticosteroid and 13% of individuals not on corticosteroid [39]. There are few studies investigating the incidence of vertebral fractures. Up to now, there are only two populationbased cohort studies investigating the incidence of vertebral fracture: the Rotterdam study [40] and the European Prospective Osteoporosis Study (EPOS) [41]. The EPOS study analysed the incidence of new vertebral fracture from 14 011 men and women aged 50 years and over and found that the age-standardized incidence of vertebral fracture was 1.1% per 100 person-years in women and 0.6% in men. The incidence also increased markedly with age in both men and women [41]. The incidence of symptomatic vertebral fractures is substantially less than the incidence rates suggested by vertebral morphometry. Several studies have found that about 33% of vertebral fractures or deformities are symptomatic [36]. A recent study from Sweden has shown that only 23% of vertebral deformities were diagnosed clinically [42]. In other words, there are two to three ‘silent’ vertebral fractures for every one that produces obvious symptoms or is recognized clinically. Vertebral deformities, whether clinically recognized or not, are related to an increase in chronic back pain and disability [43, 44] and to worse heath-related quality of life [45] and a higher risk of mortality [46, 47].
Distal Forearm Fractures Distal forearm fractures include those fractures at the distal third of the radius and/or ulna [48,49]. Distal forearm fracture is a frequent and typical osteoporotic fracture seen in the clinical setting [50, 51]. Although its consequence is less serious than hip fracture, distal forearm fracture is associated with significant pain and may be associated with severe and long-term complications [52, 53]. Similar to hip and vertebral fractures, distal forearm fracture incidence rapidly increases with advancing age in women, but this trend is less clear in men [54]. A re-analysis of data from the Rochester Epidemiology Project, a population-base descriptive study covering a 50-year period (1945–94) found that the overall incidence (per 100 000 person-years) of moderate trauma distal forearm fracture was 327 (95% CI: 312–343) in women and 54 (95% CI: 47–62) in men [54]. The results also showed the overall fracture rates in women rapidly increased between the ages of 45 and 60 years then levelled off, but no such age-related trend was observed in men. On the other
C h a p t e r 2 9 Individualized Prognosis of Fracture in Men l
hand, in a recent multicenter perspective survey [55] throughout the UK, although the same overall age-adjusted incidence of distal forearm fractures was found (368 (women) and 90 (men) per 100 000 person-years), the authors reported an agerelated secular trend, the incidence of distal forearm fractures (per 10 000 person-years) steadily increased from a baseline of 38 in women and eight in men at the age of 60 to a peak of 117 in women and 23 in men at the age of 85 and over. Similar findings were found in another 25-year follow-up, multicenter survey in the Dorset area of the UK [56]. A significant increase over time has been observed in total age-adjusted incidence rates of distal forearm fracture in men [54]. However, no significantly consistent trend in age specific incidence rates in women under the age of 75 years was observed. An increasing secular trend in the incidence rates among men was observed for all age groups. Similar trends were shown in another study [57] and an earlier study in Malmö [58] reported a twofold increase in the overall incidence of distal forearm fractures between 1953–1957 and 1980–1981.
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Table 29.1 Risk factors of osteoporotic fractures in postmenopausal Asian women Risk group
Risk factor
Non-modifiable
Advancing age Personal history of fracture as an adult History of fracture in first-degree relative Genetic factors
Potentially modifiable
Low bone mineral density Current cigarette smoking Low body weight Estrogen deficiency, early menopause or hypogonadism (in men) Long-term anticonvulsant drugs Lifelong low calcium intake Alcoholism Inadequate physical activity Poor health/frailty (e.g. rheumatoid arthritis, hyperthyroidism, dementia, impaired eyesight) Recurrent falls
Advancing Age Risk factors of fragility fracture In the prevailing concept, osteoporosis is a result of impaired bone strength which leads to an increased risk of fragility fracture [59]. The ‘bone strength’ component in this concept reflects the integration of bone mineral density (BMD) and bone quality. Bone quality is a generic term which refers to the constellation of bone architecture, metabolic turnover and damage accumulation and mineralization. While a precise definition of bone quality is still lacking, a prior fracture is considered a clinically relevant indicator of impaired bone quality. Fracture is a direct consequence of bone fragility with an additional contribution from non-musculoskeletal factors, such as fall propensity, that are affected by muscle strength and neuromuscular factors. From a public health viewpoint, risk factors of fracture can be broadly classified into two groups: modifiable and non-modifiable risk factors (Table 29.1). The risk factors not amenable to modification include advancing age, the presence of a personal history of fracture after the age 40, a history of fracture in a close relative and genetic factors that are yet to be identified. The risk factors that are potentially modifiable include current cigarette smoking, low body weight, androgen deficiency or hypogonadism, low calcium intake, excessive alcohol intake, inadequate physical activity, poor health or frailty (including rheumatoid arthritis, hyperthyroidism, impaired eyesight and dementia), long-term exposure to anticovulsant drugs and falls or recurrent falls. Among these risk factors, key risk factors include advancing age, personal history of a fragility fracture, family history of fracture and low bone mineral density.
Advancing age is clearly a major risk factor of fracture, as the incidence of fracture increases exponentially with advancing age in both men and women [1,60–62]. A longitudinal study in Sweden has shown that the 10-year probability of fracture at the forearm, humerus, spine or hip increases as much as eightfold between ages 45 and 85 for women and fivefold for men [63]. In the Dubbo Osteoporosis Epidemiology Study [6], each 5-year advancing age is associated with 1.7-fold (95% CI: 1.5–1.9) increase in fracture risk; this strength of association is actually slightly greater than that for women (RR 1.4; 95% CI: 1.3–1.5). The strength of the association between age and fracture was most pronounced for hip fracture (with relative risk being 2.3) compared with other sites. However, it seems that age does not exert an effect on the risk of Colles’ fracture (Table 29.2).
Bone Mineral Density There is a strong relationship between BMD and fracture risk, such that a BMD level one standard deviation (SD) below the mean is associated with a 1.6-fold increase in fracture risk in both men and women [66]. This BMD–fracture relationship has also been observed in non-Caucasian populations. In a recent prospective study in postmenopausal Chinese women, BMD levels one SD below the mean were associated with a twofold increase in the relative risk of fracture (95% CI: 1.6– 2.5) [67]. The magnitude of association between BMD and hip fracture risk (with relative risk being 2.2 [68] to 3.6 [69]) is equivalent to or even stronger than the association between serum cholesterol and cardiovascular disease. Thus, measurement of BMD provides a robust estimate of fracture risk in elderly men and postmenopausal women.
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Table 29.2 Effect of age on fracture risk Fracture site
Any fracture Hip fracture Vertebral fracture Colles’ fracture
Relative risk of fracture per 5-year increase in age Men
Women
1.67 (1.48–1.87) 2.31 (1.76–3.03) 1.67 (1.38–2.02) 0.99 (0.5–1.77)
1.43 (1.34–1.52) 1.95 (1.70–2.22) 1.54 (1.39–1.71) 1.30 (1.14–1.47)
Source: Derived from the Dubbo Osteoporosis Epidemiology Study [64, 65]
Given the strong association between femoral neck BMD and fracture risk, in 1994, the World Health Organization (WHO) expert panel proposed an operational definition of osteoporosis, by which a postmenopausal woman is considered to have osteoporosis if the woman’s femoral neck BMD is at least 2.5 standard deviations below the mean value in young adults [70]. The operational criteria of osteoporosis for women were subsequently adopted for men [71]. By this criterion, it has been estimated that approximately 10% of men aged 60 years or above have osteoporosis [72]. The adoption of the T-scores cut-off for men is based on the assumption that, for any given level of BMD, the absolute risk of fracture in men is similar to women [73]. However, this is not consistent with empirical data. Older men have, on average, higher BMD and lower rate of bone loss than women [72, 74]. As a group, men also have a lower risk of fracture at a later age compared to women [75]. However, data from the Dubbo Osteoporosis Epidemiology Study [68] suggest that there is an interaction between age, BMD and sex, such that, among those aged less than 75 years, for any given BMD level, men had lower risk of fracture than women, however, among those aged 75 or above, men tended to have higher risk of fracture (Figure 29.1).
Personal History of a Fragility Fracture The presence of a pre-existing fragility fracture has been shown to be a major risk for subsequent fracture [4, 46, 76, 77]. A history of previous fracture was associated with a relative risk of subsequent fracture between 1.5 and 9.5, depending on age at assessment, number of prior fractures and the site of the incident fracture. A pre-existing asymptomatic vertebral fracture increases the risk of a second vertebral fracture and non-vertebral fracture by at least fourfold [46]. Similarly, wrist fractures predict vertebral and hip fractures [4]. Patients with a hip fracture are at increased risk of a second hip fracture. Pooling the results from all studies (women and men) and for all fracture sites, the risk of subsequent fracture among those with a prior fracture at any site is 2.2 times that of people similar sex and age but without a prior fragility fracture (95% confidence interval: 1.9–2.3) (Table 29.3 [78]).
Falls In the elderly, approximately one-third of women and onefifth of men fall each year [83]. Over 90% of hip fractures are a result of a fall [84] but less than 2% of all falls result in a hip fracture [85,86]. A fall during the past 12 months is associated with an increased risk [64,67] of any fracture and hip fracture [65] independent of BMD. Family History The liability to fracture is partially determined by genetic factors [87]. Accumulated data in the past twenty years or so have strongly suggested that a family history of osteoporotic fracture is a major risk factor of fracture in women, but not in men. The Study of Osteoporotic Fractures [61], for example, identified a maternal history of hip fracture as a key risk factor for hip fracture in a population of elderly women. However, family history does not have a significant effect on fracture risk in men [82]. However, even if there is an effect, it seems the effect size is very modest, with relative risk being less than 1.2. Other Risk Factors Other risk factors of osteoporosis in men included longterm use of glucocorticosteroid (5 mg/d), hypogonadism, hyperparathyroidism [1, 88, 89], use of anticonvulsant drug, excess alcohol consumption, tobacco use, rheumatoid or other inflammatory arthritis, multiple myeloma or lymphoma, poor mental health and concomitant diseases (e.g. Cushing’s disease, chronic liver or kidney disease, pernicious anemia and gastric resection). Current smoking is associated with an increased risk of fracture in both women and men [80, 90]. However, the magnitude of association between smoking and fracture was modest, with relative risk being 1.20 (95% CI: 1.06–1.35) in women and 1.53 (95% CI: 1.27–1.83) in men. It appears that the association between smoking and fracture is partly mediated by low bone density as, after adjustment for BMD, the relative risk of osteoporotic fracture was reduced to around 1.13. Age-related decline in sex hormones may contribute to the increased risk of fracture in elderly men [91, 92]. A study from Sweden reported that free testosterone within the normal range was an independent predictor of prevalent osteoporotic fractures in elderly men [93], but this effect was not observed in the Rotterdam Study [94]. Moreover, the Framingham Study found a synergistic effect of sex hormones on fracture risk, such that men with the combination of low serum testosterone and low estradiol levels were at increased risk for incident hip fractures [95]. However, when the analysis was limited to either sex hormone alone, it revealed that serum estradiol but not testosterone was associated with hip fracture risk [95]. Data from the Dubbo Osteoporosis Epidemiology Study suggest that low levels of serum testosterone or circulating estradiol were associated with an increased risk of fragility fractures, however, when the two hormones were considered in the same model, only testosterone but not estradiol was a
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l
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Figure 29.1 Relationship between age and 10-year risk of fracture for a given BMD level (0.90, 0.80 and 0.70 g/cm2) for (A) any fracture, (B) hip fracture and (C) clinical vertebral fracture. These figures show an interaction between age and sex in terms of fracture risk. Data were derived from [64, 65].
significant predictor of fracture risk [96]. Although lower estradiol levels are associated with low bone density in men [97–99], the effect of estradiol on fracture risk appears to be independent from bone density.
Prognosis The prognosis of fracture risk has until now been largely based on the measurement of bone mineral density (BMD)
and a history of prior fracture. This is appropriate, since there is a strong association between BMD and the risk of fracture [66, 68, 100]. Furthermore, a history of fracture is also a strong risk factor of subsequent fracture [78]. In the past, treatment initiation was based on BMD measurement or the presence of a pre-existing low trauma fracture. This strategy appears to be logical and evidence-based because results from randomized clinical trials show that treating these patients (e.g. with osteoporosis and/or a prior fracture) did reduce their fracture risk [68, 101].
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Osteoporosis in Men Table 29.3 Comparison of relative risk of fracture for key risk factors for men and women
Risk factor
BMD (femoral neck) [66] Prior fracture [78] Corticosteroid use [79] Current smoking [80] Alcohol use [81] Parental history of fx [82] Maternal history of fx [82] Paternal history of fx [82] Sibling history fx [82]
Any fracture
Osteoporotic fracture
Hip fracture
Men
Women
Men
Women
Men
Women
1.47 (1.34–1.60) 2.02 (1.73–2.38) 1.67 (1.10–2.51) 1.50 (1.26–1.77)
1.45 (1.39–1.51) 1.84 (1.72–1.96) 1.39 (1.18–1.64) 1.18 (1.07–1.30)
1.01 (0.69–1.47) 1.02 (0.69–1.52) 0.93 (0.56–1.54) 2.21 (0.91–5.41)
1.34 (1.13–1.58) 1.29 (1.09–1.54) 1.34 (1.07–1.68) 1.25 (0.82–1.90)
1.60 (1.43–1.79) 1.93 (1.61–2.33) 2.16 (1.42–3.27) 1.53 (1.27–1.83) 1.04 (1.01–1.07) 1.01 (0.67–1.52) 1.03 (0.67–1.59) 0.91 (0.51–1.63) 2.21 (0.91–5.41)
1.53 (1.46–1.62) 1.85 (1.70–2.01) 1.42 (1.18–1.70) 1.20 (1.06–1.35) 1.08 (1.02–1.14) 1.38 (1.16–1.66) 1.33 (1.11–1.60) 1.42 (1.11–1.81) 1.43 (0.94–2.19)
2.42 (1.90–3.09) 2.30 (1.56–3.41) 2.62 (0.91–7.51) 1.82 (1.34–2.49) 1.07 (1.00–1.13) 1.73 (0.82–3.63) 1.56 (0.71–3.42) 1.51 (0.65–3.51) 5.71 (0.72–4.50)
2.03 (1.87–2.21) 1.77 (1.49–2.11) 2.07 (1.38–3.10) 1.85 (1.46–2.34) 1.11 (0.98–1.26) 1.75 (1.17–2.68) 1.61 (1.07–2.43) 1.00 (0.59–1.69) 2.47 (0.96–6.38)
Fx: fracture
However, it has recently been recognized that there is a problem of treatment initiation based on a BMD cut-off value. Although the risk of fracture is directly related to BMD at all levels, there is no threshold value for BMD that accurately separates those who will from those who will not sustain a fracture. Indeed, even at the lowest BMD range, only some individuals will sustain a fracture, on the other hand, a high BMD does not confer total protection against a fracture. Indeed, it has been shown that more than 50% of women and 70% of men who sustained a fracture had not had osteoporosis [102] as defined by bone density criteria alone. Therefore, the dichotomization of BMD into osteoporosis versus nonosteoporosis by a threshold can be ineffective at the population level, because treatment of individuals with osteoporosis by bone density definition will not reach the majority of men likely to fracture in the general population. Therefore, important changes are needed for that majority of individuals whose BMD measurements are at or near, on both sides, the current threshold of osteoporosis. Osteoporosis or low BMD is only one of many risk factors of fracture. At any given level of BMD, fracture risk varies widely in relation to the burden of other risk factors, such as advancing age, gender, genetics, family history of fracture, increased bone loss, low body weight, falls and smoking behavior. Thus, for any one individual, the likelihood of fracture depends on a combination of these and other risk factors [68]. This means that two individuals, both with ‘osteoporosis’, can have different risks of fracture because they have different non-BMD risk profile. Similarly, an osteoporotic individual can have the same risk of fracture as a non-osteoporotic individual due to the difference in constellation of risk factors between the two individuals. In other words, the prognosis for fracture risk can and should be individualized by using an individual’s unique risk profile. The aim of individualized prognosis is to provide an accurate and reliable prognosis of fracture for the individual and to help improve the management of the individual’s predisposition to fracture.
The approach of individualized prognosis must be distinguished from the approach of risk stratification. In risk stratification, the estimate of risk is applicable to a group of individuals rather than to an individual. For example, the stratification of BMD measurement into osteoporosis versus non-osteoporosis based on the T-score splits two men with T-scores of 2.45 and 2.50 into two distinct groups despite the trivial numerical and biologic difference and despite the plausibility that the two men may have comparable risk of fracture if other risk factors are considered. Moreover, because of the broad categories, such a stratification approach classifies an 80-year-old man with T-score of 2.5 and a 70-year-old man with T-score of 3.0 into a single group, despite the two men having very different risk profiles! In contrast to the risk grouping approach, the individualized prognosis approach recognizes that the four individuals are different and that they should have different fracture risks as one would logically expect. Thus, although the risk grouping approach is conceptually simple and sometimes useful in clinical practice, its predictive value is poorer than the individualized approach due to the arbitrariness of any numerical cut-off value [103]. Recently, we and others [64, 65, 104, 105] have developed a number of prognostic models, in which multiple risk factors are simultaneously considered in a multivariable model. Most prognostic models require tedious computation, which can be impractical in the primary care setting, even with an Internet implementation (www.fractureriskcalculator.com). One alternative approach is visually to translate a statistical model into a nomogram so that it can be more readily used in clinical practice. The nomogram was developed for predicting 5-year and 10-year risk of hip fracture (Figure 29.2) and any fracture (Figure 29.3) based on age, BMD T-scores, prior fracture history and falls. However, in some cases where BMD is not available and since BMD is highly correlated with body weight, we also developed a nomogram for predicting any fracture for a man using age, body weight, prior fracture and falls (Figure 29.4). The algorithm has been
C h a p t e r 2 9 Individualized Prognosis of Fracture in Men
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Figure 29.2 Nomogram for predicting the 5-year and 10-year probability of hip fracture for a man. Instruction for usage: Read ‘Points’ from the top scale by drawing a vertical line for each of the man’s age, T-score, prior fracture and falls. Sum these 4 point scores. Then read from the Total points and draw a vertical line down to the risk estimates in the next 5 years and 10 years. Example: Mr A, 70 years old, has a BMD T-score of 2.5, had a prior fracture and a fall in the past 12 months; his points for age is approximately 16, his BMD points is 65; prior fracture point is 6 and fall point is 2. His total points are therefore 89 and his probability of having a hip fracture is around 0.055 in the next 5 years and 0.105 in the next 10 years. In other words, in 100 men like him, one would expect 6 and 11 of them will have a hip fracture in the next 5 years and next 10 years, respectively.
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Figure 29.3 Nomogram for predicting the 5-year and 10-year probability of any fracture for a man based on age, BMD, prior fracture, and falls.
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Figure 29.4 Nomogram for predicting the 5-year and 10-year probability of any fracture for a man based on age, body weight, prior fracture, and falls.
validated in external population and the area under receiver operating characteristic curve varied between 0.76 to 0.82, indicating a very good to excellent predictive accuracy (data are not yet published). We present the following hypothetical, but typical examples to illustrate the clinical application of the nomograms. Clinical case 1: A 60-year-old man with a prior history of fracture at the spine, current BMD T-score 1.5, did not fall in the past 12 months. In Figure 29.3, 60 year old is equivalent to 12 points and T-score 1.5 scores 43 points and prior fracture scores 21 points. Because the man did not fall during the past 12 months, therefore, the points for fall were 0. The total points are thus 75. Marking the score on the ‘Total Points’ axis and drawing a vertical line from the ‘Total Points’ to obtain the 5-year and 10-year risks of fracture gives a 10-year risk of fracture for the man of 10%. Clinical case 2: A 70-year-old man with BMD T-score 2.5 (osteoporosis) without a history of fracture or a fall. Using Figure 29.3, the man’s 10-year risk of fracture is 14.3%, which is even higher than case 1. The idea of using nomograms in clinical medicine is not new. Since their introduction in 1928 [106], the literature of medicine has recorded more than 1700 nomograms in use [107]. Nomograms developed and used in oncology have clearly exhibited a better performance than risk-grouping categorization [108,109], in large part, this is because a nomogram estimates a continuous probability of an event, which yields more accurate predictions than models based
on categorical risk grouping. The use of a nomogram-based prognostic model obviates the need for grouping individuals by rather artificial thresholds and, as a result, increases the uniqueness of the risk estimate for an individual. Nomogram-based prognostic models have been shown to out-perform clinical judgment [110], because they can more objectively incorporate multiple risk factors and thus reduce the variability in risk estimates. The predicted risk of fracture is a continuous probabilistic variable ranging from 0 to 1. This raises the issue of selecting an optimal cut-off of predicted probability to classify an individual with respect to intervention. This is not an easy task, because the cut-off value – if it exists at all – depends on the complex risk-benefit consideration and, perhaps more importantly, on an individual’s perception of the importance of that risk. However, the predicted probability of fracture from the present prognostic models can be viewed as a measure of severity of osteoporosis for an individual. It is logical that individuals with high risk of fracture, regardless of their BMD levels, should be considered for treatment given evidence that treating these individuals could yield clinical benefit. However, what level (or levels) of risk should be regarded as ‘high risk’, so that an intervention can be considered cost-effective? The individualization of fracture risk can help select patients suitable for intervention. In a recent analysis, it was suggested that treatment is costeffective (based on the criteria of £30 000 per qualityadjusted life year gained) if an individual’s 10-year risk
C h a p t e r 2 9 Individualized Prognosis of Fracture in Men l
of hip fracture is between 1.2 and 9.0%, dependent on age [111]. It has been estimated that, for a 50-year-old Australian, treatment would be considered cost-effective if his 10-year risk of hip fracture is at least 1.93% [111]. However, for a 90-year-old man, the treatment would only be cost-effective if his 10-year risk is 10.8% or higher. The present nomograms can help identify such individuals for intervention. The National Osteoporosis Foundation (NOF) guidelines recommend treatment in the following clinical situations in postmenopausal women and men aged 50 years or older [112]: 1. with a hip or clinical vertebral fracture or a morphometric vertebral fracture 2. with femoral neck or lumbar spine BMD T-scores being equal to or less than 2.5 after excluding secondary cause of osteoporosis 3. with femoral neck or lumbar spine BMD T-scores between 1 and 2.5 and a 10-year risk of hip fracture 3% or a 10-year risk of major osteoporotic fracture 20%. The nomogram presented here and the FRAX model [104] in conjunction with the NOF guidelines can help select suitable individuals for intervention. The individualization of fracture prognosis may also be used to optimize the number needed to treat (NNT). In several randomized clinical trials [113], the number of patients needed to be treated to reduce one vertebral fracture compared to the untreated group ranged between 8 and 83. For hip fracture, the NNT ranged between 91 and 250 [114]. The NNT varies inversely with the background risk, such that treatment of high risk individuals inherently yields lower NNT. The large variability in the NNTs among trials is assumed to be due to the variability in fracture rates among the study samples, despite the fact that patients were selected on the basis of having osteoporosis and/or a prevalent vertebral fracture. However, the variability is expected given the multiple risk factors that affect the incidence of fractures. In the presence of such variability, selecting patients based on their absolute risk of fracture (rather than based on a BMD threshold value) may improve the consistency of therapeutic efficacy and efficiency of trials. Trials specifically testing the efficacy of multivariable risk based therapy have not been done. However, such approaches could be expected prove more cost effective and yield a more consistent NNT. An important question is whether treatment of individuals selected on the basis of absolute risk of fracture still result in reduced fracture risk. One clinical trial [115] randomized 5212 women aged 75 years and older into two groups, the placebo group receiving calcium and vitamin D and the clodronate group also receiving clodronate (800 mg daily po). Ten-year probability of fracture was computed for each woman using baseline clinical risk factors including body mass index (BMI), prior fracture, glucocorticoid use, parental hip fracture, smoking, alcohol and secondary osteoporosis. In women in the top 25th percentile of fracture probability
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(average probability of 24%), treatment reduced the risk of fracture by 23% over 3 years (hazards ratio (HR) 0.77, 95% CI 0.63–0.95). Importantly, among those in the top 10% percentile (average fracture probability of 30%), treatment reduced the fracture risk by 31% (HR 0.69, 0.53–0.90) [115]. Thus, treatment of individuals at high risk or moderate risk could reasonably be expected to reduce fractures.
Conclusion During the past three decades, several risk factors, including low bone mineral density, advancing age and a history of fracture, have been shown to be associated with fracture risk [61, 66, 69, 116–119]. Moreover, the risk of fracture increases with the cumulative presence of the number of risk factors [68]. The issue at hand is how to translate this knowledge of risk factors into prognostic models for individualizing fracture risk in clinical practice. Some prognostic models have recently been developed [64, 65, 104]. However, these models have not been externally validated and their validity and accuracy in Asian populations is not clear. Therefore, external validation should be a priority of research in the application of risk assessment models. Individualized prognosis – or the prediction of risk for an individual given a risk profile – is a fundamental to practicing medicine. Since fracture risk is determined by multiple factors, any unidimensional risk assessment is unlikely to be helpful. A multivariable-based nomogram can be an effective tool for individualizing short-term and long-term absolute risks of fracture, which can help patient counseling and selecting appropriate patients for intervention to maximize the benefit of fracture reduction in the general population.
References 1. T.V. Nguyen, J.A. Eisman, P.J. Kelly, P.N. Sambrook, Risk factors for osteoporotic fractures in elderly men, Am. J. Epidemiol 144 (1996) 255–263. 2. G. Jones, T. Nguyen, P.N. Sambrook, P.J. Kelly, C. Gilbert, J.A. Eisman, Symptomatic fracture incidence in elderly men and women: the Dubbo Osteoporosis Epidemiology Study (DOES), Osteoporos. Int. 4 (1994) 277–282. 3. S.R. Cummings, J.L. Kelsey, M.C. Nevitt, K.J. O’Dowd, Epidemiology of osteoporosis and osteoporotic fractures, Epidemiol Rev. 7 (1985) 178–208. 4. J.R. Center, D. Bliuc, T.V. Nguyen, J.A. Eisman, Risk of subsequent fracture after low-trauma fracture in men and women, J. Am. Med. Assoc. 297 (2007) 387–394. 5. J.R. Center, T.V. Nguyen, D. Schneider, P.N. Sambrook, J.A. Eisman, Mortality after all major types of osteoporotic fracture in men and women: an observational study, Lancet 353 (1999) 878–882. 6. N.D. Nguyen, H.G. Ahlborg, J.R. Center, J.A. Eisman, T.V. Nguyen, Residual lifetime risk of fractures in women and men, J. Bone Miner. Res. 22 (6) (2007) 781–788.
370
Osteoporosis in Men
7. M. Fransen, M. Woodward, R. Norton, E. Robinson, M. Butler, A.J. Campbell, Excess mortality or institutionalization after hip fracture: men are at greater risk than women, J. Am. Geriatr. Soc. 50 (2002) 685–690. 8. L. Forsen, A.J. Sogaard, H.E. Meyer, T. Edna, B. Kopjar, Survival after hip fracture: short- and long-term excess mortality according to age and gender, Osteoporos. Int. 10 (1999) 73–78. 9. J.A. Robbins, M.L. Biggs, J. Cauley, Adjusted mortality after hip fracture: from the cardiovascular health study, J. Am. Geriatr Soc. 54 (2006) 1885–1891. 10. A.N. Tosteson, D.J. Gottlieb, D.C. Radley, E.S. Fisher, L.J. Melton 3rd, Excess mortality following hip fracture: the role of underlying health status, Osteoporos. Int. 18 (2007) 1463–1472. 11. K.M. Sanders, E. Seeman, A.M. Ugoni, et al., Age- and gender-specific rate of fractures in Australia: a populationbased study, Osteoporos. Int. 10 (1999) 240–247. 12. T. Nguyen, P. Sambrook, P. Kelly, et al., Prediction of osteoporotic fractures by postural instability and bone density, Br. Med. J. 307 (1993) 1111–1115. 13. D.M. Lloyd-Jones, M.G. Larson, A. Beiser, D. Levy, Lifetime risk of developing coronary heart disease., Lancet 353 (1999) 89–92. 14. Anonymous, Lifetime risk of being diagnosed with cancer, J. Natl. Cancer Inst. 95 (2003) 1745. 15. K.M. Narayan, J.P. Boyle, T.J. Thompson, S.W. Sorensen, D.F. Williamson, Lifetime risk for diabetes mellitus in the United States, J. Am. Med. Assoc. 290 (2003) 1884–1890. 16. J.E. Compston, C. Cooper, J.A. Kanis, Bone densitometry in clinical practice., Br. Med. J. 310 (1995) 1507–1510. 17. J.A. Kanis, J.P. Devogelaer, C. Gennari, Practical guide for the use of bone mineral measurements in the assessment of treatment of osteoporosis: a position paper of the European foundation for osteoporosis and bone disease. The Scientific Advisory Board and the Board of National Societies, Osteoporos. Int. 6 (1996) 256–261. 18. M.S. LeBoff, B. Bermas, E. Ginsburg, et al. Osteoporosis. Guide to prevention, diagnosis, and treatment, 2001. Brigham and Women’s Hospital, Boston. 19. LJ. Melton III, E.J. Atkinson, M.K. O’Connor, W.M. O’Fallon, B.L. Riggs, Fracture prediction by BMD in men versus women, J. Bone. Miner. Res. 12 (Suppl 1) (1997) S362. 20. T.V. Nguyen, J.R. Center, P.N. Sambrook, J.A. Eisman, Risk factors for proximal humerus, forearm, and wrist fractures in elderly men and women: the Dubbo Osteoporosis Epidemiology Study, Am. J. Epidemiol. 153 (2001) 587–595. 21. R.W. Keen, D.J. Hart, N.K. Arden, D.V. Doyle, T.D. Spector, Family history of appendicular fracture and risk of osteoporosis: a population-based study, Osteoporos. Int. 10 (1999) 161–166. 22. R. Hu, C.A. Mustard, C. Burns, Epidemiology of incident spinal fracture in a complete population, Spine 21 (1996) 492–499. 23. K.M. Sanders, J.A. Pasco, A.M. Ugoni, et al., The exclusion of high trauma fractures may underestimate the prevalence of bone fragility fractures in the community: the Geelong Osteoporosis Study, J. Bone. Miner. Res. 13 (1998) 1337–1342. 24. C. Cooper, S. Shah, D.J. Hand, et al., Screening for vertebral osteoporosis using individual risk factors. The Multicentre Vertebral Fracture Study Group, Osteoporos. Int. 2 (1991) 48–53.
25. C. Cooper, Bone mass, muscle function and fracture of the proximal femur, Br. J. Hosp. Med. 42 (1989) 277–280. 26. R.G. Cumming, R.J. Klineberg, Epidemiological study of the relation between arthritis of the hip and hip fractures, Ann. Rheum. Dis. 52 (1993) 707–710. 27. D.G. Seeley, J. Kelsey, M. Jergas, M.C. Nevitt, Predictors of ankle and foot fractures in older women. The Study of Osteoporotic Fractures Research Group, J. Bone. Miner. Res. 11 (1996) 1347–1355. 28. J.A. Kanis, A. Oden, O. Johnell, B. Jonsson, C. de Laet, A. Dawson, The burden of osteoporotic fractures: a method for setting intervention thresholds, Osteoporos. Int. 12 (2001) 417–427. 29. G.S. Keene, M.J. Parker, G.A. Pryor, Mortality and morbidity after hip fractures., Br. Med. J. 307 (1993) 1248–1250. 30. L.E. Wehren, D.L. Orwig, J.R. Hebel, S.I. Zimmerman, J. Magaziner, Gender differences in mortality after hip fracture: the role of infection, J. Bone. Miner. Res. 18 (2003) 2231–2237. 31. A.G. Randell, T.V. Nguyen, N. Bhalerao, S.L. Silverman, P.N. Sambrook, J.A. Eisman, Deterioration in quality of life following hip fracture: a prospective study, Osteoporos. Int. 11 (2000) 460–466. 32. V. Naganathan, G. Jones, P. Nash, G. Nicholson, J. Eisman, P.N. Sambrook, Vertebral fracture risk with long-term corticosteroid therapy: prevalence and relation to age, bone density, and corticosteroid use, Arch. Intern. Med. 160 (2000) 2917–2922. 33. P.D. Delmas, L. van de Langerijt, N.B. Watts, et al., Underdiagnosis of vertebral fractures is a worldwide problem: the IMPACT study, J. Bone. Miner. Res. 20 (2005) 557–563. 34. M. Jergas, H.K. Genant, Assessment of prevalent and incident vertebral fractures in osteoporosis research, Osteoporos. Int. 14 (Suppl 3) (2003) S43–S55. 35. D.M. Black, S.R. Cummings, K. Stone, E. Hudes, L. Palermo, P. Steiger, A new approach to defining normal vertebral dimensions, J. Bone. Miner. Res. 6 (1991) 883–892. 36. G. Jones, C. White, T. Nguyen, P.N. Sambrook, P.J. Kelly, J.A. Eisman, Prevalent vertebral deformities: relationship to bone mineral density and spinal osteophytosis in elderly men and women, Osteoporos. Int. 6 (1996) 233–239. 37. E.V. McCloskey, T.D. Spector, K.S. Eyres, et al., The assessment of vertebral deformity: a method for use in population studies and clinical trials, Osteoporos. Int. 3 (1993) 138–147. 38. T.W. O’Neill, D. Felsenberg, J. Varlow, C. Cooper, J.A. Kanis, A.J. Silman, The prevalence of vertebral deformity in European men and women: the European Vertebral Osteoporosis Study, J. Bone. Miner. Res. 11 (1996) 1010–1018. 39. R.N.J.J. de Nijs, J.W. Bijlsma, W.F. Lems, et al., Osteoporosis Working Group, Dutch Society for Rheumaology. Prevalence of vertebral deformities and symptomatic vertebral fractures in corticosteroid treated patients with rheumatoid arthritis., Rheumatology (Oxford) 40 (2001) 1375–1385. 40. M. Van der Klift, C.E. De Laet, E.V. McCloskey, A. Hofman, H.A. Pols, The incidence of vertebral fractures in men and women: the Rotterdam Study, J. Bone. Miner. Res. 17 (2002) 1051–51051. 41. The EPOS Group, Incidence of vertebral fracture in Europe: results from the European Prospective Osteoporosis Study (EPOS), J. Bone. Miner. Res. 17 (2002) 716–724.
C h a p t e r 2 9 Individualized Prognosis of Fracture in Men l
42. J.A. Kanis, O. Johnell, A. Oden, et al., The risk and burden of vertebral fractures in Sweden, Osteoporos. Int. 15 (2004) 20–26. 43. M.C. Nevitt, B. Ettinger, D.M. Black, et al., The association of radiographically detected vertebral fractures with back pain and function: a prospective study, Ann. Intern. Med. 128 (1998) 793–800. 44. T.W. O’Neill, W. Cockerill, C. Matthis, et al., Back pain, disability, and radiographic vertebral fracture in European women: a prospective study, Osteoporos. Int. 15 (2004) 760–765. 45. W. Cockerill, M. Lunt, A.J. Silman, et al., Health-related quality of life and radiographic vertebral fracture, Osteoporos. Int. 15 (2004) 113–119. 46. C. Pongchaiyakul, N.D. Nguyen, G. Jones, J.R. Center, J.A. Eisman, T.V. Nguyen, Asymptomatic vertebral deformity as a major risk factor for subsequent fractures and mortality: a long-term prospective study, J. Bone. Miner. Res. 20 (2005) 1349–1355. 47. D.M. Kado, T. Duong, K.L. Stone, et al., Incident vertebral fractures and mortality in older women: a prospective study, Osteoporos. Int. 14 (2003) 589–594. 48. S.W. Carmichael, Abraham Colles 1773–1843, Clin. Anat. 14 (2001) 387–388. 49. T.B. Hunter, L.F. Peltier, P.J. Lund, Radiologic history exhibit. Musculoskeletal eponyms: who are those guys? Radiographics 20 (2000) 819–836. 50. R. Eastell, Forearm fracture., Bone 18 (1996) 203S–207S. 51. M.T. Cuddihy, S.E. Gabriel, C.S. Crowson, W.M. O’Fallon, L. Melton Jr, Forearm fractures as predictors of subsequent osteoporotic fractures, Osteoporos. Int 9 (1999) 469–475. 52. H.P. de Bruijn, The Colle’s fracture, review and literature, Acta Orthop. Scand. 58 (23) (1987) 7–25. 53. W.P. Cooney 3rd, J.H. Dobyns, R.L. Linscheid, Complications of Colles’ fractures, J. Bone Joint. Surg. 62A (1980) 613–619. 54. L.J. Melton 3rd, P.C. Amadio, C.S. Crowson, W.M. O’Fallon, Long-term trends in the incidence of distal forearm fractures, Osteoporos. Int. 8 (1998) 341–348. 55. T.W. O’Neill, C. Cooper, J.D. Finn, et al., Incidence of distal forearm fracture in British men and women, Osteoporos. Int. 12 (2001) 555–558. 56. P.W. Thompson, J. Taylor, A. Dawson, The annual incidence and seasonal variation of fractures of the distal radius in men and women over 25 years in Dorset, UK., Injury 35 (2004) 462–466. 57. S.W. Miller, J.G. Evans, Fractures of the distal forearm in Newcastle: an epidemiological survey, Age Ageing 14 (1985) 155–158. 58. U. Bengner, O. Johnell, Increasing incidence of forearm fractures. A comparison of epidemiologic patterns 25 years apart, Acta Orthop. Scand. 56 (1985) 158–160. 59. Anonymous, Osteoporosis prevention diagnosis and therapy, J. Am. Med. Assoc. 285 (2001) 785–795. 60. J.A. Kanis, O. Johnell, A. Oden, A. Dawson, C. De Laet, B. Jonsson, Ten year probabilities of osteoporotic fractures according to BMD and diagnostic thresholds, Osteoporos. Int. 12 (2001) 989–995. 61. S.R. Cummings, M.C. Nevitt, W.S. Browner, et al., Risk factors for hip fracture in white women. Study of Osteoporotic Fractures Research Group, N. Engl. J. Med. 332 (1995) 767–773.
371
62. S.L. Hui, C.W. Slemenda, C.C.J. Johnston, Age and bone mass as predictors of fracture in a prospective study, J. Clin. Invest. 81 (1988) 1804–1904. 63. R.D. Wasnich, J.W. Davis, P.D. Ross, Spine fracture risk is predicted by non-spine fractures, Osteoporos. Int. 4 (1994) 1–5. 64. N.D. Nguyen, S.A. Frost, J.R. Center, J.A. Eisman, T.V. Nguyen, Development of prognostic nomograms for individualizing 5-year and 10-year fracture risks, Osteoporos. Int. 19 (10) (2008) 1431–1444. 65. N.D. Nguyen, S.A. Frost, J.R. Center, J.A. Eisman, T.V. Nguyen, Development of a nomogram for individualizing hip fracture risk in men and women, Osteoporos. Int 18 (2007) 1109–1117. 66. O. Johnell, J.A. Kanis, A. Oden, et al., Predictive value of BMD for hip and other fractures, J. Bone. Miner. Res. 20 (2005) 1185–1194. 67. A.W. Kung, K.K. Lee, A.K. Ho, G. Tang, K.D. Luk, Tenyear risk of osteoporotic fractures in postmenopausal Chinese women according to clinical risk factors and BMD T scores: a prospective study, J. Bone. Miner. Res. 22 (7) (2007) 1080–1087. 68. N.D. Nguyen, C. Pongchaiyakul, J.R. Center, J.A. Eisman, T.V. Nguyen, Identification of high-risk individuals for hip fracture: a 14-year prospective study, J. Bone. Miner. Res. 20 (2005) 1921–1928. 69. D. Marshall, O. Johnell, H. Wedel, Meta-analysis of how well measures of bone mineral density predict occurrence of osteoporotic fractures., Br. Med. J. 312 (1996) 1254–1259. 70. J.A. Kanis, L.J. Melton 3rd, C. Christiansen, C.C. Johnston, N. Khaltaev, The diagnosis of osteoporosis, J. Bone. Miner. Res. 9 (1994) 1137–1141. 71. Writing Group for the ISCD Position Development Conference, Diagnosis of osteoporosis in men, premenopausal women, and children, J. Clin. Densitom. 7 (2004) 17–26. 72. T.V. Nguyen, J.R. Center, J.A. Eisman, Osteoporosis in elderly men and women: effects of dietary calcium, physical activity, and body mass index, J. Bone. Miner. Res. 15 (2000) 322–331. 73. J.A. Kanis, O. Johnell, A. Oden, C. De Laet, D. Mellstrom, Diagnosis of osteoporosis and fracture threshold in men, Calcif. Tissue Int. 69 (2001) 218–221. 74. N.D. Nguyen, J.R. Center, J.A. Eisman, T.V. Nguyen, Bone loss, weight loss, and weight fluctuation predict mortality risk in elderly men and women, J. Bone. Miner. Res. 22 (2007) 1147–1154. 75. T.V. Nguyen, J.A. Eisman, Risk factors for low bone mass in men, in: E.S. Orwoll (Ed.), Osteoporosis in Men, Academic Press, San Diego, 1999, pp. 335–361. 76. A.A. Ismail, W. Cockerill, C. Cooper, et al., Prevalent vertebral deformity predicts incident hip though not distal forearm fracture: results from the European Prospective Osteoporosis Study, Osteoporos. Int. 12 (2001) 85–90. 77. C.M. Klotzbuecher, P.D. Ross, P.B. Landsman, TAr Abbott, M. Berger, Patients with prior fractures have an increased risk of future fractures: a summary of the literature and statistical synthesis, J. Bone. Miner. Res. 15 (2000) 721–739. 78. J.A. Kanis, O. Johnell, C. De Laet, et al., A meta-analysis of previous fracture and subsequent fracture risk., Bone 35 (2004) 375–382.
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79. J.A. Kanis, H. Johansson, A. Oden, et al., A meta-analysis of prior corticosteroid use and fracture risk, J. Bone. Miner. Res. 19 (2004) 893–899. 80. J.A. Kanis, O. Johnell, A. Oden, et al., Smoking and fracture risk: a meta-analysis, Osteoporos. Int. 16 (2005) 155–162. 81. J.A. Kanis, H. Johansson, O. Johnell, et al., Alcohol intake as a risk factor for fracture, Osteoporos. Int. 16 (2005) 737–742. 82. J.A. Kanis, H. Johansson, A. Oden, et al., A family history of fracture and fracture risk: a meta-analysis, Bone 35 (2004) 1029–1037. 83. S.R. Lord, P.N. Sambrook, C. Gilbert, et al., Postural stability, falls and fractures in the elderly: results from the Dubbo Osteoporosis Epidemiology Study, Med. J. Aust. 160 (68485) (1994) 688–691. 84. J.A. Grisso, J.L. Kelsey, B.L. Strom, et al., Risk factors for falls as a cause of hip fracture in women. The Northeast Hip Fracture Study Group, N. Engl. J. Med. 324 (1991) 1326–1331. 85. M.C. Nevitt, S.R. Cummings, S. Kidd, D. Black, Risk factors for recurrent nonsyncopal falls. A prospective study, J. Am. Med. Assoc. 261 (1989) 2663–2668. 86. M.E. Tinetti, M. Speechley, S.F. Ginter, Risk factors for falls among elderly persons living in the community, N. Engl. J. Med. 319 (1988) 1701–1707. 87. K. Michaelsson, H. Melhus, H. Ferm, A. Ahlbom, N.L. Pedersen, Genetic liability to fractures in the elderly, Arch. Intern. Med. 165 (2005) 1825–1830. 88. S. Amin, D.T. Felson, Osteoporosis in men, Rheum. Dis. Clin. North. Am. 27 (2001) 19–47. 89. E.S. Orwoll, Osteoporosis in men, Endocrinol Metab. Clin. North. Am. 27 (1998) 349–367. 90. P. Vestergaard, L. Mosekilde, Fracture risk associated with smoking: a meta-analysis, J. Intern. Med. 254 (2003) 572–583. 91. A. Gray, J.A. Berlin, J.B. McKinlay, C. Longcope, An examination of research design effects on the association of testosterone and male aging: results of a meta-analysis, J. Clin. Epidemiol. 44 (1991) 671–684. 92. P.Y. Liu, R.S. Swerdloff, J. Veldhuis, The rationale, efficacy and safety of androgen therapy in older men: Future research and current practice recommendations, J. Clin. Endocrinol. Metab. 89 (2004) 4789–4796. 93. D. Mellstrom, O. Johnell, O. Ljunggren, et al., Free testosterone is an independent predictor of BMD and prevalent fractures in elderly men: MrOS Sweden, J. Bone. Miner. Res. 21 (2006) 529–535. 94. H.W. Goderie-Plomp, M. van der Klift, W. de Ronde, A. Hofman, F.H. de Jong, H.A. Pols, Endogenous sex hormones, sex hormone-binding globulin, and the risk of incident vertebral fractures in elderly men and women: the Rotterdam Study, J. Clin. Endocrinol. Metab. 89 (2004) 3261–3269. 95. S. Amin, Y. Zhang, D.T. Felson, et al., Estradiol, testosterone, and the risk for hip fractures in elderly men from the Framingham Study, Am. J. Med. 119 (2006) 426–433. 96. C. Meier, T.V. Nguyen, D.J. Handelsman, et al., Endogenous sex hormones and incident fracture risk in older men: the Dubbo Osteoporosis Epidemiology Study, Arch. Intern. Med. 168 (2008) 47–54. 97. S. Khosla, L.J. Melton 3rd, R.A. Robb, et al., Relationship of volumetric BMD and structural parameters at different skeletal sites to sex steroid levels in men, J. Bone. Miner. Res. 20 (2005) 730–740.
98. L. Gennari, D. Merlotti, G. Martini, et al., Longitudinal association between sex hormone levels, bone loss, and bone turnover in elderly men, J. Clin. Endocrinol. Metab. 88 (2003) 5327. 99. S. Khosla, L.J. Melton 3rd, E.J. Atkinson, W.M. O’Fallon, Relationship of serum sex steroid levels to longitudinal changes in bone density in young versus elderly men, J. Clin. Endocrinol. Metab. 86 (2001) 3555–3561. 100. W.D. Leslie, L.M. Lix, J.F. Tsang, P.A. Caetano, Single-site vs multisite bone density measurement for fracture prediction, Arch. Intern. Med. 167 (2007) 1641–1647. 101. P. Dargent-Molina, M.N. Douchin, C. Cormier, P.J. Meunier, G. Breart, Use of clinical risk factors in elderly women with low bone mineral density to identify women at higher risk of hip fracture: The EPIDOS prospective study, Osteoporos. Int. 13 (2002) 593–599. 102. N.D. Nguyen, J.A. Eisman, J.R. Center, T.V. Nguyen, Risk factors for fracture in nonosteoporotic men and women, J. Clin. Endocrinol. Metab. 92 (2007) 955–962. 103. M.W. Kattan, V. Reuter, R.J. Motzer, J. Katz, P. Russo, A postoperative prognostic nomogram for renal cell carcinoma, J. Urol. 166 (2001) 63–67. 104. J.A. Kanis, O. Johnell, A. Oden, H. Johansson, E. McCloskey, FRAX and the assessment of fracture probability in men and women from the UK, Osteoporos. Int. 19 (2008) 385–397. 105. B. Ettinger, T.A. Hillier, A. Pressman, M. Che, D.A. Hanley, Simple computer model for calculating and reporting 5year osteoporotic fracture risk in postmenopausal women, J. Womens Hlth. (Larchmt) 4 (2005) 159–171. 106. L.J. Henderson, Blood; a Study in General Physiology, Yale University Press, New Haven, 1928 London, H. Milford, Oxford University Press. 107. F.J. Bianco Jr, Nomograms and Medicine, Eur Urol, 2006 50:884-86. 108. M.W. Kattan, Nomograms are superior to staging and risk grouping systems for identifying high-risk patients: preoperative application in prostate cancer, Curr. Opin. Urol. 13 (2003) 111–116. 109. S.L. Wong, M.W. Kattan, K.M. McMasters, D.G. Coit, A nomogram that predicts the presence of sentinel node metastasis in melanoma with better discrimination than the American Joint Committee on Cancer staging system., Ann. Surg. Oncol. 12 (2005) 282–288. 110. P.L. Ross, C. Gerigk, M. Gonen, et al., Comparisons of nomograms and urologists’ predictions in prostate cancer., Semin. Urol. Oncol. 20 (2002) 82–88. 111. F. Borgstrom, O. Johnell, J.A. Kanis, B. Jonsson, C. Rehnberg, At what hip fracture risk is it cost-effective to treat? International intervention thresholds for the treatment of osteoporosis, Osteoporos. Int. 17 (2006) 1459–1471. 112. NOF Clinician’s guide to prevention and treatment of osteoporosis. (2008). National Osteoporosis Foundation, Washington DC. 113. D.M. Black, S.R. Cummings, D.B. Karpf, et al., Randomised trial of effect of alendronate on risk of fracture in women with existing vertebral fractures. Fracture Intervention Trial Research Group, Lancet 348 (1996) 1535–1541. 114. P.D. Delmas, R. Rizzoli, C. Cooper, J.Y. Reginster, Treatment of patients with postmenopausal osteoporosis is worthwhile. The position of the International Osteoporosis Foundation, Osteoporos. Int. 16 (2005) 1–5.
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115. E. McCloskey, H. Johansson, A. Oden, A. Aropuu, T. Jalava, J. Kanis, Efficacy of clodronate on fracture risk in women selected by 10-year fracture probability, J. Bone Miner. Res. 22 (2007) S131. 116. T.V. Nguyen, J.R. Center, J.A. Eisman, Femoral neck bone loss predicts fracture risk independent of baseline BMD, J. Bone. Miner Res. 20 (2005) 1195–1201. 117. H. Burger, C.E. de Laet, A.E. Weel, A. Hofman, H.A. Pols, Added value of bone mineral density in hip fracture risk scores, Bone 25 (1999) 369–374.
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118. B.C. Taylor, P.J. Schreiner, K.L. Stone, et al., Long-term prediction of incident hip fracture risk in elderly white women: study of osteoporotic fractures, J. Am. Geriatr. Soc. 52 (2004) 1479–1486. 119. P. Haentjens, P. Autier, J. Collins, B. Velkeniers, D. Vanderschueren, S. Boonen, Colles fracture, spine fracture, and subsequent risk of hip fracture in men and women. A meta-analysis, J. Bone Joint. Surg. 85A (2003) 1936–1943.
Chapter
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Physical Activity, Physical Function and Fall and Fracture Risk in Older Men Peggy Mannen Cawthon1 and Lynn Marshall2 1
San Francisco Coordinating Center, California Pacific Medical Center Research Institute, San Francisco, CA, USA Department of Medicine, Bone and Mineral Unit, Department of Public Health and Preventive Medicine, Oregon Health & Science University, Portland, OR, USA 2
Introduction
r ecommendations for the type and amount of physical activity that older adults should undertake (Table 30.1) [1]. The extensive recommendations are designed to be the minimum level of activity for older adults and pertain to both aerobic exercise as well as strength training. Because of the putative contribution of physical activity to the most important factors in the fracture pathway–skeletal integrity and fall propensity– these recommendations, if met, could result in reduced fracture incidence among the US elderly. Thus, research on the impact of these recommendations will be informative.
This chapter will describe the relation between both physical activity and physical performance with fall and fracture risk in older adults. First, an assessment of physical activity levels in both clinical and research settings will be discussed. Then, the evidence for the association between activity level and fall and fracture risk in older men will be reviewed. In the second half of the chapter, methods to assess physical performance (including muscle strength, walking speed and ability to rise from a chair) will be described. Next, changes in physical performance that occur with age in older men will be outlined. Finally, the association between physical performance and fall and fracture risk will be described.
Physical Activity Assessment Assessment of physical activity can be divided into two domains: subjective measures of activity, such as questionnaire based data; and objective measures of activity levels, such as use of accelerometers to measure movement. There are many validated instruments to measure subjectively reported
Physical activity Table 30.1 Recommendations for the type and amount of physical activity for older adults
Physical activity refers to the volitional and necessary levels of movement that an individual undertakes in his daily life, including exercise. In this section, we will describe recommendations for exercise for older adults; objective and subjective assessment of physical activity in research and clinical settings; the association between physical activity and fall risk; and the relation between physical activity and fracture risk in older men.
Do moderately intense aerobic exercise 30 minutes a day, 5 days a week or Do vigorously intense aerobic exercise 20 minutes a day, 3 days a week and Do 8 to 10 strength-training exercises, 10–15 repetitions of each exercise twice to three times per week and If you are at risk of falling, perform balance exercises and Have a physical activity plan
Recommended Levels of Activity in Older Adults The American College of Sports Medicine (ACSM) and the American Heart Association have developed specific Osteoporosis in Men
Adapted from Nelson, 2007 [1]
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physical activity in epidemiologic studies. Several instruments have been developed for the general population, including the Minnesota Leisure Time Physical Activity Questionnaire [2], the Seven Day Recall [3] and the Stanford Usual Activity Questionnaire [4]. Since older adults may engage in physical activity that is less intense, of shorter duration and less frequent than younger adults, specialized questionnaires to assess activity level in older adults have been developed [5, 6]. These include the Community Healthy Activities Model Program for Seniors (CHAMPS) Questionnaire [7], the Yale Physical Activity Survey (YPAS) [8] and the Physical Activity Scale for the Elderly (PASE) [9] among others. Many cross-sectional studies of self-reported physical activity have noted that activity levels decline across age groups, even among the oldest old [10–13]. Men consistently report more physical activity in older age (65 years) than women and this sex difference increases with advancing age [11]. Few longitudinal studies have assessed change in activity level over time; one study in the Netherlands found that total time spent on physical activity decreased 33% over a decade in elderly men [10]. The activities in which older individuals were participating changed with age as well: time spent gardening and bicycling declined, but time spent walking remained stable. Even though activity levels may decline with age, older adults may be exercising more now than ever before. For example, data from the Behavioral Risk Factor Surveillance System, a large, population-based survey, indicates that the percentage of people aged 75 and older who reported an inactive lifestyle declined from 48.5% in 1990 to 39.5% in 2000 [13]. Also during this time, the number of adults aged 75 years and older who reported regular, intense exercise almost doubled from 11.7% to 19.1%. Thus, the current cohort of older Americans may have more active lifestyles than previous generations. While self-reported physical activity questionnaires allow for report of volitional activities and are easy to field in a research setting, self-report is potentially prone to substantial measurement error [14]. In fact, a validation study conducted by Bonnefoy et al simultaneously evaluated 10 surveys of activity level used in elderly adults against the gold standard of doubly labeled water as a measure of total energy expenditure [6]. In general, agreement between the questionnaires and the gold standard was poor with correlations ranging between 0.11 and 0.63; only the Seven Day Recall and the YPAS were considered to measure accurately total energy expenditure. Such error would make it difficult to demonstrate an association between physical activity and health outcomes. Additionally, in a clinical setting, formal questionnaires regarding physical activity level may be difficult to administer and score given time constraints on patient–physician interaction. Objective measures of physical activity and function have recently been used in research studies and may have application in the clinical setting. Physical activity and energy
expenditure can be monitored by several objective methods, including pedometers to measure number of steps and accelerometers to measure counts of movement. The first large, population-based assessment of movement by accelerometers was completed in the Third National Health and Nutrition Examination Survey (NANES III) and demonstrated a sharp decline in activity across increasing age group [15]. Participants in the NHANES examination were asked to wear an accelerometer over the right hip for seven days; the accelerometer stored counts of each vertical movement over one minute epochs for up to 1 week. These count data were then translated into summary measures of physical activity. This study found that only 2.5% of older men and 2.3% of older women achieved 30 minutes of moderate or greater activity level on at least five days a week. Men were generally more active than women. However, after age 60 there was essentially no daily vigorous activity in older adults and an average of only 6–10 minutes of moderate activity daily. Thus, while subjective data suggest many adults meet recommended activity guidelines, the objective assessment of activity from accelerometers indicates that it is very rare that older adults engage in significant amounts of moderate physical activity.
Physical Activity and Fall Risk Among Older Men: Observational Studies The relation between physical activity and fall risk is somewhat paradoxical: older adults with low activity levels have been shown to have increased fall risk [16–18] and exercise interventions tend to reduce the risk of falling [19–21]. However, increased physical activity level may also increase the time at risk for falls, due to increased movement, ambulation, challenges to balance demands and changes in a person’s center of gravity [20, 22]. A systematic review published by Gregg and colleagues in 2000 noted studies that observed significant reductions in fall risk usually compared older adults who had any activity to those who were sedentary [16, 18] and no dose-response relationship was observed. Additionally, the association between low activity and fall risk was attenuated after adjustment for mobility limitations [23]. This implies that the associations between low physical activity and increased fall risk may be due to physical limitations rather than low activity per se. More recent observational studies that analyzed the influence of physical activity level on fall risk yielded mixed results. For example, in the US cohort of Osteoporotic Fractures in Men (MrOS) Study, a study of nearly 6000 men aged 65 years and older, physical activity was assessed using the PASE questionnaire [24]. Activity was analyzed as total activity level and as separate components: leisure activity, occupational activity and household activity. Falls were assessed prospectively. Overall, men in the highest quartile of total activity level were about 14% more likely (odds ratio, 1.14; 95% CI: 1.03, 1.25) to fall during follow
C h a p t e r 3 0 Physical activity, physical function and fall and fracture risk in older men l
up than men in the lowest total activity quartile. However, there was no association between leisure activity or occupational activity and fall risk. Only household activity (which includes light/heavy housework, home repair, lawn care/gardening and caregiver responsibilities) was associated with fall risk. Men in the highest quartile of household activity level had the highest risk of falls. The authors speculated that household activity, and not leisure activity, was associated with increased fall risk because some household activities, such as cleaning rain gutters or shoveling snow, are in some sense ‘mandatory’ and cannot be avoided in the same manner as voluntary exercise. Leisure activity, on the other hand, can be avoided if an older man is concerned about his fall risk. Another report from the Swedish MrOS cohort, a study of about 3000 men age 65 and older, showed that sedentary men (as assessed by a simple questionnaire) were more likely to have reported a history of falling compared to men with an active lifestyle [17]. Due to the cross-sectional nature of this report, it is not clear if men had first fallen and then reduced their activity levels, or if lower activity levels subsequently lead to increased falls. The cross-sectional nature of this report may be the reason for the apparently discrepant findings between the US and Swedish studies. Finally, a study of well-functioning older adults aged 70–80 years participating in the Health, Aging and Body Composition Study (Health ABC) found no cross-sectional association between history of falling and physical activity level [25]. As with previous findings reported in the Gregg review [20], these newer studies with discrepant results have used different methods to quantify physical activity and different methods for assessing falls. When falls have been analyzed prospectively and the compartments of activity consider separately, only increased household activity level (rather than leisure activity or occupational activity) has been associated with increased fall risk.
Physical Activity and Fall Risk in Older Men: Randomized Trials Given the discrepancies found in the observational studies and the limitations of self-reported information, data from randomized trials are needed to determine the causal association between physical activity and fall risk. As summarized by Gregg et al, a meta-analysis of randomized controlled trials in the Frailty and Injuries: Cooperative Studies of Intervention Techniques (FICSIT) program demonstrated that the general exercise resulted in a 10% reduction in the risk of falls, while balance training resulted in a 17% reduction in falls risk [20, 21]. Two more recent meta-analyses on fall interventions have been published. Both Gillespie and colleagues [26] and Chang and colleagues [27] agree that multifactorial falls intervention programs are effective at reducing the risk of falling. However, these reports have differing results for exercise interventions [28]: Chang et al report that exercise interventions (both individually
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targeted programs and group programs) reduce overall fall risk by about 20% (OR: 0.80, 95% CI: 0.66, 0.98). On the other hand, Gillespie et al suggest that only individualized, home-based exercise interventions are effective in reducing fall risk (OR: 0.86, 95% CI: 0.75, 0.99). In the Gillespie analysis, group-based programs were not deemed effective. Overall, these meta-analyses support the idea that individualized exercise interventions effectively reduce fall risk in older adults by about 15%. At the individual level, this is a relatively small risk reduction. However, given the large number of older individuals who fall, a small reduction in fall risk may have important public health implications. Other more recent trials that were not included in either the Gillepsie or Chang meta-analyses continue to provide equivocal results: a study that compared a pragmatic intervention program (which included home exercise, group exercise, walking exercise or self-care exercise) versus routine care found that the intervention had no effect on fall rates [29]. Another study that compared moderate intensity group exercise programs to a control program found that the exercise intervention was effective at reducing fall risk in pre-frail, but not frail, individuals [30]. In yet another intervention study, group exercise programs were shown to reduce fall risk by about 20% [31]. Given the evidence, it appears that exercise interventions generally reduce fall risk and that targeted, multifactorial programs may be the most effective. However, some randomized trials and meta-analyses have indicated that certain types of exercise interventions (e.g. group exercise) may not be useful in reducing fall risk. It is possible that exercise interventions are most effective in certain subpopulations, such as the pre-frail or inactive. Further research in this area is needed to refine recommendations for the types of activity programs that are effective at reducing fall risk.
Physical Activity and Fracture Risk Exercise interventions have been demonstrated to increase bone mineral density (BMD) in older adults. A meta-analysis of exercise interventions in men conducted by Kelly and colleagues examined the BMD of skeletal sites that were loaded during the exercise intervention [32]. The exercise inventions resulted in increased BMD at the specific skeletal sites by about 2.1% in the intervention groups, compared to a loss of 0.5% in the control groups. However, the difference in BMD between the intervention and control groups is fairly small (2.6%) and it is unclear if such differences in BMD would translate into clinically significant differences in fracture risk. However, in another randomized trial not included in the meta-analysis, a 6 month exercise regimen did not alter BMD in older men but did increase BMD in older women [33]. There was a small number of participants in this study (51 men) and a small difference in BMD may not have been detected. Thus, while exercise appears to improve BMD in older men at skeletal sites that
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are loaded during exercise, the resulting increase in BMD is small and may not result in reduced fracture risk. There are several prospective observational studies that have examined the association between physical activity and risk of hip fracture. As summarized in a meta-analysis by Moayyeri, men who engage in moderate to vigorous activity are about 50% less likely to have a hip fracture than those with lower activity levels (relative risk: 0.52, 95% CI: 0.44, 0.69) [34]. The definitions of activity level varied widely by study, however, so it remains unclear which specific subtype of activity (e.g. vigorous activity versus moderate activity; weight bearing versus not weight bearing) is most strongly associated with hip fracture risk. Additionally, these results have not been confirmed by a randomized controlled trial. However, it is unlikely that such a trial would be completed, as the sample size to detect a 20–30% reduction in hip fracture risk over 5 years in European men was estimated to range between 14 696 and 34 998 individuals per treatment group [34]. There have been very few observational analyses of physical activity and risk of non-spine fracture in older men. A large study of British men and women aged 20–89 years had two important findings [35]. First, bicycling in particular increased fracture risk for men and women of all ages: men who reported bicycling more than 5 hours per week had about a twofold increased risk of fracture compared to men who did not report any bicycling. Thus, the increased risk of injury from bicycling appeared to outweigh any benefit to bone density that may be associated with this exercise. This is not surprising given that bicycling is not a weight bearing exercise and that bicycling does not appear to improve bone mineral density as compared to other load bearing exercise [36]. The second finding from the British study was that increased physical activity was associated with increased fracture risk, but only in those fractures not caused by a fall (such as those from trauma). The association between greater activity and fracture risk was generally not present when fractures due to a fall were analyzed separately. Although the analyses in this report were not stratified by age, the results suggest that the association between physical activity and fracture risk may differ by age and frailty status. Results from the US cohort of the MrOS study suggest that among men aged 65 years and older, low physical activity level as measured by the PASE questionnaire is associated with an increased risk of non-spine fractures after accounting for age [37]. Men in the lowest quartile of activity level had a 42% increased risk of non-spine fracture compared to men in the third quartile; no association was seen for quartiles 2 and 4. However, the association was no longer significant after adjustment for confounding factors such as falling history, age, bone mineral density, depression and balance; the types of activity (leisure, household, occupational) were not analyzed separately. Additionally, among 1500 older men participating in the Dubbo Osteoporosis study, higher physical activity levels were protective against
osteoporotic fracture, but this association was not independent of quadriceps strength, sway and bone mineral density [38]. Finally, in a study of middle-aged Norwegian men, those most physically active had a reduced risk of a ‘lowenergetic fracture in the weight bearing skeleton’ compared to men who were sedentary. No association was seen for fractures in the areas of the skeleton that were deemed nonweight bearing [39]. In summary, higher levels of physical activity appear to be modestly protective against non-spine fracture risk, but this association tended to be attenuated or explained by confounding or mediating factors. There are only a handful of analyses of the association between physical activity and risk of vertebral fractures in older men. A report from the European Vertebral Osteoporosis Study (EVOS) examined the relationship between lifetime and current activity levels with prevalent vertebral fractures in a cohort of more than 14 000 men and women aged 50–79 years [40]. This study found that very heavy activity levels during young adulthood (15–25 years), adulthood (25–50 years) and mid-life (age 50 years) were associated with a 50–70% increased risk of vertebral fracture in men, but not in women. Regular walking reduced vertebral fracture risk in men, but not in women. In another report, physical activity was not associated increased long-term risk of vertebral fractures in men participating in the Framingham study [41]. This study was small in size (704 men and women participated) and would not have been able to detect modest associations. Thus, the associations between physical activity and vertebral fracture risk have not been extensively studied.
Physical function and performance Physical activity requires voluntarily engaging in movement of the limbs. Forces generated by muscles during movement are integral to physical functioning and therefore to the successful conduct of physical activities. Physical function and performance as defined for this chapter includes both subjective and objective assessment of physical ability. Subjective assessments of ability to complete common daily tasks, such as ability to walk 1–2 blocks or climb stairs, are commonly assessed in research studies. Additionally, objective measurement of performance in standardized tasks is increasingly assessed in clinical settings; these measurements include muscle strength, walking pace over a set distance or the ability to rise from a chair. In this section, we will describe the assessment of physical function; the changes in physical function with age; and the association between physical function and falls and fractures in older men.
Assessment of Physical Function Many tools are available to assess physical function in both epidemiological and clinical settings. Subjective assessment
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of performance is commonly evaluated by querying individuals about activities of daily living (ADLs) and instrumental activities of daily living (IADLs). ADLs generally refer to tasks related to daily care. The most common ADLs included in surveys are bathing, dressing, transferring (moving from a bed to a chair), mobility (walking a short distance or climbing stairs), using the toilet and eating. IADLs are more complex tasks. Commonly assessed IADLs include managing money, preparing meals, housework, using the telephone, managing medications and shopping for groceries or personal items. Numerous questionnaires have been used to assess limitations in the ability to complete ADLs and IADLs. Generally, the survey instruments differentiate inability to complete a task due to health reasons from not completing a task for other reasons not related to a person’s health. Some of the most commonly used instruments to assess IADL and ADLS are the Katz [42], Rosow-Breslau Functional Health Scale [43] and ADL/IADL items developed by Nagi [44]. However, there are few reports that study the association between fracture risk and ADL/IADL status. One of the more widely used instruments to assess physical function is the Short Physical Performance Battery (SPPB) developed by Guralink and colleagues [45, 46]. The SPPB includes three performance tests: walking pace (over 4 meters); repeated chair stands; and a balance test (tandem and semi-tandem stand). A score for each test is assigned and then summed; scores for the SPPB range from 0 (unable to complete any of the tests) to 12 (best performance on all three tests). The SPBB is predictive of mortality, disability and hospitalization in older adults [45, 47]. Other exams that measure physical function include: the timed up and go test [48]; the narrow walk test [49]; and the long distance corridor walk [50]. The timed up and go test measures the time needed to arise from a chair, walk 3 meters and return and sit in the chair. The narrow walk test is a measure of dynamic balance and assesses the ability to walk within a 20 cm path over 6 meters. The long distance corridor walk (LDCW) measures the ability and time to complete a 400 m walk; poor performance on the LDCW is associated with increased risk of mortality in older adults [50]. Objective measurement of physical function is very common in research studies but less common in clinical settings. The SPPB has also been developed to be used in a clinical setting; a score sheet and wall chart for administering the SPPB are available from the National Institute on Aging website (http://www.grc.nia.nih. gov/branches/ledb/sppb/index.htm). Upper and lower extremity strength and power are also commonly measured in research settings. Upper extremity strength is usually quantified as isometric grip strength (where the arm is static as the muscle is contracting) as measured on a hand-held dynamometer. Isometric leg strength can be measured with portable dynamometers or more complex equipment, such as specialized chairs. Isokinetic leg strength (where the leg is moving at constant speed as the muscle is contracting) is also measured with specialized equipment. Leg power (the amount of work done per unit of time) has
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also been assessed in research settings, using devices such as the Nottingham Power Rig [51, 52]. The use of a hand-held dynamometer may be practical in a general clinical setting, provided age-specific cut-points that define ‘weakness’ are available. However, most measures of lower extremity power or strength are cannot be used practically in the general clinical environment. Clinically, more global measures of function, such as the ability to rise from a chair, may be more useful than direct measures of strength.
Changes in Muscle Strength and Power in Older Age A hallmark of the aging process is a decline in physical ability and muscle strength. This section will describe changes in upper and lower extremity strength and power and the relation of these changes to changes in muscle mass. Given the limited availability of data on the changes in objective measures of physical performance, such as walking speed and chair stands, changes in these factors will not be reviewed in this chapter.
Upper Extremity Strength Knowledge about variation in muscle strength throughout the adult lifespan comes primarily from measurements of hand grip strength obtained in large cohort studies. Crosssectional data demonstrate consistently that grip strength is, on average, lower among older compared with younger men [53, 54]. Two cohorts that included community dwelling men aged 20 to 100 years, the Baltimore Longitudinal Study of Aging (BLSA) and the InCHIANTI study, demonstrated that average grip strength is greatest among the youngest men, which was at ages 20–29 in InCHIANTI and at ages 30–39 in the BLSA. From age 40 onward in InCHIANTI and age 50 onward in the BLSA, mean grip strength was successively lower for each decade of age, such that strength among men in their 80s was about 40% that of men in their 30s. In the BLSA cohort, upper extremity muscle power followed the same age-specific patterns as grip strength [55]. Others have demonstrated the same pattern, successively lower average grip according to age decade or 5-year age groups regardless of the age ranges studied [56–59]. Prospective studies with repeat grip strength assessments provide information about change in grip strength with aging [53, 56, 57, 59–61]. Three important observations emerge from these data. First, grip strength declines on average with aging and the decline begins at a relatively young age. In the BLSA, during follow up that averaged 9 years, men initially in their 20s or 30s gained strength. In contrast, men initially age 40 or older, on average, lost grip strength during follow up [53, 59]. The annualized rate of decline has been estimated to be about 1 kg/year [56, 59]. Loss of strength occurred in both extensor and flexor muscle groups [60, 61]. Second, the rate of grip strength loss increases with
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increasing age. In the BLSA, for men ages 40–49, 50–59, 60–69 and 70–79 annualized absolute changes in kg/year were, respectively, 0.31, 0.65, 0.78 and 1.27 [53]. Upper extremity muscle power in this cohort also declined by similar magnitudes [55]. In a cohort of men from Hawaii who were aged 45–68 at baseline, annualized percentage grip strength change ranged from 0.9% per year among men initially aged 45–49 to 1.5% among those aged 65–69 during follow-up visits that spanned 27 years [59]. Among older men, annualized percentage changes of 3% per year have been reported in cohorts with baseline age ranging from 50 to 84 years (average: 66 7) [57] and 65 years (average 74 6 years) [56]. Third, there is considerable variability in grip strength change. Although grip strength on average declines with aging, substantial proportions of men experience no change or gain strength. Rantanen et al reported that 13% of men aged 45–68 had declines of 0.5% per year [59] and Kallman et al reported that, in the BLSA, 29% of men aged 40–59 years and 15% of those age 60 years did not lose grip strength [53].
Lower Extremity Strength and Power Few studies have evaluated strength or power of lower extremity muscles. Like hand grip strength, isokinetic knee strength (Newtons per meter [N m]) is, on average, lower among older compared with younger men [62, 63]. From age 40 onward in the BLSA, mean knee strength was successively lower for each decade of age, such that strength among men in their 80s was about 50% that of men in their 30s [62, 63]. Longitudinally, knee extensor strength declined by 3% to 4% annually during follow up of about 3 years among white and black men aged 70–79 years at initial
examination in the Health Aging and Body Composition (HABC) cohort [64].
Relation of Decline in Muscle Strength to Decline in Muscle Mass Like muscle strength, lean muscle mass declines with age. Among older men, estimates of annualized percentage change in whole body lean mass are somewhat discrepant. Among men aged 45–78 years, the decline was estimated at 1.3% per year based on urinary creatine excretion [61]. Among men in their 70s, estimated declines in total body lean mass from dual energy x-ray absorptiometry (DXA) have been smaller, ranging from 0.7% per year [65, 66] to 0.3% per year [67]. Declines in leg lean mass measured with DXA, which reflect changes occurring primarily in skeletal muscle, were observed to be about 1% per year, a rate slightly greater than that for whole body lean mass [64]. Thus, rates of change in muscle strength as described above are about three times greater than rates of change in muscle mass (Figure 30.1). Early cross-sectional studies indicated a strong association between lean body mass and muscle strength [63, 68]. However, available data from large prospective cohort studies indicate that the relation between actual change in muscle mass with aging and loss of muscle strength is weak. Estimates of change in total body lean mass based on urinary creatine excretion were unrelated with change in hand grip strength ( 0.002, P 5 0.05) [53] and were only weakly related to change in knee extensor strength ( 0.01, P 0.06) or knee flexor strength ( 0.40, P 0.05) [61]. Additionally, change in leg lean mass assessed with DXA was significantly associated change in knee extensor strength
2 Lean mass
Annual % change (%/year)
1
Knee strength
0
–1 –2 –3 Men
Women
–4 –5 (a)
(b)
(c)
White (d,e) Black (d,e)
(a)
(b)
(c)
White (d,e) Black (d,e)
Figure 30.1 Changes in lean mass and knee extension strength in older men and women. Data sources [61, 64–67]. Data Sources: (a) Gallagher et al, 200066; (b) Fantin et al, 200765; (c) Hughes et al, 200261; (d) Visser et al, 200367; (e) Goodpaster et al, 200664.
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( 8.31, P 0.01). Although both Hughes et al [61] and Goodpaster et al [64] reported statistically significant associations of change in lean mass and change in muscle strength, change in lean mass accounted for less than 5% of the variance in strength change. Moreover, although physical activity contributes to muscle mass and strength, accounting for either baseline or change in physical activity did not affect the associations between muscle mass and strength. Finally, as illustrated in Figure 30.1, aging men appear to lose a greater percent of knee strength per year compared to women. Thus, we may speculate that declines in physical performance or strength may be a more important risk factor for fracture in men than in women. However, this hypothesis has yet to be formally tested.
Physical Performance and Fall Risk in Older Men There are many reports that describe the association between poor physical performance and increased risk of falling and physical function measures are commonly included in fall risk prediction models [69, 70]. Weakness is commonly reported as a risk factor for falling. A meta-analysis by Moreland et al has shown that lower extremity weakness is associated with a 1.8-fold increased likelihood of any fall (95% CI: 1.3, 2.4) and a 3.1-fold increased likelihood of recurrent falls (95% CI: 1.9, 5.0) [71]. Upper extremity weakness was more modestly associated with falls: upper extremity weakness was associated with a 1.5-fold (95% CI: 1.0, 2.3) increased likelihood of any fall and a 1.4-fold (1.3, 1.6) increased likelihood of recurrent falls. The relationship between more complex performance traits, such as walking speed and ability to rise from a chair, and fall risk has also been assessed. Many studies have found no association between preferred walking speed and fall risk [24, 72–74]. One report indicated that faster walking speed was associated with increased risk of outdoor falls, while slower walking speed was associated with increased risk of indoor falls [75]. The discrepancy may be due to the types of activity undertaken at the time of the fall. Outdoor falls may be more likely to be associated with higher activity or exercise levels that increase time at risk of falling, while falling during indoor activity may be a marker for worse frailty status. Finally, Tinetti et al demonstrated that abnormalities in balance, such as increased sway and path deviation, rather than simple walking speed alone, are important in determining fall risk [76].
Physical Performance and Fracture Risk in Older Men Despite the association between fall risk and poor physical performance, there are relatively few reports of the association between fracture risk and poor physical performance. The association between poor physical performance and risk of hip fracture has been examined in the US cohort of
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the MrOS study [49]. Physical performance was assessed in 5902 men; 77 hip fractures occurred over an average of 5.3 years of follow up. Performance tests included grip strength, leg power (from the Nottingham Power Rig), narrow walk test, walking speed (over 6 m) and a repeat chair stands test. Poor performance was associated with increased hip fracture risk. In particular, men who were unable to stand from a chair without the use of the arms were much more likely to have a hip fracture compared to men who were able to complete the repeat chair stands in the fastest quartile (multivariate hazard ratio, 8.2; 95% CI: 2.7, 25.0). Additionally, those men with the worst performance (weakest/ slowest quartile or unable) on three or more exams had an increased risk of hip fracture and the majority of the hip fractures (n 49, 64% of fractures) occurred in men with poor performance on at least three exams. These associations were independent of potential confounding factors including physical activity level and age. Therefore, poor physical performance appears to increase the risk of hip fracture and this association is independent of BMD. The inability to rise from a chair without the use of the arms is particularly predictive of fracture risk and such a measure could be easily completed in a clinical setting. Poor physical performance, specifically weak muscle strength, has been examined in a few studies as a risk factor for non-spine fractures. Ngyuen and colleagues found that weak quadriceps strength and increased body sway were independent predictors of non-spine fracture for men participating in the Dubbo Osteoporosis study [38]. Low grip strength was associated with increased risk of fragility fractures (vertebrae, proximal femur, proximal humerus, distal forearm, ramii of the pelvis and the tibia condyle) among 654 older Swedish men [77]. A report from the Longitudinal Aging Study Amsterdam (LASA) found that among older men and women, self-reported functional limitations, low physical performance test score and low grip strength were associated with an increased risk of selfreported fractures and the association was similar among both genders. Another report from the MrOS study found that inability to complete the narrow walk test was associated with a 70% increased risk of non-spine fracture in multivariate models (hazard ratio: 1.7, 95% CI: 1.2, 2.3) [37]. Other performance measures were not independently associated with non-spine fracture in this analysis. Overall, poor physical performance, including weak quadriceps or grip strength and poor balance, tends to be independently associated with non-spine fracture risk. There are very few analyses of the association between physical performance and vertebral fracture. A crosssectional analysis of 158 men found that lower grip strength was associated with prevalence of vertebral fracture; only weak muscle strength, marital status and body weight were associated with vertebral fracture in this study [78]. However, it is unclear if the lower muscle strength occurred first and then predisposed the individual to a vertebral fracture or if the
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vertebral fracture led to reduced function that then resulted in poor muscle strength. More research on the association between physical performance and vertebral fracture risk in men is needed.
References 1. M.E. Nelson, W.J. Rejeski, S.N. Blair, et al., Physical activity and public health in older adults: recommendation from the American College of Sports Medicine and the American Heart Association, Med. Sci. Sports Exerc. 39 (8) (2007) 1435–1445. 2. H.L. Taylor, D.R. Jacobs Jr, B. Schucker, J. Knudsen, A.S. Leon, G. Debacker, A questionnaire for the assessment of leisure time physical activities, J. Chronic. Dis. 31 (12) (1978) 741–755. 3. S.N. Blair, W.L. Haskell, P. Ho, et al., Assessment of habitual physical activity by a seven-day recall in a community survey and controlled experiments, Am. J. Epidemiol. 122 (5) (1985) 794–804. 4. J.F. Sallis, W.L. Haskell, P.D. Wood, et al., Physical activity assessment methodology in the Five-City Project, Am. J. Epidemiol. 121 (1) (1985) 91–106. 5. N.D. Harada, V. Chiu, A.C. King, A.L. Stewart, An evaluation of three self-report physical activity instruments for older adults, Med. Sci. Sports. Exerc. 33 (6) (2001) 962–970. 6. M. Bonnefoy, S. Normand, C. Pachiaudi, J.R. Lacour, M. Laville, T. Kostka, Simultaneous validation of ten physical activity questionnaires in older men: a doubly labeled water study, J. Am. Geriatr. Soc. 49 (1) (2001) 28–35. 7. A.L. Stewart, K.M. Mills, A.C. King, W.L. Haskell, D. Gillis, Ritter P.L. CHAMPS physical activity questionnaire for older adults: outcomes for interventions, Med. Sci. Sports. Exerc. 33 (7) (2001) 1126–1141. 8. L. Dipietro, C.J. Caspersen, A.M. Ostfeld, E.R. Nadel, A survey for assessing physical activity among older adults, Med. Sci. Sports. Exerc. 25 (5) (1993) 628–642. 9. R.A. Washburn, K.W. Smith, A.M. Jette, C.A. Janney, The Physical Activity Scale for the Elderly (PASE): development and evaluation., J. Clin. Epidemiol. 46 (1993) 153–162. 10. F.C. Bijnen, E.J. Feskens, C.J. Caspersen, W.L. Mosterd, D. Kromhout, Age, period, and cohort effects on physical activity among elderly men during 10 years of follow-up: the Zutphen Elderly Study, J. Gerontol. A Biol. Sci. Med. Sci. 53 (3) (1998) M235–M241. 11. C.J. Caspersen, M.A. Pereira, K.M. Curran, Changes in physical activity patterns in the United States, by sex and crosssectional age, Med. Sci. Sports Exerc. 32 (9) (2000) 1601–1609. 12. H.M. Dallosso, K. Morgan, E.J. Bassey, S.B. Ebrahim, P.H. Fentem, T.H. Arie, Levels of customary physical activity among the old and the very old living at home, J. Epidemiol. Commun. Hlth. 42 (2) (1988) 121–127. 13. A.H. Mokdad, W.H. Giles, B.A. Bowman, et al., Changes in health behaviors among older Americans, 1990 to 2000, Pub. Hlth. Rep. 119 (3) (2004) 356–361. 14. J.F. Sallis, B.E. Saelens, Assessment of physical activity by self-report: status, limitations, and future directions, Res. Q. Exerc. Sport. 71 (2 Suppl) (2000) S1–S14. 15. R.P. Troiano, D. Berrigan, K.W. Dodd, L.C. Masse, T. Tilert, M. McDowell, Physical activity in the United States
16.
17.
18.
19.
20.
21.
22.
23.
24.
25.
26.
27.
28. 29.
30.
easured by accelerometer, Med. Sci. Sports Exerc. 40 (1) m (2008) 181–188. J.L. O’Loughlin, Y. Robitaille, J.F. Boivin, S. Suissa, Incidence of and risk factors for falls and injurious falls among the community-dwelling elderly, Am. J. Epidemiol. 137 (3) (1993) 342–354. E.L. Ribom, E. Grundberg, H. Mallmin, et al., Estimation of physical performance and measurements of habitual physical activity may capture men with high risk to fall – data from the Mr Os Sweden cohort, Arch. Gerontol. Geriatr. 1 (2008 Nov 3). M.E. Tinetti, M. Speechley, S.F. Ginter, Risk factors for falls among elderly persons living in the community, N. Engl. J. Med. 319 (26) (1988) 1701–1777. D.M. Buchner, M.E. Cress, B.J. de Lateur, et al., The effect of strength and endurance training on gait, balance, fall risk, and health services use in community-living older adults, J. Gerontol. A Biol. Sci. Med. Sci. 52 (1997) M218–M224. E.W. Gregg, M.A. Pereira, C.J. Caspersen, Physical activity, falls, and fractures among older adults: a review of the epidemiologic evidence, J. Am. Geriatr. Soc. 48 (8) (2000) 883–893. M.A. Province, E.C. Hadley, M.C. Hornbrook, et al., The effects of exercise on falls in elderly patients. A preplanned meta-analysis of the FICSIT Trials. Frailty and Injuries: Cooperative Studies of Intervention Techniques, J. Am. Med. Assoc. 273 (17) (1995) 1341–1347. M. Speechley, M. Tinetti, Falls and injuries in frail and vigorous community elderly persons, J Am Geriatr Soc 39 (1991) 46–52. W.C. Graafmans, M.E. Ooms, H.M. Hofstee, P.D. Bezemer, L.M. Bouter, P. Lips, Falls in the elderly: a prospective study of risk factors and risk profiles, Am J Epidemiol 143 (11) (1996) 1129–1136. B.K. Chan, L.M. Marshall, K.M. Winters, K.A. Faulkner, A.V. Schwartz, E.S. Orwoll, Incident fall risk and physical activity and physical performance among older men: the Osteoporotic Fractures in Men Study, Am. J. Epidemiol. 165 (6) (2007) 696–703. N. de Rekeneire, M. Visser, R. Peila, et al., Is a fall just a fall: correlates of falling in healthy older persons. The Health, Aging and Body Composition Study, J. Am. Geriatr. Soc. 51 (6) (2003) 841–846. L.D. Gillespie, W.J. Gillespie, M.C. Robertson, S.E. Lamb, R.G. Cumming, B.H. Rowe, Interventions for preventing falls in elderly people, Cochrane Database Syst. Rev. (4) (2003) CD000340. J.T. Chang, S.C. Morton, L.Z. Rubenstein, et al., Interventions for the prevention of falls in older adults: systematic review and meta-analysis of randomised clinical trials, Br. Med. J. 328 (7441) (2004) 680. L. Gillespie, Preventing falls in elderly people, Br. Med. J. 328 (7441) (2004) 653–654. H. Luukinen, S. Lehtola, J. Jokelainen, R. Vaananen-Sainio, S. Lotvonen, P. Koistinen, Pragmatic exercise-oriented prevention of falls among the elderly: a population-based, randomized, controlled trial, Prev. Med. 44 (3) (2007) 265–271. M.J. Faber, R.J. Bosscher, A.P.M.J. Chin, P.C. van Wieringen, Effects of exercise programs on falls and mobility in frail and pre-frail older adults: a multicenter randomized controlled trial, Arch. Phys. Med. Rehabil. 87 (7) (2006) 885–896.
C h a p t e r 3 0 Physical activity, physical function and fall and fracture risk in older men l
31. S.R. Lord, S. Castell, J. Corcoran, et al., The effect of group exercise on physical functioning and falls in frail older people living in retirement villages: a randomized, controlled trial, J. Am. Geriatr. Soc. 51 (12) (2003) 1685–1692. 32. G.A. Kelley, K.S. Kelley, Z.V. Tran, Exercise and bone mineral density in men: a meta-analysis, J. Appl. Physiol. 88 (5) (2000) 1730–1736. 33. K.J. Stewart, A.C. Bacher, P.S. Hees, M. Tayback, P. Ouyang, S. Jan de Beur, Exercise effects on bone mineral density relationships to changes in fitness and fatness, Am. J. Prev. Med. 28 (5) (2005) 453–460. 34. A. Moayyeri, The association between physical activity and osteoporotic fractures: a review of the evidence and implications for future research, Ann. Epidemiol. 18 (11) (2008) 827–835. 35. P.N. Appleby, N.E. Allen, A.W. Roddam, T.J. Key, Physical activity and fracture risk: a prospective study of 1898 incident fractures among 34,696 British men and women, J. Bone Miner. Metab. 26 (2) (2008) 191–198. 36. R.S. Rector, R. Rogers, M. Ruebel, P.S. Hinton, Participation in road cycling vs running is associated with lower bone mineral density in men, Metabolism 57 (2) (2008) 226–232. 37. C.E. Lewis, S.K. Ewing, B.C. Taylor, et al., Predictors of non-spine fracture in elderly men: the MrOS study, J. Bone. Miner. Res. 22 (2) (2007) 211–219. 38. T.V. Nguyen, J.A. Eisman, P.J. Kelly, P.N. Sambrook, Risk factors for osteoporotic fractures in elderly men, Am. J. Epidemiol. 144 (3) (1996) 258–261. 39. R.M. Joakimsen, V. Fonnebo, J.H. Magnus, J. Stormer, A. Tollan, A.J. Sogaard, The Tromso Study: physical activity and the incidence of fractures in a middle-aged population, J. Bone Miner. Res. 13 (7) (1998) 1149–1157. 40. A.J. Silman, T.W. O’Neill, C. Cooper, J. Kanis, D. Felsenberg, Influence of physical activity on vertebral deformity in men and women: results from the European Vertebral Osteoporosis Study, J. Bone Miner. Res. 12 (5) (1997) 813–819. 41. E.J. Samelson, M.T. Hannan, Y. Zhang, H.K. Genant, D.T. Felson, D.P. Kiel, Incidence and risk factors for vertebral fracture in women and men: 25-year follow-up results from the population-based Framingham study, J. Bone Miner. Res. 21 (8) (2006) 1207–1214. 42. S. Katz, T.D. Downs, H.R. Cash, R.C. Grotz, Progress in development of the index of ADL, Gerontologist 10 (1) (1970) 20–30. 43. I. Rosow, N.A Breslau, Guttman health scale for the aged, J. Gerontol. 21 (4) (1966) 556–559. 44. S.Z. Nagi, An epidemiology of disability among adults in the United States, Milbank Mem. Fund Q. Health Soc. 54 (4) (1976) 439–467. 45. J.M. Guralnik, L. Ferrucci, E.M. Simonsick, M.E. Salive, R.B. Wallace, Lower-extremity function in persons over the age of 70 years as a predictor of subsequent disability, N. Engl. J. Med. 332 (9) (1995) 556–561. 46. J.M. Guralnik, E.M. Simonsick, L. Ferrucci, et al., A short physical performance battery assessing lower extremity function: association with self-reported disability and prediction of mortality and nursing home admission, J.Gerontol. 49 (2) (1994) M85–M94. 47. B.W. Penninx, L. Ferrucci, S.G. Leveille, T. Rantanen, M. Pahor, J.M. Guralnik, Lower extremity performance in
48.
49.
50.
51.
52.
53.
54.
55.
56.
57.
58.
59.
60.
61.
62.
63.
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nondisabled older persons as a predictor of subsequent hospitalization., J. Gerontol. A Biol. Sci. Med. Sci. 55 (11) (2000) M691–M697. D. Podsiadlo, S. Richardson, The timed ‘Up & Go’: a test of basic functional mobility for frail elderly persons, J. Am. Geriatr. Soc. 39 (2) (1991) 142–148. P.M. Cawthon, R.L. Fullman, L. Marshall, et al., Physical performance and risk of hip fractures in older men, J. Bone Miner. Res. 23 (7) (2008) 1037–1044. A.B. Newman, E.M. Simonsick, B.L. Naydeck, et al., Association of long-distance corridor walk performance with mortality, cardiovascular disease, mobility limitation, and disability, J. Am. Med. Assoc. 295 (17) (2006) 2018–2026. E.J. Bassey, M.A. Fiatarone, E.F. O’Neill, M. Kelly, W.J. Evans, L.A. Lipsitz, Leg extensor power and functional performance in very old men and women, Clin. Sci. (Lond.) 82 (3) (1992) 321–327. E.J. Bassey, A.H. Short, A new method for measuring power output in a single leg extension: feasibility, reliability and validity, Eur. J. Appl. Physiol. Occup. Physiol. 60 (5) (1990) 385–390. D.A. Kallman, C.C. Plato, J.D. Tobin, The role of muscle loss in the age-related decline of grip strength: cross-sectional and longitudinal perspectives, J. Gerontol. 45 (3) (1990) M82–M88. F. Lauretani, C.R. Russo, S. Bandinelli, et al., Age-associated changes in skeletal muscles and their effect on mobility: an operational diagnosis of sarcopenia, J. Appl. Physiol. 95 (5) (2003) 1851–1860. E.J. Metter, R. Conwit, J. Tobin, J.L. Fozard, Age-associated loss of power and strength in the upper extremities in women and men, J. Gerontol. A Biol. Sci. Med. Sci. 52 (5) (1997) B267–B276. E.J. Bassey, U.J. Harries, Normal values for handgrip strength in 920 men and women aged over 65 years, and longitudinal changes over 4 years in 620 survivors., Clin. Sci. (Lond) 84 (3) (1993) 331–337. K.Y. Forrest, J.M. Zmuda, J.A. Cauley, Patterns and determinants of muscle strength change with aging in older men, Aging Male 8 (3-4) (2005) 151–156. H. Frederiksen, J. Hjelmborg, J. Mortensen, M. McGue, J.W. Vaupel, K. Christensen, Age trajectories of grip strength: cross-sectional and longitudinal data among 8,342 Danes aged 46 to 102, Ann. Epidemiol. 16 (7) (2006) 554–562. T. Rantanen, K. Masaki, D. Foley, G. Izmirlian, L. White, J.M. Guralnik, Grip strength changes over 27 yr in JapaneseAmerican men, J. Appl. Physiol. 85 (6) (1998) 2047–2053. W.R. Frontera, V.A. Hughes, R.A. Fielding, M.A. Fiatarone, W.J. Evans, R. Roubenoff, Aging of skeletal muscle: a 12-yr longitudinal study, J. Appl. Physiol. 88 (4) (2000) 1321–1326. V.A. Hughes, W.R. Frontera, M. Wood, et al., Longitudinal muscle strength changes in older adults: influence of muscle mass, physical activity, and health, J. Gerontol. A Biol. Sci. Med. Sci. 56 (5) (2001) B209–B217. R.S. Lindle, E.J. Metter, N.A. Lynch, et al., Age and gender comparisons of muscle strength in 654 women and men aged 20–93 yr, J. Appl. Physiol. 83 (5) (1997) 1581–1587. N.A. Lynch, E.J. Metter, R.S. Lindle, et al., Muscle quality. I. Age-associated differences between arm and leg muscle groups, J. Appl. Physiol. 86 (1) (1999) 188–189.
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64. B.H. Goodpaster, S.W. Park, T.B. Harris, et al., The loss of skeletal muscle strength, mass, and quality in older adults: the health, aging and body composition study, J. Gerontol. A Biol. Sci. Med. Sci. 61 (10) (2006) 1059–1064. 65. F. Fantin, V. Di Francesco, G. Fontana, et al., Longitudinal body composition changes in old men and women: interrelationships with worsening disability, J. Gerontol. A Biol. Sci. Med. Sci. 62 (12) (2007) 1375–1381. 66. D. Gallagher, E. Ruts, M. Visser, et al., Weight stability masks sarcopenia in elderly men and women, Am. J. Physiol. Endocrinol. Metab. 279 (2) (2000) E366–E375. 67. M. Visser, M. Pahor, F. Tylavsky, et al., One- and two-year change in body composition as measured by DXA in a population-based cohort of older men and women, J. Appl. Physiol. 94 (6) (2003) 2368–2374. 68. R.L. Reed, L. Pearlmutter, K. Yochum, K.E. Meredith, A.D. Mooradian, The relationship between muscle mass and muscle strength in the elderly, J. Am. Geriatr. Soc. 39 (1991) 555–561. 69. S.R. Lord, R.D. Clark, Simple physiological and clinical tests for the accurate prediction of falling in older people., Gerontology 42 (4) (1996) 199–203. 70. P.A. Stalenhoef, J.P. Diederiks, J.A. Knottnerus, A.D. Kester, H.F. Crebolder, A risk model for the prediction of recurrent falls in community-dwelling elderly: a prospective cohort study, J. Clin. Epidemiol. 55 (11) (2002) 1088–1094.
71. J.D. Moreland, J.A. Richardson, C.H. Goldsmith, C.M. Clase, Muscle weakness and falls in older adults: a systematic review and meta-analysis, J. Am. Geriatr. Soc. 52 (7) (2004) 1121–1129. 72. J.M. Hausdorff, D.A. Rios, H.K. Edelberg, Gait variability and fall risk in community-living older adults: a 1-year prospective study, Arch. Phys. Med. Rehabil. 82 (8) (2001) 1050–1056. 73. M.C. Nevitt, S.R. Cummings, E.S. Hudes, Risk factors for injurious falls: a prospective study, J. Gerontol. 46 (1991) M164–M170. 74. M.C. Nevitt, S.R. Cummings, S. Kidd, D. Black, Risk factors for recurrent nonsyncopal falls: a prospective study. J. Am. Med. Assoc. 261 (1989) 2663–2668. 75. A. Bergland, G.B. Jarnlo, K. Laake, Predictors of falls in the elderly by location, Aging Clin. Exp. Res. 15 (1) (2003) 43–50. 76. M.E. Tinetti, M. Speechley, S.F. Ginter, Risk factors for falls among elderly persons living in the community, N. Engl. J. Med. 319 (1988) 1701–1777. 77. P. Gardsell, O. Johnell, B.E. Nilsson, The predictive value of forearm bone mineral content measurements in men, Bone 11 (4) (1990) 229–232. 78. C. Johansson, D. Mellstrom, K. Rosengren, A. Rundgren, A community-based population study of vertebral fractures in 85-year-old men and women, Age Ageing 23 (5) (1994) 388–392.
Chapter
31
Economic Impact of Osteoporotic Fractures (versus Women) Terence W. O’Neill arc Epidemiology Unit, University of Manchester, Manchester, UK
Background
osteoporosis [1, 2]. Furthermore, osteoporosis in men contributes substantially to overall health care costs, accounting for more hospitalizations and hospital bed days than other chronic diseases (Figure 31.1) [3, 4]. Study of the economic impact of osteoporosis in men is important. Knowledge of costs is important in helping policy makers plan health care and prioritizing areas for prevention. Cost studies may also help identify aspects of fracture management and care that may be a focus for service developments. A knowledge of the costs related to fracture is also key in helping evaluate the impact of interventions aimed at reducing fracture occurrence.
Osteoporosis is an important and increasing health problem. The clinical and public health impact is due to the associated fractures which result in substantial morbidity, mortality and health care costs. Health costs of osteoporosis have been more widely studied in women, however, there is an increasing literature that confirms osteoporosis in men poses a substantial economic impact. Current estimates of the costs of osteoporotic fractures in men aged 50 and over are $4.1 billion in the USA and €8.7 billion in Europe, which represents about 24% of the total costs of 160 000
151 152
140 000
Hospital days (n)
120 000 100 000
88 579
84 608
80 000 61 142
60 000
57 122
56 779
Diabetes
Heart failure
40 000 20 000 0
COPD
Osteoporosis
Stroke
Myocardial
Infarction
Figure 31.1 Hospital days for osteoporosis and other frequent diseases in Swiss men in the year 2000. (Reproduced from Lippuner et al. Epidemiology and direct medical costs of osteoporotic fractures in men and women in Switzerland. Osteoporos Int 2005;16:S8-S17 [3]). Osteoporosis in Men
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This chapter focuses on the economic impact of osteoporotic fractures in men and compares this, where data are available, with the impact in women. In the first part, the nature of the costs related to osteoporotic fractures incurred (including both medical and societal costs) are considered, methodological approaches to characterizing these costs are reviewed and the reasons why costs differ in men and women are discussed. The second part includes a review of cost studies that have been published from different regions and populations worldwide.
Cost of illness studies Cost of illness studies estimate the overall economic burden of disease in a defined population.
Definition of Costs Health costs related to osteoporotic fractures can be considered as direct and indirect. Direct Costs These are costs that can be considered to be related to the fracture event. They include costs related to medical and nonmedical goods and services. Direct medical costs are those which relate to inpatient, outpatient and primary care, including, for example, the cost of the hospital bed, the type of surgery/intervention, postoperative care, medications during care, the length of stay in the hospital, follow-up visits both to hospital and to primary care and the costs for investigations undertaken during or after admission. In addition, fractures are linked with personal suffering and impairment in quality of life, though these are difficult to quantify in monetary terms. Non-medical costs are those which relate primarily to social and nursing home care. Typically, costs can be disaggregated into discrete units and an average price assigned to each – the direct costs are then estimated by multiplying the average price per unit by the number of units consumed. These can then be aggregated across care to provide an estimate of the total direct cost. Indirect Costs These include the loss of productivity arising from being unable to work due to illness/death. These costs can be assessed by looking at losses in projected earnings – typically based on the amount of time away from work, though this does not account for loss of productivity of others who may be affected, including loss of earnings by informal carers. Because of higher employment levels, loss of productivity is likely to be greater in men than in women though, because most fractures occur in the elderly who are retired, those costs are generally not high.
Gender differences in economic impact The economic impact of osteoporosis and osteoporotic fractures in most developed countries is substantially greater in women than men largely because fractures are more frequent in women [5]. This is partly because the age-specific incidence of fracture is greater but also because women live longer. For example, while the age-adjusted incidence of hip fracture is approximately twice that in women as in men, because of their greater lifespan about 80% of fractures occur in women [6, 7]. In low risk populations, there is no female excess and the economic impact is likely similar in men and women [8]. Apart from a difference in the number of fractures, other reasons why costs may differ in men and women include differences in outcome (morbidity/mortality) and healthcare utilization. Most, though not all, studies suggest an increase in mortality following the major osteoporotic fractures [9, 10]. While mortality following hip fracture is greater in men than women, it is also greater in men without fracture and the extent to which hip fracture is linked with any excess mortality in men (compared to women) is uncertain [11]. In large studies, after adjustment for age, the difference in mortality following vertebral fracture in men and women is not marked [12]. Hospitalization represents a substantial component of health-care costs. However, the proportion of men and women with hip (100%), wrist (20%) and spine fracture (10%) who are admitted to hospital is broadly similar and unlikely to contribute significantly to cost differentials [13, 14]. Length of stay among those admitted to hospital varies by age and type of fracture, though is generally shorter in men than women [5, 14]. Long-term nursing home care represents a large burden of hip fracture costs, but male sex has not been identified as a significant predictor of prolonged nursing home residence following hip fracture [15]. Differences in direct costs may also contribute to differences in the economic impact of fracture. Again these vary by age and fracture type and in different settings. Unit costs of fractures of different types calculated in a recent US study are shown in Table 31.1 [2]. Indirect costs of fracture might be anticipated to be greater in men than women, however, in an elderly group, employment levels generally are low.
Methodologic approaches to defining cost of illness Total Cost Economic costs of osteoporotic fracture can be estimated using either a ‘bottom up’ or ‘top down’ approach. In the ‘bottom up’ approach, cost data are obtained from cohort studies of patients with osteoporotic fracture – typically considered to be representative of a larger target
C h a p t e r 3 1 Economic Impact of Osteoporotic Fractures (versus Women)
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l
Table 31.1 Unit costs of fracture (US dollars) for white race, by sex and age group, total USA 2005 Women
Men
50–64 years old
65–74 years 75–84 years 85 years old old old
50–64 years 65–74 years old old
75–84 years 85 years old old
Inpatient LTC* Outpatient Total first year Total, years 2–5
31 548 10 810 4947 47 304 3367
25 935 12 246 4581 42 762 3672
24 536 12 171 4524 41 232 3915
23 147 14 391 4467 42 004 4106
24 339 9798 4268 38 405 3110
20 017 11 842 3977 35 836 3579
19 836 12 325 3974 36 135 3682
19 014 12 899 3959 35 872 3804
Vertebral Inpatient LTC* Outpatient Total first year Total, years 2–5
687 126 722 1535 344
658 116 720 1494 218
872 150 744 1766 368
779 143 743 1665 361
2515 459 894 3868 677
2441 438 891 3770 656
1042 183 755 1979 401
962 167 752 1,881 385
Wrist Inpatient LTC* Outpatient Total
413 92 448 953
359 80 401 840
745 167 739 1651
651 146 656 1453
1296 290 1220 2806
1172 263 1,112 2547
772 173 762 1706
916 205 888 2008
Pelvic Inpatient LTC* Outpatient Total first year Total, years 2–5
6809 5533 3291 15 633 840
6889 9151 3330 19 370 1560
6039 9249 2919 18 208 2076
6074 12 366 2936 21 376 2220
10 072 5303 4869 20 244 732
8139 7690 3935 19 764 1272
7831 10 729 3786 22 346 1864
7032 12 811 3399 23 243 2282
Other Inpatient LTC* Outpatient Total
2071 824 397 3292
2078 827 731 3636
2466 981 868 4315
3244 1291 1142 5676
1129 449 397 1975
1107 441 390 1937
2227 886 784 3896
2657 1057 935 4649
Hip
*
LTC Long-term care. Inpatient care includes inpatient facility, inpatient physician services and short-stay inpatient rehabilitation hospital care. Outpatient care includes home care, outpatient physician services, non-medical home care, outpatient hospital, and other outpatient care. LTC includes nursing home care (skilled nursing facilities, intermediate care facilities) and disability and dependency care. Reproduced from Burge et al. Incidence and economic burden of osteoporosis-related fractures in the United States, 2005–2025. J Bone Miner Res 2007;22:465-75 [2]
population – and based on the actual costs incurred by these patients. The costs are then applied to the number of fractures which occur in a given time period (typically one year) estimated from national statistics or epidemiologic studies relevant to the country/region of interest to provide an overall cost. In the ‘top down’ approach, health care costs are based on cost data aggregated over groups of individuals and obtained from health-care providers or previous cross-sectional surveys. These are then applied to the number of fractures which occur with the costs adjusted to take account of the fact that not all fractures are related to osteoporosis. This is done by applying weights or attribution probabilities, typically derived by consensus among expert clinicians asked to estimate the likelihood that a given fracture by age, sex and site is due to osteoporosis. There are advantages and disadvantages with each approach. Studies which use a top down approach are easier
to perform though do not take account of all the costs incurred, including those related to complications, and are reliant on the validity of the osteoporotic attribution probabilities. The bottom up approach allows more accurate assessment of the economic cost, though the analyses are time consuming and, depending on the local population studied, there may be difficulties in generalizing the data to a larger population.
Attributable Cost Individuals with osteoporosis are older and have higher comorbidity levels – factors which contribute to increased costs even in the absence of fracture. For example, health costs incurred by individuals in the year prior to their sustaining a fracture are greater than in control subjects who do not [16]. To determine costs specifically related to a
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fracture event, these additional costs should be taken into consideration. Such costs are important for health care evaluation studies of interventions to reduce fracture where typically the costs of the intervention are compared with those that are potentially averted by avoiding the fracture. There are several study designs that can be used to estimate these costs. One approach is to use patients as their own control group and to compare the costs following fracture with those incurred during a comparative period of time prior to the fracture. The difference can be considered to be the excess cost which is related to the fracture – and thus the potential costs which could be saved had the fracture not occurred. Information about costs can be obtained prospectively or retrospectively. Accrual of data prospectively is costly and requires large numbers of subjects at risk of fracture, in whom there is information about health care utilization, to be followed. Accrual of data retrospectively (after the fracture has occurred) is cheaper though may be subject to errors of recording/recall. For both approaches, patients will be older in the year following fracture and costs slightly greater as a consequence, however, it is possible to make allowance or adjustment for this in the analysis. An alternative approach is to compare costs in those who sustain a fracture with the costs in a control group without fracture over a comparative time frame. The difference can be considered to be the incremental cost due to fracture. An important methodological consideration is that the morbidity experience of the fracture group should be similar (other than the fracture event) to that of the control group. Those with fracture typically have underlying osteoporosis which is associated per se with an excess morbidity and mortality: unless this is adjusted for, either in the study design (choice of control group) or the analysis, the costs related to the fracture may be overestimated. A third approach which has been used to assess the costs attributable to fracture is to follow patients from the time they sustain a fracture and to identify only the fracture related resource use. With this approach, it is possible to include all relevant costs incurred, information about costs prior to the fracture is not required and because no control group is needed the sample size does not need to be large. The main limitation, however, is determining whether or not a particular resource is related to the fracture or not.
Economic impact of osteoporotic fractures Over the past decade, and since publication of the first edition [17], there has been a significant increase in the number of studies which have considered the economic impact of osteoporotic fractures separately in men and women. Most, though not all, have focused on costs of the major
osteoporotic fractures, with hip fracture (which accounts for the greatest costs) being the most widely studied. Com parison of health-care costs in men and women is possible within individual studies, but direct comparison between studies is difficult because of differences in health care systems, patterns of treatment, unit costs, fracture occurrence and differences in study design and type of cost information obtained. In the following section, data from some of the major published studies are reviewed.
Total Costs North America One of the first reports of the costs related to fractures in North America was based on a large study of selected musculoskeletal conditions in men and women [18]. The report, based on 1977 data, estimated that the number of hospital discharges in the USA with a first diagnosis of osteoporosis was 26 000, with men comprising 20% of cases. The cost of all fractures (direct and indirect costs) was estimated at $18.1 billion. All hip fractures, not just those occurring in the elderly, were estimated to cost $7.3 billion; 40% of all fracture related costs. The study highlighted the significant contribution of nursing home costs to the overall direct medical costs of hip fracture (56%). The data were updated in 1988 when the projected total cost of all fractures in the USA was estimated at $20.1 billion, with hip fractures comprising 43% of the overall fracture costs [19]. Neither study, however, separately considered men and women in detail. In the first cost of illness survey to consider costs separately in men and women, Ray et al [20] estimated the direct medical expenditure associated with osteoporotic fracture for all persons aged 45 years and older in the USA in 1995. The study was notable in that expenditures for many types of fracture were included, though detailed information was presented for hip, spine and forearm fracture only. National health-care survey data (from the National Center for Health Statistics and the Agency for Health Care Policy and Research) were used to estimate the health resource utilization and expenditures. Indirect costs were not estimated. Osteoporosis attribution probabilities, based on expert clinician review, were used to estimate the proportion of health service utilization and expenditures of fractures that resulted from osteoporosis [21]. Overall, the cost of health care expenditure attributable to osteoporotic fractures in 1995 was $13.8 billion, of which approximately 20% ($2.7 billion) was spent on men. By site of service, 62% was spent on inpatient care, 28% nursing home care and 9% in outpatient care. Hospital costs accounted for a greater proportion of the total costs in men than women (66% versus 62%), while nursing home costs were less (23% versus 29%). Costs for hip fracture comprised a larger proportion of the total economic burden of fracture in men than women (73% versus 61% respectively). Of the total expenditure on hip fractures, 22.6% was in men.
C h a p t e r 3 1 Economic Impact of Osteoporotic Fractures (versus Women) l
In a later study, Max et al reported on costs related to osteoporosis by considering hospital discharges with a primary diagnosis of osteoporosis/fracture in men and women in California in 1988 [22]. The study also looked at indirect costs. Most subjects studied had sustained a fracture; almost one half had a hip fracture. The mean cost for an osteoporosis related hospitalization was greater in women than in men ($6025 versus $4991). Total direct costs were $634 million in men and $1.8 billion in women – with nursing home care the largest component (64% and 57% in men and women respectively). As in earlier studies, hip fractures were the most costly osteoporotic fracture, though the proportion of total expenditure devoted to hip fracture in this study was similar (64%) in men and women. Indirect costs were relatively small, less than 1% of the total, reflecting the fact that most sufferers had retired and thus had no loss of productivity, and were greater in men than women ($2.6 million and $1.7 million respectively). The most recent data from North America evaluated health costs related to osteoporotic fractures in 2005 by age gender and fracture type, including hip, wrist and spine fracture [2]. Indirect costs were not assessed in the study, though these comprise a relatively small proportion of the total costs [22]. Key data sources were fracture incidence rates based on published epidemiological data and national discharge databases, mortality rates, US population estimates and unit costs for each fracture types. Unit costs were estimated by age and sex based on inpatient, outpatient and long-term care components; these varied by age, sex and fracture type and, for hip fracture, were greater in women than men, with the converse true for fractures of the wrist and spine (see Table 31.1). A Markov model was used to estimate both the incidence of fracture and related costs in the US population aged
50–99 years. In 2005, the model predicted more than 2 million incident fractures at a cost of $16.9 billion (Table 31.2). Men accounted for 29% of the fractures and 24% of the costs ($4.1 billion). The distribution of costs by fracture differed for men compared with women with a lower proportion of the total spent on hip fracture in men (67% versus 73%) and a higher proportion spent on vertebral (10% versus 5.2%) and other fractures (15% versus 13.7%) (see Table 31.2). Costs increased with age in both men and women with the bulk of the costs spent on those aged 65 years and older (81% and 89% in men and women, respectively). Using data from a population cohort study, Witkorowicz et al analyzed the one year cost of hip fracture in men and women aged 50 years and over in Canada [23]. Health-care resources assessed included initial hospitalization, rehospitalization, rehabilitation and chronic care, long-term care, home care and informal care. Costs were determined using a bottom up approach including the cost of the individual hip fracture procedure and the patient’s length of stay. Overall costs for women were, as in the recent US study [2], higher than men ($27 793 versus $22 700). However, after adjustment for age, residence status, survival (did or did not die within 12 months) and duration of follow up, the gender difference in the fracture cost disappeared, suggesting that the effect of gender, at least on the cost of hip fracture in this study, was due to these factors. Europe Hip Fracture There are data from a number of European countries which include cost estimates for fracture in men and women. Using a ‘top down’ approach, the total direct costs of hip
Table 31.2 Fracture costs by fracture type, age and gender, USA 2005 Costs per fracture type ($ millions) Stratum
389
Hip
Vertebral
Wrist
Pelvic
Other
Total
Age (years) 50–64 65–74 75–84 85 Total
263 360 991 1127 2741
109 133 101 71 414
115 22 10 10 158
34 27 61 66 188
269 125 129 95 619
790 667 1292 1370 4119
Women Age (years) 50–64 65–74 75–84 85 Total
614 1045 3521 4138 9319
91 126 253 193 663
130 76 113 58 377
34 67 253 331 686
564 318 461 410 1752
1433 1633 4601 5129 12 797
Men
Adapted from Burge et al. Incidence and economic burden of osteoporosis-related fractures in the United States, 2005–2025. J Bone Miner Res 2007;22:465-75 [2]
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fracture in Germany in 2002 was estimated at €2200 million in women and €536 million in men. Indirect costs were relatively small, amounting to €152 million in women and €110 million Euros in men [24]. Using a bottom up approach, Reginster et al looked at the direct costs (excluding nursing home costs) of hip fractures in a cohort of 2374 patients over 60 years of age in Belgium [25]. Most data were presented in men and women combined, though data on the distribution of mean acute (hospital) costs of hip fracture by age and gender were presented. Costs were broadly similar in men and women. In a Swedish study of 180 hip fracture patients, however, the total short-term costs (within 4 months) were greater in women than men [26]. Factors significantly linked with higher costs included increasing age, type of fracture (troch anteric cervical) and poorer prefracture functional status. Vertebral Fracture There are few studies that have focused exclusively on costs related to vertebral fracture. Estimating costs is more difficult than for other fracture types as many patients do not come to clinical attention. In a recent European study, the costs of hospitalization in men and women 50 years and over was estimated using data collected at a national level [14]. The average cost of hospitalization for those with an uncomplicated vertebral fracture (without neurologic deficit) was higher for women than men (EU mean cost €3457 versus €3305) in part because length of stay was longer (13.1 versus 11.8 days) [14]. These costs were, on average, 67% of the average cost of a hip fracture for men (compared with 58% in women). It was thought the longer stay in hospital for women might be because osteoporosis is expected in women and only the more serious cases are admitted, while men may be more likely to be admitted for shorter periods for investigation to exclude secondary cause of fracture. Given the higher cost and greater number of women affected, the total cost of vertebral fracture in the EU was greater in women than men (€227 million versus €149 million) [14]. The overall cost of vertebral fracture, however, is likely to be higher as non-acute costs were not included in the analysis and may be significant [16, 27]. All Fractures Using a top down approach, Lippuner et al [28] looked at the direct costs of acute hospitalization for osteoporotic fractures in Switzerland in men and women in 1992. The mean length of hospitalization for osteoporotic fractures was greater in women than men. Fractures of the proximal lower limb contributed most to the burden of hospitalization; for women, this comprised just under a half of the total hospital bed days and, for men, one third. Using a similar daily cost of hospitalization in men and women (845 Swiss Francs), the total cost amounted to 464 million Swiss francs in women and 130 million Swiss francs for men. Inclusion
of nursing home, other non-hospital costs and indirect costs would obviously further increase these costs. In one of the few published studies to focus exclusively on men, and using a top down approach, Levy et al [29] looked at the cost of osteoporosis and related fractures in those aged 50 and over in France. Attribution probabilities were adapted from Melton [21]. A total of 23 260 acute hospitalizations in men were considered to be related to osteoporosis – 52% of which were for hip fracture. Mean cost per stay varied from €1300 for wrist fracture to €5900 for hip fracture. The total cost of acute hospitalization was €97.6 million, with hip fractures accounting for 73.2% of the total expenditure. Rehabilitation and convalescence costs were €90.8 million and outpatient costs were €9.1 million, resulting in total direct medical costs of €197.5 million. After adjusting for differences in demographics and exchange rates, these costs were about one quarter of the costs observed in the Swiss study [28] and one half of a US study [20]. Differences in unit costs may in part explain these differences. Costs in women based on an earlier survey (and inflated to 1999 prices) were about one third those in French women [30]. Using data from a range or sources, Kanis and Johnell estimated the direct cost of osteoporotic fractures in Europe (EU) at €27 billion in women and €8.7 billion in men [1]. Overall costs increased with age though there was variation in the rate of change with age by fracture type (Table 31.3). Other Regions Australia Randell et al studied the direct costs associated with 151 osteoporotic fractures occurring between 1989 and 1992 in a large cohort of elderly men (DUBBO) [31]. The median cost of hospital treated fractures was $A10 511 per fracture and non-hospitalized fractures $A455 per fracture in 1992
Table 31.3 Estimated costs of osteoporotic fractures in Europe (€000) by fracture site, age and gender Age (years)
Hip
Spine
Other
Total
Men 50–64 65–74 75–84 85 50
544 1111 1637 1264 4556
69 63 45 21 198
473 389 360 2781 4003
1086 1563 2042 4067 8757
Women 50–64 65–74 75–84 85 50
813 2751 9120 7112 19 796
101 165 152 102 521
1253 1376 2553 1992 7173
2168 4293 11 824 9206 27 491
Adapted from Kanis et al. Requirements for DXA for the management of osteoporosis in Europe. Osteoporos Int 2005;16:229-38 [1]
C h a p t e r 3 1 Economic Impact of Osteoporotic Fractures (versus Women) l
Australian dollars. There was little difference in the overall hospital costs between men and women, though for hip fracture, direct costs were significantly greater in women than men ($A18 890 versus $A12 815). Extrapolating from the sample to the Australian population, the total cost of osteoporotic fracture was estimated to be $A779 million with 21.9% of the total fracture costs in men; 53.5% of the total costs were attributable to hip fracture. Middle East Hospital costs of all patients (50 years) admitted to an orthopedic unit in an eastern Saudi Arabian province following a low trauma fractured femur were calculated. The direct costs per fracture were greater in women than in men (US$14 288 versus US$12 388), related in part to a longer hospital stay in women (20.7 versus 15.8 days) [32]. Overall costs (all fractures), however, were similar since despite the lower cost there were a greater number of men with hip fracture. This is consistent with epidemiological data from the area that suggest fracture incidence is broadly similar in men and women [33].
Attributable Costs In contrast to the data concerning total costs, less is known about the excess costs attributable to fracture in men. Excess Costs In one of the first studies to consider excess costs related to fracture in men, Zethraeus et al estimated costs for hip fracture in 1709 hip fracture patients admitted during 1992 in Stockholm, Sweden [34]. Direct costs arising in the healthcare sector and social welfare system were available during the year before and the year after the fracture event. Data regarding days in orthopedic departments and other acute hospital care costs were extracted from the inpatient database of the Stockholm county council, while data regarding days in a nursing home were extracted from the municipality database. Direct costs during the year after and the year before fracture were higher for women than men, due in part to a higher mean age in women and longer survival. The difference in costs (year after – year before) was also greater in women (US$18 985 versus US$13 373). This was true at all ages except 65–74 years where the difference was greater in men (US$16 306 versus US$12 657). Brainsky et al looked at costs before and after fracture in a group of men and women with hip fracture but did not consider costs separately in men and women [35]. Incremental Costs Using data from Olmstead County, Minnesota, Gabriel et al characterized the incremental direct medical costs (excluding nursing home costs) following osteoporotic fractures by
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comparing the costs among those who sustained a fracture with a control group who had not [36]. Cases included all county residents aged 50 years of age and older with an incident fracture due to minimal or moderate trauma during 1989–1992. Unit costs were obtained through the Mayo cost data warehouse which provides standardized estimates reflecting the national average cost of providing the service. Overall, there were 1263 case control pairs with an average age of 73.8 years and 78% were female. In a subset of 985, there were no significant differences in the excess costs for specific fractures in men and women and there were no statistically significant trends with increasing age in either sex [37]. Incremental costs in the year following fracture were US$11 241 for hip, US$1628 for wrist and US$1955 for spine fracture. Based on the age and sex specific incremental costs and using reference age, sex-specific incidence for each fracture type, it was possible to look at overall incremental costs in the year following fracture (case–control). In this analysis, the cost of all osteoporotic fractures combined was 46% greater than that for hip fractures alone in women and 47% greater in men. The results highlight the importance of considering all categories of fractures when determining the cost effectiveness of treatment or of prevention measures. In addition to looking at the difference in cases and controls (incremental costs), the authors also looked at costs in the year prior to and the year following fracture (excess costs) and were able to compare these costs with the data from the case–control analysis. Differences in costs using the two approaches were not large, though broadly, the excess cost approach resulted in a modest underestimate of the incremental costs. The latter were considered a better approximation of the true attributable cost. In the Swedish KOFOR study, the additional costs of fracture (direct and indirect) were determined by considering the costs specifically due to the fracture event within a large cohort of fracture patients. Overall costs of hip fracture were €14 920 in men and €14 033 in women. Costs increased with age in women from €11 082 at age 50 – 64 years to €18 743 age 85 , though not in men [38]. The cost increase with increasing age in women is mostly because of a rise in resource use in community care, in particular home help and accommodation. Additional costs due to wrist fracture did not vary by age or gender, while costs due to vertebral fracture did not vary by gender.
Projected Costs Life expectancy is increasing in most developed countries and, as a consequence, the number of elderly men and women will rise. The projected increase is greater for men than women: across Europe, for example, the proportion of men aged 50 years and over is set to increase by 36% between 2000 and 2050 and 26% in women [1, 39]. The increase will be most marked in the very elderly (80 years) with a 239% increase
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Table 31.4 Projected costs of osteoporotic fractures in Europe (€000 000) Calendar year
Men
Women
Men and women
2000 2005 2010 2015 2020 2025 2030 2035 2040 2045 2050
8.7 9.2 10.5 12.2 13.2 14.7 15.8 17.7 19.7 21.3 22.8
27.5 29.6 32.0 35.1 36.3 39.3 42.2 46.1 49.7 52.2 53.9
36.3 38.7 42.6 47.3 49.7 54.0 57.9 63.8 69.3 73.5 76.8
Reproduced from Kanis et al. Requirements for DXA for the management of osteoporosis in Europe. Osteoporos Int 2005;16:229– 38 [1]
in the number of men and a 160% increase in the number of women. More marked increases are projected in other regions worldwide, particularly in Asia, with a 7.6-fold increase in expected numbers of elderly men [7]. Because the rate of fractures and, in particular, hip fractures, increases exponentially with age, the number of fractures and, consequently, the economic impact of osteoporosis, is set to rise substantially. The projected increase in the cost of osteoporotic fractures between the years 2000 and 2050 (based on UK costings) across Europe are summarized in Table 31.4 [1]. For men, costs are set to increase from €8.7 billion to €22.8 billion, a 2.6-fold rise. Indeed, by 2050, the costs of fracture in men will begin to approach current costs in women. These data compare with an approximate doubling in costs in women during the same time period. The estimates may be conservative in that they do not take account of any changes in the secular trend for fracture incidence that may occur. Also, they assume no changes in health-care costs that, given ongoing improvements in health care, seem likely to rise. In the USA, the burden of osteoporotic fractures is projected to increase from a current level of $17 billion to $25.3 billion by 2025 with a quarter of the total cost being borne by men [2].
Summary Osteoporosis is an important and increasing health burden. The economic impact of osteoporosis and osteoporotic fractures in most developed countries is greater in women than men, primarily because fractures are more frequent in women. The economic impact in men is, however, substantial. Current estimates of the costs of osteoporotic fractures in men aged 50 and over are $4.1 billion in the USA and €8.7 billion in Europe, which represents about 24% of the total costs of osteoporosis. Costs are greatest for hip fracture, due to a combination of acute hospital costs and long-term
care. Direct costs tend to be lower in men than women – in part related to differences in age and length of hospital stay. Nevertheless, consideration of hip fractures alone substantially underestimates the economic burden of osteoporosis in men. The health costs related to osteoporotic fractures in men is projected to increase by 2.6-fold across Europe over the next 50 years, primarily due to increasing number of fractures as a consequence of increasing life expectancy. The projected increase will be greater in other regions, particularly Asia. There is an urgent need therefore to develop targeted, cost effective intervention and treatment programs to reduce the occurrence and associated health costs related to osteoporosis in men.
References 1. J.A. Kanis, O. Johnell, Requirements for DXA for the management of osteoporosis in Europe, Osteoporos Int. 16 (2005) 229–238. 2. R. Burge, B. Dawson-Hughes, D.H. Solomon, J.B. Wong, A. King, A. Tosteson, Incidence and economic burden of osteoporosis-related fractures in the United States, 2005–2025, J. Bone Miner Res. 22 (2007) 465–475. 3. K. Lippuner, M. Golder, R. Greiner, Epidemiology and direct medical costs of osteoporotic fractures in men and women in Switzerland, Osteoporos Int. 16 (2005) S8–S17. 4. O. Johnell, J.A. Kanis, B. Jonsson, A. Oden, H. Johansson, C. De Laet, The burden of hospitalised fractures in Sweden, Osteoporos Int. 16 (2005) 222–228. 5. C. Cooper, G. Campion, L.J. Melton III, Hip fractures in the elderly: a world-wide projection, Osteoporos Int. 2 (1992) 285–289. 6. L.J. Melton III, Epidemiology of fractures, in: B.L. Riggs, L.J. Melton III (Eds.), Osteoporosis: etiology, diagnosis and management, second ed., Lippincott-Raven, Philadelphia, 1995, pp. 225–247. 7. J.A. Kanis, on behalf of the World Health Organisation Scientific Group. Assessment of osteoporosis at the primary health care level. Technical Report, 2007. WHO Centre for Metabolic Bone Diseases, University of Sheffield. 8. S.R. Cummings, L.J. Melton III, Epidemiology and outcomes of osteoporotic fractures, Lancet 359 (2002) 1761–1767. 9. C. Cooper, E.J. Atkinson, S.J. Jacobsen, W.M. O’Fallon, L.J. Melton III, Population based study of survival after osteoporotic fractures, Am. J. Epidemiol. 137 (1993) 1001–1005. 10. J.R. Center, T.V. Nguyen, D. Schneider, P.N. Sambrook, J.A. Eisman, Mortality after all major types of osteoporotic fracture in men and women: an observational study, Lancet 353 (1999) 878–882. 11. J.A. Kanis, A. Oden, O. Johnell, C. De Laet, B. Jonsson, A.K. Oglesby, The components of excess mortality after hip fracture., Bone 32 (2003) 468–473. 12. J.A. Kanis, A. Oden, O. Johnell, C. De Laet, B. Jonsson, Excess mortality after hospitalisation for vertebral fracture, Osteoporos Int. 15 (2004) 108–112. 13. T.W. O’Neill, C. Cooper, J.D. Finn, et al., Incidence of distal forearm fracture in British men and women, Osteoporos Int. 12 (2001) 555–558.
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14. H.W. Finnern, D.P. Sykes, The hospital cost of vertebral fractures in the EU: estimates using national datasets, Osteoporos Int. 14 (2003) 429–436. 15. J. Steiner, A. Kramer, T. Eilertsen, J. Kowalsky, Development and validation of a clinical prediction rule for prolonged nursing home residence after hip fracture, J. Am. Geriatr. Soc. 45 (1997) 1510–1514. 16. S. Puffer, D.J. Torgerson, D. Sykes, P. Brown, C. Cooper, Health care costs of women with symptomatic vertebral fractures, Bone 35 (2004) 383–386. 17. A.N.A. Tosteson, Economic impact of fractures, in: E.S. Orwoll (Ed.), Osteoporosis in Men, Academic Press, San Diego, 1999, pp. 15–27. 18. T.L. Holbrook, K. Grazier, J.L. Kelsey, R.N. Stauffer, Frequency of occurrence, impact and cost of selected musculoskeletal conditions in the United States, American Academy of Orthopedic Surgeons, Chicago, 1984. 19. A. Praemer, S. Furner, D.P. Rice, Musculoskeletal conditions in the United States, American Academy of Orthopedic Surgeons, Chicago, 1992. 20. N.F. Ray, J.K. Chan, M. Thamer, L.J. Melton III, Medical expenditures for the treatment of osteoporotic fractures in the United States in 1995: report from the National Osteoporosis Foundation, J. Bone Miner Res. 12 (1997) 24–35. 21. L.J. Melton III, M. Thamer, N.F. Ray, et al., Fractures attributable to osteoporosis: report from the National Osteoporosis Foundation, J. Bone Miner Res. 12 (1997) 16–23. 22. W. Max, P. Sinnot, C. Kao, H.Y. Sung, D.P. Rice, The burden of osteoporosis in California, 1998, Osteoporos Int. 13 (2002) 493–500. 23. M.E. Wiktorowicz, R. Goeree, A. Papaioannou, J.D. Adachi, E. Papadimitropoulos, Economic implications of hip fracture: health service use, institutional care and cost in Canada, Osteoporos Int. 12 (2001) 271–278. 24. A. Konnopka, N. Jerusel, H.H. Konig, The health and economic consequences of osteopenia- and osteoporosisattributable hip fractures in Germany: estimation for 2002 and projection until 2050. Osteoporos Int 2008 [Epub ahead of print] Dec 2nd. 25. J.Y. Reginster, P. Gillet, W.B. Sedrine, et al., Direct costs of hip fractures in patients over 60 years of age in Belgium, Pharmacoeconomics 15 (1999) 507–514. 26. L. Borgquist, G. Lindelow, K.G. Thorngren, Costs of hip fracture. Rehabilitation of 180 patients in primary health care, Acta Orthop. Scand. 62 (1991) 39–48.
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27. P. Dolan, D.J. Torgerson, The cost of treating osteoporotic fractures in the United Kingdom female population, Osteoporos Int. 8 (1998) 611–617. 28. K. Lippuner, J. Overbeck, R. Perrelet, H. Bosshard, P.H. Jaeger, Incidence and direct medical costs of hospitalizations due to osteoporotic fractures in Switzerland, Osteoporos Int. 7 (1997) 414–425. 29. P. Levy, E. Levy, M. Audran, M. Cohen-Solal, P. Fardellone, J.M. Le Parc, The cost of osteoporosis in men: the French situation, Bone 30 (2002) 631–636. 30. E. Levy, Cost analysis of osteoporosis related to untreated menopause, Clin. Rheumatol. 8 (Suppl. 2) (1989) 76–82. 31. A. Randell, P.N. Sambrook, T.V. Nguyen, et al., Direct clinical and welfare costs of osteoporotic fractures in elderly men and women, Osteoporos Int. 5 (1995) 427–432. 32. D. Bubshait, M. Sadat-Ali, Economic implications of osteoporosis-related femoral fractures in Saudi Arabian society, Calcif Tissue Int. 81 (2007) 455–458. 33. A. Memon, W.M. Pospula, A.Y. Tantawy, S. Abdul-Ghafar, A. Suresh, A. Al-Rowaih, Incidence of hip fracture in Kuwait, Int. J. Epidemiol. 27 (1998) 860–865. 34. N. Zethraeus, L. Stromberg, B. Jonsson, O. Svensson, G. Ohlen, The cost of a hip fracture: estimates for 1709 patients in Sweden, Acta Orthop. Scand. 68 (1997) 13–17. 35. A. Brainsky, H. Glick, E. Lydick, et al., The economic cost of hip fractures in community-dwelling older adults: a prospective study, J. Am. Geriatr. Soc. 45 (1997) 281–287. 36. S.E. Gabriel, A.N.A. Tosteson, C.L. Leibson, et al., Direct medical costs attributable to osteoporotic fractures, Osteoporos Int. 13 (2002) 323–330. 37. L.J. Melton III, S.E. Gabriel, C.S. Crowson, A.N.A. Tosteson, O. Johnell, J.A. Kanis, Cost equivalence of different osteoporotic fractures, Osteoporos Int. 14 (2003) 383–388. 38. F. Borgstrom, N. Zethraeus, O. Johnell, et al., Costs and quality of life associated with osteoporosis-related fractures in Sweden, Osteoporos Int. 17 (2006) 637–650. 39. United Nations Population Division, World population prospects: the 2002 revision and world urban prospects, Population Division of the Department of Economic and Social Affairs of the UN Secretariat, 2003.
Chapter
32
Adverse Health Outcomes in Men with Osteoporosis Deborah T. Gold1 and Stuart L. Silverman2 1
Duke University Medical Center, Durham, North Carolina, USA Cedars-Sinai/UCLA and the OMC Clinical Research Center, Los Angeles, CA, USA
2
Introduction
Morbidity in men after osteoporotic fractures
In 2004, the Surgeon General of the USA issued the first report on osteoporosis and bone health [1]. That document reported that over 10 million American women and men had osteoporosis and another 34 million had low bone mass. Had the Surgeon General written this report 30 years earlier, in 1974, the report on osteoporosis would almost certainly have discussed only postmenopausal osteoporosis. Few lay people believed that men could have osteoporosis; few physicians and other health professionals were examining men’s bones to determine if skeletal loss had occurred. The evidence about men and osteoporosis has changed over the last 30 years [2]. Recent data suggest that at least 20% of people with osteoporosis are men. That means that 2 million men or more already have osteoporosis and another 12 million are at risk of the disease [1]. As life expectancy in the USA continues to rise, osteoporosis prevalence in men will increase. In light of these changing demographics, we need a better understanding of the incidence and gender-specific consequences of osteoporosis in men. In this chapter, we review research findings from the last decade that specifically illuminate the adverse outcomes of osteoporosis and consequent fractures in men. These outcomes include, but are not limited to, physical morbidity, psychosocial outcomes (including health-related quality of life) and mortality. Although the empirical evidence about men and their osteoporosis outcomes is somewhat limited, some recent studies have begun to help us understand what happens when men with osteoporosis experience fractures.
Osteoporosis in Men
The three most common atraumatic fractures that occur because of osteoporosis are those of the wrist or forearm, the vertebrae and the hip. We examine the incidence and/or prevalence of these three fractures in men as well as the morbidity they cause.
Wrist Fractures The pattern of wrist fractures in men is different from that in women. Women’s risk of wrist fracture begins after the menopause and continues to be substantial; however, the incidence of wrist fractures in men with osteoporosis peaks in the years between 50 and 64, then drops somewhat dramatically during the remaining years of adulthood [3]. According to findings in Dubbo, Australia, the incidence of forearm and wrist fractures in men was 33.8 per 10 000 person-years while the incidence for women was 124.6 per 10 000 personyears [4]. Symptoms following wrist fracture in both men and women include complaints of hand pain, weakness and, rarely, reflex sympathetic dystrophy (RSD), also known as complex regional pain syndrome [5]. Impairments in activities of daily living (ADL) and instrumental activities of daily living (IADL) have been reported in women post fracture but have not been studied in men [6].
Radiographic Vertebral Fractures In both men and women in The European Vertebral Osteoporosis Study (EVOS), a community-based cohort of men and women from 19 European countries, individuals
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with radiographic vertebral deformity (RVD) reported limitations in back-related activities of daily living, back pain and poorer self-rated health [7]. Multiple severe deformities were significantly associated with worse function, greater pain and poorer health status. These findings were stronger in men than in women. In a second study using EVOS data, investigators studied 756 men and 885 women who had radiographic evidence of vertebral deformities [8]. Although women with a single RVD were more likely to report back pain in association with lumbar than thoracic deformities, no such association was seen in men. Among men, nonadjacent deformities were associated with greater impaired functional disability than were adjacent deformities. Finally, the location of RVDs did not differ between men and women; some clustering occurred at the mid-thoracic region and the thoraco-lumbar junction in those with two deformities, suggesting that biomechanical factors might be the reason [9]. One of the few studies to examine racial differences in the prevalence of morphometric vertebral fractures in men used data from the Baltimore Men’s Osteoporosis Study [10]. Participants included 415 white men and 127 black men with a mean age of 74.0 5.7 years. The prevalence of these radiographic fractures was significantly higher in white men (7.3%) than in black men (7.3% versus 0.9%, P 0.01). The authors suggest that this difference may result from different bone mineral density between the two groups of men [11].
Clinical Vertebral Fractures Leidig and colleagues studied a cross-sectional clinical sample of 19 men (mean age: 52 12 years) and 51 women (mean age: 61 11 years) admitted to hospital for clinical vertebral fracture. They found a correlation between spinal deformity index and physical limitations of 0.44 (P 0.001) [12]. Of those with physical limitations, pain occurred with activity (64%), limited bending (71%) and limited rising (70%). Forty-one percent of this sample needed help with self-care. Unfortunately, data from men and women were not analyzed separately in this study. In the Canadian Multicentre Osteoporosis Study (CaMos), both men and women with clinical vertebral fractures reported lower health-related quality of life as measured by the Health Utility Index (HUI) as compared to participants without such fractures [13]. Interestingly, there were no gender differences with statistically significant deficits in pain experienced by both genders (P 0.05). Women experienced a greater impact in self-care, mobility and ambulation (P 0.05 for all) while men did not. However, it is important to note that the small sample of men may strongly influence these findings. The number of men with spine (n 9), hip (n 14) and pelvis (n 1) fractures was minuscule. It would be interesting to replicate these findings with a larger male sample.
Finally, in EVOS, investigators studied the long-term impact of fractures on long-term morbidity. They revisited participants 12 years after they experienced clinical vertebral fractures and found gender differences in long-term morbidity. While women had significantly greater current back pain than controls (42% versus 19%, P 0.006) and impaired health status (44% versus 17%, P 0.001), men reported only marginally significant current back pain (P 0.09) and had no significant reduction in health status [14].
Hip Fracture Of all osteoporotic fractures, hip fractures result in the greatest morbidity and mortality of any fractures in men. In 2005, there were 281 256 non-traumatic hip fracture hospitalizations in the USA in 67.1 million individuals aged 55 and older. Of these, 73 267 or 26% occurred in men; an incidence of 243.9/100 000. Comparable 2005 numbers for women are 207 989 non-traumatic hip fracture hospitalizations or 74% in women with an incidence of 560.5/100 000 [15]. As in women, men’s hip fracture rates increase exponentially with aging. For example, at age 55, the incidence of hip fracture in men was 23.7/100 000 which tripled by age 65 to 70.5, quadrupled again by age 75 to 319.1/100 000 and increased fivefold for ages 85 and older (1573.9/100 000). This exponential increase is essentially parallel for men and women with an average 3.5 year ‘lag’. At any age, prevalence rates for men are equivalent to those of women 3–4 years younger [15]. In both men and women, hip fracture results in marked impairment of function and physical performance [16–19]. In a study by Jette and colleagues [18], only 33% of those with intertrochanteric fractures returned to reported levels of prefracture functioning in ADLs, while 21% with subcapital hip fractures regained ADL function at one year. At 6 months after a hip fracture, approximately one fourth of patients regain prefracture levels of IADLs, with no further recovery by one year [18]. Magaziner and colleagues [17] showed that a significant proportion of older adults did not recover prefracture functional status after hip fracture. In addition, physical performance by patients who experienced hip fractures declined significantly. At 6 months, only 15% of hip fracture patients could walk independently compared to 75% at baseline; at 6 months, only 8% of these patients could climb stairs compared to 63% prefracture [20]. Further, Silverman and Zingmond [21] found that men in California were more likely to be discharged from the hospital to home after a hip fracture than were women (17.0% versus 9.5%). Men were also less likely to be sent to skilled nursing facilities than women (61.2% versus 72.4%). A similar proportion of men and women went to rehabilitation facilities (8.2% versus 7.9%). This finding is not surprising given that most men have younger wives who are able to care for them at home, while most women married older men who are either deceased or unable to provide care once a hip fracture occurs [22].
C h a p t e r 3 2 Adverse Health Outcomes in Men with Osteoporosis l
Psychosocial consequences of osteoporotic fractures in men Women with osteoporosis suffer multiple intrusions on their psychosocial functioning as a result of their fractures [23–25]. Fewer data are available about men [26].
Social Role Loss Studies examining the impact of fragility fracture on social role loss are limited. However, Greendale and colleagues [27] note that hip fracture results in significant losses in social/role function in women with only 26% returning to prefracture levels after recovery from the hip fracture. In CaMos, investigators found that those participants with fractures had substantially worse health-related quality of life (HRQOL) than those without fractures [28]. In terms of gender, men were most affected by hip fracture in the role physical domain while women were most affected in the physical functioning domain. This difference would be an interesting concept to pursue, given that many men define themselves by what they are able to do in the way of traditional role responsibilities (e.g. yard work, carrying garbage out, etc.).
Depression For almost two decades, researchers have been examining the relationship between depression and osteoporosis. Some studies used case-control designs to examine the relationship between depression or depressive symptoms and bone mineral density (BMD) in men and women and found that the relationship between low BMD and depression was stronger in men than in women [29,30]. Others used community or clinical samples to determine the cross-sectional correlation of the same variables and found that a statistically significant relationship between depressive symptoms and BMD existed only in white women [31]. Whooley and colleagues [32], in one of the few studies looking only at community-dwelling men to determine whether depressive symptoms and BMD were correlated cross-sectionally, provided support for the finding by Robbins and colleagues [31] that a significant relationship was not evident in men. However, few studies of men or women have examined depressive symptoms as an outcome of osteoporotic fracture rather than as a risk factor or predictor of osteoporosis. Even in studies of large, nationally representative samples, such as NHANES I which had a sample size of 6195 black and white adults (age range: 25–74), the relationship examined is the association between depression and subsequent hip fracture [33]. In determining the incidence of hip fractures in three categories of depressive symptoms, the investigators found that those classified in the ‘high’ depressive symptoms category had a greater incidence of hip fracture per 10 000 person-years (20.27) than did those in the intermediate (12.03) or low (10.83) categories.
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However, there is a growing literature which takes the opposite perspective and suggests that depression can result from hip fracture and its surgical repair. Researchers have well documented the fact that post-hip fracture depression and/or cognitive impairment has deleterious effects on rehabilitation [34]. Lenze and colleagues [35] examined the onset of major depressive disorder (MDD) after hip fracture, as well as possible risk factors for onset of MDD at that time. In 126 hip fracture patients age 60 years consecutively admitted to an acute care hospital who had surgical repair of the fracture, 14.2% developed MDD after hip fracture and the greatest risk period for MDD was immediately after the hip fracture. These findings, it would appear, suggest that a psychiatric intervention after hip fracture might prevent depression from developing or might minimize the impact of depressive symptoms. However, a study in England examined the impact of prevention and treatment interventions for posthip fracture depression [36]. This study did confirm previous findings that showed that approximately 42% of hip fracture patients – women and men – experienced depression after hip fracture and surgery. Of the 121 men and women who experienced surgical repair of hip fractures and became depressed immediately after the fracture, those receiving the treatment intervention did not differ from the usual care group in terms of depressive symptoms. Further, of the 172 men and women with hip fracture who were not depressed at baseline (i.e. directly after the fracture), those who received a preventive depression intervention did not differ in the development of depression from those in usual care [36]. Although we have made progress in understanding the relationship between depression and osteoporosis, much additional work remains. If we are to prevent or treat effectively post-fracture depression, we must utilize longitudinal research designs in both men and women to better understand the causal direction of the relationship.
Health-Related Quality Of Life Although an increasing number of studies of postmenopausal osteoporosis now include health-related quality of life (HRQOL) as an important outcome after fracture, few studies have examined HRQOL in men with osteoporosis and fractures. The Hertfordshire Cohort Study [37] included 737 men (mean age 64.3 2.6 years) and 675 women (mean age 65.7 2.5 years) and examined the relationship between HRQOL, measured with the SF-36 [38] and BMD. For the first time, its results showed a robust and significant correlation between quality of life and bone mineral density in men. The odds ratios between femoral neck BMD and SF-36 domains for men were as follows: physical functioning (0.72 (0.53, 0.97); P 0.03), social functioning (0.70 (0.53, 0.94); P 0.02) and general health (0.74 (0.56, 0.99); P 0.05). Relationships for
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the same domains in the women are much weaker: physical functioning (0.71 (0.50, 1.00); P 0.05), social functioning (1.16 (0.89, 1.52); P 0.27) and general health (0.97 (0.72, 1.31); P 0.83). Only 16% of the men and women in this study had experienced a fracture after age 45 [37]. In another study in England, Pande and colleagues recruited 100 consecutive men over age 50 who had a fragility fracture of the hip and were admitted to the Royal Cornwall Hospital, UK in the mid-1990s; they also recruited 100 controls who had not experienced a hip fracture [39]. The patients completed the SF-36 [38] and other scales soon after fracture and changes were analyzed at 6, 12 and 24 months post baseline. Perhaps not surprisingly, at baseline, the cases rated their HRQOL lower than did the controls. Further, the immediate impact of the fracture led to a deterioration in physical health scores but not the mental health scores. Physical health scores continuously declined until, at 2 years post fracture, they were 1.7SD below the US mean for that dimension. Two years later, there was also a significant decline in mental health scores (P 0.04). Additional declines were seen in the men with fractures as well. One year after hip fracture, only 36% of patients (17/47) walked unassisted; at 24 months, that proportion decreased to only 34% of the remaining patients (12/35). A population-based case control study was done by Ekstrom and colleagues [40] in Sweden to determine whether elderly men and women with fracture and pain (n 87) or with fracture and no pain (n 82) differed in HRQOL, life satisfaction and social activities from no fracture controls (n 239). They used the SF-12 [41] and the Life Satisfaction scale [42] to measure HRQOL and life satisfaction. Overall, this study showed that individuals with fractures had lower HRQOL (as measured by the Physical Component Summary (PCS) and the Mental Component Summary (MCS)) and life satisfaction than did controls (P 0.001). Additionally, people with fractures and pain had significantly lower scores on the PCS than did those who were fractured but had no pain and than controls (P 0.001). Unfortunately, gender specific analyses were not reported. The combination of a fracture and pain appeared to have the most profound negative outcomes in both men and women.
Mortality in men after osteoporotic fracture Excess mortality in older women from both hip and vertebral fractures has been well established [43, 44]. However, this adverse outcome of osteoporosis in men has been less well investigated, perhaps because there are no parallels with men to the large databases such as the Study of
Osteoporotic Fractures (SOF) or the Fracture Intervention Trial (FIT).
Mortality After Hip Fracture Mortality varies by fracture type, with hip fractures being the most likely to lead to death. Ioannidis and colleagues [45] studied 5-year mortality by fracture type in CaMos, a population-based Canadian cohort including both men and women. The highest death rates were seen after hip, pelvic and vertebral fractures in both men and women. Death rates following hip fracture were similar between men and women; however, men showed slightly greater long-term mortality with vertebral fractures and pelvic fractures. This was not seen with forearm fractures. Table 32.1 reflects the findings of this study. Excess deaths following hip fracture occur mainly in the first 6 months and diminish with time, although mortality may remain elevated for up to 10 years [46]. Bliuc and colleagues found an age adjusted standardized mortality ratio of 3.51 (95% CI 2.65–4.66) in men [46]. Hip fracture mortality depends on age and sex with greater survival for those under 75 years with a relative survival of 92% and a survival of only 83% for those over 75 years [47]. In virtually every study, hip fracture survival is more likely in women than in men. Poor and colleagues studied 131 men who experienced a hip fracture between 1978 and 1989 and an equal number of community-dwelling controls [48]. Of patients with fractures, 109 died during 373 personyears of follow-up observation. Only 75 of the controls died during the 742 person-years of observation. Increased comorbidity and increased age increased the risk of dying; so did mental confusion during hospitalization. It may be that the greater frequency of chronic diseases in men with hip fractures makes them more likely to die. Van Staa and colleagues used the General Practice Research Database in the UK to derive age- and genderspecific fractures rates in England and Wales between 1988 and 1998 [49]. Out of 5 million adults, about 119 317 women and 103 052 men were studied over follow up of
Table 32.1 Absolute post-fracture death rates (%) among Canadian men and women by fracture type
No fracture Hip fracture Vertebral fracture Rib Forearm Pelvis Other fracture
Men
Women
11.0 23.5 18.2 6.7 11.5 33.3 12.7
6.9 23.5 15.75 9.8 8.1 15.0 5.8
From Ioannidis G, Papaioannou A, Hopman WM et al. Absolute death rates by fracture type in Canadians. Arthritis Rheum 2008;58:S747 [45]
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11.2 million and 10.4 million person-years. Both men and women age 65 had statistically significant (P 0.05) excess mortality from hip and vertebral fractures. They also found that the 12-month survival after hip fractures is lower in men than in women: 63% versus 90% expected as compared to women [49]. Finally, in California, approximately 6% of men with hip fracture die within the first 30 days and 10% within the first 60 days post fracture [21].
Mortality After Clinical Vertebral Fractures There are gender differences in excess mortality from clinical vertebral fractures. Bliuc and colleagues found a Standardized Mortality Ratio (SMR) of 2.12 (95% CI 1.66– 2.72) in men as opposed to an SMR of 1.82 in women [46]. In the Malmo University Hospital in Sweden, investigators followed 70 men (mean age 70 years; range 50–91 years) and 187 women (mean age 72 years; range 50–96 years), all of whom had experienced a clinical vertebral fracture [14]. A mortality analysis was done over 22 years after the baseline fracture. Investigators found that the excess mortality rate was higher in men with clinical vertebral fractures than in women with the same fractures. The male mortality rate was 111.7 per 1000 patient years (versus a rate of 73.4 per 1000 patient years in control men); in women, the mortality rate was 95.1 per 1000 patient years (versus control women’s rate of 62 per 1000 patient years) [14].
Mortality After Prevalent Vertebral Fracture Prevalent vertebral fractures are associated with well-documented loss of height, kyphosis and increased mortality risk [50, 51]. When male participants in EVOS from Malmo, Sweden were studied, there was an association between prevalent vertebral fracture as defined by a reduction in vertebral height of 3SD and increased mortality risk with an age adjusted HR of 2.4 (95% CI 1.6–3.9) as compared to female participants HR 2.3 (95% CI 1.3–4.3). However, reasons for mortality differ between genders as men have greater risk of mortality due to cardiovascular and pulmonary causes while, in women, there is greater risk of cancer mortality [52]. Finally, vertebral deformity due to prevalent vertebral fracture may result in hyperkyphosis, which is a cause of increased mortality. Hyperkyphosis is associated with a 40% increase in mortality in older men and women [53].
Mortality After Subsequent Fracture Bliuc et al found that, in men, mortality after a second fracture was greater (SMR 3.53, 95% CI, 2.62–4.74) than in those with only one fracture (SMR 1.82, 95% CI 1.51– 2.18). Mortality following a second fracture declined with time but, beyond 5 years, was still higher than in the general population (SMR 1.78, 95% CI 0.96–3.31) [46].
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Conclusions Both men and women have adverse outcomes following osteoporotic fracture. Whereas men and women have loss of HRQOL with osteoporotic fracture, gender differences exist in terms of HRQOL domains affected by lower BMD and by fracture [39]. Furthermore, there are gender differences in terms of long-term morbidity and mortality [14, 28]. Morbidity post fracture is complicated by the morbidity of subsequent fractures. In men older than 50 years, clinical vertebral and non-vertebral fractures cluster in time. Yearly absolute risk of another fracture after a clinical vertebral or non-vertebral fracture is 6.1% during the first year, 2.1% yearly for the next three years and 1.6% in fifth year [54]. There are also gender differences in mortality following osteoporotic hip fracture. Men may have greater earlier mortality following hip fracture, possibly due to comorbidities. This earlier mortality following hip fracture is coupled with findings of significant loss of quality of life. Excess mortality and morbidity is of particular relevance as we now appreciate that men, like women, experience an exponential increase in the rate of hip fracture [54]. Osteoporotic fractures in men are also associated with a disease burden that is higher (in terms of disability and mortality) than common cancers (excluding lung cancer) [55]. The cost burden of men hospitalized with osteoporotic fracture is higher than the cost burden of men hospitalized with prostate cancer [56]. Despite the absence of substantial empirical data on all outcomes from osteoporotic fractures in men, the data reviewed here strongly suggest that, in men, osteoporotic fractures and their adverse outcomes have become a major public health problem that will continue to increase in size and cost as our population ages. They also remind us of the importance of osteoporosis screening in men over age 70 and men over 50 with risk factors, as currently recommended in the National Osteoporosis Foundation Clinicians’ Guide [57]. Finally, as noted by the investigators of CaMos, in men, there is a substantial gap between what we do and what we could do to detect, prevent and treat this disease [58].
References 1. US Department of Health and Human Services, Bone Health and Osteoporosis. A Report of the Surgeon General, US Department of Health and Human Services, Rockville, 2004. 2. S. Khosla, S. Amin, E. Orwoll, Osteoporosis in men, Endocr. Rev. 29 (2008) 441–464. 3. R. Burge, B. Dawson-Hughes, D.H. Solomon, J.B. Wong, A. King, A. Tosteson, Incidence and economic burden of osteoporosis-related fractures in the United States, 2005–2025, J. Bone Miner Res. 22 (2007) 465–475. 4. T.V. Nguyen, J.R. Center, P.N. Sambrook, J.A. Eisman, Risk factors for proximal humerus, forearm, and wrist fractures in elderly men and women: the Dubbo Osteoporosis Epidemiology Study, Am. J. Epidemiol. 153 (2001) 587–595.
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Osteoporosis in Men
5. A.T. Marshall, A.J. Crisp, Reflex sympathetic dystrophy, Rheumatology 39 (2000) 692–695. 6. G.A. Greendale, E. Barrett-Connor, S. Ingles, R. Haile, Late physical and functional effects of osteoporotic fracture in women: the Rancho Bernardo Study, J. Am. Geriatr. Soc. 43 (1995) 955–961. 7. C. Mathis, U. Weber, T.W. O’Neill, H. Raspe, Health impact associated with vertebral deformities: results from the European Vertebral Osteoporosis Study (EVOS), Osteoporos. Int. 8 (1998) 364–372. 8. W. Cockerill, A.A. Ismail, C. Cooper, et al., Does location of vertebral deformity within the spine influence back pain and disability? European Vertebral Osteoporosis Study (EVOS) Group, Ann. Rheum. Dis. 59 (2000) 368–371. 9. A.A. Ismail, C. Cooper, D. Felsenberg, et al., Number and type of vertebral deformities: epidemiological characteristics and relation to back pain and height loss. European Vertebral Osteoporosis Study Group, Osteoporos. Int. 9 (1999) 206–213. 10. J.K. Tracy, W.A. Meyer, M. Grigoryan, et al., Racial differences in the prevalence of vertebral fractures in older men: the Baltimore Men’s Osteoporosis Study, Osteoporos. Int. 17 (2006) 99–104. 11. J.K. Tracy, W.A. Meyer, R.H. Flores, P.D. Wilson, M.C. Hochberg, Racial differences in rate of decline in bone mass in older men: the Baltimore Men’s Osteoporosis study, J. Bone Miner Res. 20 (2005) 1228–1234. 12. G. Leidig, H.W. Minne, P. Sauer, et al., A study of complaints and their relation to vertebral destruction in patients with osteoporosis, Bone Miner 8 (1990) 217–229. 13. A. Papaioannou, C.C. Kennedy, G. Ioannidis, et al; for the CaMos Study Group. The impact of incident fractures on health related quality of life; five years of data from CaMos. Osteoporos Int 2008; DOI 10.1007/s00198-008-0743-7. Accessed 12.10.08. 14. R. Hasserius, M.K. Karlsson, B. Jonsson, I. Redlund-Johnell, O. Johnell, Long-term morbidity and mortality after a clinically diagnosed vertebral fracture in the elderly – a 12- and 22-year follow-up of 257 patients, Calcif. Tissue Int. 76 (2005) 235–242. 15. A. Mithal, S. Vadhavkar, A. Mannalithara, G. Singh, G. Triadafilopoulos, An unrecognized hazard: exponential increase in prevalence rates of osteoporotic fractures in aging men parallels that of aging women, Arthritis Rheum. 58 (2008) S742. 16. S. Katz, K.G. Heiple, T.D. Downs, A.B. Ford, C.P. Scott, Long term course of 147 patients with fracture of the hip, Surg. Gynecol. Obstet. 124 (1967) 1219–1230. 17. J. Magaziner, E.M. Simonsick, T.M. Kashner, J.R. Hebel, J.E. Kenzora, Predictors of functional recovery one year following hospital discharge for hip fracture: a prospective study, J. Gerontol. 45 (1990) M101–M107. 18. A.M. Jette, B.A. Harris, P.D. Cleary, E.W. Campion, Functional recovery after hip fracture, Arch. Phys. Med. Rehabil. 68 (1987) 735–740. 19. S.R. Cummings, S.L. Phillips, M.E. Wheat, et al., Recovery of function after hip fracture. The role of social supports, J. Am. Geriatr. Soc. 36 (1988) 801–806. 20. R.A. Marotolli, L.F. Berkman, L.M. Cooney, Decline in physical function with hip fracture, J. Am. Geriatr. Soc. 40 (1992) 861–866.
21. S.L. Silverman, D. Zingmond, Increased mortality following acute hip fractures: secular trends in California. 1990–2001, J. Bone Miner Res. 19 (2004) S49. 22. R.G. Morris, R.T. Woods, K.S. Davies, L.W. Morris, Gender differences in carers of dementia sufferers, Br. J. Psychiatr. Suppl. 10 (1991) 69–74. 23. D.T. Gold, S.D. Smith, C.W. Bales, K.W. Lyles, R.E. Westlund, M.K. Drezner, Osteoporosis in late life: does health locus of control affect psychosocial adaptation?, J. Am. Geriatr. Soc. 39 (1991) 670–675. 24. D.T. Gold, Osteoporosis and quality of life psychosocial outcomes and interventions for individual patients, Clin. Geriatr. Med. 19 (2003) 271–280. 25. K.A. Roberto, J. Bartmann, Factors related to older women’s recovery from hip fractures: physical ability, locus of control, and social support, Health Care Women Int. 14 (1993) 457–468. 26. S. Solimeo, T.J. Weber, D.T. Gold, A women’s disease? Report on men’s experiences of osteoporosis, Gerontologist 47 (2007) 606. 27. G. Greendale, E. Barrett-Connor, Outcomes of osteoporotic fracture, in: R. Marcus, D. Feldman, J. Kelsey (Eds.) Osteoporosis, Academic Press, San Diego, 2001, pp. 819–829. 28. J.D. Adachi, G. Loannidis, C. Berger, et al., Canadian Multicentre Osteoporosis Study (CaMos) Research Group. The influence of osteoporotic fractures on health-related quality of life in community-dwelling men and women across Canada, Osteoporos. Int. 12 (2001) 903–908. 29. U. Schweiger, M. Deuschle, A. Körner, et al., Low lumbar bone mineral density in patients with major depression, Am. J. Psychiatr. 151 (1994) 1691–1693. 30. U. Halbreich, N. Rojansky, S. Palter, et al., Decreased bone mineral density in medicated psychiatric patients, Psychosom. Med. 57 (1995) 485–491. 31. J. Robbins, C. Hirsch, R. Whitmer, J. Cauley, T. Harris, The association of bone mineral density and depression in an older population, J. Am. Geriatr. Soc. 49 (2001) 732–736. 32. M.A. Whooley, J.A. Cauley, J.M. Zmuda, E.M. Haney, N.W. Glynn, Depressive symptoms and bone mineral density in older men, J. Geriatr. Psychiatr. Neurol. 17 (2004) 88–92. 33. M.E. Mussolino, Depression and hip fracture risk: the NHANES I epidemiologic follow-up study, Public Health Rep. 120 (2005) 71–75. 34. E.J. Lenze, M.C. Munin, M.A. Dew, et al., Adverse effects of depression and cognitive impairment on rehabilitation participation and recovery from hip fracture, Int J Geriatr Psychiatr 19 (2004) 472–478. 35. E.J. Lenze, M.C. Munin, E.R. Skidmore, et al., Onset of depression in elderly persons after hip fracture: implications for prevention and early intervention of late-life depression, J. Am. Geriatr. Soc. 55 (2007) 81–86. 36. A. Burns, S. Banerjee, J. Morris, et al., Treatment and prevention of depression after surgery for hip fracture in older people: randomized, controlled trials, J. Am. Geriatr. Soc. 55 (2007) 75–80. 37. E.M. Dennison, H.E. Syddall, C. Statham, A. Aihie Sayer, C. Cooper, Relationships between SF-36 health profile and bone mineral density: the Hertfordshire Cohort Study, Osteoporos. Int. 17 (2006) 1435–1442. 38. J.E. Ware Jr, C.D. Sherbourne, The MOS 36-item short-form health survey (SF-36). I. Conceptual framework and item selection, Med. Care 30 (1992) 473–483.
C h a p t e r 3 2 Adverse Health Outcomes in Men with Osteoporosis l
39. I. Pande, D.L. Scott, T.W. O’Neill, C. Pritchard, A.D. Woolf, M.J. Davis, Quality of life, morbidity, and mortality after low trauma hip fracture in men, Ann. Rheum. Dis. 65 (2006) 87–92. 40. H. Ekstrom, S.D. Ivanoff, S. Elmstahl, Restriction in social participation and lower life satisfaction among fractured in pain: results from the population study ‘Good Aging in Skane’, Arch Gerontol Geriatr. 46 (2008) 409–424. 41. J. Ware Jr, M. Kosinski, S.D. Keller, A 12-item short-form health survey: construction of scales and preliminary tests of reliability and validity, Med. Care 34 (1996) 220–233. 42. B.L. Neugarten, R.J. Havinghurst, R.S. Weiner, The measurement of life satisfaction, J. Gerontol. 16 (1961) 134–143. 43. K.E. Ensrud, S.K. Ewing, B.C. Taylor for the Study of Osteoporotic Fractures Research Group, et al., Frailty and risk of falls, fracture, and mortality in older women: the study of osteoporotic fractures., J. Gerontol. A Biol. Sci. Med. Sci. 62 (2007) 744–751. 44. K.E. Ensrud, D.E. Thompson, J.A. Cauley, et al., Prevalent vertebral deformities predict mortality and hospitalization in older women with low bone mass. Fracture Intervention Trial Research Group, J. Am. Geriatr. Soc. 48 (2000) 241–249. 45. G. Ioannidis, A. Papaioannou, W.M. Hopman, et al., Absolute death rates by fracture type in Canadians, Arthritis Rheum. 58 (2008) S747. 46. D. Bliuc, D.N. Nguyen, V.E. Milch, T.V. Nguyen, J.A. Eisman, J.R. Center, Mortality risk associated with low trauma osteoporotic fracture and subsequent fracture in men and women, J. Am. Med. Assoc. 301 (2009) 513–521. 47. L.J. Melton III, Epidemiology of fractures, in: BL. Riggs, L.J Melton III (Eds.) Osteoporosis: etiology, Diagnosis and Management, Raven Press, New York, 1988, pp. 133–154. 48. G. Poor, E.J. Atkinson, W.M. O’Fallon, L.J. Melton III, Determinants of reduced survival following hip fracture in men, Clin. Orthop. 319 (1995) 260–265. 49. T.P. Van Staa, E.M. Dennison, H.G. Leufkens, C. Cooper, Epidemiology of fractures in England and Wales, Bone 29 (2001) 517–522.
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50. A.C. Scane, R.M. Francis, A.M. Sutcliffe, M.J. Francis, D.J. Rawlings, C.L. Chapple, Case-control study of the pathogenesis and sequelae of symptomatic vertebral fractures in men, Osteoporos. Int. 9 (1999) 91–97. 51. A.A. Ismail, T.W. O’Neill, C. Cooper on behalf of the EPOS study group, et al., Mortality associated with vertebral deformity in men and women: results from the European Prospective Osteoporosis study (EPOS), Osteoporos. Int. 8 (1998) 291–297. 52. R. Hasserius, M.K. Karlsson, B.E. Nilsson, I. Redlund-Johnell, O. Johnell, European Vertebral Osteoporosis Study. Prevalent vertebral deformities predict increased mortality and increased fracture rate in both men and women: a 10-year populationbased study of 598 individuals from the Swedish cohort in the European Vertebral Osteoporosis Study, Osteoporos. Int. 14 (2003) 61–68. 53. D.M. Kado, M.H. Huang, A.S. Karlamangla, E. Barrett-Connor, GA. Greendale, Hyperkyphotic posture predicts mortality in older community-dwelling men and women: a prospective study, J. Am. Geriatr. Soc. 52 (2004) 1662–1667. 54. K. Huntjens, T. van Geel, S. van Helden, P. Geusens, In men older than 50 years clinical vertebral and nonvertebral fractures cluster in time, Arthritis Rheum. 58 (2008) S941. 55. O. Johnell, J.A. Kanis, An estimate of the worldwide prevalence and disability associated with osteoporotic fractures, Osteoporos. Int. 17 (2006) 1726–1733. 56. O. Johnell, J.A. Kanis, B. Jonsson, A. Oden, H. Johansson, C. De Laet, The burden of hospitalised fractures in Sweden, Osteoporos. Int. 16 (2005) 222–228. 57. National Osteoporosis Foundation, The clinician’s guide to prevention and treatment of osteoporosis, National Osteoporosis Foundation, Washington, DC, 2008. 58. A. Papaioannou, C.C. Kennedy, G. Ioannidis, et al., CaMos Research Group (CaMos). The osteoporosis care gap in men with fragility fractures: the Canadian Multicentre Osteoporosis Study, Osteoporos. Int. 19 (2008) 581–587.
Chapter
33
Idiopathic Osteoporosis Jean-Marc Kaufman, Bruno Lapauw, Youri Taes and Stefan Goemaere Ghent University Hospital, Department of Endocrinology and Unit for Osteoporosis and Metabolic Bone Diseases, Gent, Belgium
Introduction
not distinguishable from senile osteoporosis? What about the diagnosis of idiopathic osteoporosis in men with low bone mass in the absence of prevalent fracture? In view of the lack of a generally accepted densitometry-based opera tional definition of osteoporosis in men, should the latter men without a history of fracture be labeled as having ‘idi opathic low bone mass’ rather than ‘idiopathic osteoporo sis’? Obviously, these areas of uncertainty, to name but a few, demand a pragmatic approach to the diagnosis of idiopathic osteoporosis of men. The epidemiology of idiopathic osteoporosis in men is presently largely unknown and, in any case, figures for prevalence and incidence would be expected to vary sub stantially, depending on the applied diagnostic criteria. In several series of osteoporosis in men, more than half of the subjects were found to have secondary osteoporosis. It is commonly stated that the cause of osteoporosis in men is more often secondary compared to osteoporosis in women. However, this has not been properly established. Indeed, reports on presentation and differential diagnosis of oste oporosis in men are mostly based on series collected in clinical practices and thus biased by the type of clinical practice (e.g. over-representation of rheumatoid arthritis and glucocorticoid-induced osteoporosis in a rheumatologybased practice). Furthermore, the relative prevalence of primary osteoporosis in men compared to women is likely to be underestimated in view of the much lower rate of screening and active case-finding in men, especially outside the context of major clinical fractures or presence of very well established and manifest secondary causes of oste oporosis [1–4].
Osteoporosis in men, with its clinical expression of bone fragility, may be either ‘secondary’ or ‘primary’. In sec ondary osteoporosis, the generalized quantitative and qualitative skeletal defects are an epiphenomenon and the consequence of an identifiable disease or its treatment (e.g. osteoporosis resulting from hypogonadism, gastrointesti nal malabsorption, primary hyperparathyroidism or gluco corticoid treatment) whereas, in primary osteoporosis, they are characteristics or changes inherent in the affected indi vidual. Presentations of osteoporosis considered as primary include osteoporosis linked to a specific monogenic disease (e.g. osteoporosis pseudoglioma syndrome), senile oste oporosis resulting from skeletal deterioration in aging and idiopathic osteoporosis in younger men [1–3]. It is this lat ter presentation of primary osteoporosis that is discussed in this chapter. Idiopathic osteoporosis is a diagnosis by exclusion, which implies that all established causes of osteoporosis are absent and thus also implies ignorance of the true under lying cause. In this context, one cannot assume a unique pathophysiological mechanism and idiopathic osteoporosis is undoubtedly a heterogeneous syndrome. Diagnostic cri teria are largely arbitrary and they are not carried by some general consensus or broadly endorsed guideline. Moreover, there inevitably are gray zones of overlap with other forms of osteoporosis. Potential areas of controversy are numerous. How exten sive a clinical and technical work-up to exclude secondary causes should one perform before labeling osteoporosis in a man as ‘idiopathic’? When should a risk factor identi fied in the patient’s history (e.g. high alcohol consumption, low calcium intake or high urinary calcium) no longer be regarded as a potentially contributing risk factor but rather as a secondary cause of osteoporosis in its own right? From what age in older subjects should the diagnosis of idiopathic osteoporosis no longer be made, because it is Osteoporosis in Men
Diagnosis As indicated in the introduction, idiopathic osteoporo sis is a diagnosis by exclusion and there is no generally 405
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endorsed consensus on diagnostic criteria. Main issues to be considered include bone mineral density (BMD) criteria, age, fracture prevalence and the exclusion of secondary causes.
How to Define Osteoporosis Bone mineral density criteria for osteoporosis in men are a matter of debate and there is no consensus BMD-based operational definition of osteoporosis in men [4–6]. This issue is addressed in other chapters. Briefly, when apply ing the 2.5 T-score cut-off limit for (areal) BMD by dual energy x-ray absorptiometry (DXA), similar to the com monly applied diagnostic threshold in postmenopausal women, with the T-score derived from a gender-specific ref erence population, this identifies men with a lower fracture risk than their female counterparts [6]. In epidemiological studies, fracture risk was found to be rather similar between men and women for a same absolute BMD value, which suggests that calculation of the T-score for men based on a female reference range will identify male subjects with a similar fracture risk as their female counterparts [7–9]. However, the latter findings from epidemiological studies have not been confirmed in all studies and, moreover, these observations pertain to an older age group than the men presenting with idiopathic osteoporosis [2, 6]. Finally, the use of the BMD Z-score, whereas less explicitly referring to a level of fracture risk, allows for straightforward identification of men with low bone mass relative to the expected BMD values in healthy men. The limitations of DXA, a projection technique, are well known. In this regard, techniques such as quantitative com puted tomography (QCT), which provide information on volumetric BMD, bone size and geometry, are particularly relevant to the study of the pathophysiology of idiopathic osteoporosis [2], but problems of standardization and lim ited access to dedicated software and/or hardware make them less suited for routine clinical diagnosis. A prevalent ‘major osteoporotic fracture’ is a strong independent indicator of bone fragility [10] and thus, besides and on top of a low bone mass, a valuable element for the diagnosis of osteoporosis and the identification of men at high risk of fracture. Further, whether the patient does or does not have a prevalent fracture is an element that one might have to consider when differentiating among phenotypes of idiopathic osteoporosis. Putting the focus on the clinically relevant consequences of osteoporosis, the present trend in clinical practice is to shift emphasis from ‘diagnosis of osteoporosis’ to ‘fracture risk evaluation’. In proposed algorithms, such as FRAX, also applicable to men, estimations of the 10-year abso lute fracture risk are based on combinations of clinical risk factors with or without BMD and prevalent fracture [11]. Such algorithms might be the preferable clinical approach to identify men at high fracture risk most likely to benefit
from treatment. However, they are obviously not suited to define idiopathic osteoporosis as a clinical syndrome when trying to understand its pathophysiology.
Age Developmental anomalies with deficient acquisition of peak bone mass might be a major pathophysiological mechanism in many men with idiopathic osteoporosis. Nevertheless, the diagnosis of idiopathic osteoporosis as discussed here refers to a clinical syndrome in adult men with a mature skeleton. How to justify a proposed arbitrary upper age limit for the diagnosis of idiopathic osteoporosis is an issue of potential debate related to the difficulty of distinguishing between idiopathic and senile osteoporosis in older sub jects. In men, age-specific incidence of most types of major fractures increases exponentially in the elderly, reflect ing the age-related increase of bone fragility besides an increased incidence of falls. As to date, no unique alteration of bone metabolism characteristic of senile osteoporosis has been described. Moreover, possible features of senile osteoporosis, such as tendency towards decreased bone formation and increased bone resorption, might also be encountered in idiopathic osteoporosis. Many men with idi opathic osteoporosis might present a fracture only at a later age as the consequence of (senile) bone loss superimposed on an initially low peak bone mass. In view of the inability to distinguish between older men with senile osteoporosis and men with idiopathic osteoporo sis who grew older, the diagnosis of idiopathic osteoporosis is commonly limited to men younger than 65 or 70 years [1–4], which roughly corresponds to the age when the inci dence of fractures in the male population tends to increase more steeply [7, 12–14].
Fragility Fractures The importance of a prevalent fragility fracture as a diag nostic element has been discussed earlier. In general, it is often difficult to decide whether a fracture in a patient’s history is a ‘fragility’ fracture, or rather a ‘traumatic’ frac ture [11]. For postmenopausal and senile osteoporosis, it is common practice to consider only fractures after age 50 years, but the diagnosis of idiopathic osteoporosis is often made at a younger age. On the other hand, the epidemiol ogy of fractures in men, with higher fracture incidence in males than in females from adolescence up to age 50 years, is highly suggestive for substantial contribution of trau matic fractures. This might in turn be explained by higher risk in the context of sports, on the workplace and linked to risk-taking behavior. In particular, fractures of the limbs, hands and feet are often related to trauma. Similarly, verte bral deformities as diagnosed on x-ray are more prevalent in men up to age 65 years [2, 12–14].
C h a p t e r 3 3 Idiopathic Osteoporosis l
The often made distinction between traumatic fractures and those resulting from so-called low-energy trauma, has the limitation to be a subjective one except for the more obvious cases [11]. Moreover, even fractures at younger age, although possibly not in childhood [15], and fractures associated with moderately severe trauma might be associ ated with some degree of bone fragility and increased risk of subsequent fracture, but there are few data available. Pragmatically, one can propose to consider as poten tially relevant to the diagnosis of idiopathic osteoporo sis in men any major fracture occurring in adult men that cannot be linked to a moderately severe to severe trauma. Noteworthy, distal forearm fractures in men, with an inci dence that is considerably lower than in women and shows atypically little variation during adult life, appear to be a sensitive marker of skeletal fragility in white men and pre dict a higher risk for both vertebral and hip fracture [16].
Exclusion of Secondary Causes Secondary causes of osteoporosis in men are numerous [1–4] and summarized in Table 33.1, but discussion in depth of secondary osteoporosis falls beyond the scope of this chapter. A reasonable strategy for excluding second ary causes can consist in the combination of a relatively straightforward standard set of (mostly clinical biochemis try and hormonal) screening investigations, complemented as needed by additional, more focused tests based on indi cations obtained from a careful history taking and clinical examination, or from the results of the initial biochemical screening. A thorough clinical assessment is needed for differen tial diagnosis between osteoporosis and other diseases and to detect possible underlying disease as cause of secondary osteoporosis. The medical history should address the family and fracture history, past diseases and present symptoms with special attention for common and less frequent sec ondary causes of osteoporosis, for differential diagnos tic pitfalls (e.g. osteomalacia and multiple myeloma), use of medication, lifestyle-related factors including calcium intake, exercise, use of alcohol and tobacco. In the clinical examination, attention should be paid to the anthropomet rics (body height and proportions, body mass index (BMI)), to possible signs of inherited syndromes, to signs sugges tive for causes of secondary osteoporosis, to possible con sequences of osteoporosis (e.g. thoracal spine kyphosis). The basic set of tests applied to ‘screen’ for secondary osteoporosis tends to vary according to clinician’s own biases and the characteristics of their medical practice, but the general principles are to include the tests needed to reveal major health problems (i.e. routine clinical chemis try), tests that will allow exclusion of relatively common specific causes of osteoporosis (e.g. serum calcium, testo sterone and thyroid stimulating hormone (TSH)) and tests that can be used as a common marker for a broader range
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Table 33.1 Some secondary causes of osteoporosis in men: the diagnosis of idiopathic osteoporosis is a diagnosis by exclusion Immobilization Alcoholism Endocrine disorders Hypogonadism Cushing’s syndrome Hyperparathyroidism Hyperthyroidism Diabetes mellitus (type 1) Gastrointestinal diseases Post-gastrectomy Coeliac disease Post-bariatric surgery Malabsorption syndromes (others) Inflammatory bowel disease Primary biliary cirrhosis Chronic obstructive pulmonary disease Post-transplantation Rheumatoid arthritis Hyperhomocysteinemia Neoplastic diseases Systemic mastocytosis Cystic fibrosis Homocystinuria Hypercalciuria Hemochromatosis Renal insufficiency Medication-related Glucocorticoids Anticonvulsants Chemotherapy Glitazones GnRH-analogues Anti-androgens
of possible secondary causes (e.g. low serum 25-hydroxyvitamin D and/or elevated parathyroid hormone (PTH) indi cating possible gastrointestinal malabsorption). However, no study is available that allows a proposal for a validated guideline for cost-effective investigation for secondary osteoporosis in men. In accordance with the foregoing general principles, it can be proposed that initial laboratory evaluation should include a complete blood count, a marker for inflammatory diseases (e.g. C-reactive protein), blood glucose, serum protein electrophoresis, serum ferritin and renal and liver function tests. Tests of the calciotropic axis should include serum calcium (corrected for serum albumin), phosphate, (total or bone specific) alkaline phosphatase, 25-hydroxy vitamin D and PTH. Assessment of 24 h urinary calcium excretion can reveal hypercalciuria (300 mg/24 h) or rather low calcium excretion (100 mg/24 h) as indication for low calcium intake or absorption (if no use of calcium sparing
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diuretics). Additional tests should include serum total testosterone (before 10 a.m.; if borderline, to be repeated on a separate occasion together with sex hormone binding globulin (SHBG) to calculate free/bioavailable testoster one), serum thyrotropin, serum cortisol (additional testing such as 24 h urinary free cortisol or evening salivary cor tisol if high serum value or clinical suspicion of Cushing’s syndrome). Biochemical markers of bone turnover (morn ing fasting blood sample and/or second void morning urine sample) may help differentiate between a low and a high bone turnover state, if assayed under sufficiently standard ized conditions. In many instances, spine x-ray is a needed complement to clinical evaluation, for objective documen tation of a history of clinical vertebral fracture, for differ ential diagnosis of back pain, which often is the reason for consultation, and for detection of ‘silent’ vertebral deformi ties or for confirmation and differentiation of vertebral deformities detected by DXA-based vertebral morphometry assessment. It is important to differentiate vertebral frac tures from other deformities not related to osteoporosis such as in vertebral epiphysitis (Sheuermann’s disease). Chest x-ray and abdominal ultrasound examination may be useful additional investigations in selected cases. A bone biopsy is very rarely indicated in men with severe osteoporosis and no evident cause, e.g. for exclusion of suspected systemic mastocytosis or associated osteoma lacia [1–4].
Conclusions In conclusion, idiopathic osteoporosis is a syndrome diag nosed by exclusion in adult men no older than 65 to 70 years with established low bone mass according to one of the several proposed DXA-based BMD criteria, when a reasonably comprehensive set of investigations has not revealed a secondary cause of osteoporosis. A prevalent fragility fracture is an important indicator of bone fra gility, which considerably strengthen the diagnosis of (severe) osteoporosis and helps to identify those men likely to benefit the most from treatment, but it is not generally considered a necessary condition for diagnosis.
Clinical presentation and phenotype Most commonly, the initial presentation of men with idi opathic osteoporosis may be with complaints of back pain, with a clinical fracture or on the occasion of the fortuitous finding of a vertebral fracture or diffuse osteopenia on x-ray examination performed for unrelated health problems. In reported clinical studies on idiopathic osteoporosis, all or only part of included men have a vertebral fracture, depend ing whether a prevalent vertebral fracture was an inclusion
criterion. In how far presence versus absence of a vertebral fracture contributes importantly to phenotype heterogeneity is an issue in need of further clarification.
Clinical Findings Men with idiopathic osteoporosis may be asymptomatic or present signs and symptoms of a clinical fracture. There are no clinical findings specific to men with idiopathic oste oporosis. Nevertheless, observational studies in men with idiopathic osteoporosis suggest that these men tend to have a somewhat smaller than average body size. In particular, a lower mean body weight appears to be a consistent find ing in these subjects, whether or not they have a prevalent vertebral fracture, and this appears to involve both a lower fat and lean mass [17–23]. A trend towards slightly shorter stature is reported in some [18–20,22], but not all stud ies [17, 23]. We have observed that the tendency towards slightly shorter stature results from a shorter trunk height, also in the absence of vertebral fracture, with normal length of the limbs and thus normal pubis-ground height compared to age-matched healthy controls (unpublished data).
Skeletal Phenotype In men with idiopathic osteoporosis, areal BMD, as meas ured by DXA, is usually markedly low, below the expected distribution for age, i.e. with a Z-score usually well below 2 (often a T-score below 3 using a male reference range). Although the patients have generalized low bone mass, the deficit tends to be more prominent at the axial skeleton [17, 18, 22]. The lower areal BMD results from both lower volumetric BMD and smaller bone size as indi cated by data derived from DXA at the lumbar spine and femoral neck [18, 22]. Data obtained by peripheral QCT revealed a decreased volumetric BMD for both trabecular and cortical bone at the radius and tibia and, furthermore, a decreased cortical thickness due to increased endosteal cir cumference with larger bone marrow cavity with unchanged periosteal circumference [24]. Bone histomorphometry per formed on transiliacal biopsies indicated reduced trabecu lar bone volume [25–27], trabecular thickness [25], mean wall thickness [25, 28] and cortical thickness [26, 27] with unchanged porosity [26]. Osteoid and osteoblast surfaces were reported to be reduced [26, 27], with no consistent findings on osteoid width [25, 26]. Activation frequency, erosion surfaces and mineral apposition rate were found to be unchanged [25–27], the formation rate unchanged [25] or decreased [27] and the mean resorption depth unchanged [25] or slightly increased [28]. Taken together these find ings show reduced cancellous and cortical bone volumes with indications for remodeling imbalance resulting pri marily from relatively low bone formation, without indi cation for increased bone turnover. Interestingly, Ostertag et al [29], in a cross-sectional study, reported differences
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in histomorphometric findings among men with idiopathic osteoporosis depending on whether they presented with out or with prevalent vertebral fractures. The latter men had lower trabecular bone volumes with lower trabecular connectivity and similar cortical width but greater cortical porosity compared to the men without vertebral fracture. The greater porosity resulted from higher mean area rather than density of the Haversian canals, thus suggesting greater remodeling imbalance due to greater bone resorption rather than increased turnover compared to the men without frac ture [30]. These findings suggest the existence of differ ences in phenotype between men with idiopathic low bone mass compared to men with severe osteoporosis and preva lent vertebral fracture. The question whether this represents a fundamental difference between the presentation of idi opathic osteoporosis with and without prevalent fracture or rather a different stage and severity of the disease with pos sibly additional pathophysiological mechanisms contribut ing to the fracture risk deserves further study. Moreover, taken the cross-sectional design of this study, it is not possible definitely to exclude that some of the observed differences might be a consequence of the fractures.
Physiopathology and genetics Maturational Defect or Accelerated Bone Loss? There is a convergence of clinical evidence, summarized in Table 33.2, that indicates that idiopathic low bone mass in men with or without prevalent fracture is most commonly the result of a maturational defect with deficient acquisition of bone mass, rather than being the consequence of prema ture bone loss. First, there is ample evidence that idiopathic osteoporosis in men is a ‘low bone turnover’ osteoporosis, in sharp con trast to the increased bone turnover that invariably underlies
Table 33.2 Indirect evidence for a maturational defect with deficient acquisition of bone mass as a major pathophysiological mechanism in idiopathic osteoporosis in men No indication of increased bone turnover on histomorphometry Biochemical markers do not show increased bone turnover Magnitude of bone mass deficit compared to age-matched controls is independent of age Follow up of affected men does usually not reveal rapid bone loss Besides low (volumetric) BMD subjects also have smaller bones Affected men also tend to have a smaller body size A bone mass deficit is also observed in first-degree relatives Similar phenotype with low bone mass and body weight, without increased bone turnover in up to 50% of young adult sons
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other forms of osteoporosis characterized by accelerated bone loss. Indeed, findings for histomorphometry [25–27] appear to indicate that a majority of men with idiopathic osteoporosis, including a substantial proportion of men with low bone mass and prevalent vertebral fracture, do not present with increased bone turnover [25–28]. This is corroborated by the findings for biochemical markers of bone turnover which, in most studies, were not significantly increased compared to healthy controls [18, 23, 27, 30]. An isolated increase of urinary markers of bone collagen degradation expressed in function of creatinine excretion, without changes in serum bone formation markers, in some studies [20, 31] appears to reflect low creatinine excre tion, in line with the lower lean body mass in men with idi opathic osteoporosis, rather than increased bone resorption [20]. Pietschmann et al [32] reported increased values for markers of bone resorption, without increased values for markers of bone formation, but the study was rather mod estly sized and included also older patients. Moreover, the bone mass deficit in the patients compared to age-matched controls appears largely independent of age [18, 22] and, finally, in longitudinal follow up of untreated men with idiopathic osteoporosis, we did not observe accelerated bone loss (unpublished results). Secondly, there is strong evidence pointing towards a familial, likely genetically determined, maturational defect. Indeed, there is a strong familial component with decreased BMD in first-degree relatives [17, 18, 22]. In a family study of male probands with idiopathic osteoporosis, as many as 50% of young adult sons were also affected (Z-score 2), presenting a similar phenotype with a more pro nounced deficit at the spine with low volumetric BMD and smaller bone size, with a deficit in body weight and without increased biochemical markers of bone turnover [18]. In families of male probands, a strong resemblance persisted after adjusting for environment [33]. In a complex segrega tion analysis accounting for gene-covariate interaction in 100 European pedigrees selected through a male proband, i.e. a combined analysis of two already mentioned similar family studies [17, 18], the best fitting models suggested a codominant major gene accounting for about 45% of spine and femoral neck BMDs adjusted for gender, age and BMI. However, substantial residual correlations were also found and these remained highly significant after accounting for the major gene [34]. A genome-wide linkage screen in these European pedigrees provided evidence for signifi cant or suggestive trait loci for lumbar spine (loci 17q2123, 11q12-13, and 22q11) and femoral neck BMD (locus 13q12-14) [35]. Ferrari et al [19] reported that a haplotype based on two polymorphisms in exon 9 and 18 of the LRP5 gene, respectively, was significantly associated with idiopathic osteoporosis in males. In 66 male probands with idi opathic osteoporosis, Crabbe et al [36] performed a muta tion analysis of the 23 exons and intron-exon boundaries
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and found in two men a mutation of the LRP5 gene with proven functionality. It was concluded that carrying a muta tion in the LRP5 gene is a risk factor for idiopathic oste oporosis but that, overall, idiopathic osteoporosis in men is infrequently underlied by such a mutation. Rosen et al [37] reported association of idiopathic osteoporosis in men with a polymorphic CA repeat in the insulin-like growth factor I (IGF-I) gene. Delany et al [38] described an association between polymorphisms in the 3UTR regulatory region of the osteonectin gene with BMD in Caucasian men with idiopathic osteoporosis.
Role of Hormonal Factors? Etiological considerations are per definition only specula tive, but there are interesting clues that offer directions for further research. The relative skeletal site and gender spe cificity observed in family studies suggest the possibility of alteration in bone acquisition during specific phases of pubertal development. In this regard, the observations of more pronounced bone mass and size deficits at the spine in men with idiopathic osteoporosis and of a shorter trunk height, might point towards some alterations in a late phase of pubertal development, when growth of long bones has ceased while growth of the axial skeleton is still ongoing [39]. However, this is a yet to be validated working hypoth esis and whether a defect might in fact already be apparent before puberty in affected children is presently not known. As to the hormonal factors possibly involved, it should be noted that, whereas the data point towards a develop mental defect underlying the pathogenesis of idiopathic osteoporosis in men, presently no information is available on hormonal status during the growth and pubertal develop ment in these patients. Evidence obtained in adult patients can thus only be circumstantial as observed hormonal alter ations in adults might not reliably reflect the situation dur ing development. There have been several reports of lower circulating IGF-I levels in men with idiopathic osteoporosis [27, 40, 41]. The serum levels of IGF-I in men with idiopathic oste oporosis have been reported to be positively correlated with BMD [40] and with osteoblastic surface [41] and inversely with percent eroded surfaces [27]. Lower circulating IGF-I in these patients does not result from a decreased growth hormone secretory reserve [31, 42]. Johansson et al [28] found no differences between patients and controls for growth hormone and IGF-I, but lower levels of IGF-binding protein 3 in men with idiopathic osteoporosis. Pernow et al [25] described a positive association of the IGF-I over IGFbinding proteinI levels with osteoid thickness. Low serum total and/or free estradiol in men with idi opathic osteoporosis has been found by several authors [23, 24, 32, 43, 44], but not by others [20, 30] although, in the latter reports, the authors did observe weak correlations between serum estradiol and BMD in osteoporotic men.
Albeit these data allow only for speculation on the existence of some deficit in skeletal estrogenic action during pubertal development, interestingly, we observed also lower levels of estradiol, compared to age-matched controls, in the affected young adult sons of men with idiopathic osteoporosis, but not in the sons with normal BMD [44]. Since estrogens are known to be important for skeletal maturation and miner alization during growth [45, 46], with serum (free and total) estradiol being positively correlated with areal and volumet ric BMD and negatively with endosteal circumference at age of peak bone mass in young adult men [47], a role of altered estrogen action in the deficient acquisition of bone mass and size in men with idiopathic osteoporosis can be suspected. In this regard, the bone phenotype in the men with idio pathic osteoporosis, with deficits in trabecular and cortical volumetric BMD and thinner cortices due to larger endo steal cavities [18, 24], seems to be in line with the findings of lower (free) estradiol levels. In our patients, we observed that the lower body weight, which is part of the pheno type of men with idiopathic osteoporosis, reflects in part a smaller fat mass as assessed by whole body DXA, which might in turn play a role in the lower estrogen levels, since fat tissue is a major site for aromatization of androgens. Although there have been occasional reports of lower free androgen index, a less reliable parameter of free or bioavailable testosterone serum concentrations, in men with idiopathic osteoporosis [23, 32], no consistent altera tions in serum (free or bioavailable) testosterone have been observed. A relatively consistent finding in men with idi opathic osteoporosis has been elevated serum levels of SHBG [20, 23, 30–32, 44, 48]. The lower BMI and possibly lower IGF-I levels might play a role in the higher SHBG levels which, in turn, may modulate tissue exposure to sex steroids [49].
Treatment Few prospective, randomized trials of osteoporosis thera pies have been performed in men and even less so spe cifically in men with idiopathic osteoporosis. Anderson et al [50] reported decreased bone turnover assessed by biochemical markers during testosterone treatment in an uncontrolled study of 6 months’ duration in 21 eugo nadal men with osteoporosis. Gillberg et al [51] reported an increase in BMD in men with idiopathic osteoporosis treated for 2 years with daily or intermittent subcutaneous growth hormone (GH) injections, in an uncontrolled study involving 29 patients. Kurland et al [52] conducted a rand omized, placebo-controlled double-blind trial of 18 months duration in 23 men with idiopathic osteoporosis, showing that daily subcutaneous injections of PTH (1–34) markedly increase global turnover as indicated by a marked increase of bone formation and resorption markers and resulting in a
C h a p t e r 3 3 Idiopathic Osteoporosis l
marked BMD increase at the spine with a less pronounced increase at the femoral neck. Larger randomized trials that have demonstrated increased BMD under treatment with bisphosphonates [53, 54] or teriparatide [PTH(1–34)] [55, 56] in men with osteoporosis did not include specifically patients with idi opathic osteoporosis but, in these studies, treatment effects appeared to be largely independent of baseline character istics such as age, bone turnover or prevalent sex steroid levels. Although in view of the absence of increased bone turnover or accelerated bone loss in most men with idi opathic osteoporosis, treatment with anabolic agents, such as daily injections of PTH, would seem the most logical treatment option on theoretical basis, available information seems to indicate that the patients will respond also to antiresorptive treatment with bisphosphonates [53, 54]. Primary endpoint in all randomized trials of osteoporosis therapies in men was changes in BMD and presently data on the effect of treatment on fracture risk reduction in men are very limited [53, 56]. In this context, pharmacological treatment other than calcium and vitamin D supplementa tion should be considered a priority for men with severe idiopathic osteoporosis with prevalent fractures. In younger men without prevalent fracture or indications for rapid bone loss, and thus with rather moderate absolute fracture risk, a more conservative approach seems advisable with mainly observation and advice on healthy lifestyle with calcium and vitamin D supplementation as appropriate.
Areas for further research Although some progress has been made in our understand ing of the processes underlying idiopathic osteoporosis in men, our knowledge base remains rather limited. Further progress is first of all dependent on pursued efforts for a detailed description of phenotypes with attention to anthro pometrics, bone geometry and microarchitecture, as well as histomorphometry and further hormonal and biochemical profiling. The manifestly substantial genetic component in the pathogenesis of idiopathic osteoporosis warrants pur sued genetic studies to evaluate further the impact of com mon gene variants, but also looking for major gene effects. In these studies, it is important to consider common genetic factors explaining related phenotypic characteristics. In par ticular, the common genetic determinants of skeletal status and other aspects of body composition is undoubtedly an important area for further research. Albeit available data on hormonal factors in the patho genesis of idiopathic osteoporosis in men do not yet allow for any firm conclusion, they do offer intriguing clues and warrant further research in this area. Considering the evidence for a developmental defect in the pathogenesis of idiopathic osteoporosis in a substantial proportion of affected men, the search for etiological
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clues should not be limited to adults or even to the puber tal period since individual determination of bone mass is already evident in prepubertal children. In this context, lon gitudinal follow-up study of children from affected families should provide useful information.
Acknowledgments Part of this work was supported by grant G.O662.07 from the Research Foundation Flanders (FWO; Fonds voor Wetenschappelijk Onderzoek Vlaanderen).
References 1. J.P. Bilezikian, Osteoporosis in men, J. Clin. Endocrinol. Metab. 84 (1999) 3431–3443. 2. S. Khosla, S. Amin, E. Orwoll, Osteoporosis in men, Endocrine Rev. 29 (2008) 441–464. 3. J.M. Kaufman, S. Goemaere, Osteoporosis in men, Best Pract. Res. Clin. Endocrinol. Metab. 22 (2008) 787–812. 4. J.M. Kaufman, O. Johnell, E. Abadie, et al., Background for studies on the treatment of male osteoporosis: state of the art, Ann. Rheum. Dis. 59 (2000) 765–772. 5. E. Seeman, The structural basis of bone fragility in men, Bone 25 (1999) 143–147. 6. K.G. Faulkner, E. Orwoll, Implications in the use of T-scores for the diagnosis of osteoporosis in men, J. Clin. Densitom. 5 (2002) 87–93. 7. C.E. De Laet, B.A. Van Hout, H. Burger, A.E.A.M. Weel, A. Hofman, H.A.P. Pols, Hip fracture prediction in elderly men and women: validation in the Rotterdam study, J. Bone Miner. Res. 13 (1998) 1587–1593. 8. T.W. O’Neill, M. Lunt, A.J. Silman, The relationship between bone density and incident vertebral fracture in men and women, J. Bone Miner. Res. 17 (2002) 2214–2221. 9. C.E. De Laet, M. van der Klift, A. Hofman, H.A. Pols, Osteoporosis in men and women: a story about bone min eral density thresholds and hip fracture, J. Bone Miner. Res. 17 (2002) 2231–2236. 10. J.A. Kanis, O. Johnell, C. De Laet, et al., A meta-analysis of previous fracture and subsequent fracture risk, Bone 35 (2004) 375–382. 11. J.A. Kanis, On behalf of the World Health Organization Scientific Group. Assessment of osteoporosis at the pri mary health-care level. Technical report, 2007. World Health Organization Collaborating Centre for Metabolic Bone Diseases, University of Sheffield, Sheffield. 12. T.W. O’Neill, D. Felsenberg, J. Varlow, et al., The prevalence of vertebral deformity in European men and women: the European Vertebral Osteoporosis Study, J. Bone Miner. Res. 11 (1996) 1010–1018. 13. T.P. Van Staa, E.M. Dennison, H.G. Leufkens, C. Cooper, Epidemiology of fractures in England and Wales, Bone 29 (2001) 517–522. 14. W.M. Garraway, R.N. Stauffer, L.T. Kurland, W.M. O’Fallon, Limb fractures in a defined population. I. Frequency and dis tribution, Mayo. Clin. Proc. 54 (1979) 701–707.
412
Osteoporosis in Men
15. S.R. Pye, J. Tobias, A.J. Silman, J. Reeve, T.W. O’Neill, on behalf of the EPOS Study Group, Childhood fractures do not predict future fractures: results from the European Prospective Osteoporosis Study, J. Bone Miner. Res. (2009) Epub March 31 ahead of print. 16. P. Haentjes, O. Sohnell, J.A. Kanis, et al., Evidence from data searches and life-table analysis for gender-related abso lute risk of hip fracture after Colle’s or spine fracture. Colle’s fracture as an early and sensitive marker of skeletal fragility in white men, J. Bone Miner. Res. 19 (2004) 1933–1944. 17. M.E. Cohen-Solal, C. Baudouin, M. Omouri, D. Kuntz, M.C. De Vernejoul, Bone mass in middle-aged osteoporotic men and their relatives: familial effect, J. Bone Miner. Res. 13 (1998) 1909–1914. 18. I. Van Pottelbergh, S. Goemaere, D. Zmierczak De Bacquer, J.M.I. Kaufman, Deficient acquisition of bone during matura tion underlies idiopathic osteoporosis in men, J. Bone Miner. Res. 18 (2003) 303–311. 19. S.L. Ferrari, S. Deutsch, C. Baudouin, et al., LRP5 gene polymorphisms and idiopathic osteoporosis in men, Bone 37 (2005) 770–775. 20. S.F. Evans, M.W.J. Davie, Low body size and elevated sexhormone binding globulin distinguish men with idiopathic vertebral fracture, Calcif. Tissue Int. 70 (2002) 9–15. 21. J. Macdonald, S. Evans, M.W.J. Davie, C. Sharp, Muscle mass deficits are associated with bone mineral density in men with idiopathic vertebral fracture, Osteoporos. Int. 18 (2007) 1371–1378. 22. B. Erbas, S. Ristevski, C. Poon, S. Yeung, P.R. Ebeling, Decreased spinal and femoral neck volumetric bone mineral density (BMD) in men with primary osteoporosis and their first-degree male relatives: familial effect on BMD in men, Clin. Endocrinol. (Oxf.) 66 (2007) 78–84. 23. P. Gillberg, A.G. Johansson, S. Ljunghall, Decreased estradiol levels and free androgen index and elevated sex hormonebinding globulin levels in male idiopathic osteoporosis, Calcif. Tissue Int. 64 (1999) 209–213. 24. B. Lapauw, Y. Taes, S. Goemaere, H.G. Zmierczac, J.M. Kaufman, Cortical bone size and geometry in men with idi opathic osteoporosis: further evidence for deficient estrogen action during maturation. The Endocrine Society (USA) 91st Annual Meeting, June 10-12 2009, abstract OR 13-4. 25. Y. Pernow, E.M. Hauge, K. Linder, E. Dahl, M. Sääf, Bone histomorphometry in male idiopathic osteoporosis, Calcif. Tissue Int. 84 (2009) 430–438. 26. M. Ciria-Recasens, L. Pérez-Edi, J. Blanch-Rubió, et al., Bone histomorphometry in 22 male patients with normocal ciuric idiopathic osteoporosis, Bone 36 (2005) 926–930. 27. E.S. Kurland, C.J. Rosen, F. Cosman, et al., Insulin-like growth-factor-I in men with idiopathic osteoporosis, J. Clin. Endocrinol. Metab. 82 (1997) 2799–2805. 28. A.G. Johansson, E.F. Eriksen, E. Lindh, et al., Reduced serum levels of the growth hormone-dependent insulin-like growth fac tor binding protein and a negative bone balance at the level of the individual bone remodelling units in idiopathic osteoporosis in men, J. Clin. Endocrinol. Metab. 82 (1997) 2795–2798. 29. A. Ostertag, M. Cohen-Solal, M. Audran, et al., Vertebral fractures are associated with increased cortical porosity in iliac crest bone biopsy of men with idiopathic osteoporosis, Bone 44 (2009) 413–417.
30. C. Lormeau, B. Soudan, M. d’Herbomez, P. Pigny, B. Duquesnoy, B. Cortet, Sex hormone-binding globulin, estradiol, and bone turnover markers in male osteoporosis, Bone 34 (2004) 933–939. 31. P. Gillberg, A.G. Johansson, W.F. Blum, T. Groth, S. Ljunghall, Growth hormone secretion and sensitivity in men with idiopathic osteoporosis, Calcif. Tissue Int. 68 (2001) 67–73. 32. P. Pietschmann, S. Kudlacek, J. Grisar, et al., Bone turnover markers and sex hormones in men with idiopathic osteoporo sis, Eur. J. Clin. Invest. 31 (2001) 444–451. 33. C. Baudoin, M.E. Cohen-Solal, J. Beaudreuil, M.C. De Vernejoul, Genetic and environmental factors affect bone density variances of families of men and women with oste oporosis, J. Clin. Endocrinol. Metab. 87 (2002) 2053–2059. 34. C. Pelat, I. Van Pottelbergh, M. Cohen-Solal, et al., Complex segregation analysis accounting for GxE of bone mineral den sity in European pedigrees selected through a male proband with low BMD, Ann. Hum. Genet. 71 (2007) 29–42. 35. J.M. Kaufman, A. Ostertag, A. Saint-Pierre, et al., Genomewide linkage screen of bone mineral density (BMD) in European pedigrees ascertained through a male relative with low BMD values: evidence for quantitative trait loci on 17q21-23, 11q12-13, 13q12-14, and 22q11, J. Clin. Endocrinol. Metab. 93 (2008) 3755–3762. 36. P. Crabbe, W. Balemans, A. Willaert, et al., Missense mutations in LRP5 are not a common cause of idiopathic osteoporosis in adult men, J. Bone Miner. Res. 20 (2005) 1951–1959. 37. C.J. Rosen, E.S. Kurland, D. Vereault, et al., An association between serum IGF-1 and a simple sequence repeat in the IGF-1 gene: implications for genetic studies of bone mineral density, J. Clin. Endocrinol. Metab. 83 (1998) 2286–2290. 38. A.M. Delany, D.J. McMahon, J.S. Powel, D.A. Greenberg, E.S. Kurland, Osteonectin/SPARC polymorphisms in Caucasian men with idiopathic osteoporosis, Osteoporosis Int. 19 (2008) 969–978. 39. E. Seeman, Pathogenesis of bone fragility in women and men, Lancet 359 (2002) 1841–1850. 40. S. Ljunghall, A.G. Johansson, P. Burnan, O. Kampe, E. Lindh, F.A. Karlsson, Low plasma levels of insulin-like growth fac tor 1 (IGF1) in male patients with idiopathic osteoporosis, J. Intern. Med. 232 (1992) 59–64. 41. B.Y. Reed, J.E. Zerwekh, K. Sakhaee, N.A. Breslau, F. Gottschalk, C.Y.C. Pak, Serum IGF 1 is low and correlated with osteoblastic surface in idiopathic osteoporosis, J. Bone Miner. Res. 10 (1995) 1218–1224. 42. E.S. Kurland, F.K.W. Chan, C.J. Rosen, J.P. Bilezikian, Normal growth hormone secretory reserve in men with idiopathic oste oporosis and reduced circulating levels of insulin-like growth factor-1, J. Clin. Endocrinol. Metab. 83 (1998) 1–4. 43. C.G. Carlsen, T.H. Soerensen, E.F. Eriksen, Prevalence of low serum estrogen levels in male osteoporosis, Osteoporosis Int. 11 (2000) 697–701. 44. I. Van Pottelbergh, S. Goemaere, H. Zmierczac, J.M. Kaufman, Perturbed sex steroid status in men with idiopathic osteoporosis and their sons, J. Clin. Endocrinol. Metab. 89 (2004) 4949–4953. 45. J.P. Bilezikian, A. Morishima, J. Bell, M.M. Grumbach, Increased bone mass as a result of estrogen therapy in a man with aromatase deficiency, N. Engl. J. Med. 339 (1998) 599–603.
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46. D. Vanderschueren, K. Venken, J. Ophoff, R. Bouillon, S. Boonen, Sex steroids and the periosteum – reconsidering the roles of androgens and estrogens in periosteal expansion, J. Clin. Endocrinol. Metab. 91 (2006) 378–382. 47. B. Lapauw, Y. Taes, V. Bogaert, et al., Serum estradiol is associated with volumetric bone mineral density and modu lates the impact of physical activity on bone size at the age of peak bone mass: a study in healthy male siblings, J. Bone Miner. Res. 24 (2009) 1075–1085. 48. E. Legrand, C. Hedde, Y. Gallois, et al., Osteoporosis in men: a potential role for the sex hormone binding globulin, Bone 29 (2001) 90–95. 49. A. Vermeulen, J.M. Kaufman, V.A. Giagulli, Influence of some biological indexes on sex hormone-binding globulin and androgen levels in aging or obese males, J. Clin. Endocrinol. Metab. 81 (1996) 1821–1826. 50. S.H. Anderson, R.M. Francis, R.T. Peaston, H.J. Wastell, Androgen supplementation in eugonadal men with osteoporo sis: effect of six months’ treatment on markers of bone forma tion and resorption, J. Bone Miner. Res. 12 (1997) 472–478. 51. P. Gillberg, H. Mallmin, M. Petrén-Mallmin, S. Ljunghall, A.G. Nilsson, Two years of treatment with human recombinant
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54.
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56.
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growth hormone increases bone mineral density in men with idiopathic osteoporosis, J. Clin. Endocrinol. Metab. 87 (2002) 4900–4906. E.S. Kurland, F. Cosman, D.J. McMahon, C.J. Rosen, R. Lindsay, J.P. Bilezikian, Parathormone as a therapy for idiopathic osteoporosis in men: effects on bone mineral den sity and bone markers, J. Clin. Endocrinol. Metab. 85 (2000) 3069–3076. E. Orwoll, M. Ettinger, S. Weiss, et al., Alendronate for the treatment of osteoporosis in men, N. Engl. J. Med. 343 (2000) 604–610. S. Boonen, E.S. Orwoll, D. Wenderoth, K.J. Stoner, R. Eusebio, P.D. Delmas, Once-weekly residronate in men with osteoporo sis: results of a 2-year, placebo-controlled, double-blind, multi center study, J. Bone Miner. Res. 24 (2009) 719–725. E.S. Orwoll, W.H. Scheele, S. Paul, et al., The effect of teri paratide [human parathyroid hormone (1-34)] on bone density in men with osteoporosis, J. Bone Miner. Res. 18 (2003) 9–17. J.M. Kaufman, E. Orwoll, S. Goemaere, et al., Teriparatide effects on vertebral fractures and bone mineral density in men with osteoporosis: treatment and discontinuation of therapy, Osteoporosis Int. 16 (2005) 510–516.
Chapter
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Glucocorticoid-induced Osteoporosis Gherardo Mazziotti and Andrea Giustina Department of Medical and Surgical Sciences, University of Brescia, Italy
Epidemiology
both associated with bone loss, independently of glucocorticoid treatment [12, 13]. The systemic release of inflammatory cytokines, which affect bone formation and bone resorption, may have a pathophysiological role in bone loss in these settings. Chronic obstructive pulmonary disease is usually reported as the most frequent cause of chronic glucocorticoid treatment in men [14, 15]. Endogenous hypercortisolism is less frequently a cause of GIO, although a recent paper showed that up to 10% of males attending an outpatient clinic of osteoporosis may have a subclinical Cushing’s syndrome [16]. Fragility fractures can be the presenting manifestation of Cushing’s syndrome, either clinical or subclinical [17, 18]. Limited data from cross-sectional studies show that at least 30–50% of patients with overt Cushing’s syndrome experience fractures, particularly at the vertebral level [17, 18]. The prevalence of osteoporosis in adults with Cushing’s syndrome has been suggested to be greater in males as compared to females [19]. Although remission of Cushing’s syndrome may lead to improvement in the attendant osteoporosis, recovery of bone loss is gradual and often incomplete [20].
Glucocorticoid-induced osteoporosis (GIO) is the most frequent form of secondary osteoporosis in males as well as in females [1, 2]. GIO is almost always caused by exogenous glucocorticoids which are widely used in the treatment of autoimmune, pulmonary and gastrointestinal disorders, as well as in patients after organ transplantation and with neoplastic diseases [3–5]. Approximately 1% of the population is under oral glucocorticoid treatment and, in the elderly, this prevalence rises to 2.5% [6]. Unfortunately, glucocorticoids also have several potential side effects, one of the most common being GIO with increased risk of vertebral and nonvertebral fractures [6]. In men, the fracture risk is low during midlife and increases after 65 years of age remaining lower compared with women [3]. It was calculated that the median risk score for a clinical osteoporotic fracture in men starting glucocorticoid treatment was 13, 22 and 31 for the ages 40–49, 60–69 and 80–89 years, respectively [7]. Likewise, the 10year probability to develop any osteoporotic fractures in men taking glucocorticoids is 7.5% regardless of bone mineral density (BMD), increasing to 15% in presence of a low BMD [8]. Fracture risk increases rapidly after starting oral corticosteroid treatment and is also related to the dose and duration of glucocorticoid exposure. Doses as low as 2.5– 7.5 mg of prednisolone equivalents per day can be associated with a 2.5-fold increase in vertebral fractures, but the risk is greater with higher doses used for prolonged periods [6, 9]. It is noteworthy that fracture risk returns toward baseline levels after discontinuation of oral corticosteroids, although the reversal time seems to be variable [3, 10]. The risk of osteoporotic fractures remains slightly increased in patients undergoing cyclic corticosteroid treatment at high doses [11]. Many disorders for which glucocorticoids are prescribed are themselves cause of osteoporosis. Rheumatoid arthritis and chronic obstructive pulmonary disease, for example, are Osteoporosis in Men
Pathophysiology Glucocorticoids have both direct and indirect effects on bone. The central pathophysiological mechanism of bone loss during long-term use of glucocorticoids is reduced bone formation, due to actions that affect osteoblast differentiation and function. However, during the first phases of glucocorticoid excess, significant increase in bone resorption (ultimately leading to the observed early increase of risk of fractures) may occur. Glucocorticoids may impair the differentiation of bone marrow stromal cells into cells of the osteoblastic lineage; 415
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precursor cells in the presence of glucocorticoids preferentially differentiate in to adipocytes [21]. Mechanisms involved include the induction of peroxisome proliferator activated receptor 2, the regulation of nuclear factors of the CAAT enhancer-binding protein family and the inhibition of Wnt/beta-catenin signaling [21]. Wnt signaling has emerged as a novel, key pathway for promoting osteo blastogenesis [22]. In skeletal cells in which the canonical Wnt/-catenin signaling pathway is active [23], when Wnt is absent, -catenin is phosphorylated by glycogen-synthase kinase-3 (GSK-3) and then degraded by ubiquitination. When Wnt is present, it binds to specific receptors leading to inhibition of GSK-3 activity and translocation of stabilized -catenin to the nucleus, where it associates with transcription factors to regulate gene expression [22]. Deletions of either Wnt or -catenin result in the absence of osteo blastogenesis and increased osteoclastogenesis [22]. The Wnt pathway can be inactivated by Dickkopf, an antagonist that prevents Wnt binding to its receptor complex, the expression of which is enhanced by glucocorticoids, that maintaining GSK 3- in an active state ultimately leads to the inactivation of -catenin [22, 24]. Glucocorticoids also inhibit osteoblast cell differentiation and inhibit osteoblast-driven synthesis of type I collagen, the major component of bone extracellular matrix [1]. The result is a decrease in bone matrix available for mineralization. Glucocorticoids have pro-apoptotic effects on osteo blasts and osteocytes [25]. Glucocorticoids may also affect the metabolism and function of osteocytes, modifying the elastic modulus surrounding osteocyte lacunae and causing reduced mineral to matrix ratios in the same areas with an increase in lacunar size [26]. These effects of glucocorticoids on osteocytes might account for a disproportionate loss of bone strength in relation to bone mass. The initial bone loss occurring in patients exposed to glucocorticoids may be secondary to increased bone resorption [4, 27]. In fact, glucocorticoids may increase the expression of receptor activator of NF-B ligand (RANKL) and decrease the expression of its soluble decoy receptor, osteoprotegerin (OPG) in stromal and osteoblastic cells [1, 28]. The combination of an increase in RANKL, a potent activator of osteoclasts, and a reduction in OPG, an inhibitor of RANKL action, leads to the initial phase of rapid bone loss. Glucocorticoids also enhance the expression of macrophage colony-stimulating factor (MCSF) which, in the presence of RANKL induces osteoclastogenesis [1]. Moreover, glucocorticoids have been demonstrated to upregulate receptor subunits for osteoclastogenic cytokines of the gp130 family [29]. Furthermore, glucocorticoids may decrease apoptosis of mature osteoclasts [30]. Consequently, there is increased formation of osteoclasts with a prolonged life span explaining, at the cellular level, the enhanced and prolonged bone resorption observed at least in the initial phases of GIO. The direct effects of glucocorticoids on osteoclasts also
Table 34.1 Behaviour of different parameters of spontaneous parathyroid hormone (PTH) secretion in glucocorticoid-treated versus control males Increased
Unchanged
Decreased
Pulse secretory rate* Fractional pulsatile secretion*
Total number of bursts Mean PTH concentration Mean integrated area
Tonic secretory rate*
Based on data from [32]. * P 0.05 versus controls
may contribute to a reduction of osteoblast function during glucocorticoid exposure [31]. Glucocorticoids may have also indirect effects on bone [1]. In fact, glucocorticoids may decrease calcium absorption from the gastrointestinal tract by opposing vitamin D action. Renal tubular calcium reabsorption is also inhibited by glucocorticoids. As a consequence of these effects, secondary hyperparathyroidism has been postulated to develop. However, other studies did not confirm that glucocorticoids are associated with increased baseline levels of parathyroid hormone (PTH). As a matter of fact, these two sets of evidence may be reconciled by recent data showing that glucocorticoids may significantly affect spontaneous PTH secretory dynamic in males, with a decrease in the tonic release of PTH and an increase in pulsatile bursts of the hormone (Table 34.1) [32]. Glucocorticoids may also enhance the sensitivity to PTH by changing the number of PTH receptors and their affinity for PTH [1]. Glucocorticoids may also influence the production and action of hormones that regulate bone and calcium metabolism. Although hypogonadism seems to be not contributing to GIO in experimental animals [33], in clinical conditions, decreased serum testosterone levels are frequently demonstrated in males during glucocorticoid treatment [34]. Reduced gonadotropin production and a direct effect on testosterone production from the testes may play a pathophysiological role in this regard (Figure 34.1). A direct interaction between glucocorticoids and testosterone is supported by molecular studies showing heterodimer formation between androgen and glucocorticoid receptors and mutual inhibition of transcriptional activity [35]. Hypogonadism may contribute to bone loss and fractures in GIO not only via negative effects on bone mass but also on muscle function (see Figure 34.1). In particular, hypogonadism may enhance the glucocorticoid-induced sarcopenia, thereby increasing the likelihood of falls and consequent fractures in male patients. Glucocorticoids also regulate the growth hormone/insulinlike growth factor-I (GH/IGF-I) axis [36] (Figure 34.2). GH secretion is blunted by glucocorticoids mainly via an increased hypothalamic somostatin tone and glucocorticoids also decrease IGF-I transcription in osteoblasts [37–39] (see Figure 34.2). It is interesting that blunted GH secretion
C h a p t e r 3 4 Glucocorticoid-induced Osteoporosis l
glucocorticoid molecules [42]. An increase of 11-hydroxy steroid dehydrogenase type 1 activity may possibly provide an explanation for the enhanced glucocorticoid effects in the skeleton of elderly subjects [43]. Furthermore, glucocorticoid receptor gene polymorphism may play a role in determining gender differences in bone effects of glucocorticoids [44]. In fact, there is recent evidence that glucocorticoid receptor gene polymorphism is correlated with BMD in males but not in females [45].
PITUITARY FSH LH GCs + +
TESTIS –
GCs
417
GCs TESTOSTERONE –+
+ –
BONE
MUSCLE
Figure 34.1 Systemic effects of glucocorticoids (GCs) on testosterone secretion and action in men. Solid lines indicate major effects of GCs. FSH: follicle stimulating hormone; LH: luteinizing hormone.
SS
GHRH
+ –
+
GCs
PITUITARY GH –
+ LIVER
IGF-I – +
GCs
BONE
Figure 34.2 Systemic effects of glucocorticoids (GCs) on GH/IGF-I-bone axis. Solid lines indicate major effects of GCs. GHRH: growth hormone releasing hormone; IGF-I: insulin-like growth hormone; SS: somatotropin.
in male asthmatic patients receiving inhaled corticosteroids is observed in association with reduced ultrasonometric bone density [40], suggesting that inhaled steroid-mediated inhibition of synthesis or release of GH may be involved in bone loss [40, 41]. Variable individual susceptibility to glucocorticoids may be due to differential absorption, distribution or metabolism of the steroid molecule or to the number and affinity of glucocorticoid receptors or their nuclear co-factors [42]. An attractive explanation to account for inter-individual variability among those exposed to glucocorticoids is related to a peripheral enzyme system that converts active and inactive
Diagnosis Despite the fact that glucocorticoids can cause osteoporosis and fractures, many patients receiving or initiating longterm glucocorticoid therapy are not evaluated for their bone status. The awareness of GIO seems to be much lower when males are concerned [14, 46]. In a retrospective chart review, BMD measurement was performed or prescribed only to less than 50% of men taking glucocorticoids and this was crucial for a subsequent initiation of antiosteoporotic treatment in these subjects [14]. Indeed, a consensus is still lacking on if or when to perform and how to interpret BMD measurement in males with GIO. In fact, while authoritative intervention guidelines recommend that a BMD measurement should be made in individuals starting glucocorticoid therapy and before administering bisphosphonates in all subjects taking glucocorticoids [47], other guidelines recommend BMD measurement only in subjects younger than 65 years [48]. Moreover, although BMD is highly predictive of fracture risk in men, this relationship is not as well established as in women [2]. Therefore, if, in general, the best cut-off to identify men at high risk of fracture is still not well defined, in patients with GIO, in particular, this issue is open since fractures tend to occur at lower BMD threshold than in the other forms of osteoporosis [49, 50]. This point has to be taken into account when treatment recommendations are made on the basis of BMD measurements. The intervention threshold of the Royal College of Physicians is a T-score of 1.5 and that of the American College of Rheumatology (ACR) a T-score of 1, both cut-offs that are much higher than the T-score treatment threshold of 2.5 in postmenopausal women [51]. It remains to be clarified whether these cut-offs may be of clinical utility in men taking glucocorticoids, especially when they are drawn from reference ranges obtained in women. The identification of vertebral osteoporotic fractures in patients under chronic glucocorticoid treatment may be important for the therapeutical decision-making process [48]. In fact, as in other forms of secondary osteoporosis [52–54], in GIO, vertebral fractures may be asymptomatic [55]. Therefore, since the clinical history may not be reliable, a radiological approach with morphometric analysis is often necessary for the identification of vertebral deformities.
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The Royal College of Physicians guidelines recommend evaluation of calcium metabolism in all subjects in order to select those for whom vitamin D and/or calcium supplementation are indicated [48]. In contrast, according to ACR guidelines, this metabolic assessment may not be necessary since calcium and vitamin D supplementation is recommended in all patients with GIO independently of their baseline vitamin D status [47]. The role of biochemical markers of bone turnover in the diagnostic work-up in GIO has not yet been established with their levels also varying in the different stages of the disease [56]. In fact, following the initial exposure to glucocorticoids, there is an increase in biochemical markers of bone resorption, which is followed by a long-standing suppression of markers of bone formation and bone resorption [56]. Finally, the assessment of gonadal function may be useful for the subsequent treatment of GIO. In men taking glucocorticoids, low total and free-testosterone are frequently found. This status may be combined with low or normal serum gonadotropin levels as expression of a secondary hypogonadism [34].
Therapy Guidelines published by ACR and the Royal College of Physicians advocate the following measures for the prevention and treatment of GIO: general health awareness; administration of sufficient calcium and vitamin D; reduction of the dose of corticosteroids to a minimum; and, when indicated, therapeutic intervention with bisphosphonates and other agents [51]. The ultimate goal of all these measures is to prevent fractures. Vitamin D and its analogs prevent bone loss during glucocorticoid therapy without significant differences between males and females [57, 58]. A practical point of vitamin D therapy in subjects receiving glucocorticoids relates to vitamin D resistance that is often seen in this setting. In fact, rather than maintaining 25-hydroxyvitamin D levels at a minimally adequate level, i.e. 30 ng/ml, many experts recommend the goal to be set at 40–60 ng/ml. In order to maintain these levels, patients often require amounts of 1000–2000 IU of vitamin D3 daily [58]. The early effect of glucocorticoids on bone resorption represents the rationale for the use of antiresorptive therapy [59]. Pathophysiological considerations suggest that antiresorptive treatment should be started early in patients undergoing glucocorticoid therapy [59]. Guidelines from the UK suggest that treatment in GIO is indicated in: 1. patients who are at high risk of osteoporosis, such as those taking prednisone equivalent doses higher than 7.5 mg daily, or those with personal history of fractures or those with lifestyle risk factors for osteoporosis
2. patients with low risk of osteoporosis but with T-scores below 1.5 SD, as assessed by vertebral dual energy x-ray absorptiometry (DXA) 3. patients with low risk of osteoporosis and T-score above 1.5 SD, but with a decline in vertebral BMD of at least 4.0% after one year of glucocorticoid treatment [48]. Conversely, ACR guidelines recommend bisphosphonates to be started in patients who are receiving 5 mg of prednisone equivalents daily for more than 3 months and with T-scores below 1.0 SD [47]. Indeed, there is evidence that there is still suboptimal application of these guidelines. In clinical practice, treatment with bisphosphonates seems to be prevalently based on low BMD, whereas these drugs are rarely prescribed for the prevention of GIO [14, 60]. A recent retrospective chart review showed that more than 60% of men with available BMD measurement and only 8% of subjects who did not undergo BMD evaluation were prescribed bisphosphonates for GIO [14]. Alendronate and risedronate are the only antiresorptive drugs approved for the treatment of GIO in men [61]. These drugs were shown to improve BMD in all studies in which males and females were analyzed separately, whereas the data on fractures were scanty and not always statistically conclusive, likely due to the low number of enrolled males and the short period of treatment. Alendronate administered daily was shown to increase BMD by 3.4% after one year of treatment with a slight decrease of incidence in morphometric vertebral fractures [62]. The effects of alendronate on BMD were shown to be greater after 2 years of treatment, whereas the effects on vertebral fractures in males was not demonstrated due to the low number of events during the study period [63]. One-year treatment with risedronate was shown to increase BMD by 2.1–4.8% from baseline across different skeletal sites in men with GIO [64]. Risedronate was also shown to decrease slightly vertebral fractures in those studies in which the analysis was performed separately in men and women [65, 66]. In men with GIO, testosterone administered intramuscularly induced a significant increase in lumbar BMD, without any significant effects on BMD at femoral neck [67]. The studies had BMD as primary end-point, whereas no information on bone fractures is available [68–70]. Testosterone was also shown to improve muscular performance and quality of life in men with GIO [70]. Interestingly, the beneficial effects of testosterone on bone, muscle and quality of life were shown to be independent of the prior androgen status: this observation suggests a direct anti-glucocorticoid effect of androgens, presumably via steroid receptor interactions in addition to the reversal of the systemic catabolic effect of glucocorticoids [35]. Another drug approved for the treatment of GIO in men is teriparatide. PTH is an attractive candidate for the therapy of GIO because it protects against osteoblast apoptosis and increases osteoblast cell number [22]. PTH administration
C h a p t e r 3 4 Glucocorticoid-induced Osteoporosis l
induces an initial uncoupling of bone remodeling with an early increase in bone formation followed by a more gradual increase of bone resorption [22]. According to the concept of the ‘anabolic window’, PTH rapidly stimulates osteoblast function, inducing an upregulation of osteoblastderived cytokines which eventually leads to osteoclast activation and gradual rebalancing of bone formation and resorption [22]. The efficacy of teriparatide was initially assessed in eugonadic and hypogonadic men with idiopathic osteoporosis [71]. Recently, data in GIO have also been published. In a multicenter, randomized, controlled study, the effects of teriparatide were compared with those of alendronate on lumbar spine BMD as primary end-point in 82 males and 346 females undergoing long-term glucocorticoid therapy at high risk for osteoporotic fractures, i.e. with mean baseline lumbar T-score of 2.5 and with high prevalence of fragility fractures [72]. In this clinical setting, teriparatide was significantly more effective than alendronate in increasing BMD at both the lumbar spine and total hip during an 18-month period [72]. As a secondary end-point, the incidence of new vertebral fractures was determined to be 6.1% and 0.6% in patients receiving alendronate and teriparatide, respectively [72]. Teriparatide treatment was associated with a higher frequency of undesired side effects, such as injection-site reactions, headache and dizziness [72]. In a recently performed separate analysis, teriparatide has been shown to be as effective in men as compared to women with GIO [73]. GH and IGF-I administration have been proposed to revert some of the negative effects of chronic glucocorticoid treatment on bone [39, 50]. Increases in serum osteocalcin, carboxy-terminal propeptide of type I procollagen and carboxy-terminal telopeptide of type I collagen were observed following short-term use of recombinant human GH treatment in a selected population of male and female patients receiving chronic corticosteroid treatment for non-endocrine diseases [38]. Moreover, combined therapy of GH and IGF-I counteracted selected negative effects of glucocorticoids on bone in healthy volunteers who received short-term glucocorticoid therapy [74]. Observational and controlled studies in children receiving glucocorticoid therapy for juvenile idiopathic arthritis showed that GH restored normal height velocity with a concomitant improvement in bone mineralization [75, 76]. However, the efficacy on BMD and fractures and safety of GH and IGF-I treatment in GIO needs still to be documented by prospective controlled studies.
Conclusions GIO is one of the most frequent forms of osteoporosis in men, for which the awareness is still suboptimal. Peculiar epidemiological (underlying diseases) and pathophysiological (hypogonadism) aspects characterize GIO in men. With
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regard to diagnostic as well as therapeutic measures there are no specific recommendations in males with GIO with the exception of testosterone replacement. Moreover, data concerning BMD cut-offs and treatment efficacy are often translated from the experiences in females more than based on sex-specific evidences.
References 1. E. Canalis, G. Mazziotti, A. Giustina, J.P. Bilezikian, Glucocorticoid-induced osteoporosis: pathophysiology and therapy, Osteoporos. Int. 18 (2007) 1319–1328. 2. S. Khosla, S. Amin, E. Orwoll, Osteoporosis in men, Endocr. Rev. 29 (2008) 441–464. 3. T.P. Van Staa, H.G. Leufkens, L. Abenhaim, B. Zhang, C. Cooper, Use of oral corticosteroids and risk of fractures, J. Bone Miner. Res. 15 (2000) 993–1000. 4. E. Canalis, J.P. Bilezikian, A. Angeli, A. Giustina, Perspectives on glucocorticoid-induced osteoporosis, Bone 34 (2004) 593–598. 5. J.L. Shaker, B.P. Lukert, Osteoporosis associated with excess glucocorticoids, Endocrinol. Metab. Clin. North Am. 34 (2005) 341–356. 6. T.P. van Staa, H.G. Leufkens, L. Abenhaim, B. Begaud, B. Zhang, C. Cooper, Use of oral corticosteroids in the United Kingdom, Q. J. Med. 93 (2000) 105–111. 7. T.P. van Staa, P. Geusens, H.A. Pols, C. de Laet, H.G. Leufkens, C. Cooper, A simple score for estimating the longterm risk of fracture in patients using oral glucocorticoids, Q. J. Med. 98 (2005) 191–198. 8. J.A. Kanis, E.V. McCloskey, H. Johansson, O. Strom, F. Borgstrom, A. Oden, National Osteoporosis Guideline Group. Case finding for the management of osteoporosis with FRAX – assessment and intervention thresholds for the UK, Osteoporos. Int. 19 (2008) 1395–1408. 9. G. Mazziotti, A. Angeli, J.P. Bilezikian, E. Canalis, A. Giustina, Glucocorticoid-induced osteoporosis: an update, Trends Endocrinol. Metab. 7 (2006) 144–149. 10. P. Vestergaard, L. Rejnmark, L. Mosekilde, Fracture risk associated with different types of oral corticosteroids and effect of termination of corticosteroids on the risk of fractures, Calcif. Tissue Int. 82 (2008) 249–257. 11. F. De Vries, M. Bracke, H.G. Leufkens, J.W. Lammers, C. Cooper, T.P. Van Staa, Fracture risk with intermittent highdose oral glucocorticoid therapy, Arthritis Rheum. 56 (2007) 208–214. 12. T.P. van Staa, P. Geusens, J.W. Bijlsma, H.G. Leufkens, C. Cooper, Clinical assessment of the long-term risk of fracture in patients with rheumatoid arthritis, Arthritis Rheum. 54 (2006) 3104–3112. 13. R. Nuti, P. Siviero, S. Maggi, et al., Vertebral fractures in patients with chronic obstructive pulmonary disease: the EOLO Study, Osteoporos. Int. (2008 Oct 18) [Epub ahead of print]. 14. L.M. Cruse, J. Valeriano, F.B. Vasey, J.D. Carter, Prevalence of evaluation and treatment of glucocorticoid-induced osteoporosis in men, J. Clin. Rheumatol. 12 (2006) 221–225. 15. S.F. Evans, M.W. Davie, Vertebral fractures and bone mineral density in idiopathic, secondary and corticosteroid associated osteoporosis in men, Ann. Rheum. Dis. 59 (2000) 269–275.
420
Osteoporosis in Men
16. I. Chiodini, M.L. Mascia, S. Muscarella, et al., Subclinical hypercortisolism among outpatients referred for osteoporosis, Ann. Intern. Med. 147 (2007) 541–548. 17. T. Mancini, M. Doga, G. Mazziotti, A. Giustina, Cushing’s syndrome and bone, Pituitary 7 (2005) 1–4. 18. I. Chiodini, R. Viti, F. Coletti, et al., Eugonadal male patients with adrenal incidentalomas and subclinical hypercortisolism have increased rate of vertebral fractures, Clin. Endocrinol. 70 (2008) 208–213. 19. F. Pecori Giraldi, M. Moro, F. Cavagnini, Study Group on the Hypothalamo-Pituitary-Adrenal Axis of the Italian Society of Endocrinology. Gender-related differences in the presentation and course of Cushing’s disease, J. Clin. Endocrinol. Metab. 88 (2003) 1554–1558. 20. G. Arnaldi, A. Angeli, A.B. Atkinson, et al., Diagnosis and complications of Cushing’s syndrome: a consensus statement, J. Clin. Endocrinol. Metab. 88 (2003) 5593–5602. 21. E. Canalis, A. Giustina, Glucocorticoid-induced osteoporosis: summary of a workshop, J. Clin. Endocrinol. Metab. 86 (2001) 5681–5685. 22. E. Canalis, A. Giustina, J.P. Bilezikian, Mechanisms of anabolic therapies for osteoporosis, N. Engl. J. Med. 357 (2007) 905–916. 23. J.J. Westendorf, R.A. Kahler, T.M. Schroeder, Wnt signaling in osteoblasts and bone diseases, Gene 341 (2004) 19–39. 24. F.S. Wang, J.Y. Ko, D.W. Yeh, H.C. Ke, H.L. Wu, Modulation of Dickkopf-1 attenuates glucocorticoid induction of osteo blast apoptosis, adipocytic differentiation, and bone mass loss, Endocrinology 149 (2008) 1793–1801. 25. C.A. O’Brien, D. Jia, L.I. Plotkin, et al., Glucocorticoids act directly on osteoblasts and osteocytes to induce their apoptosis and reduce bone formation and strength, Endocrinology 145 (2004) 1835–1841. 26. N.E. Lane, W. Yao, M. Balooch, et al., Glucocorticoid-treated mice have localized changes in trabecular bone material properties and osteocyte lacunar size that are not observed in placebo-treated or estrogen-deficient mice, J. Bone Miner. Res. 21 (2006) 466–476. 27. W. Yao, Z. Cheng, C. Busse, A. Pham, M.C. Nakamura, N.E. Lane, Glucocorticoid excess in mice results in early activation of osteoclastogenesis and adipogenesis and prolonged suppression of osteogenesis: a longitudinal study of gene expression in bone tissue from glucocorticoid-treated mice, Arthritis Rheum. 58 (2008) 1674–1686. 28. T. Kondo, R. Kitazawa, A. Yamaguchi, S. Kitazawa, Dexamethasone promotes osteoclastogenesis by inhibiting osteoprotegerin through multiple levels, J. Cell Biochem. 103 (2008) 335–345. 29. A. Dovio, L. Perazzolo, L. Saba, et al., High-dose glucocorticoids increase serum levels of soluble IL-6 receptor alpha and its ratio to soluble gp130: an additional mechanism for early increased bone resorption, Eur. J. Endocrinol. 154 (2006) 745–751. 30. D. Jia, C.A. O’Brien, S.A. Stewart, S.C. Manolagas, R.S. Weinstein, Glucocorticoids act directly on osteoclasts to increase their life span and reduce bone density, Endocrinology 147 (2006) 5592–5599. 31. H.J. Kim, H. Zhao, H. Kitaura, et al., Glucocorticoids suppress bone formation via the osteoclast, J. Clin. Invest. 116 (2006) 2152–2160.
32. S. Bonadonna, A. Burattin, M. Nuzzo, et al., Chronic glucocorticoid treatment alters spontaneous pulsatile parathyroid hormone secretory dynamics in human subjects, Eur. J. Endocrinol. 152 (2005) 199–205. 33. R.S. Weinstein, D. Jia, C.C. Powers, et al., The skeletal effects of glucocorticoid excess override those of orchidectomy in mice, Endocrinology 145 (2004) 1980–1987. 34. H.F. Martens, P.K. Sheets, J.S. Tenover, C.E. Dugowson, W.J. Bremner, G. Starkebaum, Decreased testosterone levels in men with rheumatoid arthritis: effect of low dose prednisone therapy, J. Rheumatol. 21 (1994) 1427–1431. 35. S. Chen, J. Wang, G. Yu, W. Liu, D. Pearce, Androgen and glucocorticoid receptor heterodimer formation, J. Biol. Chem. 272 (1997) 14087–14092. 36. A. Giustina, J.D. Veldhuis, Pathophysiology of the neuroregulation of growth hormone secretion in experimental animals and the human, Endocr. Rev. 19 (1998) 717–797. 37. A. Giustina, S. Bossoni, C. Bodini, et al., Arginine normalizes the growth hormone (GH) response to GH-releasing hormone in adult patients receiving chronic daily immunosuppressive glucocorticoid therapy, J. Clin. Endocrinol. Metab. 74 (1992) 1301–1305. 38. A. Giustina, A.R. Bussi, C. Jacobello, W.B. Wehrenberg, Effects of recombinant human growth hormone (GH) on bone and intermediary metabolism in patients receiving chronic glucocorticoid treatment with suppressed endogenous GH response to GH-releasing hormone, J. Clin. Endocrinol. Metab. 80 (1995) 122–129. 39. F. Manelli, R. Carpinteri, S. Bossoni, et al., Growth hormone in glucocorticoid-induced osteoporosis, Front. Horm. Res. 30 (2002) 174–183. 40. M. Malerba, S. Bossoni, A. Radaeli, et al., Bone ultrasonometric features and growth hormone secretion in asthmatic patients during chronic inhaled corticosteroid therapy, Bone 38 (2006) 119–124. 41. M. Malerba, S. Bossoni, A. Radaeli, et al., Growth hormone response to growth hormone-releasing hormone is reduced in adult asthmatic patients receiving long-term inhaled corticosteroid treatment, Chest 127 (2005) 515–521. 42. J.W. Tomlinson, E.A. Walker, I.J. Bujalska, et al., 11betahydroxysteroid dehydrogenase type 1: a tissue-specific regulator of glucocorticoid response, Endocr. Rev. 25 (2004) 31–66. 43. M.S. Cooper, E.H. Rabbitt, P.E. Goddard, W.A. Bartlett, M. Hewison, P.M. Stewart, Osteoblastic 11α-hydroxysteroid dehydrogenase type 1 activity increases with age and glucocorticoid exposure, J. Bone Miner. Res. 17 (2002) 979–986. 44. E.F. van Rossum, P.G. Voorhoeve, S.J. te Velde, et al., The ER22/23EK polymorphism in the glucocorticoid receptor gene is associated with a beneficial body composition and muscle strength in young adults, J. Clin. Endocrinol. Metab. 89 (2004) 4004–4009. 45. Y.M. Peng, S.F. Lei, Y. Guo, et al., Sex-specific association of the glucocorticoid receptor gene with extreme BMD, J. Bone Miner. Res. 23 (2008) 247–252. 46. D.H. Solomon, J.N. Katz, A.M. La Tourette, J.S. Coblyn, Multifaceted intervention to improve rheumatologists’ management of glucocorticoid-induced osteoporosis: a randomized controlled trial, Arthritis Rheum. 51 (2004) 383–387. 47. American College of Rheumatology, Ad Hoc Committee on Glucocorticoid-Induced Osteoporosis Recommendations for
C h a p t e r 3 4 Glucocorticoid-induced Osteoporosis l
48.
49.
50.
51.
52.
53.
54.
55.
56.
57.
58.
59.
60.
61.
62.
63.
the prevention and treatment of glucocorticoid-induced osteoporosis: 2001 update, Arthritis Rheum. 44 (2001) 1496–1503. R. Eastell, D.M. Reid, J. Compston, et al., A UK Consensus Group on management of glucocorticoid-induced osteoporosis: an update, J. Intern. Med. 244 (1998) 271–292. T.P. Van Staa, R.F. Laan, I.P. Barton, S. Cohen, D.M. Reid, C. Cooper, Bone density threshold and other predictors of vertebral fracture in patients receiving oral glucocorticoid therapy, Arthritis Rheum. 48 (2003) 3224–3229. A. Giustina, G. Mazziotti, E. Canalis, Growth hormone, insulin-like growth factors, and the skeleton, Endocr. Rev. 29 (2008) 535–559. J. Compston, US, and UK guidelines for glucocorticoidinduced osteoporosis: similarities and differences, Curr. Rheumatol. Rep. 6 (2004) 66–69. G. Mazziotti, A. Bianchi, S. Bonadonna, et al., Increased prevalence of radiological spinal deformities in adult patients with GH deficiency: influence of GH replacement therapy, J. Bone Miner. Res. 21 (2006) 520–528. P. Vestergaard, Discrepancies in bone mineral density and fracture risk in patients with type 1 and type 2 diabetes – a meta-analysis, Osteoporos. Int. 18 (2007) 427–444. G. Mazziotti, A. Bianchi, S. Bonadonna, et al., Prevalence of vertebral fractures in men with acromegaly, J. Clin. Endocrinol. Metab. 93 (2008) 4649–4655. A. Angeli, G. Guglielmi, A. Dovio, et al., High prevalence of asymptomatic vertebral fractures in post-menopausal women receiving chronic glucocorticoid therapy: a cross-sectional outpatient study, Bone 39 (2006) 253–259. S. Minisola, R. Del Fiacco, S. Piemonte, et al., Biochemical markers in glucocorticoid-induced osteoporosis, J. Endocrinol. Invest. 31 (Suppl.) (2008) 28–32. L.M. Buckley, E.S. Leib, K.S. Cartularo, P.M. Vacek, S.M. Cooper, Calcium and vitamin D3 supplementation prevents bone loss in the spine secondary to low-dose corticosteroids in patients with rheumatoid arthritis. A randomized, double-blind, placebo-controlled trial, Ann. Intern. Med. 125 (1996) 961–968. M. Doga, G. Mazziotti, S. Bonadonna, et al., Prevention and treatment of glucocorticoid-induced osteoporosis, J. Endocrinol. Invest. 31 (Suppl. 7) (2008) 53–58. M. Doga, S. Bonadonna, A. Burattin, R. Carpinteri, F. Manelli, A. Giustina, Bisphosphonates in the treatment of glucocorticoidinduced osteoporosis, Front. Horm. Res. 30 (2002) 150–164. J.R. Guzman-Clark, M.A. Fang, M.E. Sehl, L. Traylor, T.J. Hahn, Barriers in the management of glucocorticoidinduced osteoporosis, Arthritis Rheum. 57 (2007) 140–146. J. Compston, D.M. Reid, J. Boisdron, et al., Group for the Respect of Ethics and Excellence in Science. Recommendations for the registration of agents for prevention and treatment of glucocorticoid-induced osteoporosis: an update from the Group for the Respect of Ethics and Excellence in Science, Osteoporos. Int. 19 (2008) 1247–1250. K.G. Saag, R. Emkey, T.J. Schnitzer, et al., Alendronate for the prevention and treatment of glucocorticoid-induced osteo porosis. Glucocorticoid-Induced Osteoporosis Intervention Study Group, N. Engl. J. Med. 339 (1998) 292–299. J.D. Adachi, K.G. Saag, P.D. Delmas, et al., Two-year effects of alendronate on bone mineral density and vertebral fracture
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in patients receiving glucocorticoids: a randomized, doubleblind, placebo-controlled extension trial, Arthritis Rheum. 44 (2001) 202–211. D.M. Reid, R.A. Hughes, R.F. Laan, et al., Efficacy and safety of daily risedronate in the treatment of corticosteroidinduced osteoporosis in men and women: a randomized trial. European Corticosteroid-Induced Osteoporosis Treatment Study, J. Bone Miner. Res. 15 (2000) 1006–1013. S. Cohen, R.M. Levy, M. Keller, et al., Risedronate therapy prevents corticosteroid-induced bone loss: a twelve-month, multicenter, randomized, double-blind, placebo-controlled, parallel-group study, Arthritis Rheum. 42 (1999) 2309–2318. S. Wallach, S. Cohen, D.M. Reid, et al., Effects of risedronate treatment on bone density and vertebral fracture in patients on corticosteroid therapy, Calcif. Tissue Int. 67 (2000) 277–285. M.J. Tracz, K. Sideras, E.R. Boloña, et al., Testosterone use in men and its effects on bone health. A systematic review and meta-analysis of randomized placebo-controlled trials, J. Clin. Endocrinol. Metab. 91 (2006) 2011–2016. I.R. Reid, D.J. Wattie, M.C. Evans, J.P. Stapleton, Testosterone therapy in glucocorticoid-treated men, Arch. Intern. Med. 156 (1996) 1173–1177. G.M. Hall, J.P. Larbre, T.D. Spector, L.A. Perry, J.A. Da Silva, A randomized trial of testosterone therapy in males with rheumatoid arthritis, Br. J. Rheumatol. 35 (1996) 568–573. B.A. Crawford, P.Y. Liu, M.T. Kean, J.F. Bleasel, D.J. Handelsman, Randomized placebo-controlled trial of androgen effects on muscle and bone in men requiring longterm systemic glucocorticoid treatment, J. Clin. Endocrinol. Metab. 88 (2003) 3167–3176. E.S. Orwoll, W.H. Scheele, S. Paul, et al., The effect of teriparatide [human parathyroid hormone (1-34)] therapy on bone density in men with osteoporosis, J. Bone Miner. Res. 18 (2003) 9–17. K.G. Saag, E. Shane, S. Boonen, et al., Teriparatide or alendronate in glucococorticoid-induced osteoporosis, N. Engl. J. Med. 357 (2007) 2028–2039. B. Langdahl, H. Dobnig, J.R. Zanchetta, et al., Teriparatide Versus Alendronate in Glucocorticoid-Induced Osteoporosis: Results of a Subgroup Analysis in Men, Pre- and Postmenopausal Women. Poster 499, 35th European Symposium of Calcified Tissue, Barcelona, November 2008. K. Berneis, M. Oehri, M. Kraenzlin, U. Keller, Effects of IGF-1 combined with GH on glucocorticoid-induced changes of bone and connective tissue turnover in man, J. Endocrinol. 162 (1999) 259–264. S. Bechtold, P. Ripperger, W. Bonfig, R. Dalla Pozza, R. Häfner, H. Schwarz, Growth hormone changes bone geometry and body composition in patients with juvenile idiopathic arthritis requiring glucocorticoid treatment: a controlled study using peripheral quantitative computed tomography, J. Clin. Endocrinol. Metab. 0 (2005) 3168–3170. D. Simon, A.M. Prieur, P. Quartier, J. Charles Ruiz, P. Czernichow, Early recombinant human growth hormone treatment in glucocorticoid-treated children with juvenile idiopathic arthritis: 3-year randomized study, J. Clin. Endocrinol. Metab. 92 (2007) 2567–2573.
Chapter
35
Testicular Dysfunction Christian Meier1, Markus J. Seibel2 and David J. Handelsman3 1
Division of Endocrinology, Diabetes and Clinical Nutrition, University Hospital Basel, Switzerland Bone Research Program, ANZAC Research Institute, University of Sydney, Sydney NSW, Australia 3 Department of Andrology, ANZAC Research Institute, Concord Hospital, University of Sydney, Sydney NSW, Australia 2
[1]. In men, the secretion of testosterone from testicular Leydig cells is responsible for virtually all (95%) of the body’s androgen secretion with minor amount or proandrogens, such as dehydroepiandrosterone (DHEA), emanating from the adrenal glands which serve mainly as substrates for extragonadal conversion to estradiol. At puberty, testosterone secretion increases 20–30-fold to circulate for the remainder of adult life at levels 10–15 times that of children, women and castrate men. Testosterone, the principal mammalian androgen, has a complex mode of action as it can bind directly to the androgen receptor (AR) or undergo pre-receptor activation via the amplification (to dihydrotestosterone) or diversification (to estradiol) pathways [1] (Figure 35.1). The amplification pathway converts testosterone via the 5- reductase enzymes to dihydrotestosterone (DHT), a 3–10-fold more potent, pure, non-aromatizable androgen that acts solely on the AR. The diversification pathway converts testosterone to
Introduction The gonads have two distinct canonical functions – the production of functional gametes for fertilization and the secretion of gonadal steroids for sexual differentiation, maturation and near ubiquitous functional effects on organs and tissues. Consequently, gonadal dysfunction may be manifest as failure in either or both of its twin functions, such as infertility and/or steroid hormone deficiency. In men, testicular failure may become evident as isolated defects in spermatogenesis or steroidogenesis or both because the two axes operate in largely independent fashion with their inter-dependence only evident in extremes such as after orchidectomy or with complete gonadotropin deficiency. Most disorders of spermatogenesis – such as cytotoxic chemo- or radiotherapy effects on the testis or most causes of male infertility – however have essentially no, or at most, minimal clinical effects on androgen secretion or action. Conversely, acquired luteinizing hormone deficiency (LH) deficiency, such as with under-nutrition or other catabolic states that commence after completion of normal puberty and sperm production, may spare spermatogenesis. All known effects of the testis on bone are solely attributable to its gonadal steroid secretions and are unrelated to the testis’s other function of spermatogenesis. Consequently, this chapter will consider the effects of androgen (and/or estrogen) deficiency and avoid using the ambiguous term ‘hypogonadism’ which is functionally non-specific and inaccurate.
Pathways of testosterone action IE
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Androgens are synthesized from cholesterol through a multistep enzymatic pathway which shortens the side chain of cholesterol via oxidation from 27 to a 19 carbon skeleton Osteoporosis in Men
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Figure 35.1 Pathways of testosterone action. 423
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estradiol (E2) via the CYP19 (aromatase) enzyme, a widely distributed microsomal cytochrome P450 enzyme, which acts on the estrogen receptor (ER), thereby broadening the scope of testosterone action. The adrenal cortex secretes relatively large amounts of 19 carbon androgens including DHEA, DHEA sulfate and androstenedione. These androgens can be converted to biologically active estrogens, such as estradiol, or to biologically active androgens, such as testosterone and DHT, via a succession of enzymatic steps involving steroid sulfatase, 17-hydroxysteroid dehydrogenase (17-HSD) and/or 3-HSD [2]. Thus, testosterone functions not only as a potent and amplifiable androgen acting on the AR but also as a precursor for conversion to the biologically active estrogen, estradiol, which acts on the ERs. This has significance for bone in that E2 plays a major role in bone metabolism of not only women but also of men. In men, the extra-testicular aromatization of circulating testosterone to estradiol is important. Only a small proportion (15–20%) of estradiol is directly secreted by the testes, although this proportion increases with circulating blood LH levels [3]. Nevertheless, overall, only a tiny fraction (0.1%) of testosterone undergoes aromatization, whereas a larger proportion (5–10%) is 5 reduced to DHT, while the remainder is inactivated mainly by the liver. A consequence is that, except under the rare circumstances of inactivating mutations in estradiol synthesis (aromatase) or action (ER), men never become severely estrogen deficient. Conversely, administration of exogenous estrogens, such as estradiol, at sufficient doses produces androgen deficiency via negative hypothalamic feedback. Consequently, studying isolated estrogen effects in men is difficult for both practical and ethical/safety reasons. In general, depending on the relative expression and pre-receptor enzymatic activation by aromatase, 5-reductase and dehydrogenases together with the relative distribution of AR and ERs in peripheral target tissues, testosterone and its bioactive metabolites may predominantly activate either the AR and/or the ER. For bone, the pattern of expression in osteoblasts, osteoclasts and osteocytes of aromatase, 5-reductase, 17-HSD, 3-HSD enzymes and of the AR and ERs (ER and ER) supports the concept of tissue-specific pre-receptor activation and local action of gonadal steroid hormones within the skeleton. While the gender dimorphism in bone size, density and strength is attributable to androgen action, the relative effects of the direct action of testosterone relative to the contributions of pre-receptor testosterone activation to DHT and aromatization to E2, both within bone and in extra-osseous tissues, remain to be accurately apportioned. Clinical studies suggest that aromatization of testosterone to E2 plays a significant role in the regulation of bone mass, notably in relation to age-related bone loss in older men [4]. However, the relative importance of blood testosterone for accrual and maintenance of bone in men relative to pre-receptor activation remains contentious and difficult to study in decisive fashion due to ethical and practical
constraints. A recent elegant study in mice, however, provides definitive evidence on the differential roles of AR and ER for bone and body composition. Using AR, ER and double knockout mice, direct AR activation was shown to be solely responsible for the development and maintenance of male trabecular bone mass, whereas both AR and ER activation are required to optimize the acquisition of cortical bone [5]. Androgen deficiency is a clinical diagnosis based on: 1. an appropriate clinical context (presentation) 2. identification of an underlying pathological disorder of the hypothalamo-pituitary-testicular axis responsible for a sustained decreased in testicular testosterone secretion 3. biochemical confirmation of consistently low serum testosterone [6]. No single element alone is sufficient for the clinical diagnosis of chronic androgen deficiency. In particular, reduced circulating testosterone is a characteristic, non-specific hypothalamo-pituitary response to a variety of acute or chronic pathological states or diseases, including fractures, chronic pain or opiate analgesic medication [6]. Hence, a single blood testosterone measurement by any assay does not constitute a diagnosis of chronic androgen deficiency. The inaccuracy and method-dependence of commercial semi-automated platform immunoassays for testosterone [7, 8] and of so-called ‘free testosterone’ [9] is now well established. The superseding of these assays by mass spectrometry-based measurements is underway in research and larger routine clinical pathology laboratories and likely to become universal in the near future.
Age-Related Changes in Gonadal Hormones Male aging is associated with a gradual, progressive decrease in circulating testosterone [10, 11]. Longitudinal populationbased studies show that serum total testosterone concentrations decline by 1% per year in men [12], but the biological or clinical importance of such a decline remains unclear [13]. A variety of derived testosterone measures (‘free’, ‘bioavailable’), which putatively better reflect androgen action of testosterone on tissues, have been postulated as variants of the ‘free hormone’ hypothesis. This hypothesis remains unproven and lacks both adequate theoretical basis or empirical verification [9]. For example, while ‘free’ testosterone (i.e. the fraction of total testosterone not bound to sex hormone binding globulin (SHBG) or albumin) falls as SHBG (and its binding capacity) rises with age [14–16], it is unclear whether this represents more or less net androgen action at a tissue level. The ‘free’ hormone is not only more accessible to sites of hormone action but also to the, quantitatively more important, site of testosterone inactivation [17]. It remains implausible that a single static derived testosterone measure would adequately reflect androgenic action in all
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androgen-responsive tissues, including bone, given the complexity of blood-to-tissue transfer of testosterone as well as local tissue- and organ-specific androgen amplification systems which are likely to be crucial in modulating the net biological androgen action within cells. The widely used calculational formulae to estimate ‘free testosterone’ from concurrent testosterone and SHBG measurements do not correspond well to laboratory direct measurement of ‘free testosterone’, are erroneous and poorly validated [18]. Similar limitations are likely to be present for so-called ‘free estradiol’, although this variable lacks even basic validation. Despite the firmly established decline in total, free or SHBGbound testosterone with male aging, such a gradual and modest decline may not warrant replacement because older tissues may not remain as androgen responsive and the magnitude of the deficit may not be sufficient. Whether testosterone replacement is effective or safe remains to be established by appropriate interventional studies [13, 19]. Although the decline in testosterone levels with male aging is observed in virtually all studies, evidence remains conflicting whether there is any change in blood E2 with male aging [10, 11, 20]. This may be due to a combination of factors, such as the low overall proportion of testosterone converted to E2 (0.1%) so that substrate (testosterone) for aromatization is not limiting and the age-related increased aromatase activity due to the concomitant increase in fat mass [21]. Although non-SHBG bound E2 levels decrease with age (by about 50% over six decades) as a consequence of increasing SHBG concentrations [22], the biological meaning of this unvalidated, derived estradiol measure remains to be established. The single steroid binding on SHBG displays competitive binding of steroids so that the biological meaning of unbound E2 relative to the 100-fold higher molar concentrations of testosterone remains unclear. Furthermore, non-extraction direct (automated) immuno assays are especially unreliable for the very low serum estradiol concentrations present in men, children and postmenopausal women [23]. For these reasons, the biological significance for bone of ‘free’ or SHBG-bound E2 is even less well defined than for comparable derived testosterone measures. While the available evidence indicates that estradiol has significance for the male skeleton [4], the circulating blood estradiol concentrations in men are comparable with estrogen-deficient postmenopausal women raising the paradoxical issue of why bone of healthy men does not acquire the osteoporotic state of postmenopausal women. In fact, male bone actually becomes and remains larger, with higher peri- and endosteal diameters than women, which makes it even stronger than premenopausal female bone. This may be explained, at least in part, by AR-mediated effects and/or greater importance of local bone aromatase expression in male bone so that estrogen action is more dependent on local production than on systemic exposure. However, other factors, such as larger body and muscle mass in men, are also likely to be important.
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Skeletal health in androgen deficiency at various ages Bone undergoes two major changes during postnatal life of men, the accrual of bone mass during adolescence to achieve peak bone mass in early manhood and the age-related bone loss in older men. Both are multifactorial with important hormonal, environmental and genetic factors. At puberty, a dramatic increase in bone size, mass and mineral content as well as muscle mass occurs following the dramatic 20–30-fold increase in circulating testosterone levels. This leads to development of peak bone mass early in the third decade of life after which there begins a gradual decline with age in bone mineral density (BMD), although the rate of decline is less in men than in premenopausal women and especially postmenopausal women. At all ages, gonadal steroid hormones are important determinants of skeletal integrity. To appreciate the effect of gonadal steroid hormones on bone turnover, BMD and fracture risk in men, the effects of androgens are discussed separately in prepubertal and post-pubertal (adult) onset of androgen deficiency. Whether this age-related bone loss in men contributes to or is coincidental with the concomitant slow decrease in blood testosterone levels will be considered but remains unclear.
Prepubertal Onset of Androgen Deficiency Adolescence is associated with profound increases in bone mass in both sexes with significant increase in axial and appendicular bone mass [24, 25]. Maximal increases in bone mass accrual occur between 11 and 14 years of age in girls and 13 and 17 years in boys [26], with more than 90% of peak bone mass being achieved by the end of the second decade [27]. The pattern of skeletal growth in puberty differs in boys being about 2 years later, allowing for 2 more years of prepubertal statutural growth prior to epiphyseal fusion. Furthermore, the pubertal growth spurt lasts 4 years in boys, longer than the 3 years in girls [28, 29]. In concert, these differences account for the 10% greater statural height and the 25% greater peak bone mass acquired by boys during puberty. The greater bone mass of boys is largely due to their greater bone size, whereas peak volumetric bone density does not differ between young men and women. In boys, the increase in indices of bone formation and skeletal mass during pubertal development is closely linked to pubertal stage [30] and to testicular [31] and adrenal [32] androgen levels. Many chronic childhood illnesses are associated with delayed puberty and low body weight. Importantly, failure to enter puberty or pubertal arrest can occur as a consequence of primary gonadal failure (e.g. chemotherapy) or secondary to gonadotropin deficiency due to pituitary damage (e.g. as a consequence of iron overload in thalassemia major treated with regular blood
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transfusions) [33]. Anorexia nervosa, a condition of severe undernutrition associated with sex hormone deficiency is known to result in decreased bone turnover and low bone mass. The condition, which also occurs in adolescent boys, is characterized by hypothalamic-pituitary androgen deficiency, undernutrition with decreased lean body mass and impaired growth hormone action [27]. Further evidence of the importance of androgens in male bone development comes from reports showing that men with complete androgen resistance appear to have low bone density [34] and men with androgen insufficiency due to isolated gonadotropin deficiency have been shown to have abnormally low bone mass even when corrected for bone age [35]. Androgen replacement therapy in these men before epiphyseal closure resulted in rapid increase in bone mass [36–38]. It has been known for decades that neuroendocrine effects of testosterone mainly, but not exclusively, negative feedback on the hypothalamus, were mediated by local tissue aromatization of testosterone to E2 with effects manifest via both AR and ER mechanisms [39]. Recent observations suggest similar aromatization-dependent mechanisms apply to bone. The first evidence supporting this concept emerged from a report of a 28-year-old man with estrogen resistance caused by a homozygous and inactivating mutation in the estrogen receptor gene. Despite normal serum testosterone levels and elevated circulating levels of E2, he had accelerated bone turnover with increased rates of bone formation and bone resorption resulting in a bone mass in the osteopenic range [40]. Subsequently, clinical findings in men with aromatase deficiency caused by inactivating mutations in the aromatase gene and undetectable circulating E2 confirmed similar findings due to functional estrogen deficiency [41–43]. Again, bone turnover and BMD in these estrogen deficient men were markedly altered with undetectable circulating E2 levels but normal serum testosterone levels. Furthermore, estrogen treatment in men with aromatase deficiency suppressed bone resorption [43] and markedly increased bone mass [42, 43]. Although showing a striking requirement for estrogen effects in bone of men, these individual cases reflect developmentally disordered bone formed under conditions of congenital severe estrogen deficiency and it is not clear how these findings relate to the maintenance of normal mature bone developed under eugonadal conditions. Some corroboration of a role for E2 is provided by two studies suggesting an important role for E2 in maintaining mature bone in men [44, 45]. These short-term studies induced isolated estrogen deficiency by treatment with a combination of gonadotropin releasing hormone (GnRH) analog plus an aromatase inhibitor in older men and demonstrated that E2 has distinct effects in maintaining biochemical markers of bone turnover. These experimental studies were not long enough, however, to determine the net effects of induced isolated E2 deficiency on bone mass.
Post-Pubertal (Adult) Onset of Androgen Deficiency A low blood testosterone level, usually based only on a single blood sample, is present in 15–36% of men with documented osteoporosis [46, 47]. Even with better standardization of testosterone assays, this is likely to overestimate the rate of underlying chronic androgen deficiency because the impact of transient non-specific effects of acute or chronic illness, notably fractures, pain and opiate analgesics, on blood testosterone concentrations, is not accounted for. Nevertheless, it is clear that normal testicular function is crucial to maintain optimal bone integrity for men while substantial, sustained androgen deficiency has detrimental effects on bone, lowering bone density and increases fracture risk. Severe androgen deprivation by either surgical orchidectomy or medical (drug-induced) castration, such as required for palliative care of older men with incurable prostate cancer, eliminated the testicular contribution to circulating testosterone levels leading to a profound, near complete decline in circulating testosterone. The rapid decline in gonadal steroids after castration causes an accelerated bone loss and turnover with a marked increase in bone resorption unmatched by a sufficient increase in the coupled bone formation. Bone turnover, as assessed by biochemical markers of bone resorption and formation, are both increased [48– 54] and the net effect is a rapid and sustained bone loss in androgen deficient men. In older men with prostate cancer subjected to therapeutic castration, BMD is predominately reduced at the lumbar spine which decreases by 5–10% within the first year after castration [48–53, 55]. Bone loss is also observed at peripheral skeletal sites, including the hip, although to a lesser extent [50–52, 56–58]. Ultimately, bone loss after castration results in an increased risk of osteoporotic fractures [57, 59–64]. For example, Daniell et al reported that the cumulative incidence of a first osteoporotic fracture is increased more than fivefold in castrated men [57]. Of men surviving at least 5 years after prostate cancer diagnosis, 19.4% of those who underwent castration had a fracture, as compared with 12.6% of those not castrate (P 0.001). Importantly, a recent populationbased database study revealed that there is a significant relation between the number of doses of gonadotropinreleasing hormone analogs (used to induce medical castration) received during the first 12 months after diagnosis and the subsequent risk of fracture [65] (Figure 35.2). For men with prostate cancer who are at high risk for osteoporosis and fractures, clinical management should be based on radiographic and densitometric assessment. Bisphosphonates have emerged as an integral part of the management of bone loss related to castration in men with advanced, incurable prostate cancer [66]. There is, however, no established role for bisphosphonates in men with localized prostate cancer treated with curable intent using short-term medical castration as part of adjuvant, stage-reducing therapy.
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GnRH agonist, 1–4 doses (N=3763)
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Figure 35.2 Unadjusted fracture-free survival among patients with prostate cancer, according to androgen-deprivation therapy. GnRH denotes gonadotropin-releasing hormone. The number of doses is the number administered within 12 months after diagnosis. (Adapted from Shahinian et al N Engl J Med 2005;352: 154164 [65] with permission).
Men with overt androgen deficiency due to testicular or hypothalamic-pituitary dysfunction have less severe and more variable deficits in testosterone secretion and, consequently, have less marked changes in BMD and bone turnover. Most men with established chronic androgen deficiency have significantly lower bone density than age-matched controls [67–71]. Luisetto et al, however, observed that bone mass was comparable to healthy controls in 32 men with Klinefelter’s syndrome [72], a discrepancy most likely reflecting the wide phenotypic spectrum including variability in testicular function in Klinefelter’s syndrome [73, 74]. Recent European population-based record linkage studies of men with Klinefelter’s syndrome showed not only striking underdiagnosis of Klinefelter’s syndrome, with fewer than 20% diagnosed during life, but also the first evidence that chronic androgen deficiency is associated with an excess of deaths from bone fractures [75, 76]. In contrast to these mostly uniform alterations in BMD, changes in bone turnover, specifically in bone formation, are less consistent. While bone resorption is accelerated in androgen deficient men compared with eugonadal controls [70, 77, 78], bone formation may be either decreased [70, 79, 80] or increased [2, 77, 78] when assessed either by biochemical indices of bone formation or histomorphometric studies. Testosterone replacement therapy for androgen deficiency conversely decreases bone resorption [78, 81–84] and exerts an anabolic effect with increased bone formation [81, 82, 85], although some studies failed to show an increase in bone formation [78, 83, 84]. These inconsistencies are probably due to the inadequate testosterone replacement regimens widely used [86] and heterogeneity of the populations studied and tests used.
CAGn length
Figure 35.3 Body height in relation to CAGn length of the AR genes of Klinefelter patients. Inset: height distribution according to tertiles of X-weighted biallelic CAGn length (short: CAGn, 20.0 (n 27); medium: 20.0 CAGn 23.0 (n 27); long: CAGn, 23.0 (n 23)). Significant differences according to Kruskal-Wallis and post hoc tests. Levels of statistical significance are given as asterisks (* P 0.05; ** P 0.01; ***, P 0.001). (Adapted from Zitzmann et al J Clin Endocrinol Metab 2004;89: 6208-17 [91] with permission from The Endocrine Society).
Effects of Androgen Replacement in Male Hypogonadism Most studies of androgen replacement therapy in androgen deficient men report beneficial effects of increased BMD, although the gain in bone density varies between studies [38, 82–84, 87–90]. This variability is likely to be due, in part, to differences in the adequacy of testosterone replacement regimens [86], especially in the more salient longitudinal studies of the same men before and after treatment using the same dual energy x-ray absorptiometry (DXA) equipment. By contrast, cross-sectional studies introduce additional sources of variability, such as the wide variability in magnitude of testosterone deficiency according to the underlying disorders of gonadal function, as well as to different methods to quantify bone density (DXA, quantitative computed tomography (QCT)). Pharmacogenetic differences between men in the CAG triplet repeat in exon 1 of the AR, the length of which is inversely related to androgen sensitivity, also contributes to the effectiveness of testosterone treatment on bone [91] (Figure 35.3), although the magnitude of these effects appears relatively modest. The most striking increase in BMD is seen during the first year of testosterone replacement therapy and is greatest in those with the lowest initial BMD. Thereafter, bone density is maintained during longterm testosterone administration [88] (Figure 35.4), so long as adequate testosterone dosage is continued [86]. Data from prospective and retrospective studies on the effect of androgen replacement on bone density in androgen deficient men have recently been summarized [2, 92]. These studies provide mostly consistent evidence that sites with
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[78, 81–84] and increases levels of bone formation markers [81, 82, 85] resulting in increased bone mass [83, 97]. However, beneficial effects on body composition, specifically on muscle mass, most likely make some indirect contribution to the increase in BMD based on increased physical activity and/or biophysical shear force stress. Many studies now confirm that testosterone administration increases lean (i.e. muscle) mass [78, 81, 84, 94] and/or muscle strength [81, 85, 98, 99] in a dose-dependent fashion in androgen deficient men, in men with andropause as well as in eugonadal young and older men.
Duration of testosterone therapy (years)
Figure 35.4 Increase in BMD during long-term testosterone substitution therapy up to 16 years in 72 hypogonadal men. Circles indicate hypogonadal patients with first QCT measurement before initiation of testosterone replacement therapy, squares show those patients already receiving testosterone therapy at the first QCT. The dark shaded area indicates the range of high fracture risk, the unshaded area shows the range without significant fracture risk and the light shaded area indicates the intermediate range where fractures may occur. (Adapted from Behre et al J Clin Endocrinol Metab 1997;82:2386–90 [88] with permission from The Endocrine Society).
mostly cancellous bone (e.g. the spine) are more responsive to androgen deficiency and replacement than sites of predominantly cortical bone (e.g. the radius or proximal femur). Furthermore, measurements based on QCT show much greater responsiveness than studies using single or dual photon absorptiometry due to its unique measurement of trabecular bone mass. On the other hand, subcortical bone apposition appears particularly important in men and is responsible for their larger and stronger bone structure [93]. These differences may be in part due to androgen-induced changes in body composition (i.e. reduced fat and increased lean mass) which remain uncorrected in QCT measures of BMD response. Furthermore, the adequacy of testosterone regimen is an important determinant of the efficacy of testosterone replacement therapy [86]. Intramuscular testosterone ester administration, with its supraphysiological peak blood testosterone levels and maintenance of relatively high blood testosterone levels for at least 10 days after injection has more beneficial effects on bone than transdermal [94, 95] or buccal [96] testosterone administration which have difficulty maintaining physiological blood testosterone levels. However, no well-controlled prospective studies comparing the effects of different forms of testosterone on skeletal health are reported. Nor are there any adequately powered randomized controlled trials of testosterone therapy for men with either idiopathic or androgen deficiency related osteoporosis with fractures as a clinical endpoint. The effect of androgen replacement therapy on BMD is largely accounted for by androgen effects on bone turnover. In androgen deficient men, testosterone administration decreases biochemical markers of bone resorption
Partial Androgen Deficiency in Older Men In recent years, the increased life expectancy in developed countries has led to interest in reproductive health of aging men. Among the issue of greatest interest is the possibility that age-related androgen deficiency in older men may be a potentially correctable aspect of healthy aging. As an issue of growing interest to physicians as well as the wider society with interests in healthy aging and burgeoning health care costs [19], the putative somatic consequences of gradually falling testosterone concentrations include changes in bone mass. This has become one rationale for wider use of testosterone treatment of middle-aged and older men with apparent age-related, but no other pathological basis for, androgen deficiency. This has led to a massive increase, nearly 20-fold worldwide over the last decade, in testosterone prescribing. Although there is evidence that chronic androgen deficiency is associated with premature deaths due to fractures [48, 73–76], there remain no well-controlled, prospective studies evaluating whether testosterone administration for agerelated bone loss is safe and effective. Several cross-sectional and longitudinal studies have investigated the association between gonadal steroids, biochemical markers of bone turnover and bone mass in older men [22, 100–103]. One cross-sectional study including men between 23 and 90 years of age, reported inverse correlations between urinary collagen type I cross-linked N-telopeptide (NTX) levels and both ‘bioavailable’ E2 and ‘bioavailable’ testosterone [22]. However, no correlation with total estradiol or testosterone was identified and the biological meaning of such derived steroid measures, which largely reflect age-related changes in SHBG, remains dubious. In contrast, in another study of men over 51 years of age, only ‘bioavailable’ E2 levels correlated negatively with bone turnover but, again, no relationships were observed with total E2 or testosterone or various derived testosterone measures [100]. A third study found a relationship between E2 and bone resorption markers (serum and urinary NTX) but not with indices of bone formation (osteocalcin (OC), bone alkaline phosphatase (BAP)) [102]. Any conclusion about the significance of low levels of blood E2 in men is constrained by the unreliability of direct serum E2 immunoassays on which many are based [23]. Whether the low levels of circulating
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E2 in men are associated with increased bone resorption or this is an artefact of age-related increases in SHBG remains to be clarified. If such increases in bone resorption are associated with bone loss, this indicates that the usual concomitant increase in bone formation is at least partly uncoupled and under-compensated. Older men, especially after the age of 70 years, usually have substantial bone loss and are at increasing risk of osteoporotic fractures. However, the extent to which low levels of testosterone contribute to age-related bone loss in men remains unclear [2]. In analogy to markers of bone turnover, several cross-sectional and longitudinal studies have documented significant correlations between serum levels of ‘bioavailable’ or total E2 and bone density [4, 104] or change in bone mass during follow up [101–103]. In contrast, other studies fail to show consistent associations between ‘bioavailable’ testosterone and BMD or bone loss [22, 105, 106]. A recently published cross-sectional study among men in NHANES III, however, showed that men with lower ‘free’ estradiol and lower ‘free’ testosterone concentrations (calculated, not measured) were more likely to have low BMD [107]. It is unclear whether the main mechanism of estrogen action on bone is via local aromatization of testosterone to estradiol within bone or to systemic estradiol exposure. One possible explanation is that there is a threshold for estrogen action, possibly based on some critical level of blood or local estradiol. All the above-mentioned studies focus on the association between sex hormone levels and bone turnover markers and
% of Men With Low-Trauma Fracture
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BMD as surrogate markers of bone integrity. However, data on the more direct relationship between blood testosterone and E2 and rates of osteoporotic fractures are limited. A recent study from Sweden reported that ‘free’ testosterone within the normal range was independently associated with prevalent osteoporotic fractures in elderly men [108]. However, this weak relationship explained only 1% of variance and the direction of causality remained unclear. In contrast, a subset analysis from the Rotterdam Study failed to confirm an association between testosterone and fracture risk [109]. Data from the Framingham Study recently indicated a synergistic effect of sex hormones on fracture risk in that men with low serum testosterone and low E2 levels were at increased risk for incident hip fractures. Analyses restricted to either gonadal steroid alone, however, revealed that in older men, serum E2 but not testosterone was associated with hip fracture risk [110]. In these studies [109,110], however, serum testosterone levels were measured using immunoassay-based methods that are unreliable, particularly in the lower concentration range [8]. Based on the prospective Dubbo Osteoporosis Epidemiology Study and using tandem mass spectrometry for gonadal steroid measurement, we recently observed that community-dwelling elderly men with lower serum testosterone levels had increased risk of osteoporotic fracture (Figure 35.5). This effect was independent of established risk factors, such as age and BMD. In contrast there was no significant association between serum E2 levels and fracture in the presence of BMD and age [111].
Low testosterone level Intermediate testosterone level High testosterone level
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Figure 35.5 Proportion of study participants with low-trauma fractures during follow up (time-to-event analysis) according to baseline sex hormone levels, grouped by adjusted baseline serum testosterone levels (low testosterone, 294 ng/dL; intermediate testosterone, 294–559 ng/dL; and high testosterone, 559 ng/dL), P 5 0.01 for the low versus high testosterone group. (Adapted from Meier et al Arch Intern Med 2008;168:47–54 [111], with permission from The American Medical Association).
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Effect of Androgen Replacement in Men with Age-Related Androgen Deficiency
TESTOSTERONE TREATMENT EFFECT ON % CHANGE IN L2-L4 BMD
The effects of testosterone treatment on bone in older men remain inconclusive in the absence of adequately powered, sufficiently long-term, randomized placebo-controlled studies to indicate whether testosterone treatment reduces bone fractures in older men [19]. So far, few randomized placebo-controlled studies in healthy men over 50 years have examined the impact of androgen supplementation on bone represented either by bone turnover markers [112–115] and/or bone density [113–116]. All studies treated otherwise healthy, non-osteoporotic men with transdermal testosterone [113, 115], oral testosterone [116] or intramuscular (IM) testosterone injections [112, 114]. Irrespective of baseline entry criterion blood testosterone concentrations (range 10.1–13.7 nmol/L), no study showed consistent changes in bone turnover markers after 3–36 months of treatment. Only in an early small cross-over study by Tenover [112] was urinary excretion of hydroxyproline decreased in testosterone treated men while remaining unchanged in the placebo treated group. The relevance of this isolated finding using a non-specific marker of collagen turnover remains unclear. Three placebo-controlled studies investigating the effect on BMD have differed in outcome: whereas the studies by Snyder et al and Emmelot-Vonk et al showed no benefit of treatment [113, 116], the study by Kenny et al showed that testosterone prevented ongoing age-related bone loss in
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PRETREATMENT TESTOSTERONE CONCENTRATION (ng/dl)
Figure 35.6 The testosterone treatment effect on percent change in BMD during 36 months of testosterone treatment in men over 65 years of age as a function of the pretreatment serum testosterone concentration. The lower the pretreatment serum testosterone concentration the greater the effect of testosterone treatment on BMD. The treatment effect was statistically significant (P 0.01) for pretreatment serum testosterone concentrations of 10–300 ng/dL. The values shown are the mean (SE) changes in BMD during the 36 months of treatment in the testosterone-treated subjects minus those in the placebo-treated subjects (Adapted from Snyder et al J Clin Endocrinol Metab 1999;84:1966–1972 [113], with permission The Endocrine Society).
one of five bone sites [115]. Post-hoc analysis of the larger study by Snyder et al suggested that bone density gains were inversely related to pre-study baseline levels of blood testosterone [113], consistent with the idea that the benefits depend on the degree of underlying androgen deficiency (Figure 35.6). A recent study in which testosterone enantate was administered at a higher dose reported significant increases in BMD at the lumbar spine and the hip after 36 months of treatment [114], however, a reduction in dose for polycythemia was required in 25% of the participating men. In summary, from available well controlled evidence, there appears to be no consistent effect of exogenous testosterone treatment on bone turnover and limited, dose-dependent effect on BMD in older men with low-normal circulating testosterone. Results from placebo-controlled trials including elderly men with consistently lower baseline testosterone levels (i.e. below 8 nmol/L) are needed to unravel the effects of testosterone replacement on bone surrogate markers, such as BMD and bone turnover markers and, ultimately, fracture risk, morbidity and mortality [117]. In the interim, there is no basis for empirical testosterone treatment for men with idiopathic or age-related osteoporosis unless there is concomitant evidence of overt androgen deficiency.
References 1. D.J. Handelsman, Androgen physiology, pharmacology and abuse, in: L.J. de Groot (Ed.), Endocrinology, Elsevier Saunders, Philadelphia, 2009. 2. D. Vanderschueren, L. Vandenput, S. Boonen, M.K. Lindberg, R. Bouillon, C. Ohlsson, Androgens and bone, Endocr Rev. 25 (3) (2004) 389–425. 3. W. de Ronde, H.A. Pols, J.P. van Leeuwen, F.H. de Jong, The importance of oestrogens in males, Clin. Endocrinol (Oxf) 58 (5) (2003) 529–542. 4. S. Khosla, L.J. Melton 3rd, B.L. Riggs, Clinical review 144: estrogen and the male skeleton, J. Clin. Endocrinol. Metab. 87 (4) (2002) 1443–1450. 5. F. Callewaert, K. Venken, J. Ophoff, et al., Differential regulation of bone and body composition in male mice with combined inactivation of androgen and estrogen receptor-alpha, Faseb J. 23 (1) (2009) 232–240. 6. G. Sartorius, D.J. Handelsman, Testicular, dysfunction in systemic diseases, in: E. Nieschlag, H.M. Behre (Eds.) Andrology: Male Reproductive Health and Dysfunction, third edn., Springer-Verlag, Berlin, 2009. 7. J. Taieb, B. Mathian, F. Millot, et al., Testosterone measured by 10 immunoassays and by isotope-dilution gas chromatography-mass spectrometry in sera from 116 men, women, and children, Clin. Chem. 49 (8) (2003) 1381–1395. 8. K. Sikaris, R.I. McLachlan, R. Kazlauskas, D. de Kretser, C.A. Holden, D.J. Handelsman, Reproductive hormone reference intervals for healthy fertile young men: evaluation of automated platform assays, J. Clin. Endocrinol. Metab. 90 (11) (2005) 5928–5936. 9. L.P. Ly, D.J. Handelsman, Empirical estimation of free testosterone from testosterone and sex hormone-binding globulin immunoassays, Eur. J. Endocrinol. 152 (3) (2005) 471–478.
C h a p t e r 3 5 Testicular Dysfunction l
10. A. Belanger, B. Candas, A. Dupont, et al., Changes in serum concentrations of conjugated and unconjugated steroids in 40to 80-year-old men, J. Clin. Endocrinol. Metab. 79 (4) (1994) 1086–1090. 11. E. Orwoll, L.C. Lambert, L.M. Marshall, et al., Testosterone and estradiol among older men, J. Clin. Endocrinol. Metab. 91 (4) (2006) 1336–1344. 12. P.Y. Liu, J. Beilin, C. Meier, et al., Age-related changes in serum testosterone and sex hormone binding globulin in Australian men: longitudinal analyses of two geographically separate regional cohorts, J. Clin. Endocrinol. Metab. 92 (9) (2007) 3599–3603. 13. C.T. Liverman, D.G. Blazer (Eds.), Testosterone and Aging: Clinical Research Directions., National Academies Press, Washington DC, 2003. 14. J.M. Kaufman, A. Vermeulen, Declining gonadal function in elderly men, Baillières Clin. Endocrinol. Metab. 11 (2) (1997) 289–309. 15. S.M. Harman, E.J. Metter, J.D. Tobin, J. Pearson, M.R. Blackman, Longitudinal effects of aging on serum total and free testosterone levels in healthy men. Baltimore Longitudinal Study of Aging, J. Clin. Endocrinol. Metab. 86 (2) (2001) 724–731. 16. H.A. Feldman, C. Longcope, C.A. Derby, et al., Age trends in the level of serum testosterone and other hormones in middle-aged men: longitudinal results from the Massachusetts male aging study, J. Clin. Endocrinol. Metab. 87 (2) (2002) 589–598. 17. P.Y. Liu, A.K. Death, D.J. Handelsman, Androgens and cardiovascular disease, Endocr. Rev. 24 (3) (2003) 313–340. 18. G. Sartorius, L.P. Ly, K. Sikaris, R.I. McLachlan, D.J. Handelsman, Predictive accuracy and sources of variability in calculated free testosterone estimates, Ann. Clin. Biochem. (2009) in press. 19. P.Y. Liu, R.S. Swerdloff, J. Veldhuis, The rationale, efficacy and safety of androgen therapy in older men: Future research and current practice recommendations, J. Clin. Endocrinol. Metab. 89 (10) (2004) 4789–4796. 20. J.M. Kaufman, A. Vermeulen, The decline of androgen levels in elderly men and its clinical and therapeutic implications, Endocr. Rev. 26 (6) (2005) 833–876. 21. A. Vermeulen, J.M. Kaufman, S. Goemaere, I. van Pottelberg, Estradiol in elderly men, Aging. Male. 5 (2) (2002) 98–102. 22. S. Khosla, L.J. Melton 3rd, E.J. Atkinson, W.M. O’Fallon, G.G. Klee, B.L. Riggs, Relationship of serum sex steroid levels and bone turnover markers with bone mineral density in men and women: a key role for bioavailable estrogen, J. Clin. Endocrinol. Metab. 83 (7) (1998) 2266–2274. 23. A.W. Hsing, F.Z. Stanczyk, A. Belanger, et al., Reproducibility of serum sex steroid assays in men by RIA and mass spectrometry, Cancer Epidemiol. Biomarkers Prev. 16 (5) (2007) 1004–1008. 24. V. Gilsanz, D.T. Gibbens, T.F. Roe, et al., Vertebral bone density in children: effect of puberty, Radiology 166 (3) (1988) 847–850. 25. P.W. Lu, J.N. Briody, G.D. Ogle, et al., Bone mineral density of total body, spine, and femoral neck in children and young adults: a cross-sectional and longitudinal study, J. Bone Miner Res. 9 (9) (1994) 1451–1458. 26. G. Theintz, B. Buchs, R. Rizzoli, et al., Longitudinal monitoring of bone mass accumulation in healthy adolescents:
27. 28. 29. 30.
31.
32. 33. 34.
35.
36.
37.
38.
39. 40.
41.
42.
43.
44.
431
evidence for a marked reduction after 16 years of age at the levels of lumbar spine and femoral neck in female subjects, J. Clin. Endocrinol. Metab. 75 (4) (1992) 1060–1065. M. Misra, A. Klibanski, Anorexia nervosa and osteoporosis, Rev. Endocr. Metab. Disord. 7 (1-2) (2006) 91–99. E. Seeman, Invited review: pathogenesis of osteoporosis, J. Appl. Physiol. 95 (5) (2003) 2142–2151. E. Seeman, Pathogenesis of bone fragility in women and men, Lancet 359 (9320) (2002) 1841–1850. J.P. Bonjour, G. Theintz, B. Buchs, D. Slosman, R. Rizzoli, Critical years and stages of puberty for spinal and femoral bone mass accumulation during adolescence, J. Clin. Endo crinol. Metab. 73 (3) (1991) 555–563. B.J. Riis, S. Krabbe, C. Christiansen, B.D. Catherwood, L.J. Deftos, Bone turnover in male puberty: a longitudinal study, Calcif. Tissue Int. 37 (3) (1985) 213–217. L.N. Parker, Adrenarche, Endocrinol Metab. Clin. North Am. 20 (1) (1991) 71–83. N.J. Shaw, Management of osteoporosis in children, Eur. J. Endocrinol. 159 (Suppl. 1) (2008) S33–S39. S.G. Soule, G. Conway, G.M. Prelevic, M. Prentice, J. Ginsburg, H.S. Jacobs, Osteopenia as a feature of the androgen insensitivity syndrome, Clin. Endocrinol. (Oxf). 43 (6) (1995) 671–675. J.S. Finkelstein, A. Klibanski, R.M. Neer, S.L. Greenspan, D.I. Rosenthal, W.F. Crowley Jr, Osteoporosis in men with idiopathic hypogonadotropic hypogonadism, Ann. Intern. Med. 106 (3) (1987) 354–361. J.S. Finkelstein, A. Klibanski, R.M. Neer, et al., Increases in bone density during treatment of men with idiopathic hypo gonadotropic hypogonadism, J. Clin. Endocrinol. Metab. 69 (4) (1989) 776–783. O. Arisaka, M. Arisaka, A. Hosaka, N. Shimura, K. Yabuta, Effect of testosterone on radial bone mineral density in adolescent male hypogonadism, Acta. Paediatr. Scand. 80 (3) (1991) 378–380. J.P. Devogelaer, S. De Cooman, C. Nagant de Deuxchaisnes, Low bone mass in hypogonadal males. Effect of testosterone substitution therapy, a densitometric study, Maturitas 15 (1) (1992) 17–23. F. Naftolin, Brain aromatization of androgens, J. Reprod. Med. 39 (4) (1994) 257–261. E.P. Smith, J. Boyd, G.R. Frank, et al., Estrogen resistance caused by a mutation in the estrogen-receptor gene in a man, N. Engl. J. Med. 331 (16) (1994) 1056–1061. A. Morishima, M.M. Grumbach, E.R. Simpson, C. Fisher, K. Qin, Aromatase deficiency in male and female siblings caused by a novel mutation and the physiological role of estrogens, J. Clin. Endocrinol. Metab. 80 (12) (1995) 3689–3698. C. Carani, K. Qin, M. Simoni, et al., Effect of testosterone and estradiol in a man with aromatase deficiency, N. Engl. J. Med. 337 (2) (1997) 91–95. L. Maffei, Y. Murata, V. Rochira, et al., Dysmetabolic syndrome in a man with a novel mutation of the aromatase gene: effects of testosterone, alendronate, and estradiol treatment, J. Clin. Endocrinol. Metab. 89 (1) (2004) 61–70. A. Falahati-Nini, B.L. Riggs, E.J. Atkinson, W.M. O’Fallon, R. Eastell, S. Khosla, Relative contributions of testosterone and estrogen in regulating bone resorption and formation in normal elderly men, J. Clin. Invest. 106 (12) (2000) 1553–1560.
432
Osteoporosis in Men
45. B.Z. Leder, K.M. LeBlanc, D.A. Schoenfeld, R. Eastell, J.S. Finkelstein, Differential effects of androgens and estrogens on bone turnover in normal men, J. Clin. Endocrinol. Metab. 88 (1) (2003) 204–210. 46. J.P. Bilezikian, Osteoporosis in men, J. Clin. Endocrinol. Metab. 84 (10) (1999) 3431–3434. 47. B.Z. Leder, J.S. Finkelstein, Gonadal steroids and the skeleton in men, in: E.S. Orwoll, M. Bliziotes (Eds.) Contemporary Endocrinology. Osteoporosis. Pathophysiology and Clinical Management, Humana Press, Totowa, New Jersey, 2003, pp. 393–411. 48. J.J. Stepan, M. Lachman, J. Zverina, V. Pacovsky, D.J. Baylink, Castrated men exhibit bone loss: effect of calcitonin treatment on biochemical indices of bone remodeling, J. Clin. Endo crinol. Metab. 69 (3) (1989) 523–527. 49. D. Goldray, Y. Weisman, N. Jaccard, C. Merdler, J. Chen, H. Matzkin, Decreased bone density in elderly men treated with the gonadotropin-releasing hormone agonist decapeptyl (D-Trp6GnRH), J. Clin. Endocrinol. Metab. 76 (2) (1993) 288–290. 50. M.R. Smith, F.J. McGovern, A.L. Zietman, et al., Pamidronate to prevent bone loss during androgen-deprivation therapy for prostate cancer, N. Engl. J. Med. 345 (13) (2001) 948–955. 51. S.A. Stoch, R.A. Parker, L. Chen, et al., Bone loss in men with prostate cancer treated with gonadotropin-releasing hormone agonists, J. Clin. Endocrinol. Metab. 86 (6) (2001) 2787–2791. 52. T. Diamond, J. Campbell, C. Bryant, W. Lynch, The effect of combined androgen blockade on bone turnover and bone mineral densities in men treated for prostate carcinoma: longitudinal evaluation and response to intermittent cyclic etidronate therapy., Cancer 83 (8) (1998) 1561–1566. 53. S. Basaria, J. Lieb, A.M. Tang, et al., Long-term effects of androgen deprivation therapy in prostate cancer patients, Clin. Endocrinol. (Oxf). 56 (6) (2002) 779–786. 54. D. Mittan, S. Lee, E. Miller, R.C. Perez, J.W. Basler, J.M. Bruder, Bone loss following hypogonadism in men with prostate cancer treated with GnRH analogs, J. Clin. Endocrinol. Metab. 87 (8) (2002) 3656–3661. 55. J.T. Wei, M. Gross, C.A. Jaffe, et al., Androgen deprivation therapy for prostate cancer results in significant loss of bone density, Urology 54 (4) (1999) 607–611. 56. A. Berruti, L. Dogliotti, G. Gorzegno, et al., Differential patterns of bone turnover in relation to bone pain and disease extent in bone in cancer patients with skeletal metastases, Clin. Chem. 45 (8 Pt 1) (1999) 1240–1247. 57. H.W. Daniell, Osteoporosis after orchiectomy for prostate cancer, J. Urol. 157 (2) (1997) 439–444. 58. B.J. Kiratli, S. Srinivas, I. Perkash, M.K. Terris, Progressive decrease in bone density over 10 years of androgen deprivation therapy in patients with prostate cancer, Urology 57 (1) (2001) 127–132. 59. M.F. Townsend, W.H. Sanders, R.O. Northway, S.D. Graham Jr, Bone fractures associated with luteinizing hormone-releasing hormone agonists used in the treatment of prostate carcinoma, Cancer 79 (3) (1997) 545–550. 60. T. Hatano, Y. Oishi, A. Furuta, S. Iwamuro, K. Tashiro, Incidence of bone fracture in patients receiving luteinizing hormone-releasing hormone agonists for prostate cancer, BJU Int. 86 (4) (2000) 449–452. 61. M.G. Oefelein, V. Ricchuiti, W. Conrad, et al., Skeletal fracture associated with androgen suppression induced osteoporosis:
62.
63.
64.
65.
66.
67. 68.
69.
70.
71.
72.
73.
74.
75.
76.
77.
78.
79.
the clinical incidence and risk factors for patients with prostate cancer, J. Urol. 166 (5) (2001) 1724–1728. L.J. Melton 3rd, K.I. Alothman, S. Khosla, S.J. Achenbach, A.L. Oberg, H. Zincke, Fracture risk following bilateral orchiectomy, J. Urol. 169 (5) (2003) 1747–1750. M.R. Smith, M.A. Fallon, H. Lee, J.S. Finkelstein, Raloxifene to prevent gonadotropin-releasing hormone agonist-induced bone loss in men with prostate cancer: a randomized controlled trial, J. Clin. Endocrinol. Metab. 89 (8) (2004) 3841–3846. A.M. Lopez, M.A. Pena, R. Hernandez, F. Val, B. Martin, J.A. Riancho, Fracture risk in patients with prostate cancer on androgen deprivation therapy, Osteoporos Int. 16 (6) (2005) 707–711. V.B. Shahinian, Y.F. Kuo, J.L. Freeman, J.S. Goodwin, Risk of fracture after androgen deprivation for prostate cancer, N. Engl. J. Med. 352 (2) (2005) 154–164. T.H. Diamond, C.S. Higano, M.R. Smith, T.A. Guise, F.R. Singer, Osteoporosis in men with prostate carcinoma receiving androgen-deprivation therapy: recommendations for diagnosis and therapies., Cancer 100 (5) (2004) 892–899. R.M. Francis, The effects of testosterone on osteoporosis in men, Clin. Endocrinol. (Oxf). 50 (4) (1999) 411–414. D.A. Smith, M.S. Walker, Changes in plasma steroids and bone density in Klinefelter’s syndrome, Calcif Tissue Res. 22 (Suppl) (1977) 225–228. C. Foresta, G. Ruzza, R. Mioni, A. Meneghello, C. Baccichetti, Testosterone, and bone loss in Klinefelter syndrome, Horm Metab Res. 15 (1) (1983) 56–57. M. Horowitz, J.M. Wishart, P.D. O’Loughlin, H.A. Morris, A.G. Need, B.E. Nordin, Osteoporosis and Klinefelter’s syndrome, Clin. Endocrinol. (Oxf). 36 (1) (1992) 113–118. S.L. Greenspan, R.M. Neer, E.C. Ridgway, A. Klibanski, Osteoporosis in men with hyperprolactinemic hypogonadism, Ann. Intern. Med. 104 (6) (1986) 777–782. G. Luisetto, I. Mastrogiacomo, G. Bonanni, et al., Bone mass and mineral metabolism in Klinefelter’s syndrome, Osteoporos Int. 5 (6) (1995) 455–461. A. Bojesen, S. Juul, C.H. Gravholt, Prenatal and postnatal prevalence of Klinefelter syndrome: a national registry study, J. Clin. Endocrinol. Metab. 88 (2) (2003) 622–626. D.J. Handelsman, P.Y. Liu, Klinefelter’s syndrome – a microcosm of male reproductive health, J. Clin. Endocrinol. Metab. 91 (4) (2006) 1220–1222. A. Bojesen, S. Juul, N. Birkebaek, C.H. Gravholt, Increased mortality in Klinefelter syndrome, J. Clin. Endocrinol. Metab. 89 (8) (2004) 3830–3884. A.J. Swerdlow, C.D. Higgins, M.J. Schoemaker, A.F. Wright, P.A. Jacobs, Mortality in patients with Klinefelter syndrome in Britain: a cohort study, J. Clin. Endocrinol. Metab. 90 (12) (2005) 6516–6522. J.A. Jackson, M. Kleerekoper, A.M. Parfitt, D.S. Rao, A.R. Villanueva, B. Frame, Bone histomorphometry in hypogonadal and eugonadal men with spinal osteoporosis, J. Clin. Endocrinol. Metab. 65 (1) (1987) 53–58. C.Y. Guo, T.H. Jones, R. Eastell, Treatment of isolated hypo gonadotropic hypogonadism effect on bone mineral density and bone turnover, J. Clin. Endocrinol. Metab. 82 (2) (1997) 658–665. D.T. Baran, M.A. Bergfeld, S.L. Teitelbaum, L.V. Avioli, Effect of testosterone therapy on bone formation in an
C h a p t e r 3 5 Testicular Dysfunction l
80.
81.
82.
83.
84.
85.
86.
87.
88.
89.
90.
91.
92. 93. 94.
osteoporotic hypogonadal male, Calcif Tissue Res. 26 (2) (1978) 103–106. R.M. Francis, M. Peacock, J.E. Aaron, et al., Osteoporosis in hypogonadal men: role of decreased plasma 1,25-dihydroxyvitamin D, calcium malabsorption, and low bone formation., Bone 7 (4) (1986) 261–268. C. Wang, D.R. Eyre, R. Clark, et al., Sublingual testosterone replacement improves muscle mass and strength, decreases bone resorption, and increases bone formation markers in hypogonadal men – a clinical research center study, J. Clin. Endocrinol. Metab. 81 (10) (1996) 3654–3662. C. Wang, R.S. Swerdloff, A. Iranmanesh, et al., Effects of transdermal testosterone gel on bone turnover markers and bone mineral density in hypogonadal men, Clin. Endocrinol. (Oxf). 54 (6) (2001) 739–750. P.J. Snyder, H. Peachey, J.A. Berlin, et al., Effects of testosterone replacement in hypogonadal men, J. Clin. Endocrinol. Metab. 85 (8) (2000) 2670–2677. L. Katznelson, J.S. Finkelstein, D.A. Schoenfeld, D.I. Rosenthal, E.J. Anderson, A. Klibanski, Increase in bone density and lean body mass during testosterone administration in men with acquired hypogonadism, J. Clin. Endocrinol. Metab. 81 (12) (1996) 4358–4365. J.E. Morley, H.M. Perry 3rd, F.E. Kaiser, et al., Effects of testosterone replacement therapy in old hypogonadal males: a preliminary study, J. Am. Geriatr. Soc. 41 (2) (1993) 149–152. A. Aminorroaya, S. Kelleher, A.J. Conway, L.P. Ly, D.J. Handelsman, Adequacy of androgen replacement influences bone density response to testosterone in androgen-deficient men, Eur. J. Endocrinol 152 (6) (2005) 881–886. S.L. Greenspan, D.S. Oppenheim, A. Klibanski, Importance of gonadal steroids to bone mass in men with hyperprolactinemic hypogonadism, Ann. Intern. Med. 110 (7) (1989) 526–531. H.M. Behre, S. Kliesch, E. Leifke, T.M. Link, E. Nieschlag, Long-term effect of testosterone therapy on bone mineral density in hypogonadal men, J. Clin. Endocrinol Metab. 82 (8) (1997) 2386–2390. E. Leifke, H.C. Korner, T.M. Link, H.M. Behre, P.E. Peters, E. Nieschlag, Effects of testosterone replacement therapy on cortical and trabecular bone mineral density, vertebral body area and paraspinal muscle area in hypogonadal men, Eur. J. Endocrinol. 138 (1) (1998) 51–58. G. Isaia, M. Mussetta, F. Pecchio, A. Sciolla, M. di Stefano, G.M. Molinatti, Effect of testosterone on bone in hypogonadal males, Maturitas 15 (1) (1992) 47–51. M. Zitzmann, M. Depenbusch, J. Gromoll, E. Nieschlag, X-chromosome inactivation patterns and androgen receptor functionality influence phenotype and social characteristics as well as pharmacogenetics of testosterone therapy in Klinefelter patients, J. Clin. Endocrinol. Metab. 89 (12) (2004) 6208–6217. S. Khosla, S. Amin, E. Orwoll, Osteoporosis in men, Endocr. Rev. 29 (4) (2008) 441–464. E. Seeman, The growth and age-related origins of bone fragility in men, Calcif Tissue Int. 75 (2) (2004) 100–109. C. Wang, R.S. Swedloff, A. Iranmanesh, et al., Transdermal testosterone gel improves sexual function, mood, muscle strength, and body composition parameters in hypogonadal men. Testosterone Gel Study Group, J. Clin. Endocrinol Metab. 85 (8) (2000) 2839–2853.
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95. C. Wang, G. Cunningham, A. Dobs, et al., Long-term testosterone gel (AndroGel) treatment maintains beneficial effects on sexual function and mood, lean and fat mass, and bone mineral density in hypogonadal men, J. Clin. Endocrinol. Metab. 89 (5) (2004) 2085–2098. 96. C. Wang, R. Swerdloff, M. Kipnes, et al., New testosterone buccal system (Striant) delivers physiological testosterone levels: pharmacokinetics study in hypogonadal men, J. Clin. Endocrinol. Metab. 89 (8) (2004) 3821–3829. 97. M. Schubert, C. Bullmann, T. Minnemann, C. Reiners, W. Krone, F. Jockenhovel, Osteoporosis in male hypogonadism: responses to androgen substitution differ among men with primary and secondary hypogonadism, Horm Res. 60 (1) (2003) 21–28. 98. S. Bhasin, T.W. Storer, N. Berman, et al., Testosterone replacement increases fat-free mass and muscle size in hypogonadal men, J. Clin. Endocrinol Metab 82 (2) (1997) 407–413. 99. R. Sih, J.E. Morley, F.E. Kaiser, H.M. Perry 3rd, P. Patrick, C. Ross, Testosterone replacement in older hypogonadal men: a 12-month randomized controlled trial, J. Clin. Endocrinol. Metab. 82 (6) (1997) 1661–1667. 100. P. Szulc, F. Munoz, B. Claustrat, et al., Bioavailable estradiol may be an important determinant of osteoporosis in men: the MINOS study, J. Clin. Endocrinol. Metab. 86 (1) (2001) 192–199. 101. C.W. Slemenda, C. Longcope, L. Zhou, S.L. Hui, M. Peacock, C.C. Johnston, Sex steroids and bone mass in older men. Positive associations with serum estrogens and negative associations with androgens, J. Clin. Invest. 100 (7) (1997) 1755–1759. 102. S. Khosla, L.J. Melton 3rd, E.J. Atkinson, W.M. O’Fallon, Relationship of serum sex steroid levels to longitudinal changes in bone density in young versus elderly men, J. Clin. Endocrinol. Metab. 86 (8) (2001) 3555–3561. 103. L. Gennari, D. Merlotti, G. Martini, et al., Longitudinal association between sex hormone levels, bone loss, and bone turnover in elderly men, J. Clin. Endocrinol. Metab. 88 (11) (2003) 5327–5333. 104. B.L. Riggs, S. Khosla, L.J. Melton 3rd, Sex steroids and the construction and conservation of the adult skeleton, Endocr. Rev. 23 (3) (2002) 279–302. 105. G.A. Greendale, S. Edelstein, E. Barrett-Connor, Endo genous sex steroids and bone mineral density in older women and men: the Rancho Bernardo Study, J. Bone Miner Res. 12 (11) (1997) 1833–1843. 106. A.M. Kenny, K.M. Prestwood, K.M. Marcello, L.G. Raisz, Determinants of bone density in healthy older men with low testosterone levels., J. Gerontol. A. Biol. Sci. Med. Sci. 55 (9) (2000) M492–M497. 107. C.J. Paller, M.S. Shiels, S. Rohrmann, et al., Relationship of sex steroid hormones with bone mineral density (BMD) in a nationally representative sample of men, Clin. Endocrinol. (Oxf). 70 (1) (2009) 26–34. 108. D. Mellstrom, O. Johnell, O. Ljunggren, et al., Free testosterone is an independent predictor of BMD and prevalent fractures in elderly men: MrOS Sweden, J. Bone Miner Res. 21 (4) (2006) 529–535. 109. H.W. Goderie-Plomp, M. van der Klift, W. de Ronde, A. Hofman, F.H. de Jong, H.A. Pols, Endogenous sex
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110.
111.
112.
113.
Osteoporosis in Men hormones, sex hormone-binding globulin, and the risk of incident vertebral fractures in elderly men and women: the Rotterdam Study, J. Clin. Endocrinol. Metab. 89 (7) (2004) 3261–3269. S. Amin, Y. Zhang, D.T. Felson, et al., Estradiol, testosterone, and the risk for hip fractures in elderly men from the Framingham Study, Am. J. Med. 119 (5) (2006) 426–433. C. Meier, T.V. Nguyen, D.J. Handelsman, et al., Endogenous sex hormones and incident fracture risk in older men: the Dubbo Osteoporosis Epidemiology Study, Arch. Intern. Med. 168 (1) (2008) 47–54. J.S. Tenover, Effects of testosterone supplementation in the aging male, J. Clin. Endocrinol. Metab. 75 (4) (1992) 1092–1098. P.J. Snyder, H. Peachey, P. Hannoush, et al., Effect of testo sterone treatment on bone mineral density in men over 65 years of age, J. Clin. Endocrinol. Metab. 84 (6) (1999) 1966–1972.
114. J.K. Amory, N.B. Watts, K.A. Easley, et al., Exogenous testosterone or testosterone with finasteride increases bone mineral density in older men with low serum testosterone, J. Clin. Endocrinol. Metab. 89 (2) (2004) 503–510. 115. A.M. Kenny, K.M. Prestwood, C.A. Gruman, K.M. Marcello, L.G. Raisz, Effects of transdermal testosterone on bone and muscle in older men with low bioavailable testosterone levels., J. Gerontol A. Biol. Sci. Med. Sci. 56 (5) (2001) M266–M272. 116. M.H. Emmelot-Vonk, H.J. Verhaar, H.R. Nakhai Pour, et al., Effect of testosterone supplementation on functional mobility, cognition, and other parameters in older men: a randomized controlled trial, J. Am. Med. Assoc. 299 (1) (2008) 39–52. 117. S. Bhasin, G.R. Cunningham, F.J. Hayes, et al., Testosterone therapy in adult men with androgen deficiency syndromes: an endocrine society clinical practice guideline, J. Clin. Endocrinol. Metab. 91 (6) (2006) 1995–2010.
Chapter
36
Alcohol Use and Bone Health in Men Neil Binkley and Diane Krueger University of Wisconsin, Madison, Wisconsin, USA
Introduction
With the increasing number of older adults worldwide and well-known increase in fragility fracture risk with advancing age, the potential toxic effect(s) of alcohol on bone is of substantial concern. It should be appreciated that cultural and/or personal habits related to drinking alcohol may impact its metabolism in that food in the stomach slows absorption [7]. Thus, it is possible that the weekly consumption of seven units of alcohol could have markedly different physiologic effects if this intake consists of seven glasses of beer on an empty stomach in a relatively small period of time (i.e. at one setting) or of one glass of wine with supper daily. While ‘binge drinking’ is noted in some published works as a special kind of risk, this is not uniformly the case of published reports considering alcohol intake and its long-term outcomes.
Alcohol is consumed by approximately two-thirds of men across the lifespan in the USA and alcohol abuse is widely appreciated as a risk factor for fragility fracture. However, moderate alcohol consumption is associated with higher bone mineral density (BMD) and lower fracture risk. The mechanism(s) of these apparently contradictory observations are not well defined and the issues surrounding alcohol use and bone health are exceedingly complex. This chapter will review the epidemiology of alcohol use/abuse among men, explore the effects of alcohol on musculoskeletal metabolism, bone mineral density, falls and fracture risk.
Alcohol physiology Epidemiology
Ethanol is a non-essential molecule produced by fermentation of grains or fruits [1] and is consumed as a beverage (usually beer, wine or distilled spirits) or added during cooking. Small amounts of ingested ethanol are degraded by alcohol dehydrogenase in the stomach [2] and excreted via the lungs, however, the liver is the primary site of ethanol metabolism. Ethanol is metabolized by alcohol dehydrogenase and the cytochrome P450 enzyme, CYP2E1 [3, 4]. The first metabolic product, acetaldehyde, is a known carcinogen due to its mutagenic effects on DNA [5]. Thus, ethanol has obvious potential toxicity. Individual variability in response to alcohol exists in that genetic predisposition may increase the risk of alcohol abuse. Moreover, with advancing age, older adults appear to be more sensitive to alcohol toxicity [3]. Based on this age-related increase in sensitivity, the US National Institute on Alcohol Abuse and Alcoholism recommends that adults age 65 and over limit their intake to one drink per day. However, the definition of ‘safe’ intake is controversial [6]. Osteoporosis in Men
It is clear that excessive alcohol use leads to addiction and to damage of virtually all body organs [5]. In fact, the World Health Organization reports that alcohol is responsible for over 3% of all deaths worldwide. This is not surprising as is the case with most drugs, dose-dependent toxicity is seen with alcohol. Alcohol is particularly of concern for men in that more males than females consume alcohol and men, on average, consume a greater quantity [8]. Additionally, the type of alcohol ingested differs by sex, with women drinking primarily wine and men consuming primarily beer. These differences may influence outcomes due to variation in alcohol and nutrient content [9]. While alcohol consumption, in general, declines with advancing age [8, 10], alcohol use remains common among older adults. Over 50% of those greater than age 60 currently consume alcohol and approximately 25% of men over age 60 consume one or more drinks daily [11]. 435
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In attempting to summarize a diverse literature, a few generalizations seem appropriate. First, there is substantial cultural variation in alcohol consumption among men. Second, men are more likely to be regular drinkers at all ages than are women. Third, alcohol consumption remains high in men until approximately age 75 but declines thereafter [7]. Given this high prevalence of alcohol consumption across the lifespan among men, any potential effects on bone, either positive or negative, could be of substantial importance. High alcohol intakes have widespread adverse physiologic consequences and formal Diagnostic and Statistical Manual (DSM-IV) and International Classification of Diseases (ICD10) criteria exist for the diagnosis of alcohol dependence and alcohol abuse [12]. However, these formal definitions have not been uniformly applied in the published literature and/or in clinical practice. A useful clinical definition of alcohol abuse has been suggested as ‘sufficient alcohol intake to cause physical, psychiatric, or social harm’ [7]. Much of the published work relevant to bone health in men has evaluated alcoholics with very high alcohol intakes, sometimes for many years [13]. However, a substantial body of published data focuses on men with ‘moderate’ intake. Unfortunately, a consensus definition of ‘moderate’ alcohol consumption has not been applied uniformly either in studies or by governmental agencies [1]. For example, moderate daily alcohol intake is defined by the US Department of Agriculture (USDA) as 14 g/day (one drink) in women and 28 g/day (two drinks) in men [1]. However, a recent review defines moderate alcohol consumption as intake of 15–45 grams of ethanol per day (one to three standard drinks) with ‘immoderate’ intake being greater than this [1]. Others suggest that a toxicity threshold exists at 50–60 grams of ethanol daily with daily intakes greater than this being associated with adverse health consequences [1]. To confound further the definition of ‘moderate’ alcohol intake, guidelines differ for various nations [14]. For example, the acceptable daily alcohol intake for men is 20 grams in Sweden, 28 grams in the USA and 39 grams in the Netherlands [14]. Thus, what is ‘moderate’ to one, may be ‘immoderate’ to another. Additionally, it must be appreciated that all studies of alcohol intake are confounded by self-report and by identification of what constitutes one ‘unit’ of alcohol. Though a standard unit of alcohol has been defined as 8 grams of 10 ml of ethyl alcohol [9], it is reasonable that virtually no one actually measures the amount of alcohol they consume and moreover that what constitutes a ‘serving size’ may vary substantially [14]. For perspective, one unit of alcohol is the amount in a 125 ml (4 oz) glass of wine that contains 8% ethanol. However, this may not simply be ‘one glass’ as wine glasses often are capable of containing 250 ml or more. Additionally, the strength of wine has increased over time such that white and red wine often contain 12% and
15% alcohol respectively. As such, a ‘glass’ of red wine with 15% alcohol could easily contain over three units of alcohol [9]. Thus, what is reported as ‘moderate’ alcohol intake could easily differ between individuals and between published reports. Finally, self-report of alcohol intake seems likely to be confounded by individuals reporting less than they actually consumed.
Moderation; is less more? Consumption of alcohol in ‘moderate’ amounts may possibly have beneficial effects. In fact, the lowest all cause and coronary artery disease mortality is seen in those who consume one to two drinks daily. It is not surprising, therefore, that the US Department of Health & Human Services dietary guidelines for Americans states that those who consume alcohol should ‘drink alcoholic beverages in moderation’ [15]. The potential mechanism(s) by which a beneficial effect of moderate alcohol intake could occur are not well understood. One potential mechanism may be via reduction of proinflammatory cytokines in that moderate alcohol intake is associated with lower markers of inflammation [16, 17]. Additionally, the possibility that consumption of alcoholic beverages serves as a source of various nutrients, rather than simply adding ethanol to the diet, must be considered. Moreover, it is possible and, in fact likely, that moderate drinking may have beneficial effects on psychosocial function [18, 19], potentially leading to improved appetite and enhanced dietary intake [20]. Finally, moderate alcohol intake is associated with better reported quality of life and improved survival [21]. Therefore, it is possible that the reported health benefits of moderate alcohol consumption (e.g. bone density, heart disease, etc.) reflect associated, but unmeasured, healthy behaviors and is not directly the result of ethanol consumption [22, 23].
Alcohol impacts on bone and calcium homeostasis Given the complexities of evaluating alcohol use/abuse in humans, it is reasonable to turn to animal studies that have evaluated the effects of alcohol, models that are independent of the various confounding effects inherent in human studies. The rat model has generally been used most widely in evaluating the effects of alcohol on bone. In these studies (as could be expected), the alcohol dose, rat strain and age and duration of alcohol administration all influence the study outcomes. In addition to impairing overall growth, alcohol ingestion inhibits bone formation and thereby bone growth, density and strength in growing male and female rats [24–26]. These reductions persist throughout life [27].
C h a p t e r 3 6 Alcohol Use and Bone Health in Men l
Moreover, reduced weight bearing further reduces bone formation in adult male rats [28], perhaps implying that inactivity might contribute to osteoporosis development in male alcoholics. Finally, alcohol abuse may impair fracture healing due to impairment of osteoinduction [24]. To summarize, in animals, alcohol inhibits bone formation and reduces bone strength [29]. In humans, the effects of alcohol on bone are complex, multifactorial and dose dependent. Overall, as detailed below, it appears that the primary effect of high-dose alcohol on bone is suppression of osteoblastic activity. However, some studies suggest a component of increased osteoclastic resorption [29]. The inconsistencies reported in the literature likely reflect the complexities associated with human alcohol intake including dose, duration and type of alcohol consumed, concomitant nutritional deficiencies, associated toxins, e.g. smoking, presence or absence of liver disease, age, body weight and other factors. As is the case in rats, human alcohol abuse is associated with reduced osteoblast function both histologically [30] and as measured by circulating markers of bone turnover [31]. For example, circulating osteocalcin concentration is lowered by both acute and chronic alcohol intake [31–35]. The effect of alcohol abuse on bone resorption is variable; some reports finding no effect, while others suggest increased resorption [36]. Effects of alcohol on sex steroids in men is important. Acute and chronic alcohol use reduces testosterone levels in males [37]. Additionally, estrone and estradiol concentrations may be elevated in alcoholic men. Moreover, alcohol may increase estrogen receptor activity and may reduce the rate of estradiol catabolism [14]. To summarize a substantial literature in this regard, alcohol use/abuse is associated with reduced androgen levels and potentially frank hypogonadism in men along with increased levels and sensitivity to estrogens [14]. These varying effects of alcohol on sex steroids may have relevance to skeletal metabolism because of the relationship between hypogonadism in men and osteoporosis. On the other hand, the positive effects of alcohol on estrogen levels and metabolism could be beneficial to the male skeleton [38]. Clearly, overall nutritional deficits may exist in alcoholics with resulting deleterious skeletal results [35]. The nutritional deficits among alcoholics may be due to dietary neglect and/or reduced appetite due to gastritis or ulcer disease. Moreover, chronic pancreatitis and/or liver impairment may be associated with malabsorption of a multitude of nutrients, importantly including calcium and vitamin D. Consistent with this, alcohol use may cause hypocalcemia and hypomagnesemia [13]. Additionally, low vitamin D status is common among those who habitually consume alcohol [13, 35], a not surprising finding given the high prevalence of low vitamin D status worldwide. Moreover, low 1,25 dihydroxyvitamin D concentrations have been reported, potentially reflecting impaired 1-hydroxylase activity
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or alternatively increased degradation via alcohol-induced induction of the cytochrome P450 system. One would expect reduced 1,25 dihydroxyvitamin D status to be associated with calcium malabsorption and parathyroid hormone (PTH) elevation. However, alcohol intake has been reported to increase, decrease or to have no effect on serum PTH concentration. Calcium absorption has not been exhaustively studied in alcoholic men but one report identifies substantially increased calcium absorption in such individuals [32]. This unexpected finding could potentially reflect direct alcohol-induced damage to the intestinal mucosa thereby facilitating enhanced passive, i.e. paracellular, calcium absorption [35]. It is clear from the discussion above, that alcohol could potentially have varied, complex and not well-defined mechanistic impacts upon bone health that likely differs between individuals.
Bone mineral density (BMD) Alcohol abuse has been correlated with low bone mass in multiple studies [25, 33, 34]. Specifically, low bone mass has been demonstrated by both dual energy x-ray absorptiometry (DXA) and bone histomorphometry in male alcoholics [36]. In such individuals, bone histomorphometry finds reduced trabecular thickness, consistent with reduced bone formation. As a note of caution, as is the case for ‘moderation’, it is possible that these associations of low bone mass with alcohol abuse could also reflect confounding factors. In this regard, up to 80% of alcohol-dependent individuals are regular smokers [12]; a habit associated with low BMD and increased fracture risk [39]. Be that as it may, many reports confirm that alcohol abuse adversely affects bone mass. In contrast, recent data find greater alcohol consumption to be associated with higher BMD [40, 41]. For example, in the MrOS study involving almost 6000 men aged 65 and older, greater alcohol intake was associated with higher BMD [42]. In this study, even men with a history of binge drinking or problem drinking had higher BMD than those who did not. Similarly, NHANES data find higher total hip BMD among men who consume alcohol as compared to those who do not [43]. This positive association of greater alcohol intake with higher hip BMD has been quite consistently reported (Figure 36.1) in contrast to low BMD among alcoholic men. Taken together, it seems possible that the reports of low BMD among alcoholic men reflects poor nutritional status, overall poor health and/or other confounders, perhaps with a direct toxic effect of alcohol on bone formation superimposed. Consistent with this concept, some work suggests that the beneficial effects of alcohol on BMD in men may be J- or U-shaped with lower BMD at the highest intakes [45]. Though intermittent consumption of
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Bone mineral density (grams/cm2)
0.850
None Less than 1 1 to 6
0.800
7 to 13 14 or more 0.750
0.700
0.650 Total hip
Femoral neck
Figure 36.1 Association of alcohol consumption and bone mineral density. In this study of 1482 adults, total hip and femur neck BMD were progressively higher with greater alcohol consumption. Data adapted from Mukamal et al [44].
large amounts of alcohol (binge drinking) appears to have adverse skeletal consequence in rats, binge drinking did not appear to adversely affect BMD according to the NHANES data. At this time, it has not been determined conclusively whether binge drinking, at least if confined to approximately twice per month, adversely affects BMD [43]. The possibility that specific alcoholic beverages and their composition might have differential effects upon bone requires further evaluation. For example, dietary silicon intake is positively associated with BMD [46] and beer is the major source of dietary silicon intake in men [47]. Thus, it is possible that the silicon in beer could potentially mediate the reported positive effects of high alcohol (beer) intake on BMD in men in the Framingham Offspring study [45]. Similarly, resveratrol, a phytochemical compound that is a constituent of red wine, reduces ovariectomy-induced bone loss in rats [48]. Thus, estrogenic effects of resveratrol have been suggested as a mechanism to prevent bone loss in humans [49]. If true, this component may in part explain the higher BMD observed with increasing wine consumption [14]. In this regard, and confounding the effect of ‘wine’ on bone health, it should be noted that not all wine is the same in that white wine contains fewer potentially bioactive compounds than does red [9]. It is possible, and perhaps likely, that other types of alcoholic beverage would have differing effects due to the presence of nutrients such as silicon or resveratrol. Moreover, this suggests that the contribution of alcoholic beverages to overall nutrition, rather than simply as ethanol sources, must be considered. In essence, the
effects of ‘alcoholic beverages’ on bone health may be due to their contribution as ‘food’. In conclusion, though the association of moderate alcohol intake with higher BMD is becoming increasingly well established, the mechanism(s) underlying this observation remains to be determined [14].
Alcohol, falls and fractures in men Falls are a major problem for older adults [50] causing substantial morbidity and mortality. In fact, falls are the leading cause of injury-related hospitalizations and injury-related mortality for older adults [51], leading to almost 16 000 deaths annually. As chronic, heavy alcohol consumption can cause peripheral neuropathy and skeletal myopathy [52, 53], it is intuitively obvious that alcohol intake and intoxication would be associated with increased falls risk due not only to adverse neurological and muscular function but also to adverse effects on balance and judgment [54, 55]. However, the association between alcohol use and fall risk is surprisingly inconsistent. For example, in the MrOS study, intake of 14 or more drinks per week was not associated with an increased risk for falls [42]. Existing data regarding the relationship between alcohol intake and fracture risk in men are similarly controversial with some reports finding moderate alcohol intake to be protective against fractures, with others finding no association
C h a p t e r 3 6 Alcohol Use and Bone Health in Men
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l
Enter yes if the patient takes 3 or more units of alcohol daily. A unit of alcohol varies slightly in different countries from 8–10 g of alcohol. This is equivalent to a standard glass of beer (285 ml), a single measure of spirits (30 ml), a medium-sized glass of wine (120 ml). The impact of checking alcohol ‘yes’ or ‘no’ as a clinical risk factor for an osteopenic man at various ages modestly alters the FRAX-calculated 10-year fracture probability as noted in Figure 36.2. In addition to the increased fracture risk noted above, fracture healing is impaired in alcoholics. A higher incidence
7 f
6 10 year hip fracture probability
between alcohol intake and fracture risk and still other studies reporting a higher fracture risk for heavy alcohol users [56]. For example, in the MrOS study, all fractures (not just osteoporosis-related fragility fractures) were reported over a prospective follow up of 3.6 years. Despite the occurrence of approximately 250 non-vertebral fractures, no difference in overall fracture rate based on alcohol intake was found [42]. However, a trend towards lower hip fracture rates among those with higher alcohol intake was observed. Moreover, episodic heavy drinking (binge drinking) was unrelated to non-vertebral fracture risk. Similarly, in the Dubbo study, moderate alcohol intake was associated with lower fracture risk but, after adjustment for BMD, this effect was no longer statistically significant [57]. This suggests that the effect of alcohol to reduce fracture risk might be mediated via effects on BMD as noted above. A recent meta-analysis of existing data, which combined fracture risk for men and women, concluded that individuals who consume 0.5 to 1.0 drinks per day had an estimated 20% lower hip fracture risk than those who abstained, whereas those consuming more than two drinks daily had an approximately 40% increased hip fracture risk [22]. The authors note that studies evaluating hip fracture risk included those with higher alcohol intakes, which may explain the U-shaped relationship of fracture. Increasing hip fracture risk at high alcohol intake was clearly observed in longitudinal Danish studies in which consuming up to 27 drinks weekly was not associated with increased hip fracture risk, whereas men consuming 28–41 drinks were at substantially increased risk and those consuming 10 or more drinks daily were at an over fivefold increased hip fracture risk [58]. Similarly, in the MEDOS study of men from southern Europe, modest alcohol intake was not associated with increased hip fracture risk, whereas alcoholism substantially increased this risk [59]. Overall, the literature confirms that high alcohol intakes are associated with increased fracture risk in men. While the definition of ‘high intake’ is obviously a ‘moving target’ vis à vis definition, a recent report of data from multiple countries concluded that fracture risk is increased when more than two drinks daily are consumed [60]. As such, intake of three or more drinks daily is included in the WHO FRAX calculator, with the clinician being advised to:
Alcohol
5
No alcohol
4 3 2 1 0
55
65 Age
75
Figure 36.2 Effect of alcohol consumption on FRAX-estimated 10-year hip fracture risk. The 10-year hip fracture risks for a hypothetical 190 pound (86.2 kg), 73.5 inch (186.7 cm) white male in the USA with a femur neck T-score of 2.0 are presented for ages 55, 65 and 75 years. Addition of alcohol intake greater than 3 units per day substantially alters the estimated fracture probability as shown such that if a clinician were using the 3% hip fracture risk cutpoint (dashed line) for therapeutic recommendations as recommended by the NOF Guide [61], a different treatment recommendation would likely ensue. Data from www.shef. ac.uk/FRAX.
of delayed union or non-union may be the result of alcohol inhibiting new bone formation at the fracture site [29].
Issues confounding studies of alcohol use From the above, it is clear that the effect of alcohol consumption on skeletal health in men is complex. Many studies have demonstrated diverse beneficial health effects of moderate alcohol consumption to include lower risk of cardiovascular disease, stroke and even overall mortality. It must be emphasized that these studies demonstrate association, which does not necessarily indicate causality. Importantly, the presence of various medical conditions, medication use and acute health events predict a higher likelihood of abstaining from alcohol [62]. Thus, ‘unhealthy’ people appear to be less likely to drink. Given the association of ‘illness’ with increased abstinence from alcohol, it seems almost certain that studies will demonstrate a greater likelihood of alcohol consumption in ‘healthier’ individuals [10]. It is possible that this explains, or at least contributes to, the ‘J-shaped’ or ‘U-shaped’ effect of alcohol consumption observed for various diseases (Figure 36.3) including fracture.
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Relative risk
Conclusion
1
0
None
Low
Moderate
High
Figure 36.3 Conceptualization of the ‘J-shaped’ curve associated with alcohol consumption. Similar ‘J’ or ‘U-shaped’ associations with moderate alcohol intake being associated with lower risk for a variety of diseases [63, 64] (including fractures) [55] and with overall mortality [65]. Whether moderate alcohol intake is causally related to these reduced risks or is somehow indicative of better health or health behaviors remains to be determined.
Thus, it is essential to appreciate that associations noted in observational studies can in fact indicate causality, but also might be the result of chance, bias or unappreciated confounders [66]. Importantly, physiologically reasonable associations observed in observational studies may not be the result of the factor being studied (in this case alcohol consumption) but rather be due to unappreciated behavioral and/ or social factors [67]. This point has previously been demonstrated with antioxidant vitamins which were associated with reduced risk of cardiovascular disease and cancer in observational studies [68–70] but not when randomized controlled trials (RCTs) were conducted [71, 72]. While recognizing that RCTs evaluating the long-term effects of alcohol consumption will be difficult, if not impossible to conduct, it seems prudent to have healthy skepticism about the observations of health benefits from alcohol consumption. Moreover, additional confounders in the study of alcohol include the fact that people do not always drink a single type of alcoholic beverage, that alcohol metabolism is affected by when it is consumed with or without food, how rapidly it is consumed and whether there is daily or intermittent consumption. Additionally, an individual’s genetic background influences alcohol metabolism [4]. Finally, as noted earlier, the definition of what constitutes ‘one drink’, the variable methodology for data collection and the reliance on self-reported intake confounds existing studies. Given this, the advice of Balsa et al seems wise: A number of potential biases inherent in retrospective, self-reported observational studies temper any definitive statements that we can make about alcohol use and its potential health benefits [10].
In conclusion, a plethora of observational studies report a positive association between alcohol intake and BMD in men (and women) at various skeletal sites. Biologically plausible mechanisms exist to account for these findings. Thus, drinking alcohol in ‘moderation’ may well be beneficial to bone health in men, although the mechanism(s) underlying this statement remain to be defined, are likely to be complex and multifactorial and potentially do not reflect consumption of ethanol per se. Moreover, it is possible that different alcoholic beverages, notably beer and wine, may have different effects than other forms. Despite the reported beneficial effect on BMD, excessive intake of alcoholic beverages is clearly detrimental and increases fracture risk. As such, despite the difficulties of defining ‘high’ alcohol intake, including this as a clinical fracture risk factor is appropriate. Perhaps it is reasonable to consider alcohol as a drug with potential toxicities when utilized in high doses, but as a ‘nutrient’ at low doses in association with a well-balanced diet. However, despite the multiple studies relating ‘moderate’ alcohol intake with higher BMD, it is not appropriate to recommend consumption of alcoholic beverages as a way to enhance bone health. It must be appreciated that the relationship between alcohol intake and skeletal health is extraordinarily complex being influenced by a variety of physiologic, nutritional and psychosocial factors. It is therefore not surprising that these relationships remain poorly defined.
References 1. M.P. Ferreira, M.K.S. Weems, Alcohol consumption by aging adults in the United States: health benefits and detriments, J. Am. Diet Assoc. 108 (2008) 1668–1676. 2. E. Baraona, C.S. Abittan, K. Dohmen, et al., Gender differences in pharmacokinetics of alcohol, Alcohol Clin. Exp. Res. 25 (2001) 502–507. 3. P. Meier, H.K. Seitz, Age, alcohol metabolism and liver disease, Curr. Opin. Clin. Nutr. Metabol. Care 11 (2008) 21–26. 4. H.J. Edenberg, The genetics of alcohol metabolism., Alcohol Res. Hlth. 30 (2007) 5–13. 5. H.K. Seitz, F. Stickel, Molecular mechanisms of alcoholmediated carcinogenesis, Nat. Rev. Cancer 7 (2007) 599–612. 6. I. Lang, J.M. Guralnik, R.B. Wallace, et al., What level of alcohol consumption is hazardous for older people? Functioning and mortality in U.S. and English national cohorts, J. Am. Geriatr. Soc. 55 (2006) 49–57. 7. R.R. Watson (Ed.), Handbook of nutrition in the aged, second ed., CRC Press, Inc., 1994. 8. K.K. Chan, C. Neighbors, M. Gilson, et al., Epidemiological trends in drinking by age and gender: Providing normative feedback to adults, Addict. Behav. 32 (2007) 967–976. 9. H.M. Macdonald, Alcohol and recommendations for bone health: should we still exercise caution?, Am. J. Clin. Nutr. 89 (2009) 999–1000.
C h a p t e r 3 6 Alcohol Use and Bone Health in Men l
10. A.I. Balsa, J.F. Homer, M.F. Fleming, et al., Alcohol consumption and health among elders, Gerontologist 48 (2008) 622–636. 11. R.A. Breslow, B. Smothers, Drinking patterns of older Americans: national health interview surveys, 1997–2001, J. Stud. Alcohol 65 (2003) 232–240. 12. M.A. Schuckit, Alcohol-use disorders, Lancet 373 (2009) 492–501. 13. F. Santolaria, E. Gonzalez-Reimers, J.L. Perez-Manzano, et al., Osteopenia assessed by body composition analysis is related to malnutrition in alcoholic patients, Alcohol 22 (2000) 147–157. 14. R. Jugdaohsing, M.A. O’Connell, S. Sripanyakorn, et al., Moderate alcohol consumption and increased bone mineral density: potential ethanol and non-ethanol mechanisms, Proc. Nutr. Soc. 65 (2006) 291–310. 15. Anonymous, Dietary Guidelines for Americans, in: Department of Health and Human Services, US Government Printing Office, 2005. 16. I. Shai, E.B. Rimm, M.B. Schulze, et al., Moderate alcohol intake and markers of inflammation and endothelial dysfunction among diabetic men, Diabetologia 47 (2004) 1760–1767. 17. G. Szabo, Moderate drinking, inflammation and liver disease, Ann. Epidemiol. 17 (2007) S49–S54. 18. D.B. Heath, Why we don’t know more about the social benefits of moderate drinking, Ann. Epidemiol. 17 (2007) S71–S74. 19. W.L. Adams, Alcohol use in retirement communities, J. Am. Geriatr. Soc. 44 (1996) 1082–1085. 20. P.F. Jacques, S. Sulsky, S.C. Hartz, et al., Moderate alcohol intake and nutritional status in nonalcoholic elderly subjects, Am. J. Clin. Nutr. 50 (1989) 875–883. 21. J. Byles, A. Young, H. Furuya, et al., A drink to healthy aging: the association between older women’s use of alcohol and their health-related quality of life, J. Am. Geriatr. Soc. 54 (2006) 1341–1347. 22. K.M. Berg, H.V. Kunins, J.J. Jackson, et al., Association between alcohol consumption and both osteoporotic fracture and bone density, Am. J. Med. 121 (2008) 406–418. 23. N.R. Nielsen, P. Schnohr, G. Jensen, et al., Is the relationship between type of alcohol and mortality influenced by socioeconomic status?, J. Intern. Med. 255 (2004) 280–288. 24. C.H. Trevisol, R.T. Turner, J.E. Pfaff, et al., Impaired osteo induction in a rat model for chronic alcohol abuse, Bone 41 (2007) 175–180. 25. R.T. Turner, Skeletal response to alcohol, Alcohol Clin. Exp. Res. 24 (2000) 1693–1701. 26. H.W. Sampson, C. Chaffin, J. Lange, et al., Alcohol consumption by young actively growing rats: a histomorphometric study of cancellous bone, Alcohol Clin. Exp. Res. 21 (1997) 352–359. 27. H.W. Sampson, Effect of alcohol consumption of adult and aged bone: a histomorphometric study of the rat animal model, Alcohol Clin. Exp. Res. 22 (1998) 2029–2034. 28. T.E. Hefferan, A.M. Kennedy, G.L. Evans, et al., Disuse exaggerates the detrimental effects of alcohol on cortical bone, Alcohol Clin. Exp. Res. 27 (2003) 111–117. 29. D.A. Chakkalakal, Alcohol-induced bone loss and deficient bone repair, Alcohol Clin. Exp. Res. 29 (2005) 2077–2090.
441
30. D.D. Bikle, H.K. Genant, C. Cann, et al., Bone disease in alcohol abuse, Ann. Intern. Med. 103 (1985) 42–48. 31. T.H. Diamond, D. Stiel, M. Lunzer, et al., Ethanol reduces bone formation and may cause osteoporosis, Am. J. Med. 86 (1989) 282–288. 32. K. Laitinen, C. Lamberg-Allardt, R. Tunninen, et al., Bone mineral density and abstention-induced changes in bone and mineral metabolism in noncirrhotic male alcoholics, Am. J. Med. 93 (1992) 642–650. 33. C.V. Odvina, I. Safi, C.H. Wojtowicz, et al., Effect of heavy alcohol intake in the absence of liver disease on bone mass in black and white men, J. Clin. Endocrinol. Metab. 80 (1995) 2499–2503. 34. A. Garcia-Sanchez, J.L. Mundi, Effect of alcohol consumption on adult bone mineral density and bone turnover markers, Alcohol Clin. Exp. Res. 23 (1999) 1416–1417. 35. D.L. Alekel, O. Matvienko (Eds.), Influence of lifestyle choices on calcium homeostasis, Humana Press, Totowa, New Jersey, 2006. 36. D.D. Bikle, A. Stesin, B. Halloran, et al., Alcohol-induced bone disease: relationship to age and parathyroid hormone levels, Alcohol Clin. Exp. Res. 17 (1993) 690–695. 37. M.A. Emanuele, N. Emanuele, Alcohol and the male reproductive system, in: Alcoholism, National Institutes of Health, Bethesda, 2009. 38. S. Amin, Y. Zhang, C.T. Sawin, et al., Association of hypogonadism and estradiol levels with bone mineral density in elderly men from the Framingham study, Ann. Intern. Med. 133 (2000) 951–963. 39. J.A. Kanis, O. Johnell, A. Oden, et al., Smoking and fracture risk: a meta-analysis, Osteoporos. Int. 16 (2005) 55–62. 40. T.L. Holbrook, E. Barrett-Connor, A prospective study of alcohol consumption and bone mineral density., Br. Med. J. 306 (1993) 1506–1509. 41. D.T. Felson, Y. Zhang, M.T. Hannan, et al., Alcohol intake and bone mineral density in elderly men and women, Am. J. Epidemiol. 142 (1995) 485–492. 42. P.M. Cawthon, S.L. Harrison, E. Barrett-Connor, et al., Alcohol intake and its relationship with bone mineral density, falls and fracture risk in older men, J. Am. Geriatr. Soc. 54 (2006) 1649–1657. 43. K.S. Wosje, H.J. Kalkwarf, Bone density in relation to alcohol intake among men and women in the United States, Osteoporos. Int. 18 (2007) 391–400. 44. K.J. Murkamal, J.A. Robbins, J.A. Cauley, et al., Alcohol consumption, bone density and hip fracture among older adults: the cardiovascular health study, Osteoporos. Int. 18 (2007) 593–602. 45. K.L. Tucker, R. Jugdaohsing, J.J. Powell, et al., Effects of beer, wine and liquor intakes on bone mineral density in older men and women, Am. J. Clin. Nutr. 89 (2009) 1188–1196. 46. R. Judgdaohsingh, K.L. Tucker, N. Qiao, et al., Dietary silicon intake is positively associated with bone mineral density in men and premenopausal women of the Framingham Offspring cohort, J. Bone Miner. Res. 19 (2004) 297–307. 47. R. Jugdaohsing, S.H.C. Anderson, K.L. Tucker, et al., Dietary silicon intake and absorption, Am. J. Clin. Nutr. 75 (2002) 887–893. 48. Z.P. Liu, W.X. Li, B. Yu, et al., Effects of trans-resveratrol from Polygonum cuspidatum on bone loss using the ovariectomized rat model, J. Med. Food 8 (2005) 4–19.
442
Osteoporosis in Men
49. R.E. King, J.A. Bomser, D.B. Min, Bioactivity of resveratrol, Comp. Rev. Food Sci. Food Safety 5 (2006) 65–70. 50. M.E. Tinetti, M. Speechley, S.F. Giner, Risk factors for falls among elderly persons living in the community, N. Engl. J. Med. 319 (1988) 1701–1707. 51. Anonymous. Centers for Disease Control and Prevention, National Center for Injury Prevention and Control. Web-based Injury Statistics Query and Reporting System (WISQARS). 2006. 52. J. Fernandez-Sola, J.M. Nicolas, F. Fatjo, et al., Evidence of apoptosis in chronic alcoholic skeletal myopathy, Hum. Pathol. 34 (2003) 1247–1252. 53. V.R. Preedy, J.D. Adachi, Y. Ueno, et al., Alcoholic skeletal muscle myopathy: Definitions, features, contribution of neuropathy, impact and diagnosis, Eur. J. Neurol. 8 (2001) 677–687. 54. B. Resnick, P. Junlapeeya, Falls in a community of older adults: findings and implications for practice, Appl. Nurs. Res. 17 (2004) 81–91. 55. K.J. Mukamal, M.A. Mittleman, W.T. Longstreth, et al., Selfreported alcohol consumption and falls in older adults: crosssectional and longitudinal analyses of the cardiovascular health study, J. Am. Geriatr. Soc. 52 (2004) 1174–1179. 56. D.T. Felson, D.P. Kiel, J.J. Anderson, et al., Alcohol consumption and hip fractures: the Framingham study, Am. J. Epidemiol. 128 (1988) 102–110. 57. T.V. Nguyen, J.A. Eisman, P.J. Kelly, et al., Risk factors for osteoporotic fractures in elderly men, Am. J. Epidemiol. 144 (1996) 255–263. 58. S. Hoidrup, M. Gronbaek, A. Gottschau, et al., Alcohol intake, beverage preference and risk of hip fracture in men and women, Am. J. Epidemiol. 149 (1999) 993–1001. 59. J. Kanis, O. Johnell, B. Gullberg, et al., Risk factors for hip fracture in men from southern Europe: the MEDOS study, Osteoporos. Int. 9 (1999) 45–54. 60. J. Kanis, H. Johansson, O. Johnell, et al., Alcohol intake as a risk factor for fracture, Osteoporos. Int. 16 (2005) 737–742.
61. Anonymous, Clinician’s guide to prevention and treatment of osteoporosis, National Osteoporosis Foundation, Washington, DC, 2008. 62. R.H. Moos, P.L. Brennan, K.K. Schutte, et al., Older adults’ health and changes in late-life drinking patterns, Aging Mental Hlth. 9 (2005) 49–59. 63. A.A. de Lorimier, Alcohol, wine and health, Am. J. Surg. 180 (2000) 357–361. 64. D.M. Goldberg, G.J. Soleas, M. Levesque, Moderate alcohol consumption: the gentle face of Janus, Clin. Biochem. 32 (1999) 505–518. 65. R. Doll, R. Peto, J. Boreham, et al., Mortality in relation to alcohol consumption: a prospective study among male British doctors, Int. J. Epidemiol. 34 (2005) 199–204. 66. P. Jepsen, S.P. Johnsen, M.W. Gillman, et al., Interpretation of observational studies, Heart 90 (2009) 956–960. 67. D.A. Lawlor, G.D. Smith, K.R. Bruckdorfer, et al., Those confounded vitamins: what can we learn from the differences between observational versus randomised trial evidence?, Lancet 363 (2004) 1724–1727. 68. L.H. Kushi, A.R. Folsom, R.J. Prineas, et al., Dietary antioxidant vitamins and death from coronary heart disease in postmenopausal women, N. Engl. J. Med. 334 (1996) 1156–1162. 69. M.J. Stampfer, C.H. Hennekens, J.E. Manson, et al., Vitamin E consumption and the risk of coronary disease in women, N. Engl. J. Med. 328 (1993) 1444–1449. 70. E.B. Rimm, M.J. Stampfer, A. Ascherio, et al., Vitamin E consumption and the risk of coronary heart disease in men, N. Engl. J. Med. 328 (1993) 1450–1456. 71. G.S. Omenn, G.E. Goodman, M.D. Thornquist, et al., Effects of a combination of beta carotene and vitamin A on lung cancer and cardiovascular disease, N. Engl. J. Med. 334 (1996) 1150–1155. 72. C.H. Hennekens, J.E. Buring, J.E. Manson, et al., Lack of effect of long-term supplementation with beta carotene on the incidence of malignant neoplasms and cardiovascular disease, N. Engl. J. Med. 334 (1996) 1145–1149.
Chapter
37
Transplantation Osteoporosis Emily M. Stein1, Juliet Compston2 and Elizabeth Shane1 1
Columbia University College of Physicians & Surgeons, New York, NY, USA University of Cambridge School of Clinical Medicine, Cambridge, UK
2
Introduction
Skeletal effects of immunosuppressive drugs
The introduction of cyclosporine to transplantation immunology in the early 1980s resulted in marked improvement in short-term graft and patient survival and ushered in a new era for patients with end-stage renal, hepatic, cardiac, pulmonary and hematopoietic disease. However, with increasing survival of patients after transplantation, adverse skeletal effects, particularly reduced bone mass and fragility fractures, have been documented. The pathogenesis of osteoporosis following transplantation is multifactorial and includes pre-transplantation bone disease, immunosuppressive therapy, vitamin D insufficiency, hypogonadism, reduced physical activity and malnutrition (Figure 37.1) [1–4]. This review, adapted from our recent publication [5], summarizes current knowledge of post-transplantation osteoporosis. Most of the available studies have included both men and women and few data specific to men have been reported.
Glucocorticoids
Pre-transplant bone disease Hypogonadism Malnutrition
Glucocorticoids Glucocorticoids, an integral component of most transplant immunosuppression regimens, have well documented adverse effects on bone. Prednisone or methylprednisolone may be prescribed in high doses (50–100 mg of prednisone or its equivalent daily) immediately after transplantation and during episodes of severe rejection, with gradual reduction over weeks to months. Total exposure varies with the organ transplanted, the number and management of rejection episodes and the practice of individual transplantation programs. The mechanisms by which glucocorticoids increase bone loss and fracture risk are discussed in several recent reviews [6–8]. In recent years, there has been a trend toward more rapid lowering of glucocorticoid doses after transplantation or
Cyclosporine A or Tacrolimus Vitamin D deficiency
Bone formation and bone resorption
Renal Insufficiency 2° hyperparathyroidism Reduced physical activity
Bone loss and fracture
Figure 37.1 Pathogenesis of transplantation osteoporosis. (Adapted from Compston JE. Osteoporosis after liver transplantation. Liver Transpl 2003;9:321–30). Osteoporosis in Men
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rejection episodes and an increase in the use of alternative drugs to treat rejection. In more recently transplanted patients who have received lower doses of steroids, significant bone loss has been reported in some, but not all, studies and, where present, may be less rapid than previously documented [9–12]. Furthermore, early withdrawal of glucocorticoids after transplantation is associated with significantly less bone loss than more prolonged regimens [13, 14]. Whether the recent trends towards reduction in glucocorticoid dose and duration have had a specific impact on fracture risk is difficult to determine because of the other changes that have occurred concurrently in the management of patients undergoing organ transplantation.
Cyclosporines Cyclosporine (CsA) is a small fungal cyclic peptide. Its activity depends upon the formation of a heterodimer consisting of cyclosporine and its cytoplasmic receptor, cyclophilin. This cyclosporine–cyclophilin heterodimer then binds to calcineurin [15]. CsA and, similarly, tacrolimus, inhibits the phosphatase activity of calcineurin through interaction with distinct domains on the calcineurin subunit. Animal studies suggest that CsA has effects on bone and mineral metabolism that may contribute to bone loss after organ transplantation [16]. Studies examining the effects of CsA on the human skeleton have yielded conflicting results. Several have shown that kidney transplant patients receiving cyclosporine in a steroid-free regimen did not lose bone [17–19]. In contrast, in a small study of kidney transplant recipients, no difference in bone loss was detected between those who received CsA monotherapy and those who received azathioprine and prednisolone [20] and, in a recent prospective study, cumulative CsA dose was associated with bone loss in the 2 years following transplant, independent of the effect of steroids [21].
Tacrolimus (FK506) FK506 is a macrolide that binds to an immunophilin FK binding protein and blocks T-cell activation in a manner similar to CsA. FK506 has been shown to cause bone loss in the rat model comparable to that observed with CsA [22] and accompanied by similar biochemical and histomorphometric alterations. In humans, rapid bone loss has been documented after both cardiac [23] and liver transplantation [24], when FK506 is used for immunosuppression. However, other studies suggest that FK506 may cause less bone loss than CsA in humans [25, 26], likely because lower doses of glucocorticoids are required for immunosuppression.
Sirolimus (Rapamycin) Rapamycin is a macrocyclic lactone. Although it is structurally similar to FK506 and binds to the same binding
protein, the mechanism by which rapamycin induces immunosuppression is distinct from both FK506 and CsA. There is some evidence that rapamycin may have bone sparing effects in rats but its skeletal effects in humans have not been defined.
Azathioprine, Mycophenolate Mofetil and Other Drugs In the past, azathioprine was frequently used in combination with prednisone and CsA or FK506 to prevent organ rejection. However, it has largely been supplanted by myco phenolate mofetil, which does not have deleterious effects on bone in the rat [27]. The skeletal effects of other immunosuppressant agents, such as mizoribine, deoxyspergualin, brequinar sodium, liflunomide and azaspirane, are unclear.
Effect of transplantation on bone and mineral metabolism Kidney and Kidney – Pancreas Transplantation Skeletal status before transplantation In patients with severe chronic kidney disease (CKD) or end-stage kidney disease (ESKD), disturbances in calcium and phosphate metabolism, decreased calcitriol synthesis, increased synthesis and secretion of parathyroid hormone (PTH), metabolic acidosis and defective bone mineralization result in the complex form of bone disease known as renal osteodystrophy [28]. Renal osteodystrophy is almost universal in patients who undergo kidney transplantation and may be manifest as high bone turnover, due to hyperparathyroidism with or without osteitis fibrosa, low turnover or adynamic bone disease, osteomalacia or ‘mixed’ renal osteodystrophy, a combination of one or more of the aforementioned lesions. Low bone mineral density, assessed by dual energy x-ray absorptiometry (DXA), is often present and the risk of fragility fracture is increased [29, 30]. Risk factors for low bone mineral density and fractures include female gender, Caucasian race, hyperparathyroidism, adynamic bone disease, secondary amenorrhea, type I diabetes, older age, duration of dialysis, peripheral vascular disease, prior kidney transplant and diabetic nephropathy [31]. Bone loss and fracture rate after kidney transplantation (Table 37.1) Low bone mineral density (BMD) has been reported in several cross-sectional studies of patients who have undergone kidney transplantation [2, 3] and prospective studies have documented high rates of bone loss posttransplantation, particularly in the first 6–18 months [32, 33]. In a recent study of male renal transplant recipients, only 17% had normal BMD, 30% having osteoporosis at the hip or
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Table 37.1 Osteoporosis, fractures and bone loss after solid organ and bone marrow transplantation Type of transplant
Bone loss: first post-transplant year
Prevalence after transplantation Osteoporosis*
Fractures
Kidney
11–56%
Heart
25–50%
Vertebral: 3–29% Peripheral: 11–22% Vertebral: 22–35%
Liver
30–46%
Vertebral: 29–47%
Lung
57–73%
42%
Bone marrow
4–15%
5%
**
Spine: 4–9% Hip: 8% Spine: 2.5–8% Hip: 6–11% Spine: 0–24% Hip: 2–4% Spine: 1–5% Hip: 2–5% Spine: 2–9% Hip: 6–11%
Fracture incidence
Vertebral: 3–10% Peripheral: 10–50% 10–36% Vertebral: 24–65% 18–37% 1–16%
*
Accepted definitions included BMD (by dual x-ray absorptiometry) of the spine and/or hip with Z-score 2 or T-score 2.5. Definition of osteoporosis also included BMD of predominantly cortical sites such as the femoral shaft or proximal radius that are adversely affected by excessive PTH secretion. Adapted from Cohen and Shane [2]
**
lumbar spine and 41% if the distal radius site was included. Bone resorption markers were elevated in 48% [34]. Fractures are common after renal transplantation and affect appendicular sites (feet, ankles, long bones, hips) more commonly than axial sites (spine, ribs) [34]. Non-vertebral fractures are fivefold more common in males aged 25–64, and 18-fold and 34-fold more common in females aged 25–44 and 45–64, respectively, who have had a renal transplant than in the normal population [35]. Vertebral fractures have been reported in 3–10% of non-diabetic patients after renal transplantation and, in one study, the risk of hip fracture was increased by 34% in patients who underwent kidney transplant compared to those who remained on dialysis [36]. Fractures are particularly common in patients who receive kidney or kidney–pancreas transplants for diabetic nephropathy [37]. Before transplantation, hyperparathyroidism is the most common lesion on bone biopsy. However, by 6 months after transplantation, glucocorticoid effects predominate, with osteoblast dysfunction and decreased mineral apposition rate [32]. In long-term kidney transplant recipients, bone biopsy results are more heterogeneous and include osteoporosis, osteomalacia and osteitis fibrosa. Mineralization defects are common [38]. Mineral metabolism and bone turnover after kidney transplantation
PTH levels, usually elevated before transplantation, frequently remain high for some time after transplantation and may never completely normalize. Hypercalcemia and hypophosphatemia, related to persistent parathyroid hyperplasia and elevated PTH levels, occur commonly during the first few months. Persistent elevations in fibroblast growth factor-23 (FGF-23) after transplant may be related to
post-transplant hypophosphatemia. In most patients, these biochemical abnormalities are mild and resolve within the first year although, in long-term transplant recipients, persistent elevations in PTH may be associated with reduced hip BMD [39].
Cardiac Transplantation Skeletal status before transplantation Risk factors common in patients with end-stage cardiac failure that may predispose to bone loss before transplantation include exposure to tobacco, alcohol and loop diuretics, physical inactivity, hypogonadism and anorexia, which may contribute to dietary calcium deficiency. Hepatic congestion and prerenal azotemia may also affect mineral metabolism, causing mild secondary hyperparathyroidism. An increased prevalence of osteoporosis has been reported in some studies [40]. Bone loss and fracture rate after heart transplantation (see Table 37.1) Osteoporosis and fractures constitute a major cause of morbidity after cardiac transplantation. In cross-sectional studies, the prevalence of vertebral fractures in cardiac transplant recipients ranges between 18 and 50% and moderate to severe bone loss is present in a substantial proportion of subjects at both lumbar spine and femoral neck [40]. Prospective longitudinal studies have documented rates of bone loss ranging from 2.5 to 11%, predominantly during the first 3–12 months after transplantation [40–42]. While bone loss at the lumbar spine slows or stops after the first 6 months, femoral neck bone loss continues during the second half of the first year after transplantation [11, 42]; thereafter, the rate of bone loss slows or stops in the majority
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of patients with some recovery at the lumbar spine noted during the third year of observation [42]. Bone loss also slows at the hip after the first year, however, in contrast to the spine, there has been no significant recovery by the fourth post-transplant year. The results of a recent study suggest that there may be less bone loss than suggested in literature from the 1980s and early 1990s [11]. Fragility fractures are most common during the phase of rapid bone loss that characterizes the first post-transplant year. In a prospective observational longitudinal study, 36% of patients (54% of the women and 29% of the men) suffered one or more fractures of the vertebrae, ribs and hip in the first year despite daily supplementation with calcium (1000 mg) and vitamin D (400 IU) [43]. It was not possible to predict who would fracture either on the basis of pretransplant BMD or any other demographic or biochemical parameter [43]. Two European studies of cardiac transplant recipients reported similar fracture incidence with approximately 30–33% sustaining vertebral fractures during the first 3 years [44]. The risk of a vertebral fracture was higher in those patients who had lumbar spine T-scores below 1.0 (hazard ratio 3.1) [44]. However, in a more recent interventional study, the incidence of vertebral fractures during the first post-transplant year in patients who received only calcium and vitamin D was only 14% [11]. Similarly, in a prospective study of untreated patients only 12% had fractures [45], suggesting fracture rates may be lower than in the past. Mineral metabolism and bone turnover after cardiac transplantation
Biochemical changes after cardiac transplantation include sustained increases in serum creatinine [42] and decreases in 1,25 dihydroxyvitamin D concentrations. Serum testosterone concentrations decrease in men and may recover by the sixth post-transplant month [42, 46]. In a recent study, testosterone levels were lowest in the first month following transplant and reflected suppression of the hypothalamic pituitary gonadal axis by prednisone [47]. Serum osteocalcin falls precipitously and there is a sharp increase in markers of bone resorption [42, 46]. This biochemical pattern coincides with the period of most rapid bone loss and highest fracture incidence and suggests that the early post-transplant period is associated with uncoupling of formation from resorption with restitution of coupling when glucocorticoid doses are lowered. High bone turnover may also occur later in the post-transplant course, possibly due to cyclosporine-induced renal impairment.
Liver Transplantation Skeletal status before transplantation Patients with liver failure have multiple risk factors that may predispose to low bone mineral density before
transplantation and fracture after transplantation. Many patients with end-stage liver disease who are listed for liver transplantation have prevalent osteoporosis, as evidenced by low BMD and fragility fractures [48–50]. In a recent study of 360 liver transplant candidates, 38% had osteoporosis and 39% had osteopenia [51]. Bone loss and fracture after liver transplantation (see Table 37.1) Osteoporosis is also common after liver transplantation [50]. Reported rates of bone loss and fracture vary considerably after liver transplantation, but were often extremely high, particularly in earlier studies [52]. Bone loss appears to stop after 3–6 months with gradual improvement by the second and third post-transplant years. Although some investigators have reported improvement in BMD in longterm liver transplant recipients, this finding has not been uniform. More recent studies have found smaller rates of bone loss, or even absence of bone loss. Ninkovic et al found only a 2.3% loss at the femoral neck, with preservation of lumbar spine BMD one year after liver transplant [10] while Floreani et al found increases in BMD at one year [53]. Guichelaar reported higher rates of spinal bone loss after transplantation in patients with primary sclerosing cholangitis, current smokers, younger age, higher baseline BMD, shorter duration of liver disease and ongoing cholestasis [51]. Fracture incidence is highest in the first year and ranges from 24 to 65%, although fracture rates appear to be considerably lower in more recent studies [10, 50]. Glucocorticoid exposure and markers of bone turnover do not reliably predict bone loss or fracture risk. Older age and pre-transplant BMD at the femoral neck and lumbar spine were predictive of post-transplant fractures in recent prospective studies [10, 54]. Vertebral fractures prior to transplant have been shown to predict post-transplant vertebral fractures [44, 55]. In a recent study of patients who survived more than 15 years after liver transplantation, 49% had osteoporosis and 30% had sustained vertebral fractures [56]. Mineral metabolism and bone turnover after liver transplantation
Studies of calciotropic hormone levels and bone turnover markers after liver transplantation are limited. Increases in serum PTH levels during the first 3–6 months after transplantation have been reported in some, but not all, studies [50]. Measurement of markers of bone turnover has also produced conflicting results. Histomorphometric data demonstrate a low turnover state pre-transplantation, with a significant increase in remodeling rate 3 months posttransplantation, indicating that increased bone turnover is the predominant mechanism of bone loss in the early posttransplantation period [57].
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Lung Transplantation Skeletal status before lung transplantation Hypoxemia, tobacco use and glucocorticoid therapy are frequent characteristics of candidates for lung transplantation and may contribute to the pre-transplant bone loss and fractures that are particularly common in these patients [58]. Cystic fibrosis (CF) is also associated with osteoporosis and fractures due to pancreatic insufficiency, inflammation, vitamin D deficiency and calcium malabsorption and hypogonadism [59, 60]. Bone loss and fracture rate after lung transplantation (see Table 37.1) Few studies have prospectively evaluated patients after lung transplantation. However, existing data indicate increased rates of bone loss and a high prevalence of fractures, particularly at the spine [61, 62]. Risk factors for fracture and bone loss include female gender, low pre-transplant lumbar spine BMD, pre-transplant glucocorticoid therapy and higher bone turnover after transplantation. Bone turnover markers are elevated following lung transplant.
Bone Marrow Transplantation (BMT) BMT is performed with increasing frequency and is preceded by myeloablative therapy (alkylating agents and/or total body irradiation), commonly leading to profound and often permanent hypogonadism. The pathogenesis of osteoporosis after allogeneic BMT is complex and includes the effects of treatment and effects on the stromal cell compartment of the bone marrow. Low BMD has been reported in cross-sectional studies of BMT recipients and prospective studies also indicate increased rates of bone loss, particularly after allogeneic BMT [63]. There appears to be little bone loss after the first year, although the significant bone loss that occurs in the femoral neck does not appear to be regained [64]. Bone turnover markers are consistent with the pattern of decreased formation and increased resorption observed in other forms of transplantation during the first 3 months.
Evaluation and management of candidates for transplantation Evaluation (Table 37.2) All patients undergoing transplantation should have a full assessment of bone health prior to transplantation so that potentially treatable abnormalities of bone and mineral metabolism may be addressed and the skeletal condition of the patient optimized before transplantation. Risk factors for osteoporosis should be assessed and, where possible,
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Table 37.2 Skeletal evaluation of the candidate for organ transplantation In all candidates: Assess risk factors for osteoporosis, including menstrual history, history of low-trauma fractures Measure bone density (BMD) of spine and hip by DXA Obtain thoracic and lumbar spine radiographs or lateral DXA images If BMD testing reveals osteoporosis or if there are prevalent vertebral or non-vertebral fractures: Serum electrolytes, blood urea nitrogen (BUN), creatinine, calcium, phosphate, alkaline phosphatase, parathyroid hormone, 25-hydyroxyvitamin D, thyroid function tests, liver function tests (see text) In men, serum total and/or testosterone, FSH and LH Urine for calcium and creatinine
modified. Risk factors for falling (poor vision, hearing, balance and muscle strength, use of psychotropic drugs) should also be evaluated. BMD of the spine and hip should be measured in all patients before transplantation, using dual X-ray absorptiometry (DXA). Radiographs of the thoracic and lumbar spine are also important since the risk of future fracture is greater in patients with prevalent vertebral fractures; alternatively vertebral morphometry can be examined on lateral images obtained by DXA. If the pre-transplant BMD is low, a thorough biochemical evaluation should include a chemistry panel (serum electrolytes, creatinine, calcium, phosphorus, alkaline phosphatase), thyroid function tests, liver function tests, intact PTH and serum 25-OHD. In men, total and free testosterone, follicle stimulating hormone (FSH) and luteinizing hormone (LH) concentrations should be measured. Markers of bone turnover can also be measured, although their value in aiding management is debatable. Where indicated, rehabilitation therapy should be prescribed as tolerated to maximize conditioning and physical fitness. All transplant candidates should receive the recommended daily allowance (RDA) of vitamin D (400–800 IU), or as necessary, to maintain the serum 25-OHD level above 30 ng/ml (80 nmol/mL) and elemental calcium (1000– 1500 mg, depending on dietary intake and menopausal status). Calcium citrate is preferred as many of these patients take proton pump inhibitors before or after transplantation, which can reduce intestinal calcium absorption. Clinically hypogonadal men should be offered testosterone replacement. Generally accepted guidelines for gonadal hormone replacement should apply to these patients. Patients with low BMD and/or fracture before cardiac, liver, lung or bone marrow transplantation should be treated according to established clinical guidelines for women and men at high risk of osteoporotic fracture. In most
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cases, the first line option will be bisphosphonate therapy. Patients with renal osteodystrophy should be managed in accordance with the accepted clinical guidelines for this condition. After transplantation, routine monitoring of serum and urine indices of mineral metabolism is generally not indicated, except in patients with renal bone disease. Measurement of BMD should be performed at 6–12-month intervals for the first 2 years and at appropriate intervals thereafter depending on the individual clinical circumstances. Bone biopsy may be necessary in kidney transplant recipients to exclude adynamic bone disease before commencing bisphosphonate therapy.
Table 37.3 Primary prevention of bone loss in transplant recipients Measure BMD before or immediately after transplantation Consider pharmacologic therapy in all patients with low bone mass (T score between 1.0 and 2.5) or osteoporosis (T score 2.5) Use the lowest dose of glucocorticoids possible Consider alternative therapies for rejection Calcium intake of 1500 mg/d both before and after transplantation Vitamin D intake of 400–1000 IU, or as needed to maintain serum 25-OHD concentrations above 30 ng/ml (80 nmol/ml) Physical rehabilitation program both before and after transplantation Replace gonadal steroids (in clinically hypogonadal men and amenorrhoeic, premenopausal women) Begin antiresorptive therapy, preferably a bisphosphonate, before transplantation in patients with antecedent osteoporosis or low bone mass Begin antiresorptive therapy, preferably a bisphosphonate, immediately after transplantation in patients with normal or low bone mass and continue for at least the first year
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Prevention of transplantation osteoporosis (Table 37.3)
l
The major principles, which have been demonstrated consistently after kidney, liver, heart, lung, and bone marrow transplantation, and that should guide therapy of transplantation osteoporosis are as follows: rates of bone loss are most rapid immediately after transplantation fractures also occur very early after transplantation, sometimes within only a few weeks of grafting fragility fractures develop both in patients with low and those with normal pre-transplant BMD therefore, preventive strategies should be instituted immediately after transplantation both in patients with normal pre-transplant BMD and those with low BMD who have not been treated previously the long-term transplant recipient with established osteoporosis and/or fractures should not be neglected.
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There are several prospective controlled randomized studies for prevention and treatment of transplantation osteoporosis in the literature, although the quality of these studies varies. The recommendations provided herein are also based upon experience with glucocorticoid-induced osteoporosis. Available therapies of transplantation osteoporosis include antiresorptive drugs (bisphosphonates and calcitonin), as well as analogs of vitamin D and gonadal hormone replacement. Since resorption markers increase after transplantation and there is an increase in remodeling rate, attempts to prevent post-transplantation bone loss and, hopefully, fractures by inhibition of bone resorption provide a logical approach.
Bisphosphonates Bisphosphonates act by inhibiting osteoclastic bone resorption. They are approved for the treatment of osteoporosis in postmenopausal women and, in the case of alendronate
and risedronate, in men. Alendronate, risedronate and, in Europe, etidronate, are also approved for the management of glucocorticoid-induced bone loss in women and men. Several studies suggest that intravenous bisphosphonates can prevent bone loss after transplantation. Intravenous pamidronate administered in repeated doses has been shown to prevent bone loss at the lumbar spine and femoral neck in kidney [65, 66], heart [67, 68], liver [69] and lung [70, 71] transplant recipients. In two large prospective studies of patients after allogeneic BMT, intravenous pamidronate prevented lumbar spine bone loss and reduced proximal femoral bone loss [72, 73]. Some bone loss at the proximal femur still occurred, however, despite doses of up to 90 mg one study [73]. Recent randomized trials with the more potent intravenous bisphosphonates, zoledronic acid and ibandronate, have also shown significant protective effects on BMD at 6 and 12 months in recipients of liver [74, 75] and kidney [76, 77] transplants. Intravenous zoledronic acid (4 mg), given 12 months after BMT, has been shown to prevent spinal and femoral bone loss [78]. Clinical trials with oral bisphosphonates, including alendronate, risedronate and clodronate, have also shown beneficial effects on BMD. In terms of primary prevention of bone loss immediately after transplantation, several studies have compared alendronate with calcitriol. A randomized trial comparing alendronate (10 mg daily) with calcitriol (0.25 g twice daily) treatment starting immediately after cardiac transplant found that both regimens prevented bone loss at the lumbar spine and hip one year after transplant, compared with a reference group receiving only calcium and vitamin D [11]. Although alendronate and calcitriol were discontinued during the second year after cardiac transplant,
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BMD remained stable. Several recent trials found improvements in lumbar spine BMD in patients treated with alendronate or risedronate following kidney transplant [79–81] or liver transplant [82]. At present, bisphosphonates constitute the most promising approach to the prevention of transplantation osteoporosis. As with other forms of therapy, many issues remain to be resolved. These include whether or not they actually prevent fractures, since most studies have been under-powered to address this important issue, the optimal drug and route of administration, whether continuous or intermittent (cyclical) therapy should be used, at what level of renal impairment these drugs should be avoided, whether they are safe in renal transplant recipients with adynamic bone disease and whether they are beneficial in the setting of pediatric transplantation.
Vitamin D and Analogs Since most of the observational studies of bone loss after organ transplantation have included at least 400 IU of parent vitamin D in the post-transplant regimen, it is clear that the RDA for vitamin D is not sufficient to prevent transplantation osteoporosis. In two recent studies, parent vitamin D, in doses of 800 IU daily [83] or 25 000 IU monthly [12] also did not prevent bone loss after kidney transplantation. Active forms of vitamin D may be more effective. Calcidiol (25-OHD) prevented bone loss and increased lumbar spine BMD after cardiac transplantation [84] and alfacalcidiol (1--OHD) prevented or attenuated bone loss at the lumbar spine and femoral neck when given immediately after kidney transplantation [85]. Sambrook et al reported that calcitriol (0.5–0.75 mg/d) prevented spine and hip bone loss during the first 6 months after heart or lung transplantation and was as effective as cyclic etidronate [86]. Calcitriol given during the first year after kidney transplantation was associated with an increase in lumbar spine, femoral neck and forearm BMD [21]. In a stratified, placebo-controlled, randomized study, heart and lung transplant recipients received calcitriol or placebo for 12 or 24 months after transplantation [87]. While lumbar spine bone loss was similar between groups, femoral neck bone loss at 24 months was reduced only in the group that received calcitriol for the entire period. In contrast, studies of long-term kidney [88] and heart transplant patients [89] have failed to demonstrate any benefit of calcitriol. Hypercalcemia and hypercalciuria are the major side effects of therapy of these agents and regular urinary and serum monitoring is required. If hypercalcemia occurs, it must be recognized and reversed promptly because of the adverse effects on renal function and the life-threatening potential of a severely elevated serum calcium concentration. Supplemental calcium and any vitamin D preparations should be discontinued until the calcium normalizes. Treatment may subsequently be recommenced at a lower
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dose. Vitamin D analogs are generally regarded as a second line option in the management of transplantation osteoporosis, although calcium and vitamin D supplements should be used as an adjunct to bisphosphonate therapy.
Calcitonin Although both injectable and inhaled calcitonin have been used successfully to treat glucocorticoid-induced bone loss, calcitonin has not consistently been shown to have beneficial skeletal effects after transplantation, with most studies showing no benefit. In summary, calcitonin is relatively ineffective in preventing bone loss after transplantation and we would not recommend its use.
Testosterone Approximately 25% of men evaluated 1–2 years after transplantation have biochemical evidence of hypogonadism and men with low serum testosterone concentrations have been shown to lose bone more rapidly after cardiac transplantation [42, 46]. Fahrleitner et al reported that hypogonadal men treated with intravenous ibandronate had improved BMD at one year if they were treated with testosterone compared with those who were not replaced [90]. However, testosterone replacement should be reserved for men with clinical as well as biochemical evidence of hypogonadism.
Summary and conclusions In recent years, there has been significant progress in elucidating the natural history and pathogenesis of transplantation osteoporosis. It is now clear that a substantial proportion of candidates for solid organ and bone marrow transplantation already have osteoporosis. Prospective longitudinal studies have provided definitive evidence of rapid bone loss and a high incidence of fragility fractures, particularly during the first post-transplant year. Vertebral fractures occur both in patients with low and those with normal pre-transplant BMD, so that it is difficult to predict fracture risk in the individual patient. Early post-transplantation bone loss (before 6 months) is associated with biochemical evidence of uncoupled bone turnover, with increases in markers of resorption and decreases in markers of formation. Later in the post-transplantation course (after 6 months), concomitant with tapering of glucocorticoid doses, bone formation recovers and the biochemical pattern is more typical of a high turnover osteoporosis. More recent studies suggest that rates of bone loss and fracture are lower than they were before 1995. However, the rates of bone loss and fracture following transplantation remain unacceptably high. Bisphosphonates are the most consistently effective agents for the prevention and treatment of bone loss
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in organ transplant recipients. Patients should be assessed before transplantation and receive treatment for prevalent osteoporosis, if present. Primary prevention therapy should be initiated immediately after transplantation, as the majority of bone loss occurs in the first few months after grafting. Long-term transplant recipients should be monitored and treated for bone disease as well. With proper vigilance, early diagnosis and treatment, transplant osteoporosis is a preventable disease.
References 1. A. Cohen, P. Ebeling, S. Sprague, E. Shane, Transplantation osteoporosis. in: M. Favus (Ed.), Primer on the Metabolic Bone Diseases and Disorders of Bone and Mineral Metabolism, 2006, pp. 302–309. American Society for Bone and Mineral Research., Washington DC. 2. A. Cohen, E. Shane, Osteoporosis after solid organ and bone marrow transplantation, Osteoporos. Int. 14 (2003) 617–630. 3. S. Epstein, E. Shane, Transplantation osteoporosis, in: R. Marcus, D. Feldman, J. Kelsey (Eds.), Osteoporosis, Academic Press, San Diego, 2001, pp. 327–340. 4. N.M. Maalouf, E. Shane, Osteoporosis after solid organ transplantation, J. Clin. Endocrinol. Metab. 90 (2005) 2456–2465. 5. E. Stein, E. Shane, Transplantation osteoporosis, in: R. Adler (Ed.), Osteoporosis, Pathophysiology and Clinical Management, 2009, pp. 567–602. Humana Press, Totowana NJ. 6. G. Mazziotti, A. Angeli, J.P. Bilezikian, E. Canalis, A. Giustina, Glucocorticoid-induced osteoporosis: an update, Trends Endocrinol. Metab. 17 (2006) 144–149. 7. P. Sambrook, Glucocorticoid-induced osteoporosis, in: M. Favus (Ed.), Primer on the Metabolic Bone Diseases and other Disorders of Bone and Mineral Metabolism, 2006, pp. 296–302. American Society for Bone and Mineral Research, Washington DC. 8. T.P. van Staa, The pathogenesis, epidemiology and management of glucocorticoid-induced osteoporosis, Calcif. Tissue Int. 79 (2006) 129–137. 9. T.R. Mikuls, B.A. Julian, A. Bartolucci, K.G. Saag, Bone mineral density changes within six months of renal transplantation, Transplantation 75 (2003) 49–54. 10. M. Ninkovic, S. Love, B.D. Tom, P.W. Bearcroft, G.J. Alexander, J.E. Compston, Lack of effect of intravenous pamidronate on fracture incidence and bone mineral density after orthotopic liver transplantation, J. Hepatol. 37 (2002) 93–100. 11. E. Shane, V. Addesso, P.B. Namerow, et al., Alendronate versus calcitriol for the prevention of bone loss after cardiac transplantation, N. Engl. J. Med. 350 (2004) 767–776. 12. K.M. Wissing, N. Broeders, R. Moreno-Reyes, C. Gervy, B. Stallenberg, D. Abramowicz, A controlled study of vitamin D3 to prevent bone loss in renal-transplant patients receiving low doses of steroids., Transplantation 79 (2005) 108–115. 13. G. Opelz, B. Dohler, G. Laux, Long-term prospective study of steroid withdrawal in kidney and heart transplant recipients, Am. J. Transplant. 5 (2005) 720–728. 14. E.C. van den Ham, J.P. Kooman, M.L. Christiaans, J.P. van Hooff, The influence of early steroid withdrawal on body composition and bone mineral density in renal transplantation patients, Transpl. Int. 16 (2003) 82–87.
15. B.D. Kahan, Cyclosporine, N. Engl. J. Med. 321 (1989) 1725–1738. 16. R. Tamler, S. Epstein, Nonsteroid immune modulators and bone disease, Ann. NY Acad. Sci. 1068 (2006) 284–296. 17. C. Ponticelli, A. Aroldi, Osteoporosis after organ transplantation, Lancet 357 (2001) 1623. 18. W.H. Grotz, A. Mundinger, B. Gugel, V. Exner, G. Kirste, P.J. Schollmeyer, Bone fracture and osteodensitometry with dual energy x-ray absorptiometry in kidney transplant recipients, Transplant. 58 (1994) 912–915. 19. H.D. McIntyre, B. Menzies, R. Rigby, D.A. Perry-Keene, C.M. Hawley, I.R. Hardie, Long-term bone loss after renal transplantation: comparison of immunosuppressive regimens, Clin. Transplant. 9 (1995) 20–24. 20. A.M. Cueto-Manzano, S. Konel, V. Crowley, et al., Bone histopathology and densitometry comparison between cyclosporine a monotherapy and prednisolone plus azathioprine dual immunosuppression in renal transplant patients, Transplantation 75 (2003) 2053–2058. 21. M.A. Josephson, L.P. Schumm, M.Y. Chiu, C. Marshall, J.R. Thistlethwaite, S.M. Sprague, Calcium and calcitriol prophylaxis attenuates posttransplant bone loss, Transplantation 78 (2004) 1233–1236. 22. M. Cvetkovic, G.N. Mann, D.F. Romero, et al., The deleterious effects of long term cyclosporin A, cyclosporin G and FK506 on bone mineral metabolism in vivo, Transplantation 57 (1994) 1231–1237. 23. H.U. Stempfle, C. Werner, S. Echtler, et al., Rapid trabecular bone loss after cardiac transplantation using FK506 (tacrolimus)-based immunosuppression, Transplant. Proc. 30 (1998) 1132–1133. 24. K.M. Park, J.E. Hay, S.G. Lee, et al., Bone loss after orthotopic liver transplantation: FK 506 versus cyclosporine, Transplant. Proc. 28 (1996) 1738–1740. 25. E. Goffin, J.P. Devogelaer, A. Lalaoui, et al., Tacrolimus and low-dose steroid immunosuppression preserves bone mass after renal transplantation, Transpl. Int. 15 (2002) 73–80. 26. A. Monegal, M. Navasa, N. Guanabens, et al., Bone mass and mineral metabolism in liver transplant patients treated with FK506 or cyclosporine A, Calcif. Tissue Int. 68 (2001) 83–86. 27. I.R. Dissanayake, G.R. Goodman, A.R. Bowman, et al., Mycophenolate mofetil; a promising new immunosuppressant that does not cause bone loss in the rat, Transplantation 65 (1998) 275–278. 28. K. Martin, Z. Al-Aly, E. Gonzalez, Renal osteodystrophy, in: M. Favus (Ed.), Primer on the Metabolic Bone Diseases and other Disorders of Bone and Mineral Metabolism, 2006, pp. 359–366. 29. M. Coco, H. Rush, Increased incidence of hip fractures in dialysis patients with low serum parathyroid hormone, Am. J. Kidney Dis. 36 (2000) 1115–1121. 30. T.L. Nickolas, D.J. McMahon, E. Shane, Relationship between moderate to severe kidney disease and hip fracture in the United States, J. Am. Soc. Nephrol. 17 (2006) 3223–3232. 31. H.J. Ahn, H.J. Kim, Y.S. Kim, et al., Risk factors for changes in bone mineral density and the effect of antiosteoporosis management after renal transplantation, Transplant. Proc. 38 (2006) 2074–2076.
C h a p t e r 3 7 Transplantation Osteoporosis l
32. B.A. Julian, D.A. Laskow, J. Dubovsky, E.V. Dubovsky, J.J. Curtis, L.D. Quarrles, Rapid, loss of vertebral bone density after renal transplantation, N. Engl. J. Med. 325 (1991) 544–550. 33. M.K. Almond, J.T.C. Kwan, K. Evans, J. Cunningham, Loss of regional bone mineral density in the first 12 months following renal transplantation, Nephron 66 (1994) 52–57. 34. S.D. Roe, C.J. Porter, I.M. Godber, D.J. Hosking, M.J. Cassidy, Reduced bone mineral density in male renal transplant recipients: evidence for persisting hyperparathyroidism, Osteoporos. Int. 16 (2005) 142–148. 35. R. Ramsey-Goldman, J.E. Dunn, D.D. Dunlop, et al., Increased risk of fracture in patients receiving solid organ transplants, J. Bone Miner. Res. 14 (1999) 456–463. 36. A.M. Ball, D.L. Gillen, D. Sherrard, et al., Risk of hip fracture among dialysis and renal transplant recipients, J. Am. Med. Assoc. 288 (2002) 3014–3018. 37. Y.F. Smets, J.W. de Fijter, J. Ringers, H.H. Lemkes, N.A. Hamdy, Long-term follow-up study on bone mineral density and fractures after simultaneous pancreas-kidney transplantation, Kidney Int. 66 (2004) 2070–2076. 38. M. Monier-Faugere, H. Mawad, Q. Qi, R. Friedler, H.H. Malluche, High prevalence of low bone turnover and occurrence of osteomalacia after kidney transplantation, J. Am. Soc. Nephrol. 11 (2000) 1093–1099. 39. S. Akaberi, B. Lindergard, O. Simonsen, G. Nyberg, Impact of parathyroid hormone on bone density in long-term renal transplant patients with good graft function, Transplantation 82 (2006) 749–752. 40. A. Cohen, E. Shane, Bone disease in patients before and after cardiac transplantation, in: J.E. Compston, E. Shane (Eds.), Bone Disease of Organ Transplantation, Elsevier Academic Press, Burlington, 2005, pp. 287–301. 41. P.N. Sambrook, P.J. Kelly, A. Keogh, et al., Bone loss after cardiac transplantation: a prospective study, J. Heart Lung Transplant. 13 (1994) 116–121. 42. E. Shane, M. Rivas, D.J. McMahon, et al., Bone loss and turnover after cardiac transplantation, J. Clin. Endocrinol. Metab. 82 (1997) 1497–1506. 43. E. Shane, M. Rivas, R.B. Staron, et al., Fracture after cardiac transplantation: a prospective longitudinal study, J. Clin. Endocrinol. Metab. 81 (1996) 1740–1746. 44. G. Leidig-Bruckner, S. Hosch, P. Dodidou, et al., Frequency and predictors of osteoporotic fractures after cardiac or liver transplantation: a follow-up study, Lancet 357 (2001) 342–347. 45. K. Kerschan-Schindl, M. Ruzicka, S. Mahr, et al., Unexpected low incidence of vertebral fractures in heart transplant recipients: analysis of bone turnover, Transpl. Int. 21 (2008) 255–262. 46. P.N. Sambrook, P.J. Kelly, D. Fontana, et al., Mechanisms of rapid bone loss following cardiac transplantation, Osteoporos. Int. 4 (1994) 273–276. 47. J. Fleischer, D.J. McMahon, W. Hembree, V. Addesso, C. Longcope, E. Shane, Serum testosterone levels after cardiac transplantation, Transplantation 85 (2008) 834–839. 48. M. Ninkovic, S.A. Love, B. Tom, G.J. Alexander, J.E. Compston, High prevalence of osteoporosis in patients with chronic liver disease prior to liver transplantation, Calcif. Tissue Int. 69 (2001) 321–326.
451
49. O.M. Crosbie, R. Freaney, M.J. McKenna, J.E. Hegarty, Bone density, vitamin D status, and disordered bone remodeling in end- stage chronic liver disease, Calcif. Tissue Int. 64 (1999) 295–300. 50. J.E. Compston, Osteoporosis after liver transplantation, Liver Transpl. 9 (2003) 321–330. 51. M.M. Guichelaar, R. Kendall, M. Malinchoc, J.E. Hay, Bone mineral density before and after OLT: long-term follow-up and predictive factors, Liver Transpl. 12 (2006) 1390–1402. 52. R. Eastell, R.E. Dickson, S.F. Hodgson, et al., Rates of vertebral bone loss before and after liver transplantation in women with primary biliary cirrhosis. Hepatology 14 (1991) 296–300. 53. A. Floreani, A. Mega, L. Tizian, et al., Bone metabolism and gonad function in male patients undergoing liver transplantation: a two-year longitudinal study, Osteoporos. Int. 12 (2001) 749–754. 54. A. Monegal, M. Navasa, N. Guanabens, et al., Bone disease after liver transplantation: a long-term prospective study of bone mass changes, hormonal status and histomorphometric characteristics, Osteoporos. Int. 12 (2001) 484–492. 55. M. Ninkovic, S.J. Skingle, P.W. Bearcroft, N. Bishop, G.J. Alexander, J.E. Compston, Incidence of vertebral fractures in the first three months after orthotopic liver transplantation, Eur. J. Gastroenterol. Hepatol. 12 (2000) 931–935. 56. L. de Kroon, G. Drent, A.P. van den Berg, E.B. Haagsma, Current health status of patients who have survived for more than 15 years after liver transplantation, Neth. J. Med. 65 (2007) 252–258. 57. J. Vedi, S. Greer, S. Skingle, et al., Mechanism of bone loss after liver transplantation: a histomorphometric analysis, J. Bone Miner. Res. 14 (1999) 281–287. 58. E. Shane, S.J. Silverberg, D. Donovan, et al., Osteoporosis in lung transplantation candidates with end stage pulmonary disease, Am. J. Med. 101 (1996) 262–269. 59. R.M. Aris, J.B. Renner, A.D. Winders, et al., Increased rate of fractures and severe kyphosis: sequelae of living into adulthood with cystic fibrosis, Ann. Intern. Med. 128 (1998) 186–193. 60. S.L. Elkin, A. Fairney, S. Burnett, et al., Vertebral deformities and low bone mineral density in adults with cystic fibrosis, Osteoporos. Int. 12 (2001) 366–372. 61. S.L. Ferrari, L.P. Nicod, J. Hamacher, et al., Osteoporosis in patients undergoing lung transplantation, Eur. Respir. J. 9 (1996) 2378–2382. 62. E. Shane, A. Papadopoulos, R.B. Staron, et al., Bone loss and fracture after lung transplantation, Transplantation 68 (1999) 220–227. 63. P. Ebeling, D. Thomas, B. Erbas, L. Hopper, J. Szer, A. Grigg, Mechanism of bone loss following allogeneic and autologous hematopoeitic stem cell transplantation, J. Bone Miner. Res. 14 (1999) 342–350. 64. M.K. Gandhi, S. Lekamwasam, I. Inman, et al., Significant and persistent loss of bone mineral density in the femoral neck after haematopoietic stem cell transplantation: long-term follow-up of a prospective study, Br. J. Haematol. 121 (2003) 462–468. 65. S. Fan, M.K. Almond, E. Ball, K. Evans, J. Cunningham, Pamidronate therapy as prevention of bone loss following renal transplantation, Kidney Int. 57 (2000) 684–690.
452
Osteoporosis in Men
66. M. Coco, D. Glicklich, M.C. Faugere, et al., Prevention of bone loss in renal transplant recipients: a prospective, randomized trial of intravenous pamidronate, J. Am. Soc. Nephrol. 14 (2003) 2669–2676. 67. T. Bianda, A. Linka, G. Junga, et al., Prevention of osteoporosis in heart transplant recipients: a comparison of calcitriol with calcitonin and pamidronate, Calcif. Tissue Int. 67 (2000) 116–121. 68. M. Krieg, C. Seydoux, L. Sandini, et al., Intravenous pamidronate as a treatment for osteoporosis after heart transplantation: a prospective study, Osteoporos. Int. 12 (2001) 112–116. 69. P. Pennisi, A. Trombetti, E. Giostra, G. Mentha, R. Rizzoli, C.E. Fiore, Pamidronate and osteoporosis prevention in liver transplant recipients, Rheumatol. Int. 27 (2007) 251–256. 70. R.M. Aris, G.E. Lester, J.B. Renner, et al., Efficacy of pamidronate for osteoporosis in patients with cystic fibrosis following lung transplantation, Am. J. Respir Crit. Care Med. 162 (2000) 941–946. 71. A. Trombetti, M.W. Gerbase, A. Spiliopoulos, D.O. Slosman, L.P. Nicod, R. Rizzoli, Bone mineral density in lung-transplant recipients before and after graft: prevention of lumbar spine post-transplantation-accelerated bone loss by pamidronate, J. Heart Lung Transplant. 19 (2000) 736–743. 72. K. Kananen, L. Volin, K. Laitinen, H. Alfthan, T. Ruutu, M.J. Valimaki, Prevention of bone loss after allogeneic stem cell transplantation by calcium, vitamin D, and sex hormone replacement with or without pamidronate, J. Clin. Endocrinol. Metab. 90 (2005) 3877–3885. 73. A.C. Grigg, P. Shuttleworth, J. Reynolds, et al., Pamidronate therapy for one year after allogeneic bone marrow transplantation (AlloBMT) reduces bone loss from the lumbar spine, femoral neck and total hip, Blood 104 (2004) A2253. 74. M. Hommann, K. Abendroth, G. Lehmann, et al., Effect of transplantation on bone: osteoporosis after liver and multivisceral transplantation, Transplant. Proc. 34 (2002) 2296–2298. 75. B.A. Crawford, C. Kam, J. Pavlovic, et al., Zoledronic acid prevents bone loss after liver transplantation: a randomized, double-blind, placebo-controlled trial, Ann. Intern. Med. 144 (2006) 239–248. 76. W. Grotz, C. Nagel, D. Poeschel, et al., Effect of ibandronate on bone loss and renal function after kidney transplantation, J. Am. Soc. Nephrol. 12 (2001) 1530–1537. 77. M. Haas, Z. Leko-Mohr, P. Roschger, et al., Zoledronic acid to prevent bone loss in the first 6 months after renal transplantation, Kidney Int. 63 (2003) 1130–1136. 78. L. Tauchmanova, P. Ricci, B. Serio, et al., Short-term zoledronic acid treatment increases bone mineral density and marrow clonogenic fibroblast progenitors after alloge-
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89.
90.
neic stem cell transplantation, J. Clin. Endocrinol. Metab. 90 (2005) 627–634. E. Nowacka-Cieciura, T. Cieciura, T. Baczkowska, et al., Bisphosphonates are effective prophylactic of early bone loss after renal transplantation, Transplant. Proc. 38 (2006) 165–167. J.V. Torregrosa, D. Fuster, S. Pedroso, et al., Weekly risedronate in kidney transplant patients with osteopenia, Transpl. Int. 20 (2007) 708–711. J. Toro, M.A. Gentil, R. Garcia, et al., Alendronate in kidney transplant patients: a single-center experience, Transplant. Proc. 37 (2005) 1471–1472. F. Atamaz, S. Hepguler, Z. Karasu, M. Kilic, Y. Tokat, The prevention of bone fractures after liver transplantation: experience with alendronate treatment, Transplant. Proc. 38 (2006) 1448–1452. S. Al-Gabri, J. Zadrazil, K. Krejci, P. Horak, P. Bachleda, Changes in bone mineral density and selected metabolic parameters over 24 months following renal transplantation, Transplant. Proc. 37 (2005) 1014–1019. A. Cohen, P. Sambrook, E. Shane, Management of bone loss after organ transplantation, J. Bone Miner. Res. 19 (2004) 1919–1932. A.E. El-Agroudy, A.A. El-Husseini, M. El-Sayed, M.A. Ghoneim, Preventing bone loss in renal transplant recipients with vitamin D, J. Am. Soc. Nephrol. 14 (2003) 2975–2979. P. Sambrook, N.K. Henderson, A. Keogh, et al., Effect of calcitriol on bone loss after cardiac or lung transplantation, J. Bone Miner. Res. 15 (2000) 1818–1824. K. Henderson, J. Eisman, A. Keogh, et al., Protective effect of short-tem calcitriol or cyclical etidronate on bone loss after cardiac or lung transplantation, J. Bone Miner. Res. 16 (2001) 565–571. A.M. Cueto-Manzano, S. Konel, A.J. Freemont, et al., Effect of 1,25-dihydroxyvitamin D3 and calcium carbonate on bone loss associated with long-term renal transplantation, Am. J. Kidney Dis. 35 (2000) 227–236. H.U. Stempfle, C. Werner, U. Siebert, et al., The role of tacrolimus (FK506)-base immunosuppression on bone mineral density and bone turnover after cardiac transplantation: a prospective, longitudinal, randomized, double-blind trial with calcitriol, Transplantation 73 (2002) 547–552. A. Fahrleitner, G. Prenner, K.H. Tscheliessnigg, et al., Testosterone supplementation has additional benefits on bone metabolism in cardiac transplant recipients receiving intravenous bisphosphonate treatment: a prospective study, J. Bone Miner. Res. 17 (2002) S388.
Chapter
38
Management of Fractures in Men with Impaired Renal Function Paul D. Miller University of Colorado Health Sciences Center, Colorado Center for Bone Research, Lakewood, Colorado, USA
Introduction
any or all of which can impact bone strength [13, 15–19]. In addition, the pharmacokinetics (PK) of bisphosphonates are affected by altered renal function. Bisphosphonates are both filtered by the glomerulus as well as secreted by the proximal renal tubule so that their clearance exceeds that of any measurements of true GFR [20, 21]. Reduction in renal function could also alter the pharmacodynamics of bisphosphonates and bone metabolism – an unexplored area; and the clearance of bisphosphonates by hemodialysis has limited data [21–26]. There also may be clear distinctions between renal–bone biology when the reduction in GFR is due to a systemic disease that also affects the kidneys as opposed to reductions in GFR when the reduced GFR is purely an age-related phenomenon [15, 19]. This suggestion is also based on observations in the postmenopausal and male osteoporosis clinical trials where neither hyperphosphatemia nor secondary hyperparathyroidism are seen in the randomized populations even at eGFR 30 ml/min when the decline in renal function is due to age-related reductions in renal function [27–30] in contrast to hyperphosphatemia and/or secondary hyperparathyroidism, which are common in chronic kidney disease (CKD), when due to known intrinsic renal disease [16, 30–32]. These potential differences in the bone–renal–systemic biology will require prospective investigation to define differences in disease progression and/or response to therapeutic intervention [33]. This chapter explores these aspects of bone biology in men with reduced GFR. While many of the data have been acquired in women, the fundamental principles of diagnosis and management should be applicable to men as well.
In population studies of both females and males (National Health and Nutritional Examination Survey), men and women of all studied ethnicities and genders have a decline in renal function as age increases [1, 2]. Age-related reduction in kidney function defined by measurements of glomerular filtration rate (GFR) measured either directly by 24-hour urine for creatinine clearances (CrCl) or by equations which estimate the GFR (either Cockcroft-Gault or Modification in Diet for Renal Diseases (MDRD)) occur universally in most populations as age increases [3–6]. There are increasing data, however, to suggest that serum creatinine concentration alone or eGFR underestimates or overestimates the prevalence of reduced renal function in many individuals, depending on the population and methodology employed to define renal function [7–14]. These controversies demand more investigation because of their implications in screening populations for kidney failure. Until we have better data, current estimates suggest that, on average, otherwise healthy populations have 50% of a normal GFR adjusted for body mass index by age 70 years [4–6, 10]. While the first renal functional adaptive capabilities lost as age increases are maintenance of renal blood flow in dehydrated states, renal acidification and renal concentrating ability, filtration of all solutes and, therefore, excretion of these solutes becomes reduced as well. The mechanism for the decline in GFR with aging in otherwise healthy populations is unclear but it may be related to non-specific effects of vascular changes on renal blood flow [6, 13]. In the field of osteoporosis, these effects of age on renal function become important because, as renal function declines, there may be associated abnormalities in calcium– phosphorus balance, parathyroid hormone (PTH) levels and/or end-organ resistance to PTH, abnormalities in renal production of 1,25 dihydroxyvitamin D3 and/or metabolic acidosis – Osteoporosis in Men
Diagnosis of osteoporosis in stage 1–3 chronic kidney disease Osteoporosis is the most prevalent metabolic bone disease leading to fragility fractures in human beings [34–36]. While 453
Copyright 2009, 2010 Elsevier, Inc. All rights of reproduction in any form reserved.
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Table 38.1 More common metabolic bone diseases that may be associated with fragility fractures Osteoporosis (including all secondary causes of osteoporosis, including steroid-induced osteoporosis, post-solid organ transplantation) Osteogenesis imperfecta Osteomalacia Osteitis fibrosa cystica (severe) Pathological fractures (malignancies) Severe renal failure (CKD–MBD) Osteopetrosis Paget’s disease of bone
the most common condition leading to osteoporosis is estrogen deficiency, there are other metabolic bone diseases that may be associated with fragility fractures [37] (Table 38.1). Since many medical conditions can lead to osteoporosis, a simple diagnostic criterion for this metabolic bone disease has been difficult to achieve. Prior to the 1994 World Health Organization (WHO) classification of ‘normal’ versus ‘osteopenia’ versus ‘osteoporosis’ based on bone mineral density (BMD) values (‘T-scores’) [38], the diagnosis of osteoporosisis was made on the basis of low-trauma fractures [39]. Lowtrauma fractures can also be due to metabolic bone diseases that are not osteoporosis, including renal bone diseases [40, 41]. While the T-score or fractures provide a working diagnosis for osteoporosis, they are neither specific nor sensitive for separating among osteoporosis and non-osteoporotic metabolic bone diseases. For example, in most patients with low-trauma fractures, osteoporosis is the disease most often associated with skeletal fragility, but other metabolic bone diseases not characterized by any diagnostic criteria for osteoporosis may independently cause fragility fractures, such as osteomalacia and osteogenesis imperfecta, to name two. This utilization of WHO criteria or fragility fractures to define osteoporosis becomes even more problematic, as mentioned, in the heterogeneous metabolic bone diseases that may accompany chronic kidney disease (CKD). All forms of renal severe (stage 5–5D) osteodystrophy, as defined by quantitative bone histomorphometry [42] or by chronic kidney disease–metabolic bone disease (CKD–MBD) may be associated with low-trauma fractures (Table 38.2) [17, 40]. In addition, the recent development from the Kidney Disease: Improving Global Outcomes (KDIGO) classification of renal metabolic bone disease based on dynamics of mineralization, turnover and volume (abbreviated TMV) also does not provide a working diagnosis of osteoporosis [31] (Table 38.3). In an attempt to define osteoporosis by a pathophysiological mechanism, the National Institutes of Health (NIH) have held two consensus conferences on osteoporosis and have stated that osteoporosis is: ‘a systemic skeletal disease characterized by impairment in bone strength. Bone strength is a composite of bone mineral density and microarchitecture’ [43]. As accurate as the NIH consensus definition is, it still does not provide a working diagnosis of osteoporosis – one that
Table 38.2 Renal bone diseases that may be associated with fragility fractures Osteoporosis Severe osteitis fibrosa cystica Osteomalacia Mixed osteodystrophy Adynamic bone disease, including aluminum bone disease Amyloid bone disease
Table 38.3 Kidney Disease: Improving Global Outcomes (KDIGO) classification of chronic kidney disease-metabolic bone disease based on dynamic parameters of turnover-mineralization-volume KDIGO: kidney disease improving global outcomes Classification of ROD
Turnover Turnover High High Normal Normal Low
Low
Mineralization Mineralization Normal Abnormal Normal
Abnormal Moe S et al Kid Internat 2006
Volume Volume High Normal High Low Normal
Low
Reference [31]
allows clinicians to apply in patient management decisions and one that is also accepted by the United States International Classification of Disease (ICD-9) codes for reimbursement purposes. The 1994 WHO criteria offer the most pragmatic operational definition for osteoporosis, can be applied in both men and women alike and in younger patients who have secondary medical conditions associated with increased risk for low-trauma fracture [44]. While the main purpose of the WHO classification of normal, osteopenia (T score: 1.0 – 2.5) and osteoporosis was to advise international health economies of the potential future economic impact of osteoporosis, the T-score also became the pragmatic diagnostic threshold for defining these three categories in clinical practice. The T-score has also been useful to underscore an important population-based observation: more people who fracture who have osteopenia than osteoporosis by T-score because: 1 there are more people with osteopenia than osteoporosis [45, 46] 2 many other factors independent of low BMD contribute to bone strength [47, 48]. Hence, in patients with CKD who develop low-trauma fractures, the reasonable question is: is the cause of the
C h a p t e r 3 8 Management of Fractures in Men with Impaired Renal Function l
low-trauma fracture osteoporosis? In stage 1–3 CKD, there is emerging agreement that, in the absence of any other biochemical abnormality suggesting CKD–MBD, the WHO criteria or low-trauma fractures can be used to diagnose osteoporosis. In patients with stage 5–5D CKD, the answer to this question is neither straightforward nor clearly defined. In stage 5–5D CKD, the derangements in bone and mineral metabolism become so profound that they may lead to specific forms CKD–MBD of sufficient magnitude to lead to impairment in bone strength and increase risk for low-trauma fractures. There may be a fourfold increased risk of hip fracture in men and women in stage 5–5D CKD that may be seen as compared to age-matched controls [49–52]. Adynamic, severe hyperparathyroid bone disease as well as osteomalacia can be associated with a higher risk for fragility fractures than is seen in age-matched population studies of postmenopausal women or elderly men. These are bone fragility conditions that are not osteoporosis but can mimic osteoporosis by WHO criteria or the presence of fragility fractures. Thus, when the patient with severe stage 5 or 5D CKD has severe low-trauma fractures that, by themselves are life threatening, it is a reasonable question to ask if the pharmacological agents that have been shown to reduce the risk of global fractures in many other osteoporotic conditions (postmenopausal, steroid osteoporosis, elderly male osteoporosis, post-solid organ transplantation) may also be useful in severe CKD patients who may have osteoporosis.
Diagnosis of osteoporosis in stage 5–5D CKD There are no universally accepted criteria for making the diagnosis of osteoporosis in more advanced CKD patients. The diagnosis is best suggested by excluding the other forms of renal osteodystrophy (ROD) by quantitative histomorphometry or to attempt to classify the form of CKD–MBD by non-invasive means of assessing bone turnover, mineralization and volume (TMV). However, we currently lack clinical tools to accomplish TMV distinctions in individual patients. While many promising radiological techniques currently in research are examining bone microarchitecture and offer hope to be capable of defining TMV non-invasively in severe CKD, they are still in development such that, at this time, they cannot yet be used to discriminate between CKD–MBD and osteoporosis in clinical practice [53–55]. As we better refine the relationships between TMV parameters and bone strength, these non-invasive imaging technologies may, in time, become the means to correlate TMV parameters to bone strength and open up an entirely new way to classify skeletal strength and manage patients with severe CKD. In the meantime, the clinician is left with quantitative bone histomorphometry and/or biochemical markers of bone turnover to characterize the bone disease that may be
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identified for low-trauma fractures in stage 5–5D CKD. The clinician should first use biochemical markers before bone biopsy to discriminate among the forms of renal osteodystrophy since, if they can make this distinction, a biopsy may be obviated.
Biochemical markers of bone metabolism In CKD, the bone biochemical tests that are usually assessed by nephrologists during the course of declining renal function are serum phosphorus, parathyroid hormone (PTH), calcium, total alkaline phosphatase, 1,25 dihydroxyvitamin D level and serum electrolytes. For the management of postmenopausal osteoporosis, the biochemical markers of bone turnover that are measured to reflect baseline levels of bone turnover or change in bone turnover by pharmacological agents are serum or urine collagen cross-links (bone resorption markers: N-telopepetide (NTX) or C-telopeptide (CTX)), bone-specific alkaline phosphatase (BSAP), serum osteocalcin and/or propeptide type 1 collagen (bone formation markers) and 25 hydroxyvitamin D levels. Biochemical markers of bone turnover cannot be used to make a diagnosis of osteoporosis. They can, however, be used to provide data regarding the level of bone turnover and, in that manner, provide clinical guidance as to whether a patient might have high or low bone turnover and whether or not there may be bone biological effects from therapy to reduce or increase bone turnover [56–63]. While these markers have value in making these distinctions in groups of patients, they become less sensitive and specific for classifying an individual patient’s bone turnover status. In the renal field, the PTH and alkaline phosphatase are generally considered to be the most useful markers for characterizing a patient’s bone turnover and their application for group classification are outlined in Tables 38.4 and 38.5 [64, 65]. There are a few generalizable clinical points that may be useful from these tables: If a patient has an elevated (above the upper limit of the normal reference range) BSAP, adynamic bone disease is highly unlikely. Elevated BSAP could be osteomalacia, or hyperparathyroid bone disease, assuming that other secondary causes of elevated BSAP have already been excluded (Paget’s disease, metastatic cancer, for example) A ‘normal’ BSAP does not exclude adynamic bone disease, while a low BSAP is more often associated with low bone turnover An elevated PTH does not exclude adynamic renal bone disease but a low (150 pg/ml) PTH is suggestive of a low bone turnover state. A PTH six times or higher above the upper limit of normal of the reference range is far more likely to be associated with high bone turnover.
l
l
l
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Table 38.4 Ranges of parathyroid hormone as they relate to a specific form of CKD–MBD Disorder
Serum intact PTH levels (pg/mL)
Hyperparathyroidism Mild Moderate Severe hsp:1 Aluminum bone Adynamic bone Osteomalacia
200–400 350–800 700 10–500 (mostly 100) 100–150 Normal or mildly elevated
In groups of patients the PTH level can distinguish among the histological forms of renal osteodystrophy. Overlap in values are often seen between PTH and bone histology in individual patients [64]
Table 38.5 Ranges of bone-specific alkaline phosphatase as they relate to a specific form of CKD-MBD Disorder
Serum bone specific alkaline phosphatase
Hyperparathyroidism Mild Moderate Severe hsp:1 Aluminum bone Adynamic bone Osteomalacia
Normal Normal to elevated Elevated Normal Normal to low Mildly elevated
In groups of patients the BSAP can distinguish among the various histological forms of renal osteodystrophy. In individual patients there is often overlap in the BSAP and the histology [64]
Thus, in clinical practice, a patient with stage 4–5D CKD who has an elevated BSAP or very high PTH values does not have adynamic bone disease and, once other etiologies for these aberrant biochemical abnormalities have been defined, then high bone turnover from ‘high bone turnover osteoporosis’ may be a consideration. Certainly, in my opinion, if bone turnover markers suggest low bone turnover, a biopsy is necessary before initiating an antiresorptive agent [66].
Quantitative bone histomorphometry The science of double tetracycline-labeled quantitative histomorphometry was and continues to be the only clinical means to define turnover, mineralization and volume in accepted quantitative ways [67, 68]. The American Society for Bone and Mineral Research (ASBMR) committee on standardization of histomorphometric criteria developed the criteria for distinguishing among the heterogeneous forms of metabolic bone diseases (osteomalacia, adynamic bone disease, hyperparathyroid bone disease) [42]. These criteria can be used to distinguish among the various metabolic bone diseases that accompany stage 5–5D CKD including adynamic bone disease [69–71] (Figure 38.1). For patients with stage 5–5D CKD and who are suffering fragility fractures, adynamic bone disease should be excluded before initiating, off-label, an osteoporosis pharmacological agent that reduces bone turnover (bisphosphonates, calcitonin, estrogen, selective estrogen
Figure 38.1 Renal adynamic bone disease. (A) Scant trabeculae seen (black); (B) scant osteoid seen (yellow); (C) no osteoclasts seen; (D) no tetracycline labels seen [66]. (See color plate section).
C h a p t e r 3 8 Management of Fractures in Men with Impaired Renal Function l
receptor modulators or denosumab). While there is no evidence, for example, that adding a bisphosphonate to a preexisting adynamic bone is detrimental to either bone strength or systemic vascular calcification that may be linked to low bone turnover [72], it seems unreasonable to take such an approach until solid prospective data describe the harm or benefit. Hence, quantitative bone histomorphometry can discriminate among the various forms of renal osteodystrophy and, if not present in a fracturing patient with stage 4–5D CKD who also, on biopsy, has a low trabecular bone volume, probably has, by exclusion, osteoporosis.
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agents that reduce the risk for fractures in postmenopausal, male or glucocorticoid-induced osteoporosis [73, 74]. Evidence from registration clinical trials shows efficacy of these agents down to levels of renal function calculated either by serum creatinine concentrations (2.0 mg/dl) or estimated glomerular filtration rates by Cockcroft-Gault equations (eGFR) or creatinine clearance 30 ml/min. While all of the registered agents have evidence of risk reduction for vertebral fractures, patients at higher fracture risk or who have already suffered a non-vertebral fracture are more often considered candidates for bisphosphonate or teriparatide, which have evidence for global fracture risk reduction. There is prospective evidence that patients with agerelated reduction in GFR down to 30 ml/min gain a benefit from oral and intravenous bisphosphonates or teriparatide [75–80]. In addition, theses agents seem to have an excellent safety profile as measured by effects on renal adverse events. In the intravenous bisphosphonate studies of postmenopausal women, it appears that both ibandronate, even at doses of 3 mg IV every 3 months (the registered dose for postmenopausal osteoporosis) as well as zoledronic acid (5 mg/year) are safe in patients with GFR 30–35 ml/min when given as an injection (ibandronate) or 15-minute infusion (zoledronic acid). A non-inferiority study in men also has recently shown that intravenous zoledronic acid is as effective (using surrogate markers as end-points) as weekly alendronate (Figure 38.2) [81]. It is important, however, to point out that, even though there was no adverse effects of these intravenous bisphosphonates on renal function in the
Treatment of osteoporosis in CKD As previously mentioned, patients who are suffering lowtrauma fragility fractures with stage 1–3 CKD are more likely to have osteoporosis than CKD–MBD as the cause of their impaired bone strength. Though several articles have described a higher fragility fracture risk associated with age-related reduction in renal function compared with agedmatched patients with normal renal function, the specific metabolic bone disease other than osteoporosis accounting for this bone fragility has not been defined [13, 17, 19, 31]. Hence, in patients with osteoporosis and who are in stage 1–3 CKD ranges of glomerular filtration rate that do not have a known biochemical abnormality that might suggest some form of CKD–MBD, they can and should be considered for treatment with FDA-registered pharmacological
Zoledronic acid is not inferior to alendronate in increasing lumbar spine BMD (LOCF) at Month 24 relative to baseline ZOL
10
ALN
Percentage change from baseline in LS BMD
9
[p -value = 0.7935]*
8 7 6 5 4 3
3.7%
3.1% n=138
n=143 n=143
5.0% 4.3% n=136 n=136 n=142 n=142
6.5% 6.7% n=135 n=123 n=135 n=123
2 1 0
6
12
24
Months value obtained from ANCOVA on % change from baseline of BMD with treatment and center as factors and baseline LS *P-BMD as a covariate. LS Mean diff (95% CI) = -0.131 (-1.116, 0.854). Data on file, Novartis. 7| Presentation Title | Presenter Name | Date | Subject | Business Use Only
Figure 38.2 The effect of zoledronic acid (5 mg IV over 15 minutes) on lumbar spine bone mineral density change from baseline as compared to alendronate (70 mg/week) in men [81].
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Osteoporosis in Men Reclast renal safety
Short term: 9–11 day postdose monitoring in > 5000 patients1
Overall, no cumulative impact on renal function over 3 years
Changes in Calculated Creatinine Clearance* From Baseline Over Time3
1
Mean (±SE) Change From Baseline in Calculated Creatinine Clearance (mL/min)
Transient rises in serum creatinine in 1.8% of patients (vs 0.8% placebo) (P < 0.01) with resolution and all patients redosed2 The percentage of patients who had a decrease in creatinine clearance < 30 mL/min prior to the second or third infusion or at month 36 was similar between treatment groups3
Placebo (n = 3852)
0
Reclast (n = 3862)
–5
–10
–15 0
12
24
36
Months
*Cockcroft-Gault equation 1. Black DM, et al. N Engl J Med. 2007;356:1809-1822. 2. Reclast® (zoledronic acid) Injection [prescribing information]. East Hanover, NJ: Novartis Pharmaceuticals Corp; August 2007. 3. Miller P, et al. Poster presented at: 7th European Congress on Clinical and Economic Aspects of Osteoporosis and Osteoarthritis; March 28-31, 2007; Porto, Portugal. Poster P308.
Figure 38.3 Results of the effects of 3 years of IV zoledronic acid (5 mg/year) on GFR as compared with placebo In the pivotal IV (5 mg/year) zoledronic acid postmenopausal clinical trial there were equal numbers of patients that received active treatment as well as placebo that had a decline in creatinine clearance over the 3-year trial period [77].
randomized populations used for registration, safety might not be the same in patients with pre-existing renal disease from intrinsic parenchymal disease (e.g. diabetics) or in patients using other agents that could affect renal function (e.g. non-steroidal anti-inflammatory drugs), so caution should still be exercised in decisions to use intravenous bisphosphonates in specific higher-risk subpopulations. In the zoledronic acid clinical trials, a substantial proportion of the population had diabetes; no different adverse renal effects were seen between diabetic and non-diabetic patients. Also, in the zoledronic acid trials, GFR declined equally between the treated and placebo groups over time and were no different at the end of the 3-year study (Figure 38.3) [77]. However, in a short-term subset of patients where serum creatinine was measured during days 9–11 after the 15-minute infusion of zoledronic acid, there was a small but statistically significant number of patients who had a transient increase in serum creatinine concentration (0.5 to 2.0 mg/dl above baseline) during the second annual infusion (Figure 38.4) [79]. However, all of these patients had a return of their serum creatinine concentration before the next annual infusion. It is important to stress that infusions of zoledronic acid be given no faster than 15 minutes since more rapid infusion rates have been associated with acute renal failure, suggesting that the tubular damage that mimics acute tubular necrosis (ATN) is related to the Cmax and not the AUC (area under the curve). This author administers zoledronic acid over a 30-minute infusion time in patients with normal renal function or in those with stages 1–3 CKD.
In the registration trial for teriparatide, baseline measurements of GFR were not required for randomization, but patients were enrolled if their baseline serum creatinine concentration was 2.0 mg/dl [80]. In a post-hoc analysis, there was a small subset of patients who had eGFR down to 30 ml/ min (by Cockgroft-Gault) and, in this subset, teriparatide both at 20 g/day as well as 40 g/day had an anabolic effect as measured by increases in osteoblast activity markers (Figure 38.5) [27] and BMD and pooled reduction in vertebral as well as non-vertebral fracture risk (Figure 38.6) [27] similar to those with higher eGFR and without any adverse renal effects [27]. There are no teriparatide data in stage 4–5D CKD and it is important to emphasize that, in all of the teriparatide clinical trials, all patients, even those with eGFR down to 30 ml/min, had normal baseline serum intact PTH levels. It is possible that the bone biological response could differ between patients with CKD who have an elevated as compared with a normal serum PTH. This query should be investigated. Treatment decisions become more difficult to make in fracturing patients with stage 5 and 5D CKD. This is even the case when the clinician has determined to the best of his/her ability that the patient with stage 5–5D CKD has suffered a fragility fracture and has osteoporosis rather than CKD–MBD. There are no prospective data showing efficacy of any of the approved pharmacological agents to treat osteoporosis at these levels of GFR. There are data from two separate post-hoc analyses that both risedronate, using the 5 mg/day formulation (from pooled data of 9 clinical trials)
C h a p t e r 3 8 Management of Fractures in Men with Impaired Renal Function l
459
Short Term Renal Safety Sub-Group Data (n= 5,038) Placebo
Mean serum creatinine (mg/dL)
3.5
Zoledronic acid 5 mg
3 2.5 2 1.5 1 0.5 0 Baseline
Zoledronic acid n = 31 Placebo n =
10
9–11 days 2nd infusion 9–11 days 3rd infusion 9–11 days after 1st (mth 12) after 2nd (mth 24) after 3rd infusion infusion infusion 29 29 21 26 19 8
8
7
8
8
Month 36
24 7
Boonen S et al Kid Internat 2008
Figure 38.4 The short-term (9–11 days post-infusion) effect of zoledronic acid (5 mg/year) on serum creatinine concentration. After the second infusion of 5 mg zoledronic acid there was a small but significant number of patients (n 27) who had at least a doubling of their serum creatinine concentration 9–11 days post infusion as compared to placebo (n 7) (P 0.004). All serum creatinine concentrations returned to baseline before the next annual infusion of zoledronic acid [79]. Effect of Renal Function on Changes in PINP Concentrations with Teriparatide
Median change from baseline [ng/ml] (25th, 75th percentiles)
PINP (3 months)
*
200
*
150
Placebo TPTD20 TPTD40 * P<0.05 from Placebo
*
100 50
*
*
*
0 Normal (> 80 ml/min)
Moderate Mild Impairment Impairment (50–79 ml/min) (30–49 ml/min)
Miller P, et al. Osteopor Int 2007
Figure 38.5 The effect of teriparatide (rh 1-34 PTH: 20 g or 40 g/day) on osteoblastic activity marker (P1NP) change at 3 months from baseline in patients as a function of the baseline renal function (tertiles) [27].
(Figure 38.7) as well as alendronate (from the Fracture Intervention Trial where 5 mg/day was given for the first 2 years and 10 mg/day for the third year) reduced incident vertebral fractures (risedronate) or vertebral as well as all
clinical fractures (alendronate) without changing serum creatinine concentration when given at these daily registration doses for a period of 2–3 years in patients with eGFR (by Cockgroft-Gault equation) [28, 29]. Hence, these are
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Osteoporosis in Men Vertebral fracture 30 25 Fracture incidence (%)
Non-vertebral fracture 10
RR = 0.22 (0.13,0.39)
20 RR = 0.43 (0.25,0.73)
15
37/199
Placebo
8
RR = 0.53 (0.26, 1.05)
6
RR = 0.37 (0.17, 0.80)
TPTD20+40
15/246 15/292
10
4
27/244
16/593
2
5
23/483
0
Normal (> 80 ml/min)
11/485
16/383
Abnormal (< 80 ml/min)
0
Normal (> 80 ml/min)
Renal function
Abnormal (< 80 ml/min)
Renal function
Miller P, et al. Osteopor Int 2007
Figure 38.6 The effect of teriparatide (1-34 rhPTH 20 40 g/day) on vertebral fracture incidence and non-vertebral fracture risk reduction in pooled analysis of postmenopausal women and men as a function of renal function [27].
Control
30
5 mg RIS
Percent of patients
25 20 15
56% (11,78%) p = 0.021
45% (31,57%) p < 0.001
32% (14,46%) p = 0.001
10 5 0 Baseline renal impairment* Mild N = 3000
Moderate N = 2423
Severe N = 232
*Creatinine clearance estimated using the Cockcroft and Gault method [9] N Number of patients with evaluable paired spinal radiographs Miller PD et al JBMR 2005
Figure 38.7 Effect of risedronate (5 mg/day) on incident morphometric vertebral fracture risk in patients with baseline eGFR (Cockgroft Gault) divided into tertiles. Equal reduction in incident vertebral fractures in pooled risedronate clinical trials (5 mg/day) even in patients with eGFR less than 30 ml/min (none below 15 ml/min) [52].
the only data that suggest that these formulations are safe and effective for 2–3 years in patients in the postmenopausal clinical trials with eGFR reductions by Cockkroft-Gault down to 15 ml/min from age-related bone loss. Similar post-hoc data have been published on raloxifene [30]. There are no data on the efficacy or safety of bisphosphonates of any formulation on fracture risk reduction in patients with GFR 15 ml/min (stage 5 or 5D CKD). Nevertheless,
the question often arises on opinions on management of fragility fractures in this population. Here only opinion exists and is controversial and leads us to appeal for good science and randomized prospective data in these groups. In this author’s opinion, patients without fractures with stage 5 or 5D CKD should not be given bisphosphonates or teriparatide off-label. That is, treating only on the basis of low BMD and other risk factors would seem possibly to
C h a p t e r 3 8 Management of Fractures in Men with Impaired Renal Function l
be associated with greater risk than benefit. In those 5–5D CKD patients suffering fragility fractures, a bisphosphonate may be considered but only after a thorough elimination of CKD–MBD, which most often requires a bone biopsy [66, 73]. A transiliac bone biopsy is a safe procedure with little morbidity when performed in skilled hands. Once a diagnosis of osteoporosis appears to be the cause of fractures then, if one chooses to use a bisphosphonate after open informed consent of the patient, then this author halves the usual dose formulation and restricts the use to no more than 3 years. This approach is based on the known pharmaco kinetics of bisphosphonates in human beings with normal renal function: 50% of an administered dose goes to bone and 50% gets excreted by the kidney. Thus, with severe impairment of renal function, and where the dialyzability of bisphosphonates has not been well studied, it seems reasonable to give one-half the usual dose. The limitation of administration to no more than 3 years is based on the unknown, but probable, greater bone retention of bisphosphonates when excretion is impaired. It should be stressed that these approaches are based on no evidence for efficacy but are considered in extreme cases of often recurrent fragility fractures where the fractures per se pose a great risk for morbidity and mortality. These approaches should be clearly discussed with the patient, be undertaken by specialists knowledgeable in complex metabolic bone disease management and be initiated only after the disease leading to fractures is well characterized.
Conclusions No consensus exists regarding the criteria for the diagnosis of osteoporosis in stage 4 or 5–5D CKD. In higher-risk patients with stage 1–3 CKD and osteoporosis, it appears that any agent registered for osteoporosis can be used with efficacy and safety data, including the bisphosphonates and/ or teriparatide. The considerations for management become far more complex in stage 4, 5–5D CKD where the prevalence of other metabolic bone diseases and CKD–MBD increase and the WHO criteria for fragility fractures cannot be used for the diagnosis of osteoporosis. In these more severe cases of CKD (5–5D), the differential diagnosis requires careful analysis of a broad range of biochemical markers of bone turnover and, at times, quantitative bone histomorphometry, especially if management considerations include the use of bisphosphonates. It is unknown if bisphosphonates, by reducing bone turnover in a pre-existing low bone turnover state, would help or harm bone or lead to more or less cardiovascular disease. These questions must be addressed by better science and prospective data. The future application of newer non-invasive radiological tools to measure microstructure and mineralization of bone promises to help us better understand osteoporosis and CKD–MBD in a
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non-invasive manner. In clinical practice, at the current time and with current limited knowledge, treatment of osteoporosis in stage 4–5, 5D CKD is opinion based. Nevertheless, in very specific clinical cases of severe fragility fractures that, by themselves, may cause a high morbidity and mortality, bisphosphonates should be considered by experts in bone metabolism and, as with the use of any off-label application, after careful informed discussions with the patient.
References 1. S. Klawansky, E. Komaroff, P.F. Cavanaugh Jr, et al., Relationship between age, renal function and bone mineral density in the US population, Osteoporos. Int. 14 (2003) 570–576. 2. J. Coresh, B.C. Astor, T. Greene, G. Eknoyan, A.S. Levey, Prevalence of chronic kidney disease and decreased kidney function in the adult US population: Third National Health and Nutrition Examination Survey, Am. J. Kid. Dis. 41 (2003) 1–12. 3. S.K. Jassal, D. Von Muhlen, E. Barrett-Conner, Measures of renal function, bone loss and osteoporotic fracture in older adults: The Rancho Bernardo Study, J. Bone Miner. Res. 22 (2007) 203–210. 4. R.D. Lindeman, J. Tobin, N.W. Shock, Longitudinal studies on the rate of decline in renal function with age, J. Am. Geriatr. Soc. 33 (1985) 278–285. 5. R.D. Lindeman, Assessment of renal function in the old. Special considerations, Clin. Lab. Med. 13 (1993) 269–277. 6. K. Ishida, H. Ishida, M. Narita, et al., Factors affecting renal function in 119,985 adults over three years, Q. J. Med. 94 (2001) 541–550. 7. D.W. Cockcroft, M.H. Gault, Prediction of creatinine clearance from serum creatinine, Nephron 16 (1976) 31–41. 8. R.A. Lafayette, R.D. Perrone, A.S. Levey, Laboratory evaluation of renal function, in: R.W. Schrier, C.W. Gottschalk (Eds.), Diseases of the Kidney, fifth ed., Little, Brown and Company, Boston, 1993, pp. 333–370. 9. A.G. Bostom, F. Kronenberg, E. Ritz, Predictive performance of renal function equations for patients with chronic kidney disease and normal serum creatinine levels, J. Am. Soc. Nephrol. 13 (8) (2002) 2140–2144. 10. A.X. Garg, A. Papaioannou, N. Ferko, G. Campbell, J.A. Clarke, J.G. Ray, Estimating the prevalence of renal insufficiency in seniors requiring long-term care, Kidney Int. 65 (2) (2004) 649–653. 11. J. Lin, E.L. Knight, M.L. Hogan, A.K. Singh, A comparison of prediction equations for estimating glomerular filtration rate in adults without kidney disease, J. Am. Soc. Nephrol. 14 (10) (2003) 2573–2583. 12. R.J. Glassock, C. Winerals, Screening for CKD with eGFR: doubts and dangers, Clin. J. Am. Soc. Nephrol. 3 (2008) 1563–1568. 13. K/DOQI clinical practice guidelines for chronic kidney disease: evaluation, classification, stratification. Am. J. Kid. Dis. 39 (1) (2002) S1–S266. 14. R. Botev, J.P. Mallie, Reporting the eGFR and its implication for CKD diagnosis, Clin. J. Am. Soc. Nephrol. 3 (2008) 1606–1607.
462
Osteoporosis in Men
15. A. Levin, G.L. Bakris, M. Molitch, et al., Prevalence of abnormal serum vitamin D, PTH, calcium and phosphorus in patients with chronic kidney disease: results of the study to evaluate early kidney disease, Kid. Internat. 71 (1) (2007) 31–38. 16. K.A. Hruska, S.L. Teitelbaum, Renal osteodystrophy, N. Engl. J. Med. 333 (3) (1995) 166–172. 17. D.L. Andress, D.J. Sherrard, The osteodystrophy of chronic renal failure, in: R.W. Schrier (Ed.), Diseases of the Kidney and Urinary Tract, Lippincott Williams and Wilkins, Philadelphia, 2003, pp. 2735–2768. 18. R.J. Glassock, Renal osteodystrophy. disorders of divalent ions, and nephrolithiasis, NephSAP 4 (5) (2005) 239–279. 19. T.L. Nickolas, M.B. Leonard, E. Shane, Chronic kidney disease and bone fracture: a growing concern, Kid. Internat. 2 (2008) 1–11. 20. S.E. Papapoulos, Pharmacodynamics of bisphosphonates in man: implications for treatment, in: O.L.M. Bijvoet, H. Fleisch, R.E. Canfield, R.G.G. Russell (Eds.), Bisphosphonate Therapy in Acute and Chronic Bone Loss, Elsevier Science, Amsterdam, 1995, pp. 231–245. 21. C. Serge, L.M. Cremers, P. Goonaseelan, S. Papapoulos, Pharmacokinetics/pharmacodynamics of bisphosphonates, Clin. Pharmacol. 99 (6) (2005) 551–570. 22. R. Bergner, K. Dill, D.M.U. Boerner, Elimination of intravenously administered ibandronate in patients on haemodialysis: a monocentre open study, Nephrol. Dial. Transplant. 17 (2002) 1281–1285. 23. C. Serge, J. Hollander, P. Schrander van-der Meer, J. Hartigh, M. Vervloet, S. Papapopolos, Removal of intravenous pamidronate during hemodialysis, J. Bone Miner. Res. (2005). 24. A. Luhe, K.P. Kunkele, M. Haiker, et al., Preclinical evidence for nitrogen-containing bisphosphonate inhibition of farnesyl diphosphate (FPP) synthetase in the kidney: implications for renal safety, Toxicol. in Vitro. 22 (2008) 899–909. 25. J.R. Green, M.J. Rogers, Pharmacologic profile of zoledronic acid: a highly potent inhibitor of one resorption, Drug Devel. Res. 55 (2002) 210–224. 26. M.A. Perazella, G.S. Markowitz, Bisphosphonate nephrotoxicity, Kidney Int. (2008). 27. P.D. Miller, E.N. Schwartz, P. Chen, D.A. Misurski, J.H. Krege, Teriparatide in postmenopausal women with osteoporosis and impaired renal function, Osteoporos. Int. 18 (2007) 59–68. 28. P.D. Miller, C. Roux, S. Boonen, I. Barton, L. Dunlap, D. Burgio, Safety and efficacy of risedronate in patients with age-related reduced renal function as estimated by the Cockcroft and Gault method: a pooled analysis of nine clinical trials, J. Bone Miner. Res. 20 (12) (2005) 2015–2115. 29. S.A. Jamal, D.C. Bauer, K.E. Ensrud, et al., Alendronate treatment in women with normal to severely impaired renal function: an analysis of the fracture intervention trial, J. Bone Miner. Res. 22 (4) (2007) 503–508. 30. A. Ishani, T. Blackwell, S.A. Jamal, S.R. Cummings, K.E. Ensrud, MORE Investigators. The effect of raloxifene treatment in postmenopausal women with CKD, J. Am. Soc. Nephrol. 19 (7) (2008) 1430–1438. 31. S. Moe, T. Drueke, J. Cunningham, et al., Definition, evaluation, and classification of renal osteodystrophy: a position statement from Kidney Disease: Improving Global Outcomes (KDIGO), Kidney Int. 69 (11) (2006) 1945–1953.
32. G. Elder, Pathophysiology and recent advances in the management of renal osteodystrophy, Osteoporos. Int. 17 (12) (2002) 2094–2105. 33. K.A. Hruska, G. Saab, S. Mathew, R. Lund, Renal osteodystrophy, phosphate homeostasis, and vascular calcification, Semin. Dial. 20 (4) (2007) 309–315. 34. L.J. Melton III, Epidemiology worldwide, Endocrinol. Metab. Clin. N. Am. 32 (2003) 1–13. 35. R. Burge, B. Dawson-Hughes, D.H. Solomon, et al., Incidence and economic burden of osteoporosis-related fractures in the United States, 2005–2025, J. Bone Miner. Res. 22 (2007) 465–475. 36. E. Barrett-Connor, E.S. Siris, L.E. Wehren, et al., Osteoporosis and fracture risk in women of different ethnic groups, J. Bone Miner. Res. 20 (2005) 185–194. 37. P. Camacho, M. Kleerekoper, Secondary osteoporosis, Endocr. Pract. (2007). 38. WHO Study Group, Assessment of fracture risk and its application to screening for postmenopausal osteoporosis, World Health Organ. Tech. Rep. Ser. Geneva 843 (1994) 1–129. 39. P.D. Miller, S.L. Bonnick, Clinical utilization of bone mass measurements for the assessment and management of osteoporosis in the adult population, in: M. Favus (Ed.), Primer of Metabolic Bone Diseases, American Society for Bone and Mineral Research, 1999. 40. T.L. Nickolas, M.B. Leonard, E. Shane, Chronic kidney disease and bone fracture: a growing concern, Kidney Int. 2 (2008) 1–11. 41. A. Gal-Moscovici, S.M. Sprague, Osteoporosis and chronic kidney disease, Semin. Dial. 20 (5) (2007) 423–430. 42. A.M. Parfitt, M. Drezner, F. Glorieux, et al., Bone histomorphometry: standardization of nomenclature, symbols, and units. Report of the ASBMR Histomorphometry Nomenclature Committee, J. Bone Miner. Res. 2 (6) (1987) 595–610. 43. NIH Consensus Development Panel Osteoporosis Prevention Diagnosis and Therapy. J. Am. Med. Assoc. 285 (2001) . 44. S. Baim, N. Binkley, J.P. Bilezikian, et al., Official Positions of the International Society for Clinical Densitometry and executive summary of the 2007 ISCD Position Development Conference, J. Clin. Densitom. 11 (1) (2008) 75–91. 45. E. Siris, P. Miller, E. Barrett-Connor, et al., Identification and fracture outcomes of undiagnosed low bone mineral density in postmenopausal women: results from the National Osteoporosis Risk Assessment (NORA), J. Am. Med. Assoc. 286 (2001) 2815–2822. 46. S.C.E. Schuit, H.H. Oei, J.C. Witteman, et al., Fracture incidence and association with bone mineral density in elderly men and women: the Rotterdam Study, Bone 34 (1) (2004) 195–202. 47. M.L. Bouxsein, Non-invasive measurements of bone strength: promise and peril, J. Musculoskelet. Neuron. Interact. 4 (4) (2004) 404–405. 48. E. Seeman, Bone quality: the material and structural basis of bone strength, J. Bone Miner. Metab. 26 (1) (2008) 1–8. 49. A.M. Alem, D.J. Sherrard, D.L. Gillen, et al., Increased risk of hip fracture among patients with end-stage renal disease, Kidney Int. 58 (2000) 396–399. 50. A.M. Ball, D.L. Gillen, D. Sherrard, et al., Risk of hip fracture among dialysis and renal transplant recipients, J. Am. Med. Assoc. 288 (2002) 3014–3018.
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51. M. Jadoul, J.M. Albert, T. Akiba, et al., Incidence and risk factors for hip or other bone fractures among hemodialysis patients in the Dialysis Outcomes and Practice Patterns Study, Kidney Int. 70 (2006) 1358–1366. 52. C.O. Stehman-Breen, D.J. Sherrard, A.M. Alem, et al., Risk factors for hip fracture among patients with end-stage renal disease, Kidney Int. 58 (2000) 2200–2205. 53. F.W. Wehrli, M.B. Leonard, P.K. Saha, et al., Quantitative high-resolution magnetic resonance imaging reveals structural implications of renal osteodystrophy on trabecular and cortical bone, J. Magn. Reson. Imag. 20 (2004) 83–89. 54. H.K. Genant, T.F. Lang, K. Engelke, et al., Advances in the noninvasive assessment of bone density, quality, and structure, Calcif. Tissue Int. 59 (Suppl. 1) (1996) S10–S15. 55. P. Roschger, E.P. Paschalis, P. Fratzl, K. Klaushofer, Bone mineralization density distribution in health and disease, Bone 42 (3) (2008) 456–466. 56. P.D. Miller, Bone density and markers of bone turnover in predicting fracture risk and how changes in these measures predict fracture risk reduction, Curr. Osteoporos. Rep. 3 (3) (2005) 103–110. 57. P.D. Miller, M.C. Hochberg, L.E. Wehren, P.D. Ross, R.D. Wasnich, How useful are measures of BMD and bone turnover?, Curr. Med. Res. Opin. 21 (4) (2005) 545–553. 58. P.M. Chavassieux, P.D. Delmas, Bone remodeling: biochemical markers or bone biopsy?, J. Bone Miner. Res. 21 (1) (2006) 178–179. 59. P. Garnero, Biomarkers for osteoporosis management: utility in diagnosis, fracture risk prediction and therapy monitoring, Mol. Diagn. Ther. 12 (3) (2008) 157–170. 60. M. Hochberg, S. Greenspan, R. Wasnich, P. Miller, D. Thompson, P. Ross, Changes in bone density and turnover explain the reductions in incidence of nonvertebral fractures that occur during treatment with antiresorptive agents, J. Clin. Endocrinol. Metab. 87 (2002) 1586–1592. 61. M.L. Bouxsein, P.D. Delmas, Considerations for development of surrogate endpoints for antifracture efficacy of new treatments in osteoporosis: a perspective, J. Bone Miner. Res. 23 (8) (2008) 1155–1167. 62. P. Chen, J.H. Satterwhite, A.A. Licatta, et al., Early changes in biochemical markers of bone formation predict the BMD response with teriparatide in postmenopausal women with osteoporosis, J. Bone Miner. Res. 20 (6) (2005) 962–970. 63. P.D. Miller, P.D. Delmas, R. Lindsay, et al., Early responsiveness of women with osteoporosis to teriparatide following therapy with alendronate or risedronate, J. Clin. Endocrinol. Metab. (2008). 64. P.D. Miller, E.V. Lerma, Renal bone diseases, in: M. Kleerekoper, E. Siris, M. McClung (Eds.), The Bone and Mineral Manual – A Practical Guide, second ed., Elsevier Academic Press, Burlington, 2005. 65. P.D. Miller, E. Shane, Management of transplantation renal bone disease: interplay of bone mineral density and decisions
66. 67. 68.
69. 70.
71. 72.
73.
74.
75.
76.
77.
78.
79.
80.
81.
463
regarding bisphosphonate use, in: M.R. Weir (Ed.), Medical Management of Kidney Transplantation, Lippincott Williams & Wilkins, Philadelphia, 2004, pp. 359–375. P.D. Miller, The role of bone biopsy in chronic kidney disease, Clin. J. Am. Soc. Nephrol. 3 (2008) 1–11. H.M. Frost, Tetracycline-based histological analysis of bone remodeling, Calcif. Tissue Res. 3 (3) (1969) 211–237. O. Hitt, Z.F. Jaworski, A.G. Shimizu, H. Frost, Tissue-level bone formation rates in chronic renal failure, measured by means of tetracycline bone labeling, Can. J. Physiol. Pharmacol. 48 (12) (1970) 824–828. G. Coen, Adynamic bone disease: an update, J. Nephrol. 18 (2005) 117–122. A.M. Parfitt, Renal bone disease: a new conceptual framework for the interpretation of bone histomorphometry, Curr. Opin. Nephrol. Hyperten. 12 (2003) 387–403. V.M. Brandenburg, J. Floege, Adynamic bone disease – bone and beyond, Nephrol. Dial. Transplant. 3 (2008) 135–147. K.A. Hruska, G. Saab, S. Mathew, R. Lund, Renal osteodystrophy, phosphate homeostasis, and vascular calcification, Semin. Dial. 20 (4) (2007) 309–315. P.D. Miller, Is there a role for bisphosphonates in patients with stage 5 chronic kidney disease?, Semin. Dial. 20 (2007) 191–197. P.D. Miller, Bisphosphonates: pharmacology and use in the treatment of osteoporosis, in: R. Marcus, D. Feldman, D.A. Nelson, C.J. Rosen (Eds.), Osteoporosis, third ed., Elsevier Academic Press, San Diego, 2007, pp. 1725–1736. R.G. Russell, N.B. Watts, F.H. Ebetino, M.J. Rogers, Mechanisms of action of bisphosphonates: similarities and differences and their potential influence on clinical efficiacy, Osteoporos. Int. (2008). J.A. Eisman, R. Civetelli, S. Adami, et al., Efficacy and tolerability of intravenous ibandronate injections in postmenopausal osteoporosis: 2-year results from the DIVA study, J. Rheumatol. 35 (3) (2008) 488–497. D.M. Black, P.D. Delmas, R.R. Eastell, et al., Once-yearly zoledronic acid for treatment of postmenopausal osteoporosis, N. Engl. J. Med. 356 (18) (2007) 1809–1822. E.M. Lewiecki, P.D. Miller, Renal safety of intravenous bisphosphonates in the treatment of osteoporosis, Expert Opin. Drug Saf. 6 (6) (2007) 663–672. S. Boonen, D.E. Sellmeyer, K. Lippuner, et al., Renal safety of annual zoledronic acid infusions in osteoporotic postmenopausal women, Kidney Int. 74 (5) (2008) 641–648. R.M. Neer, C.D. Arnaud, J.R. Zanchetta, et al., Effect of parathyroid hormone (1-34) on fractures and bone mineral density in postmenopausal women with osteoporosis, N. Engl. J. Med. 344 (19) (2001) 1434–1441. Intravenous zoledronic acid vs alendronate in men with low bone mass. http://www.clinicaltrials.gov/ct2/show/NCTOO O9785?termreclastmen&rank5/.
Chapter
39
Primary Hyperparathyroidism in Men Claudio Marcocci1, Luisella Cianferotti1, Shonni J. Silverberg2 and John P. Bilezikian2 1
Department of Endocrinology and Metabolism, University of Pisa, Pisa, Italy Division of Endocrinology, Department of Medicine, College of Physicians and Surgeons, Columbia University, New York, USA
2
Introduction
stones, overt bone disease and specific neuromuscular dysfunction, to one that is primarily asymptomatic at the time of diagnosis [1] (Figure 39.1). In this chapter, the modern profile of PHPT will be described with specific reference to possible gender differences among men and women.
Primary hyperparathyroidism (PHPT) is one of the most frequently diagnosed endocrine disorders. Together with malignancy, PHPT is the most common cause of hypercalcemia and therefore should be considered in any subject with elevated serum calcium concentration. Following the introduction and widespread use of the multichannel autoanalyzer in the early 1970s, a four- to fivefold increase in the prevalence and incidence of the disease was appreciated. Along with the increase in incidence, the most common clinical presentation of PHPT changed from a disease that was primarily symptomatic, with hypercalcemia, kidney
Epidemiology PHPT was not a common disease when serum calcium determinations were not routinely obtained. Incidence figures
80
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70 60 50 40 30 20 10 0 Cope et al.a (1930–1965)
Heath et al.(2) (1965–1974)
Mallette et al.c (1965–1972)
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Figure 39.1 Changes in clinical manifestations of PHPT at diagnosis in subsequent epidemiological studies: increase in asymptomatic disease (filled bars) versus osteitis fibrosa cystica (gray bars) and nephrolithiasis (open bars). Osteoporosis in Men
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Copyright 2009, 2010 Elsevier, Inc. All rights of reproduction in any form reserved.
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rose dramatically when serum calcium determinations became routine in the context of the multichannel biochemistry autoanalyzer. Comparing figures before and after the introduction of the autoanalyzer at the Mayo Clinic, there was a four- to fivefold increase in the incidence of PHPT to approximately 27.7 cases per 100 000 persons per year [3]. More recent reports from USA and Europe have suggested that the incidence of PHPT may be declining, even though, in the experience of most endocrinologists, this does not appear to be the case [6, 7]. The estimated prevalence of PHPT is 3/1000 in the general population, but may be as high as 2.1% in postmenopausal women. PHPT occurs at all ages, but the incidence increases with age and peaks in the sixth decade of life. It is generally reported that men are affected much less often than women by a ratio of approximately 1:3. A Mayo Clinic update on the incidence of PHPT between 1993 and 2001 showed that the mean age at diagnosis has remained stable (52 years and 56 years, respectively) and that the majority
Incidence (per 100 000 person-years)
350
<45 yr
of cases occur in women (74%), with an overall ratio of incidence in men to women of 1:2 [6]. When PHPT is diagnosed before the age of 45, men and women appear to have relatively equal rates, the predominance of women over men becoming evident only after the menopause. The majority of patients with PHPT are postmenopausal women, often presenting within the first decade after the menopause (Figure 39.2). In the absence of large epidemiologic studies, Miller et al have analyzed patients from the Nationwide Inpatient sample, a 20% random sample of all hospital admission from 2000 to 2004 in the USA [8]. Parathyroid surgery for PHPT was used as a surrogate marker for the overall incidence of the disease. This study confirms that more women than men are affected and that the female to male ratio starts to diverge after the age of 35 years. The gender divergence with age in PHPT incidence remains unexplained. An ascertainment bias could partially account for this finding. Indeed, increased awareness 350
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Figure 39.2 Differences in PHPT incidence between men (filled bars) and women (open bars) according to age and time of evaluation in a Mayo Clinic survey. (Drawn from data published in [6]).
C h a p t e r 3 9 Primary Hyperparathyroidism in Men l
Etiology PHPT is caused by excessive secretion of PTH by one or more of the four parathyroid glands [1]. The pathophysiology of PHPT relates to the loss of normal feedback control of PTH secretion by extracellular calcium. In the majority of cases, PHPT is due to a single parathyroid adenoma (80–85%). Less commonly, in approximately 10–15% of cases, the disorder is characterized by hyperplasia of all four parathyroid glands. Multiple parathyroid adenomas (2–4%) occur much less often and parathyroid carcinoma (0.5%) is rare. These different forms of primary hyperparathyroidism may be sporadic or familial. The latter include multiple endocrine neoplasia type 1 (MEN1) and type 2 (MEN2), hyperparathyroidism–jaw tumor (HPT–JT) syndrome, familial hypocalciuric hypercalcemia (FHH) and familial isolated hyperparathyroidism. The genetic abnormalities responsible for MEN1, MEN2, HPT–JT and FHH have been identified as gene mutations of menin (MEN 1), the ret proto-oncogene (MEN 2) [12], parafibromin (HPT– JT) [13] and the calcium-sensing receptor (FHH) [14]. The clonal origin of most parathyroid adenomas implies defects in specific genes controlling PTH secretion and/or parathyroid cell growth [15]. As many as 20–40% of sporadic parathyroid adenomas may overexpress the cyclin D1 oncogene. Biallelic defects of the MEN1 tumor suppressor gene have also been shown in up to 15–20% of sporadic cases. Mutations of the HRPT2 gene have been demonstrated
in the majority of parathyroid cancers but very rarely in sporadic parathyroid adenomas.
Pathology A parathyroid adenoma is usually characterized by a collection of chief cells surrounded by a rim of normal tissue. The remaining parathyroid glands are usually normal. Parathyroid hyperplasia may affect each gland differently, ranging from glands that display only minimal histologic clues (i.e. diminished fat content) to others that are so enlarged that their appearance resembles an adenoma. Parathyroid cancer shows mitoses, fibrous bands and vascular and capsular invasion. In the absence of gross local invasion or distant metastases, the diagnosis of parathyroid cancer may be difficult to make at the time of the initial operation [16].
Signs and symptoms The classical signs and symptoms of PHPT are rarely seen today in Western countries. Overt skeletal disease, characterized by subperiosteal resorption of the distal phalanges, a ‘salt and pepper’ appearance of the skull, bone cysts and brown tumors of the long bones, is so infrequent (5%) that skeletal x-rays are rarely indicated. This does not imply that the skeleton is unaffected. In fact, bone mineral density (BMD) measurement typically shows evidence of skeletal involvement in the majority of cases [17] (Figure 39.3). Parathyroid hormone is known to be catabolic at cortical sites and anabolic at cancellous sites [18]. At cortical sites (e.g. distal third of radius), BMD is typically reduced while at cancellous sites (e.g. lumbar spine), BMD is typically not reduced
100
% Of expected
of osteoporosis in women may contribute to serum calcium and parathyroid hormone (PTH) measurement as part of osteoporosis evaluation, which is usually carried out in a population like postmenopausal women, who are at increased risk for PHPT. Ascertainment bias could also be at hand here if, for other reasons, women have their calcium measured more frequently than men. Another possibility is related to the potential role of estrogen. Estrogen has been shown to increase the sensitivity of parathyroid cells to extracellular calcium, to stimulate PTH gene transcription and secretion and to reduce the peripheral effects of PTH [9]. In addition, estrogen could influence parathyroid cell function and proliferation by stimulating the production of 1,25-dihydroxyvitamin D. At the onset of menopause, these putative effects of estrogen would be reversed, thus unmasking the underlying hyperparathyroid state. In fact, postmenopausal women do display enhanced skeletal sensitivity to PTH. During PTH infusion, estrogen-deficient women showed a greater increase in indices of bone resorption [10]. This may lead to an increase in calcium efflux from bone and consequently in serum calcium. Conversely, estrogen administration in postmenopausal women with PHPT lowers total serum calcium, likely because of its antiresorptive actions [11].
467
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Figure 39.3 Classical pattern of bone loss (BMD) in PHPT (*P 0.05 versus radius). (Reproduced from J Bone Miner Res 1989;4:283-91 with permission of the American Society for Bone and Mineral Research).
Osteoporosis in Men
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[19]. Nonetheless, about 15% of patients with PHPT have evidence of vertebral bone loss at initial diagnosis [20]. BMD at the hip, where cortical and cancellous elements are equivalently represented, is intermediate between typical measurements at the lumbar spine and distal third of radius. Histomorphometry of bone biopsy specimens in PHPT shows accelerated bone turnover, cortical thinning and relative preservation of cancellous bone microarchitecture [19]. There is no gender difference in parameters that reflect trabecular connectivity. More recently, microCT analysis of iliac crest bone biopsies has also shown no difference in any three-dimensional indices between men and women with PHPT [21]. Several studies have assessed fracture risk in selected patients with PHPT [30]. Despite preferential involvement of cortical bone in PHPT, an increased fracture rate has been reported not only at peripheral sites (forearm), but also at the spine (Table 39.1). In evaluating fracture risk in PHPT, other skeletal effects of PTH that contribute to bone quality and strength, besides BMD, should be taken into account. Enlarged cross-sectional diameter of bone, due to increased periosteal apposition and endosteal resorption may provide greater biomechanical competence for a given value of BMD. In addition, preserved cancellous
microarchitecture probably adds strength to bone in PHPT [21]. The positive effects of increased cross-sectional diameter and preserved cancellous microstructure should tend to counteract the negative effects of PTH on cortical thickness. A cross-sectional study has recently reported that fracture thresholds by BMD at all sites are lower in women with PHPT than in controls even though this has not recently been confirmed [30]. In a large cohort study from Denmark, which mainly included patients who underwent parathyroid surgery, an increase in overall fracture risk was evident in patients with PHPT up to 10 years before the diagnosis of the disease [24]. Similar data have been previously reported by Khosla et al who have retrospectively analyzed the prevalence of fracture in 407 cases of mild PHPT diagnosed among residents of Rochester, Minnesota [23]. In both studies, men had a lower fracture risk than women and fracture risk increased with advanced age at diagnosis. The risk of hip fracture seems to be slightly, if at all, increased. This is consistent with the finding that PHPT is not a dominant feature in most series of hip fracture patients [31]. The kidney is also a classical target of PHPT. Although calcium deposition in the kidney, either as nephrocalcinosis or nephrolithiasis, is much less common in PHPT than it used to be, it is still seen in 17–20% of patients. Moreover,
Table 39.1 Relative fracture risk (RR) in patients with untreated PHPT RR:all
RR:hip
RR:spine
RR:forearm
Patients and settings
References
*
Cohort
1.8 (1.3–2.3)
1.4 (0.8–2.7)
3.5 (1.3–9.7)
1.9 (1.1–3.3)
Denmark. 674 patients (26% men, 58.2 years)
Vestergaard et al 2000 [23]
Cohort register-based*
1.5 (1.1–2.0)
Denmark. 841 patients Vestergaard and (58.6 14.6 years), later Mosekilde 2003 selected for surgery [24]
Cohort register-based*
1.6 (1.1–2.3)
Vestergaard Denmark. 360 patients (65.5 16.8 years), later and Mosekilde selected for conservative 2003 [24] treatment
Cohort*
0.5 (0.1–2.0)
Cohort*
3.5 (1.2–10.1)
Cross-sectional*
5.22 (2.9–9.2)
Cohort**
1.4 (1.0–2.0)
Cohort**
0.98 (0.78–1.2)
*
3.2 (2.5–4.0)
Wilson et al 1988 [25]
Sweden. 73 patients (all women, 68 years)
Larsson et al 1989 [26]
Italy. 98 patients De Geronimo et (postmenopausal women, al 2006 [27] 61 years) 2.2 (1.6–2.9)
No surgery during follow up; Some had parathyroidectomy during follow up. Modified with permission from [64]
**
USA. 174 consecutive patients (20% men, 62 years)
USA. 407 patients (23% men) 23% surgery
Kohsla et al 1999 [22]
Sweden. 1924 patients (29% men, 65.8 years)69% surgery
Larsson et al 1993 [28]
C h a p t e r 3 9 Primary Hyperparathyroidism in Men l
PHPT remains the most common cause of calcium stone formation after idiopathic stone disease. Unlike idiopathic calcium stone formation, which largely affects men, nephrolithiasis in PHPT affects both women and men in equal proportions [32]. Scillitani et al suggest that a specific calcium sensing receptor haplotype (AGQ) is significantly associated with kidney stones [33]. Other renal manifestations of PHPT, besides nephrocalcinosis and nephrolithiasis, include hypercalciuria, which is seen in approximately 40% of cases, and unexplained reduction in renal function. The classical neuromuscular dysfunction of PHPT is virtually never seen anymore. Rather, a more vaguely defined, non-specific syndrome, characterized by a sense of weakness and easy fatigability, associated at times with neuropsychiatric and cognitive complaints, is rather common [5]. Gastrointestinal manifestations of PHPT have classically included peptic ulcer disease and pancreatitis. With the exception of the MEN1 syndrome, where PHPT and gastrinoma may coexist [34], the incidence of peptic ulcer disease in patients with PHPT is about the same as it is in the general population. Similarly, the association between PHPT and acute pancreatitis, apart from that related to hypercalcemia, remains to be established. The Mayo Clinic experience reported the occurrence of pancreatitis in only 1.5% of its patients with PHPT [35]. The cardiovascular system is a target of both PTH and hypercalcemia [5]. The incidence of hypertension is increased. Other cardiovascular abnormalities of classical PHPT include myocardial, valvular and vascular calcifications. While these overt manifestations of PHPT are rarely seen now, increased vascular stiffness and other subtle cardiovascular abnormalities may be detected in the more common, asymptomatic presentation of PHPT [36].
Clinical presentation In Western countries, most patients with PHPT present with mild hypercalcemia (usually within 1 mg/dl above the upper limit of normal range) and display neither symptoms nor complications due to hypercalcemia or excessive PTH [5]. The preponderance of asymptomatic cases is likely due to the measurement of serum calcium as part of the routine multichannel screening test. Conversely, in other regions of the world, such as the East, the Middle East and some areas of the southern hemisphere, the clinical presentation of PHPT can still be dominated by the symptomatic variant. It has been suggested that severe vitamin D deficiency, often present in those parts of the world, could account, at least in part, for this finding. Indeed, based on the actions on vitamin D to help control PTH synthesis, its deficiency could fuel the already abnormal parathyroid gland physiology to become even more active [37]. Rarely, a patient will present with a markedly elevated, life-threatening, serum
469
calcium concentration, a presentation described as acute PHPT or parathyroid crisis. A new entity, characterized by PTH elevation in the absence of hypercalcemia (normocalcemic PHPT), typifies yet another recent phenotype of the disease [38]. A concept related to this presentation is that it represents a very early manifestation of PHPT. It is usually found in patients undergoing evaluation for low BMD or in individuals who are being evaluated, in general, for skeletal health. To make this diagnosis, a comprehensive search for causes of secondary hyperparathyroidism must be undertaken. If vitamin D levels are below normal, it is necessary to re-evaluate these patients after vitamin D repletion. In some cases, the patient may become hypercalcemic, the vitamin D deficiency having masked the hypercalcemic state. In another scenario, the PTH level becomes normal, with vitamin D repletion, thus explaining the elevated PTH as due entirely to vitamin D deficiency. However, in a substantial number of patients, after vitamin D has become normal, PTH levels remain elevated and the serum calcium remains normal. When other causes of secondary hyperparathyroidism have been ruled out, such as renal insufficiency, the diagnosis of normocalcemic PHPT is made. The natural history of normocalcemic PHPT is not known but a recent study has suggested that, over time, a number of these individuals become frankly hypercalcemic [39].
Evaluation and diagnosis The diagnosis of PHPT is based on laboratory tests, particularly measurement of serum PTH [40]. The most widely used method for PTH measurement is the immunoradiometric (IRMA) or immunochemiluminometric (ICMA) assays which measure the ‘intact’ molecule (PTH(1-84)) and large carboxyterminal fragments such as (PTH(7-84)). An IRMA assay has been developed which only recognizes the whole PTH(1-84) molecule [41]. Both assays perform well in discriminating subjects with PHPT from those with non-PTH dependent hypercalcemia [42]. A simultaneous elevation of serum PTH and calcium virtually establishes the diagnosis. In some patients with PHPT, the PTH level is in the upper range of normal, but it can be considered to be abnormal when hypercalcemia is simultaneously present. The other common cause of hypercalcemia, namely malignancyassociated hypercalcemia, is characterized by suppressed levels of PTH. Very rarely, non-parathyroid malignancies produce authentic PTH. However, even in a patient with a known malignancy, hypercalcemia and elevated PTH levels, the likelihood that the patient has PHPT is much greater since ectopic PTH secretion by a malignant tumor is very rare. The only hypercalcemic conditions in which serum PTH levels may be increased, besides the rare ectopic PTH syndrome, include FHH and the use of lithium and thiazide
470
Osteoporosis in Men
diuretics. Patients with FHH usually have a family history of asymptomatic hypercalcemia and the urinary Ca/Cr clearance ratio is below 0.01 [14]. Moreover, with high penetrance, FHH is usually evident by the age of 30. Genetic studies of the CASR gene can unequivocally establish the diagnosis of FHH [14]. Although many patients with hypercalcemia associated with the use of lithium or thiazide diuretics do have PHPT, withdrawal of the medication, if it is safe to do so, and monitoring the serum calcium over the next 2–3 months can clarify the issue. Serum phosphorus is usually in the lower range of normal in PHPT. Urinary calcium is increased in about 40% of cases. The circulating 1,25-dihydroxyvitamin D concentration is elevated in about 25% of patients with PHPT, but it is of limited diagnostic value since its levels are also increased in other hypercalcemic states (sarcoidosis, other granulomatous diseases and some lymphomas) [43]. Serum levels of 25-hydroxyvitamin D are typically below normal (30 ng/ml) [44]. These measurements appear to be independent of age, sex and season [43]. BMD measurement at three sites, lumbar spine, hip and distal radius, is an essential component of the evaluation [45]. As noted above, sites enriched in cortical bone are preferentially affected as compared to the cancellous ones which may be preferentially preserved [17]. Typically, patients show a reduction of BMD at the distal third of the forearm and relative preservation at the lumbar spine, exemplifying the composition of these two sites respectively of cortical and cancellous bone. The hip region tends to show values intermediate between the forearm and the spine. A small subset of patients (15%) will be shown to have vertebral osteopenia or osteoporosis [20]. It is important to measure BMD at all three sites because information obtained from this complete densitometric analysis is used to make recommendation for surgical treatment or monitoring (see Treatment section). A spine x-ray may be obtained in women with vertebral osteopenia/osteoporosis, particularly if there is a history of height loss.
Parathyroid imaging Parathyroid glands are not always located at the traditional four poles of the thyroid gland. They may be ectopically located in the neck with intrathyroid, retroesophageal or below in mediastinal locations. Because of this point and advances in preoperative imaging approaches, localization studies are now routinely performed in patients who are going to undergo parathyroid surgery. Among non-invasive techniques, scintigraphy with technectium-99m-sestamibi and ultrasound are those most commonly used [46] (Figure 39.4). Sestamibi scanning can localize both eutopic and ectopic abnormal parathyroid glands, with an accuracy rate up to 90% in experienced hands. The use of 123I along
Figure 39.4 Parathyroid imaging: ultrasound examination and Tc99m-sestamibi scan: enlarged hyperfunctioning parathyroid gland is indicated by the arrow.
with 99Tm sestamibi can be particularly useful because this method permits computer-based ‘subtraction’ of the thyroid gland image. Ultrasonography has advantages over radio labeled sestamibi imaging by being non-invasive, relatively inexpensive and without any radiation exposure. Its accuracy is highly operator-dependent. Whether scintigraphy or ultrasound is the preferred method is really a matter of what approach the facility and/or operator is most familiar with. While it can be argued that the experienced parathyroid surgeon does not need preoperative localization to identify successfully abnormal parathyroid gland(s), it is also true that operating time is substantially reduced when preoperative localization is successful. It used to be said that preoperative imaging was mandatory for subjects who had had previous neck surgery, but it is now routinely performed in all patients who are to undergo parathyroidectomy whether or not they
C h a p t e r 3 9 Primary Hyperparathyroidism in Men l
10 0 �10 �20 �30
Lumbar Spine
Change in bone mineral density (%)
�40 �50 10 0 �10
*
*
*
�20
*
Femoral Neck
�30 �40 �50 10 0 −10
*
*
−20 −30
*
*
*
Radius
*
−40 −50 n � 36
* *
1
2
3
4
5 24
6
7
8
9
10
11
12
13
11
14
15
6
Years of follow-up
Figure 39.5 Mean (SEM) changes in BMD at three sites in patients with PHPT. Data shown are cumulative percent changes from baseline at each site in subjects who did not undergo parathyroidectomy after 1–15 years of follow up. *, P 0.05, compared with baseline. (With permission from 49).
have had previous neck surgery. If patients are to undergo minimally invasive parathyroidectomy (MIP), a procedure of choice among many parathyroid surgeons and patients, preoperative localization is required. Additional imaging procedures, including computerized tomography, magnetic resonance imaging, arteriography and selective venous sampling for PTH measurement can be performed. In selected patients in whom scintigraphy and/or ultrasound have been unsuccessful.
Natural history of mild PHPT Patients who do not meet criteria for parathyroidectomy (see below) can be safely managed conservatively. A long-term observational study, which started in 1984, has
471
described the 15-year follow up of a large group of patients followed without parathyroid surgery [47–49] (Figure 39.5). Biochemical indices of the disease remained stable up to 12 years. Thereafter, there was a tendency for the serum calcium concentration to increase. BMD remained stable for the entire period of observation at the lumbar spine and up to 8–9 years at the hip and distal third of radius. At the hip and distal third of radius sites, bone loss became significant after 8–9 years of follow up. A greater than 10% decrease of BMD at the distal third of radius was observed in nearly 60% of patients who had been followed for 15 years. Thus, long-term follow up without surgery might not be suitable for all patients. This study also showed that approximately 40% of patients who had been followed without parathyroidectomy went on to have surgery. Interestingly, there was no difference in the rate of progression of the disease between patients who initially did or did not meet the 1990 National Insitutes of Health (NIH) guidelines for surgery [50]. Three short-term randomized clinical trials of 1–3 years which included patients with mild/asymptomatic PHPT have described the course of subjects followed either with or without parathyroidectomy. Although mean biochemical, densitometric and quality of life parameters remained quite stable in patients who did not have surgery, evidence of disease progression in selected features could be demonstrated in a minority of them, despite the relatively short follow up [51–53]. The available data from longitudinal studies point to the need of medical monitoring in patients with mild PHPT who do not undergo parathyroidectomy. According to the latest guidelines for parathyroid surgery in asymptomatic PHPT [54], medical follow up includes annual measurement of serum calcium and creatinine and BMD evaluation at the spine, the hip and the radius every 1–2 years. Annual 24-hour urinary calcium and abdominal x-ray or ultrasound are no longer recommended (Table 39.2).
Surgical treatment Parathyroid surgery is a reasonable option for all patients with PHPT since the disease is cured when the abnormal parathyroid tissue is removed. All patients with specific signs or symptoms of PHPT, namely those who are symptomatic, should undergo parathyroidectomy [55]. The shift of the clinical profile of the PHPT from a symptomatic disorder towards an asymptomatic one has raised the question as to whether surgery should be recommended also in these cases. In 1990, guidelines for surgery were established by the NIH Consensus Development Conference on the Management of Asymptomatic Primary Hyperparathyroidism [50]. These guidelines were revised in 2002 [56] and, most recently, in 2008 at the Third International Workshop on the
Osteoporosis in Men
472
Table 39.2 Comparison of new and old management guidelines for patients with asymptomatic PHPT who do not undergo parathyroid surgery Measurement
1990
2002
2008
Serum calcium
Biannually
Biannually
Annually
24-h urinary calcium
Annually
Not recommended
Not recommended
Creatinine clearance (24-h urine collections)
Annually
Not recommended
Not recommended
Serum creatinine
Annually
Annually
Annually
Bone density
Annually (forearm)
Annually (3 sites)
Every 1–2 years (3 sites)a
Not recommended
Not recommended
Abdominal x-ray (ultrasound) Annually
a This recommendation acknowledges country-specific advisories as well as the need for more frequent monitoring if the clinical situation is appropriate. With permission from [54]
Table 39.3 Comparison of new and old guidelines for parathyroid surgery in asymptomatic PHPTa Measurement
1990
2002
2008
Serum calcium (upper limit 1–1.6 mg/dl of normal) (0.25– 0.4 mmol/L)
1.0 mg/dl (0.25 mmol/L)
1.0 mg/dl (0.25 mmol/L)
24-h urine for calcium Creatinine clearance (calculated) BMD
400 mg/d (10 mmol/d) Reduced by 30%
400 mg/d (10 mmol/d) Reduced by 30%
Not indicatedb Reduced to 60 ml/min
Z-score 2.0 in forearm
T-score 2.5 at any sitec
Age (years)
50
50
T-score 2.5 at any sitec and/or previous fracture fragilityd 50
a
Surgery is also indicated in patients for whom medical surveillance is neither desired nor possible. Some physicians still regard 24-h urinary calcium excretion 400 mg as an indication for surgery. c Lumbar spine, total hip, femoral neck, or 33% radius (1/3 site). This recommendation is made recognizing that other skeletal features may contribute to fracture risk in PHPT and that the validity of this cut-point for any site vis-à-vis fracture risk prediction has not been established in PHPT. d Consistent with the position established by the International Society for Clinical Densitometry, the use of Z-scores instead of T-scores is recommended in evaluating BMD in premenopausal women and men younger than 50 years. With permission from [54] b
Management of Asymptomatic Primary Hyperparathyroidism [54] (Table 39.3). According to the Guidelines, all patients with symptomatic disease are advised to have parathyroidectomy. Asymptomatic patients are advised to have surgery if they meet any one of the following criteria:
age 50 years serum calcium 1 mg/dl above the upper limit of normal creatinine clearance 60 ml/min T-score at the lumbar spine, total hip, femoral neck or distal third of radius 2.5 previous fragility fracture.
l l l l
l
Surgery is also indicated in patients in whom medical surveillance is neither desired nor possible. Compared with earlier guidelines, hypercalciuria (in the absence of
nephrolithiasis or nephrocalcinosis) is no longer regarded as an indication for parathyroidectomy, since hypercalciuria per se has not been shown to be a specific risk factor for kidney stone formation in patients with PHPT. Nonetheless, a 24-h urinary calcium measurement should be initially obtained in order to exclude FHH. It is important to bear in mind that these recommendations are guidelines; they are not rules. Whether or not, they are to be followed depends on both the physician and the patient. Some physicians will recommend surgery in all asymptomatic patients whether they meet a guideline for surgery or not. Similarly, some asymptomatic patients will seek surgery because they do not want to live with a curable disease. On the other hand, there are patients who, despite meeting one or more criteria for surgery, will opt for a non-surgical approach.
C h a p t e r 3 9 Primary Hyperparathyroidism in Men
473
l
20 Lumbar spine 15 10
Following successful parathyroidectomy, serum calcium and PTH promptly return in the normal range and the patient is cured. Markers of bone resorption rapidly decline, whereas indices of bone formation decline more gradually within 6 months. BMD at the lumbar spine and femoral neck increases, with the greatest increment in the first postoperative year [62, 63] (Figure 39.6). The rapid increase in BMD is most likely related to the remineralization of the enlarged remodeling space. BMD also increases at the distal radius, but this occurs more slowly. Positive changes in BMD are also observed in patients with mild asymptomatic PHPT who do not meet surgical guidelines [53]. Men and premenopausal women are likely to show a greater increase in lumbar spine BMD after parathyroidectomy than postmenopausal women [64]. This suggests that sex hormones can influence the extent of postoperative BMD recovery. The question of whether postoperative improvement of BMD is associated with increased bone strength and decreased fracture risk remains to be clarified. Two Danish cohort studies by Vestergaard et al have shown a reduction in fracture incidence at all sites within 10 years after parathyroidectomy, both in patients with or without previous
*
*
*
*
*
*
*
*
*
*
*
* *
0 20 Femoral neck
*
15 * *
10
* *
*
*
*
*
*
*
*
*
*
* 5 0 20 Radius
15 10 5
Clinical course after surgery
*
*
5
Change in bone mineral density (%)
Parathyroid surgery requires an experienced endocrine surgeon. Up to a few years ago, the most widely used approach was a full exploration of the neck with the identification of all four parathyroid glands and removal of the abnormal one(s). The knowledge that a single parathyroid adenoma is the most likely cause of PHPT, together with recent advances in preoperative imaging modalities and development of a rapid, intraoperative PTH assay, has led to other, less invasive surgical procedures [57]. MIP with intraoperative measurement of serum PTH after removal of the parathyroid adenoma has become the preferred procedure [58]. This operation can be performed under local or cervical block anesthesia with conscious sedation. Another more recent surgical approach is endoscopic parathyroidectomy with immediate preoperative administration of sestamibi and use of a gamma probe to help to locate the abnormal parathyroid gland during the surgery [59]. With either of these newer techniques, a fall greater that 50% of serum PTH into the normal range after parathyroidectomy indicates that all the abnormal parathyroid tissue has been removed and the operation is terminated [57]. When this drop in PTH does not occur, the operation is converted to a full neck exploration. The advantages of MIP consist in a shorter operating time and a more rapid recovery, especially when performed under local anesthesia. When performed by experienced surgeons, cure (90–95%) and the complication rate (1–3%) using MIP are similar to the standard fourgland exploration [60,61].
0
* *
*
1 2 n � 46
*
3
*
4
*
*
*
*
*
*
*
*
*
*
5 6 7 8 9 10 11 12 13 14 15 38 24 15 Years of follow-up
Figure 39.6 Mean (SEM) changes in BMD at three sites in patients with PHPT after parathyroidectomy. Data shown are cumulative percent changes from surgery at each site after 1–15 years of follow up. *, P 0.05, compared with baseline. (With permission from 49).
fractures [24,65]. More data are needed before a definitive conclusion on this important matter can be reached. The rate of kidney stone formation decreases markedly after parathyroidectomy, in those who had formed stones while their hyperparathyroidism was present, even though a small percentage (5–10%) of patients continues to form stones after surgery [32]. Although some studies have shown neurocognitive symptoms to improve after successful parathyroidectomy, randomized prospective studies are needed to clarify this point [66]. When hypertension is associated with PHPT it does not seem to improve after surgery.
Osteoporosis in Men
Medical management There are medical options for patients who do not meet surgical criteria for parathyroidectomy or are unable or unwilling to undergo surgery [67]. As previously noted, although the disease remains stable for up a decade, stability is not indefinite and a certain proportion of patients may develop criteria for surgery during follow up. Thus, medical monitoring is required in patients who are not to undergo para thyroid surgery. Patients should be encouraged to maintain an adequate intake of calcium and vitamin D because low calcium diet and vitamin D insufficiency can worsen the hyperparathyroid state. While more specific approaches have been studied in PHPT, they still must be regarded to be in their developmental stages. Oral phosphate may decrease serum calcium by 0.5–1.0 mg/dl. Because of gastrointestinal intolerance and
5.5
* *
3.5
1.5
0.5
Alendronate 12 and 24 months
�7.5
7.5
Percent change from baseline
7.5
*
A
C Alendronate 12 and 24 months
5.5
3.5
1.5
0.5
�7.5
†
†
Placebo 12 month, then Alendronate 12 months
Percent change from baseline
Percent change from baseline
7.5
risk of ectopic calcification, oral phosphate is no longer recommended as long-term treatment [67]. In postmenopausal women, estrogen therapy can be considered, particularly if they have climacteric symptoms. Estrogen use can lower total serum calcium (0.5–1.0 mg/dl), but PTH levels do not change. BMD improves at the lumbar spine and femoral neck [68]. The advantage of long-term use of estrogen needs to be considered with regard to the associated risks. Preliminary data suggest that raloxifene, a selective estrogen receptor modulator, may have similar effects on serum calcium levels, but the results are preliminary [69]. Bisphosphonates have been used as a medical approach to patients with PHPT. Early studies with first-generation bisphosphonates (etidronate and clodronate) were disappointing. Short-term studies have been performed with pamidronate and risedronate. Of all the bisphosphonates, alendronate has been most extensively studied. Rossini et al
B Alendronate 12 and 24 months
Placebo 12 month, then Alendronate 12 months
5.5 * 3.5 * 1.5
0.5
�7.5
7.5
Placebo 12 month, then Alendronate 12 months Percent change from baseline
474
D Alendronate 12 and 24 months
Placebo 12 month, then Alendronate 12 months
5.5
3.5
1.5
0.5
�7.5
Figure 39.7 Effect of alendronate on (A) lumbar spine, (B) total hip, (C) femoral neck and (D) one third distal radius BMD. *, Significantly higher than baseline (P 0.001); †, significantly higher than baseline (P 0.05). (With permission from [72]).
C h a p t e r 3 9 Primary Hyperparathyroidism in Men l
475
these placebo-treated patients were crossed over to alendronate treatment, they experienced the same increase in BMD relative to control as did the subjects who received alendronate initially. A more targeted approach is the use of calcimimetics, allosteric modulators of the calcium sensing receptor [73]. The resulting enhanced binding of calcium to the calcium sensing receptor leads to an increase in intracellular calcium and subsequent reduction in PTH synthesis and secretion. The serum calcium falls. In a multicenter, double-blind, placebo-controlled study, Peacock et al reported that most patients (73%) treated with cinacalcet, a second-generation calcimimetic, achieved stable normocalcemia, which was maintained over the entire 52-week follow up [74,75]. By week 52, only a modest reduction in PTH concentration (7.6%) was observed in the treated group, but this change was significant compared to the 7.7% increase of PTH levels in the placebo group. There was no change in urinary calcium excretion. Biochemical markers of bone turnover increased within the normal range in patients treated with cinacalcet compared to placebo. Urinary deoxypyridinoline increased in the cinacalcet group but, at one year, it was not significantly higher than in the placebo group. Conversely, in the placebo group, there was no change in any biochemical marker of bone metabolism. BMD did not change in either treatment or placebo groups. Adverse events were mild to moderate, the most frequent being nausea. Three cinacalcettreated patients developed hypocalcemia. Forty-five patients were followed in a 5-year open-label extension of this study (Figure 39.8) [75]. During this time, serum calcium
evaluated 26 elderly women who were randomly assigned either to placebo or alendronate 10 mg daily for 2 years [70]. Bone turnover markers decreased in the women given alendronate and remained suppressed for the entire followup period. Lumbar spine, total hip and total body BMD increased compare to baseline (8.6, 4.8 and 1.2%, respectively). A transient (first 3–6 months) decrease of serum calcium, phosphate and urinary calcium was also noted, whereas serum PTH significantly increased during the first year. In a double-blind, randomized clinical trial in 40 postmenopausal women, Chow et al [71] compared alendronate (10 mg/day) and placebo for 48 weeks. Active treatment was associated with significant greater mean changes of BMD at the lumbar spine and femoral neck. Alendronate was effective in decreasing serum calcium and bone turn over markers. Serum calcium decreased with alendronate but not with placebo. However, 6 months after treatment, BMD increase was maintained only at the femur. Similar BMD changes have been observed by Khan et al [72], who performed a multicenter randomized, single cross-over trial in 44 patients with PHPT, including nine men, given either placebo or alendronate (10 mg/day) (Figure 39.7). After 12 months, patients taking placebo were crossed over to active treatment with alendronate. After 2 years, alendronate was associated with a significant increase in lumbar spine BMD as compared to baseline. Total hip BMD increased at 12 months and remained stable in the following year. BMD at the one-third distal radius site did not change. There was no significant change in BMD at any of the three sites of measurement in the placebo group after 12 months. When 11.5 Placebo, n = 24
Cinacalcet, n = 21
Serum calcium (mg/dL)
11.0 10.5 10.0 9.5 9.0 8.5 Double-blind 8.0
B48 1624 36
Open-label
52 64 76 90 104 118 132 146 160 174 188 202 216 230 244 258 272 286
Study week B = Baseline of initial double-blind study Normal range (8.4–10.3 mg/dL) shaded n’s represent the number of subjects at baseline; 30 subjects completed ≥ 5 years
Figure 39.8 Sustained normalization of hypercalcemia during calcimimetic (Cinacalcet) therapy in PHPT (open circles: placebo; filled circles: Cinacalcet). Data are expressed as the mean SE. (Reproduced from J Bone Miner Res 2006;21:S38 with permission of the American Society for Bone and Mineral Research).
476
Osteoporosis in Men
was maintained in the normal range in most patients but again BMD did not change. Additional studies have provided further evidence for the effectiveness of cinacalcet hydrochloride in parathyroid cancer [76] and in severe intractable PHPT [77].
11.
12.
Summary Most aspects of PHPT present without major differences between men and women. The predominance of the disease in postmenopausal women may reflect the actions of estrogen to oppose the actions of parathyroid hormone. When this effect is lost, at the time of the menopause, the hyperparathyroid state, presumably present subclinically, becomes manifest. This formulation is consistent with the epidemiology of PHPT occurring most often in the first decade after the menopause. Since the biochemical and densitometric aspects of the disease as well as its natural history are similar between men and women, the guidelines for surgery are similar between the sexes.
References 1. J.P. Bilezikian, Primary hyperparathyroidism. in: L. DeGroot, A. Arnold (Ed.), section editor www.ENDOTEXT.org (January 1, 2007 version), MDTEXT, Inc., South Dartmouth, MA. 2. O. Cope, The study of hyperparathyroidism at the Massachusetts General Hospital, N. Engl. J. Med. 274 (21) (1966) 1174–1182. 3. H. Heath III, S.F. Hodgson, M.A. Kennedy, Primary hyperparathyroidism. Incidence, morbidity, and potential economic impact in a community, N. Engl. J. Med. 302 (4) (1980) 189–193. 4. L.E. Mallette, J.P. Bilezikian, D.A. Heath, G.D. Aurbach, Hyperparathyroidism: a review of 52 cases, Medicine 53 (2) (1974) 127–147. 5. S.J. Silverberg, E.M. Lewiecki, L. Mosekilde, M. Peacock, M.R. Rubin, Presentation of asymptomatic primary hyperparathyroidism: proceedings of the third international workshop, J. Clin. Endocrinol. Metab. 94 (2) (2009) 351–365. 6. R.A. Wermers, S. Khosla, E.J. Atkinson, et al., Incidence of primary hyperparathyroidism in Rochester, Minnesota, 1993– 2001: an update on the changing epidemiology of the disease, J. Bone Miner. Res. 21 (1) (2006) 171–177. 7. S. Adami, C. Marcocci, D. Gatti, Epidemiology of primary hyperparathyroidism in Europe, J. Bone Miner. Res. 17 (Suppl. 2) (2002) N18–N23. 8. B.S. Miller, J. Dimick, R. Wainess, R.E. Burney, Age- and sex-related incidence of surgically treated primary hyperpara thyroidism, World J. Surg. 32 (5) (2008) 795–799. 9. T. Carling, J. Rastad, A. Kindmark, E. Lundgren, S. Ljunghall, G. Akerstrom, Estrogen receptor gene polymorphism in postmenopausal primary hyperparathyroidism, Surgery 122 (6) (1997) 101–105 discussion 106. 10. C. Joborn, S. Ljunghall, K. Larsson, et al., Skeletal responsiveness to parathyroid hormone in healthy females: relationship
13.
14. 15.
16.
17.
18.
19.
20.
21.
22.
23.
24.
25.
26.
27.
to menopause and oestrogen replacement, Clin. Endocrinol. (Oxf). 34 (5) (1991) 335–339. G. Wells, P. Tugwell, B. Shea, et al., Meta-analyses of therapies for postmenopausal osteoporosis. V. Meta-analysis of the efficacy of hormone replacement therapy in treating and preventing osteoporosis in postmenopausal women, Endocr. Rev. 23 (4) (2002) 529–539. S.J. Marx, Molecular genetics of multiple endocrine neoplasia types 1 and 2, Nat. Rev. 5 (5) (2005) 367–775. J.D. Carpten, C.M. Robbins, A. Villablanca, et al., HRPT2, encoding parafibromin, is mutated in hyperparathyroidismjaw tumor syndrome, Nat. Genet. 32 (4) (2002) 676–680. E.M. Brown, Clinical lessons from the calcium-sensing receptor, Nat. Clin. Pract. 3 (2) (2007) 122–133. A. Arnold, T.M. Shattuck, S.M. Mallya, et al., Molecular pathogenesis of primary hyperparathyroidism, J. Bone Miner. Res. 17 (Suppl. 2) (2002) N30–N36. C. Marcocci, F. Cetani, M.R. Rubin, S.J. Silverberg, A. Pinchera, J.P. Bilezikian, Parathyroid carcinoma, J. Bone Miner. Res. 23 (12) (2008) 1869–1880. S.J. Silverberg, E. Shane, L. de la Cruz, et al., Skeletal disease in primary hyperparathyroidism, J. Bone Miner. Res. 4 (3) (1989) 283–291. J.M. Hock, J.M. Canalis, L.G. Raisz, Parathyroid hormone: anabolic and catabolic on bone and interactions with growth factors, (2001). M. Parisien, R.W. Mellish, S.J. Silverberg, et al., Maintenance of cancellous bone connectivity in primary hyperparathyroidism: trabecular strut analysis, J. Bone Miner. Res. 7 (8) (1992) 913–919. S.J. Silverberg, F.G. Locker, J.P. Bilezikian, Vertebral osteopenia: a new indication for surgery in primary hyperpara thyroidism, J. Clin. Endocrinol. Metab. 81 (11) (1996) 4007–4012. D.W. Dempster, R. Muller, H. Zhou, et al., Preserved threedimensional cancellous bone structure in mild primary hyperparathyroidism, Bone 41 (1) (2007) 19–24. S. Khosla, L.J. Melton 3rd, R.A. Wermers, C.S. Crowson, W. O’Fallon, B. Riggs, Primary hyperparathyroidism and the risk of fracture: a population-based study, J. Bone Miner. Res. 14 (10) (1999) 1700–1707. P. Vestergaard, C.L. Mollerup, V.G. Frokjaer, P. Christiansen, M. Blichert-Toft, L. Mosekilde, Cohort study of risk of fracture before and after surgery for primary hyperparathyroidism, Br. Med. J. 321 (7261) (2000) 598–602. P. Vestergaard, L. Mosekilde, Fractures in patients with primary hyperparathyroidism: nationwide follow-up study of 1201 patients, World J. Surg. 27 (3) (2003) 343–349. R.J. Wilson, S. Rao, B. Ellis, M. Kleerekoper, A.M. Parfitt, Mild asymptomatic primary hyperparathyroidism is not a risk for vertebral fractures, Ann. Intern. Med. 109 (12) (1988) 959–962. K. Larsson, E. Lindh, L. Lind, I. Persson, S. Ljunghall, Increased fracture risk in hypercalcemia: bone mineral content measured in hyperparathyroidism, Acta. Orthop. Scand. 60 (3) (1989) 268–270. S.D. De Geronimo, E. Romagnoli, D. Diacinti, E. D’Erasmo, S. Minisola, The risk of fractures in postmenopausal women with primary hyperparathyroidism, Eur. J. Endocrinol. 155 (3) (2006) 415–420.
C h a p t e r 3 9 Primary Hyperparathyroidism in Men l
28. K. Larsson, S. Ljunghall, U.B. Krusemo, T. Naessen, E. Lindh, I. Persson, The risk of hip fractures in patients with primary hyperparathyroidism: a population-based cohort study with a follow-up of 19 years, J. Intern. Med. 234 (6) (1993) 585–593. 29. H. Kaji, M. Yamauchi, K. Chihara, T. Sugimoto, The threshold of bone mineral density for vertebral fractures in female patients with primary hyperparathyroidism, Eur. J. Endocrinol. 153 (3) (2005) 373–378. 30. E. Vignali, G. Viccica, D. Diacinti, F. Cetani, L. Cianferotti, E. Ambrogini, C. Banti, R. Del Fiacco, J.P. Bilezikian, A. Pinchera, C. Marcocci, Morphometric vertebral fractures in postmenopausal women with primary hyperparathyroidism, J. Clin. endocrinol. Metab. 94 (7) (2009) 2306–2312. 31. M. Di Monaco, F. Vallero, R. Di Monaco, F. Mautino, A. Cavanna, Primary hyperparathyroidism in elderly patients with hip fracture, J. Bone Miner. Metab. 22 (5) (2004) 491–495. 32. C.L. Mollerup, P. Vestergaard, V.G. Frokjaer, L. Mosekilde, P. Christiansen, M. Blichert-Toft, Risk of renal stone events in primary hyperparathyroidism before and after parathyroid surgery: controlled retrospective follow up study, Br. Med. J. 325 (7368) (2002) 807. 33. A. Scillitani, V. Guarnieri, C. Battista, et al., Primary hyperparathyroidism and the presence of kidney stones are associated with different haplotypes of the calcium-sensing receptor, J. Clin. Endocrinol. Metab. 92 (1) (2007) 277–283. 34. M.L. Brandi, R.F. Gagel, A. Angeli, et al., Guidelines for diagnosis and therapy of MEN type 1 and type 2, J. Clin. Endocrinol. Metab. 86 (12) (2001) 5658–5671. 35. M.A. Bess, A.J. Edis, J.A. van Heerden, Hyperparathyroidism, and pancreatitis. Chance or a causal association?, J. Am. Med. Assoc. 243 (3) (1980) 246–247. 36. M.R. Rubin, M.S. Maurer, D.J. McMahon, J.P. Bilezikian, S.J. Silverberg, Arterial stiffness in mild primary hyperparathyroidism, J. Clin. Endocrinol. Metab. 90 (6) (2005) 3326–3330. 37. D.S. Rao, G. Agarwal, G.B. Talpos, et al., Role of vitamin D and calcium nutrition in disease expression and parathyroid tumor growth in primary hyperparathyroidism: a global perspective, J. Bone Miner. Res. 17 (Suppl. 2) (2002) N75–N80. 38. S.J. Silverberg, J.P. Bilezikian, ‘Incipient’ primary hyperparathyroidism: a ‘forme fruste’ of an old disease, J. Clin. Endocrinol. Metab. 88 (11) (2003) 5348–5352. 39. H. Lowe, D.J. McMahon, M.R. Rubin, J.P. Bilezikian, S.J. Silverberg, Normocalcemic primary hyperparathyroidism: further characterization of a new clinical phenotype, J. Clin. Endocrinol. Metab. 92 (8) (2007) 3001–3005. 40. R. Eastell, A. Arnold, M.L. Brandi, et al., Diagnosis of asymptomatic primary hyperparathyroidism: proceedings of the third international workshop, J. Clin. Endocrinol. Metab. 94 (2) (2009) 340–350. 41. P. Gao, S. Scheibel, P. D’Amour, et al., Development of a novel immunoradiometric assay exclusively for biologically active whole parathyroid hormone 1–84: implications for improvement of accurate assessment of parathyroid function, J. Bone Miner. Res. 16 (4) (2001) 605–614. 42. J.C. Souberbielle, P. Boudou, C. Cormier, Lessons from second- and third-generation parathyroid hormone assays in primary hyperparathyroidism, J. Endocrinol. Invest. 31 (5) (2008) 463–469.
477
43. B. Moosgaard, S.E. Christensen, P. Vestergaard, L. Heickendorff, P. Christiansen, L. Mosekilde, Vitamin D metabolites and skeletal consequences in primary hyperparathyroidism, Clin. Endocrinol. (Oxf.) 68 (5) (2008) 707–715. 44. M.F. Holick, Vitamin D status: measurement, interpretation, and clinical application, Ann. Epidemiol. 19 (2) (2009) 73–78. 45. P.D. Miller, J.P. Bilezikian, Bone densitometry in asymptomatic primary hyperparathyroidism, J. Bone Miner. Res. 17 (Suppl. 2) (2002) N98–N102. 46. N.A. Johnson, M.E. Tublin, J.B. Ogilvie, Parathyroid imaging: technique and role in the preoperative evaluation of primary hyperparathyroidism, Am. J. Roentgenol. 188 (6) (2007) 1706–1715. 47. S.J. Silverberg, F. Gartenberg, T.P. Jacobs, et al., Longitudinal measurements of bone density and biochemical indices in untreated primary hyperparathyroidism, J. Clin. Endocrinol. Metab. 80 (3) (1995) 723–728. 48. S.J. Silverberg, E. Shane, T.P. Jacobs, E. Siris, J.P. Bilezikian, A 10-year prospective study of primary hyperparathyroidism with or without parathyroid surgery, N. Engl. J. Med. 341 (17) (1999) 1249–1255. 49. M.R. Rubin, J.P. Bilezikian, D.J. McMahon, et al., The natural history of primary hyperparathyroidism with or without parathyroid surgery after 15 years, J. Clin. Endocrinol. Metab. 93 (9) (2008) 3462–3470. 50. Proceedings of the NIH Consensus Development Conference on diagnosis and management of asymptomatic primary hyperparathyroidism. Bethesda, Maryland, October 29–31, 1990. J. Bone Miner. Res. 6 (Suppl. 2) 1991 S1–S166. 51. D.S. Rao, E.R. Phillips, G.W. Divine, G.B. Talpos, Randomized controlled clinical trial of surgery versus no surgery in patients with mild asymptomatic primary hyperparathyroidism, J. Clin. Endocrinol. Metab. 89 (11) (2004) 5415–5422. 52. J. Bollerslev, S. Jansson, C.L. Mollerup, et al., Medical observation, compared with parathyroidectomy, for asymptomatic primary hyperparathyroidism: a prospective, randomized trial, J. Clin. Endocrinol. Metab. 92 (5) (2007) 1687–1692. 53. E. Ambrogini, F. Cetani, L. Cianferotti, et al., Surgery or surveillance for mild asymptomatic primary hyperparathyroidism: a prospective, randomized clinical trial, J. Clin. Endocrinol. Metab. 92 (8) (2007) 3114–3121. 54. J.P. Bilezikian, A.A. Khan, J.T. Potts Jr., Guidelines for the management of asymptomatic primary hyperparathyroidism: summary statement from the third international workshop, J. Clin. Endocrinol. Metab. 94 (2) (2009) 335–339. 55. R. Udelsman, J.L. Pasieka, C. Sturgeon, J.E. Young, O. H. Clark, Surgery for asymptomatic primary hyperparathyroidism: proceedings of the third international workshop, J. Clin. Endocrinol. Metab. 94 (2) (2009) 366–372. 56. J.P. Bilezikian, J.T. Potts Jr., H. Fuleihan Gel, et al., Summary statement from a workshop on asymptomatic primary hyperparathyroidism: a perspective for the 21st century, J. Bone Miner. Res. 17 (Suppl. 2) (2002) N2–N11. 57. E. Vignali, A. Picone, G. Materazzi, et al., A quick intraoperative parathyroid hormone assay in the surgical management of patients with primary hyperparathyroidism: a study of 206 consecutive cases, Eur. J. Endocrinol. 146 (6) (2002) 783–788.
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Osteoporosis in Men
58. P. Miccoli, P. Berti, G. Materazzi, C.E. Ambrosini, L. Fregoli, G. Donatini, Endoscopic bilateral neck exploration versus quick intraoperative parathormone assay (qPTHa) during endoscopic parathyroidectomy: a prospective randomized trial, Surg. Endosc. 22 (2) (2008) 398–400. 59. H. Chen, E. Mack, J.R. Starling, A comprehensive evaluation of perioperative adjuncts during minimally invasive parathyroidectomy: which is most reliable?, Ann. Surg. 242 (3) (2005) 375–380 discussion 80-83. 60. P. Miccoli, C. Bendinelli, P. Berti, E. Vignali, A. Pinchera, C. Marcocci, Video-assisted versus conventional parathyroidectomy in primary hyperparathyroidism: a prospective randomized study, Surgery 126 (6) (1999) 1117–1121 discussion 21–22. 61. J. Westerdahl, A. Bergenfelz, Unilateral versus bilateral neck exploration for primary hyperparathyroidism: five-year follow-up of a randomized controlled trial, Ann. Surg. 246 (6) (2007) 976–980 discussion 80-81. 62. S.J. Silverberg, F. Gartenberg, T.P. Jacobs, et al., Increased bone mineral density after parathyroidectomy in primary hyperparathyroidism, J. Clin. Endocrinol. Metab. 80 (3) (1995) 729–734. 63. T. Steiniche, P. Christiansen, A. Vesterby, et al., Primary hyperparathyroidism: bone structure, balance, and remodeling before and 3 years after surgical treatment, Bone 26 (5) (2000) 535–543. 64. L. Mosekilde, Primary hyperparathyroidism and the skeleton, Clin. Endocrinol. (Oxf.) 69 (1) (2008) 1–19. 65. P. Vestergaard, L. Mosekilde, Parathyroid surgery is associated with a decreased risk of hip and upper arm fractures in primary hyperparathyroidism: a controlled cohort study, J. Intern. Med. 255 (1) (2004) 108–114. 66. P. Vestergaard, L. Mosekilde, Cohort study on effects of parathyroid surgery on multiple outcomes in primary hyperparathyroidism, Br. Med. J. 327 (7414) (2003) 530–534. 67. A. Khan, A. Grey, D. Shoback, Medical management of asymptomatic primary hyperparathyroidism: proceedings of the third international workshop, J. Clin. Endocrinol. Metab. 94 (2) (2009) 373–381. 68. B.J. Orr-Walker, M.C. Evans, J.M. Clearwater, A. Horne, A.B. Grey, I.R. Reid, Effects of hormone replacement therapy
69.
70.
71.
72.
73. 74.
75.
76.
77.
on bone mineral density in postmenopausal women with primary hyperparathyroidism: four-year follow-up and comparison with healthy postmenopausal women, Arch. Intern. Med. 160 (14) (2000) 2161–2166. J.R. Zanchetta, C.E. Bogado, Raloxifene reverses bone loss in postmenopausal women with mild asymptomatic primary hyperparathyroidism, J. Bone Miner. Res. 16 (1) (2001) 189–190. M. Rossini, D. Gatti, G. Isaia, L. Sartori, V. Braga, S. Adami, Effects of oral alendronate in elderly patients with osteoporosis and mild primary hyperparathyroidism, J. Bone Miner. Res. 16 (1) (2001) 113–119. C.C. Chow, W.B. Chan, J.K. Li, et al., Oral alendronate increases bone mineral density in postmenopausal women with primary hyperparathyroidism, J. Clin. Endocrinol. Metab. 88 (2) (2003) 581–587. A.A. Khan, J.P. Bilezikian, A.W. Kung, et al., Alendronate in primary hyperparathyroidism: a double-blind, randomized, placebo-controlled trial, J. Clin. Endocrinol. Metab. 89 (7) (2004) 3319–3325. E.F. Nemeth, Pharmacological regulation of parathyroid hormone secretion, Curr. Pharm. Des. 8 (23) (2002) 2077–2087. M. Peacock, J.P. Bilezikian, P.S. Klassen, M.D. Guo, S.A. Turner, D. Shoback, Cinacalcet hydrochloride maintains long-term normocalcemia in patients with primary hyperparathyroidism, J. Clin. Endocrinol. Metab. 90 (1) (2005) 135–141. M. Peacock, S. Scumpia, M.A. Bolognese, et al., Long-term control of primary hyperparathyroidism with cinacalcet, J. Bone Miner. Res. 21 (Suppl. 1) (2006) S38. S.J. Silverberg, M.R. Rubin, C. Faiman, et al., Cinacalcet hydrochloride reduces the serum calcium concentration in inoperable parathyroid carcinoma, J. Clin. Endocrinol. Metab. 92 (10) (2007) 3803–3808. C. Marcocci, P. Chanson, D. Shoback, et al., Cinacalcet reduces serum calcium concentrations in patients with intractable primary hyperparathyroidism, J. Clin. Endocrinol. Metab. 94 (8) (2009) 2766–2772.
Chapter
40
Hypercalciuria Murray J. Favus Section of Endocrinology, Diabetes, and Metabolism University of Chicago, Chicago, Illinois, USA
Introduction
is thought to contribute to stone formation by creating a urine supersaturated with respect to Ca and either oxalate or phosphate.
In men, low bone mass and fracture have several etiologies. Primary hyperparathyroidism and other hypercalcemic states are discussed in Chapter 39. Bone loss with hypercalciuria and normal serum calcium may result from primary and secondary hypogonadal states, which are reviewed in Chapter 35. This chapter focuses on idiopathic hypercalciuria (IH), a common cause of low bone mass and the most common cause of Ca oxalate nephrolithiasis. Hypercalciuria was implicated in the pathogenesis of kidney stones in the 1930s when Flocks reported a high frequency of hypercalciuria among stone formers [1]. In the 1950s, Albright and colleagues first described IH as consisting of hypercalciuria, normal serum Ca and the absence of the known systemic hypercalciuric disorders (Table 40.1) [2]. Five percent of men in the adult population have hypercalciuria and, of them, about 10% will form a kidney stone. IH accounts for 50% of all Ca oxalate nephrolithiasis and
Clinical bone disease Fracture is the sole clinical manifestation of low bone mass in IH patients. The frequency of vertebral, hip and non-vertebral fractures in patients with a history of kidney stones is increased compared to non-stone formers and fracture rate increases with time since the initial kidney stone was reported [3]. The study in Olmstead County, Minnesota collected fracture events only on patients listed as stone formers and did not specifically analyze for hypercalciuria. Nevertheless, IH is the most common cause of kidney stone formation and, therefore, it is presumed that the data reflect fracture events in IH patients. Nevertheless, fracture rates in IH stone formers have not been determined. IH stone formers have higher rates of stone formation among first-degree relatives [1], but the frequency and pattern of low bone mass in families of IH stone formers has not been established. Asplin et al [4] followed 11 families of IH patients and documented progressive loss of hip femoral neck bone density over 3 years (Figure 40.1). Hypercalciuria in men increases the risk of osteoporosis, as 10% of adult men and women with osteoporosis have hypercalciuria, but the figure is doubled (20.7%) when just men with osteoporosis are evaluated. Thus, men may present with either low bone mass and are subsequently diagnosed with IH, or they may present with Ca nephrolithiasis and hypercalciuria and are subsequently found also to have low bone mass. Low bone mass may be detected in children at the same frequency as found in adults [5–7], suggesting that hypercalciuria is life-long. As described, the early onset of hypercalciuria may have an important impact on normal skeletal mineralization, however, skeletal growth and development in
Table 40.1 Systemic disorders of hypercalciuria with normal serum calcium: serum 1,25D levels and intestinal Ca absorption Disorder
1,25-D
ICaA
Bone mass
Cushing’s disease Furosemide Granulomatous disorders Hyperthyroidism Idiopathic hypercalciuria Immobilization Malignancy with bone metastasis Paget disease of bone Renal tubular acidosis Sarcoidosis
N ? N or I N or L N or I N N or L
L ? N-I L I N N
N-L ? N-L N-L N-L L N-L
N N or L N or I
N N-L N-I
N L N-L
1,25D: serum 1,25(OH)2D level; IcaA: intestinal Ca absorption; N: normal;I: increased; L: low; ?: no measures available. Osteoporosis in Men
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Change in neck z-score
Change in neck z-score
3 2 1 0 �1 �2
0 100 200 300 400 500 600 700 800 900
Urine calcium (mg/day)
1
0
�1
�2
0 100 200 300 400 500 600 700 800 900
Urine calcium (mg/day)
Figure 40.1 Change in BMD Z-score over 3 years in men and women with IH and their first-degree relatives is inversely correlated with initial urine Ca excretion for hip femoral neck (left panel, r 0.37, P 0.02) and lumbar spine (right panel, r 0.28, P 0.08). The ellipses contain one SD. (Reprinted with permission from Asplin et al [4] and Kidney International).
the children and adolescents is not impaired. Hypercalciuria due to a number of specific genetic defects [8] has been described in a number of families, but these are in the aggregate rare and account for only a small portion of IH. Bushinsky and colleagues [9–15] have created a colony of rats that have hypercalciuria, Ca kidney stones and low bone mass. The genetic hypercalciuric stone-forming (GHS) rats demonstrate that hypercalciuria and low bone mass can have genetic origins.
Definition of hypercalciuria Urine Ca excretion in a population of healthy adults follows a non-Gaussian distribution with most values clustered around the mean and a long tail of high values. Hypercalciuria is defined as those values above an arbitrary upper limit of normal that encompasses the long tail of high Ca excretions. Hypercalciuria can be defined in men using one or more of the following criteria: greater than 300 mg per 24 h; greater than 140 mg Ca per g urine creatinine which adjusts Ca excretion to lean body mass; and greater than 4.0 mg Ca per kg body weight [16]. High urine Ca may falsely be reported as low because of errors in sample collection, lack of an effective preservative and poor quality control of analytical techniques. Individual variation in urine Ca excretion is in part due to age, body weight and dietary composition of Ca, phosphate, sodium, protein and carbohydrates. Therefore, collecting the sample under known conditions is essential for correct interpretation. The diagnosis of hypercalciuria is based on the level of urine Ca excretion determined while the subject is at a steady state Ca intake. Some protocols advocate measuring urine Ca while ingesting a fixed Ca intake, such as a low Ca intake of 400 mg per day [17]. However, changing Ca intake may require days to weeks until a new steady state is reached and measurement of urine Ca during non-steady state conditions
could underestimate urine Ca excretion. Our practice at the University of Chicago Kidney Stone Clinic and Bone Clinic is to measure 24-hour urine Ca excretion while subjects are ingesting their usual diet and at least 2 weeks after Ca tablets and supplements have been discontinued. As there is good agreement between two 24-hour collections obtained on consecutive days, a single 24-hour urine collection may be sufficient for evaluating patients with low bone mass. Some investigators have suggested that IH be classified as absorptive, resorptive or renal leak [18, 19]. Ingestion of a low Ca diet (400 mg Ca per day for one week) that results in lowering of fasting urine Ca/creatinine below 0.11 or reduction in 24-hour urine Ca to the normal range is diagnostic of hypercalciuria that arises from an isolated increase in intestinal Ca absorption (absorptive hypercalciuria). Persistent high urine Ca excretion during low Ca intake is not compatible with a pure intestinal over-absorption of Ca and indicates some portion of the excess urine Ca arising from bone resorption. Decreased renal tubular Ca reabsorption (‘renal Ca leak’) cannot by itself sustain hypercalciuria and so must be accompanied by either high intestinal Ca absorption, increased bone resorption or both. Resorptive hypercalciuria has been used to describe patients who exhibit primarily increased bone resorption. However, intestinal Ca hyperabsorption, decreased renal tubule Ca reabsorption and bone resorption may occur simultaneously and so may be called renal leak or resorptive hypercalci uria. In GHS rats, intestinal Ca over-absorption, increased bone resorption and decreased renal tubule Ca reabsorption all occur simultaneously due to over-expression of the vitamin D receptor (VDR) in the target tissues [14, 15, 20–22].
Serum 1,25D levels 1,25D plays a pivotal role in the pathogenesis of IH. Elevated serum 1,25D levels are found in one-half to two-thirds of
C h a p t e r 4 0 Hypercalciuria
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l
Low calcium diet 160 mg/day
Low normal calcium diet 372 mg/day
Normal calcium diet 880 mg/day
640
640
480
480
320
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0
0
–160
–160
–320
–320 Net Urine Calcium absorption calcium balance
Net Urine absorption calcium
Calcium balance
Net Urine Calcium absorption calcium balance
Figure 40.2 Intestinal Ca absorption, urine Ca excretion and Ca balance in non-stone forming healthy men receiving either 1,25(OH)2D3 (hatched bars) or controls (open bars) at either low Ca, low-normal Ca or normal Ca diet. Values are mean SEM for six men per group. For Ca balance, values above the horizontal line indicate positive balance and below the line indicate negative balance. Values are from [29, 30]. (Reprinted with permission from Coe FL, Parks JH Nephrolithiasis: pathogenesis and treatment, 2nd edn, 1988. Year Book Publishers, Chicago [31]).
IH patients [23]. Elevated serum 1,25D levels are due to increased renal synthesis with normal metabolic clearance rate [24, 25]. The mechanism for the pathologic over-activity of the renal proximal tubule 25-hydroxy-1a-hydroxylase (1-OHase) is not known, but the absence of the normal suppression of the 1-OHase by high Ca intake has been described [17, 24]. One-third of IH patients have low serum P due to decreased renal proximal tubule P reabsorption [24, 26, 27]. An inverse correlation between serum P and 1,25D levels [26, 28] suggests that serum P could be the stimulus for 1,25D overproduction in some IH patients. As high Ca intake used by Broadus [24] was associated with a decrease in tubular P reabsorption, regulation of the 1-OHase in IH patients may be driven by both low P and other factors that have yet to be identified. The administration of low doses of 1,25(OH)2D3 to healthy volunteers [29, 30] in doses insufficient to cause hypercalcemia, increased intestinal Ca absorption, decreased renal tubule Ca reabsorption and reduced Ca balance from positive or neutral and to negative balance during a period of low Ca intake (Figure 40.2). Thus, even a modest excess of 1,25D can create all of the metabolic changes in Ca metabolism found
in IH. The negative Ca balance during low dose 1,25D administration strongly suggests that habitual 1,25D overproduction, as occurs in some patients with IH, can cause bone loss.
Relationship between urine Ca and bone loss A variety of non-invasive techniques have been used to quantify bone density in IH patients, however dual energy x-ray absorptiometry (DXA), which measures bone mineral density (BMD) at the lumbar spine, proximal femur and forearm, has been used most extensively. DXA scans are highly sensitive to small changes in BMD and are sufficiently reproducible to track changes in bone mass over time (see Chapter 43). Low BMDs in IH patients could be due to the effects of chronic urine Ca loss and the tendency toward negative Ca balance. However, IH is inherited in a pattern consistent with a polygenic trait, therefore low BMD could be due to genetic influences independent of hypercalciuria.
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IH. The results suggest that low Ca intake in stone formers but not non-stone formers predicts low bone mass, bone loss and increased fracture risk. Additional evidences for a pathogenic role of Ca excretion in the development of low bone mass is the observation that patients with fasting hypercalciuria or persistent hypercalciuria during dietary Ca restriction are more likely to have bone loss [28, 35–38]. Further, thiazide administration lowers urine Ca excretion and increases or stabilizes bone density [39–41]. Thus, the weight of evidence strongly supports a key role for high urine Ca excretion in the development of low BMD.
In an attempt to separate the contributions of genetic factors and hypercalciuria, Asplin et al [32] measured BMD in IH stone formers and their non-stone-forming hypercalciuric and normocalciuric first-degree relatives and found that lumbar spine and hip femoral neck Z-scores (age- and sex- adjusted standard deviations) varied inversely with urine Ca excretion in stone formers but not in non-stone formers (Figure 40.3). Over a 3-year follow up, IH subjects with the highest urine Ca excretion rates lost bone at the hip femoral neck more rapidly than non-stone formers from the same families [4]. Giannini et al [33] found that in 241 women with osteoporosis and hypercalciuria, elevated urine Ca excretion accounted for 50% of the variance in lumbar spine BMD. No similar calculation of urine calcium and bone mass has been made for men, thus, the low bone density in IH appears to be influenced by both the magnitude of the hypercalciuria and as yet unidentified genetic factors. In a cross-sectional study that used NHANES II epidemiologic data, male stone formers had lower hip BMD than men without a kidney stone history [34]. Men with a kidney stone history were more likely to report wrist and spine fractures. The difference in BMD between male stone formers and non-stone formers was observed only at lower Ca intake as estimated by level of milk consumption. While the NHANES database did not include measurements of urine Ca excretion, a considerable portion of the stone formers would be expected to have
Bone pathogenesis Macroscopic Structure Standard radiographs in IH men may reveal osteopenia of the vertebrae and/or long bones, but there is no specific pattern of mineralization of trabecular or cortical bone that specifically suggests IH bone disease. Radiographs may be normal for those with more mild reductions in BMD. Bone loss more commonly involves thoracic and lumbar vertebrae, which are predominately composed of high turnover trabecular bone. BMD of the lumbar spine may be normal or reduced in IH stone formers compared to age matched non-stone formers and to IH patients who have not formed
600
Urinary calcium, mg/day
500
400
300
200
100
–200
–100
0
100
200
300
400
500
600
Net intestinal clacium absorption, mg/day
Figure 40.3 Urine Ca excretion as a function of net intestinal Ca absorption based upon individual six-day external balance studies on 51 IH patients (open circles). Solid lines define the 95% confidence limits about the mean calculated from 195 adult non-stone formers (controls) who also underwent Ca balance. Patients and controls were studied while ingesting a stable Ca intake. The dashed line is the line of identity at which urine Ca excretion is equal to net intestinal Ca absorption. Values above and below the dashed line indicates negative and positive Ca balance, respectively. (Adapted from Asplin et al [23]).
C h a p t e r 4 0 Hypercalciuria l
stones. BMD of the femoral neck may also be reduced either as an isolated finding or along with reduced lumbar spine BMD [28, 37, 38, 42–56]. The cortical-rich midradius BMD is also reduced in some IH patients [44, 48]. Bone structural features associated with fracture risk, such as length of the femoral neck, femoral neck cross-sectional area and the calculated finite element, have not been measured.
Histomorphometry Reduction in bone formation is the most consistent finding from the relatively small number of bone biopsy samples obtained from IH men [57–60]. The bone biopsy data do not suggest a homogeneous process as bone resorption has been reported as normal or increased and mineral apposition rates are reduced. The histomorphometric changes in IH bone disease differ from other common metabolic bone diseases (Table 40.2) and should viewed as separate from osteoporosis. There is a discrepancy between the rate of bone turn over from histomorphometric parameters and bone turnover rates from bone marker measurements. Modest to moderate increases in bone formation and resorption markers are in contrast to histomorphometric changes which describe low bone turnover in the range found in postmenopausal osteoporosis. Elevated urine hydroxyproline excretion, suggestive of accelerated bone resorption, has been found in some studies [28, 36, 37, 45, 49, 61] but not in others [4, 32]. As a result, correlation between BMD and bone turnover markers has been weak. Serum bone-specific alkaline phosphatase (BSAP) levels are also increased in some patients [37, 45, 62], especially those with fasting hypercalciuria or who remain hypercalciuric during low Ca intake. Bone markers in patients with absorptive hypercalciuria tend
Table 40.2 Bone histomorphometric changes in formation and resorption in IH patients compared to other metabolic bone diseases Bone parameter
IH
PMO
HMO
HPT
GIO
OM
Formation Mineral apposition rate Mineralization lag time Osteoid volume Osteoblast activity Resorption
D Del
I I
D D
I I
D D
D D
P
I
N
P
N
P
N-I D
N I
N D
I I
N-D D
I I
N-I
I
I
I
I
I
PMO: postmenopausal osteoporosis; HMO: hypogonadal male osteoporosis; HPT: primary hyperparathyroidism; GIO: glucocorticoid-induced osteoporosis; OM: osteomalacia; N: normal; I: increased; D: decreased; Del: delayed; P: Prolonged.
483
to have levels that are not different than normocalciuric controls [49, 57, 58, 63].
Calcium metabolism Biochemical Tests Fasting serum Ca measured as either total or the ionized fraction is always normal in IH. Serum parathyroid hormone (PTH) is normal in the majority of subjects, with elevated levels found in less than 5%. Serum phosphorus is low in about 30% of subjects and serum Mg levels are normal. Renal function is generally normal as measured by serum creatinine or by calculated glomerular filtration rate (GFR), although patients with IH and recurrent nephrolithiasis are at risk for reduced GFR. Serum 25-OH-D is generally normal, indicating that vitamin D depletion is not a contributor to the pathogenesis of hypercalciuria.
Ca Balance Using data from Ca metabolic balance studies conducted in 58 IH patients and over 200 normal subjects, the plot of net intestinal Ca absorption versus urine Ca excretion (see Figure 40.3) revealed significantly higher intestinal Ca absorption in IH patients and that urine Ca excretion was even greater than absorption (negative Ca balance). Thus, over a broad range of net intestinal Ca absorption, a majority of IH patients are clearly in negative Ca balance. In normal controls, low dietary Ca intake is associated with reabsorption of filtered Ca and lower urine Ca excretion to maintain neutral or positive Ca balance. However, in 30–50% of IH patients, an inability to reduce urine Ca excretion during low Ca intake results in negative Ca balance [64]. Thus, negative Ca balance is present in patients with IH over a range of dietary Ca intake from high to low.
Intestinal Ca Transport Increased intestinal Ca absorption is found in most IH patients using a variety of techniques, including external mineral balance, fecal Ca isotope recovery and single and dual Ca isotope absorption. Kaplan et al [65] measured serum 1,25D and intestinal Ca absorption measured by fecal Ca-47 after an oral Ca-47 dose in IH patients. Serum 1,25D and Ca absorption were positively correlated in IH patients with high 1,25 D levels. However, at least 30% of subjects had normal serum 1,25D levels, but intestinal Ca absorption was not different than in those with elevated 1,25D. Thus, additional factors in addition to 1,25D must be contributing to the high intestinal Ca absorption. In the GHS rat model of human IH, increased intestinal Ca absorption occurs with normal serum 1,25D levels due to the pathologically elevated intestinal epithelial cell VDR levels [14, 15, 22].
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Osteoporosis in Men
VDR levels have not been measured in intestinal mucosa of IH patients.
Renal Ca Transport In two studies, a greater fraction of filtered load of Ca was excreted in the urine by IH men compared to non-stone formers [66, 67]. Hydrochlorothiazide and acetazolamide administration increased urine Ca, Na and Mg excretion compared to normal controls, suggesting a widespread defect in proximal tubule electrolyte and water transport in IH patients [68]. Recent studies in IH men and women show normal ultrafilterable Ca and postprandial decreases in both proximal and distal nephron Ca reabsorption [69–71]. The defect in renal Ca transport is most evident during low dietary Ca intake, when the physiologic adaptation to reduce urine Ca excretion does not occur in a large portion of IH patients [64]. PTH-mediated Ca transport is likely
not a principal mechanism for the hypercalciuria, as PTH serum levels are normal, not increased. Postprandial proximal Na reabsorption is also reduced which increases distal Ca delivery. Enhanced distal Na reabsorption prevents excess Na excretion, while there is no comparable Ca reabsorption. The molecular basis for the transport defects is not known, but GHS rats have high renal gene expression of the Ca sensing receptor (CaR) which is a major determinant of tubule Ca secretion and is a VDR-regulated gene [20, 72].
Dietary factors Dietary components may increase urine Ca excretion and lower bone mass in IH patients. The efficiency of dietary Ca absorption is incomplete and healthy subjects with normal urine Ca excrete about 6–7% of daily dietary Ca into
4
3 B
3 Vertebral BMD, Z score
Femoral neck BMD, Z score
A 2 1 0 �1
2 1 0 �1 �2
�2 �3 10
20
30
40
50
60
70
�3 10
80
Urine ammonium, mmol/day
30
40
50
60
70
80
4
3 C
D 3
2
Vertebral BMD, Z score
Femoral neck BMD, Z score
20
Urine ammonium, mmol/day
1 0 �1
2 1 0 �1 �2
�2 10
20
30
40
50
60
Urine ammonium, mmol/day
70
�3 10
20
30
40
50
60
70
Urine ammonium, mmol/day
Figure 40.4 Relation of hip femoral neck and lumbar spine BMD and urine ammonium excretion in 59 men (circles) and women (triangles) IH stone formers and their first-degree relatives from 11 families. Among non-stone formers (panels A and B) neither hip femoral neck nor spine Z-scores varied with urine ammonium excretion. In contrast, among stone formers (panels C and D) both femoral neck (r 0.04, P 0.03) and spine (r 0.066, P 0.04) BMD Z-scores varied inversely with urine ammonium excretion. (Reprinted with permission from Asplin et al [32] and Kidney International).
C h a p t e r 4 0 Hypercalciuria
485
l
the urine. In these normal subjects, hypercalciuria may be induced by ingestion of very high intakes of Ca, exceeding 1500 mg per 24 h. This is in contrast to IH patients who have hypercalciuria at normal (900 to 1000 mg per 24 h) Ca intake and, for some, during low dietary Ca intake as well. Urine Ca excretion is dependent in part upon sodium excretion and higher urine Ca excretion in IH patients persists over a wide range of sodium. Thiazide diuretics reduce urine Ca excretion through promotion of distal tubule Ca reabsorption due in part to volume contraction during sodium diuresis. Dietary protein intake is a potent regulator of urine Ca excretion. Moderate protein intake of 1.0 to 1.5 g protein per kg body weight is associated with no alteration in Ca homeostasis or urine Ca excretion. Higher protein intakes, especially derived from meats, increase urine Ca presumably by increasing titratable acid and the acid buffering function of bone, resulting in bone resorption [73–76]. The effect of proton loading on bone is mediated by bone cellular activity. A direct renal effect of protein, specifically the renal handling of the sulfur-containing amino acid methionine, also increases urine Ca excretion by a direct action on the renal tubule to lower tubule Ca reabsorption. Indeed, urine ammonium excretion in IH stone formers and their family members is a strong predictor of hip and spine BMD [32], whereas this relationship does not occur in non-stone formers (Figure 40.4). At the other extreme, men with lower protein intake are at risk for lower bone mass [76, 77].
Alkali Therapy Potassium bicarbonate decreases urine Ca excretion during long-term therapy [81, 82]. The magnitude of the lowering is greater in those with higher baseline urine Ca excretion. Potassium citrate provides a sustained alkali load compared to the short-term actions of potassium bicarbonate. Use of potassium citrate alone or in combination with Ca citrate sustains the alkali load that reduces bone loss and enhances intestinal Ca absorption in non-stone formers [83] and stone formers [84]. Dietary protein creates an acid load from the sulfur contained in the essential amino acid methionine. However, protein restriction may be more catabolic and is not recommended.
Bisphosphonates Oral bisphosphonates (alendronate, etidronate) decrease urine Ca excretion and bone resorption markers and increase BMD after 12 months of therapy in men with IH and stone formation [85, 86]. In GHS rats, alendronate decreased urine Ca excretion and Ca supersaturation [12, 87]. It is assumed that reduction in urine Ca excretion during alendronate therapy is due to decreased bone resorption rather than a direct effect on renal Ca transport.
Other Agents There are no formal studies of the effects of calcitonin or raloxifene on bone mass in IH patients. Teriparatide increases urine Ca excretion and therefore is not used
Treatment
Thiazides Long-term administration of thiazides and related diuretic agents can reduce urine Ca excretion by 40–60%. Thiazideinduced reduction in urine Ca excretion improves Ca balance [78] (Figure 40.5) and increases bone mineral density at the lumbar spine and proximal femur [41] (Figure 40.6). Observational studies in men and postmenopausal women suggest that chronic thiazide use increases bone density and reduces the risk of hip fracture [79]. Two randomized trials of thiazide in women with postmenopausal osteoporosis demonstrate modest increases in bone density after 2–3 years [40, 80]. No comparable studies have been done in men with osteoporosis and no fracture data are available.
25 Calcium (T–C), mmol/6 days
For men with IH who do not form kidney stones, the objective of treatment is to prevent fractures through stabilization or improvement in bone mass. The current approach in hypercalciuric states is to enhance urine Ca retention which, in turn, decreases bone resorption.
25 ∗∗
12.5
12.5
∗
0
0
∗
�12.5
�25
Diet
Fecal loss
∗∗∗ Urine loss
Net absorption
�12.5
Balance
�25
Figure 40.5 In seven IH patients fed a constant Ca diet, 6- day Ca balance studies prior to and after 6 months of chlorthalidone therapy revealed that the decline in urine Ca excretion exceeded the increase in fecal Ca and lower net intestinal Ca absorption. As a result, net Ca balance became positive from a negative or neutral baseline balance. *, mean difference versus baseline, P 0.05; **, P 0.02; and ***, P 0.001. (Reprinted with permission from Coe et al [78] and Kidney International).
486
Osteoporosis in Men
0.30
3
0.24
0.18
0.12 1
3
Lumbar spine’ bone mineral density: g/cm2
Urinary calcium: creatinine ratio
1.0
0.9
5 2
0.8
1
4
0.7
2 4
5
0.6
0.06 0
0
12
6
6
Serum 1,25.Dihydroxyvitamin D Level, �g/mI.
60
5
40
2
3
4
20 0
1
6
Femorial neck bone mineral density, g/cm2
0.9
12 4
0.8
3
0.7
2 5 1
0.6 12
0
Time, mo
6
12
Time, mo
Figure 40.6 Response of five men with IH and low bone mass treated with hydrochlorothiazide 25 mg twice daily, BMD was measured by DXA scans at baseline (black squares) and again 4–12 months into treatment (open squares). Urine Ca excretion (urine Ca to creatinine ratio of 0.18 and below is normal) declined in all patients (upper left panel); serum 1,25(OH)2D levels decreased in three of five (lower left panel); BMD of the lumbar spine BMD increased (right upper panel, P 0.03) and femoral neck BMD increased (right lower panel, P 0.003). Annualized increases in spine and hip femoral were 8% and 3%, respectively. (Reprinted with permission from Adams et al [41] and Annals of Internal Medicine).
because it could increase kidney stone formation in established stone-formers.
Dietary The majority of Ca oxalate or Ca phosphate stone formers have IH and therefore high dietary Ca intake will likely worsen urine Ca excretion and increase the risk of kidney stone formation. Thus, for many years, IH patients were advised to maintain a low Ca diet. However, chronic low Ca intake does not prevent Ca stones and may indeed increase their frequency [88]. Indeed, higher Ca intake decreases kidney stone formation. As dietary Ca increases, it is thought that the increased intestinal luminal Ca binds oxalate, prevents absorption and thereby lowers urine oxalate excretion.
The effect of dietary Ca restriction on bone is well known to cause negative Ca balance and bone loss [23]. Therefore, it is advised that a reasonable Ca intake of 800 to 1000 mg per day be maintained using food sources of Ca and avoiding Ca tablets. High Ca intakes often recommended for the treatment of osteoporosis should be avoided because of the high intestinal Ca absorption in IH.
Salt Intake High intake of NaCl increases urine Ca excretion in normal subjects and may increase hypercalciuria in IH patients. Salt restriction reduces urine Ca excretion toward the normal range [89], therefore IH patients should be advised to avoid cooking with salt, pre-prepared foods and adding salt at the table.
C h a p t e r 4 0 Hypercalciuria l
References 1. R. Flocks, Calcium and phosphorus excretion in the urine of patients with renal or ureteral calculi, J. Am. Med. Assoc. 113 (1939) 1466–1471. 2. P.H. Albright, P.B. Henneman, A.P. Forbes, et al., Idiopathic hypercalciuria, N. Engl. J. Med. 259 (1958) 802–807. 3. L.J. Melton III, C.S. Crowson, S. Khosla, D.M. Wilson, W.M. Fallon, Fracture risk among patients with urolithiasis: a population-based cohort study, Kidney Int. 53 (1998) 459–464. 4. J.R. Asplin, S. Donahue, J. Kinder, F.L. Coe, Urine calcium excretion predicts bone loss in idiopathic hypercalciuria, Kidney Int. 70 (8) (2006) 1463–1467. 5. V. Garcia-Nieto, J.F. Navarro, M. Monge, V.E. GarciaRodriguez, Bone mineral density in girls and their mothers with idiopathic hypercalciuria, Nephron. Clin. Pract. 94 (4) (2003) c89–c93. 6. M.G. Penido, E.M. Lima, V.S. Marino, A.L. Tupinamba, A. Franca, M.F. Souto, Bone alterations in children with idiopathic hypercalciuria at the time of diagnosis, Pediatr. Nephrol. 18 (2) (2003) 133–139. 7. A.L. Schwaderer, R. Cronin, J.D. Mahan, C.M. Bates, Low bone density in children with hypercalciuria and/or nephrolithiasis, Pediatr. Nephrol. 23 (12) (2008) 2209–2214. 8. O.W. Moe, O. Bonny, Genetic hypercalciuria, J. Am. Soc. Nephrol. 16 (2005) 729–745. 9. D.A. Bushinsky, Genetic hypercalciuric stone-forming rats, Curr. Opin. Nephrol. Hypertens. 8 (4) (1999) 479–488. 10. D.A. Bushinsky, Genetic hypercalciuric stone forming rats, Semin. Nephrol. 16 (5) (1996) 448–457. 11. D.A. Bushinsky, J.R. Asplin, M.D. Grynpas, A.P. Evan, W.R. Parker, K.M. Alexander, F.L. Coe, Calcium oxalate stone formation in genetic hypercalciuric stone-forming rats, Kidney Int. 61 (3) (2002) 975–987. 12. D.A. Bushinsky, K.K. Frick, K. Nehrke, Genetic hypercalciuric stone-forming rats, Curr. Opin. Nephrol. Hypertens. 15 (4) (2006) 403–418. 13. R.R. Hoopes Jr., R. Reid, S. Sen, C. Szppirer, P. Dixon, A.A.J. Pannett, R.V. Thakker, D.A. Bushinsky, S.J. Scheinman, Quantitative trait loci for hypercalciuria in a rat model of kidney stone disease, J. Am. Soc. Nephrol. 14 (7) (2003) 1844–1850. 14. A.J. Karnauskas, J.P. van Leeuwen, G.J. van den Bemd, et al., Mechanism and function of high vitamin D receptor levels in genetic hypercalciuric stone-forming rats, J. Bone Miner. Res. 20 (3) (2005) 447–454. 15. J. Yao, P. Kathpalia, D.A. Bushinsky, M.J. Favus, Hyperresponsiveness of vitamin D receptor gene expression to 1,25-dihydroxyvitamin D3. A new characteristic of genetic hypercalciuric stone-forming rats, J. Clin. Invest. 101 (10) (1998) 2223–2232. 16. F.L. Coe, Treated, and untreated recurrent calcium nephrolithiasis in patients with idiopathic hypercalciuria, hyperuricosuria, or no metabolic disorder, Ann. Intern. Med. 87 (4) (1977) 404–410. 17. A.E. Broadus, M. Dominguez, F.C. Bartter, Pathophysiological studies in idiopathic hypercalciuria: use of an oral calcium tolerance test to characterize distinctive
18.
19.
20.
21.
22.
23. 24.
25.
26.
27.
28.
29.
30.
31. 32.
33.
34.
487
hypercalciuric subgroups, J. Clin. Endocrinol. Metab. 47 (4) (1978) 751–760. C.Y. Pak, R. Kaplan, H. Bone, J. Townsend, O. Waters, A simple test for the diagnosis of absorptive, resorptive and renal hypercalciurias, N. Engl. J. Med. 292 (10) (1975) 497–500. C.Y. Pak, M. Oata, E.C. Lawrence, W. Snyder, The hypercalciurias. Causes, parathyroid functions, and diagnostic criteria, J. Clin. Invest. 54 (2) (1974) 387–400. J.J. Yao, S. Bai, A.J. Karnauskas, D.A. Bushinsky, M.J. Favus, Regulation of renal calcium receptor gene expression by 1,25-dihydroxyvitamin D3 in genetic hypercalciuric stoneforming rats, J. Am. Soc. Nephrol. 16 (5) (2005) 1300–1308. S. Tsuruoka, D.A. Bushinsky, G.J. Schwartz, Defective renal calcium reabsorption in genetic hypercalciuric rats, Kidney Int. 51 (5) (1997) 1540–1547. X.Q. Li, V. Tembe, G.M. Horwitz, D.A. Bushinsky, M.J. Favus, Increased intestinal vitamin D receptor in genetic hypercalciuric rats. A cause of intestinal calcium hyperabsorption, J. Clin. Invest. 91 (2) (1993) 661–667. J.R. Asplin, M. Favus, F.L. Coe, Nephrolithiasis, fifth ed.., Saunders, Philadelphia, 1996. A.E. Broadus, K.L. Insogna, R. Lang, A.F. Ellison, B.E. Dreyer, Evidence for disordered control of 1,25-dihydroxyvitamin D production in absorptive hypercalciuria, N. Engl. J. Med. 311 (1984) 73–80. K.L. Insogna, A.E. Broadus, B.E. Dryer, A.F. Ellison, J.M. Gertner, Elevated production rate of 1,25-dihydroxyvitamin D in patients with absorptive hypercalciuria, J. Clin. Endocrinol. Metab. 61 (1985) 490–495. F.H. Shen, D.J. Baylink, R.L. Nielsen, D.J. Sherrard, J.L. Ivey, M.R. Haussler, Increased serum 1,25-dihydroxyvitamin D in idiopathic hypercalciuria, J. Lab. Clin. Med. 90 (1977) 955–962. P. Bataille, R. Bouillon, A. Fournier, H. Renaud, J. Gueris, A. Idrissi, Increased plasma concentrations of total and free 1,25-(OH)2D3 in calcium stone formers with idiopathic hypercalciuria, Contrib. Nephrol. 58 (1987) 137–142. P. Bataille, J.M. Achard, A. Fournier, et al., Diet, vitamin D and vertebral mineral density in hypercalciuric calcium stone formers, Kidney Int. 39 (6) (1991) 1193–1205. W.J. Maierhofer, R.W. Gray, H.S. Cheung, Dietary calcium and serum 1,25-(OH)2 vitamin D concentrations as determinants of calcium balance in healthy men, Kidney Int. 26 (1984) 752–759. N.D. Adams, J. Lemann Jr., H.S. Cheung, Effects of calcitriol administration on calcium metabolism in healthy men, Kidney Int. 21 (1982) 90–97. F.L. Coe, J.H. Parks, Nephrolithiasis: Pathogenesis and Treatment, second ed., Year Book, Chicago, 1988. J.R. Asplin, K.A. Bauer, J. Kinder, et al., Bone mineral density and urine calcium excretion among subjects with and without nephrolithiasis, Kidney Int. 63 (2) (2003) 662–669. S. Giannini, M. Nobile, L. Dalle Carbonare, et al., Hypercalciuria is a common and important finding in postmenopausal women with osteoporosis, Eur. J. Endocrinol. 149 (2003) 2009–2013. D.S. Lauderdale, R.A. Thisted, M. Wen, M.J. Favus, Bone mineral density and fracture among prevalent kidney stone cases in the Third National Health and Nutrition Examination Survey, J. Bone Miner. Res. 16 (10) (2001) 1893–1898.
488
Osteoporosis in Men
35. S. Giannini, M. Nobile, S. Sella, L. Dalle Carbonare, Bone disease in primary hyerpcalciuria, Crit. Rev. Clin. Lab. Sci. 42 (2005) 229–248. 36. R. Pacifici, L. Rifas, et al., Increased monocyte interleukin-1 activity and decreased vertebral bone density in patients with fasting idiopathic hypercalciuria, J. Clin. Endocrinol. Metab. 71 (1990) 138–145. 37. L. Borghi, T. Meschi, A. Guerra, et al., Vertebral mineral content in diet-dependent and diet-independent hypercalciuria, J. Urol. 146 (5) (1991) 1334–1338. 38. A.M. Misael da Silva, L.M. dos Reis, R.C. Pereira, et al., Bone involvement in idiopathic hypercalciuria, Clin. Nephrol. 57 (3) (2002) 183–191. 39. A.Z. Lacroix, Thiazide diuretic agents and prevention of hip fracture, Compr. Ther. 17 (8) (1991) 30–39. 40. A.Z. LaCroix, S.M. Ott, L. Ichikawa, D. Scholes, W.E. Barlow, Low-dose hydrochlorothiazide and preservation of bone mineral density in older adults. A randomized, doubleblind, placebo-controlled trial, Ann. Intern. Med. 133 (7) (2000) 516–526. 41. J.S. Adams, C.F. Song, V. Kantorovich, Rapid recovery of bone mass in hypercalciuric, osteoporotic men treated with hydrochlorothiazide, Ann. Intern. Med. 130 (8) (1999) 658–660. 42. A. Ghazali, V. Fuentes, C. Desaint, et al., Low bone mineral density and peripheral blood monocyte activation profile in calcium stone formers with idiopathic hypercalciuria, J. Clin. Endocrinol. Metab. 82 (1) (1997) 32–38. 43. R. Caudarella, F. Vescini, A. Buffa, et al., Bone mass loss in calcium stone disease: focus on hypercalciuria and metabolic factors, J. Nephrol. 16 (2) (2003) 260–266. 44. M. Fuss, T. Pepersack, J. Van Geel, et al., Involvement of low-calcium diet in the reduced bone mineral content of idiopathic renal stone formers, Calcif. Tissue Int. 46 (1) (1990) 9–13. 45. S. Giannini, M. Nobile, L. Sartori, et al., Bone density and skeletal metabolism are altered in idiopathic hypercalciuria, Clin. Nephrol. 50 (2) (1998) 94–100. 46. I.P. Heilberg, J.R. Weisinger, Bone disease in idiopathic hypercalciuria, Curr. Opin. Nephrol. Hypertens. 15 (4) (2006) 394–402. 47. P. Jaeger, K. Lippuner, J.P. Casez, B. Hess, D. Ackermann, C. Hug, Low bone mass in idiopathic renal stone formers: magnitude and significance, J. Bone Miner. Res. 9 (10) (1994) 1525–1532. 48. F. Pietschmann, N.A. Breslau, C.Y. Pak, Reduced vertebral bone density in hypercalciuric nephrolithiasis, J. Bone Miner. Res. 7 (12) (1992) 1383–1388. 49. A. Tasca, A. Cacciola, P. Ferrarese, et al., Bone alterations in patients with idiopathic hypercalciuria and calcium nephrolithiasis, Urology 59 (6) (2002) 865–869 discussion 869. 50. A. Trinchieri, Bone mineral content in calcium renal stone formers, Urol. Res. 33 (4) (2005) 247–253. 51. A. Trinchieri, R. Nespoli, F. Ostini, F. Rovera, G. Zanetti, E. Pisani, A study of dietary calcium and other nutrients in idiopathic renal calcium stone formers with low bone mineral content, J. Urol. 159 (3) (1998) 654–657.
52. H. Tsuji, T. Umekawa, T. Kurita, et al., Analysis of bone mineral density in urolithiasis patients, Int J. Urol. 12 (4) (2005) 335–339. 53. J.R. Weisinger, Bone mineral density in idiopathic hypercalciuria: the chicken or the egg? Nephron. Clin. Pract. 94 (4) (2003) c81–c82. 54. J.R. Weisinger, Bone loss in hypercalciuria: cause or consequence?, Am. J. Kidney Dis. 33 (1) (1999) xlvi–xlviii. 55. J.R. Weisinger, New insights into the pathogenesis of idiopathic hypercalciuria: the role of bone, Kidney Int. 49 (5) (1996) 1507–1518. 56. J.R. Weisinger, E. Alonzo, E. Bellorin-Font, et al., Possible role of cytokines on the bone mineral loss in idiopathic hypercalciuria, Kidney Int. 49 (1) (1996) 244–250. 57. I.P. Heilberg, L.A. Martini, V.L. Szejnfeld, et al., Bone disease in calcium stone forming patients, Clin. Nephrol. 42 (3) (1994) 175–182. 58. H.J. Heller, F.A. Gottschalk, C.Y.C. Pak, Reduced bone formation and relatively increased bone resorption in absorptive hypercalciuria, Kidney Int. 71 (2007) 808–815. 59. T. Steiniche, L. Mosekilde, M.S. Christensen, F. Melsen, A histomorphometric determination of iliac bone remodeling in patients with recurrent renal stone formation and idiopathic hypercalciuria, Apmis 97 (4) (1989) 309–316. 60. H.H. Malluche, E. Ritz, et al., Abnormal bone histology in idiopathic hypercalciuria, J. Clin. Endocrinol. Metab. 50 (1980) 654–658. 61. J. Lemann Jr., R.W. Gray, Idiopathic hypercalciuria, J. Urol. 141 (3 Pt. 2) (1989) 715–718. 62. M. Kuczera, A. Wiecek, F. Kokot, Markers of bone turnover in patients with nephrolithiasis, Int. Urol. Nephrol. 29 (5) (1997) 523–528. 63. H. Rico, P. Paramo, J. Perez del Molino, L. Nacarino, M. Yague, Osteocalcin, parathormone and hypercalciuria, Eur. Urol. 15 (3-4) (1988) 239–242. 64. F.L. Coe, M.J. Favus, T. Crockett, et al., Effects of lowcalcium diet on urine calcium excretion, parathyroid function and serum 1,25(OH)2D3 levels in patients with idiopathic hypercalciuria and in normal subjects, Am. J. Med. 72 (1) (1982) 25–32. 65. R.A. Kaplan, M.R. Haussler, L.J. Deftos, H. Bone, C.Y. Pak, The role of 1 alpha, 25-dihydroxyvitamin D in the mediation of intestinal hyperabsorption of calcium in primary hyper parathyroidism and absorptive hypercalciuria, J. Clin. Invest. 59 (5) (1977) 756–760. 66. M. Peacock, B.E. Nordin, Tubular reabsorption of calcium in normal and hypercalciuric subjects, J. Clin. Pathol. 21 (3) (1968) 353–358. 67. N.A. Edwards, A. Hodgkinson, Metabolic studies in patients with idiopathic hypercalciuria, Clin. Sci. 29 (1) (1965) 143–157. 68. R.A. Sutton, V.R. Walker, Responses to hydrochlorothiazide and acetazolamide in patients with calcium stones. Evidence suggesting a defect in renal tubular function, N. Engl. J. Med. 302 (13) (1980) 709–713. 69. E.M. Worcester, F.L. Coe, New, insights into the pathogenesis of idiopathic hypercalciuria, Semin. Nephrol. 28 (2) (2008) 120–132.
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70. E.M. Worcester, F.L. Coe, A.P. Evan, et al., Evidence for increased postprandial distal nephron calcium delivery in hypercalciuric stone-forming patients, Am. J. Physiol. Renal Physiol. 295 (5) (2008) F1286–F1294. 71. E.M. Worcester, D.L. Gillen, A.P. Evan, et al., Evidence that postprandial reduction of renal calcium reabsorption mediates hypercalciuria of patients with calcium nephrolithiasis, Am. J. Physiol. Renal Physiol. 292 (1) (2007) F66–F75. 72. S. Bai, M.J. Favus, Vitamin D and calcium receptors: links to hypercalciuria, Curr. Opin. Nephrol. Hypertens. 15 (4) (2006) 381–385. 73. B. Fellstrom, B.G. Danielson, B. Karlstrom, et al., Effects of high intake of dietary animal protein on mineral metabolism and urinary supersaturation of calcium oxalate in renal stone formers, Br. J. Urol. 56 (3) (1984) 263–269. 74. S. Giannini, M. Nobile, L. Sartori, et al., Acute effects of moderate dietary protein restriction in patients with idiopathic hypercalciuria and calcium nephrolithiasis, Am. J. Clin. Nutr. 69 (2) (1999) 267–271. 75. B. JP, Dietary protein: an essential nutrient for bone health, J. Am. Coll. Nutr. 24 (2005) 526S–536S. 76. L.A. Martini, R.J. Wood, Should dietary calcium and protein be restricted in patients with nephrolithiasis? Nutr. Rev. 58 (4) (2000) 111–117. 77. A. Trinchieri, G. Zanetti, A. Curro, R. Lizzano, Effect of potential renal acid load of foods on calcium metabolism of renal calcium stone formers, Eur. Urol. 39 (Suppl. 2) (2001) 33–36 discussion 36–37. 78. F.L. Coe, J.H. Parks, D.A. Bushinsky, C.B. Langman, M.J. Favus, Chlorthalidone promotes mineral retention in patients with idiopathic hypercalciuria, Kidney Int. 33 (6) (1988) 1140–1146. 79. G. Jones, T. Nguyen, P.N. Sambrook, J.A. Eisman, Thiazide diuretics and fractures: can meta-analyses help? J. Bone Miner. Res. 10 (1995) 106–111.
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80. I.R. Reid, R.W. Ames, B.J. Orr-Walker, et al., Hydro chlorothiazide reduces loss of cortical bone in normal postmenopausal women: a randomized controlled trial, Am. J. Med. 109 (5) (2000) 362–370. 81. M. Marangella, M. Di Stefano, S. Casalis, S. Berutti, P. D’Amelio, G.C. Isaia, Effects of potassium citrate supplementation on bone metabolism, Calcif. Tissue Int. 74 (4) (2004) 330–335. 82. L. Frassetto, R.C. Morris Jr, A. Sebstian, Long-term persistence of the urine calcium-lowering effect of potassium bicarbonate in postmenopausal women, J. Clin. Endocrinol. Metab. 90 (2005) 831–834. 83. K. Sakhaee, N.M. Maalouf, S.A. Abrams, C.Y. Pak, Effects of potassium alkali and calcium supplementation on bone turnover in postmenopausal women, J. Clin. Endocrinol. Metab. 90 (6) (2005) 3528–3533. 84. C.Y. Pak, R.D. Peterson, J. Poindexter, Prevention of spinal bone loss by potassium citrate in cases of calcium urolithiasis, J. Urol. 168 (1) (2002) 31–34. 85. J.R. Weisinger, E. Alonzo, C. Machado, et al., Role of the bone in the pathophysiology of idiopathic hypercalciuria: effect of the aminobisphosphonate alendronate, Medicina (B Aires) 57 (1997) 45–48. 86. I.P. Heilberg, L.A. Martini, S.H. Teixeira, et al., Effect of etidronate treatment on bone mass of male nephrolithiasis patients with idiopathic hypercalciuria and osteopenia, Nephron 79 (4) (1998) 430–437. 87. D.A. Bushinsky, K.J. Neumann, J. Asplin, N.S. Krieger, Alendronate decreases urine calcium and supersaturation in genetic hypercalciuric rats, Kidney Int. 55 (1) (1999) 234–243. 88. G.C. Curhan, S.G. Curhan, Dietary factors and kidney stone formation, Compr. Ther. 20 (9) (1994) 485–489. 89. F.P. Muldowney, R. Freaney, M.F. Maloney, Importance of dietary sodium in the hypercalciuria syndrome, Kidney Int. 22 (1982) 292–296.
Chapter
41
The Skeletal Phenotype of the Male Athlete Ann E. Maloney and Clifford J. Rosen Maine Medical Center Research Institute, Scarborough, Maine, USA
Introduction
and strain. The latter is a measure of bone deformation in response to stress and is calculated by dividing change in bone length by the original length. Stress is the force applied expressed per unit area and calculated by dividing the load on the bone by its cross-sectional area. ‘Rate of strain’ describes the time over which the strain develops after the load is applied and is comparable to impact. There is a curvilinear relationship to the scalable response to load [4]. Skeletal loading is sensed by a series of mechanoreceptors, probably in the osteocyte, although the precise mechanism is unknown. Previous work showed that low intensity loading is more of a contributor to bone growth than cycle number [5].
Bone adaptation to mechanical loading is well characterized by Wolff’s law, which instructs our understanding of the skeleton in animals and humans. This law (Julius Wolff, 1836–1902) states there is a close relationship between mechanical loading and bone strength [1]. There is now substantial experimental evidence in young and older mammals that bone mineral density (BMD) increases in response to loading, thereby validating this tenet. Most intriguing, a recent analysis of an ancient skeleton (circa, 38 000 years old) not only revealed his DNA sequence but, by dual energy x-ray absorptiometry (DXA), also showed that this ancestor had fractured his left arm, but his right arm had adapted to increased loading by creating a much larger bone [2]. Modern day athletics represent a special case because training stresses both skeletal and soft tissue. Athletes train with high-intensity and often during the time of peak bone accrual, i.e. late adolescence/early adulthood [3]. Studies provide evidence that this loading can enhance areal bone mass at several skeletal sites. However, the literature is also replete with studies of the female athlete triad (amenorrhea, energy deficit, osteoporosis) [2]. The male athlete is not excluded from bone loss and fractures with excessive physical training. In this chapter, discussion of the hormonal, nutritional and genetic determinants of bone mass in the male athlete will be the focus and the relationship of these factors to peak bone acquisition will be discussed.
Measurement of bone loading and bone mass It has been reported that 60–80% of peak skeletal mass can be accounted for by genetic factors [6]. Karasik and colleagues noted that bone and muscle function similarly when loaded and may have similar genetic determinants that ultimately determine adult skeletal mass [7]. Strength, the ultimate response to loading, cannot be directly measured. Instead, dual energy x-ray absorptiometry (DXA) has been conveniently used to define bone responsiveness to loading. DXA is an accurate tool for assessing fracture risk, hence indirectly determines skeletal fragility, although there are geometric limitations, particularly when considering loading as a force that affects both endosteal and periosteal bone formation [8]. With DXA, three-dimensional objects are seen in a two-dimensional image, thereby reflecting areal changes rather than true volumetric density. Since bone size is greater in males than females areal BMD measurements are usually higher in men than women, although volumetric BMD does not differ by gender.
Principles of loading Terminology Fundamental determinants of loading are characterized by the type of load, its magnitude, the number of load cycles Osteoporosis in Men
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Similarly, recent studies suggest that age-related bone loss from both cortical and trabecular compartments may be similar in both males and females, although compensatory periosteal (outer) bone gain during aging is greater in men. As such, net cortical bone loss is less in men than women and this may impact skeletal fragility with loading, particularly during states of hypogonadism with or without energy deficits. The musculoskeletal system is comprised of both skeleton and soft tissues. In general, most studies demonstrate that muscle strength correlates with aBMD and crosssectional muscle size is increased by exercise. Hence, greater physical activity is associated with higher BMD. Results of one study show that BMD at all sites correlated with back and biceps strength (P 0.01 to P 0.0001); back strength was the most robust predictor of BMD at the trochanter, Ward’s triangle, whole body and tibia; biceps strength, age, body weight and leg strength contributed significantly to BMD at all skeletal sites, accounting for 35–52% of the variance in BMD [9]. Based on Wolff’s law, it is clear that sports-specific changes in bone mass, as well as cross-sectional and section modulus, depend on the type of loading and the site of impact. Loading can be high impact, high magnitude, repetitive or low impact or repetitive non-impact [1]. Repetitive loading also determines the site of skeletal failure and the frequency. For example, excessive running leads to metatarsal, fibula, navicular and femur fractures [10], but there is significant gender specificity for the location and severity of stress fractures in athletes [10]. In males, tibial and femoral fractures are the most common sites for stress failures. Not surprisingly, male distance runners sustain a higher number of stress fractures than athletes of other track and field events. A number of risk factors have been identified, including low BMD, dietary factors and a prior history of stress fractures. Caucasians have been found to be at higher risk for stress fractures than African-Americans, in part due to their greater aBMD. In sum, skeletal responses to loading are dependent on several key factors: frequency and intensity of exercise, periosteal responsiveness to loading, baseline bone mass, and the hormonal milieu. Another example of the effects of loading on bone metabolism and body composition of adolescent athletes was described by Lima et al [11]. Groups of adolescent male athletes were divided into two groups of impact loading or active sport types, 18 and 27 subjects, respectively. Control subjects (non-athletes) were of the same age and were only exposed to physical education classes (n 24). All of the subjects were assessed for bone mass, body composition and bone age by DXA. Researchers also measured calcium, phosphorus, bone-specific alkaline phosphatase, total testosterone, follicle stimulating hormone (FSH), lymphocyte stimulating hormone (LSH), urinary calcium to creatinine ratio and urinary deoxypyridinoline cross-links to creatinine ratio. Impact loading group members had the
highest BMD of the three groups studied and the authors relate this finding to ground-reaction force generated. Bone-specific alkaline phosphatase levels were significantly higher and testosterone levels significantly lower in the active load group, compared to the impact group. Body weight and body composition were positively correlated with aBMD in this study and in several other studies [12–14]. However, one of the principal determinants of skeletal mass remained the hormonal milieu.
Hormonal determinants of skeletal mass Gonadal steroids are critical determinants of peak bone mass and maintenance. The velocity of bone acquisition increases dramatically in boys and girls at the time of pubarche. Girls mature earlier than boys as a result of enhanced production of estradiol, coincident with a surge in growth hormone. During this critical phase, rising estradiol increases the endocortical envelope by reducing bone resorption and modestly increases bone formation. After peak acquisition, estrogen is critical for maintenance of bone mass, principally through its anti-resorptive properties. Androgens also suppress bone resorption but are much more active in stimulating periosteal bone formation. The relative balance between estrogen and androgens in both males and females regulates bone modeling and remodeling. In 1984, Wheeler et al demonstrated, however, reduced serum testosterone levels in male distance runners [15]. Although several retrospective studies confirm that chronic exercise during adolescence is associated with higher peak BMD than sedentary individuals, there is likely to be a threshold after which exercise is detrimental, particularly to the growing skeleton, and almost certainly dependent on the hormonal milieu. Deficiencies in gonadal steroids as a result of reduced nutrient intake and excessive exercise results in suppression of the hypothalamic-pituitary axis in both males and females. The suppression of luteinizing hormone (LH) and FSH may be mediated by a number of factors including high ghrelin levels. Increased endogenous glucocorticoids are a hallmark of the athlete’s triad and may exacerbate the suppression of gonadotropins and the degree of bone loss in both genders. A reduction in circulating leptin, due to lower body fat, further suppresses gonadotropins and may aggravate bone loss in both genders. Although the vast majority of studies have been conducted in females, there is no reason to believe that hypothalamic hypogonadism in male athletes is any less detrimental to endogenous gonadal steroids or subsequently to the skeleton. Male endurance athletes, such as cyclists, triathletes and swimmers, are unique in several ways and some have
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reduced levels of testosterone [16]. In one study, total testosterone and free androgen index levels were lower (P 0.05) in cyclists and triathletes than controls, with the ratio of cortisol to testosterone increased in cyclists only (P 0.05). Luteinizing hormone, sex hormone binding globulin, estrogen and cortisol concentrations were normal. No BMD or hormonal differences were found in swimmers between elite athletes and controls. Although endurance training for cyclists and triathletes induced androgen deficiency, it did not result in apparent alteration in aBMD. In another study, twelve elite runners were compared to nonathletic controls [17]. Runners were subdivided into those running 64–80 km a week or those running more than 95 km a week. BMD at the total proximal femur, femoral neck, trochanteric region and lumbar spine was measured by DXA. At baseline, there were no between-group differences in height, weight or age. Interestingly, the highest volume runners had significantly higher BMD at the total proximal femur (1.09 (0.17) versus 0.94 (0.056)), femoral neck (0.91 (0.16) versus 0.78 (0.071)) and trochanteric region (0.85 (0.14) versus 0.73 (0.053)) than controls (P 0.05). However, the differences in BMD for the proximal femur between the very high volume runners and the other two groups were not significant, nor were there differences in lumbar spine BMD, total testosterone or free testosterone between groups. There was a significant negative correlation between total testosterone (r 0.73, P 0.01) and free testosterone (r 0.79, P 0.005) and running volume in the distance runners. They conclude that long-term distance running with training volumes less than 80 km a week had a positive effect on BMD of the proximal femur. With running volumes greater than 64 km a week, training was inversely related to testosterone levels, but levels remained within the normal range. The DNASCO study aim was to investigate the effects of regular aerobic exercise training on BMD in middle-aged men [18]. The study was conducted as a population-based sample of 140 men (53–62 years), randomly assigned into the exercise and reference groups. Cardiorespiratory fitness (aerobic threshold) increased by 13% in the exercise group. They report a 2% decrease in the reference group, an agerelated change in cardiorespiratory fitness. BMD and apparent volumetric BMD (BMDvol) of the proximal femur and lumbar spine were assessed using DXA. Anthropomorphic measurements were performed at randomization and repeated serially at 2 years and up to 4 years later. Followup rates were 97% and 94% in this DNASCO cohort. Key findings of this study were the lack of association between the increase in aerobic threshold and changes in BMD. In the entire group, age-related bone loss was seen in the femoral neck BMD and BMDvol (P 0.01). BMD and BMDvol values increased with age in L2–L4 (P 0.004). The authors report an increased rate of bone loss at the femoral neck in subjects with a low energy-adjusted calcium intake (P 0.003). A decrease in body height associated with
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decreased total femoral BMD (r 0.19, P 0.04) and the change in body height was a predictor of bone loss in the femoral neck (beta 0.201).
Growth Hormone and IGF-I Growth hormone surges during puberty regulate skeletal modeling, particularly at the periosteal envelope. Animal models of growth hormone deficiency (i.e. reduced GH, impaired GH receptor activation, reduction in growth hormone receptor hormone signaling) demonstrate significant reductions in areal bone mass at virtually every site, although volumetric bone density appears to be preserved. It is still not clear whether all the effects of growth hormone on bone are indirect and mediated through induction of insulin-like growth factor-I (IGF-I) in osteoblasts versus a direct effect of GH on bone cells. Short-term exercise increases growth hormone secretion in young adults, both males and females, although the excursion is greater in the former. Long-term exercisers do not exhibit consistent increases in GH secretion. IGF-I is an abundant protein in the skeletal matrix and circulating levels are threefold higher than young normal during puberty and peak bone acquisition. In vitro, IGF-I exhibits mitogenic properties in pre-osteoblasts and can have significant effects on the late differential function of osteoblasts, particularly mineralization [19, 20]. In vivo, IGF-I also induces 1- hydroxylase, thereby enhancing calcium absorption in the gut, providing another, albeit indirect mechanism, for mineralizing an expanding collagen matrix during peak bone acquisition. There are gender differences in the relationship between serum IGF-I and measures of bone architecture. In males, serum IGF-I is related to trabecular number and cortical thickness while, in females, IGF-I relates only to cortical thickness and mass. Nutritional deprivation results in a rapid decline in circulating IGF-I, likely as a result of changes in mRNA stability. As such, in the athlete’s triad, for both men and women, circulating IGF-I is almost always reduced and this can contribute to low bone mass and increased skeletal fragility. However, in one study, serum IGF-I was higher in gymnasts than in women runners and was a predictor of bone and lean mass [21]. Changes in body composition as a result of chronic exercise activities can affect bone turnover in striking ways. The male and female athlete tends to be leaner, have greater muscle mass and less total body fat. Increased muscle mass is also directly related to greater bone mass in human and mouse studies. Moreover, greater muscle mass may enhance insulin sensitivity and improve glucose disposal. The reduced fat mass accompanying this increase in lean mass is often associated with reduced adiponectin levels. The effects of adiponectin on bone remodeling are unclear with some reports demonstrating a positive correlation and others no significant relationship.
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Surprisingly, another potential modulator of bone turnover in the male athlete may be through the PPAR pathway. Peroxisome proliferators-activated receptor-gamma (PPARG-) is essential for fat cell differentiation. It is also an insulin sensitizer. PPARG- activation directs marrow stromal cells into the adipocytic lineage rather than the osteoblastic line and polymorphisms in this gene have been associated with low bone mass, particularly in those individuals consuming a high fat diet [22]. PPAR- regulates fatty acid oxidation in muscle tissue. Genotypic differences in PPAR- may affect muscle performance, physical activity and possibly bone mass. In a cohort of 786 Russian athletes in 13 sports, Ahmetov et al noted differences in allele frequencies for PPAR- compared to 1242 non-exercising controls. They noted that 80.3% of the endurance-oriented athletes and 50.6% of power-oriented athletes had genotypic differences compared to controls. To examine the association between PPAR- from muscle biopsy in 40 young male athletes, the GG homozygotes (n 25) had significantly higher percent of slow twitch fibers than the CC homozygotes (n 4) [23]. Thus, there may be a genotype environment association that favors particular individuals with a specific haplotype pattern. Similarly, in another study, mRNA expression of PPAR-, PPAR-, PGC-1 and -1 in muscle biopsy samples was found to be increased in athletes, when compared with normally active subjects. Furthermore, mRNA expression of PPAR, PPAR, PGC-1 and -1 was reduced in spinal cord-injured subjects. Additionally, PPAR, PPAR and PGC-1 correlated with oxidative fiber content. Whether the skeletal response to exercise differs for genotypic variation in PPAR- or - will require further studies, but clearly, in the male athlete, a better understanding of the relationship between muscle and bone is needed.
Environmental and nutritional determinants of skeletal health in male athletes Because some males enter athletics with lower fitness levels, they may also be at increasing risk of injury because they may not have the conditioning necessary at the beginning of their sport season. It should be stressed that most adolescent males are not competitive athletes. In fact, with the recent trends in school funding and policy, such as No Child Left Behind (2002), fewer youths are engaging in moderate to vigorous physical activity overall. Moreover, physical education is less available for youths and extracurricular activities are out of reach for many low-income families. For example, in a national sample of youths, 37.9% of males do not play on any team sport run by their school community group in any given calendar year [24]. In contrast to this decline in activity, sedentariness is on the rise,
with 92% of all youths playing video games [25]. Likewise, increasing amounts of other sedentary screen time are reported in youths, so that about one-third of all male teenagers report using computers three or more hours a day and also report an additional three or more hours per day watching television. Since there are fewer teenagers meeting basic fitness thresholds, it is not surprising that only 3% of youths attained the ‘Healthy People 2010’ goals of adequate physical activity of sufficient intensity [26]. This lack of baseline fitness may tend to increase fracture rates in future generations, since physical activity tends to decrease over the decades of life (Figure 41.1). Sustained benefits are found in aBMD, however, when physical loading is carried out over time. Nordstrom et al showed that over 94 months in a longitudinal study of 63 athletes and 27 controls, areal BMD was higher at total body, total hip, femoral neck and humerus compared to controls (mean difference 0.04–0.12 gm/cm2, P 0.05). After 3 years, some athletes who stopped their sport participation were followed and initially lost BMD at the hip, but the former athletes still had higher BMD than controls at the femoral neck (0.12 g/m2; P 0.007) [27]. In a much longer term study of 154 Belgian men, studied over 27 years, anthropometric dimensions and sports participation are described by Van Langendonck and team [28]. Mean time spent participating in sports was almost 5 hours per week during adolescence and almost 3 hours per week during adulthood. Body mass and impact loading during adulthood were significant predictors of total body BMD and lumbar spine BMD. Investigators divided the sample into three groups consisting of high-impact sports (HH; n 18), participation during adolescence in highimpact sports and during adulthood in non-impact sports or no sports (HN; n 15) and participation during adolescence and adulthood in non-impact sports or no sports (NN; n 14). Analysis of variance revealed significant differences for lumbar spine BMD between the HH (1.12 g/cm2) group and the HN (1.01 g/cm2) and NN (0.99 g/cm2) groups (F 5.07, P 0.01). Total body BMD was also higher in the HH group at age 40 years, but not significantly (F 3.17, P 0.0515). Covariance analyses for total body BMD and lumbar spine BMD, with body mass and time spent participating in sports as covariates, confirmed these results. Typically, athletes need higher energy intake. Micro- and macronutrients may be quite variable in the athlete’s life and may influence performance and risk for injury. In a collegiate cohort of 115 male and 88 female varsity athletes at a Division I university, researchers surveyed these athletes about where they obtain information about nutrition. Male athletes tend to obtain information about nutrition from store nutritionists, fellow athletes, friends or a coach [29]. This differs from sources of information obtained by female athletes, who tend to ask family for insights about proper nutrition. Many athletes are known to select supplements,
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95% confidence interval Percent 60
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40
30
20
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0 18–24
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Age group (years)
Note: This measure reflects the definition used for the physical activity leading health indicator in Healthy people 2010. Regular leisure-time physical activity is defined as engaging in lightmoderate leisure-time physical activity for greater than or equal to 30 minutes at a frequency greater than or equal to five times per week, or engaging in vigorous leisure-time physical activity for greater than or equal to 20 minutes at a frequency greater than or equal to three times per week. The analyses excluded 697 persons (3.0%) with unknown physical activity participation. For both sexes combined, the percent of adults who engaged in regular leisure-time physical activity decreased with age. For all age groups, women were less likely than men to engage in regular leisure-time physical activity. Source: Ni et al. 2004.
Figure 41.1 Percent of adults aged 18 years and over who engaged in regular leisure time physical activity by age group and sex: USA, January–September 2003.
like energy drinks (73%), calorie replacement products (61.4%), multivitamin (47.3%), creatine (37.2%) and vitamin C (32.4%). This behavior of purchasing supplements may not be evidence-based or match ideal recommended daily allowances, but nutritional scientists have made contributions to our knowledge of skeletal health.
Calcium and Vitamin D Intake Nutrition is a very important factor in the development and maintenance of bone mass in athletes and non-athletes. But, increased physical activity does not directly lead to increases in dietary calcium [30]. On the other hand, studies of the effects of dietary calcium have shown a positive linear relationship between dietary intake of calcium and spinal trabecular bone density in female athletes [31].
Eighty to 90% of bone mineral content is composed of calcium and dietary components such as calcium and phosphorus, magnesium, zinc, copper, iron, fluoride and vitamins D, E, A and K are all required for normal bone metabolism. These fat-soluble vitamins and minerals are found in a normal diet. In addition, fresh fruits and vegetable consumption has a positive effect on BMD, at least in 10-year-old girls [32]. On the other hand, teen consumption of milk products has dropped considerably. A study of teen behavior and physical activity was conducted in Canada over 7 years. Longitudinal data were obtained from 85 boys and 67 girls aged 8 to 20 years [33]. Biological maturity was defined by the number of years of age at peak height velocity and this was linked to dietary and intake by 24-hour recall. The majority of boys met recommendations for milk product intake (87%). However, few (30%) boys
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met recommendations for vegetables and fruits. There was a marked gender difference in this North American study with higher intake by boys for almost all food groups. Importantly, intake of vegetables and fruit had a significant independent relationship on total body bone mineral content (TBBMC), 48.6 g higher in subjects with an intake of 10 servings of vegetables and fruits per day than in subjects with one serving per day. Because fruit and vegetables provide organic salts of potassium and magnesium, there is a significant buffering effect [34, 35]. Interestingly, in the Canadian study, energy intake declined from 1778 kcal per day at the height of peak height velocity to 1467 kcal per day over 4 years. One team studied a group of military recruits to understand associations between vitamin D concentrations and stress fractures [36]. Low levels of vitamin D may predict bone problems such as rickets, osteomalacia or osteoporosis. Fatigue fracture is an overuse injury seen both in athletes and in male recruits. Serum 25 (OH)D concentrations were measured in a population of recruits to determine if vitamin D was a predisposing factor for fatigue bone stress fracture. Following 800 healthy male recruits with a mean age of 19 years, they analyzed the 12-minute run, serum 25 (OH)D by enzyme immunoassay, measured weight height and body mass index as well as muscle strength. Of the original sample, 756 subjects completed the study and those without fractures constituted the control group for comparison. After 90 days, 22 recruits were identified with stress fractures (2.9%). The incidence for stress fracture was 11.6 (95% CI: 6.8–16.5) per 100 person-years. In the final multivariate analysis, the significant risk factor for stress fracture in conscripts was a low median serum 25 (OH)D level (75.8 nM), with the OR of 3.6 (95% CI: 1.2–11.1). No significant associations between body mass index (BMI) (P 0.255), age (P 0.216) or smoking (P 0.851) and bone stress fracture were found in this study population. Thus, low levels of serum 25 (OH)D may predispose to stress fractures, although circulating vitamin D may also be a surrogate marker for other disorders and muscle health. Nakamura et al described a crosssectional study to evaluate the role of the vitamin D receptor (VDR) on long-term impact loading relative to gene polymorphisms in the VDR [37]. They studied 44 highly trained young male athletes, with at least 6 years of participation in sports such as volleyball, basketball, handball and track and field athletes and 44 age-matched controls. Higher bone mineral content was noted in the athletes compared to sedentary controls due to increases in both volume and density of bone at the hip and spine. BMC was 2519 431 in controls and 3340 483 in athletes. When male athletes and non-athletes were compared by VDR genotype, increased spinal volume was found only in the athletes with the FF genotype, but not in the heterozygotes Ff. These results suggest that gene environment interactions can influence the capacity to adapt to impact loading. More
s tudies are needed to define favorable athletic genotypes for receptor subtypes.
Comparison of male athletes to the female triad It is reported that as many as 23.5% of female high school athletes or as many as 66% of other sport participants exhibit amenorrhea, negative energy balance/eating behavior disorder or the classic female athlete triad [38–40]. This syndrome also exists in male athletes, although the presentation differs. Women have oligo- or amenorrhea, a seminal part of the athlete’s triad; this brings the female athlete to medical intention relatively early. Estrogen deficiency can cause rapid bone loss principally from the trabecular skeleton, resulting in low BMD of the spine. Notwithstanding the deleterious effects of excessive loading on the intact bone, particularly running, physical activity differentially affects bone mass at the hip versus the spine. Thus, DXA measurements in the female athlete may have significant discordance between lumbar spine and femoral bone density. An overt clinical sign, such as amenorrhea does not exist for male athletes. Yet, among coaches who have worked with college male athletes, it is apparent that over-exercising and restricted eating behaviors are frequently observed, particularly in distance/endurance sports. Intense exercise coupled with disordered eating can lead to devastating changes in the skeleton, particularly during adolescence. Not only would the trajectory of peak acquisition be permanently impaired by these behaviors, but individuals could suffer career-ending changes in the musculoskeletal system. Poor fracture healing may be the first and only manifestation of disordered energy metabolism in young male athletes. Later changes include hypogonadism, infertility, gynecomastia and weight loss. These may not be detected by coaches, trainers and team mates or, if they are detected, the topic may be too sensitive for discussion by those who do not have the appropriate referral mechanisms in place to assist the athlete. Morbidity can be serious if clinically significant eating problems are diagnosed [41]. Eating disorders are increasingly more common in adolescence and young adulthood [42]. According to the Youth Risk Behavioral Survey Study, both males and females report eating problems and other risk factors that can lead to adverse skeletal health (CDC) [24]. On self-reported instruments in a national survey, 6.4% of teen females vomited or took laxatives to lose weight or keep from gaining weight during the 30 days before this survey. A smaller but significant number, 2.2%, of males were involved in behaviors of vomiting or laxative abuse prior to the survey, which is also concerning. Some of those individuals were athletes, however, this CDC-run survey was not designed to identify this subpopulation.
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The incidence of anorexia nervosa has increased and still the majority of individuals affected by disordered eating do not meet strict Diagnostic and Statistical Manual IV (DSMIV-TR) criteria for eating disorders, set by the American Psychiatric Association [41]. Incidence rates are highest for females in the 15- to 19-year-old group which is about 40% of all identified cases, with another group of individuals aged 30 to 50 affected at higher rates. Some individuals who start out with anorexia nervosa convert to bulimia nervosa, another eating disorder and bulimia is estimated to affect 0.8 males per 100 000 [44]. Anorexia nervosa in males is very difficult to quantify in terms of prevalence and incidence, primarily due to stigma. However, various eating disorders can be associated with excessive exercise, whether it be in males or females. Still, it is possible that athletes who are in intense training with twice daily sessions and multiple observers may come to attention for their eating problems sooner than others. Trainers and coaches have more responsibility and education about identifying disordered eating in athletes than they have had in previous generations. For instance, if an athlete has a history of weighing more than the cutoff weights for the sport during a significant time, coaches are now told not to allow an athlete into a lower weight category in their sport. Nutrition may be poor in athletes in weight-control sports [45]. As such, long-standing energy deficiency can have profound effects on bone density and body composition. For example, long distance female runners with high scores on an eating disorder inventory (EDI) had lower bone density measurements compared to those with low EDI scores [44].
Use of androgenic and anabolic steroids in athletics The therapeutic action of androgens has been exploited for treatment of growth delay and androgen insufficiency, but deleterious effects in males who are androgen sufficient are quite common [47]. As noted previously the ‘male triad’ of excessive exercise, hypogonadism and weight loss is particularly uncommon although likely unreported. On the other hand, surreptitious use of steroids is growing and is higher in males than females. In a study by the CDC, 5.1% (4.4–5.9) of American adolescent males report having tried anabolic steroids [24]. Anabolic steroids not only have been used to improve athletic performance but also appearance and are used in younger and younger athletes [48]. Many athletes and youths often ‘stack’ the drugs, taking doses hundreds of times larger than therapeutic levels of several drug classes over a six-week cycle and then briefly go off drug as they attempt to hide from testing. More than 600 track athletes have been caught by anti-doping testing in the last 20 years. However, there is little information about
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teen users of performance-enhancing agents because they often use veterinary agents. In addition to anabolic steroids, human growth hormone has been tried by up to 5% of 10th graders [49]. There is a known withdrawal phenomenon after stopping these substances, accompanying mood changes after the hypothalamic pituitary axes has been disrupted. Anabolic steroids with androgenic properties are often associated with gynecomastia and testicular atrophy in young males. This is related to the effect of high circulating testosterone and its conversion by aromatase to estrogen. The other well known adverse effects of steroids are on lipids, glucose, sebaceous glands, hair follicles, liver and other organs. Studies of androgen abuse also suggest changes in cognition, mood, thoughts, anxiety, body dysmorphic disorder and other neurodevelopmental conditions. Aggression, violence, mania and, less frequently, psychosis and suicide have been associated with steroid abuse [50]. Some individuals who are aggressive or who have substance-induced thought disorder secondary to steroid excess may suffer injury and fracture as a result of aggressive behavior.
Bone mass and stress fractures in male athletes: A review of the literature There are numerous studies of bone mass and exercise in adolescence and young adults and the results provide significant insight into the response of the male skeleton to loading. However, many are cross-sectional and are limited by ascertainment bias [10]. In one study of 33 Asian and Caucasian males, over a 20-month period, an exercise program of circuit training increased BMC 4.3% (0.11 g) in these boys [49]. This young cohort had a mean age of 10.2 0.5 years. Fredericson et al studied elite male soccer players compared to elite male long-distance runners aged 20 to 30 years in a cross-sectional manner [52]. After adjusting for age and percent body fat, soccer players had significantly higher spine, right hip and right leg BMD than runners. Not surprisingly, runners exhibit higher calcaneal BMD than controls. Thus, directly loaded sites benefited the most from a pattern of repetitive exercise. However, 40% of the subjects in this study had T-scores between 1 and 2.5. Andreoli et al reported on 62 male subjects aged 18 to 25 years who competed at national or international levels in judo (n 21) , karate (n 14) and water polo (n 24) [3]. A comparison group of non-athletes was chosen as a control group for comparison of those athletes who exercised at least 3 hours per week. Total BMD in controls was significantly lower than judo or karate athletes but differences were not observed between controls and water polo athletes. All athletes had more muscle mass than non-trained
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controls and was highest in water polo versus the judo and karate athletes. Skeletal adaptations to chronic non-weight-bearing exercise depend on the type of aquatic exercise (swimming or water polo) [53]. In another cross-sectional study, 43 water polo players, 26 swimmers and 30 sedentary individuals, aged 17 to 34 years, were recruited (52 men, 47 women) for evaluation. Bone mineral content (BMC) and areal bone mineral density (aBMD) of the total body and of various subregions were assessed. Compared with controls, swimmers had lower leg and total aBMD (P 0.05) and water polo players had lower leg but higher arm and trunk aBMD (all P 0.05). Swimmers and water polo athletes differed at the arms (men only), trunk and total body (all higher in water polo players, at P 0.05). Bone adaptations to water polo playing were unaffected by sex. Female swimmers, but not male swimmers, had 13% higher arm BMC than controls (P 0.05), whereas male swimmers, but not female swimmers, had 12% lower leg BMC than controls (P 0.05). This team concluded that long-term water polo playing and swimming have substantially different total and regional aBMD and purported effects are not mediated by sex in water polo athletes, however, sex may mediate the
differences between swimmers and controls. Water polo playing may be preferable over swimming for maintaining bone health; both types of aquatic exercise at the elite level of participation, however, have unfavorable effects on the lower limb bones. Another study was of 12 male Finish tennis players evaluated by peripheral quantitative computed tomography (pQCT) [54]. This followed a classic study by Kannus et al 1995 that rigorous training during childhood and after puberty conferred a great change in the dominant arm’s BMD (Figure 41.2) [55]. McClanahan and colleagues performed a cross-sectional study investigating the effects of participation in various sports on contralateral differences in BMD of upper and lower limbs [56]. BMD of arms and legs was measured using DXA in 184 collegiate athlete subjects at a Division I school. These athletes represented basketball, football, golf, soccer, tennis, cross-country, volleyball and both indoor and outdoor track and field. Results revealed greater BMD in right arms compared with left arms for all teams, with most pronounced differences observed in both men’s and women’s tennis and men’s baseball. They noted differences in lower limbs were less common and no significant differences in
Percent difference in bone mass between dominant and nondominant arm
25
20
15
10
5
0 Controls
After puberty
Before puberty
Onset of rigorous training Note: Most people (controls) have a small difference in bone mass between their dominant and nondominant arm due to greater daily, though not strenuous, use of the arm. In competitive racquet sport players (tennis or squash), the differences in the two arms are exaggerated. Moreover, if the player began rigorous training before puberty the differences can be greater than 20%. This indicates the powerful influence of physical activity during the adolescent period. Source: Kannus et al. 1995.
Figure 41.2 Bone mass differences in the playing arms of women racket players.
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lower limb BMD were found in women. In men, differences in lower limb BMD were found in football and tennis with a non-dominant leg having greater bone mass. Exercised-induced bone gain may be due to enlargement in bone size, without a change in volumetric bone density [54]. In one such study, pQCT variables were analyzed for BMC, total cross-sectional area of bone (Tot.Ar), crosssectional area of the marrow cavity (M.Cav.Ar), cortical bone (Co.Ar) and trabecular bone (Tr.Ar), volumetric density of cortical (Co.Dn) and trabecular (Tr. Dn) bone, cortical wall thickness (Co.Wi.Th), bone strength index (BSI) and principal moments of inertia (I(min) and I(max)). In the players, significant side-to-side differences, in favor of the dominant (playing) arm, were found in BMC (ranging 14–27%), Tot.Ar (16–21%), Co.Ar (12–32%), BSI (23–37%), I(min) (33–61%) and I(max) (27–67%) at all measured bone sites and in Co.Wi.Th (5–25%) at the humeral and radial shafts and distal humerus. The side-to-side M.Cav.Ar difference was significant at the proximal humerus (19%) and radial shaft (29%). Controls in Haapasalo’s group had significant dominant-to-non-dominant side differences in BMC but were less than those of the trained athletes. The playing arm’s extra bone mineral was mainly due to increased bone size, not due to a change in volumetric bone density. Interestingly, volumetric bone density was almost identical in the dominant and non-dominant arms of both players and controls. Rittweger et al used bone–muscle strength indices for the lower human leg and reported that bone architecture depends critically on the muscle cross-section and tension development [57]. Their study performed pQCT on volleyball players who were women, using men as controls. Muscle–bone strength indices (MBSIs) were developed from compression and bending. Significant correlations were found between muscle cross-sectional area and bone at all sections investigated (shank levels of the lower leg at 4.14.33 and 66% from the distal end). Fifteen of the female athletes had significantly greater Compression Index (100 bone area/muscle area) than the control (male) subjects. No gender differences in MBSI were found. Age was not a significant effect. Bone geometry (e.g. the tibial length) influenced the geometrical distribution of the bone mineral, as it was found that long bones adapted to the same compressive strength are wider than short ones. The strongest correlation for compression was observed at the sections at 14% (correlation coefficient r 0.74), where the size of bone, 4.10 0.46 cm2 bone, on average, was related to 100 cm2 muscle. To address the issue of ascertainment bias of crosssectional studies, Baxter-Jones studied characteristics of sports participants. Anthropometric determinants and sexual maturation were studied in 232 male athletes over 3 consecutive years [58]. Predicted height targets were inferred from parental heights and subjects were chosen from four sports: soccer, gymnastics, swimming and tennis. Using a linked
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longitudinal cohort study design, they were able to extract 3 years of data and map 11-year development patterns. They found that male swimmers had higher adjusted height than gymnasts and soccer players. Similarly, mean body mass was greater in male swimmers than the other groups, as was testicular volume. They also concluded that swimmers reached maturity earlier than other exercise groups, particularly gymnasts. Training of these individuals began prior to puberty suggesting that the tracking of sexual maturation in athletes depends on the sport selection and the subsequent success of the individual. Regional and total BMD were assessed in highly competitive youth, adult and master male cyclists by Nichols and colleagues [59]. Older cyclists (age 51.2 5.3 years), younger cyclists (31.7 3.5 years) and 24 non-athletes were matched by age and weight to the master cyclists. Minimum training time was 10 years for the masters, mean of 20.2 8.4 years. Younger cyclists were involved racing for 10.9 3.2 years. They used the History of Leisure Activity Questionnaire to determine the influence of BMD and self-reported total and weight-bearing activity during three life periods (12–18 years, 19–34 years and 35–49 years). BMD assessed by DXA at spine and total hip was significantly lower in the master cyclists compared to age matched controls and young adult cyclists (P 0.033). Being involved in weight-bearing activity in the teen and young adult years did not appear to influence BMD. These data show that master cyclists with a long history of training exclusively in cycling have low BMD compare to their age-matched peers. In another study, 140 Finnish male conscripts, with a mean age of 19.8 years, were studied for aerobic performance, muscle strength and body composition using DXA. The relationship between muscle strength and BMD was confirmed but, interestingly, muscle mass did not predict muscle strength in these conscripts [60]. Military recruits of both sexes, as mentioned previously, have served as the sample of several studies in non-athletic populations. When stratified for fitness, men entering service with low levels of running performance had a higher incidence of stress fractures [61]. In this particular study, gender differences in stress fracture incidence were eliminated when fitness was used as a covariate. BMD in men was analyzed in a meta-analysis of eight studies to evaluate the effect of size of exercise on bone mass [62]. BMD sites were assessed according to the sites loaded during exercise. There were mean increases of 2.1% in exercisers and 0.05% in controls. The difference was 2.6% and was statistically significant according to the techniques used in the meta-analysis. Statistical significance was found for the femur, lumbar spine and os calcis sites for older men, but not those under 31 years of age (P 0.04). Hind and Burroughs performed a meta-analysis of 22 longitudinal trials that included definitive Tanner staging
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in youths. They used online searches of the Cochrane and Medline databases [63]. Trial duration ranged from 3 to 48 months. Studies were included if they had at least two measurement points of healthy youths and not athletes. They used BMD or BMC as primary outcome measures; secondary outcome measures included structural bone parameters. Bone sites of measurement were hip, lumbar spine, and total body. With approximately 10 to 65 subjects per study and ranging in duration from 3 to 48 months, half of these selected trials included data on groundreaction force (GFR) and reported on changes in bone parameters over approximately 6 months. In girls, weightbearing exercise enhanced bone accrual, although issues of statistical modeling and sample size were considered significant limitations. Not surprisingly, the main finding of the meta-analysis was that the trials were conducted in a way that had high risk for bias because of selection, compliance and control variables. Notwithstanding, positive skeletal effects can probably be attained in both girls and boys with exercise. Studies of bone quality and volumetric BMD will be needed in future studies during bone accrual to build a stronger evidence base. Surrogate markers of bone turnover also provide insight into loading and the skeleton. One team in Washington [64] studied Division I athletes and an age-matched control group and showed that, after adjusting for BMI, urinary turnover markers were highest for rowers and runners, compared to swimmers or controls. In another study, BMD and bone markers were evaluated by repetitive impact (high, medium or low) in athletes and sedentary controls [65]. Not surprisingly, the high impact group showed the greatest increase in bone turnover markers. In a separate study of bone markers, studies of male and female judoists and swimmers showed that judoists had a higher bone mass and a higher deoxypyridinoline crosslinks to creatinine ratio (DPD/Cr), when compared with swimmers [66]. To determine the effect on bone remodeling of physical activity that induces moderate external loading on the skeleton, 38 male athletes and 10 age-matched controls were studied [67]. Bone turnover assessments were coupled with DXA findings along with biochemical markers. Serum bone-specific alkaline phosphatase, osteocalcin, urinary type I collagen C-telopeptide and calcium were assessed. Comparing controls and swimmers, adjusted BMD was higher in triathletes (P 0.05) at the total proximal femur and lower limbs. No differences in BMD were found between swimmers, cyclists or controls. Compared with controls, osteocalcin was higher (P 0.05) in triathletes and swimmers and urinary type I collagen C-telopeptide was higher in swimmers. Bone specific alkaline phosphatase was lower (P 0.05) in cyclists than in all groups. Bone turnover in athletes differed from controls. Bone turnover may be sport-practiced dependent, so that under high mechanical stress, osteogenic effects were found only in triathletes in Maimoun’s study.
Stress Fractures A number of techniques have been used to assess fractures and failure of bone in athletes. These include radionuclide bone scans, CT imaging and magnetic resonance imaging (MRI). MRI has enhanced spatial resolution and clear depiction of inflammation and repair, can be used to observe bone edema and appears to be more precise in the assessment of tibial tenderness than previous techniques [52]. For example, bone scans, CT and MRI measurements were analyzed in 42 athletes with tibial pain [68]. Initial radiography was negative for injury, but these techniques were performed within a month of onset of pain. Sensitivities of MRI, CT and bone scintigraphy were 88%, 42% and 74%, respectively. Thus MRI is superior for tibial stress injury, but CT can depict osteopenia, which may be the earliest finding of fatigue cortical bone injury. Studies assessing stress fracture incidence in track and field sports and in competitive running are numerous [69, 70]. In one study, 20–27% of athletes sustained at least one stress fracture [71]. In another study, 60% of male and female track and field athletes reported a history of stress fracture [69]. Nattiv reported a history of prior stress fractures of 64% in all athletes with the previous stress injury [72]. There are several risk fractures for stress fractures in women, such as decreased calf girth, reduced lower limb mass, discrepancy in leg length and menstrual irregularities [71, 72]. In male runners, mechanical forces, including narrower tibial diameter and lower area moment of inertia, have been correlated with fracture risk [73]. Lower body weight and lower hip eccentric strength were also considered major risk factors for stress fractures in male track and field athletes. Kiuru and colleagues conducted a cohort study of 21 male elite unit military recruits to understand bone stress injuries [74]. All of the military recruits were scanned with MRI before, after 6 weeks and after a 5-month intensive training program. Based on MRI findings, a total of 75 bone stress injuries were detected. However, a minority of them, 40% (30/75) were symptomatic. Symptoms depended on location and MRI grade of injury, with higher grades usually more symptomatic. Repeated clinical and magnetic resonance imaging assessment indicated that asymptomatic grade I bone stress injuries healed (21/25, 84%) or remained grade I and asymptomatic (3/25, 12%). They noted increased fractures toward the end of the intensive training period. The authors conclude that asymptomatic grade I bone stress injuries seem common in subjects undergoing training. Recurrent stress fractures can be a difficult problem for athletes. One group of researchers sought to identify factors predisposing athletes to multiple stress fractures with the hypothesis that certain anatomical features of the ankle are associated with multiple stress fractures of the lower extremity in athletes [75]. Nineteen of the 31 athletes they
C h a p t e r 4 1 The Skeletal Phenotype of the Male Athlete l
studied were men who had suffered at least three separate stress fractures each. They used a control group of 15 athletes without fractures who completed questionnaires about putative risk factors for stress fractures, such as training history, nutrition and, for women, hormonal history in the 12 women. DXA was performed on the lumbar spine and proximal femur. They sought to understand biomechanical features, such as structure of the foot, degree of pronation and supination, ankle dorsiflexion of the ankle, forefoot varus and valgus, leg length inequality, range of hip rotation, simple and choice reaction times and balance. A total of 114 fractures were noted in these athletes, an average of 3.7 (with a range of 3 to 6); 61% of the patients were runners with weekly running mileage of 117 km. Biomechanical forces associated with multiple stress fractures were: 1. high longitudinal arch of the foot 2. leg length inequality 3. excessive forefoot varus. High weekly training mileage was a risk for recurrent stress fractures of the lower extremities.
Conclusions The male athlete represents a unique model for studying the acquisition and maintenance of bone mass. Mechanical loading clearly impacts the skeleton in a site-specific manner, but hormonal, environmental and nutritional determinants are important covariates. Moreover, there are certain to be genetic determinants that predispose individuals to gain or loss of bone under specific training regimens. Most importantly, the paucity of well-powered longitudinal trials, particularly in the adolescent male, is apparent. Further studies are needed to delineate the developmental sequence of bone acquisition in the male athlete and to define the geometric properties of skeletal sites that are loaded in various ways.
References 1. C.B. Ruff, B. Holt, E. Trinkaus, Who’s Afraid of the Big Bad Wolff?: ‘Wolff’s Law’ and Bone Functional Adaptation, Amer. J. Phys. Anthropol. 129 (2006) 484–498. 2. 2009 Available from: http://agonist.org/20090212/how_ broken_arm_led_scientists_to_genome_of_neanderthals 3. A. Andreoli, M. Monteleone, M. Van Loan, L. Promenzio, U. Tarantino, A. De Lorenzo, Effects of different sports on bone density and muscle mass in highly trained athletes, Med. Sci. Sports Exerc. 33 (4) (2001) 507–511. 4. R. Marcus, Mechanisms of exercise effects on bone, Academic Press, San Diego, 1996. 5. R.T. Whalen, D.R. Carter, C.R. Steele, Influence of physical activity on the regulation of bone density, J. Biomechanics 21 (10) (1988) 825–837.
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6. C.W. Slemenda, J.Z. Miller, S.L. Hui, T.K. Reister, C.C. Johnston Jr, Role of physical activity in the development of skeletal mass in children, J. Bone Miner. Res. 6 (11) (1991) 1227–1233. 7. D. Karasik, D.P. Kiel, Genetics of the musculoskeletal system: a pleiotropic approach, J. Bone Miner. Res. 23 (6) (2008) 788–802. 8. E. Seeman, Sexual dimorphism in skeletal size, density, and strength, J. Clin. Endocrinol. Metab. 86 (2001) 4576–4584. 9. C. Snow-Harter, R. Whalen, K. Myburgh, S. Arnaud, R. Marcus, Bone mineral density, muscle strength, and recreational exercise in men, J. Bone Miner. Res. 7 (11) (1992) 1291–1296. 10. A. Nattiv, Stress fractures and bone health in track and field athletes, J. Sci. Med. Sport 3 (3) (2000) 268–279. 11. F. Lima, V. De Falco, J. Baima, J.G. Carazzato, R.M. Pereira, Effect of impact load and active load on bone metabolism and body composition of adolescent athletes, Med. Sci. Sports Exerc. 33 (8) (2001) 1318–1323. 12. C.W. Slemenda, T.K. Reister, S.L. Hui, J.Z. Miller, J.C. Christian, C.C. Johnston Jr, Influences on skeletal mineralization in children and adolescents: evidence for varying effects of sexual maturation and physical activity, J. Pediatr. 125 (2) (1994) 201–207. 13. J.C. Ruiz, C. Mandel, M. Garabedian, Influence of spontaneous calcium intake and physical exercise on the vertebral and femoral bone mineral density of children and adolescents, J. Bone Miner. Res. 10 (5) (1995) 675–682. 14. K. Uusi-Rasi, H. Haapasalo, P. Kannus, M. Pasanen, H. Sievanen, P. Oja, et al., Determinants of bone mineralization in 8 to 20 year old Finnish females, Eur. J. Clin. Nutr. 51 (1) (1997) 54–59. 15. G.D. Wheeler, S.R. Wall, A.N. Belcastro, D.C. Cumming, Reduced serum testosterone and prolactin levels in male distance runners, J. Am. Med. Assoc. 252 (4) (1984) 514–516. 16. L. Maimoun, S. Lumbroso, J. Manetta, F. Paris, J.L. Leroux, C. Sultan, Testosterone is significantly reduced in endurance athletes without impact on bone mineral density, Horm. Res. 59 (6) (2003) 285–292. 17. K.J. MacKelvie, J.E. Taunton, H.A. McKay, K.M. Khan, Bone mineral density and serum testosterone in chronically trained, high mileage 40–55 year old male runners, Br. J. Sports Med. 34 (4) (2000) 273–278. 18. J. Huuskonen, S.B. Vaisanen, H. Kroger, J.S. Jurvelin, E. Alhava, R. Rauramaa, Regular physical exercise and bone mineral density: a four-year controlled randomized trial in middle-aged men. The DNASCO study, Osteoporos. Int. 12 (5) (2001) 349–355. 19. G. Maccarinelli, V. Sibilia, A. Torsello, et al., Ghrelin regulates proliferation and differentiation of osteoblastic cells, J. Endocrinol. 184 (1) (2005) 249–256. 20. M. Kawai, C.J. Rosen, Insulin-like growth factor-I and bone: lessons from mice and men, Pediatr. Nephrol. 24 (7) (2009) 1277–1285. 21. C.M. Snow, C.J. Rosen, T.L. Robinson, Serum IGF-I is higher in gymnasts than runners and predicts bone and lean mass, Med. Sci. Sports Exerc. 32 (11) (2000) 1902–1907. 22. C.L. Ackert-Bicknell, S. Demissie, C.M. de Evsikova, et al., A PPARG by dietary fat interaction influences bone mass in mice and humans, J. Bone Miner. Res. 23 (9) (2008) 1398–1408.
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23. I.I. Ahmetov, I.A. Mozhayskaya, D.M. Flavell, et al., PPARalpha gene variation and physical performance in Russian athletes, Eur. J. Appl. Physiol. 97 (1) (2006) 103–108. 24. CDC. YRBSS. Accessed 2/27/09 http://www.cdc.gov/ HealthyYouth/yrbs/pdf/yrbss07_mmwr.pdf 25. D.A. Gentile, A. David, A. Walsh, normative study of family media habits, J. Appl. Devel. Psychol. 23 (2) (2002) 157–178. 26. R. Pate, M. Dowda, J. O’Neill, D. Ward, Change in physical activity participation among adolescent girls from 8th to 12th grade, J. Phys. Act Health 4 (1) (2007) 3–16. 27. A. Nordstrom, T. Olsson, P. Nordstrom, Sustained benefits from previous physical activity on bone mineral density in males, J. Clin. Endocrinol. Metab. 91 (7) (2006) 2600–2604. 28. L. Van Langendonck, J. Lefevre, A.L. Claessens, et al., Influence of participation in high-impact sports during adolescence and adulthood on bone mineral density in middleaged men: a 27-year follow-up study, Am. J. Epidemiol. 158 (6) (2003) 525–533. 29. K. Froiland, W. Koszewski, J. Hingst, L. Kopecky, Nutritional supplement use among college athletes and their sources of information, Int. J. Sport Nutr. Exerc. Metab. 14 (1) (2004) 104–120. 30. K. Kunstel, Calcium requirements for the athlete, Curr. Sports Med. Rep. 4 (4) (2005) 203–206. 31. R.L. Wolman, P. Clark, E. McNally, M.G. Harries, J. Reeve, Dietary calcium as a statistical determinant of spinal trabecular bone density in amenorrhoeic and oestrogen-replete athletes, Bone Miner. 17 (3) (1992) 415–423. 32. G. Jones, M.D. Riley, S. Whiting, Association between urinary potassium, urinary sodium, current diet, and bone density in prepubertal children, Am. J. Clin. Nutr. 73 (4) (2001) 839–844. 33. H. Vatanparast, A. Baxter-Jones, R.A. Faulkner, D.A. Bailey, S.J. Whiting, Positive effects of vegetable and fruit consumption and calcium intake on bone mineral accrual in boys during growth from childhood to adolescence: the University of Saskatchewan Pediatric Bone Mineral Accrual Study, Am. J. Clin. Nutr. 82 (3) (2005) 700–706. 34. K.L. Tucker, M.T. Hannan, D.P. Kiel, The acid-base hypothesis: diet and bone in the Framingham Osteoporosis Study, Eur. J. Nutr. 40 (5) (2001) 231–237. 35. K.L. Tucker, H. Chen, M.T. Hannan, et al., Bone mineral density and dietary patterns in older adults: the Framingham Osteoporosis Study, Am. J. Clin. Nutr. 76 (1) (2002) 245–252. 36. J.P. Ruohola, I. Laaksi, T. Ylikomi, et al., Association between serum 25(OH)D concentrations and bone stress fractures in Finnish young men, J. Bone Miner. Res. 21 (9) (2006) 1483–1488. 37. O. Nakamura, T. Ishii, Y. Ando, et al., Potential role of vitamin D receptor gene polymorphism in determining bone phenotype in young male athletes, J. Appl. Physiol. 93 (6) (2002) 1973–1979. 38. C.L. Otis, Exercise-associated amenorrhea, Clin. Sports Med. 11 (2) (1992) 351–362. 39. M. Shangold, R.W. Rebar, A.C. Wentz, I. Schiff, Evaluation and management of menstrual dysfunction in athletes, J. Am. Med. Assoc. 263 (12) (1990) 1665–1669. 40. J.F. Nichols, M.J. Rauh, M.J. Lawson, M. Ji, H.S. Barkai, Prevalence of the female athlete triad syndrome among high school athletes, Arch. Pediatr. Adolesc. Med. 160 (2) (2006) 137–142.
41. E.J. Harbottle, C.L. Birmingham, F. Sayani, Anorexia nervosa: a survival analysis, Eat Weight Disord. 13 (2) (2008) e32–e34. 42. J. Haines, D. Neumark-Sztainer, M.E. Eisenberg, P.J. Hannan, Weight teasing and disordered eating behaviors in adolescents: longitudinal findings from Project EAT (Eating Among Teens), Pediatrics 117 (2) (2006) e209–e215. 43. H.W. Hoek, D. van Hoeken, Review of the prevalence and incidence of eating disorders, Int. J. Eating Disord. 34 (4) (2003) 383–396. 44. H.W. Hoek, A.I. Bartelds, J.J. Bosveld, et al., Impact of urbanization on detection rates of eating disorders, Am. J. Psychiatr. 152 (9) (1995) 1272–1278. 45. H.J. Petrie, E.A. Stover, C.A. Horswill, Nutritional concerns for the child and adolescent competitor, Nutrition 20 (7-8) (2004) 620–631. 46. K.L. Cobb, L.K. Bachrach, G. Greendale, et al., Disordered eating, menstrual irregularity, and bone mineral density in female runners, Med. Sci. Sports Exerc. 35 (5) (2003) 711–719. 47. D. Vanderschueren, L. Vandenput, S. Boonen, M.K. Lindberg, R. Bouillon, C. Ohlsson, Androgens and bone, Endocr. Rev. 25 (3) (2004) 389–425. 48. A. Levin, Psychiatrists urged to learn signs of steroid use, Psychiatr. News 43 (24) (2008) 14–21. 49. J.M. Tokish, M.S. Kocher, R.J. Hawkins, Ergogenic aids: a review of basic science, performance, side effects, and status in sports, Am. J. Sports Med. 32 (6) (2004) 1543–1553. 50. A.J. Trenton, G.W. Currier, Behavioural manifestations of anabolic steroid use, CNS Drugs 19 (7) (2005) 571–595. 51. J.M. Kerry, A.P. Moira, M.K. Karim, J.B. Thomas, A.M. Heather, Bone mass and structure are enhanced following a 2-year randomized controlled trial of exercise in prepubertal boys, Bone 34 (4) (2004) 755–764. 52. M. Fredericson, A.G. Bergman, K.L. Hoffman, M.S. Dillingham, Tibial stress reaction in runners. Correlation of clinical symptoms and scintigraphy with a new magnetic resonance imaging grading system, Am. J. Sports Med. 23 (4) (1995) 472–481. 53. F. Magkos, S.A. Kavouras, M. Yannakoulia, M. Karipidou, S. Sidossi, L.S. Sidossis, The bone response to non-weightbearing exercise is sport-, site-, and sex-specific, Clin. J. Sport Med. 17 (2) (2007) 123–128. 54. H. Haapasalo, S. Kontulainen, H. Sievänen, P. Kannus, M. Järvinen, I. Vuori, Exercise-induced bone gain is due to enlargement in bone size without a change in volumetric bone density: a peripheral quantitative computed tomography study of the upper arms of male tennis players, Bone 27 (3) (2000) 351–357. 55. P. Kannus, H. Haapasalo, M. Sankelo, et al., Effect of starting age of physical activity on bone mass in the dominant arm of tennis and squash players, Ann. Intern. Med. 123 (1) (1995) 27–31. 56. B.S. McClanahan, K. Harmon-Clayton, K.D. Ward, R.C. Klesges, C.M. Vukadinovich, E.D. Cantler, Side-to-side comparisons of bone mineral density in upper and lower limbs of collegiate athletes, J. Strength Cond. Res. 16 (4) (2002) 586–590. 57. J. Rittweger, G. Beller, J. Ehrig, et al., Bone-muscle strength indices for the human lower leg, Bone 27 (2) (2000) 319–326. 58. A.D. Baxter-Jones, S.A. Kontulainen, R.A. Faulkner, D.A. Bailey, A longitudinal study of the relationship of
C h a p t e r 4 1 The Skeletal Phenotype of the Male Athlete l
59.
60.
61.
62.
63.
64.
65.
66.
physical activity to bone mineral accrual from adolescence to young adulthood, Bone 43 (6) (2008) 1101–1107. J.F. Nichols, J.E. Palmer, S.S. Levy, Low bone mineral density in highly trained male master cyclists, Osteoporos. Int. 14 (8) (2003) 644–649. V.M. Mattila, K. Tallroth, M. Marttinen, H. Pihlajamaki, Physical fitness and performance. Body composition by DEXA and its association with physical fitness in 140 conscripts, Med. Sci. Sports Exerc. 39 (12) (2007) 2242–2247. B.H. Jones, M.W. Bovee, J.M. Harris III, D.N. Cowan, Intrinsic risk factors for exercise-related injuries among male and female army trainees, Am. J. Sports Med. 21 (5) (1993) 705–710. G.A. Kelley, K.S. Kelley, Z.V. Tran, Exercise and bone mineral density in men: a meta-analysis, J. Appl. Physiol. 88 (5) (2000) 1730–1736. K. Hind, M. Burrows, Weight-bearing exercise and bone mineral accrual in children and adolescents: a review of controlled trials, Bone 40 (1) (2007) 14–27. J.W.O. Kane, E. Hutchinson, L.M. Atley, D.R. Eyre, Sportrelated differences in biomarkers of bone resorption and cartilage degradation in endurance athletes, Osteoarthritis and cartilage/ OARS, Osteoarthritis Research Society 14 (1) (2006) 71–76. D.L. Creighton, A.L. Morgan, D. Boardley, P.G. Brolinson, Weight-bearing exercise and markers of bone turnover in female athletes, J. Appl. Physiol. 90 (2) (2001) 565–570. T. Matsumoto, S. Nakagawa, S. Nishida, R. Hirota, Bone density and bone metabolic markers in active collegiate athletes: findings in long-distance runners, judoists, and swimmers, Int. J. Sports Med. 18 (6) (1997) 408–412.
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67. L. Maimoun, D. Mariano-Goulart, I. Couret, et al., Effects of physical activities that induce moderate external loading on bone metabolism in male athletes, J. Sports Sci. 22 (9) (2004) 875–883. 68. M. Gaeta, F. Minutoli, E. Scribano, et al., CT and MR imaging findings in athletes with early tibial stress injuries: comparison with bone scintigraphy findings and emphasis on cortical abnormalities, Radiology 235 (2) (2005) 553–561. 69. K.L. Bennell, S.A. Malcolm, S.A. Thomas, et al., Risk factors for stress fractures in female track-and-field athletes: a retrospective analysis, Clin. J. Sport Med. 5 (4) (1995) 229–235. 70. K.L. Bennell, K. Crossley, Musculoskeletal injuries in track and field: incidence, distribution and risk factors, Aust. J. Sci. Med. Sport 28 (3) (1996) 69–75. 71. K.L. Bennell, P.D. Brukner, Epidemiology and site specificity of stress fractures, Clin. Sports Med. 16 (2) (1997) 179–196. 72. A. Nattiv, J.C. Puffer, J. Casper, F. Dorey, Stress fracture risk factors, incidence and distribution: A 3 year prospective study in collegiate runners, Med. Sci. Sports Exerc. (Suppl. 5) (2000) S347. 73. K. Crossley, K.L. Bennell, T. Wrigley, B.W. Oakes, Ground reaction forces, bone characteristics, and tibial stress fracture in male runners, Med. Sci. Sports Exerc. 31 (8) (1999) 1088–1093. 74. M.J. Kiuru, M. Niva, A. Reponen, H.K. Pihlajamaki, Bone stress injuries in asymptomatic elite recruits, Am. J. Sports Med. 33 (2) (2005) 272–276. 75. R. Korpelainen, S. Orava, J. Karpakka, P. Siira, A. Hulkko, Risk factors for recurrent stress fractures in athletes, Am. J. Sports Med. 29 (3) (2001) 304–310.
Chapter
42
Inherited and Related Disorders of Bone Matrix Synthesis in Men Jay R. Shapiro Bone and Osteogenesis Imperfecta Programs, Kennedy Krieger Institute; Department of Physical Medicine and Rehabilitation, Johns Hopkins University, Baltimore, Maryland, USA
Introduction
Table 42.1 Inherited bone diseases in men
Research during the past several years has added a remarkable amount of information related to heritable diseases involving abnormalities in bone matrix synthesis (Table 42.1). Contributing to this are advances in gene recognition with the definition of mutations affecting tissue factors essential for normal bone development. The development of novel murine models, particularly those involving gene deletion, has provided important information relative to human bone disorders. Basic research in bone cell physiology has tremendously enhanced our understanding of the interactive role specific bone-related proteins, including transcription factors, receptors and their ligands, play in control of osteoblast and osteoclast differentiation and function [1]. Mesenchymal stem cells are the pool from which osteoblasts and osteocytes are derived. The transcription factor Runx2, which is expressed by mesenchymal cells, plays a major role in the determination of osteoblast commitment and differentiation [2, 3]. Osterix, a zinc finger transcription factor, promotes development of pre-osteoblasts to immature osteoblasts [2]. Recently, the Wnt-B catenin signaling pathway has been found to impact osteoblastogenesis in part by regulating transcription factors including Runx2. Other important factors directing osteoblast development are ATF4, API and homeobox proteins. These, in turn, respond to bone regulating hormones such as parathyroid hormone that activates Runx2, 1,25(OH)2 vitamin D, growth hormone and insulin-like growth factor-I (IGF-I) and glucocorticoids. Bone morphogenetic proteins (BMP), approximately 20 in number, are multifunctional members of the transforming growth factor- (TGF-) beta superfamily. BMPs are involved in embryonic and postnatal bone development by influencing mesenchymal stem cell maturation, osteoblast expansion and differentiation and bone formation. Downstream of BMP receptors, Smad proteins 1, 5, 8 in combination with Smad 4 transduce BMP signals to target genes [4, 5]. Osteoporosis in Men
Syndrome
Inheritance Protein
Osteogenesis imperfecta Bruck syndrome Marfan syndrome Ehlers–Danlos syndromes Menkes’ disease
AD, AR
Occipital horn syndrome Wilson’s disease Homocystinuria Hemochromotosis
X-linked hypophosphatasia Rett syndrome
AR AD AD, AR X-linked recessive X-linked recessive AR AR AR
CoL1A1, COLA2, CRTAP, LEPRE1 PLOD 2 FBN 1 COLV, COL III P(1B)-type ATPase ATP7A. ATP7A
X-linked
ATP7B Cystathionine B-synthase HFE (C282Y homozygotes or C282Y/H63D compound heterozygotes) TNSALP
X-linked
MeCP2
AD: Autosomal dominant; AR: autosomal recessive
Osteoclasts are derived from monocyte/macrophage precursors. Mesenchymal cell commitment to osteoclast development involves the monocyte precursor granulocytemacrophage colony forming cells responding to the cytokines MCSF, PU.i, the MITF transcription factor and members of the c-FOS family. However, it is the RANK/ RANK ligand/osteoprotegerin group stemming from osteoblasts and activated T cells acting through the NF-kB pathway that are the major factors influencing osteoclast multinucleation and differentiation [6, 7]. Considering the multiplicity of factors involved in osteo blast and osteoclast development, it is reasonable to hypothesize that mutations involving certain of these factors will explain bone disorders that are considered ‘idiopathic’ at 505
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this time. Cleidocranial dysplasia, a disorder of bone modeling due to haploinsufficiency of Runx2, is an example of a skeletal disorder secondary to mutations involving the major transcription factors regulating osteoblast development [8]. Another level of complexity is defining the relationship of genotype to phenotype. To date, this correlation has not been defined for several of these disorders. As typified by genotype/phenotype relationships in osteogenesis imperfecta, there is considerable overlap in clinical expression in the presence of mutations assumed by their location, mechanism by which the size of deletions or specific amino acid substitutions lead to either mild or severe disease [9]. Also, in Marfan syndrome, the presence of a fibrillin-1 mutation does not itself confirm the diagnosis in the absence of other supporting data.
Inherited defects in collagen synthesis (Table 42.2) The collagens comprise a large and diverse family of triple helical proteins which differ in size, structure and function. The 29 collagen types described to date with interrupted triple helices are the products of 40 genes on 12 chromosomes. Collagen proteins exhibit significant functional specificity. This ranges from type I collagen, the major structural protein in bone, ligaments and tendon, to type II collagen in cartilage to the collagens associated with basement membranes and those related to bone cells regulating endochondral bone formation. Collagens are major
Table 42.2 Inherited disorders of collagen synthesis Disease
Collagen type
Osteogenesis imperfecta Stickler syndrome Achondrogenesis type II Spondyloepiphyseal dysplasia congenital Ehlers–Danlos syndrome type IV Ehlers–Danlos syndrome type I Alport syndrome Ullrick and Bethlem myopathy Epidermolysis bullosum Multiple epiphyseal dysplasia type II
COL1A1, COL1A2 COL II COL2A1 Col2a1 COL III COL1(A1), COLV(A1,A2,A3) COL IV COL VI Col VII COL IX: A1, A2, A3 COL IX COL X
Schmid metaphyseal chondrodysplasia Otospondylomegaepiphyseal COLXI dysplasia Weissenbacher–Zweymuller syndrome COL11A2 Stickler syndrome II and III COL11A2 Marshall syndrome
components of basement membranes and vascular connective tissue. The collagen types have been grouped into classes based on their structure and source: the fibrillar collagens (types I, II, V and XI), interstitial collagens, collagens forming sheets as with basement membrane (IV and VIII) and the fibril associated collagens (FACIT), types IX, XII, XIV and XIX [10]. The collagens triple helix molecule is constructed of three polypeptide or alpha-chains arranged with a right-handed supercoil and a one residue stagger between adjacent chains. Alpha chains are identical in some collagens or may differ as the two alpha-1 and one alpha-2 chains of type I collagen. Each alpha chain has a repeating triple (Gly-X-Y) where glycine occupies the first position and other amino acids, but particularly proline or 4-hydroxyproline, occupy the second or third positions [11]. It is type I collagen synthesis by the osteoblast that directs deposition of bone matrix and the process of calcification. Tissue culture studies of osteoblasts derived from patients with osteogenesis imperfecta (OI) have shown that, in the presence of type I collagen mutations, the production of other essential bone matrix proteins is abnormal. Not only have specific bone cell matrix components (collagen, osteonectin, the large chondroitin sulfate proteoglycan, biglycan and decorin) been found to be present in reduced levels in OI bone cells, but certain matrix components (thrombospondin, fibronectin and hyaluronan) have been found to be present in elevated levels in the matrix of cultured OI osteoblasts [12].
Osteogenesis Imperfecta as a Cause of Male Osteoporosis In the majority of patients, the diagnosis of OI depends on clinical findings. These include a history of fractures having occurred at a young age, short stature, blue sclerae, dentinogenesis imperfecta, early onset hearing loss, joint hyperextensibility and scoliosis. Most, but not all, adults with OI have decreased bone mineral density measured by dual energy x-ray absorptiometry (DXA). More severely affected individuals have skeletal deformity and may be wheelchair bound [13]. Obtaining a molecular diagnosis based on DNA sequencing is helpful in an index patient or in a member of an affected family where being able to target the mutation will be helpful. One example is where prenatal testing is indicated. The molecular diagnosis of OI relies on two modalities: 1. the gel electrophoresis analysis of collagen protein synthesized by dermal fibroblasts obtained by skin biopsy 2. more preferred, the direct sequence analysis of potentially involved genes: COL1A1, Col 1A2 or CRTAP and LEPRE1 DNA that is usually obtained from blood cells. In each instance, the ability to detect mutations approaches 90%. Most patients will have mutations involving COL1A1
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or COL 1A2 genes of type I collagen. CRTAP and LEPRE1 mutations account for approximately 3% of OI patients, usually those with severe or lethal disease in which there is recessive pattern of inheritance [14, 15]. Osteogenesis imperfecta is a systemic disorder resulting from defective type I collagen synthesis. Because type I collagen is the main structural protein in bone, the major clinical features involve bone fragility expressed as increased susceptibility to fracture and resulting in bone deformity in the more severe phenotypes. The initial Sillence classification of OI has been expanded to include eight phenotypes [16]. Mutations involving type I collagen have been defined for OI types I–IV, VII and VIII. To date, the genetic basis for types V and VI OI have not been defined. For data regarding specific type I collagen mutations reported to date in OI please refer to the Collagen Mutation Database maintained by R. Dalgleish at the University of Leicester, UK: http://www.le.ac.uk/ge/collagen/ Type I OI Type I OI is relatively mild in terms of fracture incidence and skeletal deformities. Fibroblast and osteoblast cell culture studies have shown that, in type I OI, half normal amounts of type I collagen are produced as a consequence of mutations affecting one allele leading to stop codons which cause chain termination. The mutated protein is degraded in the cell nucleus leading to a ‘null allele’ effect and thus diminished secretion of normal type I procollagen into the extracellular matrix. As a result, type I OI, classified as ‘mild’ disease, exhibits relatively normal bone architecture and normal fracture healing. In other OI phenotypes, the mutated protein is secreted into the extracellular marix leading to impaired bone architecture and disordered fracture healing resulting in bone deformity. It is mild type I OI that should be considered diagnostically in young men presenting with osteoporosis. In the more severe phenotypes, types III, IV, VI–VIII, which are recognized clinically, concerns related to male osteoporosis per se involve functional impairment and therapy rather than diagnostic issues. Type II (Sillence) is a perinatal lethal disease with type I collagen mutations and type VIII OI refers to perinatal severe or lethal disease with CRTAP or LEPRE1 mutations. A consistent feature of all OI types is that the incidence of fractures decreases markedly after puberty. Thus, when males with osteoporosis are evaluated, their fracture history may be absent since puberty. Here, documenting the early fracture history is informative. The OI type I phenotype has the following characteristics: autosomal dominant pattern of inheritance, blue sclerae, early onset hearing loss in the second decade and the absence of significant skeletal deformity (Figure 42.1 and 42.2). Scoliosis is mild, usually less than 20 degrees, in type I OI. As in other OI types, approximately 25% have dentinogenesis imperfecta. Unlike the more severe phenotypes,
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normal height may be achieved in many patients but the majority are short for their age. Joint hyperextensibility is mild, that is less than 10 degrees at the elbow or knees, and patients are usually unable to place their palms on the floor with knees straight. There may be little functional impairment in type I OI. However, patients may complain of mild to moderate intermittent generalized musculoskeletal discomfort, the etiology of which remains unclear. This complaint is more frequent in children where it may be associated with a decrease in mobility.
Figure 42.1 Type I osteogenesis imperfecta: fractures are present in the right fibula and left tibia and fibula. Fractures appear to heal without significant residual deformity. Bone architecture is normal except for the presence of thin cortices.
Figure 42.2 Type I osteogenesis imperfecta: blue sclerae. (See color plate section).
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Hearing loss may be disclosed on testing in approximately 50% of men with OI but only 15% may require a hearing aid. Conductive, sensorineural or mixed patterns of loss are most frequent [17].
sclerae, dentinogenesis imperfecta, severe scoliosis that may progress with age leading to restrictive pulmonary disease and deformity of upper and lower extremities resulting from multiple fractures.
Type II OI Termed ‘perinatal lethal disease’, these infants succumb within a few weeks, usually due to pulmonary insufficiency. Characteristically, the extremities show crumpled broad bones and the ribs are ‘beaded’ due to healing intrauterine fractures (Figure 42.3). Due to type I collagen mutations, this phenotype overlaps with the recently designated type VIII OI in which CRTSAP and LEPRE1 mutations are present and the disorder is recessively inherited. Type III OI Termed ‘severe progressive OI’, this phenotype, which affects approximately 25% of OI patients, may occur as a result of mutations affecting either the COL1A1 or COLA2 genes, or as recently described, the CRTAP or LEPRE 1 genes. Type I collagen mutations are associated with autosomal dominant inheritance while the CRTAP and LEPRE1 mutations occur in patients with recessive inheritance patterns. Adult males with type III OI are usually wheelchair bound as a consequence of marked skeletal dysplasia (Figure 42.4 and 42.5). Clinical features include marked growth retardation, cranial molding, white or blue
Figure 42.3 Type II osteogenesis imperfecta: this infant succumbed to pulmonary insufficiency following birth. Multiple fractures are present in the upper and lower extremities, the ribs are ‘beaded’ due to healing intrauterine fractures.
Figure 42.4 Type III osteogenesis imperfecta: the patient demonstrates short stature, marked scoliosis with thoracic deformity. (See color plate section).
Figure 42.5 Type III osteogenesis imperfecta: this femur is narrow due to abnormal bone modeling and remodeling. There is no epiphysis, rather, the distal femur expands to encompass an area of dysplastic connective tissue. Fracture risk is increased.
C h a p t e r 4 2 Inherited and Related Disorders of Bone Matrix Synthesis in Men l
Type IV OI Termed ‘moderately severe’ OI in terms of skeletal dysplasia, this phenotype is clinically intermediate between types I and III. There is autosomal dominant inheritance. These patients have blue sclerae when young that tend to whiten with age, marked scoliosis and skeletal dysplasia involving the hips and long bones that frequently requires use of canes or walkers (Figure 42.6). Because of chest deformity and scoliosis, type IV patients develop restrictive pulmonary disease.
Figure 42.6 Type IV osteogenesis imperfecta: moderately severe OI. The patient has short stature, increased length of the upper extremities due to shortening of his legs. Braces are required to support upright position.
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Type V OI Initially described by Glorieux et al [18], type V OI, which involves approximately 5% of OI cases, is inherited in an autosomal dominant inheritance pattern. There is considerable phenotypic variability expressed in the severity of this disorder with some appearing as typical type III disease and others as the milder type I phenotype. This disorder was initially recognized by the occurrence of hyperplastic callus following fractures in affected families. Phenotypic characteristics include white sclerae, absence of dentinogenesis imperfecta, congenital dislocation of the radial heads and calcification of the interosseous membranes in the upper and lower extremities [18] (Figure 42.7). In addition to the occurrence of fractures, the functional impact of type V OI involves radial head dislocation which hampers upper extremity function by limiting pronation and supination of the forearm. Surgical correction of this has led to variable outcomes as regards improved function. OI Types VI, VII and VIII These recently described OI types are not represented in the category of male osteoporotic syndromes. However, two adult women with type VII OI have been reported [19]. Type VI OI is due to a defect in bone mineralization [20]. Patients with type VI OI present at an early age with vertebral compression and appendicular fractures. The phenotype is of moderate to severe disease. As first described by Glorieux et al [20], sclerae were white or faintly blue and dentinogenesis imperfecta was uniformly absent. No patient showed radiological signs of rickets. Lumbar spine areal bone mineral density was low. Serum alkaline phosphatase
Figure 42.7 Type V osteogenesis imperfecta: x-ray of the forearm showing dislocation of the radial head and curvature of both bones. The forearm bones are demineralized and there is non-union of fractures in both bones. The upper third and mid-radius show periosteal bone growth medially into the interosseous membrane.
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levels were elevated consistent with a mineralization defect (409 145 U/liter versus 295 95 U/liter in normals). In sharp contrast with other OI types, bone histomorphometry revealed osteopenia with hyperosteoidosis, a prolonged mineralization lag time and a decrease in mineral apposition rate. Thus, type VI OI presents an accumulation of osteoid due to a mineralization defect, but parameters of mineral metabolism are normal in these patients. The underlying genetic basis this is not known. Type VII OI was initially described in a Canadian First Nations Community in Northern Quebec [21]. There is a recessive pattern of inheritance which differs from types I, III, IV and V in which inheritance is autosomal dominant. These patients present with moderate to severe OI. Fractures are present at birth. The phenotype includes rhizomelia as a prominent clinical feature which is not seen in other OI types with the exception of lethal type II OI. Type VII patients have bluish sclerae, deformity of the lower extremities, coxa vara and osteopenia. Histomorphometric analysis of iliac crest bone is similar to that of type I OI with decreased cortical width and trabecular number and preservation of the birefringent pattern of lamellar bone. Patients with type VII OI harbor mutations involving CRTAP (cartilage-associated protein) which, in a complex with prolyl-3-hydroxylase-1 (P3H1) encoded by the LEPRE1 gene and the prolyl cis-trans isomerase cytophylin B 3, hydroxylates a single proline residue at position 986 of the triple-helical domains of type I collagen alpha1(I) and type II collagen alpha1(II) chains [22]. Successful treatment of OI patients requires close collaboration between the endocrinologist, orthopedic surgeon and physchiatrist. Adequate calcium and vitamin D supplements are useful in the maintenance of bone mass. In children, treatment with different bisphosphonates orally and intravenously, principally intravenous pamidronate (but also oral alendronate), has increased bone density, improved vertebral height where there had been compression and decreased fracture rate [23]. In adults, however, the response to bisphosphonates is less robust. In part, this may reflect the lower bone turnover rate generally observed in OI adults [24]. The author’s observational study of 94 OI adults suggests that while bone density may increase for a year or two after treatment with bisphosphonate, treatment does not decrease fracture rate in adults. Clinical trials with teraparatide and possible newer antiresorptive agents such as RANKL inhibitors or catepsin K inhibitors may provide additional treatment methods.
Bruck Syndrome Bruck syndrome (arthrogryposis multiplex congenita associated with osteogenesis imperfecta) has been linked to OI based on the presence of marked demineralization and fractures. Current classification is as follows: Bruck syndrome 1 (OIMIM%259450) is linked to chromosome 17p12. Bruck syndrome 2 (OIMIM 609220) is linked to chromosome
3q23-q24 and caused by mutation in the PLOD2 gene [25]. The proportion of cases linked to 17p12 or caused by mutations in PLOD2 is still uncertain. This syndrome is inherited as an autosomal recessive trait. There are no phenotypic differences recognized at this time between the two. Although genetically based, Bruck syndrome may be encountered in young and adolescent men. Bruck syndrome is associated with flexion contractures involving the upper and lower extremities, pterygia at the elbows, clubfeet and osteoporosis. Bruck patients have white sclerae, do not have dentinogenesis imperfecta or hearing loss. Radiologic findings include marked demineralization and deformities at the sites of previous fractures. The synthesis of type I collagen in Bruck syndrome is normal. However, there is biochemical evidence for a defect in the hydroxylation of lysine residues in the collagen type I telopeptide based on mutations in the lysyl-hydroxylase 2 gene (PLOD2). Ha-Vinh et al have reported a boy with congenital contractures with pterygia at birth and severe osteopenia with multiple fractures [26]. His urine contained low amounts of pyridinoline cross-links. He was shown to be homozygous for a novel mutation leading to an Arg598His substitution in PLOD2. This mutation was adjacent to two mutations previously reported (Gly601Val and Thr608Ile), suggesting a region susceptible to mutation in PLOD2 [26]. Although there are no published reports, osteoporosis in Bruck syndrome may be responsive to antiresorptive treatment based on results with OI patients.
Ehlers–Danlos Syndromes and Osteoporosis The Ehlers–Danlos syndromes (EDS) (OMIM 130090, 225410) present marked clinical and genetic heterogeneity involving skin, ligaments and tendons, associated with generalized tissue fragility. Ocular and vascular/organ involvement also occurs in certain EDS subtypes. A systemic connective tissue disorder, the pathophysiology of EDS is related to mutations in collagen types V, I and III, tenascin-X and mutations involving the collagen processing enzymes lysyl oxidase (EDS type VI) and procollagen N-proteinase peptidase (EDS type VII) [27]. The nosology for EDS, formerly based on 12 clinical subtypes (EDS I–XII) has been modified to include six major subtypes, based on clinical characteristics, inheritance patterns and biochemical and molecular findings. This classification, the 1997 Villefranche nosology, is presented in Table 42.3 along with the former numerically based clinical classification [28, 29]. Approximately 50% of patients have a positive family history for EDS. The major clinical characteristics of the EDS syndromes include hyperextensibility of the skin, hypermobility of joints and tissue fragility. Broad atrophic skin scars are commonplace in EDS. However, the expression of clinical features in specific phenotypes is very diverse. These range
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Table 42.3 Ehlers–Danlos syndromes: Villefranche and clinical classification, 1997 [28] Clinical classification
Characteristic features
1 Classic (AD)
EDS type I EDS type II
2 Hypermobility (AD)
EDS type III
3 Vascular (AD)
EDS type IV
4 Kyphoscoliotic type (x-linked)
EDS Type VI
5 Arthrochalasis type (AD) 6 Dermatosparaxis type (AR)
EDS types VII A and VII B EDS type VIIC
Joint hypermobility Skin hyperextensibiliy Wide atrophic scars Generalized hypermobility Mild skin elasticity Arterial/intestinal/ uterine rupture Thin translucent skin Excessive bruising Severe kyphoscoliosis Corneal and scleral rupture Lens displacement Multiple congenital dislocations Marked skin fragility Joint hyperextensibility
Clinical subtype
AD: Autosomal dominant; AR: autosomal recessive
from the classic signs in patients with the joint hypermobility syndromes (types I–III EDS) to include vascular fragility with vessel and hollow organ rupture (type IV EDS), to severe kyphoscoliosis (type VI EDS) and peridontitis (type VIII EDS). Other common features of EDS include prematurity, premature rupture of membranes, neonatal hypotonia, congenital hip dislocation, unstable gait, characteristic facies, bone fractures, motor delay, scoliosis and short stature (Figures 42.8 and 42.9). All EDS patients will have a Beighton hyperextensibility score of more than 5 points. Both autosomal dominant, recessive and X-linked inheritance (type V) patterns occur in the EDS. Mutations involving collagen types I and V and III have been defined in the classic, hypermobile and vascular subtypes. Approximately 50% of patients with the EDS classic type have been found to harbor mutations in the procollagen alpha-1 and alpha-2 chains encoded by the COL5A1 and COL5A2 genes [30]. In a manner similar to type I OI, in approximately one-third of patients, there is a null allele effect caused by mutations leading to a non-functional COL5A1 allele that results in haplo-insufficiency of type V collagen. In a smaller proportion of patients, classic type EDS is caused by a structural mutation in COL5A1 or COL5A2, resulting in the production of a functionally defective type V collagen protein. However, classic EDS has also been reported in association with mutations affecting COL1A1 or COL1A2 genes [31]. Patients with the vascular form of EDS harbor mutations involving COL3A1 encoding the pro -1 chain of type III collagen. A recessive form of EDS has been linked to gene deletion causing a deficiency of the
Figure 42.8 Ehlers–Danlos Syndrome: facial features include redundant skin around the eyes, epicanthal folds and widely spaced eyes. Patients may be described as having ‘owl-like’ or ‘parrot-like’ facies.
Figure 42.9 Ehlers–Danlos syndrome: joint hyperextensibility and multiple bruises. Atrophic wide scars are characteristic of this syndrome. Courtesy of D. Victor McKusick and Med Com Information Systems. (See color plate section).
extracellular matrix glycoprotein tenascin-X [32]. Mutations involving the collagen processing enzyme, lysyl-hydroxylase-1 (PLOD1), are causative in the kyphoscoliotic type (EDS VI) while the arthrochalasis types (type VIIA, VIIB and VIIC) result from mutations involving the procollagen N-peptidase
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or the N-terminal peptidase cleavage site in type I collagen. Similarly, in certain patients that share features of EDS and OI in that they have marked joint laxity and bone fragility, mutations in procollagen N-peptidase or mutations that alter the procollagen N-peptidase cleavage site in alpha 1(I) collagen also have been identified [33]. As in the arthrochalasis types, these mutations prevent or delay removal of the procollagen N-propeptide and cause the secretion of procollagen into the extracellular matrix. Although the impact of these mutations on osteoblast/ osteoclast function is not defined, in part because of a lack of bone histology in EDS, involvement of type V collagen is consistent with a defect in bone matrix formation. Type V collagen, a quantitatively minor collagen with wide tissue distribution, co-assembles with type I collagen as heterotypic fibrils. Similarly, mutations that impair type I procollagen processing would lead to the formation of defective bone matrix. The occurrence of osteoporosis in EDS was first reported in 1994 in 11 EDS type I and type II patients [34, 35]. Lumbar spine Z-scores in four patients aged 16–25 years varied between 1.42 and 3.01, while T-scores varied between 0.76 and 3.55 in patients aged 44–70 years. In a 1998 study, 23 type I EDS patients, mean age 38 years, had significantly lower bone mineral density (BMD) (0.9 SD) at the femur neck and at the lumbar spine (0.74 SD) when compared to age-matched non-EDS controls [36]. Of note was that the incidence of fracture in EDS patients was 10-fold that of the control group. By contrast, Carbone et al reported that lumbar spine and femoral neck bone density in 23 EDS type III patients did
not differ from that in age-matched controls when results were adjusted for body weight, height and level of physical activity [37]. Furthermore, bone biomarker measurements (bone-specific alkaline phosphatase, osteocalcin and C-carboxyterminal cross-linked telopeptide (CTx)) did not differ suggesting that bone turnover was similar to controls. Unlike the studies described above, the population assessed in this report was more homogeneous (Type III EDS). However, the numbers of EDS patients evaluated for bone mass remain small. Thus, the real incidence of osteoporosis will remain unresolved until larger numbers of patients with each clinical phenotype are studied.
Marfan syndrome and osteoporosis The Marfan syndrome (MFS, OMIM #154700) is an autosomal dominant disorder with a reported incidence of 1 per 5000 live births. As with other inherited disorders of connective tissue, MFS is a systemic disorder involving the skeleton, the heart and aorta, pulmonary and neural tissues and the eye. A severe and rapidly progressive form of MFS may present at birth. In common with other inherited connective tissue disorders, MFS is characterized by wide clinical variability with limited genotype/phenotype relationships (Figure 42.10). Because individual clinical features of MSF occur in patients who do not have the syndrome, it is important
Figure 42.10 Marfan syndrome: these two brothers have Marfan syndrome, illustrating marked phenotypic variability. The younger brother (left) displays the full syndrome: increased height, long lower segment, spinal curvature, depressed sternum and bilateral lens dislocation. The older brother also has striking skeletal involvement but normal eyes. Courtesy of Dr Victor McKusick and Med Com Information Systems. (See color plate section).
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when considering the diagnosis that one apply the established major and minor diagnostic criteria described in the Ghent nosology (1996) when: 1. evaluating an index patient with an MFS-related phenotype or 2. the member of a family in which the diagnosis has been previously established [38]. These major and minor diagnostic criteria are listed in Table 42.4. The majority of MFS patients have mutations in the fibrillin-1 gene (FBN1, MFS type 1), located on chromosome 15q21.1. More than 500 fibrillin-1 gene mutations have been
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identified [39]. About 25% of patients have new mutations: the remainder are familial cases. Mutations in the second fibrillin gene, FBN2, occur in patients with congenital contractual arachnodactly [40]. However, MFS has also been recognized in patients carrying mutations in the TGFR1 or TGFR2 genes located on chromosomes 9 and on 3p24.2-p25, respectively (MFS type II) [41]. The spectrum of genotypes has recently been broadened by the recognition of the Loeys-Dietz syndrome (marfanoid habitus, unusual facies, cleft palate, contractures and cardiovascular disease) which is also due to mutations involving TGFR1 and TGFR2 genes [42–44]. Establishment of genotype–phenotype relationships in MFS has been complicated by the large number of unique FBN1
Table 42.4 Marfan syndrome major and minor criteria [38] Skeletal system Major criteria: At least 4 of the following: (1) pectus carinatum, (2) pectus excavatum requiring surgery, (3) reduced upper-to-lower segment ratio or arm span to height ratio 1.05, (4) wrist and thumb signs, (5) scoliosis 20 degrees or spondylolisthesis, (6) reduced elbow extension (170 degrees), (7) medial displacement of the medial malleolus causing pes planus or (8) protrusio acetabulae (ascertained on radiographs) Minor criteria: Moderate pectus excavatum, joint hypermobility, high arched palate with dental crowding, or characteristic facial appearance Ocular system Major criterion: Ectopia lentis Minor criteria: Abnormally flat corneas, increased axial length of the globe or hypoplastic iris or ciliary muscle causing miosis Cardiovascular system Major criterion: Dilatation of the ascending aorta involving at least the sinuses of valsalva or dissection of the ascending aorta Minor criteria: Mitral valve prolapse, dilatation of the main pulmonary artery without valvular or peripheral pulmonic stenosis or other obvious cause before 40 years or dilatation or dissection of the descending aorta before 50 years Pulmonary system Major criterion: None Minor criteria: Spontaneous pneumothorax and apical blebs Skin and integument Major criterion: None Minor criterion: Striae atrophicae (stretch marks) not associated with marked weight changes, pregnancy or repetitive stress or recurrent or incisional hernias Dura Major criterion: Lumbosacral dural ectasia seen on CT or MRI imaging Minor criterion: None Family and genetic history Major criteria: (1) A first degree relative who meets the criteria independently, (2) a mutation in FBN1 known to cause Marfan syndrome or (3) a haplotype around FBN1, inherited by descent, known to be associated with confirmed Marfan syndrome in the family Minor criterion: None Requirements for the diagnosis of Marfan syndrome 1 For the index case: if the family and genetic history is not contributory, major criteria in at least two different organ systems and involvement in a third system 2 If a mutation known to cause Marfan syndrome is present in other family members, major criterion in one organ system and involvement of another organ system
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mutations reported, as well as by clinical heterogeneity among individuals expressing the same mutation [45]. Conversely, patients who meet the Ghent diagnostic criteria for Marfan syndrome have not been found to harbor FBN1 mutations. Fibrillin microfibrils are small (10 nm) and appear either hollow or characteristically beaded. Microfibrils are widely distributed in connective tissue forming an outer layer for mature elastic fibers and as bundles of microfibrils in nonelastic tissues. In bone, microfibrils have been localized to cement lines, Haversian canals and osteocyte lacunae. Fibrillins have a second important role as they function in binding and modulating the activity of growth factor TGF- in connective tissues including bone [46, 47]. In extracellular connective tissue, latent TGF- complexes are bound to TGF-binding proteins attached to fibrillin-1. Fibrillin microfibrils thus function as negative regulators of TGF- signaling [47, 48]. Thus, fibrillin-1 mutations in MFS disrupt this relationship and lead to activation of TFG- signaling in tissues such as the aorta. Other extracellular matrix proteins modulate fibrillin-1 growth factor interactions including fibronectin, versican, perlecan and biglycan. Also, fibrillin-1 has also been found to bind to the propeptide of BMP-7 [49]. Other growth factors, BMP 2, 4, 5 and 10 also interact with fibrillin-1 in extracellular matrix. One may hypothesize that the characteristic skeletal features of MFS reflect the interaction of multiple extracellular and bone proteins and growth factors in the presence of fibrillin-1 or TGFR mutations. Fibrillin-1 has been localized to bone and bone cells [50]. Osteoporosis has been reported in MFS patients. In 1993, Kohlmeier et al performed DXA scans on 17 women, aged 37 7.3 years, with MFS. Both femoral neck and whole body measurements were deficient but L2–L4 measurements were normal. There was no relation to scoliosis or fracture history [51]. DXA measurements in both MFS women and men aged 33 9.3 years found BMD at the hip and radius to be significantly low for age and sex-matched controls [52]; 10% of these patient reported at least one fracture. However, two earlier studies had not reported low BMD in MFS: Gray et al, using single photon densitometry, found no difference from controls and Tobias et al showed only a moderate decrease in trochanter BMD in 14 women with MFS [53, 54]. Carter et al examined BMD in 12 male and 13 female patients who fulfilled the Ghent diagnostic criteria [55]. Overall, BMD was significantly reduced in the lumbar spine, total hip and femoral neck. In women, BMD was reduced at the femoral neck (Z 0.53 0.95) and at the hip (Z 0.64 0.77). In men, BMD was reduced at the femoral neck (Z 0.48 0.84, P 0.05) with a non-significant trend to lower BMD at the hip and lumbar spine. A study of BMD in 30 adults and 21 children showed that adult males had significantly reduced femur neck BMD (T-score 1.54) while the T-scores were normal in MFS females and children [56]. A review of Z-scores in these reports suggests that values are generally in the osteopenic range, affecting cortical bone more than trabecular bone. This may explain
the tendency for proximal femur BMD to be decreased in most series. However, the gender differences in adults are unexplained. To date, there are no clinical trials testing pharmacologic treatment for bone loss in those patients where the loss is prominent. Current trials involving the effects of angiotensin II receptor blockade with losartan to slow the rate of aortic-root dilation may also provide information about the response of bone to this and related agents [57].
Hypophosphatasia in the adult male Hypophosphatasia (OMIM146300, 241500, 241510) is a rare inborn error of bone metabolism associated with dental disease (premature loss of deciduous teeth or severe caries), inadequate skeletal mineralization and fractures secondary to osteomalacia. The frequency of the disease has been estimated to be one in 100 000 persons for severe forms, but mild forms of hypophosphatasia may be more common and overlooked [58]. The phenotype of hypophosphatasia is highly variable ranging from skeletal deformity or fractures apparent in utero on ultrasound or at birth, to early tooth loss as the first evidence of the disease to adults with low alkaline phosphatase levels and few bone symptoms to those experiencing fractures [59]. Six clinical forms representing recessive and dominant modes of inheritance are recognized: perinatal (lethal), perinatal benign, infantile, childhood, adult and odontohypophosphatasia. A rare, benign prenatal form found by ultrasound and characterized by spontaneous improvement as compared to the postnatal forms has been reported [60]. The severe forms are autosomal recessive, while milder forms may be transmitted as autosomal dominant or recessive traits. Hyphosphatasic patients have deficient serum and liver/ bone/kidney alkaline phosphatase activity due to a deactivating mutation (or mutations) of the gene encoding tissue non-specific alkaline phosphatase (TNSALP). This results in reduced total serum alkaline phosphatase activity associated with elevations in serum pyridoxal 5-phosphate, urinary phosphoethanolamine and inorganic pyrophosphate [61]. Serum calcium is normal, serum inorganic phosphate is elevated and total serum alkaline levels are low but variable. Deficient TNSALP is associated with rickets in children and osteomalacia in adults. As a consequence, adults with hyphosphatasia commonly complain of leg pain due to presence of osteomalacic stress fractures involving the metatarsals and/or hip or thigh pain due to pseudofractures involving the femurs [62]. Bone mineral density (DXA) measurements may reveal normal or diminished bone mass. However, mildly affected adults may have few bone symptoms, may present a history of dental involvement or may initially present with fractures due to osteomalacia. Hypophosphatasic patients also complain of joint pain due to chondrocalcinosis and inflammation secondary to the dep osition of calcium pyrophosphate dihydrate crystals which accumulate in tissues and joints [63].
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Promising developments in treatment of hypophosphatasia involve bone-targeted enzyme replacement. This is demonstrated in recent studies in which a recombinant form of human TNALP prevented manifestations of infantile hypophosphatasia in the Akp2 / murine model of the disorder [64].
Fibrous dysplasia in adult males Fibrous dysplasia (FD) occurs as either an isolated skeletal lesion (monostotic form) or multiple bones may be affected (polyostotic form). Approximately 5% of FD patients, particularly those with polyostotic FD, may present associated with endocrine dysfunction termed the McCune–Albright syndrome (MAS). FD is caused by missense activating mutations in the GNAS gene (R201 and Q227) coding for the alpha-subunit of the stimulatory G-protein, Gsa, in the guanine nucleotide binding complex locus in chromosome 20q13 [65]. Gsa couples hormonal membrane receptors to intracellular adenyl cyclase leading to cAMP generation, activation of downstream cAMP-responsive elements, such as c-fos, c-jun, interleukin 6 (Il-6) and Il-11, promoting gene transcription culminating in: 1. increased stem cell and osteoblast function and 2. increased target organ hormone synthesis.
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By contrast, loss-of-function GNAS mutations lead to Albright’s hereditary osteodystrophy (AHO). As these mutations occur post-zygotically, FD is a non- heritable disorder. If limited to bone, the Gsa mutation results in altered osteo blastic differentiation leading to fibrous dysplasia and, often, increased bone resorption. In MAS, the presence of the activating mutations affecting endocrine organs may result in precocious puberty (testes), growth hormone excess (pituitary) and Cushing’s disease with adrenal involvement. Involvement of skin produces café-au-lait lesions which tend to cluster near the midline and have the jagged ‘coast of Maine’ border. Patients with polyostotic fibrous dysplasia often have renal phosphate wasting associated with increased production of the phosphatonin, FGF 23, by the fibrous matrix [66]. Patients with FD present with bone pain, bone deformities and pathologic fracture at one or more sites. The most commonly affected bones are the femurs, the skull and upper extremities [66, 67]. Involvement of the skull, extremities and ribs may be associated with swelling, deformity and pain (Figures 42.11 and 42.12). Craniofacial fibrous dysplasia may present as young as 16 years of age. Here, the commonest presenting symptom is facial asymmetry. As reported by Rahman et al in a series of 42 patients, 37 (88.1%) had unilateral involvement and five (11.9%) had bilateral involvement, of whom three (7.1%) had McCune–Albright syndrome [67]. Craniofacial involvement may be associated with headaches and may compromise the optic canal. Osteosarcoma occurs
Figure 42.11 Fibrous dysplasia: skull lesions of fibrous dysplasia in a 40-year-old man. The lesions are diffuse, present an irregular ‘ground glass’ and irregularly lytic appearance. Cortical thickening is present.
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Figure 42.12 Fibrous dysplasia: thoracic lesions involving ribs in a 40-year-old man whose skull lesions are pictured in Figure 42.11. These lesions are painful and have resulted in fractures.
in FD patients but is rare (1%). Malignant transformation occurs more frequently in polyostotic cases, McCune– Albright syndrome or in previously irradiated patients. The rare occurrence of benign intramuscular myxoma with fibrous dysplasia of bone is termed Mazabraud’s syndrome which may also be associated with Gsa mutations. Bisphosphonates have been used in the treatment of fibrous dysplasia to relieve bone pain and improve lytic lesions, but they are still under clinical evaluation for effectiveness in terms of resolving disease progression [68]. Calcium, vitamin D and phosphorus supplements may be useful in some patients. Surgery is also helpful to prevent and treat fractures and deformities.
Osteoporosis related to inherited defects in copper transport: menkes’ disease, occipital horn syndrome, wilson disease These disorders share a basic metabolic defect in copper metabolism based on mutations involving two genes regulating copper transport, the P-type adenosine-triphosphateases ATP7A and ATP7B [69]. Both proteins serve as copper export proteins in the cell. However, mutations in ATP7A lead to copper deficiency syndromes (Menkes’ disease, occipital horn syndrome) while mutations affecting ATP7B lead to copper overload (Wilson disease). These differences in functional outcome are related to defective copper transport across mucosal barriers in Menkes’ syndrome as contrasted
with impaired hepatic excretion into bile in Wilson disease. Differences in tissue localization and tissue distribution in ATP7A and ATP7B influence the clinical expression of these mutations [69]. Each syndrome is associated with osteoporosis, although the literature describing the pathophysiology of the different skeletal disorders is limited. In Menkes’ disease and occipital horn syndrome, there is a marked deficiency of lysyl oxidase, a copper dependent enzyme, which is essential for normal collagen and elastin cross-linking. The relation of copper excess to osteoporosis is less defined in Wilson syndrome in which concurrent hepatic disease may also influence bone mineralization. Menkes’ disease (OMIM 309400) or ‘steely hair disease’, is a rare neurodegenerative disorder caused by defective copper transport, which presents either as a severe and fatal disorder in infancy or in a milder form which overlaps with the occipital horn syndrome. Typical features of Menkes’ syndrome include early onset with recognition of the disorder in the first few months of life, abnormal brittle hair (pili torti), abnormal facies including pudgy cheeks and abnormal eyebrows, hypopigmentation, progressive cerebral degeneration, arterial rupture and thrombosis. Menkes’ disease patients have cranial wormian bones, are osteoporotic and may experience fractures. Characteristically, extremities show flared metaphyses with protrusions that may fracture [70]. The milder phenotype may have serum copper concentrations at the lower level of normal. As an example of the phenotypic overlap between mild Menkes’ syndromes and the occipital horn syndrome, Proud reported four related males, ranging in age from 4 to 38 years, with a phenotype that combined the phenotypes of classical and mild Menkes disease and occipital horn syndrome [71]. The propositus, an 18-year-old man, was evaluated following an intracerebral hemorrhage at 15 years of age and was noted to have marked hypotonia, motor delay with mental retardation, bladder diverticula, diarrhea from infancy, seizures from age 3 years, abnormal hair (pili torti), cutis laxa and multiple joint dislocations. Reduced serum copper and ceruloplasmin levels were found.
Occipital Horn Syndrome Occipital horn syndrome (OHS; OIMIM 304150), formerly known as Ehlers-Danlos syndrome type IX or X-linked cutis laxa, is a recessively inherited allelic variant of Menkes’ syndrome associated with mutations involving ATP7A [72]. It is a mild variant of Menkes’ syndrome with retained ATP7A activity leading to predominately connective tissue involvement rather than neurologic symptomatology. As a consequence of copper deficiency, lysyl oxidase activity is markedly reduced in skin samples and cultured fibroblasts [73]. The skeletal abnormalities included occipital ‘horns’ due to occipital exostoses, short broad clavicles, deformed radii, ulnae and humeri and narrowing of the rib cage (Figure 42.13). Characteristic of OHS patients are a narrow, elongated facial appearance, joint
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Figure 42.13 Occipital horn syndrome: the phenotype includes occipital exostoses, facial narrowing, short broad clavicles, narrow chest cage and hyperextensible joints.
hypermobility, elbow contractures, chronic diarrhea and bladder diverticulae. Mentzel et al have reported an 18-year-old boy with occipital horn syndrome who developed aneurysms of the splenic and hepatic arteries [74]. Multiple neurologic defects include neovascularization and reduplication of the cerebral arteries with cystic medial degeneration, focal cortical dysplasia and cerebellar hypoplasia [75]. As in Menkes’ syndrome, generalized osteoporosis of long bone is described in OHS, presumably secondary to decreased lysyl oxidase-mediated collagen cross-linking. However, studies of bone cell function or histopathology have not been reported in OHS [76].
Wilson Disease (Hepatolenticular Degeneration) and Osteoporosis Wilson disease (OMIM 277900) is an autosomal recessive disorder in which a defect in copper excretion leads to copper excess in liver, brain, kidneys and the cornea. There is considerable clinical variability in the presentation of Wilson disease, even in patients with the same gene mutation. As many as onethird of patients may present with acute liver failure and require prompt chelation therapy with penicillamine and/or liver transplantation. Due to copper deposition in the basal ganglia and kidney, there are associated and progressive neurologic, renal and psychiatric defects [77]. The disorder may present in children or young adults as hepatitis associated with splenomegaly and lead to portal hypertension. Neurological findings include incoordination, dystonia, parkinsonian features, dysarthia and dysphagia due to involvement of bulbar muscles and seizures. Wilson disease is associated with osteoporosis.
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In addition to hepatic and neurologic complications, patients with Wilson disease may develop cardiomyopathy, renal tubular acidosis, renal stones, arthropathy and Coombs-negative hemolytic anemia. A characteristic of Wilson disease is the Keyser-Fleischer corneal ring due to copper deposition in Descemet’s membrane. Patients with Wilson disease have reduced serum levels of ceruloplasmin (20 g/L, subject to age and laboratory variations), elevated total serum copper concentrations and elevated 24-h urinary free-copper excretion [78]. The gene defect in Wilson disease involves mutations in ATP7B on chromosome 13 which encodes a copper transporting P-type adenosine triphosphatase in liver. Other involved tissues, brain, kidney, lung and heart, also express this gene. To date, approximately 300 mutations, 60% of which are missense mutations, have been described [69]. The H1069Q mutation in exon 14 is most frequent in North America and the R778L mutation in exon 8 is most frequent in the Far East [69, 77]. Osteopathy in Wilson disease may take several forms and include inflammatory changes in small joints, osteomalacia, osteoarthritis in younger ages, spine osteochondritis, fractures and heterotopic ossification [79]. Osteoporosis occurs in both children and adults. Selimoglu et al measured bone mineral content and bone mineral density in 31 children aged 2 to 16 years with newly diagnosed Wilson disease and healthy controls [80]. The prevalence of osteopenia and osteoporosis in children with Wilson disease was found as 22.6% and 67.7%, respectively. BMD and BMC levels were higher in children with neurologic involvement but were not related to disease severity. One year under treatment with penicillamine and zinc did not significantly alter these parameters [80]. DXA and bone biomarker measurements and quantitative bone ultrasound (QUS) have been measured in 21 adults with Wilson disease [81]. Osteoporosis was present in 43% and abnormal QUS in 33% of adult patients [81]. Increased bone resorption was suggested by the finding of increased serum beta-C-telopeptide (CTx) and osteoprotegerin levels but no difference was found in serum RANKL levels compared to controls. Meta-analysis indicates that patients with hepatic presentation of Wilson disease are probably most effectively treated by D-penicillamine [82]. Zinc may be the preferred treatment above D-penicillamine for presymptomatic and neurologic patients. There are no reports of extended chelation treatment on bone metabolism or bone density in adult Wilson disease patients.
Hemochromatosis and osteoporosis in men Hereditary hemochromatosis (HH) is a genetic syndrome caused by iron overload. Most cases are associated with
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mutations in HFE (C282Y homozygotes or C282Y/H63D compound heterozygotes) [83]. Non-HFE associated HH is caused by mutations in other recently identified genes involved in iron metabolism. Hepcidin is an iron regulatory hormone that inhibits ferroportin-mediated iron export from enterocytes and macrophages. Defective hepcidin gene expression or function may underlie most forms of HH. With respect to factors also impacting bone, recent studies demonstrate that mutations decreasing BMP-6 expression in mice cause a rapid and massive accumulation of iron in the liver, the acinar cells of the exocrine pancreas, the heart and the renal convoluted tubules [84]. HH is almost exclusively found in populations of northern European descent. Affected target organs affected by HH include the liver, heart, pancreas, joints and skin. Diabetes mellitus and cirrhosis are late manifestations of the disease resulting from massive tissue iron overload. Hypogonadotropic hypogonadism is frequent. Compound heterozygotes have milder disease than C282Y homozygotes [85]. Osteoporosis is frequent in patients with genetic hemochromatosis. In a study of bone density in 38 French patients with hemochromatosis who were C282Y homozygotes and had normal serum vitamin D levels, DXA T-scores were 1.0 (osteopenia) in 78% and were 2.5 (osteoporosis) in 34% [86]. Hypogonadism was not implicated, rather femoral neck BMD appeared to fall with rising hepatic iron concentrations. In a similar study, bone density studies in 87 Italian patients with hereditary hemochromatosis showed osteopenia in 41% and osteoporosis in 25%. Bone density was independently associated with hypogonadism or menopausal state and the amount of iron removed by phlebotomy, but not with presence of cirrhosis. Thus, as with other organ systems, osteoporosis appeared related to the extent of iron overload [87]. Of interest is the finding that the presence of osteoporosis was not associated with the HFE genotype. Juvenile hemochromatosis (JH) is a severe form of hemochromatosis which may present in young men. JH involves rapid iron overload and leads to organ damage, typically before the age of 30. Angelopoulos et al have reported a 25-year-old man suffering from juvenile hemochromatosis, with elevated transaminase levels and progressive erectile dysfunction due to hypogonadotropic hypogonadism. This patient also had secondary osteoporosis accompanied by increased bone resorption, which primarily affected trabecular bone [88]. Chondrocalcinosis and chronic pseudo-osteoarthritis arthropathy are common osteoarticular complications of hemochromatosis (HC) [89]. Neither cirrhosis nor the amount of post-phlebotomy iron removed was associated with arthropathy. There are no reports of longitudinal changes in bone density following chronic phlebotomy therapy in patients with HH.
Homocystinuria Homocystinuria (OMIM 236250) is a rare inborn effect of sulfur metabolism due to a deficiency of cystathionine-synthase, which impairs the conversion of methionine to cysteine. Hyper-homocysteinemia is also a result of mutations affecting the gene for methylenetetrahydrofolate reductase which is important for remethylation of homocysteine. Transmitted as an autosomal recessive trait, homocystinuria is associated with high plasma homocysteine and methionine levels. The phenotype includes marfanoid habitus, lens dislocation, arterial or venous thromboses and thromboembolism, mental retardation and the early onset of generalized osteoporosis (Figure 42.14). Vertebral compression fractures may occur by the teenage years. Homocystinuric patients have mild joint contractures rather than the hypoerextensibility seen in Marfan syndrome. While these physical findings are striking in young individuals, when less prominent, they may be overlooked in adults. The diagnosis of premature osteoporosis in men (and women), particularly in the presence of marfanoid habitus or vascular thromboses, should prompt measurements of plasma and urine homocysteine. van Meurs et al have examined the relationship of mildly elevated plasma homocysteine levels to age-related fracture incidence [90]. The overall multivariable-adjusted relative risk of fracture was 1.4 for each SD increase in the naturallog-transformed homocysteine level. A homocysteine level in the highest age-specific quartile was associated with an increase by a factor of 1.9 in the risk of fracture. This association between homocysteine levels and the risk of fracture appeared to be independent of bone mineral density and other potential risk factors for fracture [90]. However, the pathophysiology of osteoporosis in homocystinuria is not well defined. Studies in animals and in humans indicate that elevated levels of homocysteine in bone may alter collagen cross-links and interfere with bone remodeling [91]. Treatment of homocystinuria due to cystathionine betasynthase deficiency includes dietary methionine restriction, folic acid, pyridoxine and betaine, which is frequently useful in patients who are not pyridoxine responsive [92].
Inherited defects in neurotropic factors related to bone Rett Syndrome in Males Rett syndrome is an X-linked neurodegenerative disorder caused by different mutations in methyl-CpG-binding protein (MeCP2) genes [93]. It is included in this chapter because features of the syndrome suggest that, in this instance, a neural transcription factor may control osteoblast/osteoclast function. Seventy to 80% of patients with features of Rett syndrome have mutations in MeCP2. Although a majority of
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Figure 42.14 Homocystinuria: marfanoid habitus in an 18-year-old boy with osteoporosis, ectopia lentis, mild contractures at the elbows, pectus carinatum and mental retardation. Courtesy of Dr Victor McKusick and Med Com Information Systems.
affected individuals are female, approximately 5% are males. As expected in an X-linked disorder, the disease is usually more severe in males as contrasted with affected females [94]. This also is demonstrated in the murine knockout (male) models of Rett syndrome in which the phenotype is more severe compared with the heterozygote (female) model. The syndrome in males, which may be variable in course, may include a congenital encephalopathy with early onset of neurologic signs and progressive mental retardation. Although severity may vary from mild to severe, the majority demonstrate movement disorders involving the trunk and the extremities with tremor, chorea, ataxia, dystonia and eventual rigidity. Stereotypic hand wringing motions are characteristic. Seizures are a common feature of the disorder. Mobility is compromised in many patients who may eventually become tetraplegic. Decreased bone density has been found in approximately 60% of subjects with Rett syndrome, at times discovered as early as 2–3 years of age and persisting into adulthood [95]. Fracture rate is increased in male and female patients [95]. Eleven percent of the author’s series of 70 Rett females between the ages of 2 and 22 have had fractures. MeCP2 acts as a global transcriptional repressor affecting neural tissue development by binding to histone modifier proteins. The presence of osteoporosis in males and females with Rett syndrome is of interest in that it adds a transcription factor to the growing number of neural factors such as leptin, NP-Y and serotonin which are now known to regulate osteoblast/osteoclast cell activity. Thus, osteoporosis and
fractures in Rett syndrome add yet another dimension to our understanding of the complex role played by the nervous system in the control of bone metabolism. To date, there is no published experience with treatment aimed at increasing bone mass in affected children and adults. Histological studies of bone biopsies from Rett females have suggested a decrease in bone formation which, if confirmed, could lead to specific treatment regimens [96].
References 1. R.T. Franceschi, C. Ge, G. Xiao, H. Roca, D. Jiang, Transcriptional regulation of osteoblasts, Cells Tissues Organs 189 (1-4) (2009) 144–152. 2. P. Marie, Transcription factors controlling osteoblastogenesis, Arch. Biochem. Biophys. 473 (2008) 98–105. 3. T. Komori, Regulation of bone development and maintenance by Runx2, Front Biosci. 13 (2008) 898–903. 4. D. Chen, M. Zhao, G.R. Mundy, Bone morphogenetic proteins, Growth Factors 22 (4) (2004) 233–241. 5. B. Li, Bone morphogenetic protein-Smad pathway as drug targets for osteoporosis and cancer therapy, Endocr. Metab. Immune Disord. Drug Targets 8 (3) (2008) 208–219. 6. Q. Zhao, J. Shao, W. Chen, Y.P. Li, Osteoclast differentiation and gene regulation, Front Biosci. 12 (2007) 2519–2529. 7. M.P. Yavropoulou, J.G. Yovos, Osteoclastogenesis – current knowledge and future perspectives, J. Musculoskelet. Neuron. Interact. 8 (3) (2008) 204–216. 8. T. Yoshida, H. Kanegane, M. Osato, et al., Functional analysis of RUNX2 mutations in cleidocranial dysplasia: novel
520
9.
10.
11. 12.
13.
14.
15.
16. 17. 18.
19.
20.
21.
22.
23.
24.
25.
Osteoporosis in Men
insights into genotype-phenotype correlations, Blood Cells Mol. Dis. 30 (2) (2003) 184–193. J.C. Marini, A. Forlino, W.A. Cabral, et al., Consortium for osteogenesis imperfecta mutations in the helical domain of type I collagen: regions rich in lethal mutations align with collagen binding sites for integrins and proteoglycans, Hum. Mutat. 28 (3) (2007) 209–221. H. Kuivaniemi, G. Tromp, D.J. Prockop, Mutations in fibrillar collagens (types I, II, III, and XI), fibril-associated collagen (type IX), and network-forming collagen (type X) cause a spectrum of diseases of bone, cartilage, and blood vessels, Hum. Mutat. 9 (4) (1997) 300–315. K.E. Kadler, C. Baldock, J. Bella, R.P. Boot-Handford, Collagens at a glance, J. Cell Sci. 120 (12) (2007) 1955–1958. N.S. Fedarko, P.G. Robey, U.K. Vetter, Extracellular matrix stoichiometry in osteoblasts from patients with osteogenesis imperfecta, J. Bone Miner. Res. 10 (7) (1995) 1122–1129. J.R. Shapiro, Osteogenesis imperfecta and other defects of bone development as occasional causes of adult osteoporosis, in: R. Marcus, D. Feldman, J. Kelsey (Eds.), Osteoporosis, Academic Press, San Diego, 2001, pp. 271–301. D. Baldridge, U. Schwarze, R. Morello, et al., CRTAP and LEPRE1 mutations in recessive osteogenesis imperfecta, Hum. Mutat. 29 (12) (2008) 1435–1442. E. Martin, J.R. Shapiro, Osteogenesis imperfecta: epidemiology and pathophysiology, Curr. Osteoporos. Rep. 5 (3) (2007) 91–97. D. Sillence, Osteogenesis imperfecta: an expanding panorama of variants, Clin. Orthop. Relat. Res. 159 (1981) 11–25. J.P. Pillion, J.R. Shapiro, Audiological findings in osteogenesis imperfecta, J. Am. Acad. Audiol. 19 (8) (2008) 595–601. F.H. Glorieux, F. Rauch, H. Plotkin, et al., Type V osteogenesis imperfecta: a new form of brittle bone disease, J. Bone Miner. Res. 15 (9) (2000) 1650–1658. C. Land, F. Rauch, R. Travers, F.H. Glorieux, Osteogenesis imperfecta type VI in childhood and adolescence: effects of cyclical intravenous pamidronate treatment, Bone 40 (3) (2007) 638–644. F.H. Glorieux, L.M. Ward, F. Rauch, L. Lalic, P.J. Roughley, R. Travers, Osteogenesis imperfecta type VI: a form of brittle bone disease with a mineralization defect, J. Bone Miner. Res. 17 (1) (2002) 30–38. L.M. Ward, F. Rauch, R. Travers, et al., Osteogenesis imperfecta type VII: an autosomal recessive form of brittle bone disease, Bone 31 (1) (2002) 12–18. A.M. Barnes, W. Chang, R. Morello, et al., Deficiency of cartilage-associated protein in recessive lethal osteogenesis imperfecta, N. Engl. J. Med. 355 (26) (2006) 2757–2764. H. Castillo, L. Samson-Fang, American Academy for Cerebral Palsy and Developmental Medicine Treatment Outcomes Committee Review Panel. Effects of bisphosphonates in children with osteogenesis imperfecta: an AACPDM systematic review, Dev. Med. Child Neurol. 51 (1) (2009) 17–29. J.R. Shapiro, E.F. McCarthy, K. Rossiter, et al., The effect of intravenous pamidronate on bone mineral density, bone histomorphometry, and parameters of bone turnover in adults with type IA osteogenesis imperfecta, Calcif. Tissue Int. 72 (2) (2003) 103–112. A.J. van der Slot, A.M. Zuurmond, A.F. Bardoel, et al., Identification of PLOD2 as telopeptide lysyl hydroxylase, an
26.
27.
28.
29.
30.
31.
32.
33.
34. 35. 36.
37.
38.
39.
40.
41.
important enzyme in fibrosis, J. Biol. Chem. 278 (42) (2003) 40967–40972. R. Ha-Vinh, Y. Alanay, R.A. Bank, et al., Phenotypic and molecular characterization of Bruck syndrome (osteogenesis imperfecta with contractures of the large joints) caused by a recessive mutation in PLOD2, Am. J. Med. Genet. A 131 (2) (2004) 115–120. B. Callewaert, F. Malfait, B. Loeys, A. De Paepe, EhlersDanlos syndromes and Marfan syndrome, Best Pract. Res. Clin. Rheumatol. 22 (1) (2008) 165–189. P. Beighton, A. De Paepe, B. Steinmann, P. Tsipouras, R.J. Wenstrup, Ehlers-Danlos syndromes: revised nosology, Villefranche, 1997. Ehlers-Danlos National Foundation (USA) and Ehlers-Danlos Support Group (UK), Am. J. Med. Genet. 77 (1) (1998) 31–37. S. Rand-Hendriksen, L.L. Wekre, B. Paus, Ehlers-Danlos syndrome – diagnosis and subclassification, Tidsskr Nor Laegeforen 126 (15) (2006) 1903–1907. F. Malfait, P. Coucke, S. Symoens, B. Loeys, L. Nuytinck, A. De Paepe, The molecular basis of classic Ehlers-Danlos syndrome: a comprehensive study of biochemical and molecular findings in 48 unrelated patients, Hum. Mutat. 25 (1) (2005) 28–37. F. Malfait, S. Symoens, J. De Backer, et al., Three arginine to cysteine substitutions in the pro-alpha (I)-collagen chain cause Ehlers-Danlos syndrome with a propensity to arterial rupture in early adulthood, Hum. Mutat. 28 (4) (2007) 387–395. J. Schalkwijk, M.C. Zweers, P.M. Steijlen, et al., A recessive form of the Ehlers-Danlos syndrome caused by tenascin-X deficiency, N. Engl. J. Med. 345 (16) (2001) 1167–1175. W.A. Cabral, E. Makareeva, A. Colige, et al., Mutations near amino end of alpha1(I) collagen cause combined osteo genesis imperfecta/Ehlers-Danlos syndrome by interference with N-propeptide processing, J. Biol. Chem. 280 (19) (2005) 19259–19269. P.C. Coelho, R.A. Santos, J.A. Gomes, Osteoporosis and EhlersDanlos syndrome, Ann. Rheum. Dis. 53 (3) (1994) 212–213. A.A. Deodhar, A.D. Woolf, Ehlers Danlos syndrome and osteoporosis, Ann. Rheum. Dis. 53 (12) (1994) 841–842. A.L. Dolan, N.K. Arden, R. Grahame, T.D. Spector, Assessment of bone in Ehlers Danlos syndrome by ultrasound and densitometry, Ann. Rheum. Dis. 57 (10) (1998) 630–633. L. Carbone, F.A. Tylavsky, A.J. Bush, W. Koo, E. Orwoll, S. Cheng, Bone density in Ehlers-Danlos syndrome, Osteoporos. Int. 11 (5) (2000) 388–392. A. De Paepe, R.B. Devereux, H.C. Dietz, R.C. Hennekam, R.E. Pyeritz, Revised diagnostic criteria for the Marfan syndrome, Am. J. Med. Genet. 62 (4) (1996) 417–426. C.L. Turner, H. Emery, A.L. Collins, et al., Detection of 53 FBN1 mutations (41 novel and 12 recurrent) and genotypephenotype correlations in 113 unrelated probands referred with Marfan syndrome, or a related fibrillinopathy, Am. J. Med. Genet. A 149A (2) (2009) 161–170. B.L. Callewaert, B.L. Loeys, A. Ficcadenti, et al., Comprehensive clinical and molecular assessment of 32 probands with congenital contractural arachnodactyly: report of 14 novel mutations and review of the literature, Hum. Mutat. 30 (3) (2009) 334–341. G. Matyas, E. Arnold, T. Carrel, et al., Identification and in silico analyses of novel TGFBR1 and TGFBR2 mutations
C h a p t e r 4 2 Inherited and Related Disorders of Bone Matrix Synthesis in Men l
42.
43.
44.
45.
46.
47.
48.
49.
50.
51.
52.
53.
54.
55.
56.
57. 58.
in Marfan syndrome-related disorders, Hum. Mutat. 27 (8) (2006) 760–769. B.L. Loeys, J. Chen, E.R. Neptune, et al., A syndrome of altered cardiovascular, craniofacial, neurocognitive and skeletal development caused by mutations in TGFBR1 or TGFBR2, Nat. Genet. 37 (3) (2005) 275–281. B.L. Loeys, U. Schwarze, T. Holm, et al., Aneurysm syndromes caused by mutations in the TGF-beta receptor, N. Engl. J. Med. 355 (8) (2006) 788–798. C. Stheneur, G. Collod-Beroud, L. Faivre, et al., Identification of 23 TGFBR2 and 6 TGFBR1 gene mutations and genotypephenotype investigations in 457 patients with Marfan syndrome type I and II, Loeys-Dietz syndrome and related dis orders, Hum. Mutat. 29 (11) (2008) E284–E295. L. Faivre, G. Collod-Beroud, B.L. Loeys, et al., Effect of mutation type and location on clinical outcome in 1,013 probands with Marfan syndrome or related phenotypes and FBN1 mutations: an international study, Am. J. Hum. Genet. 81 (3) (2007) 454–466. D. Hubmacher, K. Tiedemann, D.P. Reinhardt, Fibrillins: from biogenesis of microfibrils to signaling functions, Curr. Top Dev. Biol. 75 (2006) 93–123. G. Sengle, N.L. Charbonneau, R.N. Ono, L.Y. Sakai (Eds.), Primer on Metabolic Bone Diseases and Disorders of Mineral Metabolism, seventh ed., American Society of Bone and Mineral Research, Washington, DC, 2008. S.L. Dallas, D.R. Keene, S.P. Bruder, et al., Role of the latent transforming growth factor beta binding protein 1 in fibrillin-containing microfibrils in bone cells in vitro and in vivo, J. Bone Miner. Res. 15 (1) (2000) 68–81. K.E. Gregory, R.N. Ono, N.L. Charbonneau, et al., The prodomain of BMP-7 targets the BMP-7 complex to the extracellular matrix, J. Biol. Chem. 280 (30) (2005) 27970–27980. S. Kitahama, M.A. Gibson, G. Hatzinikolas, et al., Expression of fibrillins and other microfibril-associated proteins in human bone and osteoblast-like cells, Bone 27 (1) (2000) 61–67. L. Kohlmeier, C. Gasner, R. Marcus, Bone mineral status of women with Marfan syndrome, Am. J. Med. 95 (6) (1993) 568–572. J.M. Le Parc, P. Plantin, G. Jondeau, M. Goldschild, M. Albert, C. Boileau, Bone mineral density in sixty adult patients with Marfan syndrome, Osteoporos. Int. 10 (6) (1999) 475–479. J.R. Gray, A.B. Bridges, P.A. Mole, T. Pringle, M. Boxer, C.R. Paterson, Osteoporosis and the Marfan syndrome, Postgrad. Med. J. 69 (811) (1993) 373–375. J.H. Tobias, N. Dalzell, A.H. Child, Assessment of bone mineral density in women with Marfan syndrome, Br. J. Rheumatol. 34 (6) (1995) 516–519. N. Carter, E. Duncan, P. Wordsworth, Bone mineral density in adults with Marfan syndrome, Rheumatology (Oxf) 39 (3) (2000) 307–309. P.F. Giampietro, M. Peterson, R. Schneider, et al., Assessment of bone mineral density in adults and children with Marfan syndrome, Osteoporos. Int. 14 (7) (2003) 559–563. D.P. Judge, H.C. Dietz, Therapy of Marfan syndrome, Annu. Rev. Med. 59 (2008) 43–59. M.P. Whyte, S.L. Teitelbaum, W.A. Murphy, M.A. Bergfeld, L.V. Avioli, Adult hypophosphatasia. Clinical, laboratory, and genetic investigation of a large kindred with review of the literature, Medicine (Balt) 58 (5) (1979) 329–347.
521
59. E. Mornet, Hypophosphatasia, Orphanet. J. Rare Dis. 2 (2007) 40. 60. D.A. Stevenson, J.C. Carey, S.P. Coburn, et al., Autosomal recessive hypophosphatasia manifesting in utero with long bone deformity but showing spontaneous postnatal improvement, J. Clin. Endocrinol. Metab. 93 (9) (2008) 3443–3448. 61. J.R. Harraway, J.M. Sheard, S.J. Soule, C.M. Florkowski, P.M. George, Autosomal recessive adult-onset hypophosphatasia, Pathology 37 (6) (2005) 563–565. 62. H.M. Khandwala, S. Mumm, M.P. Whyte, Low serum alkaline phosphatase activity and pathologic fracture: case report and brief review of hypophosphatasia diagnosed in adulthood, Endocr. Pract. 12 (6) (2006) 676–681. 63. M.P. Whyte, W.A. Murphy, M.D. Fallon, Adult hypophosphatasia with chondrocalcinosis and arthropathy. Variable penetrance of hypophosphatasemia in a large Oklahoma kindred, Am. J. Med. 72 (4) (1982) 631–641. 64. J.L. Millan, S. Narisawa, I. Lemire, et al., Enzyme replacement therapy for murine hypophosphatasia, J. Bone Miner. Res. 23 (6) (2008) 777–787. 65. S. Lumbroso, F. Paris, Sultan C, European Collaborative Study. Activating Gsalpha mutations: analysis of 113 patients with signs of McCune-Albright syndrome – a European Collaborative Study, J. Clin. Endocrinol. Metab. 89 (5) (2004) 2107–2113. 66. C.E. Dumitrescu, M.T. Collins, McCune-Albright syndrome, Orphanet. J. Rare Dis. 3 (2008) 12. 67. A.M. Rahman, S.N. Madge, K. Billing, et al., Craniofacial fibrous dysplasia: clinical characteristics and long-term outcomes, Eye (2009 Jan 30). 68. R.D. Chapurlat, Medical therapy in adults with fibrous dysplasia of bone, J. Bone Miner. Res. 21 (Suppl. 2) (2006) 114–119. 69. P. de Bie, P. Muller, C. Wijmenga, L.W. Klomp, Molecular pathogenesis of Wilson and Menkes disease: correlation of mutations with molecular defects and disease phenotypes, J. Med. Genet. 44 (11) (2007) 673–688. 70. D.M. Danks, P.E. Campbell, B.J. Stevens, V. Mayne, E. Cartwright, Menkes’s kinky hair syndrome. An inherited defect in copper absorption with widespread effects, Pediatrics 50 (2) (1972) 188–201. 71. V.K. Proud, H.G. Mussell, S.G. Kaler, D.W. Young, A.K. Percy, Distinctive Menkes disease variant with occipital horns: delineation of natural history and clinical phenotype, Am. J. Med. Genet. 65 (1) (1996) 44–51. 72. D.J. Sartoris, L. Luzzatti, D.D. Weaver, J.D. Macfarlane, D.W. Hollister, B.R. Parker, I.X. Type, Ehlers-Danlos syndrome. A new variant with pathognomonic radiographic features, Radiology 152 (3) (1984) 665–670. 73. H. Kuivaniemi, L. Peltonen, K.I. Kivirikko, I.X. Type, EhlersDanlos syndrome and Menkes syndrome: the decrease in lysyl oxidase activity is associated with a corresponding deficiency in the enzyme protein, Am. J. Hum. Genet. 37 (4) (1985) 798–808. 74. H.J. Mentzel, J. Seidel, S. Vogt, L. Vogt, W.A. Kaiser, Vascular complications (splenic and hepatic artery aneurysms) in the occipital horn syndrome: report of a patient and review of the literature, Pediatr. Radiol. 29 (1) (1999) 19–22. 75. C.A. Palmer, A.K. Percy, Neuropathology of occipital horn syndrome, J. Child Neurol. 16 (10) (2001) 764–766.
522
Osteoporosis in Men
76. M. Tsukahara, K. Imaizumi, S. Kawai, T. Kajii, Occipital horn syndrome: report of a patient and review of the literature, Clin. Genet. 45 (1) (1994) 32–35. 77. P. Ferenci, Wilson’s Disease, Clin. Gastroenterol. Hepatol. 3 (8) (2005) 726–733. 78. C.M. Mak, C.W. Lam, Diagnosis of Wilson’s disease: a comprehensive review, Crit. Rev. Clin. Lab. Sci. 45 (3) (2008) 263–290. 79. H.M. Canelas, N. Carvalho, M. Scaff, A. Vitule, E.R. Barbosa, E.M. Azevedo, Osteoarthropathy of hepatolenticular degeneration, Acta. Neurol. Scand. 57 (6) (1978) 481–487. 80. M.A. Selimoglu, V. Ertekin, H. Doneray, M. Yildirim, Bone mineral density of children with Wilson disease: efficacy of penicillamine and zinc therapy, J. Clin. Gastroenterol. 42 (2) (2008) 194–198. 81. D. Hegedus, V. Ferencz, P.L. Lakatos, et al., Decreased bone density, elevated serum osteoprotegerin, and beta-cross-laps in Wilson disease, J. Bone Miner. Res. 17 (11) (2002) 1961–1967. 82. M. Wiggelinkhuizen, M.E. Tilanus, C.W. Bollen, R.H. Houwen, Systematic review: clinical efficacy of chelator agents and zinc in the initial treatment of Wilson disease, Aliment. Pharmacol. Ther. 29 (9) (2009) 99947–99958. 83. R.E. Fleming, R.S. Britton, A. Waheed, W.S. Sly, B.R. Bacon, Pathogenesis of hereditary hemochromatosis, Clin. Liver Dis. 8 (4) (2004) 755. 73, vii. 84. D. Meynard, L. Kautz, V. Darnaud, F. Canonne-Hergaux, H. Coppin, M.P. Roth, Lack of the bone morphogenetic protein BMP6 induces massive iron overload, Nat. Genet. 41 (4) (2009) 478–481. 85. O.K. Fix, K.V. Kowdley, Hereditary hemochromatosis, Minerva Med. 99 (6) (2008) 605–617. 86. P. Guggenbuhl, Y. Deugnier, J.F. Boisdet, et al., Bone mineral density in men with genetic hemochromatosis and HFE gene mutation, Osteoporos. Int. 16 (12) (2005) 1809–1814.
87. L. Valenti, M. Varenna, A.L. Fracanzani, V. Rossi, S. Fargion, L. Sinigaglia, Association between iron overload and osteoporosis in patients with hereditary hemochromatosis, Osteoporos. Int. 20 (4) (2009) 549–555. 88. N.G. Angelopoulos, A.K. Goula, G. Papanikolaou, G. Tolis, Osteoporosis in HFE2 juvenile hemochromatosis. A case report and review of the literature, Osteoporos. Int. 17 (1) (2006) 150–155. 89. F. Rollot, B. Wechsler, T.H. du Boutin le, et al., Hemochroma tosis and femoral head aseptic osteonecrosis: a nonfortuitous association? J. Rheumatol. 32 (2) (2005) 376–378. 90. J.B. van Meurs, A.G. Uitterlinden, Homocysteine and fracture prevention, J. Am. Med. Assoc. 293 (9) (2005) 1121–1122. 91. S. Blouin, H.W. Thaler, C. Korninger, et al., Bone matrix quality and plasma homocysteine levels, Bone 44 (5) (2009) 959–964. 92. D.E. Wilcken, N.P. Dudman, P.A. Tyrrell, Homocystinuria due to cystathionine beta-synthase deficiency – the effects of betaine treatment in pyridoxine-responsive patients, Metabolism 34 (12) (1985) 1115–1121. 93. M.V. Johnston, M.E. Blue, S. Naidu, Rett syndrome and neuronal development, J. Child Neurol. 20 (9) (2005) 759–763. 94. U. Moog, E.E. Smeets, K.E. van Roozendaal, et al., Neurodevelopmental disorders in males related to the gene causing Rett syndrome in females (MECP2), Eur. J. Paediatr. Neurol. 7 (1) (2003) 5–12. 95. J. Downs, A. Bebbington, H. Woodhead, et al., Early determinants of fractures in Rett syndrome, Pediatrics 121 (3) (2008) 540–546. 96. S.S. Budden, M.E. Gunness, Bone histomorphometry in three females with Rett syndrome, Brain Dev. 23 (Suppl. 1) (2001) S133–S137.
Chapter
43
Dual-Energy X-ray Absorptiometry (DXA) in Men Neil Binkley1 and Robert A. Adler2 1
University of Wisconsin, Madison, Wisconsin, USA Hunter Holmes McGuire VA Medical Center and Virginia Commonwealth University School of Medicine, Richmond, Virginia. USA
2
Introduction/Background
absorbed) to a greater degree by the mineral component of bone than by soft tissue adjacent to bone [3]. DXA employs x-ray photons of two different energies thereby permitting photon absorption by soft tissue to be factored out, which allows determination of the amount of hard tissue (i.e. bone) present. Single-energy x-ray absorptiometry (SXA) devices require immersing the measured site (e.g. forearm or heel) in a water bath to allow correction for the soft tissue contribution to photon absorption. In the USA, SXA has been replaced by DXA. With DXA, bone mineral content (BMC) can be measured in central skeletal sites (spine and hip), in peripheral sites (heel and forearm) or in the total body. DXA utilizes ionizing radiation, however, the radiation exposure for a person undergoing a DXA test is low. Specifically, current generation densitometers expose the individual to approximately three microsieverts during measurement of spine and hip BMD combined. This radiation exposure is comparable to less that one day of background radiation exposure. A useful website is provided by the US Environmental Protection Agency (www.epa.gov/ radiation/understand/calculate.html) which allows estimation of an individual’s daily radiation exposure. DXA is often regarded as the clinical ‘gold standard’ and has been used in many epidemiological studies of bone health and in virtually all pivotal prospective clinical trials leading to registration of medications to reduce fragility fracture risk. While DXA does have acknowledged limitations, it also has advantages over other technologies, including applicability of the World Health Organization (WHO) classification system, proven fracture risk assessment utility and documented effectiveness at targeting medical therapy to reduce fracture risk [4]. It is important to recognize that DXA determines ‘areal’ density (g/cm2) and not true volumetric bone density (g/cm3). Specifically, the BMC of a skeletal region is determined and these results are expressed as grams of mineral [5], while the two-dimensional image area is computed in units of cm2.
The major goal of clinical osteoporosis care is reduction of fragility fracture risk. In this regard, bone density measurement plays an integral role, enhancing estimation of risk prior to the occurrence of a fragility fracture. Methodologies to measure bone density have evolved over the last few decades with transition from the research to clinical setting being facilitated by documentation of the relationship between low bone density and fracture risk. This transition was accelerated in the mid-1990s by the World Health Organization classification based upon bone mineral density (BMD) measurement [1]. Though this initial densitometric definition applied only to postmenopausal Caucasian women, it has subsequently been applied to men and women of other races [2]. Subsequent widespread availability of instruments to measure bone mass has been associated with an increasing number of agents with proven efficacy at reducing fracture risk. In addition to these points, an aging population has led to increased clinical use of bone mass measurement. The International Society for Clinical Densitometry (ISCD) was created, in fact, to address needs related to clinical assessment of the skeleton as well as to advance knowledge in this field. Although a number of technologies exists to evaluate skeletal status and, therefore, fracture risk, this chapter will focus on the use of dual-energy x-ray absorptiometry (DXA) in men. We will review the scientific basis of DXA technology and some potential challenges and controversies regarding use of DXA in men.
Dual-energy X-ray (DXA) technology DXA is based on the principle that passage of x-ray photons through an individual is inhibited (i.e. photons are Osteoporosis in Men
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Osteoporosis in Men 1.5 cm
1cm 1.5 cm 1cm
1cm
1.5 cm
Cube size � 1 cm3 Volumetric density � 1.000 g/cm3 BMC by DXA � 1 gram Area by DXA � 1 cm2 BMD by DXA � 1.gram/1 cm2 � 1.000 g/cm2
Cube size � 3.375 cm3 Volumetric density � 1.000 g/cm3 BMC by DXA � 3.375 gram Area by DXA � 2.25 cm2 BMD by DXA � 3.375.gram/2.25 cm2 � 1.500 g/cm2
Figure 43.1 Effect of bone size on BMD as measured by DXA. Overall, BMD as measured by DXA is higher in men simply due to their larger bone size. This concept is illustrated here by two cubes of bone, both having the same volumetric BMD (1.000 grams/cm3). The extra depth present in the larger ‘male’ cube on the right leads to a substantially higher BMD as measured by DXA. Thus, with DXA, larger bone size is captured as higher areal BMD.
Areal BMD is then derived by dividing the BMC of the measured region by the area of that region (BMD BMC/area). Importantly, this two-dimensional result does not consider the third dimension of depth. As such, larger bones, having greater depth, will have a greater density as measured by DXA. Thus, individuals with larger bones (e.g. men compared with women) will have higher areal BMD even if the volumetric density is identical. This concept is expanded in Figure 43.1. Based on the above considerations, it is clear that bone size differences could be expected to explain the higher DXA-determined BMD in men compared with women. Quantitative computed tomography (QCT) studies document that this is the case. For example, QCT finds crosssectional vertebral body area to be approximately 25% larger in men than women. This larger bone size in men persists even after adjusting for body size at both the lumbar spine [6] and femur neck using NHANES DXA data [7]. Additionally, a QCT study confirmed greater vertebral size in men and established similarly larger femur neck area in males [8]. Specifically, in young adults (age 20–29 years), lumbar spine area was 35% larger and femur neck area 48% larger in males. In this same study, total volumetric BMD by QCT (mg/cm3) was lower (P 0.001) at both the lumbar spine and femur neck in young adult men than in women. Thus, the dogma that male bone density is higher than females, while correct for areal BMD as determined by DXA, is not correct when volumetric density is considered. The larger areal bone density in men than in women is due to their larger bone size. The inability of DXA to measure volumetric density is often cited as a weakness of this technique. However, as
bone size contributes importantly to bone strength [9] (and therefore ultimately to fracture risk), the ability of DXA to incorporate bone size into the measurement of areal density is likely to enhance the clinical utility of this methodology as a tool to estimate future fracture risk. Thus, measurement of areal BMD, while potentially a research weakness for DXA methodology, is actually a clinical strength for estimation of fracture risk.
Understanding DXA results The output of current DXA instruments can be confusing to the clinician as results of multiple regions of interest are presented with a variety of data (e.g. BMC, BMD, area, T-score, Z-score and percentage comparisons) being reported. However, these results can be simplified by focusing on BMD and a highly relevant, standardized score, the T-score. The BMD (in grams/cm2) is simply the result of dividing BMC (grams) by bone area (cm2) as noted above. This result is necessary for monitoring skeletal change over time (discussed below) and for deriving the standardized score (T-score or Z-score). The T-score is the number of SD above or below the average BMD value of a young adult reference population. As such, the T-score compares the individual patient with the average 20–29 year old. T-scores are calculated as follows:
Individual’s BMD BMD of the young normal reference population standard deviation of the young normal population
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In contrast, the Z-score compares an individual’s BMD with that of an average age-matched reference population in the identical manner as above, i.e.:
Individual’s BMD BMD of the agematched reference population standard deviation of the age-matched population
While the use of these standardized scores (T- and Z-scores) has advanced the field of osteoporosis diagnosis and treatment, it is essential to appreciate that the score obtained is quite dependent upon the reference population utilized. This will be discussed below in ‘Pitfalls of DXA’. The use of these standardized scores (rather than simply reporting BMD in grams/cm2) has been required due to the fact that densitometers of different manufacturers do not measure BMD in an identical manner and therefore do not obtain the same BMD. This is due to proprietary differences in generation of the dual x-ray energies, software bone edge detection paradigms and region of interest placement. As an example of such differences, BMD in grams/cm2 as measured by two major densitometer manufacturers (Hologic and GE Healthcare Lunar) will differ by approximately 10%.
What skeletal sites to measure It is the current ISCD position that the lumbar spine and proximal femur should be measured in all patients when DXA is performed with measurement of the one-third radius site when one of these regions cannot be measured [10]. This approach seems appropriate in that there exists extensive experience with BMD measurement at these sites in observational and treatment studies in both men and women. Moreover, measurement of the sites at which fragility fracture is most common with advancing age (spine, hip and wrist) seems intuitively logical and low BMD at these sites is associated with increased risk for future fracture. Although vertebral fractures obviously occur in the thoracic spine, BMD measurement at this site is not feasible as the ribs would be included in the ‘soft tissue’ regions, thereby preventing the comparison of bone and ‘soft tissue’ photon absorption. Additionally, as DXA reproducibility is enhanced with measurement of larger amounts of bone, mean BMD of L1 through L4 is utilized [10]. The current recommendation is that measurement at the lumbar spine requires at least two evaluable vertebrae. Proximal femur measurement is a summation of the femur neck, trochanter and proximal femur regions of interest. DXA also can measure and often reports a value for Ward’s region, but this area is not useful in clinical practice due to this site’s small size and the fact that the WHO classification does not apply to Ward’s area [11]. Similarly, the WHO classification does not apply to trochanteric T-scores.
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Degenerative changes in the spine become common with advancing age; over 60% of women over age 70 have radiographic evidence of spine osteoarthritis [12] and the prevalence is even higher among men [13]. These degenerative changes lead to an artifactual elevation of the lumbar spine BMD as measured by DXA [14], blunting the expected agerelated increase in osteoporosis prevalence. It may even lead to a falsely ‘normal’ BMD (Figure 43.2). As some of these degenerative changes involve the posterior aspect of the vertebral bodies, this contribution to DXA-measured BMD could potentially be reduced by the use of lateral spine BMD measurement. However, the WHO T-score based diagnostic classification does not apply to lateral spine measurement [10]. Moreover, though it seems reasonable that lateral spine measurement could be utilized for monitoring BMD change over time, the precision at this site is suboptimal, thereby reducing utility of this approach. As such, in men with spinal degenerative changes or other confounders of spine DXA, forearm measurement is appropriate along with the hip [10]. The utility of routine forearm measurement was recently explored in 2356 largely Caucasian (97%) men referred by their healthcare provider for bone mass measurement [15]. Overall, in this group, 27% (639/2356) were classified as osteoporotic at one of more skeletal sites (L1–4, femur neck, total femur or one-third radius). As shown in Figure 43.3, the lumbar spine uniquely identified 19% of men younger than age 70 with osteoporosis but only 3% of men over age 70. In contrast, the distal one-third radius uniquely identified only 5% of men younger than age 70 with osteoporosis but 14% over age 70. This study implies substantial clinical utility of forearm measurement, particularly in those men over age 70 yet, the most recent ISCD Position Development Conference did not find the existing data robust enough to recommend routine forearm measurement in all men undergoing DXA testing [16]. Additionally, it is not clear which forearm measurement region best predicts fracture in men. It should be noted that the study of Melton et al [17] demonstrated that the total forearm predicted fracture well in men; results from the one-third region were not reported. Thus, further study is needed to determine if the total forearm or one-third distal radius should be used in men. Unfortunately, the MrOS Study, which is providing important information about predicting fracture in older men, does not include forearm DXA testing.
Pitfalls in DXA In addition to the degenerative changes in the lumbar spine, other pitfalls in measurement include metallic hardware or other artifacts in, or overlying, the spine and hip, vertebroplasty/kyphoplasty artifacts and soft tissue artifacts, such as imaging contrast material. For lumbar spine DXA measurements, the vast majority of these artifacts lead to an
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Of men classified as osteoporotic (T-score � –25), % identified by skeletal site
Figure 43.2 Example of spinal degenerative changes elevating BMD as measured by DXA. In this 75-year-old man, spinal degenerative changes are evident; note the osteophytes and sclerosis at the arrows. This additional bone contributes to the ‘normal’ BMD (1.172 grams/cm2; T-score 0.4) at the L1–4 spine whereas his femur neck BMD of 0.751 grams/cm2 yields a T-score of 2.5 and thus the diagnosis of osteoporosis.
100 80
6%
4% 13%
32%
14%
Femur neck or total femur
46% 50%
60
47%
20 0
Lumbar spine (L1–4) More than 1 site
23% 14%
40
One-third radius
38%
35%
� 60 n � 650 n � �2.5 � 133
60–69.9 n � 553 n � �2.5 � 134
1%
4%
36%
35%
70–79.9 n � 674 n � �2.5 � 181
� 80 n � 487 n � �2.5 � 194
Age (years) Total n � 2356
Figure 43.3 Osteoporosis diagnosis by skeletal site in men referred for clinically indicated DXA scans. In this study of 2356 men, utility of the L1–4 spine declines with advancing age such that very few men over age 70 (3%) are identified as osteoporotic uniquely at the spine [15]. In contrast, measurement at the one third radius uniquely identifies approximately 15% of men over age 70 as osteoporotic. Thus, failure to measure this site leads to underdiagnosis in men.
artifactually elevated BMD. A notable exception is the artifact induced by laminectomy in which BMD may be reduced. External metallic artifacts, e.g. metal buttons, coins in pockets, jewelry, etc, should be removed prior to the DXA scan as these may alter the component due either to the ‘bone’ or ‘soft tissue’. An example of a soft tissue artifact altering the femur BMD result is noted in Figure 43.4. Less apparent effects of variable soft tissue thickness, e.g. a fat panniculus overlying the hip, can also impact results [18]. Contrast material or recent performance of a nuclear medicine procedure may also invalidate DXA
results. Recent reviews nicely summarize potential pitfalls in the DXA measurement [19, 20]. In addition to the patient-specific issues noted above, pitfalls in the technical and interpretative components of DXA are worthy of emphasis. DXA scan acquisition, analysis and subsequent interpretation require specific knowledge and attention to detail because poorly performed, analyzed or interpreted scans can lead to inappropriate results and subsequent incorrect therapeutic decisions. In this regard, the essential role of the technologist in acquiring and analyzing DXA data to assure quality results must be appreciated.
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Total femur BMD = 0.728 grams/cm2 Total femur T-score = –2.2
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Total femur BMD = 0.688 grams/cm2 Total femur T-score = –2.5
Figure 43.4 Example of the potential impact of soft tissue artifact on DXA results. In this image, a metallic button on the patient’s back pocket was included in the ‘soft tissue’ region (arrow in left panel). A repeat scan performed minutes later (right panel) finds a statistically significant ‘change’ in the measured total femur BMD resulted; note the least significant change in this facility is 0.024 grams/cm2. The DXA technologist must be certain that such artifacts are removed prior to DXA scan performance.
Obtaining clinically meaningful DXA results requires appropriate and consistent patient positioning on the densitometer by the technologist. Moreover, although the computer software initially identifies bone edges and places the regions of interest, the DXA technologist must carefully verify and, if/ when necessary, adjust these edges or alter region of interest placement [20]. Similarly, appropriate education and expertise of the clinician interpreting the DXA study is essential. Unfortunately, errors in DXA acquisition and/or interpretation are not rare. In fact, in a survey of over 700 clinicians, 71% reported finding incorrect DXA interpretations at least once a month with 27% finding this to occur more frequently than once per week. Moreover, 59% believed this to be a moderate or major problem in terms of being detrimental to patient care [21]. Clearly, clinician expertise in DXA interpretation is essential. In this regard, interpreting clinicians must be aware of a subtle, but potentially very important pitfall in DXA interpretation, namely changes in densitometer software normative databases. This is not simply a theoretical issue. In the past, such database changes have led to changes in diagnostic categorization when applying the WHO T-score based classification [22,23]. Such changes can occur as alterations of reference databases and may substantially affect DXA generated T- and Z-scores because these scores are dependent on the reference population mean BMD and standard
deviation. To highlight this point, consider the hypothetical example of a patient with a BMD of 0.800 grams/cm2. If the young normal population mean BMD was 1.000 grams/cm2 with an SD of 0.100 grams/cm2, the T-score for this individual would be calculated as follows: (0.800 1.000)/0.100 and thus be equal to a score of 2.0. However, if the SD of the reference population were to change only slightly, e.g. from 0.100 to 0.130 grams/cm2, the T-score would be calculated as follows: (0.800 1.000)/0.130 1.5. Thus, this patient would have a 0.5 T-score ‘difference’ despite having identical BMD values in grams/cm2. Such differences can potentially lead to differences in therapeutic recommendation. It is important, thus, that the DXA interpreter appreciate the importance of utilizing standard databases for T-score calculation and assure that no changes in the normative database occur when the densitometer software is upgraded. This can be established simply by analyzing a number of previously performed scans with the new software and documenting that the T- and Z-scores are identical to that obtained with the prior software.
DXA Normative databases When considering normative databases, it is important to recognize that there is currently no standard database for
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lumbar spine DXA T-score derivation. However, reasonable agreement exists between at least some DXA manufacturers, (e.g. Hologic and GE Healthcare Lunar) at the lumbar spine for women (mean difference of 0.3 T-score) [24], but more substantial discordance in male spine T-scores derived using the manufacturers reference databases (0.5 T-score) has been observed between GE Lunar and Norland [25]. Use of a standard reference database has been advocated to overcome this problem [25]. It might be assumed that such standardization has been achieved at the femur neck as the female age 20–29 White NHANES database is recognized as the international reference standard [10,26]. In fact, for women, there is good agreement between femur neck and total femur T-scores obtained by GE Lunar and Hologic densitometers using the NHANES database [23, 24]. When considering proximal femur T-score derivation in men, it should be recognized that two major densitometer manufacturers (GE Healthcare Lunar and Hologic) utilize different approaches to definition of the ‘femur neck’ and ‘total femur’ regions of interest. Briefly, GE Lunar places the ‘femur neck’ region of interest based upon narrowest width of the femur neck and lowest bone mass, while Hologic places the ‘femur neck’ region of interest adjacent to the greater trochanter. Additionally, the Hologic total femur region of interest extends further distally on the femur shaft than does that of GE Lunar. These differences are depicted in Figure 43.5. Such variations lead to measurement of different parts of the femur likely having differing BMD values. As a different BMD would yield a different T-score, development of standardization equations was required. To this end, the International Committee for Standards in Bone Measurement published equations to allow conversion of total femur manufacturer-specific units (grams/cm2) into standardized units based upon data
Hologic FN placement
acquired in women [27]. Although this committee appreciated a need to standardize male total femur data, it has not been performed. Subsequently, it was found that use of the total femur calibration formula produced suboptimal results for other proximal femur sites and equations for standardization of BMD at the femur neck, trochanter and Ward’s area were published [28]. These equations were developed using data from 100 white women and it is not certain that they can directly be applied to men. This was appreciated by the developers of these conversion equations [28] who stated: Strictly speaking, our formulas and analysis results apply only to white women. Because of variations in anatomy among other races or in men, the algorithms for ROI [region of interest] definition might place the ROIs in slightly different relative locations. Moreover, differences in the heterogeneity of bone among different populations can also contribute to differences in BMD that influence the cross-calibration relationships among the three DXA devices. While these BMD relationships and the resulting standardization equations can be expected to be similar to those reported here, more research is needed to determine whether these results can be extended to other races and to men. As such, it is not clear that direct application of the conversion equations to males is appropriate; study of this approach and derivation of male-specific equations, if needed, is indicated. An effort to standardize BMD in 229 healthy Belgian men has been reported. These men had lumbar spine and proximal femur BMD measured using Hologic and GE Lunar densitometers [29]. These workers made the reasonable assumption that the formulae generated in women [27,28,30,31] also applied for men (given that no male
GE lunar FN placement
Comparison FN placement
Figure 43.5 Comparison of femur neck (FN) region of interest placement. The same patient was scanned on a Hologic (left) and GE Healthcare Lunar (middle) densitometer with the femur neck region of interest (arrows) automatically placed by the respective manufacturers’ software. The Hologic and GE Lunar regions of interest are reproduced on the femur image in the right panel; it is visually apparent that different regions are identified as the ‘femur neck’ by these densitometers. Similarly, it is also apparent that the ‘total femur’ region of interest (the summation of the femur neck, trochanter and proximal femur regions) differs between these manufacturers’ with the GE Lunar region stopping more proximal than that of Hologic. Given that different regions of the proximal femur are being included in the ‘femur neck’ and ‘total femur’, it is highly probable that these regions will have a different BMD. As the NHANES III data were acquired using Hologic densitometers, it is evident that conversion equations are necessary if this database is to be applied to densitometers of other manufacturers
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standardization formulae exist) and derived standardized BMD thresholds in mg/cm2 for the diagnostic classification of osteopenia and osteoporosis. Such a standardized BMD approach clearly has merit, but has not been widely adopted.
Clinical use of DXA: diagnosis, monitoring and fracture risk assessment DXA BMD measurements can be used for diagnosis, fracture risk assessment or to monitor BMD change over time. Densitometric diagnosis allows identification of individuals at risk prior to their sustaining a fragility fracture. Fracture risk assessment is integral in assisting the clinician with therapeutic decision making and monitoring may identify a need to initiate medications or identify ‘non-responders’ to therapy. Underpinning the utility of DXA for osteoporosis diagnosis is the relationship of BMD measurement with risk for future fracture. In this regard, many reports demonstrate that lower BMD, as measured by DXA, is associated with increased fracture risk with the gradient of risk being very powerfully predictive and comparable to the association of blood pressure with cardiovascular disease risk [32–34]. Moreover, fracture reduction therapy is effective in both men and women identified for treatment based upon BMD [35].
Utility of DXA for Diagnosis For diagnosis, the World Health Organization (WHO) classification system in which the BMD T-score at the lumbar spine, femur neck, total proximal femur or one-third radius is widely utilized [10]. With this classification, a value of 2.5 or lower is consistent with the diagnosis of osteoporosis while values between 1.0 and 2.5 are consistent with
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low bone mass/osteopenia. Though this classification was developed for epidemiologic studies using data from white postmenopausal women [36], it is widely applied for diagnostic purposes in men [2,16]. Use of the term osteopenia is widespread in clinical medicine. However, this verbiage has often been criticized as implying that ‘osteopenia’ indicates that the person has a disease necessitating treatment. This is incorrect in that the WHO classification system compares an individual’s BMD with that of the average young adult. It is apparent that 50% of 30-year-old individuals will have a BMD value below average. Thus, a 30-year-old healthy man with a BMD value that is 1.2 standard deviations (SD) below average may well simply have achieved less than average bone density and is not ‘diseased’ any more than a person whose peak height is 1.2 SD below average. This below average BMD may well simply indicate acquisition of less than average BMD on a genetic basis. Such an individual is not at high fracture risk [37], should not receive a ‘disease’ diagnosis and does not require therapy to reduce fracture risk. In summary, osteopenia does not necessarily imply bone loss or increased short-term fracture risk. As such, the WHO classification should not be applied to and, in fact, T-scores should not be reported for, healthy men under age 50. Controversy exists regarding the normative database to utilize for T-score derivation in men. Some recommend use of the female white NHANES young normal population [38] while the ISCD has recommended using a male normative database [39]. As 20–29-year-old women have lower BMD than men of the same age, use of a female reference database will make the derived T-score ‘better’ and thus reduce the prevalence of osteoporosis in the male population studied. Consistent with this, data from a clinical population of 350 men whose T-scores were derived using both the female NHANES and manufacturer specific male database are shown in Figure 43.6. In this cohort, use of the
17% 25%
26%
Normal
34%
Osteopenia Osteoporosis 49%
Male database used for T-score derivation
49%
Female database used for T-score derivation
Figure 43.6 Effect of female versus male database use on T-score and osteoporosis diagnosis in men. In a cohort of 350 men referred for clinically-indicated DXA scans, use of the manufacturer’s female database at the lumbar spine and the female NHANES III reference database at the femur ‘improved’ the T-score by 0.3, 0.3 and 0.5 at the lumbar spine, femur neck and total femur respectively [40]. As a result, 9% fewer men would be classified as having ‘osteoporosis’.
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Table 43.1 Cohorts studied that included men and utilized DXA to evaluate the relationship between BMD and fracture risk in the Johnell et al study [41] Cohort
n
% male
Total person-years
Total no. fragility fractures
Total no. of hip fractures
DXA methodology
CaMos DOES EVOS Hiroshima Rochester Rotterdam Hiroshima [45]
8317 2071 4967 a 2596 993c 5776d 2356
31 39 45 31 35 42 32
23 707 15 884 14 702 9803 6185 34 055 -
262 406 270 89 241 501 297 (170F/27M)f
27 104 15 31 42 154 21 (21F/0M)
Hologic Lunar Mixedb Hologic Hologic Lunar Hologic
a
BMD measured in 3461; pencil beam DXA at 13 centers; cross-calibrated using the European spine phantom; c two cohorts; only the second included men; d femur neck BMD measured in 2432 men; f raw data from Fujiwara et al. b
female database improved T-scores by a mean difference of approximately 0.3 at the L1–4 spine, 0.3 at the femur neck and 0.5 at the total femur and thereby reduced the proportion with a diagnosis of osteoporosis [40]. Very briefly, some studies find the fracture risk in men and women to be equal at the same BMD value [34, 41, 42], suggesting that the same (i.e. female) database should be used to calculate T-scores in both genders [43]. However, using a male database to calculate T-scores is felt by some to provide a more realistic estimate of osteoporosis prevalence in men. As such, there has been debate whether male T-scores should be derived using male or female data [44]. This controversy is reviewed below. How robust are the data documenting that the same relationship between DXA-measured BMD and fracture risk exists for men and women? In this regard, review of a recent analysis involving approximately 9000 men and 29 000 women is illustrative. These authors found femur neck BMD strongly to predict hip fractures [41]. Appropriately, these data were adjusted using the SD of the young female reference range from NHANES III so that the gradient of risk in men and women could be directly compared. In this report, the gradient of risk for any osteoporotic fracture per SD decrease in BMD Z-score was 1.60 for men and 1.53 for women. Similar gradient of risks were documented for hip fracture 2.42 (men) and 2.03 (women). Given the size and complexity of this report, it seems appropriate to review the various components summarized in Table 43.1. To summarize, in this work involving over 100 000 person years of data (40 000 person-years contributed by men including 149 hip fractures [46]), the authors found no significant differences between men and women in gradient of risk of BMD for any fracture or for hip fracture. Though not included in the aforementioned report, data from the MrOS study found spine BMD also to be predictive of future fracture risk in men [46]. Thus, it is clear
that DXA measured BMD is related to future fracture risk in both men and women. A number of reports have investigated the relationship of BMD with fracture risk in men and women. Some studies find the absolute risk for hip and vertebral fractures to be similar at the same age and areal BMD for men and women; this argues that the same DXA-measured BMD (and therefore normative database for T-score derivation) should be utilized for ‘osteoporosis’ diagnosis in men and women. However, other studies disagree. Possible explanations for divergent results include the fact that the relationship of BMD with fracture risk changes with advancing age. As such, it is necessary to adjust for age to evaluate the relationship of BMD with fracture risk. Additionally, the standard deviation of BMD is not the same for men and women. For example, the total femur BMD SD is 0.140 g/cm2 in the GE Lunar male normative database, whereas it is 0.130 g/cm2 using the GE Lunar female NHANES III database [40]. This difference in standard deviation could indicate anatomic differences between men and women or, alternatively, potentially reflect different numbers of normal young adults used for calculation of the mean and standard deviation. Finally, evaluation of osteoporotic patients, rather than population based studies, could potentially lead to referral bias [26]. The Rotterdam study [47] is cited as an example of a population-based cohort in which age-adjustment was performed and a standardized SD was utilized. In this study of 7046 people, 5305 (2227 men) had their femur neck BMD measured using a Lunar DPX-L densitometer and were followed for an average of 3.8 years [43]. During follow up, 110 hip fractures were observed. Despite over 10 000 patient-years of follow up in men, only 23 hip fractures were observed. Moreover, of the 23 men who sustained hip fracture, only 15 had a BMD measurement performed. As such, despite the size and duration of this study, the number
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of men who had their BMD measured and sustained hip fracture is small. Data from Canadian Multicentre Osteoporosis Study (CaMos), a prospective evaluation of fracture incidence in seven Canadian provinces, were included in the Johnell analysis [41]. In CaMos, incident fractures over 8 years from 2484 men and 6093 women over age 50 were recently reported. Despite the size of this study and quite similar to the Rotterdam study, only 20 hip fractures in men were observed [48]. The Dubbo Osteoporosis Epidemiology Study (DOES) is a population-based assessment of men and women from Dubbo, Australia. In a subset of this cohort (960 women/689 men) followed for a median of 12 years, a total of 115 hip fractures were observed (86 in females/29 in males) [42]. Though the femur neck BMD was higher in men who sustained hip fractures than among women, (0.73 g/cm2 versus 0.64 g/cm2), after adjusting for age, the hip fracture incidence in men and women was virtually identical. Again, the number of hip fractures in men is modest. The Adult Health Study (AHS/Hiroshima) follows atomic bomb survivors and measured BMD at the spine and hip by DXA in 1994. In the report of Fujiwara et al [45], data are reported for a cohort of 2356 men and women aged 47–95 years with an average follow up of four years. In this study, vertebral fractures were diagnosed radiographically using the semiquantitative analysis of Genant. Of the 763 men in this report, 27 new vertebral fractures were identified but no hip fractures occurred. After adjusting for L2–4 or femur neck BMD and prevalent vertebral fracture, there was no gender difference in the age-specific incidence of radiographic vertebral fracture. In this study as well, only a modest number of fractures occurred among men. As a result of their analysis, Johnel et al [41] concluded: …the age-specific risk of hip fracture at a given hip BMD in men seems to be the same in women with the same BMD and age. The existing data support this conclusion. However, it is appropriate to appreciate that despite large, long-duration studies, a relatively modest number of fractures account for this conclusion. However, not all data are concordant. For example, comparing data from the MrOS study, a prospective evaluation of 5384 men age 65 years, with postmenopausal women from the SOF (Study of Osteoporotic Fractures) cohort found the non-vertebral fracture risk to be higher in women than men for all proximal femur T-scores whether derived using male or female reference data [46]. Moreover, greater differences between men and women were observed in younger men with the association between T-score and fracture risk becoming more similar in older adults [46]. An additional smaller cross-sectional study of 2067 Caucasian women and 317 Caucasian men found that men with prevalent vertebral fracture had higher BMD than did women [49].
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It is not surprising that the relationship between DXAmeasured BMD and fracture risk would be complex and controversial in that data are often less than ideal. Moreover, bone geometry and traumatic events may differ between older men and women. The importance of considering clinical factors in addition to just BMD is exemplified by the widespread adoption of the FRAX approach. Given the importance of differing bone sizes between men and women (with attendant impact on DXA-measured BMD) and the important effect that clinical factors have on fracture risk, is it plausible that DXA somehow integrates these factors and thus identifies similar fracture risk at the same BMD? Thus, the impact of bone size is worthy of consideration. It is axiomatic that larger structures possess greater structural strength than smaller ones. If men and women do sustain osteoporosis-related fractures at the same BMD, this would imply that DXA corrects for the larger male bone size and potential differences in bone geometry. A preliminary QCT report suggests that this might in fact be the case. In this study, 58 women were matched with 51 men for femur neck BMD and their QCT parameters were assessed [50]. The male femur neck area, as expected, was substantially larger, but both femur neck total volumetric BMD and trabecular BMD were substantially lower in men than women. This implies that the bone strength conveyed by larger bone size in men is offset by greater BMD losses (and therefore strength declines) leading to the same DXA measured BMD. This preliminary finding requires confirmation. Do traumatic events differ between men and women? This is an important consideration as 90% of hip fractures result from a fall [51] and women have a higher frequency of injurious falls than do men [52] with fewer than 30% of emergency department visits for unintentional fall-related injuries occurring in males [53]. Moreover, data from the National Electronic Injury Surveillance System involving 22 560 older adults treated for fall-related injuries, found fracture rate to be 2.2 times higher among women [53]. It is plausible that this lower risk of injurious falls and fractures among men reflects their greater physical activity and lesser prevalence of lower body disability [54]; factors that should only modestly be related to BMD. Perhaps by the time men are falling and sustaining hip fractures, a greater magnitude of bone and muscle loss (e.g. sarcopenia/fraility) has developed. In summary, the data relating fracture risk and BMD in men and women remain less than ideal and somewhat controversial. Potentially, it could be that the relationship differs in younger adults and becomes more similar at older ages as suggested by the data of Cummings et al [46]. If so, this could explain the similarities observed in some of the literature as hip fractures primarily occur in old age. Additionally, one could argue that the database controversy will become irrelevant given the momentum towards treatment based upon estimated fracture risk rather than on a diagnosis of ‘osteoporosis’. However, the estimations of
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fracture risk available today are based on only femoral neck BMD, eliminating potential risk based on spine or forearm BMD. Moreover, as noted above, the ‘femoral neck’ is not the same anatomic region for two major DXA manufacturers. It is also unclear if other potential clinical risk factors, such as falls, might be more important in men than women. While knowledge of fracture risk may be helpful, some data demonstrate that adherence to osteoporosis therapy is improved by patient awareness of their DXA results [55– 58]. Whether this requires a ‘diagnosis’ or similar effects can be achieved by an estimation of fracture risk has not been adequately evaluated. One report does find that a DXA test indicating ‘osteoporosis’ is associated with a high likelihood of receiving pharmacologic therapy [59]. Finally, it is reasonable to note that in all of the major osteoporosis treatment studies in men [35, 60], a male normative database was used to determine if subjects were eligible for study inclusion. Thus, we know that men with osteoporosis by DXA or clinically (osteopenia plus a history of fragility fracture) based on a male normative database will respond to available treatments. Given these uncertainties, we favor use of a male database for T-score derivation in men at this time.
Utility of DXA for Fracture Risk Assessment Ultimately, the goal of osteoporosis therapy is fracture risk reduction. In this regard, DXA can assist with fracture risk assessment. Underpinning this utility is the relationship of BMD measurement with future fracture risk as noted above. As a result of the relationship between low DXA-measured BMD and fracture risk, drug registration agencies in Europe and the USA have historically recommended that DXAmeasured BMD be utilized as an inclusion criterion for intervention studies. The documented effect of pharmacologic therapy to reduce fracture risk in patients selected for study inclusion based upon low BMD solidifies the importance of including this measurement in fracture risk estimation. However, also as noted above, factors other than BMD contribute to fragility fracture risk. Though recommendations for pharmacologic therapy have, in the past, been based largely on BMD T-score [61, 62], such an approach fails to identify many individuals who will subsequently sustain fragility fracture. An example of this phenomenon is provided by the Rotterdam study [34] in which the majority of men who sustained a fragility fracture over a mean follow up of 6.8 years did not have ‘osteoporosis’ in the hip by DXA (Figure 43.7). To some extent, this is due to there being many more people who have low bone mineral density/osteopenia than who have osteoporosis by T-score. Additionally, the relationship between BMD and fracture risk is notably affected by age [37] in that at a given T-score, older adults are at much higher short-term fracture risk than younger individuals. Part of this age effect is due to a greater likelihood of falls with advancing age. It is also probable that ‘age-related’ alterations in bone structural
90 80 Number of non-vertebral fractures in men
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70 60 50 40 30 20 10 0
Normal Osteopenia Osteoporosis Classification by femur neck BMD T-score
Figure 43.7 Non-vertebral fractures by femur neck T-score status. In the Rotterdam study, femur neck BMD was measured by DXA using a Lunar densitometer. Gender specific T-scores were calculated using the male NHANES reference population. One hundred forty five non-vertebral fractures were documented to occur in men over an average of 6.8 year follow up. Though at least 37 (25.5%) of these fractures did not appear to be classical ‘fragility’ fractures as they involved the hands, feet or skull, these results illustrate the concept that not all ‘osteoporotic’ fractures occur in men with densitometric osteoporosis. (Adapted from Schuit et al [34])
and/or material properties occur and contribute to a more fragile skeleton [41]. It is not currently possible in the clinic to evaluate such changes in ‘bone quality’. In addition to low BMD and age, other BMD-independent risk factors modify the relationship between BMD and fracture risk. It is therefore rational that fracture risk assessment be distinguished from diagnosis to allow the incorporation of clinical factors into fracture risk assessment [63]. One such clinical factor of substantial importance is prior fragility fracture [64–66]. Additionally, small body size, a parental history of hip fracture and the presence of other causes of bone loss (e.g., glucocorticoid therapy, alcohol or tobacco use), also affects fracture risk. Thus, it is apparent that low BMD is but one of the important clinical considerations that must be included in fracture risk assessment. The WHO absolute fracture risk FRAX paradigm incorporates clinical risk factors to estimate 10-year fracture probability [67, 68]. The rationale underlying FRAX is that treatment should ideally be directed not only based on BMD T-score, but also the use of other validated risk factors [69]. Risk factors were identified using data from nine prospective population-based
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cohorts including Rotterdam, EVOS/EPOS, CaMos, Rochester, Sheffield, Dubbo, Hiroshima, Gothenburg 1 and Gothenburg 2 as noted earlier in Table 43.1. FRAX is an advance in clinical care and is not difficult to use. Clinical application should be enhanced by the incorporation of FRAX calculations into routine DXA output. However, FRAX does have limitations including minimal validation in men. Though the FRAX model has been prospectively validated in 11 independent cohorts involving over one million patient-years [69,70], 10 of these 11 validation cohorts included only women. In the one validation cohort that included men (n 171), the number of fractures is not stated [71]. Thus, it will be important to validate FRAX in large populations of men with adequate numbers of fractures. Additionally, in the clinical application of FRAX, it should be appreciated that some risk factors are entered as dichotomous variables (yes, no) for which a dose–response relationship may exist; examples include tobacco and alcohol for which greater use may impart greater fracture risk. Moreover, the contributions of low spine and/or forearm BMD to fracture risk in men may need to be considered. Additionally, the contribution of other risk factors, e.g. falls risk, dementia, etc, to fracture risk must be considered for the individual patient. Consistent with this, it is important to emphasize application of clinical judgment, rather than blindly following treatment guidelines. To this end, we agree with the NOF Clinician’s Guide that states [72]: Decisions on whom to treat and how to treat should be based on clinical judgment using this Guide and all available clinical information. Finally, it should be emphasized that thresholds for intervention are not necessarily the same as a diagnostic threshold because treatment recommendations are often based on health-economic considerations, not simply BMD. The fracture risk at which therapy is ‘indicated’ will vary from country to country based upon the wealth of the nation and the amount of resources dedicated to healthcare. However, the recent availability of generic alendronate at extremely low costs impacts such cost-effectiveness analyses. It seems possible/likely that cost-effectiveness will play a minimal or no role in some treatment decisions, being replaced by the traditional clinical approach of assessing treatment benefits and potential risks for the individual patient.
Utility of DXA for Monitoring BMD Change Serial DXA scans can be performed to monitor change in BMD over time. Common clinical scenarios in which a monitoring DXA is performed include evaluation of response to therapy in patients with osteoporosis and in individuals for whom a decline in BMD would lead to initiation of therapy. When follow-up DXA scans are performed, it is necessary to use the BMD value in grams/cm2 (not the T-score) to determine if a change has occurred [73].
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Additionally, it is essential that the facility in which the DXA was performed know their BMD least significant change; this requires performance of an in vivo precision assessment using published recommendations [74]. As a generalization, changes of approximately 3–6% at the hip and approximately 2–4% at the spine are likely within the range of DXA measurement variability [72]. The ideal skeletal site to monitor is one that rapidly loses bone and/or responds rapidly to therapy. Moreover, this site should have excellent reproducibility (low least significant change). Classically, the lumbar spine is cited as the best site to monitor [73]. However, this may not be the case if spine measurement is confounded by degenerative changes. This finding may be particularly important in older men, who often will have arthritic changes that compromise spine DXA interpretation and may prevent appreciation of a decline in BMD over time. In this instance, monitoring using BMD of the total femur is appropriate. In patients in whom rapid bone loss could be expected (e.g. initiation of glucocorticoid therapy), repeating a DXA in as little as 6 months is reasonable. Additionally, performance of a monitoring DXA 1–2 years after initiating medical therapy is appropriate [10,72]. When monitoring osteoporosis treatment, either stable or increasing BMD is associated with fracture risk reduction, whereas a decline in BMD (greater or equal to the least significant change) is of concern. This may indicate suboptimal compliance or secondary causes of bone loss and has been suggested to be an indication for further investigation [73]. Finally, it should be recognized that the FRAX-estimated 10-year fracture probability does not apply to patients receiving osteoporosis treatment, thus, this value should not be included in the monitoring DXA report.
Indications for DXA testing in men Despite the proliferation of clinical guidelines related to osteoporosis (a recent search of the National Guideline Clearinghouse – www.guideline.gov; accessed 3/26/2009 – identified 136 guidelines relevant to osteoporosis), many of these exclude men. For example, the US preventive Services Task Force and the American Association of Clinical Endocrinologists, despite recommendations regarding DXA testing in postmenopausal women, have made no such recommendations for men. However, in 2008, recommendations relevant to DXA indications in men were published by the American College of Physicians (ACP) [76], the US National Osteoporosis Foundation (NOF) [72] and the International Society for Clinical Densitometry (ISCD) [10]. Salient recommendations for DXA testing in men are noted below and summarized in Table 43.2. The ACP recommendations were generated by a formal evidence-based literature review, with the aim of identifying
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Osteoporosis in Men Table 43.2 Synopsis of recommendations for DXA testing in men
Organization/society
Age ≥ 70
Prior fracture
Secondary causes including medications
Age 50–69
US NOF [72] ISCD [10, 16] OSC [78]
Yes Yes Yesd
Yesa Yes Yes
Yes Yes Targetede
Yesb Yesc Targetede
a
Fracture after age 50; with clinical risk factors; c ‘men under age 70’ without specifying a lower age limit; d justifiable in men and women after the age of 65; e ‘targeted case-finding strategies for those at increased risk (at least one major or two minor risk factors are recommended)’ b
which asymptomatic men should receive DXA testing [77]. This formal analysis ultimately led to the recommendation [76] that: Clinicians should order the measurement of bone mineral density by dual x-ray absorptiometry for men who are at an increased risk for osteoporosis and are candidates for drug therapy. The ACP report identified key risk factors for low BMDmediated fracture including increased age (70 years), low body weight (body mass index (BMI) 20–25 kg/ m2), weight loss, inactivity, prolonged glucocorticoid use, prior osteoporotic fracture and androgen deprivation therapy [77]. Unfortunately, how the clinician should employ these risk factors was not defined. As it was not specifically stated in this report, a practicing physician could reasonably conclude that any of the above noted fracture risk factors are indications for DXA testing in older men. The 2008 NOF Clinician’s Guide also recommends BMD testing for men age 70 and older, but does so regardless of clinical risk factors [72]. Additionally, the NOF Guide recommends BMD measurement for adults with a fracture after age 50, those with conditions or using medications associated with bone loss and men age 50–69 for whom the clinician has concern based upon the clinical risk factor profile. Again, specific risk factors prompting a decision to obtain DXA were not specified. The updated ISCD indications for BMD testing are very similar to those of the NOF. Finally, the Osteoporosis Society of Canada (OSC), in 2002, found that measuring BMD in men and women after the age of 65 to be justifiable [78]. It is apparent that these recent guidelines are not entirely clear regarding what constitutes a ‘risk factor’ when considering BMD measurement in men. In this regard, a large meta-analysis was performed with the purpose being identification of fracture risk factors to assist with the decision in whom to measure bone mass, to assess the relationship between such factors and fracture risk and to classify risk factors according to the strength of their association with fracture [79]. This work found age 70 years, low BMI (20–25 kg/m2), weight loss, inactivity, glucocorticoid or
anticonvulsant use and prior osteoporotic fracture to be factors conveying high risk for future fracture. Until additional guidance becomes available, use of these risk factors in assisting with the decision to obtain BMD measurement in men seems reasonable. When considering ‘screening’ tests, evaluation of their cost effectiveness is necessary. In this regard, recent work finds universal bone densitometry combined with alendronate to be highly cost effective for women over age 65 [80]. A similar analysis finds bone densitometry followed by bisphosphonate therapy to be cost effective for men at age 65 for those with a prior fracture assuming a $1000 annual drug cost and at age 70, if oral bisphosphonate costs are less than $500 per year [81]. As generic alendronate currently costs much less than this amount, it seems probable that this analysis supports routine ‘screening’ of men at age 70. However, despite the aforementioned guidelines and probable cost effectiveness, it must be appreciated that, in the USA, the Bone Mass Measurement Act of 1998, (in which Medicare reimbursement for screening bone mass measurement was approved), is largely limited to estrogendeficient women and clearly does not include screening of older men. Thus, DXA screening in older men is not currently a Medicare covered screening service. Moreover, US Medicare will support BMD testing for only a small proportion of older men, such as those on oral glucocorticoids or those who have sustained a fragility fracture. It seems probable that the absence of reimbursement for screening contributes to the under-diagnosis and under-treatment of osteoporosis in men that currently exists.
Vertebral fracture assessment Vertebral fracture epidemiology is challenging because many of these fractures are ‘silent’ or at least clinically unappreciated by the patient and their healthcare provider. Additionally, the radiographic identification of ‘vertebral fracture’ and, therefore, vertebral fracture prevalence and incidence, is highly dependent on the methodology used for
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fracture identification. For example, in a random sample of 503 women in the Study of Osteoporotic Fractures (SOF), vertebral fracture prevalence varied from 14% to 33% depending on the methodology and criteria utilized [82]. Identification of mild deformities (20–25% height reduction) is particularly challenging, especially in the setting of spinal degenerative disease, and confounds identification of fracture even in the hands of expert radiologists using radiographs [83]. Moreover, in the MINOS study (a cohort of 786 men aged 51–86 years), deformities of 25–30% in the mid-thoracic spine (T-6 to T-9) were not associated with low BMD [84]. As such, the authors suggested that deformities should not be identified as fracture in men until a 30% decrease in height is observed in the mid-thoracic spine and 25% elsewhere. Despite the difficulty in identifying vertebral deformities, it is clear that fracture prevalence increases with advancing age in men [85]. Additionally, the presence of a vertebral fracture is predictive of subsequent fracture risk in both men and women [86, 87]. Moreover, these fractures are associated with increased mortality [88, 89]. Given the above, it is apparent that identification of men with prevalent vertebral deformities will identify individuals at elevated fracture risk and therefore should enhance targeting of fracture reduction therapy. However, spine radiography is often not included in routine clinical osteoporosis assessment. Use of current generation fan beam densitometers that are capable of performing vertebral fracture assessment (VFA) examination is therefore an attractive option in fracture risk assessment. VFA is convenient in that it can be quickly performed at the same time as a clinical DXA examination. It utilizes a very low radiation dose leading to lower image resolution than standard radiography. Despite this, VFA detects the vast majority of moderate and severe (grade 2 and 3) vertebral fractures [90,91]. As noted above, the radiographic approach to vertebral fracture identification, notably ‘mild’ fractures, is challenging and there is no true ‘gold standard’ approach. However, the Genant visual semiquantitative (VSQ) approach [92] has been extensively utilized in clinical trials and is currently recommended for use with VFA [93]. In men undergoing clinically indicated DXA scans who were found to have osteopenia but had no knowledge of vertebral fracture, VFA identified 18% as having unappreciated vertebral deformities [94]. Thus, because vertebral fracture increases future fracture risk, VFA identification of unappreciated fracture should enhance prescription of fracture reducing therapy to those men at higher risk.
Indications for VFA Evidence-based indications for performing VFA have been published [93,95]. Briefly, potential indications for VFA were considered based upon the criteria that vertebral fracture identification would alter clinical management and
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patient criteria indicating a reasonable likelihood that a fracture would be identified. Fracture detection in men with low bone mass/osteopenia may well alter the therapeutic recommendation. As such, it is appropriate that VFA indications in men focused on those with osteopenia. VFA is felt to be indicated in men with osteopenia plus either age 80 years or height loss (historical of 6 cm or documented prospective loss of 3 cm). Additionally, VFA is appropriate for osteopenic men if two or more of the following are present:
l l l l
age 70–79 height loss of 3–6 cm pharmacologic or surgical androgen deficiency chronic systemic diseases associated with increased fracture risk such as rheumatoid arthritis or chronic obstructive pulmonary disease.
VFA may also be appropriate in other clinical scenarios (e.g. chronic steroid therapy) and are detailed in the work of Schousboe et al [93]. Reimbursement issues (at least in the USA) have impacted VFA use in a manner quite analogous to the underutilization of DXA. Specifically, relatively few thirdparty payers provide reimbursement for this procedure, thereby limiting widespread clinical adoption of VFA [96]. As VFA performance identifies unappreciated vertebral deformities and, therefore, likely leads to recommendation of fracture reduction therapy in 18% of osteopenic men [94], the clinical importance of this procedure seems apparent. Perhaps the emphasis upon treatment based on fracture likelihood driven by the FRAX approach will increase utilization of VFA.
Summary DXA BMD measurement is an excellent clinical tool to evaluate men who may be at risk for osteoporosis and fragility fracture. Combination of BMD data with clinical risk factors enhances the ability optimally to target pharmacologic therapy to reduce fracture risk. As vertebral fractures increase risk for future fracture, but are often clinically unappreciated, VFA performance should enhance clinical care. Appreciating the technical aspects of DXA performance and interpretation enhances application to clinical care. As undertreatment of men with fragility fracture is widespread, enhanced use of DXA is indicated. The FRAX approach will enhance identification of men at risk for fracture. The database to utilize for T-score derivation and, thus, diagnosis of osteoporosis, is controversial. We prefer use of the male normative database for two reasons. First, DXA (at least of the hip) identifies a smaller proportion of those men who will fracture than women. Secondly, clinical trial evidence exists documenting that men with osteoporosis by DXA, based on a male database, have a positive response to therapy.
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Therefore, until there is convincing evidence that a female database should be used for both sexes, we recommend that the male normative database, which is the current default database for most densitometers, continue to be used.
References 1. Anonymous, Assessment of fracture risk and its application to screening for postmenopausal osteoporosis, WHO technical report series 843 (1994) 1–129. 2. W.D. Leslie, R.A. Adler, G.E. Fuleihan, et al., Application of the 1994 WHO classification to populations other than postmenopausal Caucasian women: the 2005 ISCD Official Positions, J. Clin. Densitom. 9 (2006) 22–30. 3. G.M. Blake, H.W. Wahner, I. Fogelman, The evaluation of osteoporosis: dual energy x-ray absorptiometry and ultrasound in clinical practice, second ed., Martin Dunitz Ltd, London, 1999. 4. G.M. Blake, I. Fogelman, Role of dual-energy x-ray absorptio metry in the diagnosis and treatment of osteoporosis, J. Clin. Densitom. 10 (2007) 102–110. 5. G.M. Blake, I. Fogelman, Technical principles of dual energy x-ray absorptiometry, Semin. Nucl. Med. 27 (1997) 210–228. 6. V. Gilsanz, M.I. Boechat, R. Gilsanz, et al., Gender differences in vertebral sizes in adults: biomechanical implications, Radiology 190 (1994) 678–682. 7. A.C. Looker, T.J. Beck, E.S. Orwoll, Does body size account for gender differences in femur bone density and geometry? J. Bone Miner. Res. 16 (2001) 1291–1299. 8. B.L. Riggs, L.J.I. Melton, R.A. Robb, et al., Population-based study of age and sex differences in bone volumetric density, size, geometry and structure at different skeletal sites, J. Bone Miner. Res. 19 (2004) 1945–1954. 9. M.L. Bouxsein, D. Karasik, Bone geometry and skeletal fragility, Curr. Osteoporos. Rep. 4 (2006) 49–56. 10. S. Baim, N. Binkley, J.P. Bilezikian, et al., Official positions of the International Society for Clinical Densitometry and Executive summary of the 2007 ISCD position development conference, J. Clin. Densitom. 11 (2008) 75–91. 11. N. Binkley, J.P. Bilezikian, D.L. Kendler, et al., Official positions of the International Society for Clinical Densitometry and Executive Summary of the 2005 position development conference, J. Clin. Densitom. 9 (2006) 4–14. 12. D.L. Schneider, R. Bettencourt, E. Barrett-Connor, Clinical utility of spine bone density in elderly women, J. Clin. Densitom. 9 (2006) 255–260. 13. G. Liu, M. Peacock, O. Eilam, et al., Effect of osteoarthritis in the lumbar spine and hip on bone mineral density and diagnosis of osteoporosis in elderly men and women, Osteoporos. Int. 7 (1997) 564–569. 14. T. Rand, G. Seidl, F. Kainberger, et al., Impact of spinal degenerative changes on the evaluation of bone mineral density with dual energy x-ray absorptiometry (DXA), Calcif. Tissue Int. 60 (1997) 430–433. 15. N. Vallarta-Ast, D. Krueger, N. Binkley, An evaluation of forearm BMD measurement for diagnosis and treatment monitoring in men, J. Bone Miner. Res. 22 (Suppl. 1) (2007) S300. 16. C. Simonelli, R.A. Adler, G.M. Blake, et al., Dual-energy x-ray absorptiometry technical issues: the 2007 ISCD official positions, J. Clin. Densitom. 11 (2008) 109–122.
17. L.J.I. Melton, E.J. Atkinson, M.K. O’Connor, et al., Bone density and fracture risk in men, J. Bone Miner. Res. 13 (1998) 1915–1923. 18. N. Binkley, D. Krueger, N. Vallarta-Ast, An overlying fat panniculus affects femur bone mass measurement, J. Clin. Densitom. 6 (2003) 199–204. 19. A.E. Maghraoui, C. Roux, DXA scanning in clinical practice, Q J Med. 101 (2008) 605–617. 20. N.B. Watts, Fundamentals and pitfalls of bone densitometry using dual-energy x-ray absorptiometry (DXA), Osteoporos. Int. 15 (2004) 847–854. 21. E.M. Lewiecki, N. Binkley, S.M. Petak, DXA quality matters, J. Clin. Densitom. 9 (2006) 388–392. 22. K.G. Faulkner, L.A. Roberts, M.R. McClung, Discrepancies in normative data between Lunar and Hologic DXA systems, Osteoporos. Int. 6 (1996) 432–436. 23. N. Binkley, G.M. Kiebzak, E.M. Lewiecki, et al., Recalcula tion of the NHANES database SD improves T-score agreement and reduces osteoporosis prevalence, J. Bone Miner. Res. 20 (2005) 195–201. 24. G.M. Kiebzak, N. Binkley, E.M. Lewiecki, et al., Diagnostic agreement at the total hip using different DXA systems and the NHANES III database, J. Clin. Densitom. 10 (2007) 132–137. 25. K. McMahon, J. Nightingale, N. Pocock, Discordance in DXA male reference ranges, J. Clin. Densitom. 7 (2004) 121–126. 26. J.A. Kanis, E.V. McCloskey, H. Johansson, et al., A reference standard for the description of osteoporosis, Bone 42 (2008) 467–475. 27. J. Hanson, Letter to the editor, Standardization of femur BMD, J. Bone Miner. Res. 8 (1997) 1316–1317. 28. Y. Lu, T. Fuerst, S. Hui, et al., Standardization of bone mineral density at femoral neck, trochanter and Ward’s triangle, Osteoporos. Int. 12 (2001) 438–444. 29. S. Goemaere, D. Vanderschueren, J.M. Kaufman, et al., Dual energy x-ray absorptiometry-based assessment of male patients using standardized bone density values and a national reference database, J. Clin. Densitom. 10 (2007) 22–33. 30. H.K. Genant, S. Grampp, C.C. Gluer, et al., Universal standardization for dual x-ray absorptiometry: patient and phantom crosscalibration results, J. Bone Miner. Res. 9 (1994) 1503–1514. 31. S. Hui, S. Gao, X.H. Zhou, et al., Universal standardization of bone density measurements: a method with optimal properties for calibration among several instruments, J. Bone Miner. Res. 12 (1997) 1463–1470. 32. D. Marshall, O. Johnell, H. Wedel, Meta-analysis of how well measures of bone mineral density predict occurrence of osteo porotic fractures, Br. Med. J. 312 (1996) 1254–1259. 33. P. Szulc, F. Munoz, F. Duboeuf, et al., Bone mineral density predicts osteoporotic fractures in elderly men: the MINOS study, Osteoporos. Int. 16 (2005) 1184–1192. 34. S.C.E. Schuit, M. van der Klift, A.E.A.M. Weel, et al., Fracture incidence and association with bone mineral density in elderly men and women: the Rotterdam study, Bone 34 (2004) 195–202. 35. E.S. Orwoll, M. Ettinger, S. Weiss, et al., Alendronate for the treatment of osteoporosis in men, N. Engl. J. Med. 343 (2000) 604–610. 36. Anonymous, Assessment of fracture risk and its application to screening for postmenopausal osteoporosis, World Health Organization Technical Report Series 843 (1994) 1–129.
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37. J.A. Kanis, O. Johnell, A. Oden, et al., Ten year probabilities of osteoporotic fractures according to BMD and diagnostic thresholds, Osteoporos. Int. 12 (2001) 989–995. 38. J. Kanis, Diagnosis of osteoporosis and assessment of fracture risk, Lancet 359 (2002) 1929–1936. 39. N. Binkley, P. Schmeer, R. Wasnich, et al., What are the criteria by which a densitometric diagnosis of osteoporosis can be made in males and non-caucasians? J. Clin. Densitom. 5 (2002) s19–s27. 40. L. Wiemann, D. Krueger, N. Vallarta-Ast, et al., Effect of female database use for T-score derivation in men, (2006). 41. O. Johnell, J. Kanis, A. Oden, et al., Predictive value of BMD for hip and other fractures, J. Bone Miner. Res. 20 (2005) 1185–1194. 42. N.D. Nguyen, C. Pongchaiyakul, J.R. Center, et al., Identification of high-risk individuals for hip fracture: a 14-year prospective study, J. Bone Miner. Res. 20 (2005) 1921–1928. 43. C.E.D.H. De Laet, B.A. Van Hout, H. Burger, et al., Hip fracture prediction in elderly men and women: validation in the Rotterdam study, J. Bone Miner. Res. 13 (1998) 1587–1593. 44. K.G. Faulkner, E. Orwoll, Implications in the use of T-scores for the diagnosis of osteoporosis in men, J. Clin. Densitom. 5 (2002) 87–93. 45. S. Fujiwara, F. Kasagi, N. Masunari, et al., Fracture prediction from bone mineral density in Japanese men and women, J. Bone Miner. Res. 18 (2003) 1547–1553. 46. S.R. Cummings, P.M. Cawthon, K.E. Ensrud, et al., BMD and risk of hip and nonvertebral fractures in older men: a prospective study and comparison with older women, J. Bone Miner. Res. 21 (2006) 1550–1556. 47. J.A. Kanis, O. Johnell, A. Oden, et al., Diagnosis of osteo porosis and fracture threshold in men, Calcif. Tissue Int. 69 (2001) 218–221. 48. L. Langsetmo, D.A. Hanley, N. Kreiger, et al., Geographic variation of bone mineral density and selected risk factors for prediction of incident fracture among Canadians 50 and older, Bone 43 (2008) 672–678. 49. J.A. Cauley, J.M. Zmuda, S.R. Wisniewski, et al., Bone mineral density and prevalent vertebral fractures in men and women, Osteoporos. Int. 15 (2004) 32–37. 50. B. Srinivasan, S. Amin, B.L. Riggs, et al., Areal BMD by DXA may predict similar risk of fracture in elderly women and men due to offsetting effects of bone size and true volumetric BMD, J. Bone Miner. Res. 23 (Suppl. 1) (2008) S308. 51. T. Youm, K.J. Koval, F.J. Kummer, et al., Do all hip fractures result from a fall? Am. J. Orthop. 28 (1999) 190–194. 52. R.W. Sattin, D.A. Lambert-Huber, C.A. Devito, et al., The incidence of fall injury events among the elderly in a defined population, Am. J. Epidemiol. 131 (1990). 53. J.A. Stevens, E.D. Sogolow, Gender differences for non-fatal unintentional fall related injuries among older adults, Inj. Prev. 11 (2005) 115–119. 54. D. Oman, D. Reed, A. Ferrara, Do elderly women have more physical disability than men do? Am. J. Epidemiol. 150 (1999) 834–842. 55. D.H. Solomon, J. Avorn, J.N. Katz, et al., Compliance with osteoporosis medications, Arch. Intern. Med. 165 (2005) 2414–2419. 56. C.S. Pickney, J.A. Arnason, Correlation between patient recall of bone densitometry results and subsequent treatment adherence, Osteoporos. Int. 16 (2005) 1156–1160.
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57. S.L. Silverman, M. Greenwald, R.A. Klein, et al., Effect of bone density information on decisions about hormone replacement therapy: a randomized trial, Obstet. Gynecol. 89 (1997) 321–325. 58. A. Pressman, B. Forsyth, B. Ettinger, et al., Initiation of osteoporosis treatment after bone mineral density testing, Osteoporos. Int. 12 (2001) 337–342. 59. S.M. Cadarette, M.A.M. Gignac, S.B. Jaglal, et al., Access to osteoporosis treatment is critically linked to access to dualenergy x-ray absorptiometry testing, Med. Care 45 (2007) 896–901. 60. E. Orwoll, W.H. Scheele, S. Paul, et al., The effect of teriparatide [human parathyroid hormone (1-34)] therapy on bone density in men with osteoporosis, J. Bone Miner. Res. 18 (2003) 9–17. 61. Anonymous, Physician’s guide to prevention and treatment of osteoporosis, National Osteoporosis Foundation, Washington DC, 2003. 62. S.F. Hodgson, N.B. Watts, J.P. Bilezikian, et al., American Association of Clinical Endocrinologists medical guidelines for clinical practice for the prevention and treatment of postmenopausal osteoporosis: 2001 edition, with selected updates for 2003, Endocrine Pract. 9 (2003) 544–564. 63. J.A. Kanis, F. Borgstrom, C. De Laet, et al., Assessment of fracture risk, Osteoporos. Int. 16 (2005) 581–589. 64. P.D. Ross, J.W. Davis, R.S. Epstein, et al., Pre-existing fractures and bone mass predict vertebral fracture incidence in women, Ann. Intern. Med. 114 (1991) 919–923. 65. C.S. Colon-Emeric, R. Sloane, W.G. Hawkes, et al., The risk of subsequent fractures in community-dwelling men and male veterans with hip fracture, Am. J. Med. 109 (2000) 324–328. 66. P.D. Delmas, H.K. Genant, G.G. Crans, et al., Severity of prevalent vertebral fractures and the risk of subsequent vertebral and nonvertebral fractures: results from the MORE trial, Bone 33 (2003) 522–532. 67. M.R. McClung, Do current management strategies and guidelines adequately address fracture risk? Bone 38 (2006) S13–S17. 68. J.A. Kanis, O. Johnell, A. Oden, et al., Intervention thresholds for osteoporosis in men and women: a study based on data from Sweden, Osteoporos. Int. 16 (2005) 6–14. 69. J.A. Kanis, O. Johnell, A. Oden, et al., FRAXTM and the assessment of fracture probability in men and women from the UK, Osteoporos. Int. 19 (2008) 385–397. 70. J.A. Kanis, A. Oden, O. Johnell, et al., The use of clinical risk factors enhances the performance of BMD in the prediction of hip and osteoporotic fractures in men and women, Osteoporos. Int. 18 (2007) 1033–1046. 71. N. Yoshimura, T. Takijiri, H. Kinoshita, et al., Characteristics and course of bone mineral densities among fast bone losers in a rural Japanese community: the Miyama study, Osteoporos. Int. 15 (2004) 139–144. 72. Anonymous, Clinician’s guide to prevention and treatment of osteoporosis, National Osteoporosis Foundation, Washington, DC, 2008. 73. E.M. Lewiecki, J.L.C. Borges, Bone density testing in clinical practice, Arq. Bras. Endocrinol. Metab. 50 (2006) 586–595. 74. L. Lenchik, G.M. Kiebzak, B.A. Blunt, What is the role of serial bone mineral density measurements in patient management? J. Clin. Densitom. 5 (2002) S29–S38.
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Osteoporosis in Men
75. E.M. Lewiecki, Nonresponders to osteoporosis therapy, J. Clin. Densitom. 6 (2003) 307–314. 76. A. Qaseem, V. Snow, P. Shekelle, et al., Screening for osteo porosis in men: a clinical practice guideline from the American College of Physicians, Ann. Intern. Med. 148 (2008) 680–684. 77. H. Liu, N.M. Paige, C.L. Goldzweig, et al., Screening for osteoporosis in men: a systematic review for an American College of Physicians Guideline, Ann. Intern. Med. 148 (2008) 685–701. 78. J.P. Brown, R.G. Josse, clinical practice guidelines for the diagnosis and management of osteoporosis in Canada, Can. Med. Assoc. J. 2002 (167) (2002) S1–S34. 79. M. Espallargues, L. Sampietro-Colom, M.D. Estrada, et al., Identifying bone-mass-related risk factors for fracture to guide bone densitometry measurements: a systematic review of the literature, Osteoporos. Int. 12 (2001) 811–822. 80. J.T. Schousboe, K.E. Ensrud, J.A. Nyman, et al., Universal bone densitometry screening combined with alendronate therapy for those diagnosed with osteoporosis is highly cost-effective for elderly women, J. Am. Geriatr. Soc. 53 (2005) 1697–1704. 81. J.T. Schousboe, B.C. Taylor, H.A. Fink, et al., Cost-effectiveness of bone densitometry followed by treatment of osteoporosis in older men, J. Am. Med. Assoc. 298 (2007) 629–637. 82. H.K. Genant, M. Jergas, L. Palmero, et al., Comparison of semiquantitative visual and quantitative morphometric assessment of prevalent and incident vertebral fractures in osteo porosis: the study of osteoporotic fractures research group, J. Bone Miner. Res. 11 (1996) 984–996. 83. T. Fuerst, C. Wu, H.K. Genant, et al., Evaluation of vertebral fracture assessment by dual x-ray absorptiometry in a multicenter setting, Osteoporos. Int. (2009) in press. 84. P. Szulc, F. Munoz, F. Marchand, et al., Semiquantitative evaluation of prevalent vertebral deformities in men and their relationship with osteoporosis: the MINOS study, Osteoporos. Int. 12 (2001) 302–310. 85. D. Felsenberg, A.J. Silman, M. Lunt, et al., Incidence of vertebral fracture in Europe: results from the European
86.
87.
88.
89.
90.
91.
92.
93.
94.
95.
96.
Prospective Osteoporosis Study (EPOS), J. Bone Miner. Res. 17 (2002) 716–724. M. van der Klift, C. De Laet, E.V. McCloskey, et al., Risk factors for incident vertebral fractures in men and women: the Rotterdam study, J. Bone Miner. Res. 19 (2004) 1172–1180. L.J. Melton, E.J. Atkinson, C. Cooper, et al., Vertebral fractures predict subsequent fractures, Osteoporos. Int. 10 (1999) 214–221. R. Hasserius, M.K. Karlsson, B. Jonsson, et al., Long-term morbidity and mortality after a clinically diagnosed vertebral fracture in the elderly – a 12- and 22-year follow-up of 257 patients, Calcif. Tissue Int. 76 (2005) 235–242. V. Puisto, H. Rissanen, M. Heliovaara, et al., Mortality in the presence of a vertebral fracture, scoliosis or Scheuermann’s disease in the thoracic spine, Ann. Epidemiol. 18 (2008) 595–601. J.T. Schousboe, C.R. DeBold, Reliability and accuracy of vertebral fracture assessment with densitometry compared to radio graphy in clinical practice, Osteoporos. Int. 17 (2006) 281–289. N. Binkley, D. Krueger, R. Gagnon, et al., Lateral vertebral assessment: a valuable technique to detect clinically significant vertebral fractures, Osteoporos. Int. 16 (2005) 1513–1518. H.K. Genant, C.Y. Wu, C. Van Kuijk, et al., Vertebral fracture assessment using a semiquantitative technique, J. Bone Miner. Res. 8 (1993) 1137–1148. J.T. Schousboe, T. Vokes, S.B. Broy, et al., Vertebral fracture assessment: the 2007 ISCD Official Positions, J. Clin. Densitom. 11 (2008) 92–108. N. Vallarta-Ast, D. Krueger, C. Wrase, et al., An evaluation of densitometric vertebral assessment in men, Osteoporos. Int. 18 (2007) 1405–1410. T. Vokes, D. Bachman, S. Baim, et al., Vertebral fracture assessment: the 2005 ISCD official positions, J. Clin. Densitom. 9 (2006) 37–46. A. Laster, E.M. Lewiecki, Vertebral fracture assessment by dual-energy x-ray absorptiometry: insurance coverage issues in the United States. A white paper of the International Society for Clinical Densitometry, J. Clin. Densitom. 10 (2007) 227–238.
Chapter
44
Quantitative Ultrasound Diagnosis of Osteoporosis in Men Robert A. Adler1 and Neil Binkley2 1
McGuire Veterans Affairs Medical Center and Virginia Commonwealth University School of Medicine, Richmond, Virginia, USA University of Wisconsin, Madison, Wisconsin, USA
2
Principles of quantitative ultrasound
recently in the USA. For some years, alternatives to DXA have been sought and QUS measurements of the heel or phalanges have had some promise to be cheaper, quicker, radiation-free, relatively portable, less technologist-dependent and widely available. It might be assumed that QUS is easier to use than DXA, but there are technical issues, such as decreased reproducibility related to the lack of an image generated by the devices. It should also be noted that the World Health Organization (WHO) criterion for osteoporosis (T-score 2.5) applies only to DXA. There have been some suggestions that QUS might reflect parameters of bone quality in addition to bone quantity. Thus, there are two major ways QUS could be used: to predict fracture and to predict bone density as measured by DXA. Additionally, there have been some attempts to use QUS to monitor the response to therapy. As usual, most of the studies have been done in women, but there are some studies of QUS in men. In this chapter, we will emphasize studies in men trying to answer three questions: does QUS predict fracture in men? Can QUS be used to determine which men need DXA? Is it possible to use QUS to monitor how well an osteoporosis treatment is working?
Quantitative ultrasound (QUS) of the heel has been developed as a measure of bone quantity and possibly bone quality parameters, such as microarchitecture. These devices are based on transducers that can send and receive ultrasound waves. The transducers are placed on either side of the bone being tested, usually the heel (calcaneus). The transducers and heel are either in a water bath or, more commonly, a coupling gel is applied to both sides of the bone, allowing for transmission of the ultrasound waves. The sound waves are attenuated by soft tissue and bone because the tissues may absorb the energy (converting it to heat), reflect it or scatter it. It is important to appreciate that the available QUS devices are quite different, however, they all calculate various measures of what happens to sound waves as they pass through soft tissue and bone. Two important parameters measured are the speed of sound (SOS), which is the velocity of the waves through the tissues, and broadband attenuation (BUA), which assesses how much the waves are attenuated based on their frequency. SOS and BUA may be associated with bone strength. From these numbers, various indices have been calculated, such as the proprietary stiffness index and the quantitative ultrasound index (QUI). The measurements, calculations, normal values and techniques vary considerably among the many devices and manufacturers. Thus, the results of one QUS device cannot be directly compared to another device. Nonetheless, the general principles are shared and the specific aspects of existing devices are beyond the scope of this chapter. While dual energy x-ray absorptiometry (DXA) is considered the gold standard for the diagnosis of osteoporosis, it may not always be available, it delivers a radiation dose (albeit very small) and it is somewhat expensive, although the amount that can be charged for it has been decreasing Osteoporosis in Men
Use of QUS to predict fracture in men Early studies in women [1] suggested that QUS of the calcaneus could discriminate fracture patients in women as well as DXA. In 1997, an expert panel [2] suggested that QUS could be used to determine fracture risk in elderly women. Although some studies had suggested that QUS might reflect some aspect of bone quality, careful studies of cadaver bone [3, 4] concluded that QUS mostly reflected bone mass. Nonetheless, more recent studies in women 541
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have continued to show that QUS can predict future fracture risk. The NORA Study [5] was a landmark investigation of 200 000 women who were tested with various peripheral bone density devices and followed for a year. The peripheral devices used in the study predicted fracture well, including QUS of the calcaneus. However, QUS devices were utilized in only about 5% of the subjects. In the EPIDOS study [6], DXA was superior to QUS in predicting hip fracture in women younger than 80 years old. For women 80 years old, DXA and QUS predicted hip fracture equally well. More recently, the EPISEM cohort study [7] combined QUS with easily obtainable clinical risk factors that could predict fracture in women almost as well as using DXA plus risk factors. There are fewer QUS studies aimed at predicting fracture in men. For example Fujiwara et al [8] followed more than 3000 Japanese women and 1000 men for 5 years, finding that QUS predicted non-spine fractures well. However, there were only 31 non-spine fractures in the men, compared to 185 in the women. There were only six hip fractures among the men and, thus, although QUS predicted fracture in the entire group, it is more difficult to accept the data for the men alone, particularly for hip fracture. In the much larger EPIC-Norfolk prospective study [9] of more than 6000 men, BUA predicted total and hip fractures independently of age, weight, smoking history and history of previous fracture. Gonelli et al [10] studied 401 men referred for ‘assessment of bone status’. They had excluded men with serum 25 hydroxyvitamin D levels 25 ng/ml, those with a history of alcohol abuse, tobacco abuse or use of anticonvulsants or glucocorticoids. Of the 401 men, 133 had a history of fragility fracture. All men underwent DXA testing and QUS of heel and phalanges. After adjustment for age and body mass index (BMI), the best predictor of fracture was DXA measurement of the total hip. A stiffness index, calculated by the QUS machine, the SOS and BUA discriminated between fracture and non-fracture men almost as well. Indeed, in this particular study, there was evidence, contrary to most studies in women, that the combination of QUS of the heel added to DXA actually predicted fracture better than either technique. QUS of the phalanges was less discriminatory than that of the heel. A case might be made to perform both QUS and DXA in men at risk if doing both tests truly increased fracture risk prediction. However, in the ongoing longitudinal MrOS study of 5600 generally healthy mostly Caucasian American men, Bauer et al [11] found that QUS predicted hip and non-spine fracture almost as well as DXA, but the combination of DXA plus QUS was no better than DXA alone. Hayman et al [12] provided data on a normal North American male database for QUS in several skeletal sites. Each of the above studies used only one QUS device and, as noted above, there are several on the market, which provide measurements that cannot be directly compared. Although there is some evidence that QUS can predict
fracture in men, there is not enough evidence to advocate adding QUS to bone density measured by DXA to predict fracture. This was the conclusion of the recent osteoporosis screening guidelines for osteoporosis in men, published by the American College of Physicians [13, 14]. On the other hand, the International Society for Clinical Densitometry [15] concludes that QUS can be used by itself to predict fracture in men older than 65. Further studies will be needed to provide a definitive answer.
Use of QUS to predict when to obtain DXA in men QUS has often been used to predict bone mineral density (BMD) by the present gold standard, dual energy x-ray absorptiometry (DXA). In other words, many studies in men and in women have tested whether QUS or other less expensive and radiation-free tools can be used to screen patients to determine which ones are most likely to have low BMD by DXA. If this were the case, QUS could potentially be used to screen large populations of men and only those men who fulfilled certain QUS criteria would then have DXA performed. A study from Iceland [16] included 589 men among the 600 studied. QUS T-scores of 0.5 could predict DXA reasonably well, thus saving a proportion of men from needing DXA. Goemaere et al [17] found that DXA predicted fracture better than QUS, but that QUS could be used to predict hip DXA. On the contrary, Adler et al [18], using a different ultrasound device, did not find a QUS cut-off that could predict DXA with adequate sensitivity and specificity. Adding clinical risk factors to QUS in men with pulmonary disorders [19] did not improve prediction of DXA better than age and weight alone. In a systematic review of screening tests for osteoporosis in men, Liu et al [20] reviewed available literature on QUS prediction of osteoporosis, as defined by DXA. They found that, using a T-score cutpoint of 1.0, QUS of the heel had a sensitivity of 75% and a specificity of 66%. Using a T-score of 1.5, the sensitivity was slightly better (78%) but specificity dropped to 47%. It is important to note that the studies Liu et al reviewed used two different devices, the Sahara and Achilles instruments. Whether the proprietary T-scores generated by these devices can be compared is unknown. Liu et al then compared QUS and an index based on weight and age only, OST (osteoporosis self-assessment tool) [21]. OST is defined as (Weight (kg) Age (years)) 0.2, truncated to an integer. Various cut-offs can be used to predict DXA. Although there were not many studies to review, Liu et al found that OST predicted osteoporosis by DXA as well as or better than QUS. Since the publication of the systematic review, Lynn et al [22] studied calcaneal QUS using the Hologic Sahara instrument and OST in 4658 Caucasian and 1914 Hong Kong Chinese men.
C h a p t e r 4 4 Quantitative Ultrasound Diagnosis of Osteoporosis in Men l
They calculated an index called MOST, which was derived from weight plus QUS data (the Hologic Quantitative Ultrasound Index (QUI)) and originally studied in Chinese men [23]. MOST is defined as ((weight (kg)) 0.2 (0.1 QUI)). For the lumbar spine, total hip, or femoral neck, the area under the curve (AUC) for the receiver operating curve (ROC) was calculated for MOST and OST, as well as the QUI derived from the QUS measurement. For Caucasian men, the AUC for predicting osteoporosis by DXA was 0.799 for MOST, 0.714 for OST and 0.738 for QUI [22]. For Chinese men, the respective AUC values were 0.831, 0.759 and 0.731. Adding QUS to weight provided a small improvement over weight and age alone in predicting DXA. Thus, if QUS were used as a screening test in older men, adding weight and calculating MOST would result in fewer men having DXA performed and increasing the yield from the DXA testing. There are no studies to determine whether clinicians would choose calculating an index or ordering a QUS, or ordering a QUS plus calculating an index for screening men for osteoporosis. Thus, as has been pointed out, men are generally not screened for osteoporosis [24–26]. Using QUS in health fairs, pharmacies, men’s clubs, etc. might be a source of case finding. Nonetheless, the fact remains that many men with fracture have not had osteoporosis diagnosed, even after fracture [26, 27]. Perhaps more widespread use of QUS in men would help identify men before fracture. Importantly, standardization of scores among the various QUS devices is necessary before widespread screening will truly be of use. In the USA, Medicare, which serves as health insurance for older individuals, covers DXA for a very limited proportion of men, such as those who have fractured and those on glucocorticoid therapy. Perhaps an additional reason for DXA reimbursement for an older man could be a low QUS heel density measurement or calculation of the MOST index, based on QUS plus weight. Others might argue that while QUS is inexpensive and risk-free, calculation of OST, which requires only weight and age, is essentially free of cost and risk. In either case, the purpose of the testing would be to target DXA testing to those men who would most likely have osteoporosis by DXA. The possibility that QUS might measure some other aspect of bone health beyond bone mass makes continued research into QUS measurements important. To this end, there is some evidence that DXA predicts fracture in men less well than in women. In other words, while a low T-score by DXA puts a man at higher risk for fracture, a larger proportion of men fracture despite better DXA measurements (osteopenia (low bone mass) or even normal bone density by DXA). The classic study that suggested this was the Rotterdam Study [28]. In this study, only 21% of nonvertebral fractures occurred in men with DXA T-scores of 2.5 or lower. However, the authors only measured femoral neck bone density. In the MINOS study in France [29], men were followed for 90 months after measurement of spine, hip and total body DXA and forearm single energy x-ray
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absorptiometry (SXA). The trochanter region, whole body DXA and forearm SXA were better than femoral neck DXA for predicting fracture. Thus, DXA, as described in Chapter 43, is still the gold standard for diagnosing osteoporosis in men and the best measure for predicting fracture. Many believe that the relationship between DXA and fracture risk is very similar in men and women. Studies are needed to determine the potential for better fracture risk prediction in men from a combination of clinical risk factors, QUS, bone turnover markers, or some future technique. For now, the American College of Physicians [13] does not recommend QUS to predict osteoporosis by DXA. Although the OST calculation, which needs only weight and age measurements, appears to predict DXA fairly well in male veterans [21, 30] and a white male orthopedic population [31], other studies have not confirmed its usefulness [32]. In a very recent article [33] using OST to determine which men should have a DXA was cost effective. There are no studies demonstrating that any type of screening in men leads to better outcomes, i.e. fewer fractures.
Monitoring therapy with QUS Another possible use for QUS is to follow patients after starting osteoporosis therapy. Again, QUS is attractive because it has no radiation risk, is portable and relatively inexpensive. However, because the precision error of QUS is higher than that of DXA, it would seem unlikely that QUS could be used to monitor therapy. New devices that provide an image of the bone studied might improve precision. It should be noted that there are no studies in men utilizing QUS to document efficacy of pharmacologic therapy. There have been a few studies in women to determine if QUS can be used to follow patients after starting osteoporosis treatment. In a 4-year study [34] of alendronate treatment in 150 women, DXA was only slightly better than a QUS stiffness measurement, which was calculated from SOS and BUA in monitoring response to treatment. Individually, BUA and SOS were not as good, particularly BUA, in assessing response to treatment. More recently, Ingle et al [35] did a small study using QUS of the phalanges. The changes after alendronate were similar in QUS and DXA. Weiss et al [36] reported similar results in a 1-year study. The International Society for Clinical Densitometry Official Positions state that, at this time, QUS cannot be used to monitor therapy [15].
Conclusions Osteoporosis in men is under-diagnosed [24–26]. A technique that is inexpensive, radiation-free and portable is attractive for identifying men at risk for fracture. QUS of
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the heel is thus very appealing for increasing osteoporosis diagnosis in men. However, there are considerable technical differences among the various devices and measurements thus cannot be compared. QUS predicts fracture about as well as DXA, but osteoporosis therapy cannot be monitored by QUS. In addition, all studies of osteoporosis treatment in men (e.g. [37–39] have used DXA to define the men to be treated. Thus, there are no treatment studies of men identified for increased fracture risk solely by QUS. QUS, especially when used in the MOST calculation (which adds the influence of low body weight on osteoporosis risk), can be used to determine which men should have DXA. There are conflicting data on whether QUS should be used alone or with risk factors (such as age and weight) or whether age and weight by themselves might determine which men should have DXA. In conclusion, although QUS has the potential as a tool for osteoporosis management in men, its definitive role remains to be defined.
References 1. A.M. Schott, S. Weill-Engerer, D. Hans, F. Duboeuf, P.D. Delmas, P.J. Meunier, Ultrasound discriminates patients with hip fracture equally well as dual energy x-ray absorptiometry and independently of bone mineral density, J. Bone Miner. Res. 10 (1995) 243–249. 2. C.C. Gluer, International Quantitative Ultrasound Consensus Group, Quantitative ultrasound techniques for the assessment of osteoporosis: expert agreement on current status, J. Bone Miner. Res. 12 (1997) 1280–1288. 3. P.H.F. Nicholson, R. Muller, X.G. Cheng, et al., Quantitative ultrasound and trabecular architecture in the human calcaneus, J. Bone Miner. Res. 16 (2001) 1886–1892. 4. P.H.F. Nicholson, M.L. Bouxsein, Quantitative ultrasound does not reflect mechanical damage in human cancellous bone, J. Bone Miner. Res. 15 (2000) 2467–2472. 5. E.S. Siris, P.D. Miller, E. Barrett-Connor, et al., Identification and fracture outcomes of undiagnosed low bone mineral density in postmenopausal women: results from the National Osteoporosis Risk Assessment, J. Am. Med. Assoc. 286 (2001) 2815–2822. 6. A.M. Schott, B.K. Koupai, D. Hans, et al., Should age influence the choice of quantitative bone assessment technique in elderly women? The EPIDOS study, Osteoporos. Int. 15 (2004) 196–203. 7. C. Durosier, D. Hans, M.A. Krieg, A.M. Schott, Defining risk thresholds for a 10-year probability of hip fracture model that combines clinical risk factors and quantitative ultrasound: results using the EPISEM cohort, J. Clin. Densitom. 11 (2008) 397–403. 8. S. Fujiwara, T. Sone, K. Yamazaki, et al., Heel bone ultrasound predicts non-spine fracture in Japanese men and women, Osteoporos. Int. 16 (2005) 2107–2112. 9. K.-T. Khaw, J. Reeve, R. Luben, et al., Prediction of total and hip fracture risk in men and women by quantitative ultrasound of the calcaneus: EPIC-Norfolk prospective population study, Lancet 363 (2004) 197–202.
10. S. Gonelli, C. Cepollaro, L. Gennari, et al., Quantitative ultrasound and dual-energy x-ray absorptiometry in the prediction of fragility fracture in men, Osteoporos. Int. 16 (2005) 963–968. 11. D.C. Bauer, S.K. Ewing, J.A. Cauley, K.E. Ensrud, S.R. Cummings, E.S. Orwoll, Osteoporosis Fractures in Men (MrOS) Research Group, Quantitative ultrasound predicts hip and non-spine fracture in men: the MrOS study, Osteoporos. Int. 18 (2007) 771–777. 12. S.R. Hayman, W.M. Drake, D.L. Kendler, et al., North American male reference population for speed of sound in bone at multiple skeletal sites, J. Clin. Densitom. 5 (2002) 63–71. 13. A. Qaseem, S. Snow, P. Shekelle, R. Hopkings Jr., M.A. Forciea, D.K. Owens, Clinical Efficacy Assessment Subcommittee of the American College of Physicians, Screening for osteoporosis in men: a clinical practice guideline from the American College of Physicians, Ann. Intern. Med. 148 (2008) 680–684. 14. M.C. Hochberg, R.A. Adler, Screening for osteoporosis in men: comments on the American College of Physicians clinical guidelines, Nat. Clin. Pract. Rheumatol. 4 (2008) 626–627. 15. M.-A. Krieg, R. Barkmann, S. Gonnelli, et al., Quantitative ultrasound in the management of osteoporosis: the 2007 ISCD official positions, J. Clin. Densitom. 11 (2008) 163–187. 16. S.L. Gudmundsdottir, O.S. Indridason, L. Franzson, G. Sigurdsson, Age-related decline in bone bass measured by dual-energy x-ray absorptiometry and quantitative ultrasound in a population-based sample of both sexes, J. Clin. Densitom. 8 (2005) 80–86. 17. S. Goemaere, H. Zmierczak, I. Van Pottelbergh, J.M. Kaufman, Ability of peripheral bone assessments to predict area bone mineral density at hip in community-dwelling elderly men, J. Clin. Densitom. 5 (2002) 219–228. 18. R.A. Adler, H.L. Funkhouser, C.M. Holt, Utility of heel ultrasound bone density in men, J. Clin. Densitom. 4 (2001) 225–230. 19. R.A. Adler, H.L. Funkhouser, V.I. Petkov, et al., Osteoporosis in pulmonary clinic patients: does point-of-care screening predict central dual-energy x-ray absorptiometry? Chest 123 (2003) 2012–2018. 20. H. Liu, N.M. Paige, C.L. Goldzweig, et al., Screening for osteo porosis in men: a systematic review for an American College of Physicians guideline, Ann. Intern. Med. 148 (2008) 685–701. 21. R.A. Adler, M.T. Tran, V.I. Petkov, Performance of the osteo porosis self-assessment screening tool for osteoporosis in American men, Mayo Clin. Proc. 78 (2003) 723–727. 22. H.S. Lynn, J. Woo, J.A. Leung, et al., Osteoporotic fractures in men (MrOS) study. An evaluation of osteoporosis screening tools for the osteoporotic fractures in men (MrOS) study, Osteoporos. Int. 19 (2008) 1087–1092. 23. H.S. Lynn, E.M.C. Lau, S.Y.S. Wong, A.W.L. Hong, An osteoporosis screening tool for Chinese men, Osteoporos. Int. 16 (2005) 829–834. 24. A.C. Feldstein, G. Nichols, E. Orwoll, et al., The near absence of osteoporosis treatment in older men with fractures, Osteoporos. Int. 16 (2005) 953–962. 25. R.A. Adler, The need for increasing awareness of osteoporosis in men, Clin. Cornerstone 8 (Suppl 3) (2006) S7–S13. 26. G.M. Kiebzak, G.A. Beinart, K. Perser, C.G. Ambrose, S.J. Siff, M.H. Heggeness, Undertreatment of osteoporosis in men with hip fractures, Arch. Intern. Med. 162 (2002) 2217–2222.
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27. H. Cheng, L.C. Gary, J.R. Curtis, et al., Estimated prevalence and patterns of presumed osteoporosis among older Americans based on Medicare data, Osteoporos. Int. (3 February, 2009) published online. 28. S.C.E. Schuitt, M. van der Klift, A.E.A.M. Weel, et al., Fracture incidence and association with bone mineral density in elderly men and women: the Rotterdam study, Bone 34 (2004) 195–202. 29. P. Szulc, F. Munoz, F. Duboeuf, F. Marchand, P.D. Delmas, Bone mineral density predicts osteoporotic fractures in elderly men: the MINOS study, Osteoporos. Int. 16 (2005) 1184–1192. 30. B. Sinnott, S. Kukreja, E. Barengolts, Utility of screening tools for the prediction of low bone mass in African American men, Osteoporos. Int. 17 (2006) 684–692. 31. J.G. Skedros, C.L. Sybrowsky, G.J. Stoddard, The osteo porosis self-assessment screening tool: a useful tool for the orthopaedic surgeon, J. Bone Joint Surg. 89A (2007) 765–772. 32. J.L. Perez-Castrillon, M.G. Sagredo, R. Conde, J. del Pino-Montes, D. de Luis, OST risk index and calcaneus bone densitometry in osteoporosis diagnosis, J. Clin. Densitom. 10 (2007) 404–407. 33. K. Ito, J.P. Hollenberg, M.E. Charlson, Using the osteoporosis self-assessment tool for referring older men for bone
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densitometry: a decision analysis, J. Am. Geriatr. Soc. 57 (2009) 218–224. S. Gonelli, C. Cepollaro, A. Montagnani, et al., Heel ultrasonography in monitoring alendronate therapy: a four-year longitudinal study, Osteoporos. Int. 13 (2002) 415–421. B.M. Ingle, A.B.C. Machado, C.A. Pereda, R. Eastell, Monitoring alendronate and estradiol therapy with quantitative ultrasound and bone mineral density, J. Clin. Densitom. 8 (2005) 278–286. M. Weiss, M. Koren-Michowitz, E. Segal, S. Ish-Shalom, Monitoring response to osteoporosis therapy with alendronate by a multisite ultrasound device, J. Clin. Densitom. 6 (2003) 219–224. E. Orwoll, M. Ettinger, S. Weiss, et al., Alendronate for the treatment of osteoporosis in men, N. Engl. J. Med. 343 (2000) 604–610. J.D. Ringe, H. Faber, P. Farahmand, A. Dorst, Efficacy of risedronate in men with primary and secondary osteoporosis: results of a 1-year study, Rheumatol. Int. 26 (2006) 427–431. E.S. Orwoll, W.H. Scheele, S. Paul, et al., The effect of teriparatide (human parathyroid hormone (1-34)) therapy on bone density in men with osteoporosis, J. Bone Miner. Res. 18 (2003) 9–17.
Chapter
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Advanced Structural Assessment of Bone Using CT and MRI X. Edward Guo1, X. Sherry Liu2, and Felix W. Wehrli3 1
Department of Biomedical Engineering, Columbia University, New York, New York, USA Departments of Medicine and Biomedical Engineering, College of Physicians and Surgeons, Columbia University, New York, New York, USA 3 Department of Radiology, University of Pennsylvania, Philadelphia, Pennsylvania, USA 2
Introduction
Quantitative computed tomography (QCT) and, more recently, multidetector row CT (MDCT) have been used in assessing bone mass and structure in order to improve the diagnosis of osteoporosis and related fragility fractures [17–24]. QCT has improved the traditional aBMD measurement to include volumetric BMD (vBMD), separate analysis of cortical (ctBMD) and trabecular compartments (tBMD), cortical thickness and bone geometries. QCT technology is widely available in all major medical facilities and has demonstrated its ability to identify subtle changes in either cortical or trabecular compartments during the aging process or between differences in gender or race [17, 19, 22]. QCT, in general, has an in-plane spatial resolution of 0.5 mm and an out-ofplane thickness of around 1 mm. At this resolution, important trabecular bone architecture features cannot be visualized and quantified. However, QCT can be used clinically to measure bone mass and bone structure at the important skeletal sites, such as the proximal femur, spine and radius. Improvements in spatial resolution have been made in the emerging MDCT [18, 24]. An in-plane spatial resolution of 250 m and the out-of-plane resolution of 300 m can be achieved using MDCT, which allows for possible analyses of trabecular bone microstructure. However, QCT and MDCT involve ionizing radiation and have legitimate radiation safety concerns, especially in the younger patient population such as premenopausal women. The radiation doses for QCT and MDCT is at the order of 10 mSv, corresponding to 3 years of natural background radiation. The further improvement of spatial resolution is probably limited by this radiation safety concern. Finite element (FE) models from patient-specific QCT and MDCT images have emerged recently in osteoporotic fracture etiology and skeletal response to anti-osteoporosis interventions. Although limited by spatial resolution, these image-based FE models are quite promising in their ability to improve diagnostic efficacy in predicting fractures.
Osteoporosis, a metabolic bone disease of major proportions, is characterized by a low bone mass and microarchitectural deterioration [1]. The measurement of areal BMD (aBMD) by dual energy x-ray absorptiometry (DXA) is currently the accepted method for the diagnosis of osteoporosis and the assessment of fracture risk in postmenopausal women and men over the age of 50 years [2]. However, the measurement of aBMD by DXA has significant limitations in its ability to predict the prevalence or incidence of fractures and in assessing the efficacy of pharmacological interventions that aim to reduce fracture risk [3–8]. Recent studies in postmenopausal women have shown that half of all fractures occur when aBMD values are above the World Health Organization’s (WHO) diagnostic threshold for osteoporosis (T-score 2.5) [4,8]. These studies suggest that aspects of bone quality other than aBMD contribute to fracture risk and also that aBMD depends on the bone size and cannot delineate the independent contribution of bone density to fracture risk. Furthermore, the resolution of DXA at the spine and proximal femur is insufficient in distinguishing between the cortical and trabecular compartments and is not sensitive enough to detect cortical bone loss, for example, in hyperparathyroidism [9]. Evidence in favor of an independent role of microarchitecture as a determinant of bone’s mechanical competence and fracture risk has been documented in many studies [10–16]. Thus, there has been great interest in new imaging methods capable of visualizing and quantifying bone microstructure from which quantitative microstructural and mechanical measures can be derived for the clinical detection of osteoporosis and assessment of the efficacy of treatment intervention. There is substantial evidence that such measures better predict incident fractures and therefore could serve as alternatives to or be used in conjunction with DXA. Osteoporosis in Men
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In order to achieve enough spatial resolution for the visualization and quantification of three-dimensional (3D) trabecular bone microstructure, high-resolution CT or magnetic resonance imaging (MRI) technology have become the hallmarks of skeletal imaging in the new millennium. Highresolution micro-CT (CT) has been used to characterize non-destructively the 3D microstructure of trabecular bone in cadaveric and biopsy specimens. Critical microstructural features in trabecular microarchitecture have been identified and related to the mechanical properties of trabecular bone [25–30]. In addition, image-based FE analysis methods have been developed and shown to predict accurately the mechanical properties of trabecular bone [31–34]. The success of these techniques in providing accurate estimates of stiffness and strength has spurred the development of high-resolution in vivo imaging modalities with the expectation that a direct assessment of bone mechanical properties on the basis of high-resolution images in patients can be achieved. One such technology is micro-MRI (MRI). Besides the absence of ionizing radiation, MRI has a number of attractive features. First, it provides information on both soft and hard tissues and it has a narrower point-spread function (which determines the effective resolution at a given image voxel size) than x-ray-based devices. Another advantage is its wide distribution as a general-purpose medical imaging modality with over 10 000 systems installed worldwide. While MRI requires appropriate add-on technology in terms of radio frequency (RF) coils and imaging pulse sequence, such enhancements to general-purpose MRI systems are relatively straightforward. Among the technol ogy’s limitations are the relatively long scan times, although these are being overcome with the advent of higher field strengths and parallel imaging [35]. Furthermore, MRI functions through the detection of protons, information on bone is obtained indirectly and, thus, in general, cannot quantify mineral density, although solid-state 31P MRI techniques are currently under development and may eventually allow measurement of mineralization and porosity [36, 37]. Another new imaging method is high-resolution peripheral computed tomography (HR-pQCT). HR-pQCT is used in commercially available scanners, such as the Xtreme CT scanner, which allows for the separate analyses of trabecular and cortical bone and has the potential for quantifying the mineralization of bone tissue. Analogous to MRI, HRpQCT yields measurements of bone geometric parameters and trabecular microarchitecture that correlate with bone strength [10, 13, 38–41]. Both MRI and HR-pQCT achieve sufficient resolution for building microstructural FE models to assess bone strength, a direct measurement of bone’s resistance to fractures [10, 13, 14, 42, 43]. The major characteristics of osteoporosis are low bone mass and microarchitectural deterioration of trabecular bone with a dramatic change in trabecular architecture from plate-like to rod-like elements [44, 45]. With advances in high-resolution CT and MRI imaging for trabecular
bone, new model-independent 3D morphological analysis methods have been conceived to segment the trabecular bone network into individual trabecular plates and rods [27, 46–48]. The individual trabeculae segmentation (ITS)based morphological analysis has revealed the distinctly different roles of trabecular plates and rods in mechanical competence and failure mechanisms of trabecular bone [27, 46, 49, 50]. The initial application of this advanced morphological analysis technique in a clinical osteoporosis study of hypogonadal men has demonstrated its ability to detect the trabecular bone microstructural abnormalities in osteoporotic men as well as subtle micoarchitectural changes following hormone replacement treatment of these men [43]. In this chapter, the current status of the structural assessment of the skeleton using QCT and MDCT and clinical image-based FE models are reviewed with an emphasis on new clinical discoveries and advances. Next, the highresolution CT and MR imaging technologies are reviewed with an emphasis on microstructural assessments and functional assessments of the mechanical competence of the skeleton. The development of advanced microstructural analysis techniques in terms of ITS technology is discussed and its applications in clinical high-resolution CT and MR images will be demonstrated. CT and MRI image-based and patientspecific FE models for the assessment of mechanical competence are also highlighted. Finally, the applications of FE models in a small pilot study involving hypogonadal men treated with testosterone and the comparison of the baseline data to those in eugonadal men is reviewed to demonstrate the potential of these techniques for evaluating treatment response.
QCT and MDCT-based structural analyses in the diagnostics and monitoring of osteoporosis patients QCT of bone mass and structure has been widely used in central skeleton sites such as the lumbar spine and proximal femur where most osteoporosis-related fractures occur. The x-ray attenuation gray values in CT images are converted to the equivalent BMD values using a known density phantom scanned together with the patient. In general, the spatial resolution of QCT is around 0.5 mm in-plane and 1–3 mm out-of-plane. The reconstructed QCT images of skeletons provide a truly 3D visualization and quantification of these important skeletal sites. Therefore, QCT images of proximal femurs and spines can be used to obtain integral volumetric BMD, cortical vBMD, trabecular vBMD as well as cortical thickness, bone size such as cross-sectional area and other related measures, e.g. the moment of inertia of the cross-section (Figure 45.1).
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Figure 45.1 Typical selections of the volume of interest for QCT bone mass and structure analysis of the proximal femur and lumbar spine. (A) and (B): proximal femur, (C) and (D): lumbar spine. QCT permits separate analyses for cortical bone and trabecular bone compartments as well as cortical thickness (From Lewiecki et al, J Clin Endocrinol Metab 2009;94(1):171–80 [51], with permission).
QCT-based analyses of the proximal femur or spine have been used in many cross-sectional and perspective studies of fracture etiology and in follow ups of anti-osteoporosis interventions [17–24]. A large cross-sectional QCT study of men showed that the total vBMD at the femoral neck was only minimally related to age, whereas cortical volume was 5% smaller and medullary volume was 10% larger in the group with ages greater than 85, compared to the younger group (65–69 years) [23]. On the other hand, in the femur shaft, cortical cross-sectional area and medullar area were 9% and 22% larger, respectively, in men aged more than 85, when compared to the younger group. The neck cortical vBMD did not change with age while the shaft cortical vBMD decreased by 4% in the oldest age group. Between the oldest and youngest age groups, the total vBMD and trabecular vBMD were 9% and 22% lower in the oldest group, respectively, while the DXA femoral neck aBMD was only 4% lower. This demonstrated the importance of 3D and compartmental analyses of bone structure. While the hip fracture rates among older Black, Asian, and
Hispanic men in the USA are much lower than those of white men, the QCT study identified that Black and Asian men have greater cortical thickness and higher trabecular vBMD, despite smaller bone geometry in Asians [22]. Therefore, the QCT-based structure analyses can potentially provide better mechanistic understanding of age- or racialrelated differences in the skeleton and help to delineate the relative risk for fractures between different populations. QCT-based measurements can be used to estimate an individual’s risk for fracture. The vertebral strength can be estimated from the trabecular vBMD and cross-sectional area measurements from QCT. In addition, applied load to the lumbar vertebral body can be estimated from the body weight and height of the individual. Therefore, a risk factor defined by the applied load divided by the vertebral strength can be used for patient-specific evaluations of the vertebral fracture risk. Using this approach, important differences in vertebral bone structure, strength and relative risk for vertebral fractures between men and women were revealed [21]. Men have a larger bone size (30% larger vertebral cross-sectional
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area) and therefore higher vertebral strength (36% higher in men) than women during young age [21–29]. Since men are taller and heavier than women when they are young, the factor of risk for vertebral fractures in men is actually significantly higher than in women. However, women lose vertebral vBMD much faster than men (55% versus 39% between ages 20 and 90) and also increase the applied load on the vertebral body faster than men ( 8% versus 20% between ages 20 and 90). The consequence is that the factor of risk for vertebral fracture in women increases much faster than in men (88–99% versus 25–32%). In addition, the percentage of women 50 years of age with the factor of risk greater than 1 (certain fracture) is significantly higher than that of men 50 years of age (30% versus 12%). In order to improve the limited spatial resolution of QCT, the new generation of CT scanners, multidetector row CT, or MDCT, have been explored for skeletal imaging [18, 24, 52–55]. Instead of a linear array of detector elements, a two-dimensional array of detector elements ranging from 4 to 64 detectors is used with increased scanning speed and spatial resolution. The in-plane resolution can be as high as 250 m while the out-of-plane resolution approximates 300 m. The MDCT was recently used to evaluate the microstructural contribution of vertebral trabecular bone to the risk of vertebral fractures. At the nominal resolution of 250 250 500 m3, 3D features representing trabecular bone microstructure can be visualized (Figure 45.2) [24]. Morphological parameters, which are typically used in high resolution CT images, were calculated, such as bone volume fraction (BV/TV), trabecular thickness (Tb.Th), trabecular spacing (Tb.Sp), trabecular number (Tb.N), connectivity
and structure model index (SMI). In an application to 82 postmenopausal women (39 with vertebral fracture and 43 without fracture), MDCT-based parameters such as vBMD, BV/TV, SMI, have a significantly higher odds ratio of predicting the occurrence of vertebral fractures than aBMD [24]. MDCT has also been recently used in assessing vertebral microstructure in osteoporotic women in response to parathyroid hormone treatment. All MDCT-based microstructural parameters except the degree of anisotropy (DA) detected a significant improvement upon treatment and these microstructural parameters were partially independent of BMD [18]. At 250 m resolution, which is close to the typical trabecular thickness, MDCT cannot accurately represent trabecular architecture, especially those thin trabeculae. Several ex vivo studies have compared microstructural parameters measured by MDCT with either the gold standard high resolution CT or HR-pQCT [52–55]. These validation studies indicate that there are moderate but significant correlations between microstructural parameters measured by MDCT and those of higher resolution CT scanner, except trabecular thickness. A recent study suggests that 3D fuzzy segmentation approaches can yield accurate measurements of trabecular distance in MDCT images in comparison to HR-pQCT images [55]. Therefore, special imaging processing approaches may improve the quantification of trabecular microstructure in MDCT images in the future. In theory, QCT or MDCT, containing the 3D structure and bone mass of the spine and hip, should provide additional and better assessment of structure and cortical/trabecular contribution to fracture risk. However, the
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Figure 45.2 Representative 2D and 3D MDCT images of the third lumbar spine. Top: a 62-year-old woman without vertebral fracture. Bottom: a woman of the same age with a vertebral fracture in her thoracic spine. Visible differences in trabecular microstructure can be seen from the original 2D slices (A and B), thresholded 2D slices (C and D) and the 3D thresholded images (E and F). (From Ito et al, J Bone Miner Res 2005;20(10):1828–36 [24] with permission).
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prospective studies of fracture risk using these technologies are still ongoing. It remains to be seen whether QCT or MDCT can predict fracture risk better than aBMD by DXA. A recent prospective study using hip QCT in the Osteoporotic Fractures in Men Study (MrOS) indicates that QCT-derived parameters such as percentage of cortical volume, minimal cross-sectional area and trabecular BMD were independently related to hip fracture risk [19]. However, overall hip fracture prediction was not improved relative to aBMD by additional QCT parameters.
CT imaging and individual trabeculae segmentation (its)based morphological analysis CT currently provides the highest spatial resolution of all the non-destructive imaging modalities with resolutions as high as 10 m [56]. An invasive bone biopsy followed by CT-based morphological analyses can effectively quantify the trabecular bone microstructure (Figure 45.3) [57–60]. While traditional metric measurements of the trabecular network are based on
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a model-dependent stereological method [61], the emergence of non-destructive 3D assessment by CT has advanced the characterization of trabecular bone networks toward 3D model-independent methods [57–59]. Morphological analyses of trabecular bone by CT typically includes quantifications of BV/TV, bone surface density (BS/TV) and direct 3D model-independent measures of trabecular thickness (Tb.Th*), trabecular spacing (Tb.Sp*) and trabecular number (Tb.N*). In addition, non-metric measures provide insight into the 3D branching nature of trabecular bone by connectivity density (Conn.D) [26, 62–64], trabecular type (plate versus rod) by structure model index (SMI) [44, 58, 60] and orientation of trabecular network by degree of anisotropy (DA) [65–67]. Using high resolution CT technology and large collections of ex vivo samples, the sex differences of bone microstructure at multiple skeletal sites have been examined [68]. As shown in Figure 45.4 with samples of average property, there are clear differences existing between men and women, especially in radius, femoral neck, and femoral trochanter. Indeed, quantitative measurements of BV/TV, SMI and Tb.Th* at the distal radius, femoral neck and femoral trochanter and Tb.Sp* and Conn.D at the distal radius and femoral neck are significantly different between men and women [68]. Therefore, sex
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differences in microstructure at the distal radius and proximal femur may contribute to the significantly higher number of osteoporotic fractures in women than in men. In spite of its success for the evaluation of the 3D architecture of trabecular and cortical bone, the traditional CT morphological analysis can evaluate the morphology of trabecular bone at a global level without identification of trabecular plates and rods even though the two types of structure are fundamentally different. Recently, two research groups have independently studied the relative importance of trabecular types (plates and rods) in the architecture and mechanical properties of trabecular bone and developed image processing techniques volumetrically to segment 3D trabecular bone microstructure as a collection of trabecular plates and rods [27, 46–49]. Using a 3D digital topological analysis (DTA) technique, a complete volumetric decomposition
technique has been developed to segment both individual rods and plates with well-defined trabecular orientation (Figure 45.5) [46]. With the completely decomposed individual trabecular elements, quantitative assessment of trabecular plate or rod thickness and orientation distributions is possible for 3D human trabecular bone images. In this manner, histograms of trabecular orientation and thickness can be obtained for trabecular plates and rods of three anatomic sites and the inter-site variance of plate and rod distributions have been quantified (Figures 45.6 and 45.7). The distribution of trabecular plate and rod orientation provides quantitative evidence showing that the majority of trabecular plates are orientated along the principal direction of loading, whereas most trabecular rods serve as transverse connections between the longitudinal plates, confirming early qualitative or histomorphometric observations [69, 70]. Among the three anatomic
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Figure 45.5 Illustration of complete volumetric decomposition on images of trabecular bone samples (2.1 2.1 1.3 mm3) from different anatomical sites: (A) femoral neck, (B) tibia and (C) vertebral body. (Left) Trabecular bone structures with the trabecular type labeled for each voxel. Plate voxels are shown in dark gray, rod voxels in light gray. (Right) Completely decomposed trabecular bone structures with individual trabeculae labeled by color for each voxel. (A) 119 plates and 51 rods; (B) 72 plates and 46 rods; (C) 50 plates and 42 rods. (From Liu et al, J Bone Miner Res 2008;23(2):223-35 [46], with permission).
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Figure 45.6 Top: schematic representations of trabecular plate and rod orientation. (A)–(C) Histogram of orientations of trabecular plate (left) and rod (right) along X3-axis within different anatomical sites: (A) femoral neck, (B) tibia and (C) vertebral body. (From Liu et al, J Bone Miner Res 2008;23(2):223–35 [46], with permission).
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pTb.Th FN
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pTb.Th rTb.Th
6000
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5000 4000
rTb.Th
3000 2000 1000 0
0
30 60 90 120 150 180 210 240 270 300 330 360
pTb.Th And rTb.Th (µm)
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TIBIA 4000
pTb.Th rTb.Th
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pTb.Th rTb.Th
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30 60 90 120 150 180 210 240 270 300 330 360
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pTb.Th And rTb.Th (µm)
Figure 45.7 Histograms of trabecular plate and rod thickness within different anatomical sites: (A) femoral neck, (B) tibia and (C) vertebral body. (From Liu et al, J Bone Miner Res 2008;23(2):223–35 [46], with permission).
sites, trabecular plates in the tibia show the best alignment with the principal direction of loading, while most trabecular rods in the vertebral body align with the transverse plane of principal loading direction. In addition, ITS segmentation allows for the quantification of the roles of trabecular plates and rods in determining the mechanical properties and failure mechanism of trabecular bone. The data suggest that trabecular plates contribute significantly and dominantly to the anisotropic elastic modulus and yield strength of trabecular bone [27, 46, 49]. In contrast, trabecular rods appear to represent the weakest link in trabecular bone networks as they fall first during compression [49]. The distinctly different roles of rods and plates in determining stiffness and strength of trabecular networks justify defining a set of morphological parameters which extend current nomenclatures (Table 45.1). In later sections of HR-pQCT and MRI, the applications of ITS in clinical resolution images of peripheral sites will be discussed, illustrating its great potential as a novel morphological tool.
High resolution peripheral quantitative ct (HR-pQCT) HR-pQCT is a recently developed in vivo non-invasive imaging modality that can assess bone mass and bone quality at the distal radius and tibia [39, 41, 71, 72]. 3D datasets provided by HR-pQCT permit the separate analyses of trabecular and cortical bone [73, 74] and the measurement of specific geometric parameters that correlate with bone strength, such as endosteal and periosteal circumferences, cortical area and thickness [74, 75]. Moreover, with its voxel size of 80 m, HR-pQCT yields measurements of trabecular microarchitecture, including trabecular thickness, number and separation (Figure 45.8). Since the 82 m voxel size is of the same order as the thickness of a typical human trabecula, HR-pQCT does not use standard CT model-independent measurements for patient analyses, instead, a semi-derived method developed for a precursor HR-pQCT model is used for BV/TVd, Tb.N*, Tb.Th and
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Table 45.1 New morphological parameters from 3D ITS analysis Microstructural parameters
Definition
Bone volume fraction BV/TV Plate bone volume fraction pBV/TV Rod bone volume fraction rBV/TV Plate tissue fraction pBV/BV Rod tissue fraction rBV/BV Mean trabecular plate thickness pTb.Th (mm) Mean trabecular rod thickness rTb.Th (mm) Trabecular plate numerical density pTb.N (1/mm) Trabecular rod numerical density rTb.N (1/mm) Mean trabecular rod length rTb.l (mm) Mean trabecular plate surface area pTb.S (mm2) Plate–rod junction density P-R Junc.D (1/mm3) Rod–rod junction density R-R Junc.D (1/mm3) Plate–plate junction density P-P Junc.D (1/mm3)
Total volume of bone voxels/bulk volume Total volume of plate bone voxels/bulk volume Total volume of rod bone voxels/bulk volume Total volume of plate bone voxels/total volume of bone voxels Total volume of rod bone voxels/total volume of bone voxels Average thickness of trabecular plates Average diameter of trabecular rods Cubic root of total number of trabecular plates/bulk volume Cubic root of total number of trabecular rods/bulk volume Average length of trabecular rods Average surface area of trabecular plates Total number of P–R junctions/bulk volume Total number of R–R junctions/bulk volume Total number of P–P junctions/bulk volume
Figure 45.8 Representative 3D reconstructed HR-pQCT images of distal radius and tibia from a healthy subject. Clearly, these images show the distinct features of cortical and trabecular compartments, indicating the feasibility of 3D morphological analysis of trabecular microstructure.
Tb.Sp [72]. MacNeil and Boyd scanned 10 cadaveric radii using both HR-pQCT and CT and reported that the morphological parameters measured by HR-pQCT correlated well with CT measures [41]. A comprehensive study using cadaveric tibiae, which were scanned by both HR-pQCT and CT, has also demonstrated excellent correlations between corresponding microstructural parameters measured by HR-pQCT and those by CT (Figure 45.9). These parameters have been shown to detect sensitively microarchitectural changes that lead to increased fragility [38, 72, 76]. Boutroy et al, reported that HR-pQCT discriminates between osteopenic postmenopausal women with and without fractures and found that those with fractures have decreased trabecular density, lower trabecular bone volume (BV/TV) and increased variability in trabecular separation [39]. More recently, Sornay-Rendu et al reported that architectural alterations of the trabecular and cortical bone of postmenopausal women as assessed by HR-pQCT are associated with vertebral and non-vertebral fractures and these alterations are partially independent of decreased BMD [77]. In addition, the ITS applications in HR-pQCT images of osteoporotic women have demonstrated its ability to
detect abnormalities in trabecular microstructure (Figure 45.10). For example, the ITS technique detected significant differences in all ITS-based morphological parameters except pTb.Th and rTb.Th in both the distal tibia and radius in idiopathic osteoporotic young women [78]. These alterations in trabecular bone microstructure were correlated with significant reductions in anisotropic elastic moduli determined by HR-pQCT-based FE analyses. This result demonstrates the potential of this novel ITS-based morphological analysis technique in detecting subtle microstructural deteriorations in osteoporotic trabecular bone. A validation study using registered HR-pQCT and CT images of human cadaveric tibiae has indicated, in general, excellent correlations of trabecular plate-derived parameters (r2 0.45–0.9) and significant but weaker correlations of trabecular rodderived parameters (r2 0.21–0.46) between HR-pQCT and CT. While further studies are needed, microstructural measurements by HR-pQCT and new imaging analysis techniques, such as ITS, will likely inaugurate a new era of non-invasive quantitative skeletal imaging.
Magnetic resonance imaging (MRI) MRI is an important focus for in vivo trabecular bone histomorphometry because of the advantages of having an absence of ionizing radiation, high innate contrast between bone and marrow and a widely distributed population of general-purpose clinical MRI instruments [11, 15, 16, 79–87]. MRI permits the visualization and quantification of trabecular network architecture at voxel sizes comparable to trabecular thickness, which make it sufficient for resolving individual microstructural elements and quantifying network topology. The choice of the anatomic site is dictated by considering the signal-to-noise ratio (SNR), which
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0.22
y = 0.05 + 0.88x
0.18 0.16 0.14 0.12 0.1
E y = 0.23 + 1.11x
r2 = 0.83
p < 0.001
1.1 1 0.9 0.8
0.1
0.5 0.6 0.7 0.8 Tb.Sp (mm, HR-pQCT)
H
2.5 y = –0.10 + 0.82x
0
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0.5 1 1.5 2 SMI (HR-pQCT)
2.5
0.16 0.15 0.14
0.04 0.06 0.08 0.1 Tb.Th (mm, HR-pQCT)
24 22
r2 = 0.92
p < 0.001
20 18 16
8
I r2 = 0.44
9 10 11 12 BS/BV (1/mm, HR-pQCT)
2.2 2
13
6.5 y = 2.49 + 0.58x
6
p < 0.01
r2 = 0.26
p < 0.05
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1.8 0
0.17
0.2 0.4 0.6 0.8 1 1.2 1.4 Ct.Th (mm, HR-pQCT)
2.4
1
2
r = 0.64
14
y = 0.40 + 1.04x
1.5
0.18
y = –40 + 2.0x
p < 0.001
r2 = 0.81
p < 0.001
2
F
0.3
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y = 0.11 + 0.67x p < 0.001
r2 = 0.90
0.4
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0.19
0.12 0.02
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1.2 1.4 1.6 1.8 2 Tb.N∗ (1/mm, HR-pQCT)
y = 0.12 + 0.41x
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Ct.Th (mm, µCT)
Tb.Sp∗ (mm, µCT)
1
(HR-pQCT)
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1.1
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BV/TVd
0
r = 0.87
p < 0.001
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0.03 0.06 0.09 0.12 0.15 0.18
G
1.3
y = 0.24 + 0.56x
2
0.9
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D
C
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p < 0.001
0.2 BV/TV (µCT)
r2 = 0.91
Tb.Th∗ (mm, µCT)
0.24
Tb.N∗ (1/mm, µCT)
A
Conn.D (µCT)
556
1.5
1.6 1.7 DA (HR-pQCT)
1.8
2.5 1.5
2
2.5 3 3.5 4 4.5 Conn.D (HR-pQCT)
5
Figure 45.9 Correlation between microstructural measurements of HR-pQCT images of the distal tibia and their respective CT gold standards.
Figure 45.10 The ITS decomposition of trabecular bone microstructure in clinical HR-pQCT images from idiopathic osteoporotic women (n 31, aged 23–49). Trabecular bone sub-volumes are selected from (A) distal tibia and (B) radius and segmented into individual trabecular plates and rods (represented by different shades, (C) tibia and (D) radius). The ITS-based morphological analysis revealed significant alterations in all ITS morphological parameters except pTb.Th and rTb.Th while comparing IOP subjects with age-matched control subjects (n 26).
C h a p t e r 4 5 Advanced Structural Assessment of Bone Using CT and MRI l
confines the locations to those that permit either the use of a closely coupled volume transmit–receive coil or surface coil arrays – the distal radius [15, 80, 88], the distal tibia [82–84] and the calcaneus [11, 16, 87, 89] (see Figure 45.11). Achievable voxel sizes (at an SNR sufficient to perform the processing and analysis algorithms reliably, typically 10) range from 137 137 350 m3 in the distal radius [15, 80] to 172 172 700 m3 in the calcaneus [11]. Measurements of structural variables at the proximal femur, albeit at a considerably lower resolution, have also been reported but are not practical in clinical applications at the present stage [90]. In MR spin-echo imaging, unlike in CT, the point-spread function that determines resolution is about 20% greater than the voxel size. Thus, the effective MR resolution at a 160 m isotropic voxel size is similar to the resolution achievable by HR-pQCT. However, the in-plane resolution of MRI is typically higher than the through-plane resolution, which is determined by the thickness of the image slice and which is usually three times larger than the in-plane resolution [15, 16, 40, 60, 81]. Due to the partial volume effect and an anisotropic voxel size, a two-dimensional approach similar to a histomorphometric measurement has been used to quantify trabecular microstructure by measures of BV/TV, Tb.Th, Tb.N and Tb.Sp and has been shown to be capable of detecting changes in trabecular microstructure caused by metabolic bone diseases [16, 87, 91–93]. By scaling the image voxel to an isotropic resolution, the MR images can also be analyzed by standard CT microstructure measures [57–59], namely the 3D model-independent morphological analysis, and can yield excellent correlations with most high-resolution CT measurements (Table 45.2) except Tb.Th. The trabecular bone network consists of interconnected plate-like and rod-like trabeculae. However, few methods specifically take the trabecular type characteristics into consideration when analyzing the trabecular network. Digital topological analysis (DTA) is able to convert trabecular rods to curves and plates to surfaces and identify the topological
Table 45.2 Linear equation and correlations (r2) between measurements of registered MRI and CT images from human cadaveric tibiae (n 25) Parameter
Slope
Intercept
r2
BV/TV Tb.N* (1/mm) Tb.Th* (mm) Tb.Sp* (mm) Ct.Th (mm) BS/BV (1/mm) SMI DA Conn.D
0.98 1.08 NA 1.01 1.23 1.68 1.02 0.67 1.72
0.06 0.10 NA 0.05 0.30 0.80 0.58 1.02 0.92
0.79* 0.93* NS 0.97* 0.87* 0.33‡ 0.67* 0.36‡ 0.51†
*
P 0.001, †P 0.01, ‡P 0.05
557
class for each skeleton voxel as eight classes: interior point of surface (S); edge point of surface (SE); junction point of surface (SS); junction point of surface and curve (SC); interior point of curve (C); curve end point (CE); junction point of curves (CC); and isolated point [94–96]. In the application of DTA on MR images of trabecular bone, other than S, SE, SS, SC, C, CE and CC voxel density, a series of topological parameters are derived including the fraction of all bone voxels in the skeleton (DENS), profile edge voxel density (PE), profile interior voxel density (PI), all surface voxel density (SURF S SE SS), all curve voxel density (CURV C CC PE/2), all junction voxel density (JUNC SC SS CC), surface to curve ratio (SCR SURF/CURV) and topological erosion index (EI, (C CE SE PE CC)/(S SS)) [15]. In a study of postmenopausal osteoporosis, MRI of the radius was performed on 79 women with a wide range of BMD scores and vertebral deformity statuses. SURF, SCR and EI from DTA were found to be significantly lower in the deformity group than the control group, suggesting that conversions of trabecular plates to rods and disruption of rods are involved with postmenopausal osteoporosis [15]. In the analysis of MRI images of trabecular bone from eugonadal and hypogonadal men, there was a significant difference in SCR and EI between the eugonadal and hypogonadal group, whereas BMD showed no significant difference between the groups [83]. Moreover, the effect of testosterone treatment on trabecular bone microarchitecture was also successfully traced by DTA-based topological parameters: significant changes in SCR and EI were found after 24 months of treatment in the severely testosterone-deficient hypogonadal group but no significant change in the control group [82]. The above studies suggest that DTA technique is capable of detecting the subtle, yet significant microarchitecture change in trabecular bone at diseased status as well as in response to treatments. A recent study examined 98 postmenopausal women who were subjected to MRI at the distal tibia and radius and measures of topology and scale of the trabecular bone network were computed [97] (Figure 45.11). A spinal deformity index (SDI) was obtained from morphometric measurements of midline sagittal MR images of the thoracic and lumbar spine in order to evaluate the associations between structure and deformity burden. Multiple structural indices at the distal radius were correlated with the SDI. Among these were topological surface density (a measure of trabecular plates) and trabecular bone volume fraction, which were inversely correlated with SDI (P 0.0001). Combinations of two structural parameters accounted for up to 30% of the variation in SDI (P 0.0001) independent of spinal BMD, which was not significantly correlated. This and other studies demonstrate the potential of noninvasive and non-ionizing assessment of bone quality and microstructure in osteoporosis patients [15, 82, 83, 97, 98]. Although, MRI has a limited spatial resolution, the initial validation of ITS-based morphological analyses
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Figure 45.11 MRI of the distal radius (upper row) with their respective virtual cores (lower row) from three subjects exemplifying a wide range in bone quality represented by the topological parameters which vary by over an order of magnitude between the extremes. (From Ladinsky et al J Bone Miner Res 2008;23(1):64–74 [97], with permission).
Relative changes in hypogonadal group
15% 10%
Month 6 Month 12 Month 24
∗
# #
5%
# #
#
#
0% –5% –10%
∗
∗
pBV/TV rBV/TV pTb.N rTb.N pTb.Th rTb.Th pTb.S
rTb.l
ITS-based morphological parameters
Figure 45.12 Changes of ITS-based morphological parameters in the hypogonadal group after 6, 12 and 24 months of treatment relative to the baseline. Values shown are means SE. #P 0.05 and *P 0.01 indicate significant difference compared to the baseline. (From Zhang et al, J Bone Miner Res 2008;23(9):1426–34 [43], with permission).
in MRI demonstrated similar trends that were found in HR-pQCT, mainly excellent correlations in plate-derived parameters and weaker correlations in rod-derived parameters between MRI and CT. With this caveat in mind, the ITS-based morphological analysis has been applied to clinical MR images of distal tibia virtual biopsies from men suffering from hypogonadal osteoporosis at a baseline and after 24 months of testosterone treatment (Figure 45.12). The ITS-based morphological analyses identified a significantly lower trabecular plate bone volume fraction (pBV/TV) and trabecular plate thickness (pTb.Th) in hypo gonadal men compared to eugonadal men at the baseline. Furthermore, the ITS-based morphological analyses found
a significantly higher pBV/TV and pTb.Th after 24 months of treatment in hypogonadal men, suggesting that the testosterone treatment improved the tibial trabecular bone microstructure in hypogonadal men via a significant increase in trabecular plate thickness and trabecular plate bone volume fraction, which implies that the architecture became more ‘plate-like’. These observations are consistent with previous topological analyses but with greater specificity and quantification [82, 83]. However, some caution is advised with respect to the trabecular rod-related parameters (rBV/ TV and rTb.N) and trabecular plate surface area (pTb.S) at the limited resolution of clinical MRI. Nevertheless, this study demonstrates the plausibility of ITS-based analyses in clinical MR images to estimate individual trabecular plate morphologies, which has been shown to be important in the mechanical properties of trabecular bone [27, 46, 49].
Image-based FEA This biomechanical modeling strategy converts each voxel of an image into a single finite element to create 3D specimen-specific models that can provide an accurate and direct estimate of bone’s fracture resistance. Since the resulting computational models integrate whole bone geometry and the trabecular and cortical compartments of CT and MR scans, image-based FEA promises to be a powerful tool for the clinical assessment of bone strength and fracture risk [10, 13, 14, 31, 34, 43, 91, 92, 99, 100]. FE analysis based on QCT images has been validated ex vivo and strongly predicts femoral and vertebral strength [101, 102]. Non-invasive QCT data can be used to construct patient-specific FE models for fracture risk assessment and evaluation of pharmaceutical interventions (Figure 45.13)
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70 y.o.
LOW
HIGH
64 y.o.
Figure 45.13 Patient-specific QCT-based FE models of vertebral body (left) and proximal femur (right). Gray scale code indicates BMD dependent materials strength (adopted from Melton et al J Bone Miner Res 2007;22(12):1885–92 [12] and Keaveny et al, J Bone Miner Res 2008;23(12):1974–82 [104], with permission).
[12, 18, 51, 103–105]. Mechanical competence quantified by either stiffness or strength can be directly estimated on a patient-specific basis. These mechanical properties directly relate to fracture risk of the skeleton. With the estimation of mechanical burdens at the spine or proximal femur, the factor-of-risk, defined as the ratio of estimated force to bone strength, can be estimated. This approach has been used to assess vertebral and hip fracture risk [12, 105] and changes in strength following anti-osteoporosis interventions [51, 103, 104, 106, 107]. Although the power for prospective prediction of fracture is similar to aBMD, the FE determined strength or the factor-of-risk was significantly associated with fracture, independent of aBMD, suggesting the potential ability of QCT-based FE biomechanical analysis prospectively to predict fragility fractures in men and women. The strength of patient-specific FE analysis of QCT scans also includes the ability of parametric studies to assess the contributions to fracture risk or efficacy of treatment from various skeletal factors, such as bone geometry, cortical and trabecular compartments. For example, in a parathyroid hormone (PTH) and alendronate study, the bone strength increased in response to either PTH, alendronate, or combination which primarily resulted from the increase in trabecular compartment [104]. Using this parametric approach, the FE analysis also identified that one year of PTH treatment has a negative strength effect associated with a change in the external bone geometry, while alendronate treatment for two years has a positive strength effect. FE analyses based on high-resolution CT of trabecular bone have been validated by comparison with experimental measurements of elastic and yield properties [31, 34, 107– 109]. However, in order for microstructural and image-based FE analyses to become standard clinical tools, the data from HR-pQCT and MRI must be thoroughly validated and compared with the current gold standard – CT. Only a few ex vivo validation studies have compared HR-pQCT and CT images of the distal radius [41, 42, 110]. MacNeil
and Boyd tested the accuracy of HR-pQCT on cadaver forearms by comparing the measurements with those obtained from CT and demonstrated significant correlations between most of them [41]. They also compared the strength of the distal radius as estimated by HR-pQCT-based FE models with the strength obtained by mechanical testing on the same sample set and found that the two are highly correlated [110]. In addition, MRI-based FE analysis has not been validated against CT for whole distal tibia and radius. Recently, using registered MRI, HR-pQCT and CT images from human cadaveric tibiae, the image-based FE analyses of whole distal tibia segments from MRI and HR-pQCT have been compared directly to those from CT. The elastic stiffness predicted by MRI or HR-pQCT-based FE models was highly correlated with those predicted by CT based models (r2 0.96 for both imaging modalities). Two recently published studies [10, 13] that evaluated the properties of wrist bone using HR-pQCT suggested that the deteriorated microstructure and lower estimated mechanical properties were associated with wrist fracture in postmenopausal women. On the other hand, MRI and image-based FE analyses of calcaneal trabecular bone from postmenopausal females who had undergone treatment with either placebo, 5 mg or 10 mg idoxifene for 12 months have shown significant changes in estimated elastic moduli in response to treatment despite undetectable changes in either BMD or BV/TV [14]. These data suggest that significant changes in estimated elastic moduli of trabecular bone may precede any measurable changes in bone density. In the previously described MRI study of distal tibiae in hygonadal men, MRI-based FE analyses were also performed to estimate the anisotropic elastic moduli from tibial trabecular bone subvolumes at the baseline as well as following the testosterone treatment. The estimated elastic moduli (E11, E33, G31 and G12) in the hypogonadal men were found to be significantly lower than those in the eugonadal controls (Figure 45.14). In the worst cases, the estimated elastic
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125% ∗
100%
∗
∗
75%
50% A
G23
G31
15%
Month 6 Month 12 Month 24
∗
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∗
∗
∗
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24 12 8 0
24 12 8 0
E33
24 12 8 0
24 12 8 0
E22
24 12 8 0
24 12 8 0
E11
Relative changes in hypogodandal group
Noamalized by modulus of eugonadal group at 0 month
150%
–10%
G12
Elastic moduli
E11 B
E22
E33
G23
G31
G12
Elastic moduli
Figure 45.14 (A) Normalized elastic moduli of both hypogonadal and eugonadal groups (normalized by the corresponding modulus in the eugonadal group at baseline). (B) Relative changes in elastic moduli of the hypogonadal group from baseline at 6, 12 and 24 months of treatment. Values shown are means SE (standard errors). #P 0.05 and *P 0.01 indicate significant difference compared to the baseline. (From Zhang et al, J Bone Miner Res 2008;23(9):1426-34 [43], with permission).
moduli E11 and G31 were only 77% and 74% of that of eugonadal men, respectively. There was no change in any parameter in the eugonadal group in the longitudinal assessments of estimated elastic moduli over 24 months as expected (see Figure 45.14). In contrast, several estimated elastic moduli (E22, E33, G23, and G12) increased after 24 months of hormone replacement treatments but no changes were detected at earlier time points of treatment (see Figure 45.14). It is noteworthy to point out that the four estimated elastic moduli (E22, E33, G23, and G12) within the hypogonadal group that significantly increased were the moduli that had relatively smaller differences as compared to those of the eugonadal group before the treatment. No significant changes were detected for the other two estimated moduli, E11 and G31, although these two estimated moduli of the hypogonadal group had an initial deficit of 23% or greater relative to the eugonadal group (see Figure 45.14). With the increasing availability of high-resolution in vivo MRI for clinical assessment of osteoporosis, image-based FE modeling is likely to provide new insight for the detection, management and treatment of patients with bone diseases in the future.
Conclusion Microscopic skeletal imaging analysis and FE modeling using CT or MRI have demonstrated great potential in structural assessments of skeleton integrity. The routine applications of rigorous image-based FE analyses, especially non-linear analyses for bone strength, will become a regular part of bone fragility and structural assessments. Advances in computational technology and instrumentation
will likely further improve the resolution and efficiency of skeletal microimaging modalities for the detection, treatment and monitoring of osteoporosis and fragility fractures in the new millennium. However, the breakthroughs of both CT and MR-based structural assessments of skeletal status will be in the area of new microstructural assessment techniques and biomechanical/image-based predictive models such as image-based FE models. The CT resolution is ultimately limited by safe radiation exposure dosages while the MRI struggles with the signal to noise ratio and scanning time. On the other hand, the continuous and significant improvements in computational power in the next decade will allow the development of more powerful and elaborate 3D morphological analysis techniques, such as the ITS and other more accurate and efficient computational biomechanical models based on patient images. However, the challenges in both CT and MR rely on how we can achieve high-resolution images (50 m) while remaining within reasonable radiation dosages or scanning times at central skeleton sites such as the lumbar spine and proximal femur. If somehow high-resolution imaging at the spine and proximal femur is achieved, it is possible that the image analysis and biomechanical and computational modeling technologies based on these high-resolution images discussed in this chapter can finally surpass the areal BMD assessments by DXA in predicting fragility fractures.
Acknowledgments This work is partially supported by National Institutes of Health grants: R01 AR053156, R01 AR051376, R21 AR049613 and R01 AR055647.
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References 1. NIH Consensus Development Panel on Osteoporosis Prevention, Consensus Development Conference Report: Prophylaxis and treatment of osteoporosis, Osteoporos. Int. 1 (2) (1991) 114–117. 2. P.D. Miller, 2006 Clinical use of bone mass measurements in adults for the assessment and management of osteoporosis, in: M.J. Favus (Ed.), Primer on the Metabolic Bone Disease and Disorders of Mineral Metabolism, American Society for Bone and Mineral Research, Washington DC sixth ed., 2006, pp. 150–161. 3. S.L. Hui, C.W. Slemenda, C.C. Johnston Jr, Age and bone mass as predictors of fracture in a prospective study, J. Clin. Invest. 81 (6) (1988) 1804–1809. 4. K.L. Stone, D.G. Seeley, L.Y. Lui, et al., BMD at multiple sites and risk of fracture of multiple types: long-term results from the Study of Osteoporotic Fractures, J. Bone Miner. Res. 18 (11) (2003) 1947–1954. 5. E.S. Siris, P.D. Miller, E. Barrett-Connor, et al., Identification and fracture outcomes of undiagnosed low bone mineral density in postmenopausal women: results from the National Osteoporosis Risk Assessment, J. Am. Med. Assoc. 286 (22) (2001) 2815–2822. 6. P.D. Delmas, E. Seeman, Changes in bone mineral density explain little of the reduction in vertebral or nonvertebral fracture risk with anti-resorptive therapy, Bone 34 (4) (2004) 599–604. 7. P.D. Delmas, How does antiresorptive therapy decrease the risk of fracture in women with osteoporosis? Bone 27 (1) (2000) 1–3. 8. S.C. Schuit, M. van der Klift, A.E. Weel, et al., Fracture incidence and association with bone mineral density in elderly men and women: the Rotterdam Study, Bone 34 (1) (2004) 195–202. 9. A.M. Parfitt, A structural approach to renal bone disease, J. Bone Miner. Res. 13 (8) (1998) 1213–1220. 10. S. Boutroy, B. van Rietbergen, E. Sornay-Rendu, F. Munoz, M.L. Bouxsein, P.D. Delmas, Finite element analyses based on in vivo HR-pQCT images of the distal radius is associated with wrist fracture in postmenopausal women, J. Bone Miner. Res. 23 (3) (2008) 392–399. 11. N. Boutry, B. Cortet, P. Dubois, X. Marchandise, A. Cotten, Trabecular bone structure of the calcaneus: preliminary in vivo MR imaging assessment in men with osteoporosis, Radiology 227 (3) (2003) 708–717. 12. L.J. Melton III, B.L. Riggs, T.M. Keaveny, et al., Structural determinants of vertebral fracture risk, J. Bone Miner. Res. 22 (12) (2007) 1885–1892. 13. L.J. Melton III, B.L. Riggs, G.H. van Lenthe, et al., Contribution of in vivo structural measurements and load/ strength ratios to the determination of forearm fracture risk in postmenopausal women, J. Bone Miner. Res. 22 (9) (2007) 1442–1448. 14. B. van Rietbergen, S. Majumdar, D. Newitt, B. MacDonald, M.R.I. High-resolution, and micro-FE for the evaluation of changes in bone mechanical properties during longitudinal clinical trials: application to calcaneal bone in postmenopausal women after one year of idoxifene treatment, Clin. Biomech. 17 (2) (2002) 81–88.
561
15. F.W. Wehrli, B.R. Gomberg, P.K. Saha, H.K. Song, S.N. Hwang, P.J. Snyder, Digital topological analysis of in vivo magnetic resonance microimages of trabecular bone reveals structural implications of osteoporosis, J. Bone Miner. Res. 16 (8) (2001) 1520–1531. 16. T.M. Link, S. Majumdar, P. Augat, et al., In vivo high resolution MRI of the calcaneus: differences in trabecular structure in osteo porosis patients, J. Bone Miner. Res. 13 (7) (1998) 1175–1182. 17. G. Sigurdsson, T. Aspelund, M. Chang, et al., Increasing sex difference in bone strength in old age: the Age, Gene/ Environment Susceptibility-Reykjavik study (AGESREYKJAVIK), Bone 39 (3) (2006) 644–651. 18. C. Graeff, W. Timm, T.N. Nickelsen, et al., Monitoring teriparatide-associated changes in vertebral microstructure by high-resolution CT in vivo: results from the EUROFORS study, J. Bone Miner. Res. 22 (9) (2007) 1426–1433. 19. D.M. Black, M.L. Bouxsein, L.M. Marshall, et al., Proximal femoral structure and the prediction of hip fracture in men: a large prospective study using QCT, J. Bone Miner. Res. 23 (8) (2008) 1326–1333. 20. B.L. Riggs, L.J. Melton III, R.A. Robb, et al., Population-based analysis of the relationship of whole bone strength indices and fall-related loads to age- and sex-specific patterns of hip and wrist fractures, J. Bone Miner. Res. 21 (2) (2006) 315–323. 21. M.L. Bouxsein, L.J. Melton III, B.L. Riggs, et al., Age- and sex-specific differences in the factor of risk for vertebral fracture: a population-based study using QCT, J. Bone Miner. Res. 21 (9) (2006) 1475–1482. 22. L.M. Marshall, J.M. Zmuda, B.K. Chan, et al., Race and ethnic variation in proximal femur structure and BMD among older men, J. Bone Miner. Res. 23 (1) (2008) 121–130. 23. L.M. Marshall, T.F. Lang, L.C. Lambert, J.M. Zmuda, K.E. Ensrud, E.S. Orwoll, Dimensions and volumetric BMD of the proximal femur and their relation to age among older US men, J. Bone Miner. Res. 21 (8) (2006) 1197–1206. 24. M. Ito, K. Ikeda, M. Nishiguchi, et al., Multi-detector row CT imaging of vertebral microstructure for evaluation of fracture risk, J. Bone Miner. Res. 20 (10) (2005) 1828–1836. 25. R.W. Goulet, S.A. Goldstein, M.J. Ciarelli, J.L. Kuhn, M.B. Brown, L.A. Feldkamp, The relationship between the structural and orthogonal compressive properties of trabecular bone, J. Biomech. 27 (4) (1994) 375–389. 26. J. Kabel, A. Odgaard, B. van Rietbergen, R. Huiskes, Connectivity and the elastic properties of cancellous bone, Bone 24 (2) (1999) 115–120. 27. X.S. Liu, P. Sajda, P.K. Saha, F.W. Wehrli, X.E. Guo, Quantification of the roles of trabecular microarchitecture and trabecular type in determining the elastic modulus of human trabecular bone, J. Bone Miner. Res. 21 (10) (2006) 1608–1617. 28. D. Ulrich, B. van Rietbergen, A. Laib, P. Ruegsegger, The ability of three-dimensional structural indices to reflect mechanical aspects of trabecular bone, Bone 25 (1) (1999) 55–60. 29. B. Van Rietbergen, A. Odgaard, J. Kabel, R. Huiskes, Relationships between bone morphology and bone elastic properties can be accurately quantified using high-resolution computer reconstructions, J. Orthop. Res. 16 (1) (1998) 23–28. 30. P.K. Zysset, M. Sonny, W.C. Hayes, Morphology-mechanical property relations in trabecular bone of the osteoarthritic proximal tibia, J. Arthrop. 9 (2) (1994) 203–216.
562
Osteoporosis in Men
31. G. Bevill, S.K. Eswaran, A. Gupta, P. Papadopoulos, T.M. Keaveny, Influence of bone volume fraction and architecture on computed large-deformation failure mechanisms in human trabecular bone, Bone 39 (6) (2006) 1218–1225. 32. F.J. Hou, S.M. Lang, S.J. Hoshaw, D.A. Reimann, D.P. Fyhrie, Human vertebral body apparent and hard tissue stiffness, J. Biomech. 31 (11) (1998) 1009–1015. 33. A.J. Ladd, J.H. Kinney, D.L. Haupt, S.A. Goldstein, Finiteelement modeling of trabecular bone: comparison with mechanical testing and determination of tissue modulus, J. Orthop. Res. 16 (5) (1998) 622–628. 34. G.L. Niebur, M.J. Feldstein, J.C. Yuen, T.J. Chen, T.M. Keaveny, High-resolution finite element models with tissue strength asymmetry accurately predict failure of trabecular bone, J. Biomech. 33 (12) (2000) 1575–1583. 35. S. Banerjee, S. Choudhury, E.T. Han, et al., Autocalibrating parallel imaging of in vivo trabecular bone microarchitecture at 3 Tesla, Magn. Reson. Med. 56 (5) (2006) 1075–1084. 36. S. Anumula, J. Magland, H.H. Ong, et al., Measurement of phosphorus content in normal and osteo-malacic rabbit bone by solid-state 3D radial imaging. ISMRM 14th Scientific Meeting, p 590, 2006. ISMRM, Seattle. 37. Y. Wu, J.L. Ackerman, H.M. Kim, C. Rey, A. Barroug, M.J. Glimcher, Nuclear magnetic resonance spin-spin relaxation of the crystals of bone, dental enamel, and synthetic hydroxyapatites, J. Bone Miner. Res. 17 (3) (2002) 472–480. 38. A. Laib, P. Ruegsegger, Calibration of trabecular bone structure measurements of in vivo three-dimensional peripheral quantitative computed tomography with 28-microm-resolution microcomputed tomography, Bone 24 (1) (1999) 35–39. 39. S. Boutroy, M.L. Bouxsein, F. Munoz, P.D. Delmas, In vivo assessment of trabecular bone microarchitecture by highresolution peripheral quantitative computed tomography, J. Clin. Endocrinol. Metab. 90 (12) (2005) 6508–6515. 40. R. Krug, J. Carballido-Gamio, A.J. Burghardt, et al., Assessment of trabecular bone structure comparing magnetic resonance imaging at 3 Tesla with high-resolution peripheral quantitative computed tomography ex vivo and in vivo, Osteoporos. Int. 19 (5) (2008) 653–661. 41. J.A. Macneil, S.K. Boyd, Accuracy of high-resolution peripheral quantitative computed tomography for measurement of bone quality, Med. Eng. Phys. 29 (10) (2007) 1096–1105. 42. J.A. MacNeil, S.K. Boyd, Load distribution and the predictive power of morphological indices in the distal radius and tibia by high resolution peripheral quantitative computed tomography, Bone 41 (1) (2007) 129–137. 43. X.H. Zhang, X.S. Liu, B. Vasilic, et al., In vivo microMRIbased finite element and morphological analyses of tibial trabecular bone in eugonadal and hypogonadal men before and after testosterone treatment, J. Bone Miner. Res. 23 (9) (2008) 1426–1434. 44. M. Ding, I. Hvid, Quantification of age-related changes in the structure model type and trabecular thickness of human tibial cancellous bone, Bone 26 (3) (2000) 291–295. 45. A. Laib, J.L. Kumer, S. Majumdar, N.E. Lane, The temporal changes of trabecular architecture in ovariectomized rats assessed by MicroCT, Osteoporos. Int. 12 (11) (2001) 936–941. 46. X.S. Liu, P. Sajda, P.K. Saha, et al., Complete volumetric decomposition of individual trabecular plates and rods and its morphological correlations with anisotropic elastic moduli
47.
48.
49.
50.
51.
52.
53.
54.
55.
56.
57.
58.
59.
60.
61.
in human trabecular bone, J. Bone Miner. Res. 23 (2) (2008) 223–235. M. Stauber, R. Muller, Volumetric spatial decomposition of trabecular bone into rods and plates – a new method for local bone morphometry, Bone 38 (4) (2006) 475–484. M. Stauber, L. Rapillard, G.H. van Lenthe, P. Zysset, R. Muller, Importance of individual rods and plates in the assessment of bone quality and their contribution to bone stiffness, J. Bone Miner. Res. 21 (4) (2006) 586–595. X.S. Liu, G. Bevill, T.M. Keaveny, P. Sajda, X.E. Guo, Micromechanical analyses of vertebral trabecular bone based on individual trabeculae segmentation of plates and rods, J. Biomech. 42 (3) (2009) 249–256. X.S. Liu, X.H. Zhang, X.E. Guo, Contributions of trabecular rods of various orientations in determining the elastic properties of human vertebral trabecular bone, Bone (2009). E.M. Lewiecki, T.M. Keaveny, D.L. Kopperdahl, et al., Once-monthly oral ibandronate improves biomechanical determinants of bone strength in women with postmenopausal osteoporosis, J. Clin. Endocrinol. Metab. 94 (1) (2009) 171–180. J.S. Bauer, T.M. Link, A. Burghardt, et al., Analysis of trabecular bone structure with multidetector spiral computed tomography in a simulated soft-tissue environment, Calcif. Tissue Int. 80 (6) (2007) 366–373. G. Diederichs, T.M. Link, M. Kentenich, et al., Assessment of trabecular bone structure of the calcaneus using multi-detector CT: correlation with microCT and biomechanical testing, Bone 44 (5) (2009) 976–983. G. Diederichs, T. Link, K. Marie, et al., Feasibility of measuring trabecular bone structure of the proximal femur using 64slice multidetector computed tomography in a clinical setting, Calcif. Tissue Int. 83 (5) (2008) 332–341. A. Krebs, C. Graeff, I. Frieling, et al., High resolution computed tomography of the vertebrae yields accurate information on trabecular distances if processed by 3D fuzzy segmentation approaches, Bone 44 (1) (2009) 145–152. P.J. Thurner, P. Wyss, R. Voide, et al., Time-lapsed investigation of three-dimensional failure and damage accumulation in trabecular bone using synchrotron light, Bone 39 (2) (2006) 289–299. T. Hildebrand, A. Laib, R. Muller, J. Dequeker, P. Ruegsegger, Direct three-dimensional morphometric analysis of human cancellous bone: microstructural data from spine, femur, iliac crest, and calcaneus, J. Bone Miner. Res. 14 (7) (1999) 1167–1174. T. Hildebrand, P. Ruegsegger, Quantification of bone microarchitecture with the structure model index, Comput. Methods Biomech. Biomed. Engin. 1 (1) (1997) 15–23. T. Hildebrand, P. Ruegsegger, A new method for the modelindependent assessment of thickness in three-dimensional images, J. Microsc. 185 (1997) 67–75. A. Laib, D.C. Newitt, Y. Lu, S. Majumdar, New modelindependent measures of trabecular bone structure applied to in vivo high-resolution MR images, Osteoporos. Int. 13 (2) (2002) 130–136. A.M. Parfitt, C.H. Mathews, A.R. Villanueva, M. Kleerekoper, B. Frame, D.S. Rao, Relationships between surface, volume, and thickness of iliac trabecular bone in aging and in osteoporosis. Implications for the microanatomic and cellular mechanisms of bone loss, J. Clin. Invest. 72 (4) (1983) 1396–1409.
C h a p t e r 4 5 Advanced Structural Assessment of Bone Using CT and MRI l
62. L.A. Feldkamp, S.A. Goldstein, A.M. Parfitt, G. Jesion, M. Kleerekoper, The direct examination of three-dimensional bone architecture in vitro by computed tomography, J. Bone Miner. Res. 4 (1) (1989) 3–11. 63. J.H. Kinney, A.J. Ladd, The relationship between threedimensional connectivity and the elastic properties of trabecular bone, J. Bone Miner. Res. 13 (5) (1998) 839–845. 64. A. Odgaard, Three-dimensional methods for quantification of cancellous bone architecture, Bone 20 (4) (1997) 315–328. 65. J. Kabel, B. van Rietbergen, A. Odgaard, R. Huiskes, Constitutive relationships of fabric, density, and elastic properties in cancellous bone architecture, Bone 25 (4) (1999) 481–486. 66. A. Odgaard, E.B. Jensen, H.J. Gundersen, Estimation of structural anisotropy based on volume orientation, J. Microsc. 157 (Pt 2) (1990) 149–162 A new concept. 67. A. Odgaard, J. Kabel, B. van Rietbergen, M. Dalstra, R. Huiskes, Fabric and elastic principal directions of cancellous bone are closely related, J. Biomech. 30 (5) (1997) 487–495. 68. F. Eckstein, M. Matsuura, V. Kuhn, et al., Sex differences of human trabecular bone microstructure in aging are sitedependent, J. Bone Miner. Res. 22 (6) (2007) 817–824. 69. L. Mosekilde, Age-related changes in vertebral trabecular bone architecture – assessed by a new method, Bone 9 (4) (1988) 247–250. 70. L. Mosekilde, Aging of bone, Rev. Clin. Gerontol. 8 (1998) 281–296. 71. S. Khosla, B.L. Riggs, E.J. Atkinson, et al., Effects of sex and age on bone microstructure at the ultradistal radius: a population-based noninvasive in vivo assessment, J. Bone Miner. Res. 21 (1) (2006) 124–131. 72. A. Laib, H.J. Hauselmann, P. Ruegsegger, In vivo high resolution 3D-QCT of the human forearm, Technol. Health Care 6 (5-6) (1998) 329–337. 73. H.K. Genant, T.F. Lang, Engelke K Advances in the noninvasive assessment of bone density, quality, and structure, Calcif. Tissue Int. 59 (Suppl. 1) (1996) S10–S15. 74. G. Guglielmi, P. Schneider, T.F. Lang, G.M. Giannatempo, M. Cammisa, H.K. Genant, Quantitative computed tomography at the axial and peripheral skeleton, Eur. Radiol. 7 (10) (1997) 32–42. 75. P. Augat, C.L. Gordon, T.F. Lang, H. Iida, H.K. Genant, Accuracy of cortical and trabecular bone measurements with peripheral quantitative computed tomography (pQCT), Phys. Med. Biol. 43 (10) (1998) 2873–2883. 76. R. Muller, T. Hildebrand, P. Ruegsegger, Non-invasive bone biopsy: a new method to analyse and display the threedimensional structure of trabecular bone, Phys. Med. Biol. 39 (1) (1994) 145–164. 77. E. Sornay-Rendu, S. Boutroy, F. Munoz, P.D. Delmas, Alterations of cortical and trabecular architecture are associated with fractures in postmenopausal women, partially independent of decreased BMD measured by DXA: the OFELY study, J. Bone Miner. Res. 22 (3) (2007) 425–433. 78. X.S. Liu, P.T. Yin, X.H. Zhang, et al., HR-pQCT and individual trabeculae segmentation based morphological analyses can detect abnormal trabecular microstructure in premenopausal women with idiopathic osteoporosis, Trans. Orthop. Res. Soc. 34 (2009) 430.
563
79. F.W. Wehrli, P.K. Saha, B.R. Gomberg, S. Hee Kwon, Noninvasive assessment of bone architecture by magnetic resonance micro-imaging-based virtual bone biopsy, Proc. IEEE 91 (10) (2003) 1520–1542. 80. F.W. Wehrli, S.N. Hwang, J. Ma, H.K. Song, J.C. Ford, J.G. Haddad, Cancellous bone volume and structure in the forearm: noninvasive assessment with MR microimaging and image processing, Radiology 206 (2) (1998) 347–357. 81. F.W. Wehrli, Structural and functional assessment of trabecular and cortical bone by micro magnetic resonance imaging, J. Magn. Reson. Imaging 25 (2) (2007) 390–409. 82. M. Benito, B. Vasilic, F.W. Wehrli, et al., Effect of testosterone replacement on trabecular architecture in hypogonadal men, J. Bone Miner. Res. 20 (10) (2005) 1785–1791. 83. M. Benito, B. Gomberg, F.W. Wehrli, et al., Deterioration of trabecular architecture in hypogonadal men, J. Clin. Endocrinol. Metab. 88 (4) (2003) 1497–1502. 84. F.W. Wehrli, P.K. Saha, B.R. Gomberg, et al., Role of magnetic resonance for assessing structure and function of trabecular bone, Top. Magn. Reson. Imaging 13 (5) (2002) 335–355. 85. L. Pothuaud, D.C. Newitt, Y. Lu, B. MacDonald, S. Majumdar, In vivo application of 3D-line skeleton graph analysis (LSGA) technique with high-resolution magnetic resonance imaging of trabecular bone structure, Osteoporos. Int. 15 (5) (2004) 411–419. 86. C.M. Phan, M. Matsuura, J.S. Bauer, et al., Trabecular bone structure of the calcaneus: comparison of MR imaging at 3.0 and 1.5 T with micro-CT as the standard of reference, Radiology 239 (2) (2006) 488–496. 87. T.M. Link, Saborowski, K. Kisters, et al., Changes in calcaneal trabecular bone structure assessed with high-resolution MR imaging in patients with kidney transplantation, Osteoporos. Int. 13 (2) (2002) 119–129. 88. S. Majumdar, D. Newitt, A. Mathur, et al., Magnetic resonance imaging of trabecular bone structure in the distal radius: relationship with X-ray tomographic microscopy and biomechanics, Osteoporos. Int. 6 (5) (1996) 376–385. 89. J.C. Lin, M. Amling, D.C. Newitt, et al., Heterogeneity of trabecular bone structure in the calcaneus using magnetic resonance imaging, Osteoporos. Int. 8 (1) (1998) 16–24. 90. R. Krug, S. Banerjee, E.T. Han, D.C. Newitt, T.M. Link, S. Majumdar, Feasibility of in vivo structural analysis of high-resolution magnetic resonance images of the proximal femur, Osteoporos. Int. 16 (11) (2005) 1307–1314. 91. D.C. Newitt, S. Majumdar, B. van Rietbergen, et al., In vivo assessment of architecture and micro-finite element analysis derived indices of mechanical properties of trabecular bone in the radius, Osteoporos. Int. 13 (1) (2002) 6–17. 92. D.C. Newitt, B. van Rietbergen, S. Majumdar, Processing and analysis of in vivo high-resolution MR images of trabecular bone for longitudinal studies: reproducibility of structural measures and micro-finite element analysis derived mechanical properties, Osteoporos. Int. 13 (4) (2002) 278–287. 93. S. Majumdar, M. Kothari, P. Augat, et al., High-resolution magnetic resonance imaging: three-dimensional trabecular bone architecture and biomechanical properties, Bone 22 (5) (1998) 445–454. 94. P.K. Saha, B.B. Chaudhuri, Detection of 3-D simple points for topology preserving, IEEE Trans. Pattern Anal. Mach. Intell. 16 (10) (1994) 1028–1032.
564
Osteoporosis in Men
95. P.K. Saha, B.B. Chaudhuri, 3D digital topology under binary transformation with applications, Comput. Vis. Image Underst. 63 (3) (1996) 418–429. 96. P.K. Saha, B.B. Chaudhuri, D.D. Majumder, A new shape preserving parallel thinning algorithm for 3D digital images, Pattern Recogn. 30 (12) (1997) 1939–1955. 97. G.A. Ladinsky, B. Vasilic, A.M. Popescu, et al., Trabecular structure quantified with the MRI-based virtual bone biopsy in postmenopausal women contributes to vertebral deformity burden independent of areal vertebral BMD, J. Bone Miner. Res. 23 (1) (2008) 64–74. 98. F.W. Wehrli, G.A. Ladinsky, C. Jones, et al., In vivo magnetic resonance detects rapid remodeling changes in the topology of the trabecular bone network after menopause and the protective effect of estradiol, J. Bone Miner. Res. 23 (5) (2008) 730–740. 99. Y. Chevalier, D. Pahr, H. Allmer, M. Charlebois, P. Zysset, Validation of a voxel-based FE method for prediction of the uniaxial apparent modulus of human trabecular bone using macroscopic mechanical tests and nanoindentation, J. Biomech. 40 (15) (2007) 3333–3340. 100. T.M. Keaveny, E.F. Morgan, G.L. Niebur, O.C. Yeh, Biomechanics of trabecular bone, Annu. Rev. Biomed. Eng. 3 (2001) 307–333. 101. R.P. Crawford, C.E. Cann, T.M. Keaveny, Finite element models predict in vitro vertebral body compressive strength better than quantitative computed tomography, Bone 33 (4) (2003) 744–750. 102. J.H. Keyak, Improved prediction of proximal femoral fracture load using nonlinear finite element models, Med. Eng. Phys. 23 (3) (2001) 165–173.
103. T.M. Keaveny, D.W. Donley, P.F. Hoffmann, B.H. Mitlak, E. V. Glass, J.A. San Martin, Effects of teriparatide and alendronate on vertebral strength as assessed by finite element modeling of QCT scans in women with osteoporosis, J. Bone Miner. Res. 22 (1) (2007) 149–157. 104. T.M. Keaveny, P.F. Hoffmann, M. Singh, et al., Femoral bone strength and its relation to cortical and trabecular changes after treatment with PTH, alendronate, and their combination as assessed by finite element analysis of quantitative CT scans, J. Bone Miner. Res. 23 (12) (2008) 1974–1982. 105. E.S. Orwoll, L.M. Marshall, C.M. Nielson, et al., Finite element analysis of the proximal femur and hip fracture risk in older men, J. Bone Miner. Res. 24 (3) (2009) 475–483. 106. C. Graeff, Y. Chevalier, M. Charlebois, et al., Improvements in vertebral body strength under teriparatide treatment assessed in vivo by finite element analysis: results from the EUROFORS Study, J. Bone Miner. Res. 24 (10) (2009) 1672–1680. 107. G.L. Niebur, J.C. Yuen, A.J. Burghardt, T.M. Keaveny, Sensitivity of damage predictions to tissue level yield properties and apparent loading conditions, J. Biomech. 34 (5) (2001) 699–706. 108. G.L. Niebur, M.J. Feldstein, T.M. Keaveny, Biaxial failure behavior of bovine tibial trabecular bone, J. Biomech. Eng. 124 (6) (2002) 699–705. 109. C.H. Kim, X.H. Zhang, G. Mikhail, et al., Effects of thresholding techniques on microCT-based finite element models of trabecular bone, J. Biomech. Eng. 129 (4) (2007) 481–486. 110. J.A. Macneil, S.K. Boyd, Bone strength at the distal radius can be estimated from high-resolution peripheral quantitative computed tomography and the finite element method, Bone 42 (6) (2008) 1203–1213.
Chapter
46
Diagnostic Approach: Vertebral Fracture Assessments Piet Geusens1 and Willem Lems2 1
Department of Internal Medicine, Subdivision of Rheumatology, Maastricht University Medical Center, Maastricht, The Netherlands; Biomedical Research institute, University Hasselt, Belgium 2 Department of Rheumatology, Vrije Universiteit Amsterdam; VU Medisch Centrum, afd. Reumatologie 3A64, Amsterdam, The Netherlands
Introduction
clinical applicability of spine imaging for diagnosing VFs. We report on available data in men but, for some technical aspects of assessments, we specify when data are only available in women.
Vertebral fractures (VF) are a special group of fractures, both in men and in women. On the one hand, diagnosis of VF is a challenge in epidemiologic studies and in clinical practice as most VF do not present with the acute signs and symptoms of a fracture (so-called ‘silent’ VF or deformations) [1] and are under-diagnosed [2]. On the other hand, the prevalence and incidence of morphometric VF in men increases with age and VFs, whether clinical or silent, are associated with increased morbidity [3–5], increased mortality [6] and increased risk of subsequent vertebral and non-vertebral fractures [6, 7–9]. Identifying VF is clinically relevant. It provides a means to identify patients who have a high subsequent fracture risk, independent of other risks, and helps to identify patients who are likely to benefit most from drug treatment to reduce subsequent fracture risk [1, 2]. The standard approach for assessment of VF is a lateral radiographic view of the vertebrae, but VF can now also be diagnosed using dual-energy photon absorptiometry (DXA) [2]. However, even when optimal x-rays are available, many VF are missed [10, 11]. The assessment of VF is hampered by the lack of a gold standard for the definition of a VF, which varies between studies in the literature [2]. When an abnormality in the shape or deformation of a vertebra is found, the question arises to what degree this indicates the presence of a true osteoporosis-related fracture or whether it is the result of normal variations in vertebral height or other conditions [2]. We review the clinical relevance of recognizing VF, the methods to measure VF (with emphasis on x-ray and DXA), the definitions of VF, differential diagnosis and the
Osteoporosis in Men
Problems associated with identification of prevalent and incident VF The clinical expression of osteoporosis is the occurrence of a fracture. Almost all non-spine fractures are the result of a trauma and cause pain and loss of function that brings patients under immediate medical attention and allows doctors to diagnose the fracture. In contrast, diagnosing VF requires imaging of the spine as most VF do not present with the acute signs and symptoms of a fracture [2] and are not related to trauma [12], which results in under-diagnosis of VF [13]. Another problem is that the methods used for diagnosing VF remain an ongoing subject of debate and vary between studies [2]. Using quantitative morphometry (QM), changes in vertebral shape and deformities are described as mild, moderate or severe fractures based on percent deformity without need for a control population, or compared to controls in standard deviations (SD). However, QM is cumbersome to apply indiscriminately to all vertebrae in clinical practice [14–17] and pure QM is associated with false positive (in the case of non-fracture deformity) and false negative results (such as subtle endplate depressions) [2]. Consequently, some combination of visual inspection (semiquantitative (SQ) approach) and quantification of vertebral heights is considered necessary for
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diagnosis, but criteria for visual inspection also vary between studies [18–20]. Clinically silent VF are often missed, even when x-rays of the spine are available [10, 11]. Their clinical significance can be considered lower in the context of severe co-morbidity with bad prognosis or because deformities are considered to be mild and not clinically relevant [2]. However, it is becoming more and more clear that a vertebral deformity is an independent risk factor of both future vertebral and non-vertebral fractures [1, 2].
Why are vertebral fractures relevant in men? Recognizing VF in men is clinically relevant because of their high prevalence and clinical consequences. First, clinical and radiographic VF represent a substantial proportion of all fractures in men and the prevalence and incidence increases with age at about one-third to one-half as compared to women [21, 22], but varies according to definitions of VF [2]. In the European Vertebral Osteoporosis Study (EVOS), the agestandardized prevalence of vertebral deformity was estimated to be the same for both men and women, either 12 or 20%, depending on the criteria used to define vertebral deformity [21]. However, below age 65 years, men had a higher prevalence of vertebral deformity than women whereas, after this age, the trend was reversed [21]. In both men and women, the prevalence of vertebral deformity increased with age, although the increase was greater in women after age 65 years [21]. In the European Prospective Osteoporosis Study (EPOS) study, incident VF (20% change/ 4 mm of any vertebral height and with a deformity of at least 3 SD) was similar between men and women of 55–59 years and increased with age, more so in women than in men [22]. In the Canadian Multicenter Osteoporosis Study (CaMos) cohort, 22% of men had quantitative (Q) VF of 3 SD and 7% of 4 SD [23]. In the French MINOS study of men between 51 and 85 years, 23% of men had any VF of 20%, 16% had a VF of 25% and 8% had a VF of 30% at T6–T9 or 25% at other levels [24]. In healthy Moroccan men, previously undiagnosed SQ VF have been reported in 16% for mild and in 14% for moderate/severe VF [25]. In that study, the prevalence of mild and moderate/severe VF was 16% and 14%, respectively, in men with osteopenia, as compared to 62% and 38%, respectively, in men with osteoporosis [25]. SQ VF were found in 25% of women and men presenting with a clinical non-spine fracture, of which 73% were moderate/ severe [26] and in 32% of men referred for densitometry without history of clinical fractures [27]. In men with a hip fracture, the odds ratio for a Q VF (3 SD) was 3.6 (CI: 1.9–6.6) [28]. In that study the prevalence of Q VF (3 SD) in men older than 60 years varied between 59 and 79% in hip fracture patients as compared to 14 to 62% in controls, depending on age. Thus, a substantial proportion of men
have a previously unknown VF, even if only moderate/severe fractures are considered [29–31]. Second, VF are associated with increased morbidity. An SQ VF of 20% in men is associated with lower energy, poorer sleep, pain, immobility and social isolation [3]. Severe vertebral deformities are related to functional impairment and negative health outcomes, particularly in men [4, 5]. Third, in men between 50 and 80 years, Q VF (3 SD) are associated with a more than doubling the risk of mortality during a 10-year follow up [6], but not at short-term during a mean of 2.1 years [7]. The increase in mortality was related to co-morbidities, such as cardiovascular and pulmonary diseases. In men older than 60 years in the Dubbo study, the presence of a Q VF (3 SD) was associated with a fivefold increased mortality over 4 years of follow up [32]. Fourth, VF in men increase the risk of subsequent fractures, independent of BMD and clinical risk factors [6–9, 33]. In a population-based study in the USA in men, the presence of a prevalent clinical VF confers a significant fourfold increased risk for any subsequent fractures, a fivefold increase of subsequent hip and a 33-fold increase (95% CI: 24–43) of subsequent clinical VF [8, 34]. In the EVOS study, SQ VF (3 SD) increased by threefold the risk of any subsequent fracture, but not for subsequent osteoporotic fractures [9]. A Q VF (3 SD) was associated with a hazard ratio of 5.0 for any subsequent fracture and of 5.5 for new Q VF (3 SD) [32]. In women and men in the EPOS study, the incidence of VF (change of 20%/4 mm) was dependent on baseline number and severity of Q VF, but results in men were not reported separately [35]. Q VF status (3 SD) along with age and BMD predicted future fracture risk in men (as well as in women) with greater simplicity and higher prognostic accuracy than consideration of the risk factors included in FRAX [31]. After a clinical fracture, subsequent clinical fractures cluster in time, i.e. the risk for subsequent clinical fractures, is much higher in the short term than in the long term [36–39]. This has been shown for repeat clinical fractures in a population of postmenopausal women in general practices [37], in women and men older than 50 years presenting at an emergency unit with a clinical fracture [38] (both studies in the Netherlands) and in men in the Dubbo study in Australia [39]. In a large survey of 10 405 men hospitalized because of a clinical VF in Sweden, the risk ratio for a subsequent clinical fracture (spine, hip, forearm or humerus) was highest immediately (1–2 years) after the clinical VF and remained increased but at a lower level during an 8-year follow up [34]. The risk ratio at short term (within 6 months) and long term (within 4 years) was particularly high in the young (50–60 years). The risk ratio was twofold higher following low-energy trauma than in the case of highenergy trauma [35]. In view of clustering of fractures in time, especially after clinical fractures, men presenting with a VF should have immediate clinical attention to prevent subsequent fractures [38].
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Establish the presence of VF: when is a deformity a true osteoporotic fracture? The interpretation of the radiographic appearance of vertebrae on lateral spine images is challenging and controversial as the distinction between physiological and pathological vertebral height loss is not always clear [2]. As a result, there is no current ‘gold standard’ for the definition of a vertebral fracture. The International Society for Clinical Densitometry (ISCD) therefore recommends a three-step process, combining visual, SQ and, if needed, requires a meticulous approach by an experienced reader [40]. First, by visual inspection one has to decide whether the size and shape of a vertebra is normal. Several algorithms have been developed to discriminate normal from abnormal shapes, taking into account the wide range in intra- and inter-individual variation of vertebral shape (see below). Next, images should be checked for radiographic signs that can give information about associated conditions that would suggest that the deformity is the result of processes other than bone loss (e.g. infection or neoplasm) and conditions that could interfere with projection or measurements (Table 46.1). Lastly, the type and severity of VF should be described and QM measurement may be used to confirm and/or document the severity of deformity. In the clinical context (e.g. in the differential diagnosis of metastatic bone disease or to decide about pain treatment by vertebroplasty or kyphoplasty), other techniques (nuclear bone scanning, CT and MRI) may be needed to evaluate whether the VF is recent or associated with metastatic bone disease [2, 41].
Table 46.1 Situations in which vertebral deformities are reported not to be related to osteoporotic VF or to interfere with appropriate interpretation of changes in vertebral shape [2, 39, 40] Scheurmann’s disease Mild or slightly wedged vertebrae without endplate impression in the mid-thoracic region Osteoarthritis with osteophytes or with wedging without endplate impression Traumatic VF Developmental abnormalities, such as balloon disks Short vertebral height Deformation due to metabolic disorders, such as osteomalacia ‘Step-like’ endplates A deep inferior endplate A Cupid’s bow appearance of the endplate Suspicion of bone metastasis Problems with imaging: upper thoracic image quality, scoliosis, inappropriate patient positioning, surgery artifacts
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Imaging approaches for the identification of VF Plain Radiography (x-Ray) The standard imaging approach for assessment of vertebral fracture is radiography of the thoracolumbar spine, with lateral views to evaluate the shape and, eventually, additional anteroposterior (AP) views to exclude other abnormalities that can affect vertebral shape (Figure 46.1) [2, 29, 41]. X-rays provide high resolution of detail. On the other hand, x-rays magnify the real size of the vertebrae and are associated with obliquity of the vertebral body images which increases with the distance from the x-ray plate and from the vertebra on which the x-ray is focused [2]. The effective irradiation dose for a lateral lumbar spine x-ray is 600 Sv [2], which is lower than CT.
VF Assessment (VFA) by Dual-Energy Absorptiometry (DXA) Vertebral appearance and shape can also be evaluated on digitized lateral spine images generated by dual-energy x-ray absorptiometry (DXA) (Figures 46.1, 46.2). In the literature, this method has been described as morphometric x-ray absorptiometry (MXA), x-ray absorptiometry (XA), vertebral x-ray absorptiometry (VXA), instant vertebral assessment (IVA), lateral vertebral assessment (LVA) and dual-energy vertebral assessment [2, 40]. Due to the multiplicity of acronyms, the International Society for Clinical Densitometry (ISCD) has established the standard term of ‘vertebral fracture assessment’ (VFA) to denote densitometric spine imaging for the purpose of identifying VFs with any brand of densitometer [2, 40]. The lateral spine images can be captured onsite at the time that the patient has a measurement of bone density of spine and hip by DXA. Fan-beam generated images with either single- or dual-energy mode give plan-parallel height projections and thus reflect the real heights of the vertebrae at any level. Due to overlying ribs and vascular structures, image resolution is not as good as with x-ray, especially above the T7 level [44]. The low sensitivity for vertebral deformities in the upper thoracic spine is clinically less relevant, since the majority of osteoporotic fractures occur between T7 and L3 [6, 45]. With recent improvements in image quality for x-ray absorptiometry, preliminary studies indicate promising results on visual assessment of the scan images [46–49]. Because the low effective irradiation is 3 Sv [50] and measurement time is short, VFA may be useful for routine screening of patients referred for bone density assessments or for monitoring of patients on therapy. VFA can be particularly useful in patients with osteopenia, since the presence or absence of a vertebral deformity results in a start (or not) of anti-osteoporotic drugs. Recently, it has been
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Figure 46.1 Plain radiography and vertebral fracture assessment by DXA.
Figure 46.2 Example of layout of VFA image for quantitative morphometry.
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shown that a vertebral deformity can be detected in 20% of women with osteopenia [51]. In men with VF referred for bone densitometry, 31% of those with osteopenia had a previously undiagnosed SQ VF, most of which were moderate/ severe [27]. The additional value of a vertebral deformity has no impact on the treatment decision in patients with osteoporosis [40]. However, new VFs can occur even during appropriate drug treatment. The availability of a baseline VFA would then be helpful to decide whether a VF is new, which could lead to re-evaluation and eventual adaptation of alternative drug treatment.
Computed Tomography (CT), Magnetic Resonance Imaging (MRI) and Nuclear Bone Scanning CT scanning gives excellent image resolution but is less available, more costly, more inconvenient and involves greater radiation exposure than standard radiography. CT is helpful for the differential diagnosis of changes in vertebral shape, such as rheumatic spondylodiscitis in ankylosing spondylitis, metastatic bone disease or multiple myeloma [52]. MRI is helpful to determine if diseases other than osteoporosis may be responsible for the fracture (e.g. malignancy) and to estimate the time since the fracture occurred [53]. Recent VF are characterized by the presence of bone edema (Figure 46.3). Image resolution is excellent with MR and there is no ionizing radiation, but availability may be limited, the cost is high and patient inconvenience (e.g. scheduling, travel time, claustrophobia) may be an issue. Longitudinal slices of CT and MRI can be helpful to detect changes in the endplate that can be obscured on lateral X-rays (Figures 46.4, 46.5). Nuclear bone scanning can provide information about the age of the fracture and may show abnormalities that result from other skeletal disorders but has poor resolution, Radiography
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high cost, exposure to radiation and, sometimes, poor availability and high patient inconvenience [54]. It is important to realize that only the finding of a positive signal in the first phase of the nuclear bone scanning supports a vertebral fracture. If the chronic phase is positive, this can also be resulting from other conditions such as spondylarthrosis. MRI and nuclear bone scanning are helpful to identify other fractures than those of the vertebral bodies, such as fractures of the dorsal arch.
Strategies for VF Identification The ‘gold standard’ of vertebral fracture definition would be a standardized, reproducible approach that differentiates true osteoporotic fracture (or, in a broader context, bone failure-related fracture) from normal variation or nonfracture deformity, both on x-ray and VFA [2, 40]. However, of the established approaches, there is no one method that satisfies all of these criteria. Several strategies are available to evaluate the shapes of vertebrae and to interpret their clinical significance in the context of osteoporosis. Qualitative approach A pure qualitative approach to define the presence of a VF (with visual assessment without thresholds for height loss) allows an examiner to exclude erroneous variation of vertebral shape, but it is a pure subjective assessment with poor interobserver agreement and reproducibility [40, 41]. Quantitative Vertebral Morphometry (QM) Quantitative vertebral morphometry (QM) is performed by a six-point approach using a screen cursor on original x-rays by a hand-held device or using semiautomatic or automatic measurement computer guided devices on digitized images [56]. The six points correspond to the four MRI
CT
Figure 46.3 Multiple VF: MRI showing edema around the fractures, indicating recent VFs. Note that the lesions are more visible on CT and MRI.
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Figure 46.4 Endplate impressions. Note that the impressions are not visible on VFA, difficult to discern on radiography, but clearly visible on CT image.
Figure 46.5 Patient with ankylosing spondylitis shows a vertebral deformity with osteosclerosis and osteophyte on radiography. MRI clearly shows extensive erosive lesions at the endplates.
corners of the vertebral body and the mid-points of the endplates. From these points, anterior (AH), middle (MH) and posterior (PH) height are measured for each vertebra from T4 to L5; anterior–posterior ratio: AH/PH; middle–posterior ratio: MH/PH; posterior–posterior adjacent ratio: PH/PH1, PH/PH1. The results of measurements are then used in morphometric algorithms and compared to normative values from the literature. Several approaches have been proposed and tested to quantify the shapes of vertebrae [14–17, 41] and data are available in men from Eastell et al [15] and McCloskey et al [17]. Eastell et al’s algorithm [15] defines a VF if any of the ratios falls 3 SD below the vertebra-specific mean ratio in normal women. The algorithm developed by McCloskey et al [17] requires the fulfillment of two criteria to detect a vertebral fracture: a reduction in the ratios as described by Eastell et al as well as a reduction in the ratios calculated with the predicted posterior height. For a given vertebral level, the ‘mean predicted posterior height’ is calculated from the measured posterior height of four adjacent vertebrae in the patient under study and the mean posterior heights of the four adjacent vertebrae in normal individuals. For estimating the ‘mean predicted posterior height’ the
formulas described by McCloskey et al are used [17]. At each vertebral level, the mean predicted posterior height is used to determine the presence or absence of reduction of posterior, anterior and middle height in that order. After the most cephalic vertebra has been fully assessed, the algorithm then moves caudally, examining each vertebra in turn. Vertebrae with posterior height reduction lying above the vertebra under examination are excluded from the calculation of the mean predicted posterior heights. Pure QM is both objective and reproducible [41]. However, it lacks specificity for osteoporotic VF. It does not take into account other reasons for deformities. A vertebral deformity identified quantitatively may therefore represent true fracture, but may equally represent a non-fracture deformity such as osteoarthritis, Scheuermann’s disease or other developmental abnormality [40, 41], resulting in increased risk of false-positive results. In the EVOS study, half of the VF identified by QM were classified by radiologists as non-fracture deformities [41]. This is particularly the case for mild deformities. In women, VF of 20% or more are related to subsequent fracture risk, independent of BMD, as are the number and severity of VF. In contrast, mild deformities are not related to low BMD [24] or fracture
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risk [22]. In men of the EVOS study, all VF of 3 SD at the anterior, mid- or posterior height (alone or combination) were related to low BMD in the spine, except for anterior and posterior deformities of 3 SD with no deformation at the midpoint [42]. Moderate and severe Q VF of 30% decrease in vertebral height in T6–T9 and of 25% at other levels were related to low BMD, while mild VF were not [24]. Prevalent VF (3 SD) were related to low BMD, but less in men than in women [43]. It is also unclear to what degree mild deformities may represent ‘gradual’ fractures, a concept that still is controversial [41]. A disadvantage of QM is that the threshold cannot be used easily in clinical practice. The necessary algorithm is available on some DXA devices, with automatic reporting once the vertebrae are measured. Several other factors limit the use of QM. Vertebral dimensions vary among populations from different countries [57] and between men and women [58] and vertebral heights measured by densitometric methods differ from those measured from conventional radiographs because of magnification and obliquity [2]. Semiquantitative Morphometry (SQ) SQ combines QM with visual assessment. Visual inspection of the spine images has the advantage that deformities that are unrelated to vertebral fracture can be ruled out by an expert reader. The SQ evaluation is based on the SQ grading scheme devised by Genant et al [18]. Identification of a prevalent vertebral fracture by SQ is based on the appearance of apparent reduction in vertebral body height and the identification of radiological characteristics of fracture at the vertebral endplate. It also takes into account changes at the cortical margin. A mild grade 1 deformity is defined by an approximately 20–25% reduction in anterior, middle (compared to posterior) and/or posterior height and a 10–20% reduction in area; a moderate grade 2 deformity is defined by a 25–40% reduction in any height and a 20–40% reduction in area; and a severe grade 3 deformity is defined by a 40% reduction in any height and area. The Genant SQ methodology has been used successfully in clinical trials and clinical practice for many years [2, 40]. SQ techniques can be easily applied in clinical practice and have been validated by comparison with other methods [2]. The spinal deformity index (SDI) has recently been described as the sum of all of the SQ grades of vertebra T4 through L4 [59]. The SDI has been shown to have a monotonic association with the risk of subsequent vertebral and non-vertebral fractures in women [59], but no such study is available in men.
Algorithm-Based Qualitative Assessment of Vertebral Fracture (ABQ) Recently, a modified visual approach, known as algorithmbased qualitative assessment of vertebral fracture (ABQ), has been proposed as an alternative for the identification of
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prevalent vertebral fractures [19]. The ABQ method differs from the SQ method in two ways. First, ABQ focuses on depression of the central endplate and is based on the earlier finding that incident VF always demonstrated radiographic evidence of change at the vertebral endplate [19, 60] (see Figure 46.4). Secondly, the ABQ method introduces the concept of differential diagnosis of short vertebral height, introduced by Ferrar et al [41] and which refers to the finding that some adults have vertebrae that exhibit longstanding short anterior height in developmentally small vertebrae [2, 40, 41]. The ABQ algorithm uses a decision-making algorithm with three outcomes for classification of the vertebral appearances: normal, non-fracture deformity (or variation in vertebral shape due to other causes) and osteoporotic fracture. The pathway for non-fracture deformity includes visual inspection and criteria for the differential diagnosis. ABQ is reliable in women [60]. VFs defined by ABQ are related to low BMD in men [61].
Comparisons Between Algorithms for Diagnosing and Grading VF Between SQ and ABQ In the MrOS study, the agreement between SQ and ABQ was only moderate (kappa: 0.58) [61]. Agreement was poor for diagnosis of mild fractures (kappa: 0.36), but was excellent for diagnosis of moderate to severe VF (kappa: 0.93). Discordance was mainly related to differential classification of mild thoracic deformities without endplate impression (Figure 46.6). Reasons for the diagnosis of non-osteoporotic VF by ABQ included Scheuermann’s disease (18%), normal variations (10%), traumatic/pathologic (30%), degenerative changes (5%), developmental variation (5%), Schmorl’s nodules and osyteophytes (3%), senile kyphosis (3%) and misclassification of normal vertebrae (20%) [41]. The definition of a traumatic VF is not well defined. They can be reported by the patient in the medical history, but self-reported fractures are not always reliable [62].
Between Standard Radiography and VFA Standard radiography and VFA differ in image quality, population differences, XR technique, magnification, obliquity and differences in derivation of a group of ‘normal’ vertebrae [63]. In the review of Ferrar et al (41), quantitative assessment of vertebral deformities from VFA has been shown to have moderate-to-good agreement with radiological assessment of spinal radiographs. The approach has been limited by problems associated with the quantitative methods in general, the relatively poor spatial resolution and the poor quality of some images at the higher thoracic vertebrae due to overlying ribs and vascular structures. The prevalence
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Figure 46.6 Mild wedging of mid-thoracic vertebrae without endplate impression.
and incidence of vertebral deformities vary according to the morphometric method and cut-points used and are also influenced by false-positive and false-negative identification of vertebral deformity arising from radiographic projection or marking error. The placement of middle height markers is particularly problematic when the divergent x-ray beam produces an oblique projection, giving the vertebral endplates an elliptical appearance.
Identification of Incident VF The identification of incident VF should take into account that images should be comparable and without differences in image magnification, repositioning errors and x-ray focal spot size that influence obliquity [2]. Incident fractures can be defined as a new deformation of a previously normal vertebra (a method most often used in clinical trials), any further reduction at the same endplate or new fractures at the opposite endplate (by ABQ) or a progression of one or more grades in the SQ method [41]. The least significant change in level of deformity has not been documented, but changes of 15% have been reported to predict the occurrence of new SQ VF within one year, at least in women [63]. For identification of incident vertebral deformities, the precision error for vertebral height measurements is greater in patients with established osteoporosis [65] and may be further increased when there is progression in a previous fracture [66].
Clinical Application of VF Assessments Indications for Imaging of t he Spine in the Context of Detecting VF In clinical practice, x-rays of the spine are part of the process of diagnosis and differential diagnosis of many spinal diseases, including vertebral fractures. In the context of diagnosing VF by radiography, no recommendations on clinical indications for radiographs of the spine were found in a recent upgraded guideline [67]. The clinical application of diagnosing VF using VFA was upgraded in 2007 by an international panel of experts from the USA and the EU within the ISCD [2, 40]. This official document reviews VFA and indicates a grading system on quality of evidence, level of recommendation and applicability. The ISCD suggests that imaging of the spine should (only) be considered when the results may influence clinical management. The ISCD panel indicates that the following indications may be appropriate for VFA in men: Men with low bone mass (osteopenia) by BMD criteria, plus one of the following:
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age 80 years or older historical height loss greater than 6 cm (2.4 in) prospective height loss greater than 3 cm (1.2 in) self-reported vertebral fracture (not previously documented) two or more of the following: age 70–79 years self-reported prior non-vertebral fracture historical height loss of 3–6 cm on pharmacologic androgen deprivation therapy or following orchiectomy l l l l
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chronic systemic diseases associated with increased risk of vertebral fractures (e.g. moderate to severe chronic obstructive pulmonary disease, seropositive rheumatoid arthritis, Crohn’s disease) men on chronic glucocorticoid therapy (equivalent to 5 mg or more of prednisone daily for 3 months or longer) men with osteoporosis by bone density criteria (total hip, femoral neck or lumbar spine T-score 2.5), if documentation of one or more vertebral fractures will alter clinical management.
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The ISCD advises that the Genant visual semiquantitative (SQ) method is the current clinical technique of choice for diagnosing vertebral fractures with VFA. The panel suggests additional spine imaging be performed following a VFA: two or more mild (grade 1) deformities without any moderate or severe (grade 2 or grade 3) deformities lesions in vertebrae that cannot be ascribed to benign causes vertebral deformities in a patient with a known history of a relevant malignancy. Indeed, VFA is designed to detect VFs and not other abnormalities [2, 39].
u nevaluable vertebrae, deformed vertebrae, whether or not the deformities are consistent with vertebral fracture and unexplained vertebral and extra-vertebral pathology [40]. Since the diagnosis and differential diagnosis of vertebral fracture requires special expertise, specific education in the interpretation of spine images is necessary. One educational course is available at the website of the International Osteoporosis Foundation (IOF) [72].
Additional areas for research The International Society for Clinical Densitometry suggests that several issues deserve further research: what is the prevalence of prevalent vertebral fracture on VFA in subsets of men defined by age, levels of BMD, use of glucocorticoids? how predictive are deformities consistent with prevalent vertebral fracture on VFA (as opposed to standard radiographs), endplate depression that does not result in at least 20% mid-vertebral height loss, spinal deformity index (SDI) and reduced anterior vertebral height without endplate depression, for subsequent vertebral and nonvertebral fractures? what is the impact of documentation of one or more vertebral fractures on physician and patient fracture prevention behavior?
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In addition, colitis ulcerosa, ankylosing spondylitis and sarcoidosis are potential indications for spine imaging, as these conditions are associated with an increased risk for VF in men [68–71]. Imaging of the spine is not indicated if the decision to start or continue pharmacological therapy for osteoporosis would not be influenced by finding vertebral fractures. As reimbursement of treatment with teriparatide and preotact by governmental organizations is dependent on prevalent and/or incident VF, VFA or other VF assessment may be necessary. A baseline VFA in patients starting with anti-resorptives would be helpful to diagnose incident VF during follow up.
Describing VF In publications that involve vertebral fracture detection, the imaging method (x-ray, VFA) and the algorithm utilized for VF identification should be specified [40]. Fracture diagnosis is a three-step process and should include: 1. visual evaluation 2. differential diagnosis of deformities (osteoporosis versus other reasons) 3. assessment of grade/severity. QM alone is not recommended because it is unreliable for differential diagnosis. The severity and number of VF may be determined using SQ assessment criteria developed by Genant et al [18]. The severity of deformity may be confirmed by morphometric measurement if desired. Caution is needed for concluding that mild deformities are VF, particularly when such deformities are observed in the thoracic spine [40]. The VFA report should comment on
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Conclusions Diagnosing VF requires expertise in interpreting changes in shape of vertebrae and should include SQ evaluation with visual examination, exclusion of non-fracture deformities or other pathologies and quantification of the deformity. Automatic image analysis programs can be helpful. Mild deformations, especially at the mid-thoracic regions, should be interpreted with caution. VFA is a low-cost, low-irradiation imaging technique that can be integrated in clinical practice at the time DXA is performed. Imaging of the spine allows the identification of men at high risk of subsequent vertebral and non-vertebral fractures, independent of BMD. Thus, imaging of the spine is helpful to identify high risk men in the absence of osteoporosis and in whom drug treatment could reduce the risk of fractures.
References 1. S. Khosla, S. Amin, E. Orwoll, Osteoporosis in men, End. Rev. 29 (4) (2008) 441–464. 2. E.M. Lewiecki, A.J. Laster, Clinical review: clinical applications of vertebral fracture assessment by dual-energy x-ray absorp tiometry, J. Clin. Endocrinol. Metab. 91 (11) (2006) 4215–4222. 3. A.C. Scane, R.M. Francis, A.M. Sutcliffe, M.J. Francis, D.J. Rawlings, C.L. Chapple, Case-control study of the pathogenesis and sequelae of symptomatic vertebral fractures in men, Osteoporos. Int. 9 (1999) 91–97.
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4. H. Burger, P.L.A. Van Daele, K. Grashuis, et al., Vertebral deformities and functional impairment in men and women, J. Bone Miner. Res. 12 (1997) 152–157. 5. C. Matthis, U. Weber, T.W. O’Neill, H. Raspe, Health impact associated with vertebral deformities: results from the European Vertebral Osteoporosis Study (EVOS), Osteoporos. Int. 8 (1998) 364–372. 6. R. Hasserius, M.K. Karlsson, B.E. Nilsson, I. Redlund-Johnell, O. Johnell, European Vertebral Osteoporosis Study Prevalent vertebral deformities predict increased mortality and increased fracture rate in both men and women: a 10-year populationbased study of 598 individuals from the Swedish cohort in the European Vertebral Osteoporosis Study, Osteoporos. Int. 14 (2003) 61–68. 7. A.A. Ismail, T.W. O’Neil, C. Cooper, et al., Mortality associated with vertebral deformity in men and women: results from the European Prospective Osteoporosis Study (EPOS), Osteoporos. Int. 8 (1998) 291–297. 8. L.J. Melton III, E.J. Atkinson, C. Cooper, W.M. O’Fallon, B.L. Riggs, Vertebral fractures predict subsequent fractures, Osteoporos. Int. 10 (1999) 214–221. 9. O. Johnell, J.A. Kanis, A. Oden, et al., Fracture risk following an osteoporotic fracture, Osteoporos. Int. 15 (2004) 175–179. 10. S.H. Gehlbach, C. Bigelow, M. Heimisdottir, S. May, M. Walker, J.R. Kirkwood, Recognition of vertebral fracture in a clinical setting, Osteoporos. Int. 11 (7) (2000) 577–582. 11. N. Kim, B.H. Rowe, G. Raymond, H. Jen, et al., Underreporting of vertebral fractures on routine chest radio graphy. Am. J. Roentgenol. 182 (2) (2004) 297–300. 12. B.Y. Jonsson, K. Siggeirsdottir, B. Mogensen, H. Sigvaldason, G. Sigursson, Fracture rate in a population-based sample of men in Reykjavik, Acta Orthop. Scand. 75 (2004) 195–200. 13. W.F. Lems, Clinical relevance of vertebral fractures, Ann. Rheum. Dis. 66 (1) (2007) 2–4. 14. L.J. Melton III, S.H. Kan, M.A. Frye, H.W. Wahner, W.M. O’Fallon, B.L. Riggs, Epidemiology of vertebral fractures in women, Am. J. Epidemiol. 129 (1989) 1000–1011. 15. R. Eastell, S.L. Cedel, H.W. Wahner, B.L. Riggs, L.J. Melton III, Classification of vertebral fractures, J. Bone Miner. Res. 6 (1991) 207–215. 16. H.W. Minne, G. Leidig, C. Wüster, et al., A newly developed spine deformity index (SDI) to quantitate vertebral crush fractures in patients with osteoporosis, Bone Miner. 3 (4) (1988) 335–349. 17. E.V. McCloskey, T.D. Spector, K.S. Eyres, et al., The assessment of vertebral deformity: a method for use in population studies and clinical trials, Osteoporos. Int. 3 (1993) 138–147. 18. H.K. Genant, C.Y. Wu, C. van Kuijk, M.C. Nevitt, Vertebral fracture assessment using a semiquantitative technique, J. Bone Miner. Res. 8 (1993) 1137–1148. 19. G. Jiang, R. Eastell, N.A. Barrington, L. Ferrar, Comparison of methods for the visual identification of prevalent vertebral fracture in osteoporosis, Osteoporos. Int. 11 (2004) 887–896. 20. D.M. Black, L. Palermo, M.C. Nevitt, et al., Comparison of methods for defining prevalent vertebral deformities: the Study of Osteoporotic Fractures, J. Bone Miner. Res. 10 (1995) 890–902. 21. T.W. O’Neill, D. Felsenberg, J. Varlow, C. Cooper, J.A. Kanis, A.J. Silman, The prevalence of vertebral deformity in European men and women: the European vertebral osteo porosis study, J. Bone Miner. Res. 11 (1996) 1010–1018.
22. D. Felsenberg, A.J. Silman, M. Lunt, et al., Incidence of vertebral fracture in Europe: results from the European Prospective Osteoporosis Study (EPOS), J. Bone Miner. Res. 17 (2002) 716–724. 23. S.A. Jackson, A. Tenenhouse, L. Robertson, Vertebral fracture definition from population-based data: preliminary results from the Canadian Multicenter Osteoporosis Study (CaMos), Osteoporos. Int. 11 (8) (2000) 680–687. 24. P. Szulc, F. Munoz, F. Marchand, P.D. Delmas, Semiquantitative evaluation of prevalent vertebral deformities in men and their relationship with osteoporosis: the MINOS study, Osteoporos. Int. 12 (4) (2001) 302–310. 25. A. El Maghraoui, A. Mounach, S. Gassim, M. Ghazi, Vertebral fracture assessment in healthy men: prevalence and risk factors, Bone 43 (3) (2008) 544–548. 26. S.J. Gallacher, A.P. Gallagher, C. McQuillian, P.J. Mitchell, T. Dixon, The prevalence of vertebral fracture amongst patients presenting with non-vertebral fractures, Osteoporos. Int. 18 (2) (2007) 185–192. 27. N. Vallarta-Ast, D. Krueger, C. Wrase, S. Agrawal, N. Binkley, An evaluation of densitometric vertebral fracture assessment in men, Osteoporos. Int. 18 (10) (2007) 1405–1410. 28. R. Hasserius, O. Johnell, B.E. Nilsson, et al., Hip fracture patients have more vertebral deformities than subjects in population-based studies, Bone 32 (2) (2003) 180–184. 29. S. Kaptoge, G. Armbrecht, D. Felsenberg, et al., Whom to treat? The contribution of vertebral X-rays to risk-based algorithms for fracture prediction. Results from the European Prospective Osteoporosis Study, Osteoporos. Int. 17 (9) (2006) 1369–1381. 30. S. Kaptoge, G. Armbrecht, D. Felsenberg, et al., EPOS Study Group. When should the doctor order a spine X-ray? Identifying vertebral fractures for osteoporosis care: results from the European Prospective Osteoporosis Study (EPOS), J. Bone Miner. Res. 19 (12) (2004) 1982–1993. 31. P. Chen, J.H. Krege, J.D. Adachi, et al., The CaMos Research Group. Vertebral fracture status and the World Health Organization (WHO) risk factors for predicting osteoporotic fracture risk, J. Bone Miner. Res. 24 (2009) 495–502. 32. C. Pongchaiyakul, N.D. Nguyen, G. Jones, J.R. Center, J.A. Eisman, T.V. Nguyen, Asymptomatic vertebral deformity as a major risk factor for subsequent fractures and mortality: a long-term prospective study, J. Bone Miner. Res. 20 (8) (2005) 1349–1355. 33. http://www.shef.ac.uk/FRAX/. Last visited: 01 02 09. 34. C.M. Klotzbuecher, P.D. Ross, P.B. Landsman, T.A. Abbott III, M. Berger, Patients with prior fractures have an increased risk of future fractures: a summary of the literature and statistical synthesis, J. Bone Miner. Res. 15 (4) (2000) 721–739. 35. J. Reeve, M. Lunt, D. Felsenberg, et al., European Prospective Osteoporosis Study Group. Determinants of the size of incident vertebral deformities in European men and women in the sixth to ninth decades of age: the European Prospective Osteoporosis Study (EPOS), J. Bone Miner. Res. 18 (9) (2003) 1664–1673. 36. O. Johnell, A. Oden, F. Caulin, J.A. Kanis, Acute and long-term increase in fracture risk after hospitalization for vertebral fracture, Osteoporos. Int. 12 (3) (2001) 207–214. 37. T.A. van Geel, S. van Helden, P.P. Geusens, B. Winkens, G.J. Dinant, Clinical subsequent fractures cluster in time after first fractures, Ann. Rheum. Dis. 68 (1) (2009) 99–102.
C h a p t e r 4 6 Diagnostic Approach: Vertebral Fracture Assessments l
38. S. van Helden, J. Cals, F. Kessels, P. Brink, G.J. Dinant, P. Geusens, Risk of new clinical fractures within 2 years following a fracture, Osteoporos. Int. 17 (3) (2006) 348–354. 39. J.R. Center, D. Bliuc, T.V. Nguyen, J.A. Eisman, Risk of subsequent fracture after low-trauma fracture in men and women, J. Am. Med. Assoc. 297 (4) (2007) 387–394. 40. J.T. Schousboe, T. Vokes, S.B. Broy, et al., Vertebral fracture assessment: the 2007 ISCD official positions, J. Clin. Densitom. 11 (1) (2008) 92–108. 41. L. Ferrar, G. Jiang, J. Adams, R. Eastell, Identification of vertebral fractures: an update, Osteoporos. Int. 16 (7) (2005) 717–728. 42. M. Lunt, D. Felsenberg, J. Reeve, et al., Bone density variation and its effects on risk of vertebral deformity in men and women studied in thirteen European centers: the EVOS Study, J. Bone Miner. Res. 12 (11) (1997) 1883–1894. 43. J.A. Cauley, L. Palermo, M. Vogt, et al., Prevalent vertebral fractures in black women and white women, J. Bone Miner. Res. 23 (9) (2008) 1458–1467. 44. D. Vosse, C. Heijckmann, R. Landewé, D. van der Heijde, S. van der Linden, P. Geusens, Comparing morphometric X-ray absorptiometry and radiography in defining vertebral wedge fractures in patients with ankylosing spondylitis, Rheumatology (Oxf) 46 (11) (2007) 1667–1671. 45. M. Van Der Klift, C.E.D.H. De Laet, E.V. McCloskey, A. Hofman, H.A.P. Pols, The incidence of vertebral fractures in men and women: the Rotterdam study, J. Bone Miner. Res. 17 (2002) 1051–1056. 46. L. Ferrar, G. Jiang, R. Eastell, N.F. Peel, Visual identification of vertebral fractures in osteoporosis using morphometric X-ray absorptiometry, J. Bone Miner. Res. 18 (2003) 933–938. 47. S.L. Greenspan, E. von Stetten, S.K. Emond, L. Jones, R.A. Parker, Instant vertebral assessment: a noninvasive dual Xray absorptiometry technique to avoid misclassification and clinical mismanagement of osteoporosis, J. Clin. Densitom. 4 (2001) 373–380. 48. J.A. Rea, J. Li, G.M. Blake, P. Steiger, H.K. Genant, I. Fogelman, Visual assessment of vertebral deformity by X-ray absorptiometry: a highly predictive method to exclude vertebral deformity, Osteoporos. Int. 11 (2000) 660–668. 49. T.J. Vokes, L.B. Dixon, M.J. Favus, Clinical utility of dualenergy vertebral assessment (DVA), Osteoporos. Int. 14 (11) (2003) 871–888. 50. G.M. Blake, J.A. Rea, I. Fogelman, Vertebral morphometry studies using dual-energy X-ray absorptiometry, Semin. Nucl. Med. 27 (3) (1997) 276–290. 51. J.C. Netelenbos, W.F. Lems, P.P. Geusens, et al., Spine radiographs to improve the identification of women at high risk for fractures, Osteoporos. Int. 20 (2009) 1347–1352. 52. S.T. Quek, W.C. Peh, Radiology of osteoporosis, Semin. Musculoskelet. Radiol. 6 (3) (2002) 197–206. 53. A. Baur, O. Dietrich, M. Reiser, Diffusion-weighted imaging of bone marrow: current status, Eur. Radiol. 13 (7) (2003) 1699–1708. 54. S.F. Hain, I. Fogelman, Nuclear medicine studies in metabolic bone disease, Semin. Musculoskelet. Radiol. 6 (4) (2002) 323–329. 55. L.R. Hedlund, J.C. Gallagher, Vertebral morphometry in diagnosis of spinal fractures, Bone Miner. 5 (1988) 59–67.
575
56. P.P. Smyth, C.J. Taylor, J.E. Adams, Vertebral shape: automatic measurement with active shape models, Radiology 211 (1999) 571–578. 57. T.W. O’Neill, J. Varlow, D. Felsenberg, et al., Variation in vertebral height ratios in population studies, J. Bone Miner. Res. 9 (1994) 1895–1907. 58. T.W. O’Neill, J. White, R. Eastell, A.J. Silman, The influence of sex on morphometric indices of vertebral deformity, J. Orthop. Rheum. 6 (1993) 29–32. 59. G.G. Crans, H.K. Genant, J.H. Krege, Prognostic utility of a semiquantitative spinal deformity index., Bone 37 (2) (2005) 175–179. 60. L. Ferrar, G. Jiang, J.T. Schousboe, C.R. DeBold, R. Eastell, Algorithm-based qualitative and semiquantitative identification of prevalent vertebral fracture: agreement between different readers, imaging modalities, and diagnostic approaches, J. Bone Miner. Res. 23 (3) (2008) 417–424. 61. L. Ferrar, G. Jiang, P.M. Cawthon, et al., Osteoporotic Fractures in Men (MrOS) Study. Identification of vertebral fracture and non-osteoporotic short vertebral height in men: the MrOS study, J. Bone Miner. Res. 22 (9) (2007) 1434–1441. 62. A.A. Ismail, T.W. O’Neill, W. Cockerill, et al., Validity of self-report of fractures: results from a prospective study in men and women across Europe. EPOS Study Group. European Prospective Osteoporosis Study Group, Osteoporos. Int. 11 (3) (2000) 248–254. 63. J.A. Rea, P. Steiger, G.M. Blake, E. Potts, I.G. Smith, I. Fogelman, Morphometric X-ray absorptiometry: reference data for vertebral dimensions, J. Bone Miner. Res. 13 (3) (1998) 464–474. 64. R. Lindsay, S.L. Silverman, C. Cooper, et al., Risk of new vertebral fracture in the year following a fracture, J. Am. Med. Assoc. 285 (3) (2001) 320–323. 65. J.A. Rea, M.B. Chen, J. Li, E. Marsh, et al., Vertebral morphometry: a comparison of long-term precision of morphometric X-ray absorptiometry and morphometric radiography in normal and osteoporotic subjects, Osteoporos. Int. 12 (2) (2001) 158–166. 66. C.Y. Pak, A. Ho, J. Poindexter, R. Peterson, K. Sakhaee, Quantitation of incident spinal fractures: comparison of visual detection with quantitative morphometry, Bone 18 (4) (1996) 349–353. 67. http://www.nice.org.uk/Guidance/TA160. Last visited: 01 02 09. 68. A.C. Heijckmann, M. Drent, B. Dumitrescu, et al., Progressive vertebral deformities despite unchanged bone mineral density in patients with sarcoidosis: a 4-year follow-up study, Osteoporos. Int. 19 (6) (2008) 839–847. 69. A.C. Heijckmann, M.S. Huijberts, E.J. Schoon, et al., High prevalence of morphometric vertebral deformities in patients with inflammatory bowel disease, Eur. J. Gastroenterol. Hepatol. 20 (8) (2008) 740–747. 70. P. Geusens, D. Vosse, S. van der Linden, Osteoporosis and vertebral fractures in ankylosing spondylitis, Curr. Opin. Rheumatol. 19 (4) (2007) 335–339. 71. T.P. van Staa, P. Geusens, J.W. Bijlsma, H.G. Leufkens, C. Cooper, Clinical assessment of the long-term risk of fracture in patients with rheumatoid arthritis, Arthritis Rheum. 54 (10) (2006) 3104–3112. 72. http://www.iofbonehealth.org/. Last visited: 01 02 09.
Chapter
47
The Use of Bone Biopsies in the Diagnosis of Male Osteoporosis Erik Fink Eriksen and Johan Halse Department of Endocrinology and Internal Medicine, Aker University Hospital, Oslo; Spesialistsenteret Pilestredet Park, Oslo, Norway
Introduction
Age-dependent changes in bone properties in females
The incidence of fractures is higher in men than women from adolescence through mid life. This difference is ascribed to a difference in high energy fractures between the two genders. After 50 years, however, the incidence of fractures increases with aging in men as well as women, but the age-adjusted incidence of both hip and vertebral fractures in men is about half of that in women [1]. This difference has several causes:
Histomorphometry analyses of bone biopsies after tetracycline double labeling is still the only investigational method permitting detailed evaluation of the remodeling process. The characteristics of bone remodeling in females at different ages have been elucidated in much more detail than in men. Bone fragility in postmenopausal osteoporosis is the result of a decrease in bone mass and architectural decay in both cortical and cancellous bone. In women, several studies have demonstrated significant increases in bone turnover with age as reflected in an average doubling of remodeling indices reflecting bone turnover [2–4]. Recker et al [4] performed a detailed analysis across the menopause towards old age in women and found that bone turnover increased abruptly in early menopause and was even higher in old women. Compared to premenopausal women, old postmenopausal women exhibited a 75% increase. This increase in bone turnover in early menopause is ascribed to loss of endogenous estrogen production, while secondary hyperparathyroidism due to vitamin D deficiency plays a more dominant role in older women. The high turnover state causes accelerated bone loss, because each remodeling unit has a negative bone balance due to insufficient bone formation to match the amount of bone removed during bone resorption [5, 6]. The high turnover state not only causes architectural deterioration of cancellous bone, but also leads to thinning of cortical bone with increasing age. The endosteal surface of cortical bone is the area of bone with the highest resorptive activity. Thus, a high turnover state will, in particular, affect resorptive activity at this site [7]. Abnormalities in the material properties of bone (collagen and mineral) may also contribute to skeletal fragility.
1. men have a higher accretion of bone during growth and achieve a higher peak bone mass than women 2. adult men display a larger bone size than women 3. women display accelerated bone loss around menopause and the high turnover associated with this acute loss of endogenous estrogen causes more pronounced disintegration of the cancellous network than in men with aging. Another important difference pertaining to osteoporosis pathogenesis between males and females is the higher prevalence of secondary osteoporosis in men. While around 20% of osteoporotic women exhibit other diseases causing bone loss and fracture, the prevalence of secondary osteoporosis in men has been cited to be 40–50% in most studies. The purpose of this chapter is twofold: 1. to review how bone biopsies have helped us understand the differences in bone remodeling between males and females that are responsible for the different bone loss patterns in the two sexes 2. to review the role of bone biopsies in the elucidation of possible secondary causes in male osteoporosis. Finally, we will review possible new information on bone quality, which can be gained from studies of bone biopsies.
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Paschalis et al [8] used Fourier transform infrared imaging techniques to assess collagen cross-links and crystallinity of osteoporotic bone and found osteoporotic bone displaying older crystals than normal bone. The relative contribution of such changes to bone fragility in postmenopausal osteoporosis is, however, still unclear.
Changes in bone remodeling with age in males The data on changes in remodelling with age in males are conflicting. A few studies reported significant reductions in osteoid and mineralizing surfaces with age [9, 10]. Several other investigators were unable to detect significant changes in formation surfaces with age or dynamic indices (mineralizing surfaces, mineral appositional rate, bone formation rate) [11–14]. A few studies compared bone formation parameters in males and females and all failed to demonstrate major differences [15]. One study reported significant increases in indices of bone formation with increasing age in women, while males showed no such relation [14, 16]. Males, however, displayed higher mean bone formation rates and mean labeled surfaces than women [14]. As mentioned above, changes in bone mass depend not only on turnover, but also the remodeling balance at each individual bone multicellular unit (BMU). Only a few studies have reported data pertaining to this issue. Generally, erosion depth as well as wall thickness decrease with increasing age [17, 18]. While balance at the BMU level was not analyzed in men only, one study found a change towards a more negative balance in women as they entered menopause [19]. Moreover, this study demonstrated that estrogen substitution reversed the negative balance.
Changes in bone structure with aging in males and females In postmenopausal osteoporosis, bone architecture is deteriorating by transformation of cancellous plates to rods. This starts with the negative remodeling balance causing thinning of the trabeculae and subsequent osteoclast hyperactivity creating perforations of thin trabeculae leading to loss of connectivity [17, 20, 21]. These changes reduce the biomechanical competence of cancellous bone and increase fracture risk [22, 23]. One study reported the reduction in iliac cancellous bone volume of males between ages 20 and 70–80 years amounting to about 30%, which seems less marked than in
women (42%) [24]. Another study, however, was unable to demonstrate any change in bone volume or cortical thickness with age in males, while females displayed significant reductions of both indices with increasing age [14]. The age-related thinning of bone structural units (BSI) is the same in males and females, but cancellous separation is lower in aged males than in aged females, suggesting a better preservation of the cancellous microarchitecture in males. Cancellous bone volume in idiopathic male osteoporosis is 35% lower than that of age-matched controls and of the same magnitude as the bone loss observed in females (38%) [24]. In a more recent study using newer and more stereologically correct methodology, these differences were corroborated by Vesterby [25] who used assessments of marrow star volume in vertebrae to assess potential differences in cancellous bone architecture between the two sexes. Star volume is a measure of the disconnectedness of trabeculae and increases with increasing deterioration of cancellous bone architecture. When plotting star volume against age in males and females, the slope of the regression line was steeper for females than males, reflecting the occurrence of more cancellous perforations in females and thus more pronounced cancellous separation (Figure 47.1). The general picture emerging from studies on bone structural changes in males and females is the presence of more pronounced deterioration of cancellous bone architecture in women than in males. Women display more pronounced disruption of trabecular continuity, while males show trabecular thinning, but trabecular continuity is preserved [15, 26] (Figure 47.2).
Histomorphometry in male osteoporosis Histomorphometry studies in males with osteoporosis are mostly of small size and often lack good control materials. As in women, osteoporosis in men is characterized by reduced cancellous bone volume, increased cancellous separation, cortical thinning and increased cortical porosity [24, 27–29]. One study has reported reduced wall thickness in osteoporotic men [30]. In younger men with low energy fractures, these changes seem less pronounced [31]. Modifications of bone microarchitecture independently of bone mineral density (BMD) have been reported in osteoporotic men with vertebral fracture when compared with osteoporotic men without fracture [32]. As in women, bone loss results mainly from a decreased bone formation [13, 28, 33], but increased bone resorption contributes [13, 34–36]. Hordon and Peacock [37] studied 78 unselected patients (68 women, 10 men) with femoral neck fracture and found
C h a p t e r 4 7 The Use of Bone Biopsies in the Diagnosis of Male Osteoporosis l
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Vm.space mm3
Lumbar vertebra
150
A
100
50
0 0
Lumbar vertebra
150
25
50
75
100
25
50 Age, years
75
100
B
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0 0
Figure 47.1 Changes in marrow star volume with age in females (upper panel) and males (lower panel). Note the steeper slope in females reflecting more severe deterioration of cancellous bone structure. (From Vedi et al. Histomorphometric analysis of bone biopsies from the iliac crest of normal British subjects. Metab Bone Dis Relat Res 1982;4:231–36 [26] with permission).
cancellous bone volume to be 15% in 72% of patients. Histological abnormalities occurred in 56 of the 78 biopsies. Based on histomorphometry, the authors classified patients into four groups: 1. normal histomorphometry (bone volume greater than 15%, osteoid surfaces less than 24%, mineralizing surface greater than 60%) (seen in 28%) 2. 29% revealed osteoporosis as the only abnormality (bone volume less than 15%, osteoid surface less than 24%, mineralizing surface greater than 60%) 3. 18% exhibited osteomalacia (osteoid surfaces greater than 24%, mineralizing surface less than 60%, osteoid width greater than 13 m)
4. 17% displayed decreased mineralizing surfaces. Of the remainder, five had increased osteoid surface and six had insufficient osteoid to assess mineralizing surface. The incidence of osteoporosis and osteomalacia increased with age, so that, in subjects over the age of 90, osteomalacia occurred in 29% of patients. Legrand et al [38] studied bone structure in transiliac bone biopsies obtained from 152 men with a BMD T-score 2.5 at the lumbar spine or hip. Simultaneously, they registered risk factors for osteoporosis, like age, body mass index (BMI), alcohol intake, corticosteroid therapy, hypogonadism and chronic diseases, and a risk
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Table 47.1 Causes of male osteoporosis in 110 Danish males
A
B
Primary osteoporosis Secondary osteoporosis Steroid induced Alcoholism Hypogonadism Immobilization Rachitis Hypogonadism alcohol Hypogonadism steroid
61% 39% 13% 10% 5% 2% 2% 1% 1%
Secondary osteoporosis Predominantly A
Predominantly B
In most studies [34, 41] , including our own analysis of 110 male patients with osteoporosis shown in Table 47.1, the most prevalent secondary cause is glucocorticoid use (GIO), followed by alcoholism and hypogonadism. Causes like immobilization and rachitis and combinations of hypogonadism with alcoholism or GIO are more rarely seen.
Corticosteroid-Induced Osteoporosis Figure 47.2 Changes in cancellous bone structure in males and females. Driven by the increased bone turnover after menopause, women display more trabecular perforations than males.
factor score was constructed. They found that men with two risk factors exhibited a lower BMD, thinner cortices and a significant higher star volume, reflecting more pronounced deterioration of cancellous bone architecture, than those with only one or no risk factor (idiopathic osteoporosis). Men with at least three risk factors revealed an even lower BMD, reduced cancellous bone volume (BV/TV) and cortical thickness. These men exhibited a more marked disorganization of the cancellous network, as reflected in increased trabecular separation and star volume and increased vertebral fracture risk. Although men generally have larger bone sizes than women, males with vertebral or hip fractures have reduced bone size. The reduced bone size may be due to reduced periosteal apposition during growth or aging, or both [39]. Osteocytes play a pivotal role in the regulation of bone remodeling. These cells act as mechanosensors in bone and osteocyte apoptosis triggers bone resorption and new remodeling events. Mullender et al [40] reported osteocyte density to be higher in healthy females, with mainly reductions in cancellous number, than in healthy males, with mainly cancellous thinning. The authors therefore hypothesized that different degrees of osteocyte apoptosis may explain the different gender-related bone loss patterns. No correlation was found, however, between structural or remodeling indices and osteocyte density.
Glucocorticoids impair osteoblast recruitment, proliferation and function. Moreover, they induce osteoblast and osteocyte apoptosis [42]. The reduced osteoblast activity manifests itself as reduced thickness of completed cancellous osteons causing cancellous thinning [43]. Increased bone resorption, as reflected in increased erosion surface and osteoclast number, has also been reported [44–46]. Increased osteoclast differentiation is observed at the beginning of treatment with corticosteroids, but increased resorption surfaces are not always increased in corticosteroidinduced osteoporosis [43]. Bone loss and fracture risk are related to the dose and duration of glucocorticoid exposure [47]. Bone loss is rapid during the first 12 months, with a significant decrease of lumbar spine BMD in particular, emerging about 3 months after initiation treatment [48]. Generally, doses in excess of 7.5 mg prednisolone equivalents are considered clearly detrimental to bone health, but newer studies have demonstrated that even lower doses 2.5–5 mg/day and inhaled steroids increase fracture risk [49, 50]. The bone loss of corticosteroid osteoporosis mainly affects the spine and ribs, but peripheral fracture incidence including hip fracture is also increased [51]. In cross-sectional studies, vertebral fracture prevalence has been reported to be twofold higher than controls, but the risk decreases after cessation of therapy. The risk of fractures in corticosteroid-induced osteoporosis is higher than would be expected from the decrease in BMD, which suggests that other factors apart from decreased BMD play a role [52]. There is no evidence that the deterioration of bone microarchitecture in GIO differs significantly between
C h a p t e r 4 7 The Use of Bone Biopsies in the Diagnosis of Male Osteoporosis l
males and females. Decreased wall thickness is a relatively constant finding, but the consequences in terms of cancellous thinning and further deterioration of cancellous bone architecture seems dose dependent. At low cumulative doses (10 g prednisone), trabeculae are thinner, but connectivity is preserved. At high doses (10 g of prednisone), trabeculae are thin, less numerous and disconnected. Decreased cancellous connectivity is usually seen when cancellous bone volume is lower than 11% [43, 46, 53]. As the changes in bone remodeling and architecture in GIO show a pronounced overlap with changes seen in primary osteoporosis, a bone biopsy will yield little extra information beyond imaging techniques, assessment of BMD and bone markers.
Hypogonadism Several recent studies indicate that a decrease in circulating estrogens derived from aromatization of androgens is one of the main drivers of the age-dependent bone loss in males. Therefore, it is not surprising that hypogonadism in men results in a high turnover state, similar to that seen in women after menopause. The age-related reduction in sex steroid levels is, however, more gradual in men than in women. This may explain the differences in architectural changes in males versus females. The more abrupt loss of estrogen around menopause causes an abrupt onset of a high turnover state with more severe osteoclastic hyperactivity and, thus, more trabecular perforations occur in females [54]. Albeit clear correlations between fading circulating levels of estradiol and BMD loss in males have been clearly demonstrated [55], the same has not been the case for histomorphometry indices. Fassbender et al [56] investigated the role of sex steroids in 100 male patients aged 30–78 with secondary osteoporosis and their association to established markers of bone turnover, BMD and bone histomorphometry. Multivariate analysis failed to demonstrate any significant correlation between BMD or histomorphometry indices and serum levels of testosterone or estradiol. Jackson et al [57] published bone histomorphometry data after in vivo double tetracycline labeling and related biochemical data from 14 men referred for evaluation of symptomatic spinal osteoporosis. Six patients had previously undiagnosed hypogonadism, while eight exhibited normal gonadal function and no diseases known to elicit secondary osteoporosis. Bone histomorphometry revealed no differences in structural measurements or resorption indices between the two groups. However, compared to reference values for normal postmenopausal women, osteoblast surface, mineralizing surface and formation rate were normal or modestly increased in the hypogonadal men and significantly reduced in the idiopathic group in accordance with the presence of a high turnover state in hypogonadism. Formation indices fell substantially in three of four hypogonadal men
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after 7–14 months of therapy with testosterone and calcium supplementation, further supporting the presence of increased bone turnover state in hypogonadism. In the studies conducted so far, it is difficult to separate changes in remodeling caused by low testosterone from changes caused by low estrogen because the two most often go together. Thus, whether isolated testosterone deficiency with normal estrogens leads to differences in remodeling and structural changes versus estrogen deficiency in males is unknown. The general picture emerging is, however, similar to that seen in postmenopausal women, with the distinct difference that the loss of sex steroids occurs more gradually in men and, therefore, the disruption of cancellous bone architecture is less severe. It is, however, impossible to separate histologically hypogonadism from other causes of secondary osteoporosis in men.
Alcoholism Crilly et al [58] studied bone mass and related metabolic variables in 50 males known to be, or to have been, regular alcohol abusers. Subjects were divided into those who were still drinking and those who had abstained for at least 3 months. Moreover, the first group was further subdivided into moderate and heavy drinkers. Fifty percent of subjects exhibited at least two low energy fractures of the spine. Bone histomorphometry was available in half the patients. Lumbar bone mineral density and iliac crest cancellous bone volume were significantly lower in spinal crush fracture cases. Parathyroid hormone, testosterone and urinary cortisol measurements showed no difference between groups. There were essentially no differences between those with and those without fractures in terms of bone formation and resorption parameters in biopsies. Current drinkers, however, showed lower osteoid seam width and osteoblast surface than abstainers. Mineralization lag time was prolonged and mineralization rate was lower in the drinkers. The bone formation period was prolonged in the drinkers. Among resorption indices only the resorption period showed a significant prolongation. The authors concluded that alcoholism primarily exerted negative effects on bone formation with less pronounced suppressive effects on bone resorption. Alkaline phosphatase and hydroxyproline excretion were higher in patients with than in those without fractures. Diamond et al [59] studied 28 patients currently drinking ethanol (‘drinkers’) and 12 claiming not to have consumed any ethanol for at least 6 months (‘abstainers’). These groups were compared to normal subjects without clinical or biochemical evidence of liver disease. Forearm bone mineral density, spinal bone mineral density and iliac crest cancellous bone area were significantly lower in the alcoholic patients compared with controls, but these values did not differ between the drinkers and abstainers. The drinkers, however, exhibited significantly less osteoblast activity, as reflected in histomorphometry formation indices,
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than the abstainers. No differences in resorption parameters were demonstrable. Osteocalcin concentrations were higher in the abstainers than in drinkers, further suggesting osteo blast impairment in alcoholism. The picture emerging from these studies is that the primary result of alcoholism is impairment of osteoblast function. In patients who fracture, the development of a high turnover state, further exacerbating bone loss due to osteoblast insufficiency, seems to be a contributing factor. None of these features, however, permit an exact diagnosis of alcoholic bone disease from histological analysis of bone biopsies.
Osteomalacia Osteomalacia is characterized by a defect of mineralization due to calcium and phosphate deficiencies that mainly result from a poor gut absorption due to vitamin D deficiency, but drugs (e.g. fluoride, etidronate), aluminum intoxication and disorders of phosphate metabolism (e.g. X-linked phosphatemic rickets, autosomic dominant hypophosphatemic rickets, oncogenic osteomalacia) also cause mineralization defects. Renal osteodystrophy constitutes a specific subgroup of secondary hyperparathyroidism/osteomalacia, where the changes seen in other cases of vitamin D deficiency are exacerbated by phosphate retention and the other electrolyte disturbances associated with renal impairment. Vitamin D deficiency induces secondary hyperparathyroidism due to the lowering of plasma calcium. At the tissue level, this is reflected first in increased bone turnover with normal osteoid parameters. However, patients with more severe deficiency will eventually develop mineralization defects as reflected in increased osteoid surface and width and prolonged mineralization lag time. This is the basis of the histomorphometry HVO classification of osteomalacia [60, 61]. Infrared imaging of calcified tissue shows that the matrix is undermineralized, with differences in mineral content within trabeculae but without evidence of an abnormal organic matrix or alteration in the crystal size and perfection [62]. The histologic picture emerging from analyses of biopsies from patients with osteomalacia is very specific and of great value in the workup of skeletal fragility of unknown causes. This is reflected in the study by Ballanti et al [63] that investigated the diagnostic sensitivity of bone histomorphometry in different metabolic bone diseases. The diagnostic sensitivity of histomorphometry was particularly high in cases with greatly increased osteoid and/or resorption features, as in renal osteodystrophy (ROD). All the remodeling indicators were particular in delineating advanced or severe forms of mixed ROD (mROD). Not surprisingly osteoid indicators were the most sensitive parameters in ROD with predominant osteomalacia, while osteoclastic and osteoid indicators were very sensitive in ROD with predominant hyperparathyroidism (hROD). Sensitivity was generally low in uremic patients without bone changes and in patients with idiopathic osteoporosis (OP).
Hyperparathyroidism The skeletal manifestations of primary hyperparathyroidism (PHP) are variable, but include osteopenia and increased risk of vertebral and non-vertebral fractures [64]. Bone loss seems to depend on disease severity, with mild hyperparathyroidism showing very little loss of bone at vertebral and non-vertebral sites The major consequence of primary hyperparathyroidism is an increase in bone turnover, which is reflected initially in an increased extension of resorption and later formation surfaces and increased osteoclast number. The augmentation of formation is reflected in an increase in the osteoid surfaces, osteoblast number and mineral apposition rate, which is the rate of the primary mineralization [65–68]. Despite this accelerated bone remodeling, cancellous bone volume is maintained with a thinning of trabeculae but a preservation of cancellous bone connectivity [65–68]. In contrast to postmenopausal osteoporosis, the coupling between resorption and formation remains balanced in primary hyperparathyroidism with an augmentation of the osteoblast activity and lifespan or a decreased erosion depth that results in a normal or increased balance at the BMU level [65]. Erosion depth and wall thickness are both decreased by about 20%, which is responsible for the preservation of BMU balance [65, 69]. The reduced erosion depth is probably the main reason for the reductions in the degree of trabecular perforations and excellent preservation of cancellous bone architecture. While cancellous architecture is generally preserved in PHP, cortices are consistently thinner and more porous [69–71]. The negative effects of the increased porosity and thinning on cortical bone architecture, which may explain the increased fracture risk at cortical sites, are partly counteracted by the increase in the cross-sectional bone area demonstrated in primary hyperparathyroidism [72]. Quantitative microradiography has shown a decrease of the mean degree of mineralization of bone matrix, which is presumably related to the high turnover. The main feature of primary hyperparathyroidism is an increase in resorption and formation indices due to high turnover but, at the same time, a discrepant preservation of trabecular connectivity. The most severe impact is seen in cortical bone, where increased porosity and thinning is demonstrable. Thus, bone strength in hyperparathyroidism is a function of many variables, such as bone density, bone size and microarchitecture. Diagnostically, the presence of a high turnover state with reservation of cancellous bone architecture raises the suggestion of primary hyperparathyroidism. Usually, however, the diagnosis has been made from assessment of PTH and ionized or total calcium in serum.
Hyper- and Hypothyroidism A history of thyrotoxicosis increases the future risk of osteoporotic fractures [73]. Histomorphometrically, hyperthyroidism
C h a p t e r 4 7 The Use of Bone Biopsies in the Diagnosis of Male Osteoporosis l
is characterized by bone loss at the cancellous and cortical envelopes and increased cortical porosity. The bone loss in hyperthyroidism results from a combination of increased bone turnover as reflected in increased resorption and formation surfaces and a pronounced negative balance at the level of individual BMUs [74, 75]. Bone histology in hypothyroidism shows changes which are the distinct opposite of those seen in thyrotoxicosis. The disease is histomorphometrically characterized by low turnover and a pronounced positive balance at the BMU level [76, 77]. As the vast majority of thyroid patients are female, this disease plays a minor role as cause of secondary osteoporosis in males. Thus, the histological diagnosis plays no practical role in the workup of such patients.
Liver Disease To study the pathogenesis of osteoporosis in patients with chronic liver disease, Diamond et al performed histomorphometry analysis in 80 patients with various types of chronic liver disease [78]. The results were compared with results obtained in 40 healthy controls. Cancellous bone volume and trabecular thickness were significantly reduced in both men and women with chronic liver disease. Osteoporosis as defined by histologic parameters was present in 17 (21%) patients with no significant differences in prevalence rates among the various hepatic disorders. No patient showed histologic evidence of osteomalacia, although mineralization lag times were prolonged. Patients with alcoholic liver disease, hemochromatosis and cholestatic liver disease displayed lower bone turnover rates and osteoblast surfaces than patients with chronic active hepatitis. Furthermore, the presence of hepatic cirrhosis was associated with reduced bone formation rates and lower osteoblast surfaces. Similar findings were reported by Guichelaar et al [79] and Hodgson et al [80]. The latter study also found reduced wall thickness in patients with primary biliary cirrhosis. One study suggests that vitamin D supplementation may offset these changes [81].
Hematologic Disease Myeloproliferative or other hematologic diseases constitute rare causes of secondary osteoporosis in males. The main diseases affecting bone mass are myeloma, mastocytosis and hemochromatosis, which are well-known causes of secondary osteoporosis in both men and women. Siddiqui et al performed a prospective pathology review and histomorphometry analysis of 40 transcortical trephine bone biopsies from donors for bone allografts and examined by light microscopy and semiautomated histomorphometry [82]. Light microscopic and histomorphometry analysis detected one case with suspected chronic myeloproliferative disorder and three specimens showed severe osteoporosis. Another study reported signs of hematologic disease or malignant
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marrow infiltration in 16% of patients in a 99 patient cohort undergoing bone biopsy over 14 years [83]. The main diagnostic in the malignant diseases is marrow infiltration of malignant cells. In the more benign diseases (mastocytosis, hemochromatosis), the general histomorphometry picture emerging is that of reduced cancellous bone volume and cortical thinning. However, the distinct diagnosis in mastocytosis depends on the demonstrations of excessive infiltration with mast cells [84], while the diagnosis of hemochromatosis depends on the demonstration of positive staining for iron [85]. A few reports describing osteoporosis associated with general lymphocytosis and lymphoid nodules in the marrow space have also been published [86].
Pituitary Disease Cushing’s disease has been dealt with above in relation to GIO, while the effects of prolactinoma were described under its main manifestation, hypogonadism. Disturbances in the growth hormone-insulin-like growth factor (GH-IGF) axis have, however, also been invoked a possible contributors to bone loss and osteoporotic fractures. Johansson et al [87] compared men with idiopathic osteoporosis to healthy men, with respect to 24-h urinary excretion of GH and serum levels of IGF-I and II and IGF binding proteins. Moreover, histomorphometry indices in the two groups were compared. In the patients, serum concentrations of IGF binding protein-3 (IGFBP-3) were reduced by 46% while other GH and IGF levels were similar. Histomorphometry analyses revealed a reduction in mean wall thickness resulting in a significant negative balance at each BMU. Bravenboor et al [88] studied transiliac bone biopsies from 36 GH deficient men who were adequately substituted. The analyses revealed a slight average increase in cancellous bone volume with slight elevation of erosion surfaces, while osteoid thickness, osteoid surface, mineralizing surface and mineralization lag time were unperturbed. Thus, the data on bone changes during GH-IGF deficiency are conflicting, without any consistent pattern emerging.
Osteogenesis Imperfecta (OI) OI is an inherited disorder characterized by increased bone fragility with recurrent fractures that leads to skeletal deformities in severe cases. Histologically, OI is characterized by a low bone mass, reduced cancellous bone volume and cortical thickness due to decreased bone formation at the cellular level [89]. In children bone turnover is increased, while found decreased in adults.
Osteopetrosis, Pycnodysostosis Despite the profound increases in bone mass, patients with these inherited diseases suffer low energy fractures. In
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both diseases, the predominant feature is increased cancellous bone volume with a thick cortices and thick trabeculae. In osteopetrosis, deficient osteoclast activity results in the presence of osteoclasts without ruffled borders or clear zone and remnants of calcified cartilage in mature bone. Also, in both diseases, histomorphometry indices of bone formation are usually reduced [90, 91]. Diagnostically, the typical radiographic features in both diseases coupled with the excessively high BMD are most important.
Indications for bone biopsies in male osteoporosis As outlined above, the changes in bone histology associated with primary male osteoporosis are not sufficiently specific to warrant routine biopsies. The main indication for bone biopsy is to diagnose potential cases of secondary osteoporosis. The three dominant causes of secondary osteoporosis in males – GIO, alcoholism and hypogonadism – however, do not produce changes in bone histology permitting classification beyond what can be achieved with a combination of clinical presentation, imaging and assessment of biochemical markers. With the exception of renal osteodystrophy, where histological classification of bone turnover is still important and may delineate possible treatment modalities, classification of bone turnover from histological analysis rarely yields information beyond what is obtainable with biochemical markers of bone turnover. The choice of anabolic over antiresorptive therapies might theoretically be facilitated from histological assessment of bone structure, i.e. if trabecular disintegration is very severe, one might favor anabolics. The intrabone variation in structure is, however, very high and valuable information on bone quality beyond BMD can be obtained from classification of vertebral fracture severity and number of fractures [92]. Thus, a bone biopsy is rarely warranted in the workup of male osteoporosis, except when malignant disease, rare cases of osteomalacia and a few genetic disorders are suspected as possible causes.
the availability of a biopsy specimen and will probably gradually be replaced with high-resolution quantitative computed tomography (QCT) methods, which will permit assessment of bone structure in larger areas of the skeleton. Another limitation of these x-ray based methods is the fact that the delineation between bone and non-bone has problems when a lot of new bone with a lower degree of mineralization is formed, as seen after treatment with anabolic regimens like PTH [93]. Detailed information about biochemical and biophysical properties of bone matrix from bone sections are now possible. Fourier transform infrared imaging (FTIRI) and Rahman spectroscopy offer insights in both collagen and mineral quality, while bone mineral also can be studied with microradiography or backscattered scanning electron microscopy. The mean degree of tissue mineralization is influenced by the rate of bone remodeling in patients with vertebral fractures. Although the mean degree of mineralization of bone matrix seems unperturbed in osteoporosis, the frequency distribution is different, suggesting a greater heterogeneity in osteoporotic patients than in controls [94]. A decreased mineral content and an increased mineral crystallinity have been found in osteoporosis with high bone turnover [8]. Overall, however, the contribution of mineral abnormalities to fragility in postmenopausal osteoporosis is still unclear. Several age-dependent modifications of collagen matrix and mineral occur during aging and in osteoporosis. Decreased collagen fibril size, decreased collagen crosslinking and increased lysine hydroxylation have all been reported in osteoporotic bone [95, 96]. Changes in type I collagen isomerization, which is reflected in an increased ratio / urinary C-telopeptide, predict an increased risk of fracture in postmenopausal women [97]. Increased fracture risk associated with the Ss polymorphism in the COL1A1 (Sp1) gene causing an increased ratio of 1(I) relative to 2(I) protein is also associated with increased skeletal fragility [98, 99]. As diagnostic tools, however, these methods are not yet ready for implementation in clinical practice.
Conclusion Future aspects The biomechanical competence of bone is not just a function of bone structure, but also depends on the quality of bone matrix and its mineralization. In recent years, great progress has been made in the assessment of these qualities. MicroCT provides better, volume based, three-dimensional estimates of cancellous and bone structure than the twodimensional estimates derived from classical histomorphometry analysis. However, even microCT estimates still demand
Compared to females, cancellous bone seems more connected in male osteoporosis. No differences with respect to cortical thinning have been established, however. As summarized above, most cases of primary male osteoporosis do not have distinctive features separating them clearly from biopsies obtained in normal males. Therefore, the diagnosis of primary male osteoporosis relies more heavily on assessment of bone mass by DXA and biochemical markers of bone remodeling. With the high prevalence of secondary causes underlying osteoporosis in males, delineation of these causes is
C h a p t e r 4 7 The Use of Bone Biopsies in the Diagnosis of Male Osteoporosis l
very important. As summarized above, however, most of these secondary causes are readily identified from the overall clinical picture, imaging and serum biochemistries. Kann et al summarized their experience with bone biopsies in metabolic bone disease restricted to untypical, unclear and complicated cases [83]. The study was performed to evaluate its role and relevance in routine use. A total of 99 horizontal transiliac bone biopsies performed over a time period of 14 years to elucidate further skeletal disease in one center were analysed, equal to 0.003% of patient consultations. Bone biopsies were performed in 63 osteoporotic males and 18 premenopausal osteoporotic females without other detectable endocrine abnormalities as reflected in serum and urine biochemistry. In 16 patients, the biopsy was performed due to suspicion of systemic/malignant disease such as mastocytosis, osteogenesis imperfecta, non-secreting plasmocytoma, metastatic infiltration. Two patients had biopsies due to decreasing bone mineral density under anti-osteoporotic treatment. The most frequent diagnoses besides osteoporosis were normal histology, mild osteoporosis and hyperosteoidosis. In some cases, pathological findings in bone marrow were detected. In most cases (82/99), the bone biopsy led to changes to or initiation of medical treatment. Following histopathological diagnosis, 16 patients did not receive any anti-osteoporotic treatment. In six patients, further diagnostic procedures were initiated because of bone histology. Bone biopsy was well tolerated and complications were rare and mild. The conclusion was that, despite all progress in non-invasive diagnostic procedures for metabolic bone diseases, such as osteoporosis, there remains a small but significant subset of patients who may benefit from inclusion of bone biopsy into the diagnostic procedure. Thus, while bone biopsies have yielded a wealth of important information on bone remodeling in disease states, including male osteoporosis, their role is limited in the workup of male osteoporosis. Exceptions are cases where malignant disease, rare cases of osteomalacia and a few genetic disorders are suspected as possible causes.
References 1. C. Cooper, L.J. Melton, Epidemiology of osteoporosis, Trends Endocrinol. Metab. 3 (1992) 224–229. 2. R. Eastell, P.D. Delmas, S.F. Hodgson, E.F. Eriksen, K.G. Mann, B.L. Riggs, Bone formation rate in older normal women: concurrent assessment with bone histomorphometry, calcium kinetics, and biochemical markers, J. Clin. Endocrinol. Metab. 67 (1988) 741–748. 3. Z.H. Han, S. Palnitkar, D.S. Rao, D. Nelson, A.M. Parfitt, Effects of ethnicity and age or menopause on the remodeling and turnover of iliac bone: implications for mechanisms of bone loss, J. Bone Miner. Res. 12 (1997) 498–508 [Erratum appears in J Bone Miner Res 1999;14(4):660.]. 4. R. Recker, J. Lappe, K.M. Davies, R. Heaney, Bone remodeling increases substantially in the years after menopause and remains increased in older osteoporosis patients, J. Bone Miner. Res. 19 (2004) 1628–1633.
585
5. E.F. Eriksen, B. Langdahl, A. Vesterby, J. Rungby, M. Kassem, Hormone replacement therapy prevents osteoclastic hyperactivity: a histomorphometric study in early postmenopausal women, J. Bone Miner. Res. 14 (1999) 1217–1221. 6. E.F. Eriksen, S.F. Hodgson, R. Eastell, S.L. Cedel, W.M. O’Fallon, B.L. Riggs, Cancellous bone remodeling in type I (postmenopausal) osteoporosis: quantitative assessment of rates of formation, resorption, and bone loss at tissue and cellular levels, J. Bone Miner. Res. 5 (1990) 311–319. 7. J.P. Brown, P.D. Delmas, M. Arlot, P.J. Meunier, Active bone turnover of the cortico-endosteal envelope in postmenopausal osteoporosis, J. Clin. Endocrinol. Metab. 64 (1987) 954–959. 8. E.P. Paschalis, F. Betts, E. DiCarlo, R. Mendelsohn, A.L. Boskey, FTIR microspectroscopic analysis of human iliac crest biopsies from untreated osteoporotic bone, Calcif. Tissue. Int. 61 (1997) 487–492. 9. J.A. Aaron, J.C. Gallagher, B.E.C. Nordin, Seasonal variation in histological osteomalacia in femoral-neck fractures, Lancet II (1974) 84–85. 10. B.L. Clarke, P.R. Ebeling, J.D. Jones, et al., Changes in quantitative bone histomorphometry in aging healthy men, J. Clin. Endocrinol. Metab. 81 (1996) 2264–2270. 11. F. Melsen, L. Mosekilde, Tetracycline double-labeling of iliac trabecular bone in 41 normal adults, (1978) 99–102. 12. P. Chavassieux, P.J. Meunier, Histomorphometric approach of bone loss in men, Calcif. Tissue Int. 69 (2001) 209–213. 13. H.K. Delichatsios, J.M. Lane, R.S. Rivlin, Bone histomorphometry in men with spinal osteoporosis, Calcif. Tissue. Int. 56 (1995) 359–363. 14. E. Dahl, K.P. Nordal, J. Halse, A. Attramadal, Histomor phometric analysis of normal bone from the iliac crest of Norwegian subjects, Bone Miner. 3 (1988) 369–377. 15. J.E. Aaron, P.A. Shore, R.C. Shore, M. Beneton, J.A. Kanis, Trabecular architecture in women and men of similar bone mass with and without vertebral fracture: II. three-dimensional histology, Bone 27 (2000) 277–282. 16. M.P. Akhter, J.K. Otero, U.T. Iwaniec, D.M. Cullen, G.R. Haynatzki, R.R. Recker, Differences in vertebral structure and strength of inbred female mouse strains, J. Musculoskel. Neuron. Interact. 4 (2004) 33–40. 17. E.F. Eriksen, Normal and pathological remodeling of human trabecular bone: three dimensional reconstruction of the remodeling sequence in normals and in metabolic bone disease, Endocrine. Rev. 7 (1986) 379–408. 18. J. Kragstrup, H.J. Gundersen, F. Melsen, L. Mosekilde, Estimation of the three-dimensional wall thickness of completed remodeling sites in iliac trabecular bone, Metab. Bone Dis. Relat. Res. 4 (1982) 113–119. 19. E.F. Eriksen, B. Langdahl, A. Vesterby, J. Rungby, M. Kassem, Hormone replacement therapy prevents osteoclastic hyperactivity: a histomorphometric study in early postmenopausal women, J. Bone Miner. Res. 14 (1999) 1217–1221. 20. A.M. Parfitt, Implications of architecture for the pathogenesis and prevention of vertebral fracture, Bone 13 (Suppl. 2) (1992) S41–S47. 21. M.E. Arlot, P.D. Delmas, D. Chappard, P.J. Meunier, Trabecular and endocortical bone remodeling in postmenopausal osteoporosis: comparison with normal postmenopausal women, Osteoporos. Int. 1 (1990) 41–49.
586
Osteoporosis in Men
22. H.K. Genant, P.D. Delmas, P. Chen, et al., Severity of vertebral fracture reflects deterioration of bone microarchitecture, Osteoporos. Int. 18 (2007) 69–76. 23. M. Kleerekoper, A.R. Villanueva, J. Stanciu, D.S. Rao, A.M. Parfitt, The role of three-dimensional trabecular microstructure in the pathogenesis of vertebral compression fractures, Calcif. Tissue. Int. 37 (1985) 594–597. 24. P. Chavassieux, P.J. Meunier, Histomorphometric approach of bone loss in men, Calcif. Tissue. Int. 69 (2001) 209–213. 25. A. Vesterby, Star volume of marrow space and trabeculae in iliac crest: sampling procedure and correlation to star volume of first lumbar vertebra, Bone 11 (1990) 149–155. 26. S. Vedi, J.E. Compston, A. Webb, J.R. Tighe, Histomorpho metric analysis of bone biopsies from the iliac crest of normal British subjects, Metab. Bone Dis. Relat. Res. 4 (1982) 231–236. 27. H.M. Perry, M.D. Fallon, M. Bergfeld, S.L. Teitelbaum, M.V. Avioli, Osteoporosis in young men, 142 (1982) 1295–1296. 28. J.E. Zerwekh, K. Sakhaee, N.A. Breslau, F. Gottschalk, C.Y. Pak, Impaired bone formation in male idiopathic osteoporosis: further reduction in the presence of concomitant hypercalciuria, Osteoporos. Int. 2 (1992) 128–134. 29. R.M. Francis, M. Peacock, D.H. Marshall, A. Horsman, J. Aaron, Spinal osteoporosis in men, Bone Miner. 5 (1989) 347–357. 30. M.C. de Vernejoul, J. Bielakoff, M. Herve, et al., Evidence for defective osteoblastic function. A role for alcohol and tobacco consumption in osteoporosis in middle-aged men, Clin. Orthop. Relat. Res. (1983) 107–115. 31. L.D. Hordon, M. Peacock, Osteomalacia and osteoporosis in femoral neck fracture, Bone Miner. 11 (1990) 247–259. 32. E. Legrand, M. Audran, P. Guggenbuhl, et al., Trabecular bone microarchitecture is related to the number of risk factors and etiology in osteoporotic men, Microsc. Res. Tech. 70 (2007) 952–959. 33. E.S. Kurland, C.J. Rosen, F. Cosman, et al., Insulin-like growth factor-I in men with idiopathic osteoporosis, J. Clin. Endocrinol. Metab. 82 (1997) 2799–2805. 34. N. Kelepouris, K.D. Harper, F. Gannon, F.S. Kaplan, J.G. Haddad, Severe osteoporosis in men, Ann. Intern. Med. 123 (1995) 452–460. 35. P. Chavassieux, P.J. Meunier, Histomorphometric approach of bone loss in men, Calcif. Tissue. Int. 69 (2001) 209–213. 36. J. Halse, K.P. Nordal, A. Attramadal, E. Dahl [Idiopathic osteoporosis in middle-aged men – a ‘new’ disease?], Tidsskr. Nor. Laegeforen. 114 (1994) 439–442. 37. L.D. Hordon, M. Peacock, Osteomalacia and osteoporosis in femoral neck fracture, Bone Miner. 11 (1990) 247–259. 38. E. Legrand, M. Audran, P. Guggenbuhl, et al., Trabecular bone microarchitecture is related to the number of risk factors and etiology in osteoporotic men, Microsc. Res. Tech. 70 (2007) 952–959. 39. E. Seeman, Growth in bone mass and size – are racial and gender differences in bone mineral density more apparent than real? J. Clin. Endocrinol. Metab. 83 (1998) 1414–1419. 40. M.G. Mullender, D.D. van der Meer, R. Huiskes, P. Lips, Osteocyte density changes in aging and osteoporosis, Bone 18 (1996) 109–113. 41. E. Legrand, M. Audran, P. Guggenbuhl, et al., Trabecular bone microarchitecture is related to the number of risk factors and etiology in osteoporotic men, Microsc. Res. Tech. 70 (2007) 952–959.
42. R.S. Weinstein, J.R. Chen, C.C. Powers, et al., Promotion of osteoclast survival and antagonism of bisphosphonateinduced osteoclast apoptosis by glucocorticoids, J. Clin. Invest. 109 (2002) 1041–1048. 43. D.W. Dempster, Bone histomorphometry in glucocorticoidinduced osteoporosis, J. Bone Miner. Res. 4 (1989) 137–141. 44. D.W. Dempster, M.A. Arlot, P.J. Meunier, Mean wall thickness and formation periods of trabecular bone packets in corticosteroid-induced osteoporosis, Calcif. Tissue. Int. 35 (1983) 410–417. 45. P.J. Meunier, D.W. Dempster, C. Edouard, M.C. Chapuy, M. Arlot, S. Charhon, Bone histomorphometry in corticosteroid-induced osteoporosis and Cushing’s syndrome, Adv. Exp. Med. Biol. 171 (1984) 191–200. 46. C.L. Dalle, P.M. Chavassieux, M.E. Arlot, P.J. Meunier, Bone histomorphometry in untreated and treated glucocorticoidinduced osteoporosis, Fron. Horm. Res. 30 (2002) 37–48. 47. P. Vestergaard, L. Rejnmark, L. Mosekilde, Fracture risk in patients with chronic lung diseases treated with bronchodilator drugs and inhaled and oral corticosteroids, Chest 132 (2007) 1599–1607. 48. E. Canalis, G. Mazziotti, A. Giustina, J.P. Bilezikian, Glucocorticoid-induced osteoporosis: pathophysiology and therapy, Osteoporos. Int. 18 (2007) 1319–1328. 49. T.P. Van Staa, H.G. Leufkens, L. Abenhaim, B. Zhang, C. Cooper, Use of oral corticosteroids and risk of fractures, J. Bone Miner. Res. 20 (2005) 1487–1494. 50. J.H. Toogood, A.B. Hodsman, Effects of inhaled and oral corticosteroids on bone, Ann. Allergy 67 (1991) 87–90. 51. T.P. Van Staa, H.G. Leufkens, C. Cooper, The epidemiology of corticosteroid-induced osteoporosis: a meta-analysis, Osteoporos. Int. 13 (2002) 777–787. 52. E. Canalis, G. Mazziotti, A. Giustina, J.P. Bilezikian, Glucocorticoid-induced osteoporosis: pathophysiology and therapy, Osteoporos. Int. 18 (2007) 1319–1328. 53. D. Chappard, N. Josselin, C. Rouge-Maillart, E. Legrand, M.F. Basle, M. Audran, Bone microarchitecture in males with corticosteroid-induced osteoporosis, Osteoporos. Int. 18 (2007) 487–494. 54. A.M. Parfitt, High bone turnover is intrinsically harmful: two paths to a similar conclusion. The Parfitt view, J. Bone Miner. Res. 17 (2002) 1558–1559. 55. S. Khosla, L.J. Melton III, B.L. Riggs, Estrogens and bone health in men, Calcif. Tissue. Int. 69 (2001) 189–192. 56. W.J. Fassbender, M. Balli, B. Gortz, B. Hinrichs, H.E. Kaiser, H.S. Tracke, Sex steroids, biochemical markers, bone mineral density and histomorphometry in male osteoporosis patients, In Vivo 14 (2000) 611–618. 57. J.A. Jackson, M. Kleerekoper, A.M. Parfitt, D.S. Rao, A.R. Villanueva, B. Frame, Bone histomorphometry in hypogonadal and eugonadal men with spinal osteoporosis, J. Clin. Endocrinol. Metab. 65 (1987) 53–58. 58. R.G. Crilly, C. Anderson, D. Hogan, L. AquerriereRichardson, Bone histomorphometry, bone mass, and related parameters in alcoholic males, Calcif. Tissue. Int. 43 (1988) 269–276. 59. T. Diamond, D. Stiel, M. Lunzer, M. Wilkinson, S. Posen, Ethanol reduces bone formation and may cause osteoporosis, Am. J. Med. 86 (1989) 282–288.
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60. A.M. Parfitt, I. Oliver, A.R. Villanueva, Bone histology in metabolic bone disease: the diagnostic value of bone biopsy, Orthop. Clin. N. Am. 10 (1979) 329–345. 61. A.M. Parfitt, S. Qiu, D.S. Rao, The mineralization index – a new approach to the histomorphometric appraisal of osteomalacia, Bone 35 (2004) 320–325. 62. D. Faibish, A. Gomes, G. Boivin, I. Binderman, A. Boskey, Infrared imaging of calcified tissue in bone biopsies from adults with osteomalacia, Bone 36 (2005) 6–12. 63. P. Ballanti, R.C. Della, E. Bonucci, S. Milani, C.V. Lo, B. Imbimbo, Sensitivity of bone histomorphometry in the diagnosis of metabolic bone diseases, Pathol. Res. Pract. 185 (1989) 786–789. 64. S. Khosla, L.J. Melton III, R.A. Wermers, C.S. Crowson, W. O’Fallon, B. Riggs, Primary hyperparathyroidism and the risk of fracture: a population-based study, J. Bone Miner. Res. 14 (1999) 1700–1707. 65. E.F. Eriksen, L. Mosekilde, F. Melsen, Trabecular bone remodeling and balance in primary hyperparathyroidism, Bone 7 (1986) 213–221. 66. M. Parisien, S.J. Silverberg, E. Shane, D.W. Dempster, J.P. Bilezikian, Bone disease in primary hyperparathyroidism, Endocrinol. Metab. Clin. N. Am. 19 (1990) 19–34. 67. P. Christiansen, T. Steiniche, A. Vesterby, L. Mosekilde, I. Hessov, F. Melsen, Primary hyperparathyroidism: iliac crest trabecular bone volume, structure, remodeling, and balance evaluated by histomorphometric methods, Bone 13 (1992) 41–49. 68. P.D. Delmas, P.J. Meunier, E. Faysse, E.C. Saubier, Bone histomorphometry and serum bone gla-protein in the diagnosis of primary hyperparathyroidism, World J. Surg. 10 (1986) 572–578. 69. E.F. Eriksen, Primary hyperparathyroidism: lessons from bone histomorphometry, J. Bone Miner. Res. 17 (Suppl. 2) (2002) N95–N97. 70. S.J. Silverberg, E. Shane, C.L. de la, et al., Skeletal disease in primary hyperparathyroidism, J. Bone Miner. Res. 4 (1989) 283–291. 71. H. Brockstedt, P. Christiansen, L. Mosekilde, F. Melsen, Reconstruction of cortical bone remodeling in untreated primary hyperparathyroidism and following surgery, Bone 16 (1995) 109–117. 72. J.P. Bilezikian, M.L. Brandi, M. Rubin, S.J. Silverberg, Primary hyperparathyroidism: new concepts in clinical, densitometric and biochemical features, J. Intern. Med. 257 (2005) 6–17. 73. P. Vestergaard, L. Rejnmark, J. Weeke, L. Mosekilde, Fracture risk in patients treated for hyperthyroidism, Thyroid 10 (2000) 341–348. 74. E.F. Eriksen, L. Mosekilde, F. Melsen, Trabecular bone remodeling and bone balance in hyperthyroidism, Bone 6 (1985) 421–428. 75. P.J. Meunier, [Hyperthyroidism and osteoporosis]. [French], Ann. Endocrinol. 56 (1995) 57–59. 76. E.F. Eriksen, L. Mosekilde, F. Melsen, Kinetics of trabecular bone resorption and formation in hypothyroidism: evidence for a positive balance per remodeling cycle, Bone 7 (1986) 101–108. 77. B.L. Langdahl, A.G. Loft, E.F. Eriksen, L. Mosekilde, P. Charles, Bone mass, bone turnover and body composition
78.
79.
80.
81.
82.
83.
84.
85.
86.
87.
8 8. 89.
90.
91.
92.
93.
94.
587
in former hypothyroid patients receiving replacement therapy, Eur. J. Endocrinol. 134 (1996) 702–709. T.H. Diamond, D. Stiel, M. Lunzer, D. McDowall, R.P. Eckstein, S. Posen, Hepatic osteodystrophy. Static and dynamic bone histomorphometry and serum bone Gla-protein in 80 patients with chronic liver disease, Gastroenterology 96 (1989) 213–221. M.M. Guichelaar, M. Malinchoc, J. Sibonga, B.L. Clarke, J.E. Hay, Bone metabolism in advanced cholestatic liver disease: analysis by bone histomorphometry, Hepatology 36 (2002) 895–903. S.F. Hodgson, E.R. Dickson, R. Eastell, E.F. Eriksen, S.C. Bryant, B.L. Riggs, Rates of cancellous bone remodeling and turnover in osteopenia associated with primary biliary cirrhosis, Bone 14 (1993) 819–827. J.A. Cuthbert, C.Y. Pak, J.E. Zerwekh, K.D. Glass, B. Combes, Bone disease in primary biliary cirrhosis: increased bone resorption and turnover in the absence of osteoporosis or osteomalacia, Hepatology 4 (1984) 1–8. S.A. Siddiqui, J.F. Lipton, V.J. Vigorita, J. Evangelista, E. Bryk, Bone biopsy as a screening technique for bone bank allograft donation, Am. J. Orthop. 33 (2004) 123–126. P.H. Kann, A. Pfutzner, G. Delling, G. Schulz, S. Meyer, Transiliac bone biopsy in osteoporosis: frequency, indications, consequences and complications. An evaluation of 99 consecutive cases over a period of 14 years, Clin. Rheumatol. 25 (2006) 30–34. M. Salles, S. Holgado, J.T. Navarro, et al., [Osteoporosis as a first manifestation of systemic mastocytosis. Study of 6 cases], Med. Clin. (Barc) 128 (2007) 216–218. T. Diamond, D. Stiel, S. Posen, Osteoporosis in hemochromatosis: iron excess, gonadal deficiency, or other factors? Ann. Intern. Med. 110 (1989) 430–436. V.J. Vigorita, M.K. Suda, J.M. Lane, Osteoporosis with idio pathic nodular lymphoid hyperplasia of the marrow, Arch. Pathol. Lab. Med. 107 (1983) 276–277. A.G. Johansson, E.F. Eriksen, E. Lindh, et al., Reduced serum levels of the growth hormone-dependent insulin-like growth factor binding protein and a negative bone balance at the level of individual remodeling units in idiopathic osteoporosis in men, J. Clin. Endocrinol. Metab. 82 (1997) 2795–2798. Bravenboor, et al, 1996 F. Rauch, R. Travers, A.M. Parfitt, F.H. Glorieux, Static and dynamic bone histomorphometry in children with osteogenesis imperfecta, Bone 26 (2000) 581–589. F. Rauch, R. Travers, A.M. Parfitt, F.H. Glorieux, Static and dynamic bone histomorphometry in children with osteogenesis imperfecta, Bone 26 (2000) 581–589. H. Brockstedt, J. Bollerslev, F. Melsen, L. Mosekilde, Cortical bone remodeling in autosomal dominant osteopetrosis: a study of two different phenotypes, Bone 18 (1996) 67–72. N. Fratzl-Zelman, A. Valenta, P. Roschger, et al., Decreased bone turnover and deterioration of bone structure in two cases of pycnodysostosis, J. Clin. Endocrinol. Metab. 89 (2004) 1538–1547. H.K. Genant, P.D. Delmas, P. Chen, et al., Severity of vertebral fracture reflects deterioration of bone microarchitecture, Osteoporos. Int. 18 (2007) 69–76. Y. Jiang, J.J. Zhao, B.H. Mitlak, O. Wang, H.K. Genant, E.F. Eriksen, Recombinant human parathyroid hormone
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(1-34) [teriparatide] improves both cortical and cancellous bone structure, J. Bone Miner. Res. 18 (2003) 1932–1941. 95. T.E. Ciarelli, D.P. Fyhrie, A.M. Parfitt, Effects of vertebral bone fragility and bone formation rate on the mineralization levels of cancellous bone from white females, Bone 32 (2003) 311–315. 9 6. H. Oxlund, M. Barckman, G. Ortoft, T.T. Andreassen, Reduced concentrations of collagen cross-links are associated with reduced strength of bone, Bone 17 (1995) 365S–371S. 97. E.P. Paschalis, E. Shane, G. Lyritis, G. Skarantavos, R. Mendelsohn, A.L. Boskey, Bone fragility and collagen cross-links, J. Bone Miner. Res. 19 (2004) 2000–2004.
98. P. Garnero, P. Cloos, E. Sornay-Rendu, P. Qvist, P.D. Delmas, Type I collagen racemization and isomerization and the risk of fracture in postmenopausal women: the OFELY prospective study, J. Bone Miner. Res. 17 (2002) 826–833. 99. V. Mann, S.H. Ralston, Meta-analysis of COL1A1 Sp1 polymorphism in relation to bone mineral density and osteoporotic fracture, Bone 32 (2003) 711–717. 100. V. Mann, E.E. Hobson, B. Li, et al., A COL1A1 Sp1 binding site polymorphism predisposes to osteoporotic fracture by affecting bone density and quality, J. Clin. Invest. 107 (2001) 899–907.
Chapter
48
Overall Approach to the Evaluation and Treatment of Osteoporosis in Men Eric S. Orwoll Bone and Mineral Unit, Oregon Health & Science University, Portland, Oregon, USA
The chapters in this book provide detailed information concerning many of the factors that inform the clinical evaluation of osteoporosis in men and the process of deciding on therapeutic intervention. In this chapter, the intent is to integrate this information in a way that yields a current approach for use in clinical situations.
Espallargues et al [6] and, more recently Liu et al [7] and Papaioannou [8], examined the world’s literature to identify factors associated with both low BMD and/or fracture in men. Risk factors for fracture include those that appear to be mediated via an association with either skeletal fragility or those that may act by increasing the risk of falls. That some of these factors are associated with increased fracture risk independent of BMD is of critical importance in clinical decision making in both men and women since it is the combination of these factors plus BMD that determines fracture risk and thus should determine diagnostic and therapeutic aggressiveness. Several professional organizations have developed clinical recommendations for selecting men who should have a diagnostic evaluation (Table 48.2). Concerns have been voiced about the quality of clinical practice guidelines [11] and, in fact, these recommendations have been variably derived by processes based on expert opinion or objective data; each approach has merit since available research information is inadequate to provide objective evidence for many commonly encountered clinical situations. Also, whereas large epidemiological studies (e.g. that underlie the WHO recommendations) provide robust conclusions at the population level, they commonly do not address the vagaries inherent in individual patient management. There are several consistent recommendations that emerge and that represent reasonable current guidelines, with the understanding that future developments will undoubtedly provide modifications. Men should be considered for diagnostic evaluation if they:
Diagnostic Considerations Unfortunately, guidelines for efficient, cost-effective evaluations of patients having, or suspected of having, osteoporosis are poorly validated for either sex. Current practice is based on existing knowledge of the epidemiology and clinical characteristics of osteoporosis [1, 2] rather than upon models that have been carefully tested in prospective studies. Nevertheless, the information available concerning men has expanded considerably in the last decade and allows the formulation of a reasonable approach (Figure 48.1).
Which Men Should be Selected for Evaluation? Men are rarely evaluated or treated for osteoporosis [3, 4], in part because recognition of the problem in both lay and professional groups is not as widespread as it is for osteoporosis in women. In addition, the clinical situations that should prompt an evaluation are less well defined in men, thus leading to uncertainty in the definition of approaches that are appropriate in routine clinical situations. A host of clinical factors have been associated with low bone mineral density (BMD) or fracture (Table 48.1), but many of these reports involve small numbers of cases and lack adequate study power to provide confident estimates of the degree of risk. Using objective criteria of study design, Osteoporosis in Men
experience fracture after age 50 (regardless of trauma). This recommendation is based on consistent findings that clearly indicate that these men are at increased risk of subsequent fracture and are more likely to have low BMD
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Possible metabolic bone disease – low trauma fracture, or fracture after age 50 years – radiographic indication of bone loss – medical condition associated with risk
Bone mineral density measurement
Normal BMD
Reduced BMD
No further W/U – observe, with preventative measures
Thorough history, physical exam; routine laboratory testing, including serum 25(OH)D
Explanation of bone loss apparent
No apparent explanation for bone loss
Undertake evaluation of male osteoporosis, including: serum testosterone/LH 24-hr urine calcium additional testing as dictated by the clinical situation
Institute appropriate therapy to treat underlying cause
Explanation apparent
No apparent explanation Empiric therapy
Figure 48.1 A general scheme for the evaluation of men suspected of having increased fracture risk.
[12]. Moreover, even men who experience traumatic fracture are more likely to have low BMD [13]. have potent risk factors for bone loss and fracture. The medical conditions and medications that have been associated with bone loss are numerous [14] and, in many of these cases, the associations are based on relatively weak data. However, some are well documented, including advanced age, low weight, significant glucocorticoid use, rheumatoid arthritis and hypogonadism (for instance in the case of androgen deprivation therapy for prostate cancer). In these cases, clinical judgment is needed to assess not only the impact of individual risk factors on the patient’s skeletal status and fracture risk, but also the importance of combinations of risk factors (a commonly encountered situation). The World Health Organization has developed an algorithm [15] (http://www.shef.ac.uk/FRAX) that combines these and other factors to enable a calculation of a man’s future (10-year) risk of fracture. Based on analyses of large, longitudinal studies, it provides a useful platform upon which to make additional therapeutic and diagnostic decisions. However, there are drawbacks to the use of FRAX [16–18] and additional individual-level patient information (e.g. dose of glucocorticoids, degree of renal
insufficiency) is important in judging risk and the need for additional diagnostic testing.
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Measures of Bone Mineral Density BMD is highly predictive of fracture risk in men and, in patients who have experienced fracture or who have conditions associated with low BMD, the measurement of BMD should be strongly considered. As above, clinical judgment is needed to make a decision to measure bone density in men with the conditions not so clearly related to fracture risk. In these situations, BMD measurements can be useful in several ways, including contributing to the diagnosis of skeletal fragility, gauging its severity and guiding decisions concerning therapy. Therefore, bone mineral density measurements have become a common part of the evaluation of fracture risk in men, but there are a number of challenging issues that still confront the choice and interpretation of those measures. For instance: Generalized screening of older men with bone density measures has been recommended in men over 70 years [19] and is worth further evaluation as a strategy. However, a recent cost-effectiveness analysis supported generalized
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Table 48.1 Primary and secondary causes of osteoporosis in men
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screening only in those over 80 years, as well as in men over the age of 65 years who have previously experienced a fracture [20] How the presence of an increased fall risk should influence the decision to measure BMD is not well understood in men or women. Since fall risk is an independent risk factor for fracture, it may be prudent to consider BMD measures in fall-prone men to discover those at particularly high fracture risk. Moreover, there are clinically simple ways to gauge fall propensity and that are also associated with fracture. These include determining a patient’s ability to rise from a chair without using his hands and walking speed [21, 22]. Although it is reasonable that the presence of increased fall risk should prompt BMD measures, in terms of making decisions about additional diagnostic or therapeutic intervention, the added value of assessing BMD in these men has not been clearly determined.
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Age-related osteoporosis Idiopathic osteoporosis Secondary osteoporosis Alcoholism Glucocorticoid excess (endogenous or exogenous) Hypogonadism (e.g. hormonal suppressive therapy for prostate cancer) Hyperparathyroidism Hyperthyroidism Gastrointestinal disorders Malabsorption syndromes Inflammatory bowel disease, gluten enteropathy Primary biliary cirrhosis Post-gastrectomy Hypercalciuria Chronic obstructive pulmonary disease Post-transplant osteoporosis Neuromuscular disorders Systemic illnesses Rheumatoid arthritis Multiple myeloma Other malignancies Masocytosis Medication/drug-related Glucocorticoids Anticonvulsants Thyroid hormone Chemotherapeutics Lifestyle choices Cigarette smoking Sedentary lifestyle Adapted from [5]
Choosing Among Forms of BMD Measures Dual energy x-ray absorptiometry (DXA) is readily available, there are well developed reference data for its use, low DXA BMD levels are strongly related to fracture risk in men [23, 24] and pharmacological therapies appear to be effective in men chosen on the basis of low DXA BMD levels. For all these reasons, DXA must be considered the first choice for assessing bone strength in men. On the other hand, ultrasound measurements are relatively simple and inexpensive and low ultrasound measures are also associated with increased fracture risk in men [25]. Unfortunately, normative data are not well established for ultrasound and ultrasound criteria for choosing men for pharmacological therapy are not validated. Using ultrasound to determine which men should receive DXA measures is probably not
Table 48.2 Some professional organizations that have recommendations for the diagnosis and treatment of osteoporosis in men Organization National Osteoporosis Foundation (USA)
Source of recommendations
Expert opinion and independent data analysis UK National Osteoporosis Expert opinion Guideline Group International Society of Expert opinion Clinical Densitometry American College of Quantitative Physicians literature review
Reference or website The National Osteoporosis Foundation (NOF) Clinician’s Guide to prevention and treatment of osteoporosis 2008. http://www.nof.org/professionals/NOF_Clinicians_ Guide.pdf http://www.iofbonehealth.org/download/osteofound/filemanager/iof/csa/consensusguidelines/nogg-executive-summary.pdf http://www.iscd.org/Visitors/pdfs/ISCD2007OfficialPositions-CombinedAdultandPediatric.pdf Qaseem et al [9] MacLean et al [10]
Additional guidelines can be found at http://www.iofbonehealth.org/health-professionals/national-regional-guidelines/evidence-based-guidelines.html and http://www.gfmer.ch/Guidelines/Osteoporosis/Osteoporosis_mt.htm#Male%20osteoporosis
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effective [26] and combining ultrasound with DXA seems to offer little additional advantage in identifying fracture risk [25]. Finally, while quantitative computed tomography (QCT) is gaining popularity as a research tool to examine changes in trabecular and cortical vBMD with aging and various diseases, it should be noted that diagnostic criteria for QCT-based vBMD measurements have not been established. DXA T-score criteria for diagnosing osteopenia and osteoporosis cannot be used with this modality and, in fact, there is not sufficient information concerning the relationship of CT measures and fracture risk to substantiate the use of CT measures in men in the clinical setting.
true, this offers a potential explanation for the lack of sex differences in studies of hip fractures, which usually occur in late life [27]. In addition to these issues, some have been concerned that the use of diagnostic cutoffs in men that are based on reference ranges in women would reduce the number of men identified as at risk [28], a conundrum in view of the frequency of fractures in men. In the absence of well powered prospective studies involving both sexes, several organizations have recommended the use of male specific reference ranges (http://www.iscd.org) and in clinical practice, it remains common to judge BMD results in light of sex-specific reference ranges and T-scores. The diagnosis of osteoporosis in men is commonly made at a BMD T-score level of 2.5 but, in fact, there is no obvious T-score that should dictate clinical decisions about additional evaluation or therapy. Rather, with lower levels of BMD, the clinical concern should be greater. For instance, in men with BMD T-score levels of 1.5, the presence of other risk factors for fracture may trigger additional diagnostic measures or therapeutic intervention. BMD T-score levels below 2 to 2.5 commonly prompt the consideration of pharmacological therapy. Unfortunately, there are no large scale therapeutic trials in men that allow estimates of the costeffectiveness of treatment based on baseline BMD levels. Rather than using a young normal reference range (male or female), it would be preferable to utilize a diagnostic
The Criteria for Determining Low BMD in Men The bone density criteria that should be used to identify men with high fracture risk and, thus, in need of intervention, are controversial. Although it is clear that there is an inverse association between DXA BMD and fracture risk, the specifics of the relationship are not as well established in men as in women. Some have suggested that the relationship between the absolute level of bone density and fracture risk is the same in men and women [27] while others have noted sex differences (Figure 48.2) [23]. Interestingly, in the latter studies, sex differences were most apparent at younger ages and became less apparent in older men. If
0.30
Female Male
0.24 0.18 0.12 0.06 0.00 –6
Non-vertebral fractures, 80+ year olds 0.36 3-year fracture risk, %
3-year fracture risk, %
Non-vertebral fractures, 65–69 year olds 0.36
0.24 0.18 0.12 0.06 0.00 –6 –5 –4 –3 –2 –1 0 1 2 Total hip BMD T-score (gender specific normals)
0.18 0.12 0.06 –5 –4 –3 –2 –1 0 1 2 Total hip BMD T-score (female normals)
Non-vertebral fractures, 65–69 year olds 0.36 3-year fracture risk, %
3-year fracture risk, %
Female Male
Female Male
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0.00 –6
–5 –4 –3 –2 –1 0 1 2 Total hip BMD T-score (female normals)
Non-vertebral fractures, 65–69 year olds 0.36 0.30
0.30
0.30
Female Male
0.24 0.18 0.12 0.06 0.00 –6 –5 –4 –3 –2 –1 0 1 2 Total hip BMD T-score (gender specific normals)
Figure 48.2 Three-year risk of fracture (and 95% confidence limits) by sex-specific total hip BMD T-score and age in older women and men. T-scores for males using male normal values for the total hip are equivalent to the following BMD values: T-score of 2 0.753 g/cm2; T-score of 1 0.897 g/cm2; T-score of 0 1.041 g/cm2. T-scores for females using female normal values for the total hip are equivalent to the following BMD values: T-score of 2 0.698 g/cm2; T-score of 1 0.820 g/cm2; T-score of 0 0.942 g/cm2. T-scores for both sexes using female normal values for the total hip are equivalent to the following BMD values: T-score of 2 0.698 g/cm2; T-score of 1 0.820 g/cm2; T-score of 0 0.942 g/cm2. Reproduced from Cummings et al. [23].
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criterion based on absolute fracture risk at a given absolute BMD level, a goal that has been addressed by the WHO in models incorporating clinical risk factors with or without BMD to predict 10-year probabilities of hip or other major osteoporotic fractures in women and men. Those models have recently been published [29] and the resulting diagnostic tool (FRAX) is widely available (http://www.shef.ac.uk/ FRAX). The extensive population data used to derive these strategies strongly suggest that the 10-year risk of fracture at any absolute BMD is similar in men and women and, in FRAX, the contribution of BMD to fracture risk is not sex-specific. This approach is endorsed by the International Osteoporosis Foundation (http://www.iofbonehealth.org) as well as by the National Osteoporosis Foundation in the USA (http://www.nof.org/). What should a clinician do when faced with excellent data (e.g. WHO) that support a non-sex specific approach for assessing fracture risk based on BMD measures while there is also additional information that suggests the presence of an influence of sex? At this point, it seems most appropriate to recognize that most available data support the similarity of the BMD–fracture risk relationship in men and women. It may be that there are sex differences in the association of BMD to fracture risk but, if so, they appear to be relatively modest. Until there are more data that can be used to refine the interpretation of BMD measures in a way that accommodates sexual influences, it is reasonable to adopt a sex neutral approach to assigning risk based on BMD measures. This would require the elimination of the sex-specific assignment of T-score values in favor of an absolute fracture risk model (i.e. the approach taken by WHO). Since men commonly experience fractures and yet few would be characterized as ‘osteoporotic’ using femalebased BMD categories (T-scores), the issues that must be addressed concerning sexual differences in the relationship between BMD measures and fracture risk include: are there differences in the causation of fractures in men and specifically do men fracture more often because of falls/trauma and less often due to inherent skeletal fragility? are there structural or material properties differences in men versus women that are not reflected in areal BMD measures but that cause skeletal fragility in men?
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Laboratory Evaluation The history and physical examination can provide evidence of genetic, nutritional/environmental, social, medical or pharmacological factors that contribute to the cause of osteoporosis. Over and above that information, laboratory assessments probably augment the clinician’s ability to determine the causation of skeletal fragility and thus to design rational therapeutic strategies. Of particular concern, osteomalacia is estimated to be present in 4–47% of men with femoral fractures, with most reports suggesting the
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prevalence in these patients is 20% [30, 31]. The exact magnitude of the problem presented by osteomalacia in men is uncertain, but the differential diagnosis of low bone mass and fractures in men must include osteomalacia. This becomes particularly imperative because the treatment for osteomalacia differs considerably from that of osteoporosis. Unfortunately, the diagnostic yield and cost effectiveness of laboratory studies in men with low bone density is unknown and resolving this issue is important for moving the field forward. Routine Lab Assessments Routine laboratory testing should include levels of serum creatinine, calcium, phosphorus, alkaline phosphatase and liver function tests, as well as a complete blood count. Given the widespread prevalence of vitamin D deficiency [32], serum 25-hydroxyvitamin D levels should also be obtained in patients with primary or secondary male osteoporosis. However, given the potential variability of assays for 25hydroxyvitamin D levels [33], use of a validated assay (preferably using mass spectroscopy) is important in assessing vitamin D status. If, on the basis of this information, there is evidence for medical conditions associated with bone loss (e.g. hyperparathyroidism, malignancy, Cushing’s syndrome, thyrotoxicosis, malabsorption, etc.) a more definitive diagnosis should be pursued with appropriate testing. In men with reduced bone mass and in whom no clear pathophysiology is identified by the routine methods above, additional testing might include a 24-hour urine calcium and creatinine, to identify idiopathic hypercalciuria; and serum sex steroid levels. Sex Steroid Measures Currently, testosterone is the standard assessment tool for detecting hypogonadism, but serum estradiol levels are more closely associated with BMD than are those of testosterone. Moreover, recent studies have documented that estradiol measures are predictive of fracture risk in men and are apparently more useful than are testosterone measures [34]. Mass spectrometry-based assays for low levels of serum estradiol are more accurate and precise and it is becoming increasingly apparent that it may be more useful to measure estradiol concentrations in men. Moreover, serum testosterone and estradiol levels are not highly correlated [35] and men who have less aromatase activity could present with low estradiol concentrations without low testosterone levels. It is now necessary to develop the clinical algorithms to incorporate estradiol measures as part of the evaluation of osteoporosis in men. These recent studies also support additional observations. First, bioavailable or free levels of testosterone and estradiol are much more predictive of fracture risk than are measures of total sex steroid levels. Therefore, the use of total testosterone and estradiol levels may not be useful in clinical
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situations. Second, in light of the well established difficulties in accurately measuring sex steroids using radioimmunoassay methods, it is probably appropriate to utilize more accurate mass spectrometry based assays. Finally, the most robust studies of the effects of sex steroids on fracture risk in men [34] also support the influence of sex hormone globulin measures as having independent utility in the assessment of fracture risk in men. In sum, it may be that the field is on the cusp of a clear change in the clinical approach to using sex steroid measures for assessing fracture risk in men; from a non-specific assessment of gonadal status with the use of total testosterone measures to a much more accurate and nuanced assessment using bioavailable or free measures of estradiol and testosterone further supplemented by measures of sex hormone binding globulin (SHBG). Other Measures Other measures may be appropriate depending on the clinical context (e.g. parathyroid hormone, 24-hour urine cortisol, immunological markers of sprue, etc.) but there is little information concerning their usefulness unless there are specific clinical indications for obtaining them. Similarly, higher levels of biochemical markers of bone turnover appear to be related to increased bone loss and fracture [36–38], but whether they add practical information over that provided by BMD measures is uncertain.
Treatment considerations Therapy of osteoporosis in men is less well defined than in women. There have been few trials of osteoporosis therapies performed specifically in male populations, the available trials are relatively small and, in most, the endpoint has been change in BMD. Thus, a critical issue is that they lack the power confidently to address drug effects on fracture risk [39]. This is a major deficiency in the available information concerning the treatment of osteoporosis in men. However, for the most common osteoporosis therapies (bisphosphonates and parathyroid hormone), the effects on BMD in men appear very similar to those in women and this finding underlies the regulatory approval of these therapies for the treatment of osteoporosis in men. Figure 48.1 depicts a scheme for deciding on therapy in men who present with osteoporosis. Several issues deserve specific comment: 1. The scheme starts with the recognition of a man who may have a metabolic bone disease and who may be at increased risk of fracture; a few of the most prominent indicators of increased risk are included. 2. The initial screening test suggested is a BMD measurement. That approach seems reasonable, but there may be situations in which other measures are appropriate even
if a BMD measurement is not clearly abnormal. For instance, some patients with osteomalacia may have a relatively normal BMD and a strong suspicion of osteomalacia may prompt additional evaluation (e.g. a measure of 25(OH)D level) in that situation. 3. The presence of reduced BMD should prompt additional testing. Although a typical threshold may be based on a T-score (2.0 to 2.5), the BMD threshold for determining the need for additional testing is dependent on the clinical situation (for instance, an older patient, a man who has experienced fractures or a man on systemic glucocorticoid therapy may deserve further evaluation at a higher BMD than other men). As is embodied in the FRAX algorithm, the decision for diagnostic or therapeutic intervention should incorporate factors in addition to BMD. 4. The treatment choice for an osteoporotic man must be made on the basis of his individual characteristics. In men with risk factors for bone loss or fracture, those risk factors should be addressed as appropriate. For instance, vitamin D deficiency, hyperthyroidism, malabsorption, etc. should each be carefully considered and addressed before pharmacological therapy with an osteoporosis drug is undertaken. 5. Since there is an absence of clinical trials designed to assess the effects of drug treatments on fracture risk reduction in men, decisions concerning therapy must be made on safety and efficacy data from trials with outcomes based on BMD responses and extrapolating from larger, more definitive trials in postmenopausal women. At this point, there appear to be no meaningful sex differences in response to available anti-osteoporosis drugs. 6. Whereas in postmenopausal women there are many trials aimed at the prevention of postmenopausal bone loss and formulations of drugs specifically for that purpose (e.g. 35 mg of alendronate per week), there are few, if any, similar trials in men, despite the finding that bone loss in men accelerates with age and there are men in clinical situations in which osteoporosis has not yet been diagnosed but who are at high risk of its future development if untreated. Decisions in this setting must be made by extrapolating from the data in postmenopausal women. Since there seem to be no major sex differences in the effects of available drugs, it may be presumed that lower doses of bisphosphonates may serve to prevent bone loss in men not yet osteoporotic. 7. Sex steroid therapy of men with osteoporosis is complex, as discussed below. At present, it is reasonable to treat hypogonadal symptoms with testosterone (in the absence of contraindications and with appropriate safety monitoring) but to treat hypogonadal men at high fracture risk with a drug (bisphosphonate or parathyroid hormone) that has been better demonstrated to be effective for skeletal indications. Testosterone treatment may be useful for the prevention of future bone loss in hypogonadal men, but the issue has been inadequately studied.
C h a p t e r 4 8 Overall Approach to the evaluation and treatment of Osteoporosis in Men l
Bisphosphonates Several trials of bisphosphonates in men have shown benefit. For instance, in a trial involving 241 men aged 31–87 years with low BMD (spine or hip BMD T-score 2.0), alendronate had positive results on bone mass at the spine and hip. Although the trial was not powered for a fracture outcome, the results suggest that therapy reduced the rate of vertebral fracture [40]. In similar studies, risedronate increased BMD and appeared to reduce vertebral fracture risk in older men [41, 42]. In one very small study in men following stroke, risedronate appeared to reduce the risk of hip fracture [43]. The increase in BMD resulting from bisphosphonate therapy in men appears to be very similar to that previously reported in postmenopausal women [40, 44]. Moreover, BMD changes in response to therapy are as great in men with low free testosterone levels as in those with normal levels [40], suggesting that bisphosphonates should be effective in men with hypogonadism. Preliminary reports indicate similarly beneficial effects of both zoledronic acid and ibandronate in men with low bone density. Bisphosphonates are also effective in men with secondary causes of osteoporosis [45], have positive effects on BMD in men receiving glucocorticoids [46–48] and are effective in preventing bone loss in states of immobilization [49], repetitive loading (stress fractures) [50] and in inflammatory conditions (e.g. rheumatoid arthritis) [51]. In sum, bisphosphonates appear to have similar effects in men and women and indications for the treatment of established osteoporosis appear to be similar. Because of their efficacy and overall safety, bisphosphonates should be the first-line therapy for men with low BMD. Bisphosphonate Use During Androgen Deprivation Therapy for Prostate Cancer Men who receive anti-androgen therapy for prostate carcinoma are at risk of bone loss and fractures [52, 53] and antiresorptive therapy should provide some protection for those patients. In fact, a number of well designed trials have demonstrated the effectiveness of bisphosphonates in preventing bone loss in these men [54]. Although no large trials with a fracture endpoint are yet available, it is reasonable to utilize bisphosphonates to avoid bone loss in men receiving androgen deprivation therapy, particularly when baseline BMD is low or there are other risk factors for fracture.
Parathyroid Hormone (Teriparatide) Parathyroid hormone (PTH) therapy is effective in increasing BMD in men with primary osteoporosis [55, 56] and its use is associated with evidence of an early increase in remodeling, essentially identical to that seen in women [57]. Moreover, therapy appears to reduce the likelihood of vertebral fractures [58]. The studies available are of small size and short duration and thus there is no evidence of
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non-vertebral fracture reduction. Nevertheless, the similarity of the effects in men with those seen in larger antifracture studies on women strongly suggests PTH therapy should be useful in both sexes. Simultaneous therapy with bisphosphonate appears to blunt the effects of parathyroid hormone in men as it does in women [59, 60]. Although the effectiveness of parathyroid hormone administration in the prevention of fractures in men, either alone or in concert with other agents, remains unclear, its potential appears similar in men and women [61]. The choice of whether to treat with parathyroid hormone or a bisphosphonate raises similar difficulties in men as in women, with the additional challenge that there are no fracture risk reduction data for these two approaches in men. In that context, it is appropriate to utilize similar paradigms in men and women.
Calcitonin From a theoretical perspective, calcitonin should be useful in reducing osteoclastic activity in at least some patients with osteoporosis or in those at risk of continuing bone loss, but there are few data. The available studies are small and most are not adequately designed. In an uncontrolled, 12-month trial of subcutaneously administered cyclical calcitonin (100 IU three times per week for 3 months, followed by 3 months without calcitonin) in men with vertebral osteoporosis, small benefits were noted in spinal and proximal femoral bone density, as compared to baseline [62]. Intranasal calcitonin decreased biochemical markers of bone turnover and had a beneficial effect on spine BMD [63]. Studies of the effectiveness of intranasal calcitonin in men include one open label study [64] that suggested therapy reduced the risk of vertebral fracture. Although calcitonin may have some effectiveness, it should rarely be used in the treatment and prevention of bone loss in men. There may be some clinical situations that preclude using other drugs with more clearly documented effectiveness and, in them, calcitonin may be useful.
Thiazide Diuretics Thiazide administration may have positive effects on bone mass, rates of bone loss and hip fracture risk in men [65, 66]. For instance, in case-controlled trials, the use of thiazides reduced the rate of loss in calcaneal bone density by 49% compared to controls and the relative risk of hip fracture was halved by exposure to thiazides for more than 6 years [67]. Similarly, thiazide use in men was associated with an adjusted odds ratio of femur fracture of 0.2 (95% CI 0.1–0.7) [68]. Other diuretics did not seem to impart the same benefits. Unfortunately, none of the available studies has been randomized or controlled, so a confident estimate of the magnitude of the protective effect is not possible. The mechanism for the positive effect is unclear, but it has been postulated to stem from the hypocalciuric
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effects of thiazides. In fact, one study showed an increase in BMD resulted from thiazide use in men with hypercalciuria [69]. Although not appropriately considered a primary treatment modality, a thiazide is probably the diuretic of choice in osteoporotic patients (other considerations not withstanding).
Strontium Ranelate Strontium ranelate administration has interesting effects on bone remodeling in that it appears to induce an increase in bone formation as well as a reduction in bone resorption and results in improved BMD and reduced fracture risk in women [70]. The effects of strontium should not be sex specific and studies of the usefulness of strontium therapy in men are underway, but results are not yet available.
Sex Steroid Therapy Sex steroids exert complex effects on bone. Whereas there may be treatment opportunities with both estrogens and androgens, there is very little information concerning the effects of estrogens in the therapeutic context and most treatment trials for low BMD have involved testosterone. Estrogen Although estrogens exert important effects on bone remodeling, there have been few attempts to use estrogen administration to prevent or improve bone mass in men. There is an appropriate reluctance to induce adverse effects (e.g. gynecomastia) and studies of the effects of even low dose estrogen on bone in men are not available. Two small, short-term trials of raloxifene in older men with low BMD suggested that selective estrogen receptor modulators could have positive effects on bone remodeling [71, 72], at least in the subset of men with low endogenous estrogen levels. Of course, treatment with testosterone also results in an increase in estrogen levels via the effects of aromatase and the effects of testosterone therapy on bone (below) are probably at least in part the results of estrogen action. Estrogen is not routinely available for treatment of skeletal abnormalities in men, its efficacy is unknown and its safety is uncertain. Testosterone Replacement in Hypogonadal Adult Men Hypogonadism is associated with increased bone loss and fracture. Testosterone therapy in hypogonadal men positively affects bone mass, at least in most patient groups [73]. The increase in bone mass with testosterone sex hormone binding globulin therapy can be expected to be modest in the short term (up to 24 months), but Behre et al noted an increase in spinal trabecular BMD of 20% in the first year
of testosterone therapy in a group of hypogonadal men and further increases thereafter [74]. The most marked increases were observed in those with the lowest testosterone levels before therapy. Using micro-magnetic MRI imaging, Benito et al [75] noted that trabecular architecture appeared to improve in hypogonadal men treated with testosterone. Most studies of testosterone replacement have included younger men, but there is a suggestion that, in older men with hypogonadism, the response to therapy can be expected to be similar to that in younger adult patients [74, 76]. Despite the generally positive tenor of most studies of the skeletal effects of testosterone replacement, in some patient groups, for instance those with Klinefelter’s syndrome, the advantage associated with androgen therapy is questionable, as the available studies report very mixed results [77]. This may be because the level of androgen deficiency in Klinefelter’s syndrome (as in the case of some other causes of hypogonadism) is quite variable. These findings suggest the need to consider carefully the potential benefits of androgen replacement in each patient individually. In addition to the generally positive effects of androgen replacement therapy on BMD in hypogonadal men, additional benefits may be gained from the increases that have been noted in strength and lean body mass in these patients [78]. Since lean body mass and strength have been correlated with bone mass and a reduced propensity to fall, they may further serve to promote bone health and reduce fracture risk. However, thus far, therapeutic trials of testosterone have included BMD as the primary endpoint and the effects of testosterone therapy on fracture risk are unknown. The most efficacious doses and routes of androgen administration for the prevention/therapy of bone loss in men remain uncertain. The specific testosterone levels necessary for an optimal effect have not been defined. Current recommendations are to attempt to achieve testosterone concentrations similar to those of normal young men. Testosterone Replacement in Andropause There is considerable controversy concerning the use of testosterone replacement therapy in older men, including its usefulness and safety in men at risk for fracture. The Institute of Medicine recommended a series of clinical trials to help determine the efficacy of testosterone for several important outcomes [79]. Those trials are being developed and should provide additional information concerning bone. Although available data are few, trials of intramuscular testosterone administration in older men with low testosterone levels have suggested that it may result in increased strength and improved body composition [78] and that bone mass and biochemical indices of remodeling may improve [80]. Thus far, positive effects on bone density are more apparent in men treated with intramuscular testosterone than with transdermal administration [81, 82], suggesting that
C h a p t e r 4 8 Overall Approach to the evaluation and treatment of Osteoporosis in Men l
higher testosterone levels may be necessary to achieve these results. Trials to date have selected men who have relatively low testosterone levels, without regard to baseline estradiol concentrations. The choice of pharmacological therapy in older men with osteoporosis and low sex hormone levels is difficult. Whereas testosterone therapy is indicated in men with symptoms of hypogonadism, the absence of information concerning the effectiveness of testosterone on the prevention of fractures reduces its attractiveness as a primary osteoporosis therapy. The use of testosterone therapy in osteoporotic men is made more problematic by the uncertainties surrounding the practical use of testosterone for skeletal indications (see below). On the other hand, bisphosphonate treatment appears to be effective regardless of gonadal function. Similarly, parathyroid hormone therapy also induces improvement in BMD in men with low sex steroid levels [55]. Thus, in older men with osteoporosis, it may be more appropriate to treat with an established osteoporosis drug regardless of gonadal function. It may be that there is a subset of older men with low sex steroid levels who may respond more briskly (e.g. men with low estradiol levels). If such a subset is identified in the future, replacement therapy could be targeted for its benefit. Selective androgen receptor modulators are being developed and promise to be useful as osteoprotective agents while reducing adverse effects on prostate, lipids, etc [83]. Animal studies suggest that selective estrogen receptor modulators may have encouraging effects in males [84].
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Unresolved Issues Concerning Testosterone Therapy and Bone Important questions remain unresolved concerning the role of testosterone treatment in the prevention/therapy of osteo porosis in hypogonadal men, including: the degree of hypogonadism (level of testosterone or estradiol) at which adverse skeletal effects begin to occur is uncertain and hence it is difficult to choose those patients who would benefit from replacement whether it is useful to assess estrogen concentrations in the diagnosis of hypogonadal bone disease in men and whether estrogen measurements are useful to monitor the success of testosterone therapy how long any increases in bone mass can be sustained and what eventual treatment effect can be expected, given that in general, available testosterone treatment studies are of relatively short duration to what extent testosterone may reduce fractures via effects on fall risk, since the increase in bonemass that appears to accompany testosterone therapy is of uncertain usefulness in preventing fractures whether pre-treatment age, duration of hypogonadism, degree of osteopenia, remodeling state and associated medical conditions affect the therapeutic response to testosterone is relatively unknown the potential adverse effects of long-term androgen therapy (e.g. prostate, lipids).
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Calcium and Vitamin D Testosterone Therapy in Secondary Forms of Metabolic Bone Disease A variety of systemic illnesses and medications are associated with lowered testosterone levels and it has been postulated that relative hypogonadism may contribute to the bone loss that also accompanies many of these conditions. For instance, renal insufficiency, glucocorticoid excess, post-transplantation, malnutrition and alcoholism are all associated with osteopenia and with low testosterone concentrations. Although there is little experience with testosterone supplementation in these patients, there may be advantages to skeletal health as well as to other tissues (muscle, red cells, etc.). In a randomized study of cross-over design, Reid et al [85] reported that testosterone therapy apparently improved bone density and body composition in a small group of men receiving glucocorticoids. In a double-blind, placebo controlled study, testosterone replacement was shown to have beneficial effects on BMD in glucocorticoid-treated men [86]. The number of patients affected by conditions associated with low testosterone levels is potentially quite large and more information is needed to understand the role of androgen replacement in the prevention/therapy of concomitant bone loss.
Calcium intake is probably important in the achievement of optimal peak bone mass in boys [87], as well as the prevention of bone loss later in life. Certainly, vitamin D insufficiency is common in older men and low vitamin D levels have been linked to lower BMD [88] and an increased risk of falls [89]. However, few prospective studies have addressed the specific benefits of calcium and vitamin D supplementation in men. No bone density benefit was observed from calcium/ vitamin D supplementation in an already well nourished population of men (mean dietary calcium intake 1000 mg/day) [90] and no anti-fracture benefit was observed in a large trial of vitamin D supplementation in older men and women with relatively high baseline intakes [91]. Dietary calcium intake was not found to be related to fracture rate in the men followed as part of the Health Professionals Follow-up Study [92]. On the other hand, an improvement in bone density was noted in healthy older men in response to a calcium and vitamin D supplement, while placebo treated men lost bone [93]. Calcium and vitamin D3 fortified milk improved femoral bone structure in older men [94] and low dietary calcium intake has been linked to higher fracture risk in other studies [95]. Although calcium and vitamin D supplementation have not been demonstrated to reduce fracture risk in men [96, 97], on the basis of available information,
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the US Institute of Medicine recently recommended that men should have a calcium intake of 1200 mg/day and a vitamin D intake of 800 IU. Others have recently suggested a vitamin D intake of 1000 IU per day or more [32, 98]. A reasonable approach, therefore, is to suggest a calcium intake of at least 1200 mg/day in both preventative as well as therapeutic situations. An NIH Consensus Development Conference has suggested the somewhat higher calcium intake of 1500 mg/day in men after 65 years [99].
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Exercise Whereas an exercise prescription is difficult to generate with currently available information, activity is probably beneficial in several ways. Reductions in strength and coordination contribute to fracture via an increased risk of falling [100]. In addition, inactivity is associated with bone loss and exercise may aid in maintaining bone mass. Specific exercise prescriptions to accomplish these goals have not been confirmed in men or women, although strength can be dramatically increased and risk of falls reduced in the elderly with achievable levels of exercise [101]. That fracture rates are lower in elderly men who exercise modestly buttresses this contention [102]. Falls and fall prevention strategies have been reviewed [103, 104].
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References 1. E. Orwoll, R. Klein, Osteoporosis in men: epidemiology, pathophysiology, and clinical characterization, in: R. Marcus, D. Feldman, D. Nelson, C. Rosen (Eds.), Osteoporosis, second edn., Academic Press, San Diego, 2008, pp. 1055–1094. 2. D. Vanderschueren, S. Boonen, Bouillon R. Osteoporosis and osteoporotic fractures in men: a clinical perspective, Baillières Best Pract. Res. Clin. Endocrinol Metab. 14 (2000) 299–315. 3. G.M. Kiebzak, G.A. Beinart, K. Perser, C.G. Ambrose, S.J. Siff, M.H. Heggeness, Undertreatment of osteoporosis in men with hip fracture, Arch. Intern. Med. 162 (2002) 2217–2222. 4. A.C. Feldstein, G. Nichols, E. Orwoll, et al., The near absence of osteoporosis treatment in older men with fractures, Osteoporos Int. 16 (2005) 953–962. 5. L. Gennari, J.P. Bilezikian, Osteoporosis in men, Endocrinol Metab. Clin. North. Am. 36 (2007) 399–419. 6. M. Espallargues, L. Sampietro-Colom, M.D. Estrada, et al., Identifying bone-mass-related risk factors for fracture to guide bone densitometry measurements: a systematic review of the literature, Osteoporos Int. 12 (2001) 811–822. 7. H. Liu, N. Paige, C. Goldzweig, et al., Screening for osteo porosis in men: a systematic review and background paper for a guideline of the American College of Physicians, Ann. Intern. Med. 148 (9) (2007) 685–701. 8. A. Papaioannou, C.C. Kennedy, A. Cranney, et al., Risk factors for low BMD in healthy men age 50 years or older: a systematic review, Osteoporos Int. 20 (2009) 1–12. 9. A. Qaseem, V. Snow, P. Shekelle, R. Hopkins Jr, M.A. Forciea, D.K. Owens, Screening for osteoporosis in men:
18.
19.
20.
21.
22.
23.
24.
25.
a clinical practice guideline from the American College of Physicians, Ann. Intern. Med. 148 (2008) 680. C. MacLean, S. Newberry, M. Maglione, et al., Systematic review: comparative effectiveness of treatments to prevent fractures in men and women with low bone density or osteo porosis, Ann. Intern. Med. 148 (2008) 197. A. Cranney, L. Waldegger, I.D. Graham, M. Man-Son-Hing, A. Byszewski, D.S. Ooi, Systematic assessment of the quality of osteoporosis guidelines, BMC Musculoskelet Disord. 3 (2002) 20. C.E. Lewis, S.K. Ewing, B.C. Taylor, et al., Osteoporotic Fractures in Men Study Research Group, Predictors of nonspine fracture in elderly men: the MrOS study, J. Bone. Miner. Res. 22 (2007) 211–219. D.C. Mackey, L.Y. Lui, P.M. Cawthon, et al., High-trauma fractures and low bone mineral density in older women and men, J. Am. Med. Assoc. 298 (2007) 2381. National Osteoporosis Foundation, Clinician’s guide to prevention and treatment of osteoporosis, National Osteoporosis Foundation, Washington, DC, 2008. WHO, FRAX: Fracture Risk Assessment Tool, World Health Organization, Geneva, 2008. N.B. Watts, E.M. Lewiecki, P.D. Miller, S. Baim, National Osteoporosis Foundation. Clinician’s guide to prevention and treatment of osteoporosis and the World Health Organization fracture risk assessment tool (FRAX): what they mean to the bone densitometrist and bone technologist, J. Clin. Densitom. 11 (2008) 473–477. N.B. Watts, B. Ettinger, M.S. LeBoff, FRAX Facts, J. Bone. Miner. Res. 24 (2009) 975–979. E.M. Lewiecki, N.B. Watts, New guidelines for the prevention and treatment of osteoporosis, South. Med. J. 102 (2009) 175–179. Writing Group for the IPDC, Diagnosis of osteoporosis in men, premenopausal women, and children, J. Clin. Densitom. 7 (2004) 17–26. J.T. Schousboe, B.C. Taylor, H.A. Fink, et al., Cost-effectiveness of bone densitometry followed by treatment of osteoporosis in older men, J. Am. Med. Assoc. 298 (2007) 629–637. P. Mannen Cawthon, R.L. Fullman, et al., Physical performance and risk of hip fractures in older men, J. Bone. Miner. Res. 23 (2008) 1037–1044. K.E. Ensrud, S.K. Ewing, P.M. Cawthon, et al., A comparison of frailty indexes for the prediction of falls, disability, fractures, and mortality in older men, J. Am. Geriatr. Soc. 57 (2009) 492–498. S.R. Cummings, P.M. Cawthon, K.E. Ensrud, J.A. Cauley, H.A. Fink, E.S. Orwoll, BMD and risk of hip and nonvertebral fractures in older men: a prospective study and comparison with older women, J. Bone. Miner. Res. 21 (2006) 1550–1556. N.D. Nguyen, C. Pongchaiyakul, J.R. Center, J.A. Eisman, T.V. Nguyen, Identification of high-risk individuals for hip fracture: a 14-year prospective study, J. Bone. Miner. Res. 20 (2005) 1921–1928. D.C. Bauer, S.K. Ewing, J.A. Cauley, K.E. Ensrud, S.R. Cummings, E.S. Orwoll, Osteoporotic Fractures in Men Research Group. Quantitative ultrasound predicts hip and non-spine fracture in men: the MrOS study, Osteoporos Int. 18 (2007) 771–777.
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26. R.A. Adler, H.L. Funkhouser, C.M. Holt, Utility of heel ultrasound bone density in men, J. Clin. Densitom. 4 (2001) 225–230. 27. O. Johnell, J.A. Kanis, A. Oden, et al., Predictive value of BMD for hip and other fractures, J. Bone. Miner. Res. 20 (2005) 1185–1194. 28. L.J. Melton, E.S. Orwoll, R.D. Wasnich, Does bone density predict fractures comparably in men and women? Osteoporos Int. 12 (2001) 707–709. 29. J.A. Kanis, O. Johnell, A. Oden, H. Johansson, E. McCloskey, FRAX and the assessment of fracture probability in men and women from the UK, Osteoporos Int. (2008) DOI 10.1007/ s00198-007-0543-5:(in press; available online). 30. L.D. Hordon, M. Peacock, Osteomalacia and osteoporosis in femoral neck fracture, Bone Miner. 11 (1990) 247–259. 31. T.J. Wilton, D.J. Hosking, E. Pawley, A. Stevens, L. Harvey, Osteomalacia and femoral neck fractures in the elderly patient, J. Bone Joint Surg. 69B (1987) 388–390. 32. M.F. Holick, Vitamin D deficiency, N. Engl. J. Med. 357 (2007) 266–281. 33. N. Brinkley, D.E. Krueger, C.S. Cowgill, et al., Assay variation confounds the diagnosis of hypovitaminosis D: a call for standardization, J. Clin. Endocrinol. Metab. 89 (2004) 3152–3157. 34. D. Mellström, L. Vandenput, H. Mallmin, et al., Older men with low serum estradiol and high serum SHBG have an increased risk of fractures, J. Bone Miner Res. 23 (2008) 1552–1560. 35. E. Orwoll, L.C. Lambert, L.M. Marshall, et al., Group OFiMS. Testosterone and estradiol among older men, J. Clin. Endocrinol. Metab. 91 (2006) 1336–1344. 36. C. Meier, T.V. Nguyen, J.R. Center, M.J. Seibel, J.A. Eisman, Bone resorption and osteoporotic fractures in elderly men: the dubbo osteoporosis epidemiology study, J. Bone Miner Res. 20 (2005) 579–587. 37. T.V. Nguyen, C. Meier, J.R. Center, J.A. Eisman, M.J. Seibel, Bone turnover in elderly men: relationships to change in bone mineral density, BMC Musculoskelet Disord. 8 (2007) 13. 38. C. Meier, P.Y. Liu, D.J. Handelsman, M.J. Seibel, Endocrine regulation of bone turnover in men, Clin. Endocrinol (Oxf) 63 (2005) 603–616. 39. C. Maclean, S. Newberry, M. Maglione, et al., Systematic review: comparative effectiveness of treatments to prevent fractures in men and women with low bone density or osteo porosis, Ann. Intern. Med. 148 (2007) 197–213. 40. E. Orwoll, M. Ettinger, S. Weiss, et al., Alendronate for the treatment of osteoporosis in men, N. Engl. J. Med. 343 (2000) 604–610. 41. S. Boonen, P. Delmas, D. Wenderoth, K. Stoner, R. Eusebio, E. Orwoll, Risedronate safe and effective in men with osteo porosis: a 2-year double-blind randomized placebo-controlled multicenter study, Osteoporos Int. 17 (2006) S106–S107. 42. J.D. Ringe, H. Faber, P. Farahmand, A. Dorst, Efficacy of risedronate in men with primary and secondary osteoporosis: results of a 1-year study, Rheumatol Int. 26 (2006) 427–431. 43. Y. Sato, J. Iwamoto, T. Kanoko, K. Satoh, Risedronate sodium therapy for prevention of hip fracture in men 65 years or older after stroke, Arch. Intern. Med. 165 (2005) 1743–1748. 44. J.R. Tucci, R.P. Tonino, R.D. Emkey, C.A. Peverly, U. Kher, A.C. Santora, Effect of three years of oral alendronate treatment
45.
46.
47.
48.
49.
50.
51.
52.
53.
54.
55.
56.
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60.
599
in postmenopausal women with osteoporosis, Am. J. Med. 101 (1996) 488–501. Y.V. Ho, A.G. Frauman, W. Thomson, E. Seeman, Effects of alendronate on bone density in men with primary and secondary osteoporosis, Osteoporos Int. 11 (2000) 98–101. K.G. Saag, R. Emkey, T.J. Schnitzer, et al., Alendronate for the prevention and treatment of glucocorticoid-induced osteo porosis, N. Engl. J. Med. 339 (1998) 292–299. D.M. Reid, R.A. Hughes, R.F.J.M. Laan, et al., Efficacy and safety of daily residronate in the treatment of corticosteroidinduced osteoporosis in men and women: a randomized trial, J. Bone. Miner. Res. 15 (2000) 1006–1013. J. Iwamoto, T. Takeda, Y. Sato, Effects of antifracture drugs in postmenopausal, male and glucocorticoid-induced osteo porosis – usefulness of alendronate and risedronate, Expert Opin Pharmacother 8 (2007) 2743–2756. A.D. LeBlanc, T.B. Driscol, L.C. Shackelford, H.J. Evans, N.J. Rianon, S.M. Smith, Alendronate as an effective countermeasure to disuse induced bone loss, J. Musculoskelet. Neuron. Interact 2 (2002) 335–343. C. Milgrom, A. Finestone, V. Novack, et al., The effect of prophylactic treatment with risedronate on stress fracture incidence among infantry recruits., Bone 35 (2004) 418–424. S.J. Jarrett, P.G. Conaghan, V.S. Sloan, et al., Preliminary evidence for a structural benefit of the new bisphosphonate zoledronic acid in early rheumatoid arthritis, Arthritis Rheum 54 (2006) 1410–1414. S.L. Greenspan, P.S. Coates, S.M. Sereika, J.B. Nelson, D.L. Trump, N.M. Resnick, Bone loss after initiation of androgen deprivation therapy in patients with prostate cancer, J. Clin. Endocrinol Metab. 90 (2005) 6410–6417. V.B. Shahinian, Y.F. Kuo, J.L. Freeman, J.S. Goodwin, Risk of fracture after androgen deprivation for prostate cancer, N. Engl. J. Med. 352 (2005) 154–164. M.R. Smith, Androgen deprivation therapy for prostate cancer: new concepts and concerns, Curr. Opin. Endocrinol Diabetes Obes. 14 (2007) 247–254. E.S. Orwoll, W.H. Scheele, S. Paul, et al., The effect of teriparatide [Human Parathyroid Hormone (1-34)] therapy on bone density in men with osteoporosis, J. Bone. Miner. Res. 18 (2003) 9–17. E.S. Kurland, F. Cosman, D.J. McMahon, C.J. Rosen, R. Lindsay, J.P. Bilezikian, Parathyroid hormone as a therapy for idiopathic osteoporosis in men: effects on bone mineral density and bone markers, J. Clin. Endocrinol. Metab. 85 (2000) 3069–3076. J. Satterwhite, K. Melnick, L. O’ Brien, S. Myers, M. Heathman Men and postmenopausal women with osteoporosis have similar lumbar spine bone mineral density responses to recombinant human parathyroid hormone (1-34) despite pharmacokinetic and biochemical marker differences, Arthritis Rheum. 44 (Suppl) (2001) S255. J.M. Kaufman, A. Vermeulen, The decline of androgen levels in elderly men and its clinical and therapeutic implications, Endocr. Rev. 26 (2005) 833–876. J.S. Finkelstein, A. Hayes, J.L. Hunzelman, J.J. Wyland, H. Lee, R.M. Neer, The effects of parathyroid hormone, alendronate, or both in men with osteoporosis, N. Engl. J. Med. 349 (2003) 1216–1226. J.S. Finkelstein, B.Z. Leder, S.A.M. Burnett, et al., Effects of teriparatide, alendronate, or both on bone turnover in
600
61.
62.
63.
64.
65.
66.
67.
68.
69.
70.
71.
72.
73.
74.
75.
76.
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osteoporotic men, J. Clin. Endocrinol. Metab. 91 (2006) 2882–2887. M. Girotra, M.R. Rubin, J.P. Bilezikian, The use of parathyroid hormone in the treatment of osteoporosis, Rev. Endocr. Metab. Disord. 7 (2006) 113–121. L. Erlacher, J. Kettenbach, H. Kiener, W. Graninger, F. Kainberger, P. Pietschmann, Salmon calcitonin and calcium in the treatment of male osteoporosis: the effect on bone mineral density, Wien. Klin Wochenschr 109 (1997) 270–274. G.P. Trovas, G.P. Lyritis, A. Galanos, P. Raptou, E. Constantelou, A randomized trial of nasal spray salmon calcitonin in men with idiopathic osteoporosis: effects on bone mineral density and bone markers, J. Bone. Miner. Res. 17 (2002) 521–527. E. Toth, E. Csupor, S. Meszaros, et al., The effect of intranasal salmon calcitonin therapy on bone mineral density in idiopathic male osteoporosis without vertebral fractures – an open label study, Bone 36 (2005) 47–51. A.Z. LaCroix, J. Wienpahl, L.R. White, et al., Thiazide diuretic agents and the incidence of hip fracture, N. Engl. J. Med. 322 (1990) 286–290. D.J. Morton, E.L. Barrett-Connor, S.L. Edelstein, Thiazides, and bone mineral density in elderly men and women, Am. J. Epidemiol. 139 (1994) 1107–1115. R. Wasnich, J. Davis, P. Ross, J. Vogel, Effect of thiazide on rates of bone mineral loss: a longitudinal study., Br. Med. J. 301 (1990) 1301–1305. R.M.C. Herings, B.H.C. Stricker, A. de Boer, A. Bakker, F. Sturmans, A. Stergachis, Current use of thiazide diuretics and prevention of femur fractures, J. Clin. Epidemiol. 49 (1996) 115–119. J.S. Adams, C.F. Song, V. Kantorovich, Rapid recovery of bone mass in hypercalciuric, osteoporotic men treated with hydrochlorothiazide, Ann. Intern. Med. 130 (1999) 658–660. S. O’Donnell, A. Cranney, G.A. Wells, J.D. Adachi, J.Y. Reginster, Strontium ranelate for preventing and treating postmenopausal osteoporosis, Cochrane Database Syst Rev 3 (2006) [update of Cochrane Database Syst Rev CD005326; PMID: 16856092].CD005326. P.M. Doran, B.L. Riggs, E.J. Atkinson, S. Khosla, Effects of raloxifene, a selective estrogen receptor modulator, on bone turnover markers and serum sex steroid and lipid levels in elderly men, J. Bone. Miner. Res. 16 (2001) 2118–2125. M.R. Smith, M.A. Fallon, H. Lee, J.S. Finkelstein, Raloxifene to prevent gonadotropin-releasing hormone agonist-induced bone loss in men with prostate cancer: a randomized controlled trial, J. Clin. Endocrinol. Metab. 89 (2004) 3841–3846. S. Bhasin, G.R. Cunningham, F.J. Hayes, et al., Testosterone therapy in adult men with androgen deficiency syndromes: an endocrine society clinical practice guideline, [erratum appears in J. Clin. Endocrinol. Metab. 91 (2006) 1995–2010. H.M. Behre, S. Kliesch, E. Leifke, T.M. Link, E. Nieschlag, Long-term effect of testosterone therapy on bone mineral density in hypogonadal men, J. Clin. Endocrinol. Metab. 82 (1997) 2386–2390. M. Benito, B. Vasilic, F.W. Wehrli, et al., Effect of testosterone replacement on trabecular architecture in hypogonadal men, J. Bone. Miner. Res. 20 (2005) 1785–1791. J.E. Morley, H.M. Perry III, F.E. Kaiser, et al., Effects of testosterone replacement therapy in old hypogonadal males: a preliminary study, J. Am. Geriatr. Soc. 41 (1993) 149–152.
77. F.H.W. Wong, K.K. Pun, C. Wang, Loss of bone mass in patients with Klinefelter’s syndrome despite sufficient testosterone replacement, Osteoporosis Int. 7 (1993) 281–287. 78. S.T. Page, J.K. Amory, F.D. Bowman, et al., Exogenous testosterone (T) alone or with finasteride increases physical performance, grip strength, and lean body mass in older men with low serum T, J. Clin. Endocrinol. Metab. 90 (2005) 1502–1510. 79. 2004 Committee on assessing the need for clinical trials of testosterone replacement therapy. In Testosterone and aging: clinical research directions, (Eds.), Liverman CT, Blazer DG, The National Academic Press, Washington, DC, 2004. pp 1-10. 80. J.K. Amory, N.B. Watts, K.A. Easley, et al., Exogenous testosterone or testosterone with finasteride increases bone mineral density in older men with low serum testosterone, J. Clin. Endocrinol. Metab. 89 (2004) 503–510. 81. P.J. Snyder, H. Peachey, P. Hannoush, et al., Effect of testosterone treatment on bone mineral density in men over 65 years of age, J. Clin. Endocrinol. Metab. 84 (1999) 1966–1972. 82. K.S. Nair, R.A. Rizza, P. O’Brien, et al., DHEA in elderly women and DHEA or testosterone in elderly men, N. Engl. J. Med. 355 (2006) 1647–1659. 83. A. Negro-Vilar, Selective androgen receptor modulators (SARMs): a novel approach to androgen therapy for the new millennium, J. Clin. Endocrinol. Metab. 84 (1999) 3459–3462. 84. W. Gao, J.D. Kearbey, V.A. Nair, et al., Comparison of the pharmacological effects of a novel selective androgen receptor modulator, the 5alpha-reductase inhibitor finasteride, and the antiandrogen hydroxyflutamide in intact rats: new approach for benign prostate hyperplasia, Endocrinology 145 (2004) 5420–5428. 85. I.R. Reid, D.J. Wattie, M.C. Evans, J.P. Stapleton, Testosterone therapy in glucocorticoid-treated men, Arch. Intern. Med. 156 (1996) 1173–1177. 86. B.A.L. Crawford, P.Y. Liu, M.T. Kean, J.F. Bleasel, D.J. Handelsman, Randomized placebo-controlled trial of Androgen effects on muscle and bone in men requiring longterm systemic glucocorticoid treatment, J. Clin. Endocrinol. Metab. 88 (2003) 3167–3176. 87. C.C. Johnston, J.Z. Miller, C.W. Slemenda, et al., Calcium supplementation and increases in bone mineral density in children, N. Engl. J. Med. 327 (1992) 82–87. 88. M.T. Hannan, H.J. Litman, A.B. Araujo, et al., Serum 25-hydroxyvitamins D and bone mineral density in a racially and ethnically diverse group of men, J. Clin. Endocrinol. Metab. 93 (2007) 40–46. 89. A. Cranney, T. Horsley, S. O’Donnell, et al. Effectiveness and safety of vitamin D in relation to bone health. Evidence Report/ Technology Assessment no. 158 prepared by the University of Ottawa evidence-based practice center (UO-EPC) under contract no. 290-02-0021. AHRQ publication no. 07-E013, Agency for Healthcare Research and Quality, Rockville, MD, August 2007. 90. E.S. Orwoll, S.K. Oviatt, M.R. McClung, L.J. Deftos, G. Sexton, The rate of bone mineral loss in normal men and the effects of calcium and cholecalciferol supplementation, Ann. Intern. Med. 112 (1990) 29–34. 91. P. Lips, W.C. Graafmans, M.E. Ooms, P.D. Bezemer, L.M. Bouter, Vitamin D supplementation and fracture incidence
C h a p t e r 4 8 Overall Approach to the evaluation and treatment of Osteoporosis in Men l
92.
93.
94.
95.
96.
97.
in elderly persons. A randomized, placebo-controlled clinical trial, Ann. Intern. Med. 124 (1996) 400–406. W. Owusu, W.C. Willett, D. Feskanich, A. Ascherio, D. Spiegelman, G.A. Colditz, Calcium intake and the incidence of forearm and hip fractures among men, J. Nutr. 127 (1997) 1782–1787. B. Dawson-Hughes, S.S. Harris, E.A. Krall, G.E. Dallal, Effect of calcium and vitamin D supplementation on bone density in men and women 65 years of age or older, N. Engl. J. Med. 337 (1997) 670–676. R.M. Daly, S. Bass, C. Nowson, Long-term effects of calciumvitamin-D3-fortified milk on bone geometry and strength in older men., Bone 39 (2006) 946–953. J.R. Center, D. Bliuc, T.V. Nguyen, J.A. Eisman, Risk of subsequent fracture after low-trauma fracture in men and women., J. Am. Med. Assoc. 297 (2007) 387–394. A.M. Grant, A. Avenell, M.K. Campbell, et al., Oral vitamin D3 and calcium for secondary prevention of low-trauma fractures in elderly people (Randomised Evaluation of Calcium Or vitamin D, RECORD): a randomised placebo-controlled trial., Lancet 365 (2005) 1621–1628. H. Smith, F. Anderson, H. Raphael, P. Maslin, S. Crozier, C. Cooper, Effect of annual intramuscular vitamin D on fracture risk in elderly men and women – a populationbased, randomized, double-blind, placebo-controlled trial., Rheumatology 46 (2007) 1852–1857.
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98. J. Cannell, B. Hollis, M. Zasloff, R. Heaney, Diagnosis and treatment of vitamin D deficiency, Expert Opin. Pharmacother 9 (2008) 107–108. 99. NIH. NIH Consensus statement (Number 4 edn)., National Institutes of Health, Bethesda, 1994 100. P. Kannus, H. Sievanen, M. Palvanen, T. Jarvinen, J. Parkkari, Prevention of falls and consequent injuries in elderly people, Lancet 366 (2005) 1885–1893. 101. M.E. Tinetti, D.I. Baker, G. McAvay, et al., A multifactorial intervention to reduce the risk of galling among elderly people living in the community, N. Engl. J. Med. 331 (1994) 821–827. 102. A. Paganini-Hill, A. Chao, R.K. Ross, B.E. Henderson, Exercise and other factors in the prevention of hip fracture: The Leisure World study., Epidemiology 2 (1991) 16–25. 103. B. Beck, R. Marcus, Skeletal effects of exercise in men, in: E.S. Orwoll (Ed.), Osteoporosis in Men: the Effects of Gender on Skeletal Health, Academic Press, San Diego, 1999, pp. 129–155. 104. S.D. Berry, D.P. Kiel, Falls as risk factors for fracture, in: R. Marcus, D. Feldman, D. Nelson, C. Rosen (Eds.), Osteoporosis, Academic Press, San Diego, 2008, pp. 911–917.
Chapter
49
Diagnostic Thresholds for Osteoporosis in Men John A. Kanis, Eugene V. McCloskey, Helena Johansson and Anders Oden WHO Collaborating Centre for Metabolic Bone Diseases, University of Sheffield Medical School, Sheffield, UK
Introduction
and inclusion criteria for drug trials and a basis for health technology assessments. The strength of these diagnostic categories as a reference standard has been the fashioning of a common approach to describe the disease. Developments since 1994, however, have eroded their value. These include the development of many new technologies for the measurement of bone mineral, the plethora of skeletal sites available for assessment, an increased understanding of osteoporosis in men (not provided for in the WHO reports) and the move towards risk-based assessment. These considerations have resulted in a revision of diagnostic criteria [4–6]. The revisions that impact on the description of osteoporosis in men are discussed in this chapter.
The internationally agreed description of osteoporosis is: ‘A systemic skeletal disease characterized by low bone mass and microarchitectural deterioration of bone tissue with a consequent increase in bone fragility and susceptibility to fracture’ [1]. This description captures the notion that low bone mass is an important component of the risk of fracture, but that other abnormalities occur in the skeleton that contribute to skeletal fragility. Thus, ideally, clinical assessment of the skeleton should capture all these aspects of fracture risk. At present, however, the assessment of bone mineral is the only aspect that can be readily measured in clinical practice and it now forms the cornerstone for the diagnosis of osteoporosis. In 1994, the World Health Organization (WHO) published diagnostic criteria for osteoporosis in postmenopausal women, intended primarily for descriptive epidemiology [2, 3]. The following four general descriptive categories were proposed for women using measurements of bone mineral density (BMD) at the spine, hip or mid-radius:
Diagnosis of osteoporosis A major departure from the earlier WHO definitions has been the provision of diagnostic criteria for men. The following four general descriptive categories have been proposed by the WHO for adult men and women using measurements of dual energy x-ray absorptiometry (DXA) at the femoral neck [6]:
Normal. A value for BMD that is higher than 1 SD below the young adult reference mean (T-score greater than or equal to 1 SD) Low bone mass (osteopenia). A value for BMD more than 1 SD below the young adult mean, but less than 2.5 SD below this value (T-score 1 and 2.5 SD) Osteoporosis. A value for BMD 2.5 SD or more below the young adult mean (T-score less than or equal to 2.5 SD). Severe osteoporosis (established osteoporosis). A value for BMD 2.5 SD or more below the young adult mean in the presence of one or more fragility fractures.
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Normal. A value for BMD that is higher than 1 SD below the young adult female reference mean (T-score greater than or equal to dual energy x-ray absorptiometry 1 SD). Low bone mass (osteopenia). A value for BMD more than 1 SD below the young female adult mean, but less than 2.5 SD below this value (T-score 1 and 2.5 SD). Osteoporosis. A value for BMD 2.5 SD or more below the young female adult mean (T-score less than or equal to 2.5 SD). Severe osteoporosis (established osteoporosis). A value for BMD 2.5 SD or more below the young female adult mean in the presence of one or more fragility fractures.
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The recommended reference range is the Third National Health and Nutrition Examination Survey (NHANES III) reference database for femoral neck measurements in white women aged 20–29 years [7], as previously recommended by the International Osteoporosis Foundation [8]. These diagnostic criteria for osteoporosis are similar to those previously proposed by the WHO in 1994 [2, 3], but differ by designating a reference site (the femoral neck), specifying a young normal reference range and by accommodating diagnostic criteria for non-white women and for men. The reasons for these clarifications are reviewed briefly below.
BMD and fracture risk in men and women
3.0
Any
Hip
Any osteoporotic
2.0 RR/SD
606
1.0
0
M
F
M+F
M
F
M+F
M
F
M+F
Age (years)
Diagnostic criteria for men Suitable diagnostic cut-off values for osteoporosis in men have been less well defined than those for white women. Many investigators and equipment manufacturers have reported T-score values that use a male reference range which, in turn, has led to a T-score of 2.5 SD being used widely and uncritically as a diagnostic criterion for men. The more reasoned approach is to base definitions on the clinical correlates of BMD and to determine the differences between men and women. The many studies that have examined fracture risk in men and women have come to disparate conclusions concerning the relationship between fracture risk and BMD [9–13]. There are several reasons for these discrepancies: first, the relation between BMD and fracture risk changes with age [14–16], so that age-adjustment is required. Secondly, a difference between sexes in the gradient of risk (relative risk per SD decrease in BMD) could be the result of differences in the SD of measurements [17]. Thirdly, data derived from separate male and female populations or from referral populations of osteoporotic men and women [10, 18] are likely to be biased. These problems can be avoided by sampling populations at random and expressing risk as a function of BMD or standardized T-scores and with age adjustment. There are two components of risk that need to be addressed. The first is whether there are differences in the gradient of risk between men and women. The second is to determine whether there are differences in absolute risk between men and women for any given BMD when age is taken into account.
Gradient of Risk The gradient of risk in the context of BMD measurements describes the increase in fracture risk for each unit decrease in BMD. The unit used is commonly the SD. It is evident that the same denominator (SD) must be used when comparing gradients of risk in this way. Thus, a common SD should be used in comparing the performance characteristics of BMD in men with women.
Figure 49.1 Gradient of risk per SD decrease in Z-score of BMD in men and women for any fracture, an osteoporotic fracture and for hip fracture [16]. The SD used was the young female reference range of NHANES III.
The relationship between BMD and fracture risk has been examined most extensively in a meta-analysis of the primary data from 12 population-based cohorts comprising 39 000 men and women [16]. The gradients of risk afforded by BMD at the femoral neck for the prediction of any fracture, any osteoporotic fracture and hip fracture are shown in Figure 49.1. Gradients of risk were highest for hip fracture, lowest for any fracture and intermediate for osteoporotic fracture. There was no difference in the gradient of risk between men and women. The small and non-significant differences became even less with adjustment for age. In this study, a significant effect of age was shown on the gradient of risk, but the interaction of age and gradient of risk was the same in men as that observed in women. For peripheral measurements of BMD, gradients of risk were, as expected, lower, but there was no difference between men and women.
Absolute Risk Although gradients of risk are similar between men and women, absolute risks may differ. However, the few comparative studies available show that the risk of hip fracture is similar in men and women for any given absolute value for BMD measured mainly at the hip [11, 14, 16, 19–20]. In the Rotterdam study [20], the relationship between hip fracture incidence and BMD at the proximal femur was identical in men and women at any given age. Similar findings were reported for the EVOS study [11]. In this age and sex-stratified sample of 6000 men and women from 13 European centers, the age-adjusted incidence of vertebral fracture was similar between men and women for any given BMD measured at the hip or spine. Likewise, the risk of vertebral fracture is also similar in men and women for any given BMD [11].
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Hip fracture probability in men and women with a prior fracture (UK) Average BMD for women
Without BMD
Probability (%)
15 10
Men Women 10
5 5
0
50
55
60 65 70 Age (years)
75
80
0
50
55
60 65 70 Age (years)
75
80
Figure 49.2 Ten-year probability of hip fracture in men and women from the UK computed from the FRAX® tool in the absence of BMD (left) and at a fixed BMD for age (right).
There is increasing interest in expressing fracture risk in terms of probability. The metric used in the WHO FRAX® tool is the 10-year probability of fracture [4, 21, 22]. Probability depends not only on the fracture hazard, but also on the death hazard. The relationship between hip fracture probability and age is shown in Figure 49.2. As expected, probabilities are higher in women than in men in the absence of information on BMD, reflecting the higher incidence of hip fracture in women (left panel). When probabilities are computed at a fixed femoral neck BMD at each age (a Z-score of 0 in this example), the differences between men and women largely disappear. There are, however, differences at the older ages where the 10-year probability of hip fracture is greater in women than in men due to the higher risk of death in men compared with women. These studies indicate that a similar cut-off value for hip BMD that is used in women can be used in the diagnosis of osteoporosis in men.
Normative reference ranges The prevalence of osteoporosis, as defined by the T-score, depends critically upon the reference range adopted and the technology used. For example, in Caucasian women at the age of 60 years, the T-score may vary from 0.7 to 2.5 SD, depending on the technique used [23, 24] (Table 49.1). In addition, for any one technique, the T-score, and hence the prevalence of osteoporosis, will depend on the referent used to compute the T-score. As noted above, it is recommended that the US reference data generated from the NHANES III study [7] serve as a reference standard for the proximal femur, but the prevalence of osteoporosis depends
Table 49.1 Estimate of the average T-score at the age of 65 years in women Measurement site
Technique
T-score at age 60 years
Spine Spine Heel Spine Forearm Femoral neck Total hip Heel
QCT Lateral DXA Achilles DXA DXA DXA DXA Sahara
2.5 2.2 1.5 1.3 1.4 1.2 0.9 0.7
Adapted from Kanis JA, Glüer CC for the Committee of Scientific Advisors, International Osteoporosis Foundation. An update on the diagnosis and assessment of osteoporosis with densitometry. Osteoporos Int 2000;11:192–202 [23]
on the age range and sex used to denote the young adult normal range. For example, the prevalence of osteoporosis in men from Sweden at the age of 70 years is 8.6% when the young adult value corresponds to that computed between the ages of 20 to 29 years using a male reference range from NHANES III, but is 6.4% when calculated between the ages of 20 to 39 years. When a female reference database is used, the prevalences are 7.6% and 4.0%, respectively [25]. Further examples are provided in Table 49.2. There is thus a compelling case to have a standardized reference range. That recommended by the WHO is the female Caucasian population aged 20–29 years. Thus, the threshold for diagnosing osteoporosis using DXA at the femoral neck is 0.558 g/cm2 – a cut-off value that applies to men as well as women. The reasons for choosing the femoral neck
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Table 49.2 Estimated prevalence (%) of osteoporosis in men from Sweden according to the reference range used for femoral neck BMD Age (years) Reference
50
60
70
80
5.5 3.4 1.6
8.6 6.4 2.7
15.4 12.6 5.8
4.8 2.4 0.7
7.6 4.0 1.3
14.0 8.1 3.1
Using a male reference range 20–29 20–39 50
2.8 1.9 0.6
Using a female reference range 20–29 20–39 50
2.4 1.0 0.3
Data extracted from Kanis JA, Johnell O, Oden A, Jonsson B, De Laet C, Dawson A. Risk of hip fracture according to the World Health Organisation criteria for osteopenia and osteoporosis. Bone 2000;27:585-90 [25]
is that this site has been the most extensively validated and provides a gradient of fracture risk as high as or higher than that of many other techniques [16, 26]. Moreover, the hip is the site of highest clinical relevance, since hip fracture is the dominant complication of osteoporosis in terms of morbidity and cost [27]. The choice of a reference site holds true in principle for many other multifactorial diseases. For example, in essential hypertension, measurements made at the leg may differ substantially from measurements made at the arm. In the field of osteoporosis, as for hypertension, it is appropriate to select a standardized site for the purposes of diagnosis. There is, however, an argument to be made for using the total hip measurement, since this site has a better reproducibility than measurements made at the femoral neck because a larger area of bone is involved. Reference data are also available for the total hip [7], but the evidence to date does not suggest improvement in fracture prediction [28]. A similar argument can be raised for the diagnostic use of measurements of BMD at the lumbar spine, which are widely used in clinical practice. The principal reason why these still are not considered is that their ability to predict fracture has not been as adequately validated as BMD measurements derived from the femoral neck. An important error of accuracy is aortic calcification and osteoarthrosis, the prevalence of both of which increases progressively with age. These considerations should not be taken to infer that the use of other techniques or other sites do not have clinical utility for the management of patients where they have been shown to provide information on fracture risk. The objectives of bone mineral measurement are to provide diagnostic criteria, prognostic information on the risk of future fractures and a baseline on which to monitor the natural history of the treated or untreated patient. The multiple sites and technologies available have increased the armamentarium at our disposal for clinical research and for the management of patients. This is important because no one site or technique sub-serves all the clinical requirements
of a bone mineral measurement. For example, even with DXA, the use of measurements at a single site is problematic. Whereas hip fracture risk is more accurately assessed by DXA at the hip than by DXA at the forearm, measurement at the forearm may detect skeletal losses earlier in secondary causes of osteoporosis than measurements at the spine or hip; neither the hip nor forearm is a particularly responsive site for monitoring of treatment. Thus, each site and technique has its own unique performance characteristics and the information provided by each will describe the clinical characteristics, fracture risk and epidemiology of osteoporosis differently. Against this background, there is a need for a reference standard for describing osteoporosis, but this should not be taken to infer that other sites do not have clinical utility for the management of patients. When the NHANES III reference standard is used, approximately 10 million men and women over the age of 50 years have osteoporosis in the USA. The prevalence of osteoporosis for men from Sweden using this criterion is shown in Table 49.2 [25]. Approximately 6% of men and 21% of women aged 50–84 years are classified as having osteoporosis. The prevalence of osteoporosis in men and women for some other regions is shown in Table 49.3 [4]. The prevalence of osteoporosis in men over the age of 50 years is about one third that in women – comparable to the difference in lifetime risk of an osteoporotic fracture in men and women [25]. Differences in BMD in different regions of the world only vary by approximately one SD [29] (Table 49.4). Small differences may explain, in part, regional differences in fracture rates, for example the lower fracture rates reported from Canada compared to the USA or Sweden [30]. Notwithstanding, the variations in BMD between populations appear to be substantially less than variations in fracture risk. Indeed, age- and sex-specific risks of hip fracture differ more than 10-fold, even within Europe [30–33]. These differences are very much larger than can be accounted for by any differences in BMD between
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Table 49.3 Prevalence (%) of osteoporosis in population-based cohorts from different regions of the world by age and sex Age (years) Study
Region
50
60
70
80
90
Europe Europe Canada Netherlands Australia USA Japan
2.4 0.6 0.5 1.0 0.5 1.0 0.9 0.6
4.8 1.4 1.5 2.2 1.4 2.0 2.2 1.7
7.6 3.7 4.3 4.8 4.1 4.1 5.1 4.3
14.0 9.2 11.6 10.4 11.4 8.2 11.4 10.4
– 21.0 27.9 20.8 28.2 15.7 23.5 22.6
Europe Europe Canada Netherlands Australia USA Japan
5.4 3.8 2.9 4.0 3.6 1.9 5.6 3.4
12.3 8.5 7.8 9.2 8.8 6.2 10.7 8.5
24.5 17.9 19.1 19.8 20.0 18.8 19.5 19.2
43.3 33.9 39.8 37.6 39.1 44.8 32.8 37.7
– 54.6 64.9 59.4 62.2 73.9 49.7 61.3
Men Sweden EVOS CaMos Rotterdam Dubbo Rochester Hiroshima All cohorts Women Sweden EVOS CaMos Rotterdam Dubbo Rochester Hiroshima All cohorts
Reproduced with permission of WHO Collaborating Centre for Metabolic Bone Diseases, University of Sheffield, UK [4, 25].
Table 49.4 Mean (SD) spine and femoral neck BMD (g/cm2) adjusted using linear regression to age 35 years, height 170 cm and weight 70 kg in men and age 35 years, height 160 cm and weight 60 kg for women. Differences between centers are highly significant (P 0.001 for all) Men Spine
Ankara Beijing Cape Town Debrecen Manila Moscow Obninsk Santiago Sao Paulo Shanghai Singapore Toronto Zagreb
Women Femoral neck
Spine
Femoral neck
Mean
SD
Mean
SD
Mean
SD
Mean
SD
1.060 1.082 1.077 0.967 1.054 1.067 1.132 1.080 0.957 0.992 1.058 1.062 0.998
0.147 0.128 0.172 0.124 0.144 0.152 0.139 0.137 0.166 0.103 0.148 0.159 0.144
0.946 0.908 0.898 0.874 0.920 0.969 0.950 0.935 0.852 0.832 0.920 0.882 0.854
0.139 0.121 0.131 0.137 0.134 0.144 0.115 0.128 0.147 0.094 0.133 0.183 0.110
1.037 1.115 1.109 1.033 1.055 1.058 1.085 1.103 0.998 1.000 1.083 1.139 1.042
0.130 0.105 0.150 0.104 0.143 0.136 0.129 0.126 0.151 0.117 0.135 0.148 0.099
0.872 0.857 0.864 0.818 0.817 0.868 0.849 0.874 0.840 0.793 0.842 0.860 0.850
0.109 0.102 0.115 0.087 0.111 0.131 0.111 0.110 0.142 0.105 0.119 0.123 0.114
From Parr et al. Contribution of calcium and other dietary components to global variations in bone mineral density in young adults. Food Nutr Bull 2002;23(3 Suppl):180-84 [29].
communities. In Asia, hip fracture risk is lower than in Northern Europe or the USA, but BMD is also lower [29, 34, 35]. In view of the disparity between population fracture risks and BMD, it is uncertain whether reference ranges drawn from local populations would be of any added value.
It would seem appropriate to use the large and adequately sampled NHANES III reference values until further research tempers this view [8]. A caveat, however, is that the same BMD in different geographic locations (or in different ethnicities) does not necessarily carry the same risk of fracture.
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Limitations There are a number of limitations in the general application of DXA for the diagnosis of osteoporosis which should be recognized [36]. The presence of osteomalacia, a complication of poor nutrition in the elderly, will underestimate total bone mass because of decreased mineralization of bone. Osteoarthrosis at the spine or osteoarthritis at the hip are common in the elderly and contribute to the density measurement, but not necessarily to skeletal strength. Heterogeneity of density due to osteoarthrosis, previous fracture or scoliosis is more problematic at the lumbar spine, but can often be detected on the scan and, in some cases, excluded from the analysis. Some of these problems can be overcome with adequately trained staff and rigorous quality control [37]. As mentioned, the DXA image is two-dimensional and therefore provides an areal BMD rather than a true volumetric BMD. As a consequence, the computation of BMD is sensitive to changes in bone size. For example, areal bone density will overestimate true volumetric bone density in individuals with large bones. In adults, this error is fortuitously beneficial since larger bones in general also have higher strength. Additionally, men have larger bones than women. Thus, this ‘error’ may improve fracture prediction in adults. The clinical consequences of osteoporosis are fragility fractures, the causation of which is multifactorial. This includes factors related to falls as well as additional skeletal factors not captured by BMD, such as the microarchitectural organization of bone. For example, the incidence of hip fracture increases about 40-fold between the ages of 50 and 80 years in many countries; over the same interval, BMD decreases. From the change in BMD and the known relationship between BMD and fracture risk, hip fractures would be expected to increase only about fourfold [25]. Thus, the contribution of BMD to hip fracture risk is a relatively small component of age-dependent risk. The contribution of BMD to other fracture outcomes is even less, because the gradient of risk per SD change is lower than that at the hip for hip fracture prediction. These limitations of BMD indicate that BMD will never discriminate completely between patients who will or have fractured from those without fracture. This provides the rationale for incorporating independent clinical risk factors to improve fracture prediction by BMD [4, 38–42]. Although the sensitivity of BMD for fracture prediction is low over most reasonable assumptions, the specificity is high [39, 43]. Thus, many fractures will occur in individuals with BMD values in the normal range, but fracture risk there is quite low. By contrast, fracture risk is very high in individuals with osteoporosis. There is an appropriate analogy with several other multifactorial diseases, such as hypertension and stroke. Blood pressure is continuously distributed in the population (as is BMD) and hypertension is an important cause of stroke (high specificity). But many individuals with stroke are normotensive (low sensitivity).
There is a growing awareness that treatments should be targeted on the basis of fracture risk rather than solely on the information provided by a BMD test. As mentioned, several clinical risk factors provide information on fracture risk over and above that captured by BMD [4, 39]. The measurement of risk most suited for their integration is the absolute risk, expressed as the probability of fracture within a given time frame, e.g. the 10-year fracture probability in %. Thus, intervention thresholds will be based on fracture risk and differ, therefore, from diagnostic thresholds. In this context, it is relevant to question the need for diagnostic criteria when the field is moving towards risk-based assessment and intervention. These developments will certainly decrease the clinical utility of the T-score, but they will, however, take time to implement into routine clinical practice. Notwithstanding, diagnostic criteria remain of value in quantifying the burden of disease and the development of strategies to combat osteoporosis in the foreseeable future.
References 1. Consensus Development Conference, Diagnosis, prophylaxis and treatment of osteoporosis, Am. J. Med. 94 (1993) 646–650. 2. World Health Organization, Assessment of fracture risk and its application to screening for postmenopausal osteoporosis Technical Report Series 843, WHO, Geneva, 1994. 3. J.A. Kanis, L.J. Melton, C. Christiansen, C.C. Johnston, N. Khaltaev, The diagnosis of osteoporosis, J. Bone Miner. Res. 9 (1994) 1117–1141. 4. J.A. Kanis on behalf of the World Health Organization Scientific Group, Assessment of osteoporosis at the primary health-care level, Technical Report, WHO Collaborating Centre, University of Sheffield, UK, 2008. 5. World Health Organization, Assessment of osteoporosis at the primary health care level, WHO, Geneva, 2007 (www.who. int/chp/topics/rheumatic/en/index.html/). 6. J.A. Kanis, E.V. McCloskey, H. Johansson, A. Oden, L.J. Melton, N. Khaltaev, A reference standard for the description of osteoporosis, Bone 42 (2008) 467–475. 7. A.C. Looker, H.W. Wahner, W.L. Dunn, M.S. Calvo, T.B. Harris, S.P. Heyse, Updated data on proximal femur bone mineral levels of US adults, Osteoporos. Int. 8 (1998) 468–486. 8. J.A. Kanis, C.C. Glüer for the Committee of Scientific Advisors, International Osteoporosis Foundation, An update on the diagnosis and assessment of osteoporosis with densito metry, Osteoporos. Int. 11 (2000) 192–202. 9. E. Orwoll, Assessing bone density in men, J. Bone Miner. Res. 15 (2000) 1867–1870. 10. P.L. Selby, M. Davies, J.E. Adams, Do men and women fracture bones at similar bone densities, Osteoporos. Int. 11 (2000) 153–157. 11. M. Lunt, D. Felsenberg, J. Reeve, et al., Bone density variation and its effects on risk of vertebral deformity in men and women studied in thirteen European centers: the EVOS Study, J. Bone Miner. Res. 12 (1997) 1883–1894. 12. T. Nguyen, P. Sambrook, P. Kelly, et al., Prediction of osteoporotic fractures by postural instability and bone density, Br. Med. J. 307 (1993) 1111–1115.
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13. L.J. Melton III, E.J. Atkinson, M.K. O’Connor, W.M. O’Fallon, B.L. Riggs, Bone density and fracture risk in men, J. Bone Miner. Res. 13 (1998) 1915–1923. 14. J.A. Kanis, O. Johnell, A. Oden, C. De Laet, D. Mellstrom, Diagnosis of osteoporosis and fracture threshold in men, Calcif. Tissue Int. 69 (2001) 218–221. 15. S.L. Hui, C.W. Slemenda, C.C. Johnston, Age and bone mass predictors of fracture in a prospective study, J. Clin. Invest. 81 (1998) 1804–1809. 16. O. Johnell, J.A. Kanis, A. Oden, et al., Predictive value of bone mineral density for hip and other fractures, Osteoporos. Int. 20 (2005) 1185–1194. 17. L.J. Melton III, E.S. Orwoll, R.D. Wasnich, Does bone density predict fractures comparably in men and women? Osteoporos. Int. 12 (2001) 707–709. 18. S.R. Cummings, P.M. Cawthon, K.E. Ensrud, J.A. Cauley, H.A. Fink, E.S. Orwoll Osteoporotic Fractures in Men (MrOS) Research Groups; Study of Osteoporotic Fractures Research Groups, BMD and risk of hip and nonvertebral fractures in older men: a prospective study and comparison with older women, J. Bone Miner. Res. 21 (2006) 1550–1556. 19. C.E. de Laet, M. van der Klift, A. Hofman, H.A. Pols, Osteoporosis in men and women: a story about bone mineral density thresholds and hip fracture risk, J. Bone Miner. Res. 17 (2002) 2231–2236. 20. C.E.D.H. de Laet, B.A. Van Hout, H. Burger, A. Hofman, A.E.A.M. Weel, H.A.P. Pols, Hip fracture prediction in elderly men and women: validation in the Rotterdam Study, J. Bone Miner. Res. 13 (1998) 1587–1593. 21. B. Dawson-Hughes, A.N. Tosteson, L.J. Melton III et al. National Osteoporosis Foundation Guide Committee, Implications of absolute fracture risk assessment for osteoporosis practice guidelines in the USA, Osteoporos. Int. 19 (2008) 449–458. 22. J.A. Kanis, E.V. McCloskey, H. Johansson, O. Strom, F. Borgstrom, A. Oden, and the National Osteoporosis Guideline Group, Case finding for the management of osteoporosis with FRAX® – Assessment and intervention thresholds for the UK, Osteoporos. Int. 19 (2008) 1395–1408. 23. J.A. Kanis, C.C. Glüer for the Committee of Scientific Advisors, International Osteoporosis Foundation, An update on the diagnosis and assessment of osteoporosis with densito metry, Osteoporos. Int. 11 (2000) 192–202. 24. K.G. Faulkner, E. von Stetten, P. Miller, Discordance in patient classification using T-scores, J. Clin. Densitom. 2 (1999) 343–350. 25. J.A. Kanis, O. Johnell, A. Oden, B. Jonsson, C. De Laet, A. Dawson, Risk of hip fracture according to the World Health Organisation criteria for osteopenia and osteoporosis, Bone 27 (2000) 585–590. 26. D. Marshall, O. Johnell, H. Wedel, Meta-analysis of how well measures of bone mineral density predict occurrence of osteo porotic fractures, Br. Med. J. 312 (1996) 1254–1259. 27. L.J. Melton III, Adverse outcomes of osteoporotic fractures in the general population, J. Bone Miner. Res. 18 (2003) 1139–1141. 28. O. Johnell, J.A. Kanis, A. Oden, et al., A comparison of total hip BMD as a predictor of fracture risk: a meta-analysis, J. Bone Miner. Res. 20 (Suppl. 1) (2005) S4.
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29. R.M. Parr, A. Dey, E.V. McCloskey, et al., Contribution of calcium and other dietary components to global variations in bone mineral density in young adults, Food Nutr. Bull. 23 (3 Suppl.) (2002) 180–184. 30. J.A. Kanis, O. Johnell, C. De Laet, B. Jonsson, A. Oden, A.K. Oglesby, International variations in hip fracture probabilities: implications for risk assessment, J. Bone Miner. Res. 17 (2002) 1237–1244. 31. L. Elffors, E. Allander, J.A. Kanis, et al., The variable incidence of hip fracture in Southern Europe. The MEDOS Study, Osteoporos. Int. 4 (1994) 253–263. 32. W.E. Bacon, S. Maggi, A. Looker, et al., International comparison of hip fracture rates in 1988–1989, Osteoporos. Int. 6 (1996) 69–75. 33. O. Johnell, B. Gullberg, E. Allander, J.A. Kanis, The apparent incidence of hip fracture in Europe: a study of national register sources. MEDOS Study Group, Osteoporos. Int. 2 (1992) 298–302. 34. L.J. Melton III, The prevalence of osteoporosis, J. Bone Miner. Res. 12 (1997) 1769–1771. 35. P.D. Ross, Y. He, A.J. Yates, et al., Body size accounts for most differences in low density between Asian and Caucasian women: the EPIC study group, Calcif. Tissue Int. 59 (1996) 339–343. 36. J.A. Kanis, P. Delmas, P. Burckhardt, C. Cooper, D. Torgersonon, behalf of the European Foundation for Osteoporosis and Bone Disease, Guidelines for diagnosis and management of osteo porosis, Osteoporos. Int. 7 (1997) 390–406. 37. N. Binkley, J.P. Bilezikian, D.L. Kendler, E.S. Leib, E.M. Lewiecki, S.M. Petak, Summary of the international society for clinical densitometry 2005 position development conference, J. Bone Miner. Res. 22 (2007) 643–645. 38. D.M. Black, M. Steinbuch, I. Palermo, et al., An assessment tool for predicting fracture risk in postmenopausal women, Osteoporos. Int. 12 (2001) 519–528. 39. J.A. Kanis, D. Black, C. Cooper et al. International Osteo porosis Foundation; National Osteoporosis Foundation, A new approach to the development of assessment guidelines for osteoporosis, Osteoporos. Int. 13 (2002) 527–536. 40. J.A. Kanis, F. Borgstrom, C. De Laet, et al., Assessment of fracture risk, Osteoporos. Int. 16 (2005) 581–589. 41. K. Siminoski, W.D. Leslie, H. Frame, et al., Recommendations for bone mineral density reporting in Canada: a shift to absolute fracture risk assessment, J. Clin. Densitom. 10 (2007) 120–123. 42. C.E. Lewis, S.K. Ewing, B.C. Taylor et al. Osteoporotic Fractures in Men (MrOS) Study Research Group, Predictors of non-spine fracture in elderly men: the MrOS study, J. Bone Miner. Res. 22 (2007) 211–219. 43. E. Siris, P. Miller, E. Barrett-Connor, et al., Identification and fracture outcomes of undiagnosed low bone mineral density in postmenopausal women. Results from the National Osteoporosis Risk Assessment, J. Am. Med. Assoc. 286 (2001) 2815–2822.
Chapter
50
Cost-Effectiveness of Interventions to Reduce Osteoporosis-Related Fractures in Men: Current Data, Controversies, and Challenges John T. Schousboe Park Nicollet Health Services, Minneapolis; Division of Health Policy & Management, School of Public Health University of Minnesota, Minnesota, USA
Introduction
Based on the age-specific femoral neck T-score and Z-score thresholds below which the hip fracture risk exceeds this threshold and the proportion of Caucasian men age 55 to 84 below these Z-score thresholds [6], a minimum of 4 million Caucasian men would be eligible for drug therapy each year. For fracture prevention therapy with a yearly cost of $250, the total yearly cost to treat these men could be as high as $1 billion. These costs may be an appropriate expenditure of societal resources but, given their magnitude, the cost-effectiveness of such a large and expensive intervention program certainly bears scrutiny. Moreover, the incidence and societal burden of Alzheimer’s disease, cardiovascular disease, diabetes mellitus and other chronic diseases are also increasing, creating substantial competition for societal resources [7]. Faced with these realities, most industrialized countries now explicitly consider the cost-effectiveness of proposed new health-care technologies or health-care programs that require some upfront financial investment before they approve them [8, 9]. To be sure, the use of cost-effectiveness data to set health policy remains controversial and these data remain guides for rather than determinants of policy [10–12]. While approval of new health-care diagnostic and therapeutic technologies or application of pre-existing ones to new populations in the USA are not routinely done on the basis of cost-effectiveness criteria, the Veterans Health Administration [9] and some managed care organizations [8] now also consider cost-effectiveness analyses when making decisions about inclusion of pharmaceutical agents on their formularies.
Osteoporosis and related fractures continue to be a major, growing cause of morbidity and health-care costs throughout the world in both industrialized and industrializing countries. Although the incidence and total cost, respectively, of fractures related to osteoporosis are only onehalf and one-third that of women, the societal burden of fractures related to osteoporosis is substantial even when considering men alone [1–3]. Osteoporotic fractures were estimated to result in $2 billion in direct medical costs among American men in 2005 and these costs are projected to rise by an additional 49% by 2025 [1]. Among Swiss men, osteoporotic fractures were the cause of more days in hospital than stroke, myocardial infarction, diabetes mellitus and heart failure in 2000 [4]. Given the high incidence of osteoporosis and the substantial proportion of the older male population considered to be at high risk of fracture, the societal costs to identify those men at high risk of fracture and then treat them to reduce their fracture risk is also huge. Performing bone densitometry as per the guidelines of the US National Osteoporosis Guidelines for all US men aged 70 and older as of the 2000 US census (assuming a cost per test of $2, the 2007 median US Medicare reimbursement rate [5]) would cost initially $21 million and repeating these tests once every two years $10 million per year. Moreover, current guidelines suggest that pharmacologic fracture prevention therapy should be offered to all men age 55 and older with an estimated 10-year hip fracture risk of 3% or higher. Osteoporosis in Men
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While the Centers for Medicare and Medicaid services (CMS) are by statute prevented from using cost-effectiveness data when making coverage decisions [13], CMS does have the ability to use cost-effectiveness data when determining how much to reimburse for a particular diagnostic or therapeutic intervention and when designing payment-forperformance initiatives that increasingly are being used to incentivize providers toward use of some health-care technologies and away from others [14]. The Medicare Payment Advisory Commission has recommended that CMS expand its use of cost-effectiveness analyses in these ways to improve the efficiency of health-care expenditure for the populations covered by these programs [14] and the American College of Physicians has issued a Position Statement articulating the need for comparative effectiveness research to include costeffectiveness [15]. Given the high incidence of osteoporotic fractures in elderly men and their projected increase over the next 20 years, it is clear that the cost-effectiveness of identifying those men who are at high risk of fracture is of significant importance for health-care payers and societies that have limited budgets with which to address the health-care needs of their constituents. Moreover, in the absence of robust, credible cost-effectiveness data supporting the efficiency of interventions to identify those men at high risk of fracture and treat them, there is a real risk that funding the identification of men at risk of fracture and treatment to lower that risk will be given lower priority by health-care payers than what is warranted. In this chapter, we will first review the features of high quality cost-effectiveness studies. With these in mind, the eight cost-effectiveness studies of osteoporosis detection and treatment that to date have been applied to men will be reviewed, describing the strengths and shortcomings of each. The uncertainties regarding the cost-effectiveness of osteoporosis detection and treatment in men that remain will be discussed and a future research agenda to address these shortcomings suggested.
Characteristics of good health economic modeling studies Cost-effectiveness assessments estimate the costs of healthcare interventions relative to their health benefits. The relative cost-effectiveness of one intervention to address a health problem compared to another is expressed as the incremental cost-effectiveness ratio (ICER): (CostsIntervention Costs Comparator )/ (Health BenefitsIntervention Health Benefits Comparator ) where the comparator can be a competing intervention strategy or no intervention. Typically, an intervention will prevent the development of a clinical event, modeled
as a health state, that is associated with a reduced health status or quality of life. Hence, health benefits can be expressed as specific events, such as number of fractures averted. More commonly, health benefits are expressed as quality adjusted life years, or QALYs, which are generally postulated to be lower for some period of time after a fracture compared to someone who has not had a fracture [16]. This metric allows the net health benefits to be expressed as a single value for those interventions that change health status in more than one way. For example, raloxifene may reduce the incidence and quality of life loss from both vertebral fracture and breast cancer [17]. For health-care payers, this also allows the efficiency of health-care intervention programs that address different medical problems within the population to be compared and can inform expenditure decisions. Most cost-effectiveness studies are computer modeling rather than empirical studies, for many reasons [18–20]. First, many health-care interventions have long-term consequences for quantity and quality of life and randomized and observational studies are rarely carried out long enough to capture those long-term consequences. Second, few randomized or observational studies collect quality of life data so that the health benefits of the intervention(s) can be expressed as QALYs gained. Third, randomized and most observational studies are not generally representative of the population at large and modeling is required to assess the costs and health benefits of the intervention(s) for segments of the population poorly represented in the empiric studies. Estimates of cost-effectiveness, however, are often quite sensitive to how the interventions are structured in the model, as well as model inputs such as the incidence of the target condition, costs of the intervention, effectiveness of the intervention and the quality of life loss associated with clinical events such as fractures, breast cancer, cardiovascular disease events and so on. Therefore, there are a myriad number of ways in which cost-effectiveness models can be biased and, for these reasons, the US Preventive Services Task Force commissioned a task force in the 1990s to establish good practices for cost-effectiveness modelers in order to improve the transparency, consistency, quality and informative value of published cost-effectiveness studies [17]. First, the institution or entity from whose perspective the study is being conducted needs to be identified. If the societal perspective is employed, all costs and benefits of the modeled interventions for all members of society need to be included. If the health plan or health-payer perspective is used, then costs of informal care by family and friends and out of pocket costs by patients are not relevant because they are not borne by health payers. Implicit in this, all adverse consequences of the interventions must be identified. For example, if side effects cause significant loss of quality of life or additional health-care costs, excluding them from the model will significantly bias the estimated costeffectiveness in favor of the intervention. If the additional costs and/or quality of life loss from an adverse event are
C h a p t e r 5 0 Cost-Effectiveness of Interventions to Reduce Osteoporosis-Related Fractures in Men l
not a transient, one-time phenomenon but rather accumulate over time, then typically the model needs to include a health state for that adverse event to capture fully these costs and/or quality of life loss. If the societal perspective is adopted, then many argue that the costs of added life years should be added [21, 22]. The principle behind the addition of these costs is that, if an intervention actually does improve life expectancy, then the net consumption of these individuals during the years of added life expectancy is a cost from the intervention that has to be borne by society at large. Retired elderly populations typically do consume significantly more resources (such as housing, food, medical care for remaining health problems) than they produce. Second, the time horizon of the study needs to be clearly stated [19]. This refers to the time span over which the model calculates accumulated costs and health benefits. If an intervention results in costs or benefits that accrue beyond the time horizon of the study, again their exclusion will bias the results of the study. For example, most costeffectiveness studies of fractures use a life-time horizon to capture fully the long-term care nursing home costs and quality of life loss thought to be life-long consequences for a minority of those who suffer a hip fracture. Third, model parameters (be they costs, rates of health events or estimates of quality of life associated with health states) need to be estimated as much as possible from welldone empiric studies that enrolled populations representative of those for whom the results of the cost-effectiveness model are claimed to be applicable. A corollary to this is that the target population for the cost-effectiveness study needs to be clearly identified. The sources of these parameters need to be clearly identified. Those parameter estimates that can be derived from large well-done meta-analyses tend to carry more weight than parameter estimates from small studies and/or one single larger study. Fourth, the methods of estimation of costs associated with the intervention and direct medical costs for incident events (such as fractures or adverse medication reactions) need to be stated clearly, if not directly in the main publication of the study or in the technical report of the study, then with clear references to publications that fully disclose those details [23]. For example, studies that estimate the direct medical costs of fractures that count only those units of health-care utilization associated with a primary fracture diagnosis code may underestimate the true direct medical costs associated with that fracture. Fifth, if quality-adjusted life years are used as the measure of health benefits, the method of estimation of disutility associated with incident events needs either to be clearly delineated in the main publication or technical report of the study, or else reference other studies that fully disclose those details [16]. The specific way that disutility associated with incident events is modeled can have a significant impact on the estimated cost-effectiveness of health interventions.
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Sixth, the discount rates used in the study, specifically, the rates at which future costs and benefits are devalued relative to the present, need to be specified. The concept of discounting is based on the psychologic concept of time preference, which refers to the degree to which humans prefer to enjoy consumption now than to defer that consumption such that future costs and benefits have less value than in the present time [24]. The discount rate for monetary resources has been theorized to be equal to the marginal rate of return on very safe investments (2.5–5% per year), but discount rates for health benefits are more controversial. The US Public Health Service Panel on Cost-Effectiveness in Health and Medicine has recommended that costs and health benefits be discounted equally at 3% per year [24]. The National Institute of Clinical Excellence in the UK in the past recommended a discount rate of 6% for costs and 1.5% for health benefits but now recommends that both be discounted at 3.5% [25], although some still argue for disounting health benefits less than costs [26]. The cost-effectiveness of prevention programs, where intervention costs are incurred in proximal time periods and health benefits realized in distal time periods, will appear to be significantly more attractive if health benefits are discounted at a much lower rate than costs than if these two discount rates are assumed to be equal. Seventh, specifically with respect to fracture prevention anti-resorptive agents, the offset of fracture reduction benefit needs to be specified. Oral bisphosphonates bind sufficiently strongly to bone such that small amounts can be found in the urine years after their discontinuation. There is suggestive evidence, based on changes in markers of bone metabolism following a few to several years of oral bisphosphonate therapy, that fracture reduction benefit may persist for some period of time after their discontinuation [27]. The assumed changes with fracture reduction benefit following discontinuation of drug therapy need to be clearly stated in cost-effectiveness studies of fracture prevention therapy.
Review of cost-effectiveness studies in men The far majority of the cost-effectiveness studies of fracture prevention interventions have focused on postmenopausal women [28–31]. Eight studies to date of treatment of men at high risk of fracture to prevent fractures have been done, six of which focused on older men within the population at large and two of which concerned those men on chronic systemic glucocorticoid therapy (Tables 50.1 and 50.2). This section will review each of these studies in detail considering foremost the characteristics of well-done costeffectiveness studies.
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Osteoporosis in Men Table 50.1 Male osteoporosis modeling studies
Study
Population
Perspective, time horizon
Health states
Included costs, sources
Included QALYs, sources
Older males aged 71 with the characteristics of the FIT population. Male Fx rates Malmo Sweden Kanis et al 2005 [33] Hypothetical male population starting age 50 to 80. Absolute 10-year hip Fx risk at which Rx is cost-effective calculated
Societal and health payer, lifetime (age 100)
Well, hip Fx, clinical Direct medical costs EQ-5D estimates acute Fx patients vertebral Fx, wrist Costs of added life fracture (societal perspective). Malmo Sweden Upfront screening costs not included
Health payer (added life year costs excluded)
Schwenkglenks and Lippuner 2007 [34]
Societal, lifetime
Direct medical costs from Sweden, 2001 US$ Costs of intervention; $200 to $500 Non-hip Fx costs expressed as hip Fx equivalents Hip fracture, vertebral Direct medical fracture, wrist cost data from fracture Switzerland, 2000 Swiss CHF
Borgstrom et al 2004 [32]
Hypothetical cohorts men and women aged 50; Rx of those with femoral neck T-score 2.5 Schousboe 2007 [35] Hypothetical cohorts USA men aged 65–85 with and without prior fracture. Rx of those with femoral neck T-score 2.5 Schousboe 2008 [36] Hypothetical Cohorts USA Men and Women without prior fracture, age 65–85; Rx of those with femoral neck T-score 2.5 Tosteson et al Hypothetical cohorts 2008 [37] of US men & women aged 50 to 85, according to ethnicity (white, AfricanAmerican, Hispanic, Asian) Rx based on 10-year absolute fracture risk Van Staa et. al Men and women age 2007 [38] 40 in UK GPRD database on chronic glucocorticoid Rx
Kanis et al 2007 [39] Men and women aged 50 to 80 ever treated with oral glucocorticoid therapy, duration undefined Fx: Fracture; Rx: treatment
Hip fracture, clinical vertebral fracture, wrist, prox hum, other (dist femur, prox tibia [women], pelvis, rib, sternum, scapula, clavicle)
Hip Fx from Malmo Sweden. All other from NOF 1998 assumptions. Nonhip Fx QALY loss expressed as hip Fx equivalents EQ-5D estimates acute Fx patients Malmo Sweden
Societal, until age 105
Direct medical cost Hip, clinical estimates Rochester, vertebral, MN, 2004 US$ radiographic vertebral, wrist, other
EQ-5D estimates acute Fx patients Malmo Sweden
Societal, until age 105
Hip, clinical vertebral, radiographic vertebral, wrist, other
Direct medical cost estimates Rochester, MN Jan 2008 US$
EQ-5D estimates acute Fx patients Malmo Sweden
Societal, until age 100
Hip, clinical Direct medical cost vertebral, wrist, other estimates Rochester, MN 2005 US$
EQ-5D estimates acute Fx patients Malmo Sweden
Health payer, 6 years Hip, clinical vertebral, radiographic vertebral, wrist, proximal humerus Both health payer and Hip, clinical societal, lifetime vertebral, wrist, proximal humerus, other (ribs, pelvis, clavicle, scapula, sternum)
Population-based QALYs for overall direct medical UK population. fracture costs for UK QALYs saved was only through avoiding mortality attributed to fracture Population-based EQ-5D estimates direct medical acute Fx patients fracture costs for UK Malmo Sweden
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Table 50.2 Male osteoporosis modeling studies Drug therapy, effectiveness
Treatment duration, offset
Borgstrom et al 2004 [32] 3% costs 3% health benefits
Alendronate RR hip: 0.49, wrist 0.52, clin vert 0.46
5 years Rx, 5 years offset
Kanis et al 2005 [33]
3% costs 3% health benefits
35% all fractures (base case) varied from 10% to 50%
5 years Rx, 5 years offset
Schwenkglenks and Lippuner 2007 [34]
3% costs 3% health benefits
FN T-score 2.5: Age 85 RR 0.5 all Fxs Age 85 RR 0.6 all Fxs FN T-score 2.5: RR 0.7 vert Fx RR 1.0 other Fxs
5 years Rx, 5 years offset
Schousboe 2007 [35]
3% costs
RR vert Fx 0.36
5 years Rx, 5 years offset
3% health benefits
RR non-vert Fx 0.73
3% costs 3% health benefits
RR vert Fx 0.36 RR non-vert Fx 0.73
Study
Schousboe 2008 [36]
Discount rates
5 years Rx, 5 years offset
Results Health plan perspective: €5314/QALY Societal perspective: €14 843/QALY Costs/QALY sensitive to fracture rates, discount rates, offset of Fx reduction benefit, prevalent vertebral fracture status 10-year hip Fx probability at which Rx was costeffective was 1.98 aged 50 to 6.16 for men aged 80 Results very sensitive to assumed effectiveness of drug, especially for hip fracture, offset time of Rx benefit, cost of drug therapy. Less sensitive to discount rates, duration of Rx 1 DXA for women age 50–74 with a fracture followed by universal DXA preferred 2 No intervention preferred for men without a prior fracture 1 DXA & alendronate preferred over no intervention for men with prior fracture age 65 and older 2 DXA & alendronate preferred over no intervention for men without prior fracture aged 80 & older For without a prior fracture, drug cost $500/year; DXA screen & treat is cost-effective for men aged 65: 0% to 45% men aged 75: 47% to 81% men aged 85: 89% to 100% Depending on societal willingness to pay for health benefits (Continued)
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Osteoporosis in Men Table 50.2 (Continued) Drug therapy, effectiveness
Treatment duration, offset
3% costs 3% health benefits
RR All fractures 0.65
5 years Rx, 5 years offset
Van Staa et al 2007 [38]
6% costs 1.5% health benefits
5 years Rx, RR on oral bisphosphonate versus No 1 year offset Rx vertebral Fx 0.56, hip Fx 0.62 other Fxs 0.81
Kanis et al 2007 [39]
6% costs 1.5% health benefits
RR Risedronate: base case: vert Fx 0.33 non-vert Fx 1.0 Secondary case: RR vert Fx 0.57, hip Fx 0.61 all other Fx 0.81
Study
Discount rates
Tosteson et al 2008 [37]
5 years Rx, 5 years offset
Results Absolute 10-year hip fracture risks for both men and women all ethnicities above which Rx is cost-effective: Aged 50: 2.4% to 2.5% men and women Aged 60: 2.9% to 3.0% women, 3.8% to 4.2% men Aged 70: 3.8% to 4.2% women, 4.4% to 5.1% men Aged 80: 4.0% to 4.3% women, 3.7% to 4.3% men Costs per QALY gained for Rx of men 5 mg prednisone per day: £41 000 15 mg prednisone per day: £30 000 Costs per QALY gained with Rx (regardless of BMD) No Rx benefit for nonvertebral fracture If history prior fracture: aged 50, £175 000; aged 75, £35 000 No history prior fracture: aged 50, £351 000; aged 75, £72 000 Rx benefit for nonvertebral fracture included If history prior fracture: aged 50, £115 000; aged 75, £3000 No history prior fracture: aged 50, £235 000; aged 75, £23 000
Fx: Fracture; Rx: treatment; DXA: dual energy x-ray absorptiometry
Studies of Intervention for Elderly Men at High Risk of Fracture Based on Bone Mineral Density Three studies have estimated the cost-effectiveness of antiresorptive treatment of older men who specifically are known to have low bone mineral density. Borgstrom and colleagues examined the cost-effectiveness of alendronate therapy for a hypothetical male population with the same age and femoral neck bone mineral density as the female population with
prevalent vertebral fracture that enrolled in the Vertebral Fracture Arm of the Fracture Intervention Trial (FIT) [32]. Post hip fracture, post clinical vertebral fracture and post wrist fracture were included as health states, but fractures at other sites were not included. Age-specific fracture probabilities were assumed to be those of the male Swedish population, adjusted for the mean bone mineral density of the hypothetical cohorts. The upfront costs of screening bone densitometry to identify the treatment cohort were not included. The mean age and femoral neck T-score of men with prevalent vertebral
C h a p t e r 5 0 Cost-Effectiveness of Interventions to Reduce Osteoporosis-Related Fractures in Men l
fracture, respectively, were assumed to be 71 years and 2.7. From a health-payer perspective, the cost per QALY gained with 5 years of alendronate therapy compared to no intervention was €5314. For the analysis assuming a societal perspective with costs of added life years included, the cost per QALY gained for alendronate therapy was €14 843/QALY. In the clinical fracture arm of FIT that enrolled women without prevalent vertebral fracture, non-vertebral fracture reduction could be demonstrated only for that subset with a femoral neck T-score of 2.5 or lower [40]. Borgstrom and colleagues also examined the cost-effectiveness of 5 years of alendronate therapy for a hypothetical male population without prevalent vertebral fracture with the same mean age of the Clinical Fracture Arm of FIT (69 years) and a femoral neck bone mineral density T-score of 2.5 or lower. Again, the upfront costs of screening bone densitometry to identify the treatment cohort were not included. The costs per QALY gained from the health-payer and societal perspectives, respectively, were €48 805 and €59 285 and, hence, alendronate for men without prevalent vertebral fracture for this scenario was judged not to be cost-effective. However, for those without prevalent vertebral fracture, alendronate was assumed to reduce the risk only of incident hip fractures and not of clinical vertebral or wrist fractures. These results were also sensitive to the assumed offset of fracture reduction benefit following discontinuation of alendronate. The costs per QALY gained were fivefold higher under the assumption of immediate loss of fracture reduction benefit compared to assuming a gradual 10-year loss of fracture reduction benefit after discontinuation of alendronate. The apparent cost-effectiveness of alendronate was also moderately sensitive to changes in discount rates and the assumed quality of life loss attributable to fractures. The analyses assumed 100% compliance and did not include sensitivity analyses assuming lower levels of compliance. Importantly, this study did not include fractures at skeletal sites other than the spine, hip or wrist. Moreover, incident radiographic (but clinically unapparent) fractures were not included. Given that they are not recognized clinically, the direct medical costs attributable to them may only be slight. They have, however, been shown nonetheless to be associated with some loss of quality of life and occur two to three times as frequently as clinically recognized vertebral fractures [41, 42]. Hence the exclusion of these fractures does bias upward the costs per QALY gained of alendronate therapy in this study. Schwenkglenks and Lippuner examined the costeffectiveness of alendronate therapy of elderly Swiss men and women, explicitly including the upfront costs of bone densitometry to identify the treatment cohort [34]. They modeled a complex intervention strategy of bone densitometry starting at age 50 for those who had a clinical fracture followed by 5 years of alendronate therapy for that subset with a femoral neck T-score of 2.5 or lower, combined with universal bone densitometry for the remaining men without a prior clinical fracture at ages of 65, 75 or 85 years. The authors reasoned
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that incident clinical fractures may appropriately trigger bone densitometry and treatment for those with osteoporosis and that, therefore, by the time the remaining population reaches a set universal bone densitometry screening age they will be at a lower fracture risk by virtue of those with prior clinical fracture already having been screened. They correctly noted that prior cost-effectiveness studies of universal bone densitometry that assumed that the entire population would receive their first bone density screening test at the specified universal screening age regardless of prior clinical fractures would underestimate the costs per QALY gained of the intervention if, in actual practice, those with prior clinical fractures were screened and treated before the universal screening age. Even assuming 100% compliance, the costs per QALY gained for men under this complex strategy utilizing universal bone densitometry for the men who had not had a clinical fracture by age 65, 75 and 85, respectively, were 150 000, 96 000 and 93 000 Swiss francs (CHF), well above the assumed societal willingness to pay per QALY gained threshold of 50 000 CHF. As expected, if a simpler strategy of model entry at ages 65, 75 or 85 were employed (i.e. assuming no densitometry and treatment of men at younger ages who had a clinical fracture), the costs per QALY gained for those age 65, 75 and 85, respectively, were lower at 136 000 CHF, 60 000 CHF and 31 000 CHF. Numerous studies of persistence with oral bisphosphonate therapy in actual clinical practice show a rapid decrease over the first year of therapy of those persisting with therapy with slower further decreases in persistence in subsequent years [43, 44]. When persistence with alendronate therapy was assumed to decrease over the first year of treatment from 100% to 65% and from 65% to 45% over the subsequent 4 years, then the costs per QALY gained with the complex strategy utilizing universal bone densitometry at ages 65, 75 and 85, respectively, were higher at 197 000 CHF, 123 000 CHF and 119 000 CHF. These results were again quite sensitive to a number of important parameters. Realistic changes in the assumed cost of alendronate, assumed baseline fracture risk in the population, discount rates and, especially, the assumed fracture reduction efficacy of alendronate produced more than twofold changes in the estimated cost per QALY gained with the complex intervention strategy. The assumed fracture reduction efficacy of alendronate in this study is especially noteworthy because it was assumed to be equal in men and women based on clinical trials that only enrolled women. The results were also moderately sensitive to the assumed preventable mortality attributable to hip fracture, disutility of fractures and the upfront diagnostic work-up costs before initiation of alendronate therapy. While this study did include incident radiographic (but clinically unapparent) vertebral fractures, incident fractures at skeletal sites other than the hip, spine or wrist were not included. Their exclusion biases upward the estimated costs per QALY gained of the intervention strategies.
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Schousboe and colleagues examined the cost-effectiveness of bone densitometry followed by 5 years of oral bisphosphonate therapy for that subset with a femoral neck Tscore of 2.5 or lower (assuming young male norms) for US Caucasian men at five screening ages (65, 70, 75, 80 and 85 years of age). Men who had a prior clinical fracture were considered separately from men without a prior clinical fracture [35]. For the base analysis, alendronate costs were assumed to be the mean wholesale price of alendronate in 2004, well before generic alendronate was available in the US market. This study not only included radiographic and clinical vertebral fractures, hip and wrist fractures, but also fractures at other skeletal sites (proximal and distal humerus, proximal forearm, sternum, clavicle, scapula, ribs, pelvis, distal femur, patella and tibia). The assumed efficacy of oral bisphosphonate therapy was based on the available randomized clinical trial data of alendronate therapy in elderly men. Persistence with oral bisphosphonate therapy was assumed to decrease from 100% to 65% at 1 year and from 65% to 55% from 1 to 5 years after onset of drug therapy. The costs per QALY gained for men with a prior clinical fracture ranged from $4,700 (2004 US dollars) for 85-yearold men to $48 000 for 65-year-old men. Among men without a prior clinical fractures, the costs per QALY gained for the intervention strategy ranged from $34 000 for 85-yearold men to $130 000 for 65-year-old men. Under the base case assumptions (including an assumed societal willingness to pay per QALY gained of $50 000), the intervention strategy appeared to be cost-effective for all men with a prior clinical fracture age 65 and older and for men without a prior clinical fracture age 80 and 85. However, if the cost of drug therapy was assumed to be less than $500 (2004 dollars) per year, then the intervention strategy appeared to be cost-effective even for 70-year-old men. The cost per QALY gained was only slightly higher if bisphosphonate therapy was given for those with a femoral neck T-score of 2.0 or lower and was only slightly lower if bisphosphonate therapy was given only to those with a femoral neck T-score of 3.0 or lower. Raising the T-score treatment threshold increases the proportion of those screened who are treated and therefore lowers the upfront screening cost per treated person, but this is offset by the fact the cohort selected for treatment is also at lower risk of fracture such that the number needed to treat to prevent a fracture is raised. As was true in other studies, these results were especially sensitive to both drug treatment cost and the assumed fracture reduction efficacy of drug therapy and moderately sensitive to assumptions regarding fracture rates, fracture disutility, medication adherence, the assumed relative risks of fractures associated with decreases in bone mineral density, prior clinical fracture and discount rates. Bone mineral density is not only determined by age and prior clinical fracture status but also by body weight [45–47] such that, among men without a prior clinical fracture, those that have lower body weight will have a higher pre-test probability of having bone density below a
treatment threshold value, which may effectively reduce the upfront bone densitometry screening costs per treated person. To test this, Schousboe and colleagues have extended their model to establish first for Caucasian men without a prior clinical fracture the pre-test probabilities of femoral neck osteoporosis being present at which the cost per QALY gained of the screen and treat strategy would be equal to the assumed societal willingness to pay per QALY gained [36]. The body weights for elderly Caucasian men which corresponded to these pre-test probabilities were calculated next from NHANES data and the proportions of Caucasian men below these weight thresholds in the US population calculated. If the societal willingness to pay per QALY gained is assumed to be $30 000 per QALY gained and drug therapy is assumed to cost $250 per year then, among Caucasian men without a prior fracture, the screen and treat strategy would be cost-effective for 91% of those 85 years of age, for 64% of those aged 75 years and for 26% those aged 65 years. If the assumed societal willingness to pay per QALY gained is $75 000 then, among Caucasian men without a prior fracture, bone densitometry followed by oral bisphosphonate therapy would be cost-effective for virtually all of those aged 85 years, 83% of those aged 75 years and 49% of those aged 65 years. In summary, these three studies are relatively consistent in showing that bone densitometry followed by oral bisphosphonate treatment for those with osteoporosis by bone density criteria is cost-effective compared to no intervention for older men if they have a prevalent vertebral fracture or a prior clinical fracture. For older men with neither a prevalent vertebral fracture nor a prior clinical fracture, the cost-effectiveness of bone densitometry followed by oral bisphosphonate therapy is less clear-cut. Although Schwenkglenks and Lippuner did not show this strategy to be cost-effective at any age, they did not include fractures at skeletal sites other than the spine, hip and wrist [34] and hence they may have underestimated the cost-effectiveness of intervention among these men. Bone densitometry followed by oral bisphosphonate therapy may be cost-effective for the oldest and thinnest of men without prior fracture. However, these results are quite sensitive not only to drug cost but also the assumed fracture reduction benefit of fracture prevention therapies. Unfortunately, a grand total of only 691 men have participated in a total of three separate randomized clinical trials of an oral bisphosphonate versus placebo [48–50] and meta-analyses of these have been unable to yield credible estimates of the non-vertebral fracture reduction efficacy of these medications in men [51].
Studies of Intervention for Elderly Men at High Risk of Fracture Based on Absolute 10-Year Fracture Risk There has been much dissatisfaction with the practice of tethering pharmacologic fracture prevention treatment to bone mineral density, largely because there are so many
C h a p t e r 5 0 Cost-Effectiveness of Interventions to Reduce Osteoporosis-Related Fractures in Men l
other factors that drive fracture risk including age, glucocorticoid use, prior fractures and prevalent vertebral fractures [52–55]. Cost-effectiveness studies that model fracture risk not in terms of bone density but rather in terms of absolute 10-year fracture risk have the large advantage that with this one metric they can incorporate many risk factors that predict fracture independently of each other. Kanis and colleagues calculated 10-year hip fracture risk thresholds at which 5 years of a theoretical fracture prevention agent would be cost-effective for the older female populations of Sweden [33] and the UK [56]. These authors subsequently extended these calculations for other European countries as well as Japan and the USA [57] incorporating differences in population fracture rates and estimated societal willingness to pay per QALY gained (estimated in each country to be two times the per capita gross domestic product). These models included not only hip, vertebral and wrist fractures, but also fractures of the humerus, pelvis, sternum, scapula, distal femur and ribs. Based on the proportion of fractures at each of these skeletal sites at each age and the ratios of disutility and costs of these fractures relative to hip fractures, these models are unique in that they expressed all costs and disutilities as ‘hip fracture equivalents’. Only one of these studies explicitly estimated the 10year absolute hip fracture risk thresholds at which 5 years of oral bisphosphonate therapy is cost-effective in older men [33]. Assuming a 35% reduction of all fractures from a hypothetical fracture prevention agent costing $500 (2001 US dollars), a gradual 5-year offset of fracture reduction benefit after a 5-year treatment period and a societal willingness to pay per QALY gained of $45 000, the 10-year absolute hip fracture risk at which pharmacologic intervention was cost-effective ranged from 1.98% for Swedish men aged 50 (4.8 times the risk of average 50-year-old men) to 6.31% for Swedish men aged 85 (0.87 times the risk of average 85-year-old men). These results implied that use of this hypothetical fracture prevention therapy would be costeffective for more than half of Swedish men over age 80. Compared to age-matched women, the absolute 10-year hip fracture risks above which intervention was estimated to be cost-effective were slightly higher in men under age 65, but slightly lower in men aged 65 and older. Subsequently, a similar extensive cost-effectiveness modeling study has been done for the US population to estimate absolute 10-year fracture risks above which pharmacologic fracture prevention therapy is cost-effective [37]. This study, done with a lifetime horizon from the health-payer perspective, has expanded the evaluation of cost-effectiveness of pharmacologic fracture prevention therapy to US nonCaucasian populations, providing estimates of the 10-year absolute hip and major osteoporotic (clinical vertebral, hip, wrist and proximal humerus) fracture rates above which intervention would be judged to be cost-effective for men and women of Caucasian, African-American, Hispanic and Asian-American ethnicity. Fracture prevention therapy was
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again assumed to reduce all fractures by 35%, regardless of either the 10-year fracture risk or the constellation of risk factors that determine that risk. This study included not only the four major osteoporotic fractures but also rib and pelvis fractures and was noteworthy in evaluating the cost-effectiveness of therapy under different assumptions of societal willingness to pay (WTP) per QALY gained. For the base case analysis, fracture disutility was assumed to last only for 5 years following an incident fracture. Remarkably, the absolute 10-year hip fracture risks above which pharmacologic fracture therapy was costeffective was quite similar across ethnic groups, ranging between 2.4 and 2.5% for 50-year-old men and between 4.8% and 5.1% for 70-year-old men. The results changed little when the assumed societal WTP per QALY gained was changed over the range of $50 000 to $75 000. Results were also shown to be sensitive to assumed drug cost and to the assumed duration of disutility following fractures, especially for those under age 70. This study did assume 100% medication compliance and did not include fixed upfront screening costs from the use of bone densitometry, which may be important if bone densitometry is used in the determination of absolute 10-year fracture risk. These omissions may lead to a downward bias in the estimated absolute 10-year fracture risk thresholds above which pharmacologic therapy is judged to be cost-effective. A major potential weakness of the fracture prevention therapy cost-effectiveness studies based on absolute fracture risk is that they all assume a fracture reduction benefit of 35% regardless of the specific pharmacologic agent used, the skeletal site of fracture and the specific constellation of risk factors that together render an individual’s absolute 10-year fracture risk. These studies also include, but downplay, the importance of bone densitometry of determining fracture risk and selection of individuals for whom pharmacologic fracture prevention therapy is indicated and, indeed, the algorithms that have been constructed by the World Health Organization (FRAX™) allow the determination of absolute fracture risk without bone mineral density. This is appropriate if fracture reduction benefit from these agents is consistent regardless of bone mineral density. The cost-effectiveness of fracture prevention therapy, however, has been consistently shown to be highly sensitive to the assumed fracture reduction benefit of the agent used [35, 58, 59]. Therefore, if fracture reduction benefit is related to bone mineral density, then the validity of these models is to some degree compromised. This will be discussed further in a subsequent section of this chapter.
Cost-Effectiveness Modeling Studies for Prevention of Fractures Associated with Glucocorticoid Therapy Chronic glucocorticoid therapy has been consistently shown to be a substantial risk factor for fracture in both sexes at all ages, regardless of ethnicity, independent of bone mineral
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density [7, 60–64]. Moreover, the proportion of fractures that occur at different skeletal sites is slightly different in glucocorticoid users compared to the general population, with rib, hip and, especially, spine fractures comprising larger percentages of the overall fracture burden among glucocorticoid users compared to age and sex-matched controls [63]. For these reasons, two additional studies that have specifically assessed the cost-effectiveness of intervention to prevent fracture among men on chronic glucocorticoid therapy are worthy of discussion. Van Staa and colleagues have estimated the costeffectiveness of oral bisphosphonate therapy among men and women in the General Practice Research Database (GPRD) of the UK [38]. The model contained seven health states, including no fracture, hip fracture, clinical vertebral fracture, radiographic (but clinically unapparent) vertebral fracture, humerus or tibia fracture, other fractures (radius, ulna, clavicle, scapula, rib, or sternum) and death. Fracture probabilities were calculated within the model for each individual on chronic glucocorticoid therapy in the GPRD database using Cox proportional hazard models with age, sex, duration and mean dose of glucocorticoid therapy, glucocorticoid indication and other clinical risk factors including prior clinical fracture history, fall history, body mass index, smoking history and presence of other co-morbidities that had previously been shown in the GPRD to be associated with fracture as predictor variables. A 6-year time horizon was employed, with the intervention strategy consisting of a 5-year treatment period followed by one year off of therapy. Fracture reduction benefit was lost over this last year off of drug therapy. Fracture reduction benefit from oral bisphosphonate therapy was assumed to be the same as had been shown in a large meta-analysis for postmenopausal women. For all men age 40 or older on glucocorticoid therapy in the GPRD database, the cost per QALY gained was estimated to be £41 000 for those treated with 5 mg of prednisone per day and £30 000 for those treated with 15 mg of prednisone per day. The estimated costs per QALY gained were just slightly lower for those men under age 60 than for men aged 60 and older. According to underlying diagnosis, the costs were lower per QALY gained for those with rheumatoid arthritis, polymyalgia rheumatica, polyarteritis and inflammatory bowel disease compared to those with respiratory disease or other indications for glucocorticoid therapy. Interestingly, the costs per QALY gained for those at highest risk of fracture based on clinical risk factors was little different than for those at lower risk of fracture, largely because a higher fracture risk was also associated with a lower life expectancy. This study likely overestimates the cost per QALY gained for several main reasons. First, vertebral fractures are underreported in the GPRD and, hence, the health benefits from preventing vertebral fractures was underestimated. Second, this study only employed a 6-year time horizon. However, hip fractures are likely to cause some level of long-term care costs beyond 6 years and, if hip and clinical vertebral fractures do
cause some level of permanent disutility, then again the cost savings and health benefits from preventing these fractures will be underestimated. Third, the offset of fracture reduction benefit was set at only one year. If after 5 years of oral bisphosphonate therapy fracture reduction benefit persists for longer than one year, as would seem likely from the FLEX study, the cost savings and health benefits of intervention are underestimated by this model. Hence, although the societal willingness to pay per QALY gained in the UK is often estimated at £30 000 per QALY gained, this study does lend some support to oral bisphosphonate medication use for men aged 40 and older being treated with more than 5 mg of prednisone per day on a chronic basis. Unfortunately, these results are not directly applicable to other countries. Kanis and colleagues have published the most extensive systematic review of fractures associated with chronic systemic glucocorticoids use, along with a cost-utility analysis of pharmacologic fracture prevention therapy to prevent fractures in both men and women on chronic systemic glucocorticoid therapy [39]. Analyses of available randomized controlled trials (RCTs) showed a clear substantial reduction of radiographic vertebral fracture with only two agents versus placebo, among glucocorticoid treated adult men and women, specifically risedronate and calcidiol. No effect of any agent on non-vertebral fracture incidence was apparent, although these RCTs were all small and underpowered to find differences in non-vertebral fracture incidence. While only a minority of those enrolled in these trials were men, a vertebral fracture reduction benefit with risedronate compared to placebo was evident when limiting the analysis to men and the magnitude of this benefit was the same as for women. The cost-effectiveness model assumed population-based rates of fracture for UK men and women, adjusted for the relative risk of fractures attributable to glucocorticoid therapy derived from a very large meta-analysis of seven very large cohort studies and for bone mineral density and prior fracture for those analyses where these risk factors were also considered. A 10-year time horizon was used and only hip, clinical vertebral, wrist and humerus fractures were considered. Disutility attributable to fractures was assumed to persist for only 2 years after an incident fracture. The direct medical costs of fractures were derived primarily from UK population-based data. Men and women were not modeled separately, based on data suggesting that absolute fracture risks for men and women at the same age and absolute bone mineral density (expressed as gm/cm2) are the same. Assuming only a vertebral fracture reduction benefit, the cost per QALY gained to treat those without a prior fracture ranged from £72 000 for those aged 75 to £351 000 for those age 50. Among those without a prior fracture, the costs per QALY gained ranged from £35 000 for those aged 75 to £175 000 for those aged 50. The 95% confidence intervals included the commonly cited cost-effectiveness threshold of £30 000 only for those age 70 and 75 with a prior fracture. Considering bone mineral density, the costs
C h a p t e r 5 0 Cost-Effectiveness of Interventions to Reduce Osteoporosis-Related Fractures in Men l
per QALY gained were below £30 000 for men and women aged 70 or 75 only for those with a femoral neck T-score of 3.5 or worse. For those with a prior fracture, the costs per QALY gained were below £30 000 for those aged 70 or 75 with a femoral neck T-score of 2.5 or worse and for those aged 50 with a femoral neck T-score of 4.0 or worse. Secondary analyses were done assuming the same fracture reduction benefits with oral bisphosphonate therapy as has been shown for postmenopausal women with osteoporosis by bone density criteria or a prevalent vertebral fracture (relative risks on therapy for vertebral, hip and non-hip non-vertebral fractures, respectively, of 0.57, 0.61 and 0.81). The cost-effectiveness of oral bisphosphonate therapy under this scenario was much more favorable; costs per QALY gained were below £30 000 for those without a prior fracture aged 75 and older and for those with a prior fracture aged 65 and older. Considering femoral neck bone density, the cost of oral bisphosphonate per QALY gained was below £30 000 for those aged 75 without a prior fracture with a bone density T-score of 2.0 or worse and for those aged 50 without a prior fracture with a bone density T-score of less than 3.0 or worse. For those with a prior fracture, the cost of oral bisphosphonate per QALY gained was below £30 000 for those aged 75 with a bone density T-score of 1.5 or worse and for those aged 50 without a prior fracture with a bone density T-score of 2.0 or worse. The cost-effectiveness estimates presented in these analyses are biased downward for men who have not had bone mineral density measured, as men have higher mean ageadjusted BMD than women. With that caveat aside, however, these cost-effectiveness estimates are conservative for several reasons. A 10-year time horizon was used, so any long-term care costs beyond that horizon attributable to incident fractures would not be included. Disutility attributable to fractures was assumed not to extend beyond 2 years after their occurrence, but this may be unrealistic, particularly for hip and clinical vertebral fractures. Radiographic but clinically unrecognized vertebral fractures were not considered, but these do cause some morbidity. Fractures at skeletal sites other than the spine, hip, proximal humerus and wrist were not considered, but these fractures account for about 30% of fracture direct medical costs and modest additional disutility burden due to fractures. Moreover, these results are not applicable to areas of the world with higher population-based fracture rates, such as the Scandinavian countries and the USA or other countries with substantially lower fracture rates.
Controversies and challenges in health economic modeling of fracture prevention strategies Drawing firm conclusions with respect to which men should be treated with fracture prevention therapies continues to be
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difficult on account of many uncertainties with respect to both health economic modeling strategies and the parameter estimates that populate those models. Further empirical studies may help improve the validity of some of the assumptions implicit in these models. This section will discuss these uncertainties and illustrate the effect of some different modeling assumptions on the cost-effectiveness of treatment of older US men, using the same base-case model used in a published study.
What is Society Willing to Pay for QALY Gained? Given that societal resources to pay for health-care interventions are not limitless, human societies in general explicity or implicitly limit health care in some fashion. The main underlying raison d’être of health economic modeling is to estimate what health-care interventions are likely to yield the greatest health benefits for a given fixed level of healthcare expenditure. The World Health Organization norm is to assume that the societal willingness to pay per QALY gained in any given country is one to three times the per capita gross domestic product (GDP) [65]. However, this figure surely is dependent upon not only on overall societal wealth, but also on the QALYs within the population that can be saved. Arguably, the number of QALYs that could be saved is increasing within industrialized and industrializing countries with advancement of medical technology and as the population age structure and population disease burden increases. If societal wealth does not grow correspondingly, then available resources may have to be spread more thinly, putting downward pressure over time on societal willingness to pay per QALY thresholds. Cost-effectiveness studies that present their data in a way that allows estimation of cost-effectiveness across a range of societal willingness to pay thresholds are therefore likely to be more informative for health-care policy.
How Well Do Available Fracture Prevention Strategies Work for Non-Vertebral Fracture? As has been shown in many of the cost-effectiveness modeling studies reviewed in this chapter [35, 58, 59], the costs per QALY gained of fracture prevention medications are quite sensitive to the assumed fracture reduction benefit from use of those medications. For men, there are credible estimates only for radiographic vertebral fracture reduction efficacy for oral bisphosphonate therapy for older men and men on chronic glucocorticoid therapy. Moreover, there remains substantial controversy over whether or not the nonvertebral fracture reduction benefit from currently available fracture prevention therapies is associated with bone mineral density. While one study of an oral bisphosphonate did not find any correlation between clinical fracture reduction benefit and bone mineral density [66], others have found that the non-vertebral fracture reduction benefit of oral
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bisphosphonates to be significantly less among those who do not have osteoporosis by bone density criteria [40, 67]. Further randomized trials of men and women who are at high risk of fracture but who do not have osteoporosis by bone density criteria are required to settle this controversy. As noted previously, the validity of cost-effectiveness estimates of fracture prevention therapies for populations that have neither osteoporosis by bone density criteria nor a prevalent vertebral fracture depends on the answer to this question:
What are the Disutilities of Osteoporotic Fractures? It is noteworthy that virtually all cost-effectiveness studies of osteoporosis therapies done to date either use fracture disutility estimates supplied by expert opinion or those from one relatively small study of Swedish elderly men and women [68]. There is currently an effort to replicate this study in other countries, such that with larger numbers of subjects from a variety of countries more credible fracture disutility estimates are available. This study will be important to improve further the credibility of cost-effectiveness modeling studies of fracture prevention interventions, given their moderate sensitivity to the assumed disutility of fractures. Unfortunately, this study will not supply disutility estimates beyond 18 months after incident fractures. Future cost-effectiveness modeling studies should include sensitivity analyses around the assumed duration of disutility attributable to fractures, as one recently has done.
How Long Does Fracture Reduction Benefit Last After Medication is Discontinued? Not surprisingly, the apparent cost-effectiveness of fracture prevention therapies is sensitive to how long fracture
r eduction benefit is assumed to last following their discontinuation (called fracture reduction offset). While one study has shown how changes in bone mineral density and markers of bone turnover change after discontinuation of alendronate following a 5-year treatment course compared to continuation of the drug, this study was not powered to evaluate differences in fracture outcomes between the treatment groups [27]. In the absence of trials large enough to give credible estimates for this parameter, it will be important that cost-effectiveness studies continue to do sensitivity analyses with different offsets of fracture reduction benefit.
What is the Effect of Non-Compliance with Fracture Prevention Medication on the CostEffectiveness of Their Use? Non-compliance with fracture prevention medication is common, with a recent meta-analysis estimating that only 42% persist with therapy more than one year [44]. While this does reduce the estimated fractures prevented, this is at least to some degree offset by the cost of the intervention being reduced by less medication consumption [69]. As a result, the estimated cost per QALY gained rises only slightly under two assumptions: that there is little fixed upfront screening costs to identify those who will be treated and that the fracture reduction benefit loss is proportional to the reduction of medication consumption. While some studies of the association between medication compliance and fracture reduction benefit do suggest this relationship is linear [70], others suggest that fracture reduction benefit may lost disproportionately to the reduction in medication consumption [71]. If fracture reduction benefit is lost disproportionately to reduced medication consumption, then the costs per QALY gained rise substantially (Figure 50.1). Further studies of the association between compliance and
Cost per QUALY gained (2008 U.S.$)
150 000 DXA Cost Included No
Yes
100 000
50 000
0
1.0/1.0
0.6/0.6 Adherence / Efficacy
0.6/0.3
Figure 50.1 Association of loss of fracture reduction benefit from non-compliance with cost-effectiveness. Treatment of 75-year-old Caucasian US men with femoral neck T-score 2.5, oral bisphosphonate therapy cost $500 per year. Left hand bars: 100% compliance, 100% of maximum fracture reduction benefit; middle bars: 60% compliance, 60% of maximum fracture reduction benefit; right hand bars: 60% compliance, 30% of maximum fracture reduction benefit. All other parameters as base-case model in reference.
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fracture reduction benefit, adjusted for age, bone mineral density and other fracture risk factors are needed.
Is There a Disutility from Taking Fracture Prevention Medication? Because randomized controlled trials of oral bisphosphonates have generally not shown any clear excess toxicity compared to those on placebo, cost-effectiveness studies have generally assumed no disutility or direct medical costs from treatment-related side effects. However, a re-analysis of the Fracture Intervention Trial suggests that there may be a modest 0.5% excess risk of atrial fibrillation associated with use of alendronate [72, 73]. If this is true of bisphosphonates as a drug class, then cost-effectiveness studies done to date may have underestimated the costs per QALY gained with use of these agents. Consistent with the widespread non-persistence and non-compliance that has been extensively documented with fracture prevention therapies, qualitative research studies have suggested that many patients find that having to take medication per se, even in the absence of side effects, can be associated with a sense of unease related to concerns about the long-term safety of and dependence upon medication [74–76]. Since preventive drug therapy requires that many individuals be treated to prevent one event, even a small decrement of quality of life of 0.005 from taking drug therapy per se can profoundly increase the cost per QALY gained for a fracture prevention therapy [77].
What Is the role of Bone Densitometry? Most of the cost-effectiveness modeling studies done to date, especially those that select those for treatment on the basis of absolute 10-year fracture risk rather than bone mineral density per se, do not explicitly include the upfront costs of bone densitometry. Given that absolute 10-year fracture risk can be estimated without bone densitometry, this is reasonable at least for base case analyses. However, in some countries, most notably the USA, bone mineral density is highly likely to be used in the estimation of absolute fracture risk. Exclusion of the upfront screening costs will result in a mild underestimation of the costs per QALY gained (see Figure 50.1). When these costs are included, the cost-effectiveness study essentially becomes a test of an intervention with two components, the screening test itself and use of the fracture reduction medication. Under the assumption that the magnitude of fracture reduction benefit of drug therapies is unrelated to bone mineral density, however, then the true test of the cost-effectiveness of bone densitometry would be to compare the costs and health benefits of selection of a treatment cohort without bone density versus one with bone density. Even in the context of FRAX™, when a similar proportion of the older population is selected for treatment with
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or without bone densitometry, those selected with the aid of bone densitometry are at higher risk of hip fracture [54]. Hence, even if the benefit of fracture prevention therapies is unrelated to bone mineral density, bone densitometry may be cost-effective. New cost-effectiveness studies of bone densitometry are needed in the context of using absolute fracture risk to select those for therapy to re-establish the populations for whom use of bone densitometry is cost-effective.
Conclusions Although the cost-effectiveness of fracture reduction interventions has been more extensively studied for postmenopausal women than for men, eight cost-effectiveness studies specifically applicable to men have been published in the last 4 to 5 years. Those studies that have modeled treatment based on bone mineral density have suggested that bone densitometry followed by treatment of those with osteoporosis by bone density criteria is cost-effective for all men aged 65 and older who have had a prior fracture. Whether or not bone densitometry is cost-effective for men in the absence of a prior fracture remains controversial and depends greatly on assumptions regarding non-vertebral fracture reduction benefit in men, the assumed cost of drug therapy, the duration of fracture reduction benefit following drug discontinuation, the disutility of fractures, the assumed relationship between medication compliance and fracture reduction benefit, fracture rates in the target population and the societal willingness to pay for health benefits. Despite these uncertainties, in the future, cost-effectiveness modeling studies may play a larger role in medical intervention coverage decisions by health payers, given the increasing cost pressures on health payers and the increasing population disease burden within aging populations. To the extent that proposed intervention strategies to reduce the burden of fractures among both men and women are not accompanied by fully credible modeling studies demonstrating good value relative to the cost of those interventions, there is a risk that health payers will underfund those strategies relative to interventions for other health care problems for which costeffectiveness studies have better documented their value.
References 1. R. Burge, et al., Incidence and economic burden of osteoporosis-related fractures in the United States, 2005–2025, J. Bone Miner. Res. 22 (3) (2007) 465–475. 2. L.J. Melton, et al., Perspective: how many women have osteo porosis? J. Bone Miner. Res. 7 (1992) 1005–1010. 3. N.D. Nguyen, et al., Residual lifetime risk of fractures in women and men, J. Bone Miner. Res. 22 (6) (2007) 781–788. 4. M. Schwenkglenks, et al., A model of osteoporosis impact in Switzerland 2000–2020, Osteoporos. Int. 16 (6) (2005) 659–671. 5. Centers for Medicare and Medicaid Services. Physician Fee Schedule Search 2007. 2007 [cited March 4, 2007]; Available
626
6.
7. 8.
9.
10.
11.
12.
13.
14.
15.
16.
17. 18. 19.
20. 21.
22. 23.
24.
Osteoporosis in Men
from: http://www.cms.hhs.gov/PFSlookup/02_PFSSearch. asp/ . A.C. Looker, et al., Updated data on proximal femur bone mineral levels of US adults, Osteoporos. Int. 8 (5) (1998) 468–489. J.A. Kanis, et al., A meta-analysis of prior corticosteroid use and fracture risk, J. Bone Miner. Res. 19 (6) (2004) 893–899. B.S. Bloom, Use of formal benefit/cost evaluations in health system decision making, Am. J. Manag. Care 10 (5) (2004) 329–335. A. Garcia-Altes, S. Ondategui-Parra, P.J. Neumann, Crossnational comparison of technology assessment processes, Int. J. Technol. Assess. Health Care 20 (3) (2004) 300–310. A.S. Detsky, A. Laupacis, Relevance of cost-effectiveness analysis to clinicians and policy makers, J. Am. Med. Assoc. 298 (2) (2007) 221–224. M. Sculpher, M. Drummond, M. Buxton, The iterative use of economic evaluation as part of the process of health technology assessment, J. Hlth. Serv. Res. Policy 2 (1) (1997) 26–30. S.D. Grosse, S.M. Teutsch, A.C. Haddix, Lessons from costeffectiveness research for United States public health policy, Annu. Rev. Public Hlth. 28 (2007) 365–391. P.J. Neumann, A.B. Rosen, M.C. Weinstein, Medicare and cost-effectiveness analysis, N. Engl. J. Med. 353 (14) (2005) 1516–1522. Medicare Payment Advisory Commission. Using clinical and cost-effectiveness information in medicare. In Report to the Congress: Issues in a Modernized Medicare Program. Medicare Payment Advisory Commission, Washington, DC, 2005. N. Kirschner, S.G. Pauker, J.W. Stubbs, Information on costeffectiveness: an essential product of a national comparative effectiveness program, Ann. Intern. Med. 148 (12) (2008) 956–961. M.R. Gold (Ed.), et al., Identifying and Valuing Outcomes, in Cost-Effectiveness in Health and Medicine, Oxford University Press, New York, 1996, pp. 82–134. M.R. Gold (Ed.), et al., Cost-Effectiveness in Health and Medicine, Oxford University Press, New York, 1996. J. Goldie, Public health policy and cost-effectiveness analysis, J. Natl. Cancer Inst. Monog. 31 (2003) 102–110. G.W. Torrance, J.E. Siegel, B.R. Luce, et al., Framing and designing the cost-effectiveness analysis, in: M.R. Gold (Ed.), Cost-Effectiveness in Health and Medicine, Oxford University Press, New York, 1996, pp. 54–81. M.J. Buxton, et al., Modelling in economic evaluation: an unavoidable fact of life, Hlth. Econ. 6 (3) (1997) 217–227. M. Johannesson, D. Meltzer, R.M. O’Conor, Incorporating future costs in medical cost-effectiveness analysis: implications for the cost-effectiveness of the treatment of hypertension, Med. Decis. Making 17 (4) (1997) 382–389. D. Meltzer, Accounting for future costs in medical costeffectiveness analysis, J. Hlth. Econ. 16 (1) (1997) 33–64. B.R. Luce, et al., Estimating costs in cost-effectiveness analysis, in: M.R. Gold (Ed.), Cost-Effectiveness in Health and Medicine, Oxford University Press, New York, 1996, pp. 176–213. J. Lipscomb, M.C. Weinstein, G.W. Torrance, et al., Time preference, in: M.R. Gold (Ed.), Cost-Effectiveness in Health and Medicine, Oxford University Press, New York, 1996, pp. 213–214.
25. National Institute for Health and Clinical Excellence (NICE). Guide to the methods of technology appraisal. 2008. URL: http://www.nice.org.uk/media/B52/A7/TAMethods GuideUpdatedJune2008.pdf/ , (accessed 9.12.08). 26. W.B. Brouwer, et al., Need for differential discounting of costs and health effects in cost effectiveness analyses, Br. Med. J. 331 (7514) (2005) 446–448. 27. D.M. Black, et al., Effects of continuing or stopping alendronate after 5 years of treatment: the Fracture Intervention Trial Long-term Extension (FLEX): a randomized trial, J. Am. Med. Assoc. 296 (24) (2006) 2927–2938. 28. J.T. Schousboe, Cost-effectiveness modeling research of pharmacologic therapy to prevent osteoporosis-related fractures, Curr. Rheumatol. Rep. 9 (1) (2007) 50–56. 29. J.T. Schousboe, Cost effectiveness of screen-and-treat strategies for low bone mineral density: how do we screen, who do we screen and who do we treat? Appl. Health Econ. Hlth. Policy 6 (1) (2008) 1–18. 30. R.L. Fleurence, C.P. Iglesias, J.M. Johnson, The cost effectiveness of bisphosphonates for the prevention and treatment of osteoporosis: a structured review of the literature, Pharmacoeconomics 25 (11) (2007) 913–933. 31. N. Zethraeus, et al., Cost-effectiveness of the treatment and prevention of osteoporosis – a review of the literature and a reference model, Osteoporos. Int. 18 (1) (2007) 9–23. 32. F. Borgstrom, et al., Cost effectiveness of alendronate for the treatment of male osteoporosis in Sweden, Bone 34 (6) (2004) 1064–1071. 33. J.A. Kanis, et al., Intervention thresholds for osteoporosis in men and women: a study based on data from Sweden, Osteoporos. Int. 16 (1) (2005) 6–14. 34. M. Schwenkglenks, K. Lippuner, Simulation-based costutility analysis of population screening-based alendronate use in Switzerland, Osteoporos. Int. 18 (11) (2007) 1481–1491. 35. J.T. Schousboe, et al., Cost-effectiveness of bone densitometry followed by treatment of osteoporosis in older men, J. Am. Med. Assoc. 298 (6) (2007) 629–637. 36. J.T. Schousboe, et al., Influence of body weight on costeffectiveness of bone densitometry and treament for osteo porosis among older women and men without prior fracture, J. Bone Miner. Res. 23 (Suppl.) (2008) S124. 37. A.N. Tosteson, et al., Cost-effective osteoporosis treatment thresholds: the United States perspective, Osteoporos. Int. 19 (4) (2008) 437–447. 38. T.P. van Staa, et al., Individual fracture risk and the costeffectiveness of bisphosphonates in patients using oral glucocorticoids, Rheumatology (Oxford) 46 (3) (2007) 460–466. 39. J.A. Kanis, et al., Glucocorticoid-induced osteoporosis: a systematic review and cost-utility analysis, Hlth. Technol. Assess. 11 (7) (2007) iii–iv ix–xi, 1–231. 40. S.R. Cummings, et al., Effect of alendronate on risk of fracture in women with low bone density but without vertebral fractures: results from the Fracture Intervention Trial, J. Am. Med. Assoc. 280 (24) (1998) 2077–2082. 41. H.A. Fink, et al., What proportion of incident radiographic vertebral deformities is clinically diagnosed and vice versa? J. Bone Miner. Res. 20 (7) (2005) 1216–1222. 42. C. Cooper, et al., Incidence of clinically diagnosed vertebral fractures: a population-based study in Rochester, Minnesota, 1985–1989, J. Bone Miner. Res. 7 (2) (1992) 221–227.
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43. J.A. Cramer, et al., A systematic review of persistence and compliance with bisphosphonates for osteoporosis, Osteoporos. Int. 18 (8) (2007) 1023–1031. 44. P. Kothawala, et al., Systematic review and meta-analysis of real-world adherence to drug therapy for osteoporosis, Mayo Clin. Proc. 82 (12) (2007) 1493–1501. 45. S.M. Cadarette, et al., The validity of decision rules for selecting women with primary osteoporosis for bone mineral density testing, Osteoporos. Int. 15 (5) (2004) 361–366. 46. R.A. Adler, M.T. Tran, V.I. Petkov, Performance of the osteo porosis self-assessment screening tool for osteoporosis in American men, Mayo Clin. Proc. 78 (6) (2003) 723–727. 47. M.C. Hochberg, et al., Validation of a risk index to identify men with an increased likelihood of osteoporosis, J. Bone Miner. Res. 17 (Suppl. 1) (2002) S231. 48. E. Orwoll, et al., Alendronate for the treatment of osteoporosis in men, N. Engl. J. Med. 343 (9) (2000) 604–610. 49. J.D. Ringe, et al., Alendronate treatment of established primary osteoporosis in men: 3-year results of a prospective, comparative, two-arm study, Rheumatol. Int. 24 (2) (2004) 110–113. 50. J.D. Ringe, et al., Efficacy of risedronate in men with primary and secondary osteoporosis: results of a 1-year study, Rheumatol. Int. 26 (5) (2006) 427–431. 51. A.M. Sawka, et al., Does alendronate reduce the risk of fracture in men? A meta-analysis incorporating prior knowledge of antifracture efficacy in women, Musculoskelet. Disord. 6 (2005) 39. 52. E.S. Siris, et al., The effect of age and bone mineral density on the absolute, excess, and relative risk of fracture in postmenopausal women aged 50–99: results from the National Osteoporosis Risk Assessment (NORA), Osteoporos. Int. 17 (4) (2006) 565–574. 53. C.L. Deal, Absolute fracture risk, Curr. Rheumatol. Rep. 9 (1) (2007) 66–70. 54. J.A. Kanis, et al., The use of clinical risk factors enhances the performance of BMD in the prediction of hip and osteoporotic fractures in men and women, Osteoporos. Int. 18 (8) (2007) 1033–1046. 55. E. Seeman, J.A. Eisman, 7: Treatment of osteoporosis: why, whom, when and how to treat. The single most important consideration is the individual’s absolute risk of fracture, Med. J. Aust. 180 (6) (2004) 298–303. 56. J.A. Kanis, et al., Intervention thresholds for osteoporosis in the UK, Bone 36 (1) (2005) 22–32. 57. F. Borgstrom, et al., At what hip fracture risk is it cost-effective to treat? International intervention thresholds for the treatment of osteoporosis, Osteoporos. Int. 17 (10) (2006) 1459–1471. 58. J.T. Schousboe, et al., Cost-effectiveness of alendronate therapy for osteopenic postmenopausal women, Ann. Intern. Med. 142 (9) (2005) 734–741. 59. J.A. Kanis, et al., Cost-effectiveness of preventing hip fracture in the general female population, Osteoporos. Int. 12 (5) (2001) 356–361. 60. M. Steinbuch, T.E. Youket, S. Cohen, Oral glucocorticoid use is associated with an increased risk of fracture, Osteoporos. Int. 15 (4) (2004) 323–328.
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61. T.P. van Staa, et al., Oral corticosteroids and fracture risk: relationship to daily and cumulative doses, Rheumatology (Oxford) 39 (12) (2000) 1383–1389. 62. L.J. Walsh, et al., The impact of oral corticosteroid use on bone mineral density and vertebral fracture, Am. J. Respir. Crit. Care Med. 166 (5) (2002) 691–695. 63. A.W. Popp, et al., Glucocorticosteroid-induced spinal osteoporosis: scientific update on pathophysiology and treatment, Eur. Spine J. 15 (7) (2006) 1035–1049. 64. C.E. McEvoy, et al., Association between corticosteroid use and vertebral fractures in older men with chronic obstructive pulmonary disease, Am. J. Respir. Crit. Care Med. 157 (3 Pt 1) (1998) 704–709. 65. WHO, Macroeconomics and health: investing in health for economic development, World Health Organization, Geneva, 2001. 66. E.V. McCloskey, et al., Clodronate reduces the incidence of fractures in community-dwelling elderly women unselected for osteoporosis: results of a double-blind, placebo-controlled randomized study, J. Bone Miner. Res. 22 (1) (2007) 135–141. 67. M.R. McClung, et al., Effect of risedronate on the risk of hip fracture in elderly women. Hip Intervention Program Study Group, N. Engl. J. Med. 344 (5) (2001) 333–340. 68. F. Borgstrom, et al., An economic evaluation of strontium ranelate in the treatment of osteoporosis in a Swedish setting: based on the results of the SOTI and TROPOS trials, Osteoporos. Int. 17 (12) (2006) 1781–1793. 69. O. Strom, et al., Incorporating adherence into health economic modelling of osteoporosis, Osteoporos. Int. 20 (1) (2009) 23–34. 70. V. Rabenda, et al., Adherence to bisphosphonates therapy and hip fracture risk in osteoporotic women, Osteoporos. Int. 19 (6) (2008) 811–818. 71. E.S. Siris, et al., Adherence to bisphosphonate therapy and fracture rates in osteoporotic women: relationship to vertebral and nonvertebral fractures from 2 US claims databases, Mayo Clin. Proc. 81 (8) (2006) 1013–1022. 72. S.R. Heckbert, et al., Use of alendronate and risk of incident atrial fibrillation in women, Arch. Intern. Med. 168 (8) (2008) 826–831. 73. S.R. Cummings, A.V. Schwartz, D.M. Black, Alendronate and atrial fibrillation, N. Engl. J. Med. 356 (18) (2007) 1895–1896. 74. J. Benson, N. Britten, Patients’ decisions about whether or not to take antihypertensive drugs: qualitative study, Br. Med. J. 325 (7369) (2002) 873. 75. C.G. Unson, et al., Nonadherence and osteoporosis treatment preferences of older women: a qualitative study, J. Womens Hlth. (Larchmt) 12 (10) (2003) 1037–1045. 76. N. Britten, O.C. Ukoumunne, M.G. Boulton, Patients’ attitudes to medicines and expectations for prescriptions, Hlth. Expect 5 (3) (2002) 256–269. 77. B. Jonsson, et al., Cost-effectiveness of fracture prevention in established osteoporosis, Osteoporos. Int. 5 (2) (1995) 136–142.
Chapter
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Nutritional Therapy for Skeletal Health in Men Diana M. Antoniucci1 and Deborah E. Sellmeyer2 1
University of California, San Francisco; Physicians Foundation of California Pacific Medical Center, Division of Endocrinology, Diabetes and Osteoporosis, San Francisco, California, USA 2 Metabolic Bone Center, The Johns Hopkins Bayview Medical Center, Baltimore, Maryland, USA
Introduction
clinical trials examining the effects of energy and/or protein supplementation in patients who suffered a recent hip fracture. These trials are limited by small sample sizes, significant numbers of subjects lost to follow up, inadequate blinding of the intervention and variability of the outcomes assessed. However, overall analysis of these trials showed that subjects who received nutritional supplementation had a lower incidence of the combined outcome of mortality and post-fracture complications [1]. Nasogastric tube feedings do not seem to provide added benefit to oral feedings except in very thin patients and were poorly tolerated in some studies. Supplementation with increased protein does appear to shorten the length of stay in a rehabilitation setting and the incidence of complications after hip fracture, but has not been shown to reduce mortality. Men represented a minority of the subjects in these trials of energy and protein supplementation after hip fracture, too few to examine for gender differences in outcomes. Soy protein supplementation in men has been examined in a single trial [2]. Daily supplements of 40 g of soy protein compared to 40 g of milk protein increased serum insulin-like growth factor I (IGF-I) in men aged 59.2 17.6 (mean SD) years, but did not affect markers of bone turnover. Among studies employing caloric restriction or caloric restriction with exercise in overweight men, bone density decreases along with weight loss. Weight loss via exercise alone may not result in decreased bone density [3]. As the changes in bone density with weight loss are relatively small, approximately 2–3% over 12 months, and larger individuals tend to have higher bone density at baseline, the effect of caloric restriction and weight loss on future fracture risk in overweight subjects is not clear.
Most of the research relating nutrition to bone outcomes is from preclinical or epidemiologic data. Epidemiologic data are particularly challenging in the area of nutrition because individuals do not consume isolated nutrients, they consume whole foods, making it difficult to tease apart the influences of individual nutrients provided by the same food item. Additionally, food choices are influenced by environmental and socioeconomic factors that can independently impact bone density and fracture risk. The very nature of skeletal outcomes adds additional challenges as several years and hundreds of subjects are needed to evaluate effects on bone mineral density; sample sizes needed for fracture studies number in the thousands. Inducing long-term eating behavioral changes in large numbers of individuals is difficult as is developing a nutritional intervention and placebo that can be effectively blinded. For these reasons, clinical trial data on nutritional interventions for osteoporosis are limited in general and particularly in men. Nutrition intervention trials that included at least some male subjects will be reviewed in this chapter, but much more research will be needed to develop full recommendations for maximizing skeletal health in men.
Macronutrients Energy and Protein While there are no trials evaluating the effects of energy or protein supplementation on bone density or prevention of fractures, there have been nearly two dozen randomized Osteoporosis in Men
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Calcium and vitamin D Calcium Calcium balance studies have demonstrated that the calcium intake threshold for adults is approximately 1100–1200 mg per day [4]. This means that if baseline intake already is at this threshold level, additional intake would not be expected to improve skeletal health. Intestinal calcium absorption and intake decline with age in men. A cross-sectional study in 62 healthy men aged 30–92 years demonstrated a decline in serum calcium and 25-hydroxy vitamin D (25OHD) concentrations with advancing age [5]. These findings were associated with an increase in plasma parathyroid hormone (PTH) levels with aging and declining renal function. All these age-related changes in calcium metabolism can have deleterious consequences on bone mineral metabolism. Overall, there are very few trials studying the effects of calcium supplementation alone (in the absence of concomitant vitamin D supplementation) on bone mineral density (BMD) in men and none evaluating effects on fracture. In a 1994 study, Chevalley et al studied 93 ambulatory subjects (82 women, 11 men) aged 62–87 years and observed that femoral neck BMD remained stable in subjects given 800 mg of daily elemental calcium supplementation, whereas it decreased in unsupplemented patients [6]. This study included primarily women, making it difficult to draw any conclusions directly applicable to men. Peacock and colleagues attempted to separate the effects of calcium versus vitamin D supplementation on BMD changes [7]. These investigators studied the impact of 750 mg calcium or 600 international units (IU) of cholecalciferol versus placebo daily on bone loss in 122 healthy men with a mean age of 75.9 years. This study also included 316 women and, because there were no significant sex main-effects or sex-by-treatment interactions in any of the variables, results for men and women were combined. The median dietary intake of calcium during the study was 716 mg/d. Over the 4 years of the study, the placebo group lost BMD and the calcium group did not lose BMD; the loss of BMD in the cholecalciferol group was intermediate in size and not significantly different from either of the other groups. It was also noted that the benefits of calcium supplementation on BMD were greatest among those participants who had the lowest serum 25OHD concentrations at baseline. The authors concluded that calcium supplementation prevented BMD loss, whereas cholecalciferol supplementation was less effective, but it was most beneficial in those people who had the lowest dietary calcium intake and lowest serum 25OHD levels.
Calcium with Vitamin D Two randomized controlled trials testing the effect of calcium and vitamin D supplementation on bone loss in men
have been reported. Orwoll and colleagues [8] treated 86 healthy men aged 30–87 years with 1000 mg calcium and 1000 IU cholechalciferol or placebo daily for 3 years. The primary outcome of the study was rate of change in bone mineral content measured by single-photon absorptiometry at the radius and by dual-energy computed tomography at the spine. The investigators found no significant difference in the primary outcome at any site between the groups. The mean daily calcium intake of the study subjects was 1159 mg/d, an intake that is near the intake threshold discussed above, suggesting that the rate of bone loss is not affected by calcium and vitamin D supplementation in a well-nourished male population. Dawson-Hughes et al [9] studied the effects of 500 mg calcium plus 700 IU cholecalciferol per day or placebo on changes in BMD measured by dual-energy x-ray absorptiometry (DXA) at the hip, spine and total body over 3 years of treatment. Subjects included 176 healthy men aged 65 years and older (mean age 71 years). These subjects had a mean dietary daily intake of 700 mg of calcium and 200 IU of vitamin D. In contrast to the findings in the Orwoll study [8], supplementation with calcium and vitamin D reduced bone loss at the femoral neck, spine and total body in this study. The overall study results showed a reduced risk of non-vertebral fracture in the calcium and vitamin D supplemented group, but only five men had a fracture during the study and only two men, both in the placebo group, had a fracture classified as osteoporotic. The RECORD trial set out to study the efficacy of oral vitamin D and calcium therapy for secondary prevention of fractures in elderly community dwellers who had suffered a recent fracture [10]. The study of 5292 people over 70 years of age (85% of whom were women) had a factorial design– subjects were randomly assigned to 800 IU daily cholecalciferol, 1000 mg daily calcium, 1000 mg calcium with 800 IU cholecalciferol daily or placebo for 24–62 months. The primary outcome was new low-trauma fractures. The groups did not differ in the incidence of all new fractures and there were no differences noted in the effects of any of the treatment arms between men and women. By 2 years into the study, compliance with supplements had dropped to 54.5% and 8.5% of participants had died. It has been postulated that the poor compliance rate may in part explain the lack of an effect found in this trial. It is also notable that only a small subset of participants (1.1%) had their serum 25OHD level measured, so the vitamin D status of the study population at baseline remains largely unknown. It is therefore difficult to conclude that vitamin D with or without calcium does not provide secondary prevention of fractures at least in those people who are vitamin D deficient. This trial did not discuss baseline calcium intake in the study population, making it difficult to determine if part of the reason why no benefit was seen from calcium therapy had to do with the calcium intake threshold theory outlined above.
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Vitamin D Vitamin D and Fracture Prevention A Dutch study investigated the effects of supplementation with 400 IU oral cholecalciferol versus placebo daily for 3.5 years on the incidence of hip fractures and other limb fractures (Colles’, humerus, ankle, foot or leg) [11]. The study included 2578 participants (1916 women and 662 men) with a mean age of 80 years and a mean dietary calcium intake, estimated from a subset of 348 women, of 868 mg/d. The study did not show any benefit of vitamin D on fracture prevention. Serum 25OHD concentrations were measured in 10% of participants at baseline and one year into the study. These measurements demonstrated similar baseline levels between the treatment and placebo group, but a markedly improved serum 25OHD concentration in the treatment group at 1 year. Nonetheless, it has been felt that the likely cause of a lack of benefit from vitamin D in this trial was the low dose of supplementation used. Similar results were noted in a trial of 1144 nursing home residents (25% men) with mean age 85 years, who were randomized to 400 IU cholecalciferol versus placebo for 2 years [12]. Study participants had a mean daily calcium intake of 446 mg. The intervention did not decrease the rate of hip or non-vertebral fractures. Despite an increase in serum 25OHD levels with vitamin D supplementation, there was no change in serum PTH or calcium levels. No treatment effect differences were noted in participants based on dietary calcium intake, though the overall study size was fairly small, limiting interpretation of subgroup analyses. Trivedi and colleagues [13] treated 2686 community dwellers (2037 men and 649 women) aged 65–85 years with 100 000 IU oral cholecalciferol or placebo every 4 months over 5 years to determine the effect of oral cholecalciferol on fractures and mortality. The researchers found that vitamin D therapy reduced the risk for first osteoporotic fractures (relative risk, RR: 0.67, 95% confidence interval, CI: 0.48–0.93, P 0.02). They did not observe decreased mortality in response to vitamin D therapy. The findings were consistent in men and women, suggesting that high dose cholecalciferol therapy every 4 months can prevent osteoporotic fractures in men. Smith and colleagues studied the effects of 3-yearly intramuscular injections of 300 000 IU ergocalciferol on fracture risk in 9440 people (4354 men, 5086 women) over the age of 75 years [14]. They found no benefit of vitamin D supplementation in preventing non-vertebral fractures or falls. Law et al studied 3717 (24% male) elderly people living in residential care homes in the UK [15]. They randomized the participants to receive either 100 000 IU oral ergocalciferol or placebo every 3 months and determined the effects of therapy on incidence of non-vertebral fractures and falls. Serum 25OHD concentrations were measured in 1% of subjects on vitamin D therapy at baseline, 1 month and 3 months after the first dose. Serum vitamin D concentrations did increase in response to vitamin D supplementation,
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with no concomitant decrease in serum PTH. The researchers found no effect of vitamin D supplementation on the incidence of fractures or falls. Results were not provided separately for men and women. Overall, it seems that there are no overwhelming data to support the use of vitamin D as the sole treatment for fracture prevention in patients with osteoporosis or at high risk for fracture. However, data do support the use of calcium with vitamin D supplementation as standard therapy for osteoporotic patients. This is important for all patients, including those on pharmacologic osteoporosis therapy (e.g. bisphosphonates or teriparatide) as all these agents have been studied in trials with concurrent calcium and vitamin D supplementation. Vitamin D and Fall Prevention There are epidemiologic data suggesting that both men and women with lower serum 25OHD concentrations are at higher risk of falls compared to those with vitamin D sufficiency. However, randomized controlled trials of vitamin D supplementation have not uniformly demonstrated a decreased risk of falls in those participants who received vitamin D supplementation. Flicker and colleagues studied 625 assisted living facility residents, 5% of whom were men [16]. Study subjects were randomized to ergocalciferol 10 000 IU weekly, later switched to 1000 IU daily or placebo along with 600 mg calcium daily for 2 years. The overall study results showed a decrease in the incidence of falling with vitamin D supplementation. No subanalysis including men only is provided. Pfeifer and colleagues studied the effects of treatment with either 1000 mg daily calcium or 1000 mg daily calcium with 800 IU vitamin D for a year in 242 community dwelling seniors with mean age 77 years (range 70–91 years) and a baseline serum 25OHD below 31 ng/ml [17]. Men comprised 25% of study participants. Although supplementation was discontinued after the first 12 months of study, observation and data gathering as well as blinding continued for another 8 months. The authors found that vitamin D with calcium supplementation resulted in a significant decrease in the risk of first falls at 12 months and that this effect was even greater at month 20. Again, no subanalysis looking at men separately is provided. Bischoff-Ferrari et al studied the effect of 3-year supplementation with 700 IU cholecalciferol and 500 mg calcium daily or placebo on the risk of falling at least once in 199 community dwelling men 65 years or older [18]. The supplements had no effect on fall risk in men. As mentioned above, both the Smith et al [14] and Law et al [15] studies also demonstrated no decreased risk of falls in men provided vitamin D supplementation. Overall, the data on the effects of vitamin D supplementation in preventing falls in men is rather scant, but the few data available do not provide convincing evidence that vitamin D therapy decreases the risk of falls.
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Other nutrients Vitamin K Men comprised 164 of the 452 subjects in a randomized trial of 500 g phylloquinone given with 600 mg of calcium and 400 IU of vitamin D. Results were presented for the entire study population and by gender. Compared to placebo, there was no difference in the change in bone mineral density or bone turnover markers among male subjects during the 3-year trial [19].
B Vitamins A supplement containing 1 mg folate, 500 g vitamin B12 and 10 mg vitamin B6 did not result in any differences in bone turnover markers compared to placebo after 2 years in 276 subjects over age 65 years with elevated plasma homocysteine levels at baseline [20]. In contrast, among 628 subjects with residual hemiplegia one year after an ischemic stroke who were randomized to a supplement containing 5 mg of folate and 1500 g of mecobalamin or placebo, the number of hip fractures per 1000 patient-years was reduced from 43 in the placebo group to 10 in the treatment group [21]. Approximately 50% of the subjects in these two studies were male; no gender specific results were presented.
Fiber Among 237 men between the ages of 40 and 80 years who were randomized to a 13.5 g per day wheat bran fiber supplement for 3 years, there was no difference in change in bone mineral density at the one third radius site compared to a 2 g per day fiber control group [22].
Conclusion There are limited data on the ability of nutritional interventions to improve skeletal outcomes in men. Reductions in fracture have been shown only for calcium and vitamin D in older individuals and for combination folate and B12 supplements in stroke patients. There are a few data suggesting that energy and protein supplements reduce complications following hip fracture. However, while dietary counseling has been shown to improve calcium intake in patients with osteoporotic fractures, counseling was not successful in improving protein or energy intake, even in a population with low intakes at baseline [23]. Thus, there remains considerable work to be done, both in conducting rigorous randomized trials of nutritional interventions for bone outcomes, but also in developing successful strategies to implement those interventions.
References 1. A. Avenell, H.H. Handoll, Nutritional supplementation for hip fracture aftercare in older people, Cochrane. Database. Syst. Rev. (4) (2006) CD001880. 2. D.A. Khalil, E.A. Lucas, S. Juma, B.J. Smith, M.E. Payton, B.H. Arjmandi, Soy protein supplementation increases serum insulin-like growth factor-I in young and old men but does not affect markers of bone metabolism, J. Nutr. 132 (9) (2002) 2605–2608. 3. D.T. Villareal, L. Fontana, E.P. Weiss, et al., Bone mineral density response to caloric restriction-induced weight loss or exercise-induced weight loss: a randomized controlled trial, Arch. Intern. Med. 166 (22) (2006) 2502–2510. 4. H. Spencer, L. Kramer, M. Lesniak, M. De Bartolo, C. Norris, D. Osis, Calcium requirements in humans. Report of original data and a review, Clin. Orthop. Rel. Res. 184 (1984) 270–280. 5. E.S. Orwoll, D.E. Meier, Alterations in calcium, vitamin D, and parathyroid hormone physiology in normal men with aging: relationship to the development of senile osteopenia, J. Clin. Endocrinol. Metab. 63 (6) (1986) 1262–1269. 6. T. Chevalley, R. Rizzoli, V. Nydegger, et al., Effects of calcium supplements on femoral bone mineral density and vertebral fracture rate in vitamin-D-replete elderly patients, Osteoporos. Int. 4 (5) (1994) 245–252. 7. M. Peacock, G. Liu, M. Carey, et al., Effect of calcium or 25OH vitamin D3 dietary supplementation on bone loss at the hip in men and women over the age of 60, J. Clin. Endocrinol. Metab. 85 (9) (2000) 3011–3019. 8. E.S. Orwoll, S.K. Oviatt, M.R. McClung, L.J. Deftos, G. Sexton, The rate of bone mineral loss in normal men and the effects of calcium and cholecalciferol supplementation, Ann. Intern. Med. 112 (1) (1990) 29–34. 9. B. Dawson-Hughes, S.S. Harris, E.A. Krall, G.E. Dallal, Effect of calcium and vitamin D supplementation on bone density in men and women 65 years of age or older, N. Engl. J. Med. 337 (10) (1997) 670–676. 10. A.M. Grant, A. Avenell, M.K. Campbell, et al., Oral vitamin D3 and calcium for secondary prevention of low-trauma fractures in elderly people (randomised evaluation of calcium or vitamin D, RECORD): a randomised placebo-controlled trial, Lancet 365 (9471) (2005) 1621–1628. 11. P. Lips, W.C. Graafmans, M.E. Ooms, P.D. Bezemer, L.M. Bouter, Vitamin D supplementation and fracture incidence in elderly persons. A randomized, placebo-controlled clinical trial, Ann. Intern. Med. 124 (4) (1996) 400–406. 12. H.E. Meyer, G.B. Smedshaug, E. Kvaavik, J.A. Falch, A. Tverdal, J.I. Pedersen, Can vitamin D supplementation reduce the risk of fracture in the elderly? A randomized controlled trial, J. Bone Miner. Res. 17 (4) (2002) 709–715. 13. D.P. Trivedi, R. Doll, K.T. Khaw, Effect of four monthly oral vitamin D3 (cholecalciferol) supplementation on fractures and mortality in men and women living in the community: randomised double blind controlled trial. BMJ. 2003 Mar 1; 326 (7387): 469. 14. H. Smith, F. Anderson, H. Raphael, P. Maslin, S. Crozier, C. Cooper, Effect of annual intramuscular vitamin D on fracture risk in elderly men and women – a population-based, randomized, double-blind, placebo-controlled trial, Rheumatology (Oxford) 46 (12) (2007) 1852–1857.
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15. M. Law, H. Withers, J. Morris, F. Anderson, Vitamin D supplementation and the prevention of fractures and falls: results of a randomised trial in elderly people in residential accommodation, Age Ageing 35 (5) (2006) 482–486. 16. L. Flicker, R.J. MacInnis, M.S. Stein, et al., Should older people in residential care receive vitamin D to prevent falls? Results of a randomized trial, J. Am. Geriatr. Soc. 53 (11) (2005) 1881–1888. 17. M. Pfeifer, B. Begerow, H.W. Minne, K. Suppan, A. Fahrleitner-Pammer, H. Dobnig, Effects of a long-term vitamin D and calcium supplementation on falls and parameters of muscle function in community-dwelling older individuals, Osteoporos. Int. 20 (2) (2009) 315–322. 18. H.A. Bischoff-Ferrari, E.J. Orav, B. Dawson-Hughes, Effect of cholecalciferol plus calcium on falling in ambulatory older men and women: a 3-year randomized controlled trial, Arch. Intern. Med. 166 (4) (2006) 424–430. 19. S.L. Booth, G. Dallal, M.K. Shea, C. Gundberg, J.W. Peterson, B. Dawson-Hughes, Effect of vitamin K sup-
20.
21.
22.
23.
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plementation on bone loss in elderly men and women, J. Clin. Endocrinol. Metab. 93 (4) (2008) 1217–1223. T.J. Green, J.A. McMahon, C.M. Skeaff, S.M. Williams, S.J. Whiting, Lowering homocysteine with B vitamins has no effect on biomarkers of bone turnover in older persons: a 2-y randomized controlled trial, Am. J. Clin. Nutr. 85 (2) (2007) 460–464. Y. Sato, Y. Honda, J. Iwamoto, T. Kanoko, K. Satoh, Effect of folate and mecobalamin on hip fractures in patients with stroke: a randomized controlled trial, J. Am. Med. Assoc. 293 (9) (2005) 1082–1088. Z. Chen, W.A. Stini, J.R. Marshall, M.E. Martinez, et al., Wheat bran fiber supplementation and bone loss among older people, Nutrition 20 (9) (2004) 747–751. S.Y. Wong, E.M. Lau, W.W. Lau, H.S. Lynn, Is dietary counselling effective in increasing dietary calcium, protein and energy intake in patients with osteoporotic fractures? A randomized controlled clinical trial, J. Hum. Nutr. Diet. 17 (4) (2004) 359–364.
Chapter
52
Exercise Programs for Patients with Osteoporosis Dieter Felsenberg1 and Martin Runge2 1
Zentrum Muskel- & Knochenforschung, Charité-Universitätsmedizin Berlin, Campus Benjamin Franklin, Freie Universität & Humboldt-Universität Berlin, Berlin, Germany 2 Aerpah Clinic Esslingen, Esslingen, Germany
Goals of exercise in patients with osteoporosis
of exercise prescription is effective in preventing falls and postponing sarcopenia and eventually disability? Instead of fracture incidence, bone mass, respectively bone strength, has often been chosen as the outcome parameter of exercise interventions, operationalized by diverse methods of densitometry. The results are inconclusive and controversial, a finding which can partly be explained by inherent methodological limitations of the dual energy x-ray absorptiometry (DXA) measurement, different populations and different interventions. In the field of exercise, describing the details of an intervention is more difficult than in pharmaceutical prescriptions. So it is not really surprising that, until now, there is neither convincing evidence nor common consensus about the best prescription of exercise for osteoporotic patients. The vague agreement that physical activity is beneficial for osteoporosis is very limited if it goes into detail. Looking for adequate outcome parameters besides fracture incidence, the following three relations could constitute our conceptual framework: the relations between:
The primary goal of osteoporosis management is the prevention of fractures. Thus, the key question of this chapter is: what kind of physical activity is the best prescription for our patients with osteoporosis? Precisely speaking: what kind of exercise prescription can reduce the risk of osteoporosis-related fractures? In an osteoporosis-specific perspective, the reduction of fractures is the appropriate primary outcome parameter for an exercise program, analogously to pharmacotherapy. But, until now, no randomized controlled trials (RCT) with enough statistical power have been conducted to prove a significant reduction of fractures by exercise interventions. Thus, in respect to RCT-based evidence, we cannot conclusively answer our key question if we restrict the approach to osteoporotic fractures. For many reasons, it may be adequate to broaden the goals of exercise to muscle function, falls and the postponing of mobility-related disability. The rationale for this approach is the fact that osteoporotic fractures are the result of both decreased bone strength and falls and fall risk is a consequence of age-associated neuromuscular decline. This ‘geriatric’ perspective addresses fall risk, sarcopenia and onset of disability additionally to fractures and bone strength. Osteoporotic fractures are seen as a part and a manifestation of the age-associated decline of the neuromuscular–skeletal system, eventually resulting in disability. Referring to osteoporosis as disorder of the muscle–bone unit, the term sarcopenia is increasingly recognized as important; it is defined as age-associated decline of muscle mass, in a broader (and more adequate) sense as decline of muscle function. According to this approach, the aforementioned key question can be completed: which kind Osteoporosis in Men
1. muscle and bone 2. osteoporotic fractures and age-related falls 3. osteoporosis in the context of sarcopenia, frailty and disability. and 1. given, that peak forces of muscles, which the bones are habitually loaded with, are the key determinants of bone strength in age-associated osteoporosis, regaining and sustaining muscle force is a necessary and reasonable exercise goal 2. given that the majority of non-vertebral fractures and a fair portion of vertebral fractures are both the result of diminished bone strength and falls, reducing the fall rate is a reasonable goal 635
Copyright 2009, 2010 Elsevier, Inc. All rights of reproduction in any form reserved.
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3. osteoporosis-related fractures are sharing numerous risk factors with falls and frailty and are correlated with multiple factors of the disablement process [1–4]. Therefore we should include these issues in our discussions.
Conclusion Lacking published evidence in respect to fracture prevention, an exercise design has to be referred to complementary parameters and indirect evidence, derived from physics, (patho)physiology, animal studies, clinical experience and observational studies. As adequate outcome parameters, bone strength, muscle mass and function, fall risk and postponing disability can be seen. What is the target population for an exercise programme? The target population are patients with osteoporosis or high-risk for osteoporosis and, more generally, any individual, who is identified of being at increased risk for decline of bone, muscle and functional independence. The prerequisites for this high risk status, however, can start very early, before puberty. The loss of muscle and bone with its functional consequences does affect all aging people, but the degree to which it occurs varies greatly between individuals. Therefore, we have to stratify the population and target our interventions both to the general population and to defined high risk groups.
Pitfalls in assessing exercise interventions Designing and judging exercise studies comprise a number of specific problems and pitfalls. It is difficult to administer a quantified and reproducible exercise program to a sufficient number of people over a period of months and years. To list a number of pitfalls and limitations: 1. the influence of any kind of physical activity on bone mass or bone strength, muscle mass and their functional consequences is a long-term effect. Is the duration of the intervention sufficient for the intended endpoint? For example, Snow and co-workers report results of weighted vest exercises with jumping, which did not lead to significant bone gain after 9 months of invention, but prevented 4.4% bone loss at the hip after 5 years of training [5] 2. in exercise interventions compliance and adherence are more vulnerable and usually lower than in pharmaceutical studies, especially in the long run, and more difficult to be controlled. The cessation of exercise, overtly declared or hidden, is a limiting factor. The precise amount of intervention that has been delivered is difficult to monitor
3. description and ‘dosage’ of exercises are crucial: what kind of movement has been performed? What are the accurate parameters of the exercises, expressed in terms of physics (Force load? Rate of force development? Velocity? Power?) What is the time course of a certain exercise? How long is a single session? What is the frequency of lessons? Exercise is a dynamic process: does the protocol comprise a structured progress of the interventions over time? We will explain that force loading of bones cannot be estimated without reference to terms of physics like leverage, moment and stiffness 4. site-specificity of the exercise: which regions of the body are really trained by the prescribed exercises? To understand the effect of exercises on the body, the force transmission by levers must be taken into account. For example, on one-legged jumping, the torques and lever actions of M. gluteus medius and the paravertebral muscles are completely different compared to two-legged jumping, generating completely different force loading. 5. do the outcome-parameters match to the exercise goal? e.g. fracture prevention and DXA-bone mineral density (BMD) changes are not directly related to each other, especially because bone adaptation to force loading is primarily a matter of geometry [6]. Exercise can have very different effects in relation to different movement parameters. Exercise-induced changes can be very different, related to different outcome measures like performed exercises, isometric strength or power output [7]. Exercise effects have been proven to be highly specific, inducing the greatest changes in the performed exercise itself. Reading exercise studies with these questions bearing in mind, most studies reveal limitations which make generalization and interpretation difficult. Referring to anatomy and physics is indispensible for the interpretation of conflicting results.
The role of physics, anatomy and physiology for designing and assessing exercise interventions Compelling evidence indicates that bone strength depends on the forces the bones are loaded with (Wolff’s law; Utah paradigm, mechanostat [8–11]). Given that bone deformation is the stimulus that regulates bone modeling and remodeling, ‘force’ is the determining parameter. In physics, ‘force’ is defined as that which changes movement and causes deformation. In common medical terminology, ‘strength’ is used both for ‘maximum voluntary muscle force’ and in relation to bone as ‘bone strength’ to describe the fracture load, i.e. the threshold of applied force which is able to break a bone. Force loading of the body and its different parts depends on leverage and stiffness. A helpful model to understand the mechanical concept of stiffness and force loading can easily
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be performed by a short self-examination. Jumping down from the height of a chair with a two-legged landing on the forefeet ‘as soft as possible’ generates ground reaction forces in the magnitude of 150–200% body weight to one leg in individuals with a good neuromuscular coordination, applied in the region of distal metatarseal bones. A stiff landing generates ground reaction forces up to 400% body weight to one leg. The forces the legs are loaded with can be calculated as quotient of kinetic energy in the moment of ground contact divided by the breaking distance (crumble zone). The breaking distance is determined by muscle tension, in terms of physics ‘stiffness’ ( force/distance). Thus, regulation of muscle tension determines the stiffness of the body. High stiffness means a short breaking distance high force loading. To calculate the force loading of bones the leverage has to be referred to. The scheme of Figure 52.1 demonstrates the force loading of the lower leg during jumping on one leg. On stiff serial jumping on the forefoot without touching the ground with the heel, a ground reaction force of about threefold body weight can be measured. The foot can be seen as see-saw lever system with the axis of the ankle joint as fulcrum. The threefold accelerated gravitational forces of the body are applied on the distal metatarsal bones, generating a torque, which can be calculated as product of the applied force times length of the lever. The calf muscles counter this torque, acting on a 1:3 shorter lever. Thus, in one-leg jumping on the forefoot, the lower leg is loaded with forces of 12–14-fold of body weight. This example demonstrates the indispensable importance of physics in the discussion of exercise impact on bones.
Force on tibia during one leg jump on forefoot Typical ground reaction force after puberty: 3.0 × body weight Force on tibia: 7200 N + 2400 N = 9600 N
3.0 × body weight of 80 kg = 2400 N
= 12 times body weight
Muscle: 3 × 2400 N = 7200 N
3
1
FGround = 3.0 × 800 N = 2400 N
Figure 52.1 One-legged jumping without touching the ground with the heel results in a ground reaction force of about threefold of the body weight, which is applied at the forefoot. Counteracting the momentum by acting on a 1:3 shorter lever, the plantar flexors have to generate a force equal to ninefold of body weight. Calculating the total force the lower leg is loaded with, a force of threefold body weight has to be added, resulting in 12-fold of body weight. Graph and calculation by H. Schiessl.
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In medical articles, often non-quantified or even nonquantifiable terms are used to describe exercises, like ‘highintensity’, ‘mild’, ‘moderate’, ‘vigorous’, ‘non-strenuous’, ‘weight-bearing’, ‘brisk walking’ etc, and so the description of physical activity is often not sufficiently accurate to assess leverage, stiffness and force loading of the administered exercises. Referring to the impact of force loading, another parameter is indispensible: rate of force development. Referring to some findings, it makes a difference how fast the bones are loaded. We still have a poor understanding how the bones transfer the deformations as signal to the cellular level and we do not know which parameter of a movement is the best stimulus for bone formation. But, without accurate quantification of the applied forces, we will never find the answer. The rate of force development describes the steepness of the force–time curve (Figure 52.2), which results on jumping out of the kinetic energy and stiffness. On one-legjumping on the forefoot, the force peak of threefold body weight (BW) is reached after about 150 ms, corresponding to a rate of force development of about 20 BW/s. A highly interesting study has shown that exercise effects on bone depend on movements with a higher level of acceleration and deceleration, causing a higher rate of force development on loading [12]. Human movement is a complex process of which muscle force is only one factor. Jones and Round report a catchy example [13]. In most people, the non-dominant arm has about 10% less strength if isometrically measured by hand grip. Throwing a ball as far as possible with the dominant and non-dominant arm reveals a far greater difference. The neuromuscular programs which are necessary for generating high power over the time of throwing (Power times time energy!) are not available for the non-dominant arm, despite nearly equal isometric strength. To remind the reader: preventing falling does require fast muscular reactions. To describe locomotion, force must be combined with velocity, expressed as ‘force times velocity power’ and, additionally, coordination must be taken into account. When discussing coordination, respectively postural control, motor learning must be considered. A classic study of Rutherford and colleagues has demonstrated that the variable ‘force’ is a very limited outcome parameter [7]. Seventeen young healthy volunteers had participated in strength training, which resulted in an increase of 160–200% of the weights that could be lifted. The increase in maximum isometric force was only 3–20% and no significant change could be found in power output. These findings highlight the importance of task specificity and appropriate outcome parameters. As a consistent finding, the greatest effects have been found by measuring the training exercise itself. Many data suggest that neuro muscular adaptation is highly specific for muscle group, magnitude of force and power, velocity and other modes of training [13]. Given the fact that the large motor units,
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Figure 52.2 Mechanography of one-legged jumping (Leonardo mechanography, Novotec Medical Pforzheim, Germany). Male, 57 years, generating a ground reaction force of 3.17-fold of body weight.
which comprise fast twitch fibers (type IIa and IIx), are much stronger and faster than the type I slow twitch ones, exercises for strengthening bones and preventing falls must aim at these fast components of muscles. It is known that these fibers are recruited during muscle action of more than 70% of the 1-repetition maximum [13, 14].
Bone strength and fall risk: two different goals, two different relationships to muscle The differentiation between force and power is important, especially in respect to fall prevention. It is current knowledge that the magnitude of force is the determinant for bone formation but, in preventing a fall, the muscles’ response to perturbations has to be the combination of force and velocity (plus accuracy, i.e. coordination). ‘Power’ as product of force and velocity represents this functional demand and has found to be more closely related to locomotor performances and aging than force [15, 16].
Force as an isolated parameter can only be measured without movement, i.e. isometrically. Regarding locomotion, it is a self-evident requirement that velocity has to be taken into account. It is common knowledge that muscular force generation strongly depends on contraction velocity [13]. This can be derived from the mechanisms of the filament gliding theory, the actin–myosin interactions and numerous physiological experiments. The force–velocity curve and Hill’s equation describe the physiological fact that muscle fibers cannot maintain the force level with increasing velocity of contraction. Therefore, exercises must be described by their power output. In a careful study of the determinants of lower-body muscle power in early postmenopausal women, the correlation between vertical jumping height as valid measure of power and knee extension force was only r 0.251, lower than the correlation to muscle density as representation of fat infiltration of the muscle [17]. Power can explain more of the variance of gait performance than force [18]. The IN CHIANTI study [17] has identified that muscle power is more strongly correlated to physical
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Bipedal locomotion and one-leg-standing
80
BM Specific Jumping Power [W kg–1]
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20 Men: r = 0.86, y = 77.4 – 0.62 x Women: r = 0.81, y = 55.5 – 0.42 x 0 0
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Figure 52.3 Two-legged jumping of a group of physically competent women (n 169) and men (n 89) from 18 to 88 years of age, without any disease or disorder affecting locomotion. y-axis: total power output on two-legged jumping, measured by a Leonardo mechanography plate (Novotec Medical, Pforzheim Germany) as Watt per kg body weight. x-axis: age in years. This sample had no age-dependent decline of muscle cross-sectional area at the lower leg, but a strongly age-correlated decline on power output. The variance decreases with age!
performance than impairment in force. According to these findings, power training has been proven more effective for improving physical function than strength training [19]. Power output has been repeatedly found to be more strongly age-associated than muscle mass or muscle force [16, 20, 21]. Runge and colleagues have found that, in a sample of high-functioning men (n 89) and women (n 169) between 18 and 88 years, who have been selected by an assessment battery as to be free from any disease or disorder influencing locomotor performance, the crosssectional area of lower leg muscles, measured by peripheral quantitative computed tomography (pQCT), showed no age-dependent decline, whereas the body weight specific power output on counter jumping demonstrated a strong correlation to age (r 0.86 and r 0.81 in men and women, respectively) explaining 75% of variance in men (Figure 52.3) [16]. The correlations of body weight specific peak force (0.66 and 0.75 in men and women) and lower leg muscle cross-sectional area (0.04 and 0.15 in men and women respectively) with age were weaker. The strong correlation of power output with age highlights the relevance of the parameter ‘power’ for assessing locomotion. Data of master athletes have convincingly confirmed this finding, finding an equal age-associated decline of specific power in men and women [22].
Bipedal gait is a demanding neuromuscular activity. The center of gravity of the human body is positioned high above the ground and the small base of support is continuously moved forwards and sideward. Controlling the kinetic energy of the moving body over a changing small base of support generates an inherent instability and requires a neuromuscular capacity, which has to be maintained by continuous practice. Even short periods of bed rest or immobilization deteriorate our balance. The complexity of gait can be described in two mechanical models: the body as a mass spring system can be described as an inverted pendulum with spring-like and pendulum-like oscillations. During walking and running, humans, like other animals, continuously convert kinetic energy to potential energy and vice versa. During each step, a part of the kinetic energy is absorbed by elastic elements of muscles and tendons and restored in the phase-adapted elastic rebound [23]. The whole body acts like an inverted pendulum and serial elastic elements (muscles and tendons) are stretched like a spring to store energy [23, 24]. Spring compliance enables the storage of elastic energy to reduce muscle work. So the force loading of the stance leg can be seen as the ‘significant moment’ of locomotion. During walking and running, the center of gravity has reciprocally to be transferred to the stance leg. The neuromuscular control of this movement phase is the essence of locomotion [25]. Based on this concept, very practical conclusions can be derived. Given that falling to the side is the main pathomechanism of hip fractures, further given that motor learning is highly specific, exactly this motor task can be seen as the bottleneck of neuromuscular aging and thus as primary goal of balance training. According to this, a recent review has found that successful exercise intervention against falls comprised high-demanding one-legged balance exercise [26]. One-leg standing with closed eyes clearly reveals that sideward body sway is more difficult to control than the anterior-posterior sway. Jumping forward to immediate standing on one leg compared to sideway jumping confirms that observation. Only one-legged force loading trains the muscles which counteract the torques in the frontal plane of the hip. The leverage of the M. gluteus medius in the frontal plane is comparable with the leverage at the feet. The consequences for an exercise design are self-evident.
The skeleton as tensegrity structure The term ‘strength’ characterizes the resistance of a bone to fracture. The strength of a structure is, besides material properties, determined by its geometry, as can be learned from any arch, bridge or piece of furniture, and the principles of engineering they are based on. Smashing some cups
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with a hammer or by falling is an amusing experiment to learn something about strength, fracture threshold, forces, their point of application and the dependence of strength on geometry and direction of force. No one will ever try to break a ruler with its small side upwards. These examples explain the dependence of strength on the direction of force loading. Corresponding to these facts, the fracture threshold depends strongly on fall mechanisms [27, 28]. The strength of a falling skeleton in the moment of impact does not depend on bones alone. The skeletal design of the body can be understood in analogy to the ‘tensegrity concept’ of architecture (cf. Kenneth Snelson’s Needle Tower). Tensegrity is a portmanteau of tension and integrity, coined by Richard Buckminster Fuller. Tensegrity is the exhibited strength of a structure, ‘when push and pull have a win-winrelationship to each other’ (Wikipedia). In the human skeleton, the bones act as a lever, pulled around joint axes by the muscles. Bones are pushing (compression), muscles are pulling (tension), so the strength of the structure is a result of their balanced action. It is not an isolated bone which hits the ground on falling, but it is a tensegrity structure, whose strength (‘fragility’) depends strongly on the tension within muscles and tendons in the very moment of impact and on the tissue the bones are covered with [29, 30]. This explains how complex, non-linear and multifactorial the pathogenetic chain is between DXA–BMD and fracture [27, 28].
DXA–BMD as outcome parameter of exercise interventions On the background of the presented facts and principles of physics, the relevance of DXA–BMD as an outcome measure for exercises is questionable. The erroneous, confusing use of the term ‘bone mineral density’ is worth its own textbook. The limitations of DXA-measured ‘bone mineral density’ should be paid attention to. Despite the widely known limitations of the planar projection of bones as surrogate for bone strength, DXA–BMD is often used as the outcome parameter of exercise studies without discussing the inherent pitfalls and despite the fact that the complex adaptations of bones to force loading cannot accurately be measured by planar projection. The measurement unit of DXA–BMD is ‘g/cm2’ and this concept reflects bone mass and not real density (g/cm3). DXA–BMD as a surrogate of bone mass cannot perceive smaller geometrical adaptations of bone to physical activity. Bolotin states that ‘systematic inaccuracies in DXA– BMD measurements may readily exceed 20% at typical in vivo lumbar vertebral sites, especially for osteopenic/osteoporotic, postmenopausal and elderly patients’ [31]. The results of DXA are size-dependent, a source of considerable misjudgment [32]. Further limitations emerge from the different composition of soft tissue, which leads to additional mistakes [31, 32]. The compelling conclusion is that DXA
bone densitometry does not give accurate and reliable estimates of a person’s true bone strength [33, 34]. It has often been proven by clinical experience (cf. bone changes in poliomyelitis) and studies that bones respond to exercise with geometrical changes which cannot be measured by DXA [6]. Thus, inferences from exercise studies with DXA–BMD as the outcome parameter must be interpreted with utmost caution and with careful respect to its limitations.
Relationships between muscle and bone: the muscle–bone unit The primary function of bones is to act as levers, in order to convert muscle actions to movements. Bones are designed to withstand the forces they are loaded with during locomotion. Their continuous remodeling is determined by the peak forces of muscles, which causes a certain magnitude of deformation (strain). Bones and muscles are linked together in a control loop, where the magnitude of strain is detected by the osteocytes. The stress–strain curve represents this relationship. If the deformation reaches a certain ‘set point’, bone is added, if peak forces fall habitually below a threshold, bone loss is initiated (Figure 52.4 [35]). In modern science, the German physician Julius Wolff [36] was the first to publish this relationship, known as Wolff’s law: form follows function. The impact of the force loading can be seen in the trajectories of the trabeculae in the epiphyses of long bones. Harold Frost, Webster Jee and numerous co-workers have published a compelling body of data to support this model (mechanostat model, Utah paradigm) [11, 35, 37, 38]. According to this model, muscle mass, muscle force and bone mass and bone strength are strongly correlated, as numerous studies have proved. In a classic work, Schiessl et al have demonstrated this relationship with a re-analysis of data of 788 Argentinian boys and girls. This analysis shows that bone mass corresponds to 5% of muscle mass (Figure 52.5). Hormones mediate the impact of muscle forces on bones by modifying the set point of the control loop. The pubertal increase of the slope of the girls’ curve is explained by the function of estrogen in regulating the muscle–bone control loop. Under the influence of estrogen, girls enhance the amount of bone in relation to their muscle mass compared with boys, a mechanism of storage of calcium for lactation [11]. If the peak muscle forces the bones are loaded with are critically reduced by disease, inactivity, pareses, life style factors, experimental protocols or the environmental conditions, bone mass and strength are reduced. This relationship is site-specific, i.e. bone is added or reduced exactly in this region where the muscle forces are reduced. Pareses can be seen as ‘experimenta naturae’. A pure regional muscle disease, like poliomyelitis, results in smaller and abnormal shaped bones in the affected limb. In spinal cord injuries, an obligatory sublesional bone loss can be observed
C h a p t e r 5 2 Exercise Programs for Patients with Osteoporosis l
130 25 20 15 10 5 Bone turnover (arb. units)
Stress/N/mm2
Mechanostat: control loop bone adaptation keeps strain constant
Fracture
Disuse
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+
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Remodeling 0
1000 2000 Strain/µStrain H.Frost, Anat. Rec. 1987
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Figure 52.4 Control loop of bone adaptation to load. The ‘mechanostat’ keeps strain constant by adding bone (formation), if the strain generated by muscle forces, exceeds about 1500 microstrain [8].
3500 r = 0.995 3000 r = 0.88 Whole body BMC [g]
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[39, 40]. In animal experiments, the bones are affected by de-loading or overloading, which are acted on by the muscles under consideration [41]. In an impressive animal study, Umemura and colleagues could demonstrate that ‘five jumps per day’ have been found enough stimulation to increase significantly bone mass and femur strength of rats in a bending test [42]. Also, different kind of sports can be seen as models for the effects of de-loading or overloading of bones by muscle actions. In general, sports with high force loading by jumping, like soccer or volley ball, are correlated with high bone mass [43, 44]. Sports are a good model to demonstrate the sitespecificity of force loading. Tennis and squash players are models for unilateral loading of well-defined body parts. Their playing arms develop larger and stronger bones [45]. This adaptation is a complex process with changes of the geometry, which cannot completely recorded by a planar technique like DXA [46]. From the associations of different types of sport with the regional response of bone, it can be concluded that high force loading is more effective in increasing bone mass and strength than ‘low impact movements’. Comparison of swimmers and bikers with sports which include higher force loading, are convincing [47, 48] and long distance running even shows a negative dose–response association between endurance activities and bone mass: the longer the distances the lower the bone mass [49, 50]. From these relationships, we can get a first impression of what kind of physical activity could be beneficial for bone strength.
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Figure 52.5 The figure plots the findings of 345 boys (open circles) and 443 girls (crosses), each data point representing an age group one year older than the group to the left. y-axis: whole body bone mineral content as index of bone strength in grams; x-axis: total lean body mass in grams as index of muscle force, demonstrating a strong relationship: bone mass and lean body mass are strongly correlated, bone mass accounting for 5% of lean body mass. The change in the relation between bone mass and muscle mass of the girls’ curve at the onset of puberty represents an additional storage of bone under the influence of estrogen.
In accordance with these findings in observational studies, higher level of physical activities are consistently positively correlated with better bone parameters, higher muscle mass and better function, fewer falls and fewer fractures and a later onset of disability [51–54]. In men and women, hip fracture incidence has been found to be associated with decreased physical activity [1, 55, 56]. In a prospective cohort study of 3262 men over a follow-up period of 21 years, an adjusted hazard ratio of men participating in vigorous physical activity compared with men not participating was 0.38 (95% CI; 0.16–0.91, P 0.03 [57]). In the Study of Osteoporotic Fractures, a prospective cohort study of 9704 non-black women 65 years or older, very active women (fourth and fifth quintile) had a reduction of 36% in hip fractures (relative risk 0.64, 95% CI 0.45–0.89) compared with the least active women [56]. The data suggest a dose–response relationship to the ‘intensity’ of physical activity, because ‘moderately to vigorously active women’ had statistically significant reductions of 42% in risk for
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hip and 33% in risk for vertebral fractures, compared with the lowest quintile. Sedentary lifestyle has been found to be a risk factor for osteoporotic fractures. In the Brazilian Osteoporosis Study, sedentary life style is even more strongly correlated to fractures in men than in women (OR 6.3 versus 1.6 [58]). Rosenberg summarizes these results in an editorial in the Annals of Internal Medicine with the request: Let’s get physical [59]. Gait performance in particular has been consistently been proven as highly predictive for age-related adverse events up to disability and mortality [2, 60, 61]. Compromised gait performance in community-residing adults has been found to be correlated with greater risk of institutionalization and death, the risk has been found strongly related to the severity of impairment [62]. A robust correlation is consistently found, even in longitudinal design, between hand grip strength and both mortality and onset of disability in late life. A 25-year prospective study has proven that hand grip strength of middle-aged men (45–68 years old) was highly predictive of disability in their late life and mortality [63, 64]. Other studies have confirmed this predictive value of hand grip strength [29]. Neuromuscular performance measures of force, power and locomotion have consistently been found to be strongly correlated with fall risk, especially gait velocity, chair rising, force (hand grip) and balance. Two test procedures of lower extremity function have been found to be good independent predictors of falling and fractures: chair rising – representing muscle force and power – and tandem maneuvers – representing lateral postural capacity. Quantifying these performances by timed tests enables us to stratify populations at risk and evaluate therapy effects [65–72]. Frailty, operationalized in different ways, has been found significantly correlated with falls and fractures [73]. This finding can be explained by pathophysiological relations between an age-related decline of multiple body systems to falls, fractures and functional dependency. Aging is facing a complex scenario of highly intertwined structural and functional deficits, of which the decline of muscle and bone is just one part. A comprehensive diagnostic and therapeutic approach should include as many contributors as possible. Age-related bone changes cannot be sufficiently explained or counteracted without respect to muscles, kidneys, hormones, immunologic and cardiovascular processes and even psychiatric deficits. A patient with a deep depression will exert a low habitual level of muscular activity with the consequence of diminished force loading of bones. A core element of frailty is decreased physical activity, a status with high correlation to fractures [3].
Sarcopenia and age-associated functional decline Decline of muscle mass and function, operationalized in many different ways, has consistently been found to be
associated with falls, fractures and functional decline [74–76]. In men and women with a skeletal muscle mass index (skeletal muscle mass/body mass times 100) below two standard deviations of young adult values, the likelihood of functional impairment and disability was approximately two times greater in older men and three times greater in older women than in men and women with a normal index [77]. In a prospective 10-year follow-up study, stronger back muscles have been shown to reduce the incidence of vertebral fractures [78]. Sarcopenia (Greek: loss of flesh) is a term which has been coined by Rosenberg indicating the age-associated loss of muscle mass [4, 79]. A generally accepted operationalization has not yet been reached, but there is emerging consensus, that sarcopenia is a functionally relevant loss of lean body mass or appendicular muscle mass with implications for (loco)motor performances and functional independence [4, 80]. The pathogenesis is not yet completely understood, but it seems to be a multifactorial process in which ‘disuse’ is a crucial and perhaps reversible contributor. Inflammatory and hormonal processes are deeply involved, but it is an open discussion which certain factors are a cause or consequence. Ferrucci and co-workers found a significant steeper parallel decline of muscle force and physical performance measures in older women with high interleukin-6 serum levels [75]. The correlation between muscle density as an indicator of fat infiltration and muscle power underlines the importance of muscle composition (fat content) as a factor of sarcopenia and optional goal of therapy [17]. Sarcopenia is seen as part of a general age-related decline of biological systems which is discussed under the label of disablement process or frailty [3]. As expected, the loss of muscle mass is linked with a decline of muscle function and functional independence, as numerous studies have found. Lower extremity muscle mass has been proven as a strong independent predictor of severe functional impairment and was strongly associated with muscle force (r 0.78 [81]). Aging does not only affect muscle mass, but also cellular and structural properties of muscle and tendons. The aging muscle suffers a loss of fiber elasticity and specific force and shortening velocity [82]. A recent review identified a number of risk factors which both contribute to the frailty syndrome and increased hip fracture risk, hypothesizing that these risk factor are also pathogenetic mechanisms: falls, weight loss, sarcopenia, insulin-like growth factor-I (IGF-I), vitamin D and proinflammatory cytokines [83]. In the MINOS study, low skeletal muscle mass of elderly men has been found associated with increased risk of falls, impaired balance and narrower bones with thinner cortices [84]. The Health, Aging and Body Composition Study has investigated whether low leg muscle mass and greater fat infiltration in the muscle were associated with poor lower extremity performance (6-m walk, repeated chair stands). Both smaller mid-thigh muscle area and greater fat infiltration have been found associated with poorer lower extremity performance in well-functioning older men and women [54, 85]. Loss of
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muscle mass alone cannot completely explain the decrease in muscle function [86]. A number of age-associated changes contribute to this process like loss of alpha motor neurons, structural changes of the muscle itself, e.g. measured as fat infiltration by radiographic density and, additionally, changes of connective tissue within the muscles and in tendons. Narici and co-workers could prove that these changes at least partly can be reversed by resistance training [87]. Finally, the age-associated neuromuscular decline, measurable as loss of force, power and postural control, converges to a certain number of compromised performances: walking, chair rising and sideway postural control, measured by one-leg standing, narrow walking, tandem maneuvers or more complicated balance tests. Muscle impairment in older men and women can be quantified with locomotor performances that represent pivotal everyday activities. Test procedures like timed walking, timed up and go test, chair rising without using one’s arms, standing or walking foot by foot in the tandem position and one-legged standing, have been proven as valid assessment tools for predicting falls, fractures, impending disability and immobility [1, 88, 89]. The classic study of Guralnik and colleagues [2] has introduced the ‘short physical performance battery (SPPB)’ and impressively revealed the association between lower-extremity performances and the impending onset mobility limitation and disability. A very similar set of neuromuscular performances has been found predictive for falls [65–70]. The MrOS study has proven that, in particular, the repeated chair stand performance was strongly related to hip fracture in men [90]. Men unable to perform this exam had an eightfold risk of hip fracture compared with participants in the fastest quartile (multivariate hazard ratio 8.15 (95% CI, 2.65–25.03)). Also, the combination of poor test results has been found predictive; 64% of hip fractures occurred in the group of men with the poorest performance in three exams. Poor performances in three tests indicated a multivariate hazard ratio of 3.14 (95% CI, 1.46–6.73) compared to men with better results [90]. In an 8-year prospective population based cohort study of 2928 women (Osteoporosis Risk Factor and Prevention Study OSTPRE [89]), investigating the association between functional capacity and fractures, the inability to stand on one foot for 10 seconds increased the risk of hip fracture nine- to 11-fold (hazard ratio with 95% CI, 1.98–42.00). These findings are in accordance with the aforementioned analyses of gait mechanics. Summarizing these data, performance tests have been proven as feasible, valid and reliable and therefore indispensable tools to predict falls, fractures and disability and are therefore proposed as tools for evaluating the effect of therapeutic interventions. These correlations represent strong evidence that sarcopenia, bone strength, falls, fractures and disability are intertwined into a common pathogenetic pathway that has to be addressed by tailored interventions.
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Osteoporosis-related fractures and falls In the Dubbo Osteoporosis Epidemiology Study (1358 women, 858 men, 60 years), the mortality-adjusted life time risk of fracture has been estimated to be 44% for women and 25% for men and 65% (95% CI, 58–73) for women and 42% (CI 95%, 24–71) for men with osteoporosis [91]. It is self-evident that decreased bone strength plays a causal role in the pathogenesis of fractures and it has been proven in numerous studies that DXA-measured BMD has strong correlations with different kinds of fractures, but it is astonishing how falls are neglected as risk factors for fractures [92]. Bone strength is really not the only risk factor for fractures. Compelling data suggest that falling is the single strongest risk factor for fractures [1, 34, 93–97]. Of hip fracture patients 50–80% have no osteoporosis, referred to as a DXA–BMD T-score of 2,5 [98, 99]. In a Norwegian study, nine out of ten fractures in the elderly have been found to be caused by a fall and even more than 90% of hip fractures result from a fall [100]. Recent data of the Osteoporotic Fractures in men study (MrOS) confirm these findings revealing that six clinical risk factors predicted the risk of non-spine fractures in men independent of DXA– BMD: tricyclic antidepressant use, previous fracture after the age of 50, inability to complete a narrow walk trial, falls in the previous year, age 80 years and depressed mood [101]. Especially powerful was the prediction of fracture if an individual was host to three or more clinical risk factors (4.9% of men). This status was associated with a fivefold risk compared to men without any risk factor (48% of men), independent of DXA–BMD. Being in the lowest DXA–BMD tertile with three or more clinical risk factors was associated with a 15-fold risk, compared to men without clinical risk factors in the highest DXA–BMD tertile. Vertebral fractures have often been presented as quasi ‘pure’ osteoporotic fractures, primarily depending on bone strength. Data from the Mr OS study suggest changing this perspective. The rate of incident vertebral fractures rose from 0.7% in men aged 65–69 years to 5% 85 years; 57.3% of vertebral fractures were precipitated by a fall and most men with incident clinical vertebral fractures did not have osteoporosis [102]. Falling from a standing height generates enough energy to break even a non-osteoporotic elder femur. Using simple physics illustrates this point. Given a fall of a mass of 50 kg from a height of 0.80 m, decelerated by a soft tissue of 4 cm thickness, the potential energy (which equals the kinetic energy in the moment of impact) can be calculated as 400 J (500 N, height 0.8 m). Because energy (5work) is the product of force times distance, we have to divide the energy by the decelerating distance to get the resulting force: 400 J divided by 0.04 m tissue thickness results in a force of 10 000 N with which the femur is loaded. That can hardly be called a ‘minimal’ trauma.
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The importance of falls in the pathogenesis of so-called ‘osteoporotic’ fractures is increasingly being recognized. A remarkable recent publication has collected a lot of data and arguments for ‘shifting the focus in fracture prevention from osteoporosis to falls’ [34]. The authors have collected convincing evidence that fall prevention may be more effective for the prevention of fractures than the established pharmaceutical approach addressing bone strength, because falling and not bone strength (especially not DXA measured BMD) may be the strongest risk factor for fractures, especially sideways falling with impact on the greater trochanter. For designing exercise interventions, the finding that sideways falling is strongly associated with hip fractures is of utmost importance. Nevitt and Cummings [103] published a multivariate analysis about fall mechanisms and found that landing on or near the hip increased the fracture risk to an odds ratio of 32.5 (95% CI; 9.9, 107.1). Confirming this finding, Robinovitch et al found a 30fold increase in risk [104] and Schwartz and colleagues [55] found, in a case control study of 214 elderly men, an increase of hip fractures in men who reported hitting the hip/thigh in a fall (OR 97.8, 95% CI, 31.7–302). Cummings and colleagues [1] have published convincing data that the hip fracture risk of white women is the combined result of both decreased bone mass and factors which are not bone-related. Among their list of independent hip fracture risk factors there are genetic factors and mobility-related variables, which can also be found as risk factors for falls and functional decline. This overlapping of risk factors for fractures, falls and onset of disability suggest that locomotor function and its underlying biological systems represent a common pathological pathway for agerelated decline of functional independence in general [105]. Pathophysiological arguments and empirical findings suggest that osteoporosis-related fractures have a complex multifactorial origin, comprising factors related to muscle, bone and the neuronal system, which are influencing each other, converging in a common pathway of osteoporosis, sarcopenia, fall risk, frailty and eventually premature disability. For designing an anti-osteoporosis exercise program, this multitude of interactions is not a nuisance, but a chance. Seeing this intertwined bundle of lines, which result in a fracture, each line can be seen as a distinctively addressed goal for therapeutic interventions. It is the combination of osteoporosis, sarcopenia and neuromuscular decline which results in a steep age-associated increase in incidence and prevalence of falls, fractures and disability, so generating a great burden for individual patients, their care persons and the health system in general. Thus, osteoporosis management should be planned in the context of the aging process, namely sarcopenia, frailty and the onset of disability.
Exercise interventions and bone strength The results of studies with the outcome parameter of bone strength are inconsistent and conflicting. An annoying example is the conflicting evidence whether walking is effective in increasing bone mass (DXA–BMD). Each and any position can be supported by some studies. Three recent meta-analyses came to completely different results: walking has a significant positive effect on lumbar DXA– BMD but not on the femur [106] meta-analysis showed no significant change in DXA– BMD at lumbar spine and inconsistent positive effects at the femoral neck [107] analysed results showed walking to be effective on both DXA–BMD of the spine and the hip [108].
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A number of studies with weight-lifting (progressive resistance training) or other interventions with ‘high-impact’ found positive effects on DXA–BMD [108, 109], others found no effect [110, 111] or even a decrease in vertebral bone mass by weight training [112]. A major problem is the aforementioned limitation of DXA to measure geometrical responses of bone. In some studies, the exercise effect was different if measured with computerized tomography and with DXA [113]. Some studies report findings which are especially important for further research and can explain some discrepancies and conflicting results. In a study of Jamsa and colleagues [12], the association between the intensity of physical activity and bone mineral density at the proximal femur, using long-term quantification of daily physical activity, has been investigated. The study subjects were 64 women (aged 35–40 years), who carried an accelerometer for 12 months to quantify their daily physical activity. Physical activity that induced acceleration levels exceeding 3.6 g was positively correlated with the bone mineral density change at the proximal femur, the association being strongest at the femoral neck at 5.7 g (r 0.416, P 0.001). This finding underlines the importance of high force loading with a high rate of force development. Another explanation for different results seems to be the length of follow up. A study by Snow and colleagues [5] highlights the importance of a long-term follow up to detect effect of exercise on bones. It took 5 years until a significant difference in bone properties could be found. One important observational study is worthwhile to be registered with the methodological limitation of missing a randomization. Sinaki et al [111] have investigated the long-term effect of stronger back muscles on the spine; 50 healthy white postmenopausal women, aged 58–75 years, after completion of a 2-year randomized, controlled trial, have been followed up for 8 years. Twenty-seven subjects had performed progressive, resistive back-strengthening
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exercises for 2 years and 23 had served as controls. The difference in bone mineral density, which was not significant between the two groups at baseline and 2-year follow up, was significant at 10-year follow up (P 0.0004). The incidence of vertebral compression fracture was 14 fractures in 322 vertebral bodies examined (4.3%) in the control group and six fractures in 378 vertebral bodies examined (1.6%) in the intervention group (chi-square test, P 0.0290). The relative risk for compression fracture was 2.7 times greater in the control group than in the patients who had performed progressive resistance exercises for the back muscles. A number of studies have successfully administered jumping as an intervention [114, 115]. Despite the heterogeneity and methodological limitations of studies with DXA–BMD as outcome parameter, a number of conclusions seem to be justified regarding the response of bone to exercise: high force loading is more effective than low force loading [116–118] the response is primarily related to a geometric adaptation and not to mass [6, 45] the response is better in men than in women [119] the response of bones to exercise is better in the prepubertal than postpubertal and premenopausal than postmenopausal skeleton [116, 120] the response of bones is site-specific [45, 117, 121] beneficial effects are lost after cessation [122].
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changes [125]. Men seem to respond better to resistance training than women related to myofiber hypertrophy [126]. It has been proven that even frail elderly and institutionalized men and women can gain muscle mass, muscle force and, simultaneously, a better functional status and spontaneous activity in response to high-intensity strength training [30, 127]. A Cochrane review came to the conclusion that, among older people (aged 60 plus), progressive resistance strength training had a large positive effect on strength (41 trials, 1955 participants, but with statistical heterogeneity) and leads to modest improvements of functional limitations [128, 129]. Musculoskeletal injuries were detected in most of the studies that prospectively observed adverse events. The group of Narici et al showed that muscles and even tendons of elderly men respond positively to resistance training [87, 130, 131]. Also muscle power could be increased in elderly [82] and also the age-associated fat infiltration [132].
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Effect of exercise intervention on muscle structure and muscle function Given the strong evidence that both bone strength and fall risk depend on muscle forces and muscle power respectively, maintaining and increasing muscle mass, strength and power are reasonable goals of exercise. Maintaining muscles is a prerequisite of successful aging, because functional independence is strongly dependent on locomotion and its corresponding organ systems. Since the remarkable work of Fiatarone and co-workers, it has numerously been proven that elderly and even nonagenarians do respond to progressive resistance training by increasing strength and muscle mass [123, 124]. There is compelling evidence that progressive resistance training in the elderly can positively influence muscle function and muscle mass. Numerous studies have shown substantial increases in muscle force measured by the one repetition maximum in response to 8–12 weeks of strength training (3 to 4 times per week at 70–90% of the 1 repetition maximum). In addition, a subset of these reports has also reported significant increases in muscle size either by computed tomography (CT) analysis of muscle cross-sectional area (9–17%) or by biopsy examination of muscle fiber size
Effect of exercise interventions on risk factors for falls, fractures and onset of disability As aforementioned, a number of postural and locomotor performances have been consistently found associated with falls, fractures and functional decline, among which gait velocity, sit-to-stand movements (chair rising) and sideway balance (tandem maneuvers) are prominent. These variables are not only statistically risk factors, but likely pathogenetically linked with falls, factures and the resulting functional decline. Exercises seem to have significant beneficial effects on balance [133], but progressive resistance training may not be the appropriate intervention for balance improvement [134, 135]. Given that the ultimate exercise goal is the prevention of future adverse events, it is necessary and reasonable to have a direct continuous measure of exercise effects for planning, evaluating and adapting exercises. There is compelling evidence that exercise can improve gait velocity, sit-to-stand movements and balance in elderly men and women. A recent review about effective exercise for the prevention of falls concludes that greater effects are seen in exercises that challenge balance, i.e. standing on one leg [26]. Falls and fractures can be seen as steps of the disablement process, which eventually results in disability, i.e. need of personal care in the activities of daily living. So it is promising that locomotor performances can be maintained and the onset of disability postponed by exercise interventions [136–139]. Prevention of falls and fractures is not the only way to prevent disability. Exercise as a component of a fall prevention program could maintain mobility without
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reducing the number of falls [138]. The development of disability can occur insidiously without a catastrophic event like a fracture [140].
Exercise interventions and fall prevention Age-associated falls have been conceptualized as a geriatric syndrome with a certain array of independent risk factors [141]. Since the 1970s, a number of research groups have collected a convincing body of knowledge about ageassociated falling and its risk factors [65–70]. Based on this research, a number of successful multicomponent interventions have been performed to reduce the rate of falling in different populations. Tinetti et al published the results of a multifactorial intervention against falls using risk factors for identifying a high-risk group [142]. During a 1-year followup period, 47% of the control group suffered a fall, but only 35% of the intervention group (P 0.04, adjusted incidence ratio 0.69, 95% CI 0.52–0.90). Components of the intervention were adjustment of medication, education, recommendation of behavioral change and home exercise programs. Another multicomponent RCT [143] with elderly people presenting to the emergency department after a fall resulted in a reduction of falls and recurrent falls (OR 0.39, 95% CI 0.23–0.66 resp. OR 0.33 95% CI 0.16–0.68). Preventing falls with Tai chi exercises has found broad attention [144]. In an impressive series of randomized controlled trials, it has been proven that the home-based Otago Exercise Program is able significantly to reduce the rate of falls. The program comprises force and balance exercises and is individually progressively over time adapted by a trained professional. In the first study among women over 80 years of age, Campbell and colleagues found a significant reduction of falls over a 12month period (0.47 between group difference, CI 0.04–0.8 [145]). The reduction of falls remained significant after the second year [146]. The Otego Exercise Program was also successful in reducing falls if delivered by a trained community nurse and in routine health care [147, 148]. In several studies, group exercise, comprising balance and strength training, could significantly reduce fall rate [149, 150]. A number of exercise interventions failed to reduce falls [151–153]. Summarizing the results of interventions against falls a number of reviews concluded that multicomponent interventions against falls, including exercise as major component, are effective in reducing falls [26, 154–156].
Whole body vibration Whole body vibration is a new approach to improve neuromuscular functions and bone strength. The findings are
not completely conclusive, partly because of significant differences in samples, technical application of vibration and other details of the training regime. With whole body vibration, a number of fracture- and disability-related muscle functions and locomotor performances in elderly could be improved: muscle force [157, 158], muscle power, measured as chair rising [159], gait [160, 161], fracture [162], balance [163], chronic lower back pain [164]. Based on published findings, own clinical experience, own RCTs [164, 165] and aforementioned analyses of human locomotion, the authors prefer side-alternating, reciprocating whole body vibration with frequencies between 10 and 30 Hz as intervention for improving back pain, balance, muscle mass and muscle power in elderly patients. The method is increasingly being investigated.
Risk of exercises Physical activity and exercises cannot be administered without the risk of adverse events. Motor learning and progressive resistance training have to be administered on a demanding level [124]. To repeat activities which can be perfectly managed will not result in improvements of neuromuscular and locomotor competence. It is the essence of training to adapt responsive body systems to a higher level and, therefore, therapy and training have to be performed at the limits of ability. This inherently is associated with some risk. Most exercise intervention studies do not report major adverse events, but injuries cannot completely be avoided [128]. According to the authors’ clinical experience, a well instructed and professionally supervised device-based resistance training and side-alternating whole body vibration are not associated with a high risk of serious injuries. It is beyond the scope of this chapter to go into details, but it has to be considered by which measures injuries and cardiovascular events can be prevented. This issue is carefully covered by the American College of Sports Medicine Resource Manual [166]. In any case, exercise prescriptions have to be adapted to the individual pathology and level of motor competence. They have to be started at the individual level of competence and have to be adapted to the individual’s progress. Therefore, a risk assessment and continuous functional assessment, which is referred to the exercise goals, is an integral part of any intervention.
Recommendations for designing and prescribing exercise programs for patients with osteoporosis Of course, there are still a lot of relevant ‘missing links’ in our knowledge about the best exercise prescription for preventing
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falls, fractures and a premature onset of disability. But, to the authors’ best knowledge, a number of recommendations are justified. They are based on the above collected references and the presented concept of physics and physiology of movement and the muscle–bone-unit. They refer to elderly men and women with increased risk of osteoporosis- and fall-related fractures and in a long-term perspective to men and women with an increased risk of premature onset of disability. We recommend as our conclusions that additionally to physical activities, which improve endurance and cardiovascular fitness, an individually tailored exercise program should be prescribed in order to maintain or improve bone strength, muscle mass, neuromuscular functions and, eventually, locomotion and activities of daily living (ADL) independence. By exercise programs, neuromuscular risk factors for osteoporosis, falls, fractures and disability onset have been improved, fall rate has been reduced and the onset of disability might have been postponed. Such exercises may also be able to reduce fracture rate. Individually tailoring of exercises should be based on a neuromuscular and locomotor assessment with reliable and valid test procedures. Monitoring exercise effects requires directly available measurements. Additionally to measurements of bone strength and muscle structure, a (loco)motor assessment can identify high-risk patients. Besides, a continuous neuromuscular–skeletal exercise program can be recommended to any person who wants to live long into a functionally independent old age. In particular, gait velocity, chair rising and tandem maneuvers (SPPB [2]) have been proven as valid measurements of mobility. On the level of organ function (impairment), exercises should aim at increasing and maintaining muscle mass, muscle structure, muscle force, muscle power, inter- and intramuscular coordination and flexibility. On a functional level, gait velocity, chair rising, stair climbing and measures of sideward balance (tandem, one-legged standing) are feasible and relevant goals. Scientific terminology requires accurate references to physics. Leonardo mechanography is a reliable, valid, sensitive and feasible new technique, which results in objective measures for ground reactions forces, so force loading and power output during unrestricted every-day movements can be assessed in accordance to the terms of physics [167]. Regarding the exercise effects on these direct available variables, it can be inferred that significant improvements can be seen as indicators of a decreased the risk of falls, fractures and premature disability. Admittedly, this is an optimistic perspective, based more on inferences than on robust evidence, but it is our ‘best guess’ from available data. A comprehensive neuromusculo–skeletal exercise program should address differently relevant anatomical body parts and fitness components: muscle mass and muscle force, especially the muscles surrounding the hip
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muscle power resp. power output (i.e. force times velocity), because power is an indispensable variable to describe movement postural control, especially sideward balance control and last but not least, flexibility.
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Flexibility (i.e. stretching exercises) is scarcely systematically investigated but, based on clinical experience and physiological conclusions, it is a necessary component of musculoskeletal fitness, because without elastic eccentric movements, energy storage and quick release is hindered. Our clinical experience with jumping mechanography reveals that loss of eccentric phases during countermovements is an early and common sign of aging muscles (unpublished own data). This proposed program, which aims primarily at bone strength and fall risk, should be completed by a cardiovascular oriented endurance program. Progressive resistance exercises have been proven as a feasible, effective and safe part of any age-related program to counteract fall risk, sarcopenia, osteoporosis and functional decline, but should be completed by exercises which address balance and power. Performances representing sideward balance, like tandem maneuvers and one-leg standing, have been found as indicators of fall and fractures risk and have been part of successful multifactorial interventions. Traditional Asian exercises like Tai Chi are a good source and appropriate example for the design of exercise programmes [144]. Unilateral hopping and jumping exercises should be components of a comprehensive program. The rationale for this recommendation is the abovementioned analysis of bipedal gait and the strong association of hip fractures with a sideward falling. Sideward postural control is an important bottleneck of aging human locomotion. Side-alternating whole body vibration is a promising new approach to improve neuromuscular–skeletal impairments.
Future developments and demands In order to compare exercise interventions, some requirements are proposed: the applied type of exercise must be described in reproducible quantifications (force, velocity, power, duration, frequency) RCT with the outcome ‘onset of disability’, falls and fractures should be conducted adverse effects should be carefully and prospectively monitored muscle function as outcome variables should be measured in accordance with physics with objective, reliable and valid measurements.
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There is still al lot of research to be done until we can conclusively answer our leading question: which kind of
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exercise is the best prescription for osteoporotic patients? In the meantime, we have to refer our recommendations to the best available knowledge which the authors have tried to present in this chapter.
References 1. S.R. Cummings, M.C. Nevitt, W.S. Browner, et al., Risk factors for hip fracture in white women. Study of Osteoporotic Fractures Research Group, N. Engl. J. Med. 332 (12) (1995) 767–773. 2. J.M. Guralnik, L. Ferrucci, E.M. Simonsick, M.E. Salive, R.B. Wallace, Lower-extremity function in persons over the age of 70 years as a predictor of subsequent disability, N. Engl. J. Med. 332 (9) (1995) 556–561. 3. L.P. Fried, C.M. Tangen, J. Walston, et al., Cardiovascular Health Study Collaborative Research Group. Frailty in older adults: evidence for a phenotype, J. Gerontol. A. Biol. Sci. Med. Sci. 56 (3) (2001) 146–156. 4. I.H. Rosenberg, Sarcopenia: origins and clinical relevance, J. Nutr. 127 (1997) 990S–991S. 5. C.M. Snow, J.M. Shaw, K.M. Winters, K.A. Witzke, Longterm exercise using weighted vests prevents hip bone loss in postmenopausal women, J. Gerontol. A. Biol. Sci. Med. Sci. 55 (9) (2000) 487–488. 6. N. Ashizawa, K. Nonaka, S. Michikami, et al., Tomographical desription of tennis-loaded radius: reciprocal relation between bone size and volumetric BMD, J. Appl. Physiol. 86 (4) (1999) 1347–1351. 7. O.M. Rutherford, C.A. Greig, A.J. Sargeant, D.A. Jones, Strength training and power output: transference effects in the human quadriceps muscle, J. Sports Sci. 4 (2) (1986) 101–107. 8. HM. Frost, Bone ‘mass’ and the ‘mechanostat’: a proposal, Anat. Rec. 219 (1) (1987) 1–9. 9. H.M. Frost, Changing views about ‘osteoporoses’ (a 1998 overview), Osteoporos. Int. 10 (5) (1999) 345–352. 10. H.M. Frost, The Utah paradigm of skeletal physiology, ISMNI, Athens, Greece, 2004. 11. H. Schiessl, H.M. Frost, W.S.S. Jee, Estrogen and bonemuscle strength and mass relationships, Bone 22 (1) (1998) 1–6. 12. T. Jamsa, A. Vainionpaa, R. Korpelainen, E. Vihriala, J. Leppaluoto, Effect of daily physical activity on proximal femur, Clin. Biomech. 21 (1) (2006) 1–7. 13. D.A. Jones, J.M. Round, Skeletal Muscle in Health and Disease, Manchester and New York, 1990, pp. 98–114. 14. D. Jones, J. Round, A. de Haan, Skeletal Muscle from Molecules to Movement, Edinburgh, 2004, pp. 45–48. 15. J.F. Bean, S.G. Leveille, D.K. Kiely, S. Bandinelli, J.M. Guralnik, L. Ferrucci, A comparison of leg power and leg strength within the InCHIANTI study: which influences mobility more?, J. Gerontol. A. Biol. Sci. Med. Sci. 58 (8) (2003) 728–733. 16. M. Runge, J. Rittweger, C.R. Russo, H. Schiessl, D. Felsenberg, Is muscle power output a key factor in the age-related decline in physical performance? A comparison of muscle cross section, chair-rising test and jumping power, Clin. Physiol. Funct. Imaging 24 (6) (2004) 335–340. 17. S. Sipila, S.O. Koskinen, D.R. Taaffe, et al., Determinants of lower-body muscle power in early postmenopausal women, J. Am. Geriatr. 52 (6) (2004) 939–944.
18. A. Cuoco, D.M. Callahan, S. Sayers, W.R. Frontera, J. Bean, R.A. Fielding, Impact of muscle power and force on gait speed in disabled older men and women, J. Gerontol. A. Biol. Sci. Med. Sci. 59 (11) (2004) 1200–1206. 19. T.A. Mitzko, M.E. Cress, J.M. Slade, C.J. Covey, S.K. Agrawal, C.E. Doerr, Effect of strength and power training on physical function in community-dwelling older adults, J. Gerontol. A. Biol. Sci. Med. Sci. 58 (2) (2003) 171–175. 20. F. Lauretani, C.R. Russo, S. Bandinelli, et al., Age-associated changes in skeletal muscles and their effect in mobility: an operational diagnosis of sarcopenia, J. Appl. Physiol. 95 (5) (2003) 1851–1860. 21. T. Kostka, Quadriceps maximal power and optimal shortening velocity in 335 men aged 23-88 years, Eur J. Appl. Physiol. 95 (2-3) (2005) 140–145. 22. I. Michaelis, A. Kwiet, U. Gast, et al., Decline of specific peak jumping power with age in master runners, J. Musculoskelet. Neuronal. Interact. 8 (1) (2008) 64–70. 23. G.A. Cavagna, P. Franzetti, N.C. Heglund, P. Willems, The determinats of the step frequency in running, trotting and hopping in man and other vertebrates, J. Physiol. 399 (1988) 81–92. 24. G.A. Cavagna, Storage and utilization of elastic energy in skeletal muscle, Exerc. Sport Sci. Rev. 5 (1977) 29–89. 25. F. Saibene, A.E. Minetti, Biomechanical and physiological aspects of legged locomotion in humans, Eur. J. Appl. Physiol. 88 (4-5) (2003) 297–316. 26. C. Sherrington, J.C. Whitney, S.R. Lord, R.D. Herbert, R.G. Cumming, J.C. Close, Effective exercise for the prevention of falls: a systematic review and meta-analysis, J. Am. Geriatr. Soc. 56 (12) (2008) 2234–2243. 27. W.C. Hayes, E.R. Myers, J.N. Morris, T.N. Gerhart, H.S. Yett, L.A. Lipsitz, Impact near the hip dominates fracture risk in elderly nursing home residents who fall, Calcif. Tissue Int. 52 (3) (1993) 192–198. 28. S.N. Robinovitch, T.A. McMahon, W.C. Hayes, Force attenuation in trochanteric soft tissues during impact from a fall, J. Orthop. Res. 13 (6) (1995) 956–962. 29. S. Stenholm, P. Sainio, T. Rantanen, et al., High body mass index and physical impairments as predictors of walking limitation 22 years later in adult Finns, J. Gerontol. A. Biol. Sci. Med. Sci. 62 (8) (2007) 859–865. 30. W.J. Evans, Effects of exercise on body composition and functional capacity of the elderly, J. Gerontl. A. Biol. Sci. Med. Sci. 50 (1995) 147–150. 31. H.H. Bolotin, H. Sievanen, Inaccuracies inherent in dual-energy x-ray absorptiometry in vivo bone mineral density can seriously mislead diagnostic/prognostic interpretations of patient-specific bone fragility, J. Bone Miner. Res. 16 (5) (2001) 799–805. 32. S.P. Nielsen, The fallacy of BMD: a critical review of the diagnostic use of dual x-ray absorptiometry, Clin. Rheumatol. 19 (3) (2000) 174–184. 33. H.H. Bolotin, DXA in vivo BMD methodology: an erroneous and misleading research and clinical gauge of bone mineral status, bone fragility, and bone remodelling, Bone 41 (1) (2007) 138–154. 34. T. Järvinen, H. Sievänen, K.M. Khan, A. Heinonen, P. Kannus, Shifting the focus in fracture prevention from osteoporosis to falls, Br. Med. J. 336 (7636) (2008) 124–126. 35. H.M. Frost, Defining osteopenias and osteoporoses. Another view (with insights from a new paradigm), Bone 20 (5) (1997) 385–391.
C h a p t e r 5 2 Exercise Programs for Patients with Osteoporosis l
36. J. Wolff, Über die innere Architectur und ihre Bedeutung für die Frage vom nochenwachstum, Arch. Pathol. Anat. Physiol. 50 (1870) 389–450. 37. H.M. Frost, Changing concepts in skeletal physiology: Wolff’s law, the mechanostat and the ‘Utah paradigm’, J. Hum. Biol. 10 (1998) 599–605. 38. E. Schoenau, From mechanostat theory to development of the ‘functional muscle-bone-unit’, J. Musculoskelet. Neuronal. Interact. 5 (3) (2005) 232–238. 39. L. Giangregorio, N. McCartney, Bone loss and muscle atrophy in spinal cord injury: epidemiology, fracture prediction, and rehabilitation strategies, J. Spinal Cord Med. 29 (5) (2006) 489–500. 40. P. Eser, A. Frotzler, Y. Zehnder, L. Wick, H. Knecht, J. Denoth, H. Schiessl, Relationship between the duration of paralysis and bone structure: a pQCT study of spinal cord injured individuals, Bone 34 (5) (2004) 869–880. 41. J.D. Currey, Bones: Structure and Mechanics, Princeton University Press, Princeton, 2002. 42. Y. Umemura, T. Ishiko, T. Yamauchi, M. Kurono, S. Mashiko, Five jumps per day increase bone mass and breaking force in rats, J. Bone Miner. Res. 12 (9) (1997) 1480–1485. 43. J.W. Bellew, L. Gehrig, A comparison of bone mineral density in adolescent female swimmers, soccer players, and weight lifters, Pediatr. Phys. Ther. 18 (1) (2006) 19–22. 44. A. Wittich, C.A. Mautalen, M.B. Oliveri, A. Bagur, F. Somoza, E. Rotemberg, Professional football (soccer) players have a markedly greater skeletal mineral content, density and size than age- and BMI-matched controls, Calcif. Tissue Int. 63 (2) (1998) 112–117. 45. S. Kontulainen, H. Sievanen, P. Kannus, M. Pasanen, I. Vuori, Effect of long-term impact-loading on mass, size, and estimated strength of humerus and radius of female racquet-sports players: a peripheral quantitative computed tomography study between young and old starters and controls, J. Bone Miner. Res. 18 (2) (2002) 352–359. 46. S. Adami, D. Gatti, V. Braga, D. Bianchini, M. Rossini, Sitespecific effects of strength training on bone structure and geometry of ultradistal radius in postmenopausal women, J. Bone Miner. Res. 14 (1) (1999) 120–124. 47. D. Sabo, A. Reiter, J. Pfeil, A. Gussbacher, F.U. Niethard, Modification of bone quality by extreme physical stress. Bone density measurements in high-performance athletes using dualenergy x-ray absorptiometry, Z. Orthop. 134 (1) (1996) 1–6. 48. J. Morel, B. Combe, J. Francisco, J. Bernard, Bone mineral density of 704 amateur sportsmen involved in different physical activities, Osteoporos. Int. 12 (2) (2001) 152–157. 49. M.L. Hetland, J. Haarbo, C. Christiansen, Low bone mass and high bone turnover in male long distance runners, J. Clin. Endocrinol. Metab. 77 (3) (1993) 770–775. 50. M. Burrows, A.M. Nevill, S. Bird, D. Simpson, Physiological factors associated with low bone mineral density in female endurance runners, Br. J. Sports Med. 37 (1) (2003) 67–71. 51. M.K. Karlsson, A. Nordqvist, C. Karlsson, Sustainability of exercise-induced increases in bone density and skeletal structure, Food Nutr. Res. 52 (2008) Epub 2008 Oct 1. 52. A. Moayyeri, The association between physical activity and osteoporotic fractures: a review of the evidence and implications for future research, Ann. Epidemiol. 18 (11) (2008) 827–835. 53. K. Michaelsson, H. Olofsson, K. Jensevik, et al., Leisure physical activity and the risk of fracture in men, PLoS Med. 4 (6) (2007) 199.
649
54. M. Visser, B.H. Goodpaster, S.B. Kritchevsky, et al., Muscle mass, muscle strength, and muscle fat infiltration as predictors of incident mobility limitations in well-functioning older persons, J. Gerontol. A. Biol. Sci. Med. Sci. 60 (3) (2005) 324–333. 55. A.V. Schwartz, J.L. Kelsey, S. Sidney, J.A. Grisso, Characteristics of falls and risk of hip fracture in elderly men, Osteoporos. Int. 8 (3) (1998) 240–246. 56. E.W. Gregg, J.A. Cauley, D.G. Seeley, K.E. Ensrud, D.C. Bauer, Physical activity and osteoporotic fracture risk in older women. Study of Osteoporotic Fractures Research Group, Ann. Intern. Med. 129 (2) (1998) 81–88. 57. U.M. Kujala, J. Kaprio, P. Pekka Kannus, S. Sarna, M. Koskenvuo, Physical activity and osteoporotic hip fracture risk in men, Arch. Intern. Med. 160 (2000) 705–708. 58. M.M. Pinheiro, R.M. Ciconelli, L.A. Martini, M.B. Ferraz, Clinical risk factors for osteoporotic fractures in Brazilian women and men: the Brazilian Osteoporosis Study (BRAZOS), Osteoporos. Int. (2008) Epub ahead of print. 59. I.H. Rosenberg, Let’s Get Physical, Ann. Intern. Med. 129 (2) (1998) 133–134. 60. J.M. Guralnik, L. Ferrucci, C.F. Pieper, et al., Lower extremity function and subsequent disability: consistency across studies, predictive models, and value of gait speed alone compared with the short physical performance battery, J. Gerontol. A. Biol. Sci. Med. Sci. 55 (4) (2000) 221–231. 61. A.B. Newman, E.M. Simonsick, B.L. Naydeck, et al., Association of long-distance corridor walk performance with mortality, cardiovascular disease, mobility limitation, and disability, J. Am. Med. Assoc. 295 (17) (2006) 2018–2026. 62. J. Verghese, A. LeValley, C.B. Hall, M.J. Katz, A.F. Ambrose, R.B. Lipton, Epidemiology of gait disorders in communityresiding older adults, J. Am. Geriatr. Soc. 54 (2) (2006) 255–261. 63. T. Rantanen, J.M. Guralnik, D. Foley, et al., Midlife hand grip strength as a predictor of old age disability, J. Am. Med. Assoc. 281 (6) (1999) 558–560. 64. T. Rantanen, T. Harris, S.G. Leveille, et al., Muscle strength and body mass index as long-term predictors of mortality in initially healthy men, J. Gerontol. A. Biol. Sci. Med. Sci. 55 (3) (2000) 168–173. 65. M.E. Tinetti, T.F. Williams, R. Mayewski, Fall risk index for elderly patients based on number of chronic disabilities, Am. J. Med. 80 (3) (1986) 429–434. 66. M.E. Tinetti, M. Speechley, S.F. Ginter, Risk factors for falls among elderly persons living in the community, N. Engl. J. Med. 319 (26) (1988) 1701–1707. 67. A.J. Campbell, M.J. Borrie, G.F. Spears, Risk factors for falls in a community-based prospective study of people 70 years and older, J Gerontol 44 (4) (1989) 112–117. 68. M.C. Nevitt, S.R. Cummings, S. Kidd, D. Black, Risk factors for recurrent nonsyncopal falls: a prospective study, J. Am. Med. Assoc. 261 (18) (1989) 2663–2668. 69. M.C. Nevitt, S.R. Cummings, E.S. Hudes, Risk factors for injurious falls: a prospective study, J. Gerontol. 46 (5) (1991) 164–170. 70. A.S. Robbins, L.Z. Rubenstein, K.R. Josephson, B.L. Schulman, D. Osterweil, G. Fine, Predictors of falls among elderly people. Results of two population-based studies, Arch. Intern. Med. 149 (7) (1989) 1628–1633. 71. V.S. Stel, J.H. Smit, S.M. Pluijm, P. Lips, Balance and mobility performance as treatable risk factors for recurrent falling in older persons, J. Clin. Epidemiol. 56 (7) (2003) 659–668.
650
Osteoporosis in Men
72. M. Pijnappels, P.J. van der Burg, N.D. Reeves, J.H. van Dieën, Identification of elderly fallers by muscle strength measures, Eur. J. Appl. Physiol. 102 (5) (2008) 585–592. 73. K.E. Ensrud, S.K. Ewing, Taylor BC0, et al., Comparison of 2 frailty indexes for prediction of falls, disability, fractures, and death in older women, Arch. Intern. Med. 168 (4) (2008) 382–389. 74. I. Janssen, R.N. Baumgartner, R. Ross, I.H. Rosenberg, R. Roubenoff, Skeletal muscle cutpoints associated with elevated physical disability risk in older men and women, Am. J. Epidemiol. 159 (4) (2004) 413–421. 75. L. Ferrucci, W.J.H. Brenda, S. Volpato, et al., Change in muscle strength explains accelerated decline of physical function in older women with high interleukin-6 serum levels, J. Am. Geriatr. Soc. 50 (12) (2002) 1947–1954. 76. R.H. Whipple, L.I. Wolfson, P.M. Amerman, The relationship of knee and ankle weakness to falls in nursing home residents: an isokinetic study, J. Am. Geriatr. Soc. 35 (1) (1987) 13–20. 77. I. Janssen, S.B. Heymsfield, R. Ross, Low relative skeletal muscle mass (sarcopenia) in older persons is associated with functional impairment and physical disability, J. Am. Geriatr. Soc. 50 (5) (2002) 889–896. 78. M. Sinaki, E. Itoi, H.W. Wahner, et al., Stronger back muscles reduce the incidence of vertebral fractures: a prospective 10 year follow-up of postmenopausal women, Bone 30 (6) (2002) 836–841. 79. R.N. Baumgartner, K.M. Koehler, D. Gallagher, et al., Epidemiology of sarcopenia among the elderly in New Mexico, Am. J. Epidemiol. 147 (8) (1998) 755–763. 80. F. Lauretani, CR. Russo, S. Bandinelli, et al., Age-associated changes in skeletal muscles and their effect on mobility: an operational diagnosis of sarcopenia, J. Appl. Physiol. 95 (5) (2003) 1851–1860. 81. K.F. Reid, D.M. Callahan, R.J. Carabello, E.M. Phillips, W.R. Frontera, R.A. Fielding, Lower extremity power training in elderly subjects with mobility limitations: a randomized controlled trial, Aging Clin. Exp. Res. 20 (4) (2008) 337–343. 82. J. Ochala, W.R. Frontera, D.J. Dorer, J. Van Hoecke, L.S. Krivickas, Single skeletal muscle fiber elastic and contractile characteristics in young and older men, J. Gerontol. A. Biol. Sci. Med. Sci. 62 (4) (2007) 375–381. 83. Y. Rolland, G. Abellan van Kan, A. Benetos, et al., Frailty, osteoporosis and hip fracture: causes, consequences and therapeutic perspectives, J. Nutr. Health Aging 12 (5) (2008) 335–346. 84. P. Szulc, T.J. Beck, F. Marchand, P.D. Delmas, Low skeletal muscle mass is associated with poor structural parameters of bone and impaired balance in elderly men – the MINOS study, J. Bone Miner. Res. 20 (5) (2005) 721–729. 85. M. Visser, S.B. Kritchevsky, B.H. Goodpaster, et al., Leg muscle mass and composition in relation to lower extremity performance in men and women aged 70 to 79: the health, aging and body composition study, J. Am. Geriatr. Soc. 50 (5) (2002) 897–904. 86. M.V. Narici, N. Maffulli, C.N. Maganaris, Ageing of human muscles and tendons, Disabil. Rehabil. 30 (20-22) (2008) 1548–1554. 87. M.V. Narici, C.N. Maganaris, Adaptability of elderly human muscles and tendons to increased loading, J. Anat. 208 (4) (2006) 433–443.
88. M. Karkkainen, T. Rikkonen, H. Kroger, et al., Association between functional capacity tests and fractures: an eightyear prospective population-based cohort study, Osteoporos. Int. 19 (8) (2008) 1203–1210. 89. T.M. Gill, C.S. Williams, M.E. Tinetti, Assessing risk for the onset of functional dependence among older adults: the role of physical performance, J. Am. Geriatr. Soc. 43 (6) (1995) 603–609. 90. P.M. Cawthon, R.L. Fullman, L. Marshall, et al., Osteo poroctic Fractures in Men (MrOS) Research Group. Physical performance and risk of hip fractures in older men, J. Bone Miner. Res. 23 (7) (2008) 1037–1044. 91. N.D. Nguyen, H.G. Ahlborg, J.R. Center, J.A. Eisman, T.V. Nguyen, Residual lifetime risk of fractures in women and men, J. Bone Miner. Res. 22 (6) (2007) 781–788. 92. J.A. Kanis, Diagnosis of osteoporosis and assessment of fracture risk, Lancet 359 (2002) 1929–1936. 93. G. Poor, E.J. Atkinson, W.M. O’Fallon, L.J. Melton 3rd, Predictors of hip fractures in elderly men, J. Bone Miner. Res. 10 (12) (1995) 1900–1907. 94. S.C.E. Schuit, M. van der Klift, A.E. Weel, et al., Fracture incidence and association with bone mineral density in elderly men and women: the Rotterdam Study, Bone 34 (1) (2004) 195–202. 95. P. Kannus, S. Niemi, J. Parkkari, et al., Why is the agestandardized incidence of low-trauma fractures rising in many elderly populations?, J. Bone Miner. 17 (8) (2002) 1363–1367. 96. P. Kannus, H. Sievanen, M. Palvanen, T. Jarvinen, J. Parkkari, Prevention of falls and consequent injuries in elderly people, Lancet 366 (2005) 1885–1893. 97. S. Kaptoge, L.I. Benevolenskaya, A.K. Bhalla, et al., Low BMD is less predictive than reported falls for future limb fractures in women across Europe: results from the European Prospective Osteoporosis Study, Bone 36 (3) (2005) 387–398. 98. K.L. Stone, D.G. Seeley, L.Y. Lui, et al., Osteoporotic Fractures Research Group. BMD at multiple sites and risk of fracture of multiple types: long-term results from the study of osteoporotic fractures, J. Bone Miner. Res. 18 (11) (2003) 1947–1954. 99. S.A. Wainwright, L.M. Marshall, K.E. Ensrud, et al., Hip fracture in women without osteoporosis, J. Clin. Endocrinol. Metab. 90 (2005) 2787–2793. 100. R. Norton, A.J. Campbell, T. Lee-Joe, E. Robinson, M. Butler, Circumstances of falls resulting in hip fractures among older people, J. Am. Geriatr. Soc. 45 (9) (1997) 1108–1112. 101. C.E. Lewis, S.K. Ewing, B.C. Taylor, et al., Osteoporotic Fractures in Men (MrOS) Study Research Group. Predictors of non-spine fracture in elderly men: the MrOS study, J. Bone Miner. Res. 22 (2) (2007) 211–219. 102. S.S. Freitas, E. Barnett-Connor, K.E. Ensrud, et al., Osteoporotic Fractures in Men (MrOS) Research Group. Rate and circumstances of clinical vertebral fractures in older men, Osteoporos. Int. 19 (5) (2008) 615–623. 103. M.C. Nevitt, S.R. Cummings, Type of fall and risk of hip and wrist fractures: the study of osteoporotic fractures, J. Am. Geriatr. Soc. 42 (8) (1994) 909. 104. S.N. Robinovitch, L. Inkster, J. Maurer, B. Warnick, Strategies for avoiding hip impact during sideways falls, J. Bone Miner. Res. 18 (7) (2003) 1267–1273.
C h a p t e r 5 2 Exercise Programs for Patients with Osteoporosis l
105. T.M. Gill, C.S. Williams, M.E. Tinetti, Assessing risk for the onset of functional dependence among older adults: the role of physical performance, J. Am. Geriatr. Soc. 43 (6) (1995) 603–609. 106. K.M. Palombaro, Effects of walking-only interventions on bone mineral density at various skeletal sites: a meta-analysis, J. Geriatr. Phys. Ther. 28 (3) (2005) 102–107. 107. J.M. Martyn-St, S. Carroll, Meta-analysis of walking for preservation of bone mineral density in postmenopausal women, Bone 43 (3) (2008) 521–531. 108. D. Bonaiuti, B. Shea, R. Iovine, et al., Exercise for preventing and treating osteoporosis in postmenopausal women, Cochrane Database Syst Rev. (3) (2002) CD000333. 109. R.K. Fuchs, J.J. Bauer, C.M. Snow, Jumping improves hip and lumbar spine bone mass in prepubescent children: a randomized controlled trial, J. Bone Miner. Res. 16 (1) (2001) 148–156. 110. G.A. Kelley, K.S. Kelley, Efficacy of resistance exercise on lumbar spine and femoral neck bone mineral density in premenopausal women: a meta-analysis of individual patient data, J. Womens Health (Larchmt) 13 (3) (2004) 293–300. 111. M. Sinaki, H.W. Wahner, E.J. Bergstralh, et al., Three-year controlled, randomized trial of the effect of dose-specified loading and strengthening exercises on bone mineral density of spine and femur in nonathletic, physically active women, Bone 19 (3) (1996) 233–244. 112. J.C. Rockwell, A.M. Sorensen, S. Baker, et al., Weight training decreases vertebral bone density in premenopausal women: a prospective study, J. Clin. Endocrinol. Metab. 71 (4) (1990) 988–993. 113. M.E. Nelson, E.C. Fisher, F.A. Dilmanian, G.E. Dallal, W.J. Evans, A 1-y walking program and increased dietary calcium in postmenopausal women: effects on bone, Am. J. Clin. Nutr. 53 (5) (1991) 1304–1311. 114. R.K. Fuchs, C.M. Snow, Gains in hip bone mass from highimpact training are maintained: a randomized controlled trial in children, J. Pediatr. 141 (3) (2002) 357–362. 115. E.J. Bassey, M.C. Rothwell, J.J. Littlewood, D.W. Pye, Preand postmenopausal women have different bone mineral density responses to the same high-impact exercise, J. Bone Miner. Res. 13 (12) (1998) 1793–1796. 116. D. Kerr, A. Morton, I. Dick, R. Prince, Exercise effects on bone mass in postmenopausal women are site-specific and load-dependent, J. Bone Miner. Res. 11 (2) (1996) 218–225. 117. E.J. Bassey, S.J. Ramsdale, Increase in femoral bone density in young women following high-impact exercise, Osteoporos. Int. 4 (2) (1994) 72–75. 118. L. Welsh, O.M. Rutherford, Hip bone mineral density is improved by high-impact aerobic exercise in postmenopausal women and men over 50 years, Eur. J. Appl. Physiol. Occup. Physiol. 74 (6) (1996) 511–517. 119. G.F. Maddalozzo, C.M. Snow, High intensity resistance training: effects on bone in older men and women, Calcif. Tissue Int. 66 (6) (2000) 399–404. 120. K. Hind, M. Burrows, Weight-bearing exercise and bone mineral accrual in children and adolescents: a review of controles trials, Bone 40 (1) (2007) 14–27. 121. K.M. Winters-Stone, C.M. Snow, Site-specific response of bone to exercise in premenopausal women, Bone 39 (6) (2006) 1203–1209. 122. U. Englund, H. Littbrand, A. Sondell, G. Bucht, U. Pettersson, The beneficial effects of exercise on BMD are lost after
123.
124.
125.
126.
127.
128.
129.
130.
131.
132.
133.
134.
135.
136.
137.
138.
651
cessation: a 5-year follow-up in older post-menopausal women, Scand. J. Med. Sci. Sports (May 22, 2008) Epub ahead of print. M.A. Fiatarone, E.C. Marks, N.D. Ryan, C.N. Meredith, L.A. Lipsitz, W.J. Evans, High-intensity strength training in nonagenarians. Effects on skeletal muscle, J. Am. Med. Assoc. 263 (22) (1990) 3029–3234. M.A. Fiatarone, E.F. O’Neill, N.D. Ryan, Exercise training and nutritional supplementation for physical frailty in very elderly people, N. Engl. J. Med. 330 (25) (1994) 1769–1775. R.A. Fielding, The role of progressive resistance training and nutrition in the preservation of lean body mass in the elderly, J. Am. Coll. Nutr. 14 (6) (1995) 587–594. M.M. Bamman, V.J. Hill, G.R. Adams, et al., Gender differences in resistance-training-induced myofiber hypertrophy among older adults, J. Gerontol. A. Biol. Sci. Med. Sci. 58 (2) (2003) 108–116. E.F. Binder, K.E. Yarasheski, K. Steger-May, et al., Effects of progressive resistance training on body composition on frail older adults: results of a randomized, controlled trial, J. Gerontol. A. Biol. Sci. Med. Sci. 60 (11) (2005) 1425–1431. N. Latham, C. Anderson, D. Bennett, C. Stretton, Progressive resistance strength training for physical disability in older people, Cochrane Database Syst. Rev. (2003) CD002759. N.K. Latham, D.A. Bennett, C.M. Stretton, C.S. Anderson, Systematic review of progressive resistance strength training in older adults, J. Gerontol. A. Biol. Sci. Med. Sci. 59 (1) (2004) 48–61. N.D. Reeves, M.V. Narici, C.N. Maganaris, Effect of resistance training on skeletal muscle-specific force in elderly humans, Appl. Physiol. 96 (3) (2004) 885–892. J. Ochala, D. Lambertz, J. Van Hoecke, M. Pousson, Changes in muscle and joint elasticity following long-term strength training in old age, Eur. J. Appl. Physiol. 100 (5) (2007) 491–498. D.R. Taaffe, T.R. Henwood, M.A. Nalls, D.G. Walker, T.F. Lang, T.B. Harris, Alterations in muscle attenuation following detraining and retraining in resistance-trained older adults, Gerontology (December 5, 2008) Epub ahead of print. T.E. Howe, L. Rochester, A. Jackson, P.M. Banks, V.A. Blair, Exercise for improving balance in older people, Cochrane Database Syst. Rev. 17 (4) (2007) CD004963. R. Orr, J. Raymond, M. Fiatarone Singh, Efficacy of progressive resistance training on balance performance in older adults : a systematic review of randomized controlled trials, Sports Med. 38 (4) (2008) 317–343. R. Daniels, E. van Rossum, L. de Witte, G.I. Kempen, W. van den Heuvel, Interventions to prevent disability in frail community-dwelling elderly: a systematic review, BMC Health Serv. Res. 8 (2009) 278. J. Jensen, L. Nyberg, E. Rosendahl, Y. Gustafson, L. LundinOlsson, Effects of a fall prevention program including exercise on mobility and falls in frail older people living in residential care facilities, Aging Clin. Exp. Res. 16 (4) (2004) 83–92. T.M. Gill, D.I. Baker, M. Gottschalk, P.N. Peduzzi, H. Allore, A. Byers, A program to prevent functional decline in physically frail, elderly persons who live at home, N. Engl. J. Med. 347 (14) (2002) 1068–1074. T.M. Gill, H. Allore, T.R. Holford, Z. Guo, Hospitalization, restricted activity and the development of disability among older persons, J. Am. Med. Assoc. 292 (17) (2004) 2115–2124.
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Osteoporosis in Men
139. A.D. Beswick, K. Rees, P. Dieppe, S. Ayis, R. Goberman-Hill, J. Horwood, S. Ebrahim, Complex interventions to improve physical function and maintain independent living in elderly people: a systematic review and meta-analysis, Lancet 371 (9614) (2008) 725–735. 140. T.M. Gill, H. Allore, T.R. Holford, Z. Guo, The development of insidious disability in activities of daily living among community-living older persons, Am. J. Med. 117 (7) (2004) 484–491. 141. American Geriatrics Society, British Geriatrics Society, and American Academy of Orthopaedic Surgeons Panel on Falls Prevention: Guideline for the Prevention of Falls in Older Persons, J Am Geriatr Soc, 49(2001), 664–72. 142. M.E. Tinetti, D.I. Baker, G. McAvay, et al., A multifactorial intervention to reduce the risk of falling among elderly people living in the community, N. Engl. J. Med. 331 (13) (1994) 821–827. 143. J. Close, M. Ellis, R. Hooper, E. Glucksman, S. Jackson, C. Swift, Prevention of falls in the elderly trial (PROFET): a randomised controlled trial, Lancet 353 (9147) (1999) 93–97. 144. S.L. Wolf, H.X. Barnhart, N.G. Kutner, E. McNeely, C. Coogler, T. Xu, Reducing frailty and falls in older persons: an investigation of Tai Chi and computerized balance training. Atlanta FICSIT Group. Frailty and Injuries: Cooperative Studies of Intervention Techniques, J. Am. Geriatr. Soc. 44 (1996) 489–497. 145. A.J. Campbell, M.C. Robertson, M.M. Gardner, R.N. Norton, M.W. Tilyard, D.M. Buchner, Randomised controlled trial of a general practice programme of home based exercise to prevent falls in elderly women, Br. Med. J. 315 (7115) (1997) 1065–1069. 146. A.J. Campbell, M.C. Robertson, M.M. Gardner, R.N. Norton, D.M. Buchner, Falls prevention over 2 years: a randomized controlled trial in women 80 years and older, Age Ageing 28 (6) (1999) 513–518. 147. M.C. Robertson, N. Devlin, M.M. Gardner, A.J. Campbell, Effectiveness and economic evaluation of a nurse delivered home exercise programme to prevent falls. 1: Randomised controlled trial, Br. Med. J. 322 (7288) (2001) 697–701. 148. M.C. Robertson, M.M. Gardner, N. Devlin, R. McGee, A.J. Campbell, Effectiveness and economic evaluation of a nurse delivered home exercise programme to prevent falls. 2: Controlled trial in multiple centres, Br. Med. J. 322 (7288) (2001) 701–704. 149. D. Skelton, S. Dinan, M. Campbell, O. Rutherford, Tailored group exercise (Falls Management Exercise – FaME) reduces falls in community-dwelling older frequent fallers (an RCT), Age Ageing 34 (6) (2005) 6363–6369. 150. A. Barnett, B. Smith, S.R. Lord, M. Williams, A. Baumand, Community-based group exercise improves balance and reduces falls in at-risk older people: a randomised controlled trial, Age Ageing 32 (2003) 407–414. 151. S.R. Lord, J.A. Ward, P. Williams, M. Strudwick, The effect of a 12-month exercise trial on balance, strength, and falls in older women: a randomized controlled trial, J. Am. Geriatr. Soc. 43 (11) (1995) 1198–1206. 152. R.O. Morgan, B.A. Virnig, M. Duque, E. Abdel-Moty, C.A. Devito, Low-intensity exercise and reduction of the
153.
154.
155.
156.
157.
158.
159.
160.
161.
162.
163.
164.
165.
166.
167.
risk for falls among at-risk elders, J. Gerontol. A. Biol. Sci. Med. Sci. 59 (10) (2004) 1062–1067. M. Steinberg, C. Cartwright, N. Peel, G. Williams, A sustainable programme to prevent falls and near falls in community dwelling older people: results of a randomised trial, J. Epidemiol. Community Hlth. 54 (3) (2000) 227–232. G. Feder, C. Cryer, S. Donovan, Y. Carter, Guidelines for the prevention of falls in people over 65. The Guidelines’ Develop ment Group, Br. Med. J. 321 (7267) (2000) 1007–1011. L.D. Gillespie, W.J. Gillespie, M.C. Robertson, S.E. Lamb, R.G. Cumming, B.H. Rowe, Interventions for preventing falls in elderly people, Cochrane Database Syst. Rev. (4) (2003) CD000340. J.T. Chang, S.C. Morton, L.Z. Rubenstein, et al., Interven tions for the prevention of falls in older adults: systematic review and meta-analysis of randomised clinical trials, Br. Med. J. 328 (2004) 1–7. C. Delecluse, M. Roelants, S. Verschueren, Strength increase after whole-body vibration compared with resistance training, Med. Sci. Sports Exerc. 35 (6) (2003) 1033–1041. M. Roelants, C. Delecluse, S.M. Verschueren, Wholebody-vibration training increases knee-extension strength and speed of movement in older women, J. Am. Geriatr. Soc. 52 (6) (2004) 901–908. M. Runge, G. Rehfeld, E. Resnicek, Balance training and exercise in geriatric patients, J. Musculoskel. Interact. 1 (1) (2000) 54–58. K. Kawanabe, A. Kawashima, I. Sashimoto, T. Takeda, Y. Sato, J. Iwamoto, Effect of whole-body vibration exercise and muscle strengthening, balance, and walking exercises on walking ability in the elderly, Keio. J. Med. 56 (1) (2007) 28–33. O. Bruyere, M.A. Wuidart, E. Di Palma, et al., Controlled whole body vibration to decrease fall risk and improve health-related quality of life of nursing home residents, Arch. Phys. Med. Rehabil. 86 (2) (2005) 303–307. N. Gusi, A. Raimundo, A. Leal, Low-frequency vibratory exercise reduces the risk of bone fracture more than walking: a randomized controlled trial, BMC Musculoskelet. Disord. 7 (2006) 92. W.H. Cheung, H.W. Mok, L. Qin, P.C. Sze, K.M. Lee, K.S. Leung, High-frequency whole-body vibration improves balancing ability in elderly women, Arch. Phys. Med. Rehabil. 88 (7) (2007) 852–857. J. Rittweger, K. Just, K. Kautzsch, P. Reeg, D. Felsenberg, Treatment of chronic lower back pain with lumbar extension and whole-body vibration exercise: a randomized controlled trial, Spine 27 (17) (2002) 1829–1834. D. Blottner, M. Salanova, B. Püttmann, et al., Human skeletal muscle structure and function preserved by vibration muscle exercise following 55 days of bed rest, Eur. J. Appl. Physiol. 97 (3) (2006) 261–271. L.A. Kaminsky (Ed.), ACSM’s resource manual for guidelines for exercise testing and prescription, fifth ed., ACSM, Philadelphia, 2006. J. Rittweger, H. Schiessl, D. Felsenberg, M. Runge, Reproducibility of the Jumping Mechanography As a Test of Mechanical Power Output in Physically Competent Adult and Elderly Subjects. J Am Geriatr Soc 52 (2004) 128–131.
Chapter
53
Calcitonin: History, Physiology, Pathophysiology and Therapeutic Applications Sunil J. Wimalawansa Professor of Medicine, Endocrinology & Metabolism; Director, Regional Osteoporosis Center, Department of Medicine, Robert Wood Johnson Medical School, New Brunswick, New Jersey, USA
Introduction
lung [12] and alimentary tract in Ciona intestinalis [13]. Amino acid comparisons of human calcitonin (h-CT) with fish calcitonins (eel (e-CT) and salmon (S-CT)) are illustrated in Figure 53.1. Ultimobranchial glands have been shown as the source of calcitonin in dogfish, chicken [7] and in other avian species [15], whereas the lung is the major source of calcitonin in the lizard [16]. Two different calcitonins have been identified in birds [17], reptiles and in mammals [18]. An immunoreactive-human calcitonin (i-CT)-like molecule has been demonstrated in the nervous system of protochordates and cyclostome myxine [19], in neural ganglia of Ciona intestinalis, an immediate ancestor of the vertebrate, but lacking a skeleton [19–21] and in the ultimobranchial body of the amphibian, Rana pipiens [22]. i-CT has also been shown in the central nervous system of the pigeon [23]. Although calcitonin has been shown in the pituitary gland by both immunofluorescent studies [24] and by radioimmunoassay (RIA) of pituitary extracts [25, 26], demonstration of calcitonin synthesis in the pituitary by cDNA probes has not been successful [27].
Calcitonin is a single chain polypeptide hormone with a 1–7 disulfide bridge at the amino terminus and a carboxyterminal proline amide. All calcitonins share this pattern. This hormone was first discovered in 1962 [1] and so named because of its ability to lower plasma calcium levels. Initial studies on sheep suggested the parathyroid gland as the source of calcitonin [1]. Later, the source of this calcium-lowering factor localized to the thyroid gland [2, 3]. During the past three decades, extensive investigations have enhanced our understanding of the structure, biosynthesis, physiology and pharmacology of calcitonin [4]. This chapter will not consider properties attributed to calcitonin actions beyond the skeleton, such as its use in migraine, arthritis, inflammatory disorders, cardiovascular effects or potential vasoactive properties.
Synthesis and localization Calcitonin is synthesized by the parafollicular cells (C-cells) of the thyroid gland in mammals [2, 3, 5, 6] and by the C-cells associated with the ultimobranchial gland in lower vertebrates [7, 8]. C-cells are derived from the neural crest [9] and migrate forward to localize in the ultimobranchial body in lower vertebrates and as parafollicular cells in man [5] and related species [10, 11]. However, during this migration, C-cells may concentrate in regions other than the thyroid and ultimobranchial body. The localization of C-cells also may vary in different species. For example, they are also localized with the Kulchitsky cells of human Osteoporosis in Men
Structure of calcitonin and its measurements Calcitonin has been well conserved during evolution. Calcitonin from nine different species has been identified and 12 sequences have been reported (Table 53.1). Six of the invariant amino acid residues are clustered at the amino terminal and two are at the carboxyterminal end of the peptide molecule. Furthermore, all calcitonins have a 1–7 disulfide bridge and proline-amide at the C-terminus. All 32 amino 653
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Ser Leu
Cys
Ser
Asn
Gly
Lys
Val
Thr
Met
Leu
Gly
Lys
Val
Cys
Thr
Leu
Leu
Thr
Ser
H
Ser
Ser
Tyr
Gln Asp
Glu
Phe
Leu His
NH2
Ala
Thr Ala
Gly Val Ser
Leu His
Lys
Pro Thr
Asn
Glu
Gly
Val
Asp
Ile
Ala
Thr
Asn
Arg Thr
Gln
Leu
Phe
Leu
Gln
His
Gln
Tyr Pro
Thr Phe
Tyr
Arg
Figure 53.1 Primary amino acid sequence of human calcitonin (in the center cascade), in comparison with the salmon (outer) and eel (inner) calcitonins. The variations of amino acid sequences from human calcitonin are indicated (From Wimalawansa, 1995, Reproduced with permission from RG Landes Co, Austin) [14].
acids are required for its hypocalcemic bioactivity and its osteoclast inhibitory actions. Substitution of some of these amino acids in some synthetic calcitonin preparations (e.g. synthetic eel-CT), enhances its half-life via resisting degradation, thereby increasing circulatory half-life, and its biological activity; but substitution of amino acids also enhances allergenicity. Calcitonin is produced as a precursor molecule. A number of post-translational modifications including cleavage and C-terminal amidation occurs prior to secretion of the mature form of biologically active calcitonin(132) [28]. The release of calcitonin from C-cells is stimulated by cations such as Ca2 and Mg2 and also by glucagons, dibutyryl cyclic AMP, theophylline [29], gastrin and cholecystakinin. Calcitonin causes a dose-dependent elevation of cyclic AMP levels [30, 31] and the effects of calcitonin on osteoclasts can be mimicked by dibutyryl cyclic AMP [32]. Measurement of plasma i-CT levels (i.e. for hypersecretion) has been used as a screening and diagnostic test for C-cell hyperplasia in pre-malignant and malignant C-cell disease (i.e. families of patients with medullary thyroid carcinoma (MTC)). There are a number of diagnostic-stimulation tests available for detecting MTC, including infusion of calcium or injection of pentagastrin.
Physiological role of calcitonin Physiological concentrations of calcitonin are thought to have a tonic effect to restrict osteoclastic bone resorption. The physiological role of calcitonin is to maintain skeletal mass during periods of calcium ‘stresses’ such as growth,
pregnancy and lactation (i.e. when the skeleton needs to be preserved, Figure 53.2). In pregnancy and lactation, retention of calcium by the fetus and secretion of calcium into milk may occur at the expense of the maternal skeleton (i.e. stimulation via parathyroid hormone-related protein (PTHrP)) and prolactin; in these situations, increased secretion of calcitonin is likely to exert a counter regulatory effect to preserve the maternal skeletal mineral content by controlling excessive bone resorption. Sex-steroid hormones, testosterone and estrogen, both stimulate the synthesis of calcitonin by C-cells. Although calcitonin is one of the endogenous regulators of calcium homoeostasis, acting principally on bone, it also has a direct action on the kidneys and on the gastrointestinal tract. Calcitonin receptors are present predominantly in osteoclasts, but they are also present in the kidney and in the brain, especially in the hypothalamus. It also has a direct as well as indirect effect on the central nervous system; modulation of pain and neuromodulatory activities [28]. The osteoclast, with over a million calcitonin receptors, is the main target cell for calcitonin [30, 33]. Within a few minutes of calcitonin administration, the osteoclast retracts its pseudopodia; as a consequence it reduces its motility, cell size and bone resorption activity (Figures 53.3A and B) [32, 34–37]. Cells become immobile for hours and cease to resorb bone. During excavation of bone, osteoclasts liberate enzymes (e.g. metaloprolinases and acid phosphatases) and acids (HCl), which subsequently hydrolyze the bone matrix leaving multiple pits (Figures 53.3C and D). It has been shown that physiological levels of plasma calcitonin are capable of controlling these osteoclast-associated activities.
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l
Table 53.1 Amino acid sequences of the nine fully characterized and two *predicted calcitonins Man
Rat
S-1
S-2
S-3
Eel
*Chick
Bov
Porc
Ovi
*Man2
1 Cys 2 Gly 3 Asn 4 Leu 5 Ser 6 Thr 7 Cys 8 Met 9 Leu 10 Gly 11 Thr 12 Tyr 13 Thr 14 Gln 15 Asp 16 Phe 17 Asn 18 Lys 19 Phe 20 His 21 Thr 22 Phe 23 Pro 24 Gln 25 Thr 26 Ala 27 Ile 28 Gly 29 Val 30 Gly 31 Ala 32 Pro
– – – – – – – – – – – – – – – Leu – – – – – – – – – Ser – – – – – –
– Ser – – – – – Val – – Lys Leu Ser – Glu Leu His – Leu Gln – Tyr – Arg – Asn Thr – Ser – Thr –
– Ser – – – – – – – – Lys Leu Ser – – Leu His – Leu Gln – – – Arg – Asn Thr – Ala – Val –
– Ser – – – – – Val – – Lys Leu Ser – – Leu His – Leu Gln – – – Arg – Asn Thr – Ala – Val –
– Ser – – – – – Val – – Lys Leu Ser – Glu Leu His – Leu Gln – Tyr – Arg – Asp Val – Ala – Thr –
– Ala Ser – – – – Val – – Lys Leu Ser – Glu Leu His – Leu Gln – Tyr – Arg – Asp Val – Ala Glu Thr –
– Ser – – – – – Val – Ser Ala – Trp Lys – Leu – Asn Tyr – Arg – Ser Gly Met Gly Phe – Pro Glu Thr –
– Ser – – – – – Val – Ser Ala – Trp Arg Asn Leu – Asn – – Arg – Ser Gly Met Gly Phe – Pro Glu Thr –
– Ser – – – – – Val – Ser Ala – Trp Lys – Leu – Asn Tyr – Arg Tyr Ser Gly Met Gly Phe – Pro Glu Thr –
Tyr Ser – – – – – Leu Gln – – – Leu – Tyr Leu Lys Asn – – Met – – Gly Ile Asn Phe – Pro Gln Ile –
*The invariant residues are clustered at the two ends of the molecule. S: Salmon; Bov: bovine; Porc: porcine; Ovi: ovine; Man: predicted. From Wimalawansa, 1995, Reproduced with permission from RG Landes Co, Austin) [14].
Calcitonin deficiency has been postulated to be an etiological factor in the pathogenesis of pregnancy-associated, as well as postmenopausal osteoporosis [38]. This is an attractive hypothesis considering its anti-bone-resorbing action. However, this hypothesis has not been confirmed either with regard to circulating calcitonin or calcitonin secretory capacity in response to intravenous calcium infusion [39, 40]. A number of studies have shown that synthetic salmon calcitonin transiently increases or stabilizes bone mass [4, 41, 42]. A beneficial effect of synthetic salmon calcitonin has also been reported when used at a daily dosage of 100 MRC units (IU) administered intramuscularly or subcutaneously for 2 years, as determined by total body calcium measurements by quantitative computerized tomography and by neutron activation analysis [41, 43]. Over the past four decades, there has been interest in the relationship of calcitonin to osteoporosis, both as a
pathogenetic factor (i.e. suboptimal secretion of calcitonin) and as a potential therapeutic agent. Postmenopausal women tend to have lower plasma calcitonin levels and a reduced secretory response to stimulation by calcium (poor calcitonin reserves), than premenopausal women and age-matched men. Moreover following natural or surgical menopause, there is a fall in the circulating level of i-CT. Accelerated bone loss during menopause has been attributed to the sudden decrease in estrogen, but it is also possible that associated reductions in calcitonin levels may be contributory. Moreover, circulatory calcitonin levels and calcitonin reserves in the C-cells of the thyroid both increase following administration of estrogen. An increase in calcitonin secretion, in turn, decreases osteoclast activity as a physiological control to decrease bone resorption. Therefore, in deficiency states, it may appear attractive to restore levels (i.e. calcitonin replacement therapy). In the black population, the
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Uterus
DA Placenta
secretion
Prolactin +
ejection
+
Oxytocin +
PTH-rp
– Thyroid gland
Plasma calcium
PTH-rp
+ Gut
CT PTH Parathyroid gland
1, 25 (OH)2D3
– +
+ +
+
Kidney Bone
Figure 53.2 Postulated functions of calcitonin during ‘calcium stress’ periods. Calcitonin takes part together with other calcium regulating hormones and factors such as 1,25(OH)2D3, parathyroid hormone (PTH), PTH-related protein (PTHrP), in maintaining the calcium homeostasis.
presence of higher levels of serum calcitonin, growth hormone and 17-estradiol may be contributory to the higher bone mass observed in comparison to Caucasians.
Biological effects of calcitonin Calcitonin acts directly on osteoclasts to inhibit their bone resorption activity [34, 44]. Calcitonin is also capable of inhibiting the increased bone turnover induced by parathyroid hormone (PTH) and PTHrP. Therefore, calcitonin has been used as a therapy for bone diseases that are characterized by excessive resorption. The immediate hypocalcemic action of calcitonin (i.e. when bone turnover is high) is due to the direct inhibition of excessive osteoclastic bone resorption. Therefore, it is not surprising that calcitonin is an effective agent in diseases characterized by excessive bone resorption such as Paget’s disease and a number of other metabolic bone disorders (Table 53.2). However, in recent years, more potent drugs, such as bisphosphonates, have superseded the use of calcitonin as first line therapy for both Paget’s disease and osteoporosis. Both in vivo and in vitro bioassays, such as the inhibitory effect of calcitonin on osteoclast activity [45] are tedious and expensive [37]. Therefore, for clinical purposes, plasma i-CT levels are measured with either radioimmunoassay [46] or by enzyme-linked imuunosorbent (ELISA) assays [47].
Although calcitonin has been used successfully for treating Paget’s disease, globally, it has achieved wider use in the treatment of osteoporosis. In contrast to the treatment of patients with Paget’s disease or hypercalcemia of malignancy, where high doses of calcitonin are needed, much smaller doses of calcitonin (i.e. subcutaneous administration of 50 IU, two to three times/week, or 200 IU intranasally) are used for the treatment of osteoporosis. Calcitonin is also used by some as an adjunct therapy to relieve pain following osteoporosis fractures [48, 49].
Clinical pharmacology Inhibition of bone resorption due to calcitonin follows a direct inhibitory effect of it on the osteoclast (see Figure 53.3). Calcitonin also causes a reduction in osteoclast numbers when given over several months. It is not clear whether a decrease in number of osteoclasts is a consequence of its effects on osteoclasts themselves or an independent effect on its precursor cells [50]. This effect seems to be important in treatment of several metabolic bone diseases. A plasma calcium-lowering effect of calcitonin is not seen in normal adults because of the relatively slow overall rate of bone turnover. Therefore, the administration of calcitonin has little or no effect on plasma calcium in normal adults. However, when bone turnover is high, as for example in
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A
B
C
D
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Figure 53.3 (A) Phase-contrast microscopy appearance of a normal osteoclast after 2 hours of incubation in a culture medium; (B) appearance of the same cell, 90 minutes after addition of salmon calcitonin (50 pg/ml) into the medium (magnification 320); (C) scanning electron microscopic picture of an osteoclast on a bone slice (high power 10.6 K); (D) resorption pits created by osteoclast on a devitalized bone slices (low power 6.2 K) with permission from Tim Arnett, PhD, University of London). Arrows indicate osteoclast cells and resorption pits.
children, or in disease states such as Paget’s disease, or hypercalcemic statuses, administration of calcitonin can be followed by reductions in circulatory calcium levels. Several pharmacological actions of calcitonin in the gastrointestinal system have also been reported; it enhances the intestinal secretion of sodium, potassium, chloride and water and inhibits both gastric emptying and acid secretion. It also inhibits the secretion of several gastrointestinal regulatory peptides, including gastrin, insulin, pancreatic glucagons, motilin, pancreatic polypeptide and, perhaps, gastric inhibitory peptide. Calcitonin also inhibits (albeit weakly) the secretion of pituitary hormones, including growth hormone, thyroid-stimulating hormone and luteinizing hormone.
Commercially available calcitonin preparations Various calcitonin preparations available include natural porcine calcitonin, synthetic human calcitonin, synthetic salmon calcitonin (s-CT) (Salcatonin, Miacalcin) and a
synthetic eel calcitonin analog (Elcatonin). In some countries, the only available form of calcitonin still is the injectable preparation. Using injectable calcitonin formulations, a dose of 50 IU three to four times a week is currently recommended for treatment of osteoporosis. The main drawback with calcitonin is its high cost and potential decrease in efficacy with time, in cases using animal CTs, it could be due to the development of neutralizing antibodies. From a therapeutic point of view, calcitonin can be administered by intravenous, intramuscular, subcutaneous or by intranasal routes. All forms of calcitonin should be stored at 4°C and protected from light. Shelf life is approximately 2 years. Salmon calcitonin nasal spray (Miacalcin) is a synthetic molecule which is more potent than human calcitonin. Its major action is the inhibition of bone resorption by a direct action on osteoclast cells. Miacalcin nasal spray, 200 IU once daily is the Food and Drug Administration- (FDA-) approved dose for the treatment of postmenopausal osteoporosis. Because of its weaker efforts, this agent should be reserved for those patients who refuse or cannot tolerate other potent anti-osteoporosis agents or for short-term use
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Table 53.2 List of conditions that are associated with increase of decrease of circulating calcitonin levels Conditions associated with calcitonin underproduction
Conditions associated with calcitonin overproduction
Osteoporosis
Calcitonin-secreting tumor
Pregnancy-induced osteoporosis
Medullary carcinoma of the thyroid
Postmenopausal Senile
C-cell hyperplasia Other hormone secreting tumors (neuroendocrine tumors)
Secondary to other endocrine Other conditions disorders Thyroidectomy Acute gastritis Atrophic gastritis Gastrointestinal bleeding Graves disease Hepatic surgery Heroin addict Hypercalcemia Lithium intoxication Myocardial infarction Neonatal hypocalcemia Pancreatitis Pernicious anemia Peptic ulcer Pseudo-hypoparathyroidism Renal disorders Stress or trauma Thyroid surgery Toxic shock
in patients with acute bone pain (e.g. vertebral crush fracture syndrome) [51].
Loss of Efficacy of Calcitonin After prolonged administration, calcitonin may lose its beneficial effects on bone due to the downregulation of receptors, the development of neutralizing anti-calcitonin antibodies (following the use of non-human calcitonins) or increased enzyme-mediated catabolism of the peptide. The first can be avoided by administration of smaller doses of calcitonin less frequently, and the second by switching nonhuman calcitonin to synthetic or genetically engineered human calcitonin [51]. Non-human calcitonins can be allergenic, with about 50% of patients developing antibodies within 2–3 years of use. However, this leads to actual clinical resistance (e.g. neutralizing antibodies) only in less than one-third of patients. Resistance to calcitonin can develop with longterm treatments and prolonged in-vitro experiments with calcitonin. It can manifest as a primary resistance (or nonresponse), plateau phenomenon or secondary (or rebound)
resistance (also known as the ‘escape phenomenon’ or as late desensitization). Secondary resistance also includes resistance of immunological origin associated with the antibody formation. Primary resistance or primary non-response Some patients exhibit primary resistance to calcitonin, with no or practically no response to normal therapeutic doses and often, still no response even when the dose is raised to as much as 500 IU/day (s-CT) or 5 mg/day (h-CT). Such patients are very few and are classed as true non-responders, likely due to be due to calcitonin receptor abnormality. The plateau phenomenon In patients exhibiting the plateau phenomenon – which might be basically a biochemical phenomenon in most cases – administration of calcitonin induces a partial fall in serum alkaline phosphatase, but the response is inadequate and the levels cannot be brought to fall within the normal range in patients with Paget’s disease, whatever the type or the dose of calcitonin used. Possible explanations include secondary hyperparathyroidism, the presence of antibodies to calcitonin, a reduction in the number of calcitonin receptors and the presence of calcitonin-resistant osteoclasts (perhaps a receptor abnormality). Plateau phenomenon is poorly understood. For example, no further reduction in alkaline phosphatase levels is obtained in affected Paget’s patients even by withdrawing and then re-instituting calcitonin. However, some of the patients who exhibit this phenomenon do not have demonstrable amounts of antibodies to calcitonin. Some patients, on the other hand, exhibiting this plateau phenomenon in only one of these aspects, will continue to experience relief of symptoms or histological or radiological improvements. Secondary resistance In secondary resistance, the initially normal inhibitory effect of calcitonin on bone resorption is lost at some stage and the patient becomes unresponsive. Sometimes there is even an exacerbation of the pathological process (i.e. rebound). Secondary resistance occurs with most calcitonins and in about half of cases it is not accompanied by the formation of antibodies. In practice, some degree of secondary resistance is common. Paget’s patients who are treated with calcitonin for 5 years, for example, were reported to have serum alkaline phosphatase and urinary hydroxyproline levels as much as 50% higher than the lowest levels they have previously attained, some patients in fact returning to pretreatment levels. Nevertheless, the calcitonin used in these studies remained fully active, as shown by the significant increase in both serum alkaline phosphatase and urinary hydroxyproline following cessation of treatment. In patients with
C h a p t e r 5 3 Calcitonin: History, Physiology, Pathophysiology and Therapeutic Applications
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l
4 Mean yearly change VBMC (%)
hypercalcemia of neoplastic origin, e.g. salmon calcitonin 100–200 IU every 8–12 hours induced a rapid fall in blood calcium (1–2 mg/dL) over the first 24 hours. However, from about the third day onwards, hypercalcemia returns despite continued treatment. In many hematological malignancies, however, the calcium lowering response can be sustained when calcitonin is co-administered with glucocorticoids. Use of the combination of calcitonin with intravenously administered bisphosphonates is a useful method to bring down rapidly the elevated serum calcium and to maintain it lower for a longer period. It is believed that the rapid effect of this combination approach is due to the effects of calcitonin, while the more prolonged and persistent effect is due to the bisphosphonate. Like other anti-resorptive therapies, calcitonin also eventually decreases the bone-formation phase, thereby producing a new, lower steady state of bone turnover. Consequently, increases in bone mass are generally seen only during the first 2–3 years of treatment with calcitonin. Thereafter, one can only hope to maintain the bone mass. It may be possible to minimize this problem by administration of calcitonin in a cyclical fashion (e.g. administration of nasal calcitonin 200 IU/day, in cycles of 4 to 6 months). Although calcitonin prevents bone loss associated with corticosteroid treatment, it is unclear how calcitonin and other anti-resorptive agents reduce bone loss, since corticosteroids are thought to depress the osteoblast-mediated bone formation rather than stimulate bone resorption.
n=12
2 n=34
n=9
n=18
0 E2/P + CT –2
CT
–4 E2/P –6 Placebo –8
Figure 53.4 Percentage changes of vertebral trabecular bone mineral content (VBMC) per year in early postmenopausal women treated with hormone replacement therapy (HRT), calcitonin (CT), a combination of calcitonin and HRT or a placebo therapy for 2 years. E2/P: estrogen and progesterone. (Modified from MacIntyre et al., 1988 [53]).
osteoporosis, conditions with enhanced bone catabolism, osteogenesis imperfecta, controlling bone loss during longterm administration of prednisone or heparin and in chronic renal insufficiency. All these disorders are associated with excessive osteoclastic activity and calcitonin can be used as an adjuvant therapy.
Osteoporosis Therapeutic uses Calcitonin has been used for the past four decades to treat patients with various bone disorders, especially those characterized by accelerated bone resorption. Indications for the therapeutic use of calcitonin are disorders involving hypercalcemic states, such as with bony metastases, vitamin-D intoxication, Paget’s disease, high-bone turnover osteoporosis, pain associated with osteoporotic fractures or bone metastases and Sudeck’s atrophy. Since calcitonin is a peptide, it is difficult to administer orally. However, with research into various delivery systems and chemical modifications of the calcitonin molecule, it may eventually be possible for calcitonin or its analogs to be administered orally or via the buccal–mucosal route. Bone pain following vertebral fractures or osteolysis due to neoplasms is another indication for calcitonin therapy. Calcitonin has also been used successfully in patients with algo-neurodystrophy or Sudeck’s atrophy, a syndrome caused by various factors including painful post-traumatic osteoporosis, reflex dystrophy or iatrogenic neurotrophic disorders. In addition to these established uses of calcitonin, beneficial effects have also been reported in prevention of osteoporosis associated with immobilization, pregnancy-associated
Although the ideal treatment for osteoporosis should increase bone mass, an inhibitor of bone resorption (such as calcitonin and bisphosphonates) should arrest further bone loss [48, 52]. Calcitonin, albeit a weaker agent, has been shown to stabilize bone mass in patients with osteoporosis [41, 49]. It is most likely to be of greatest benefit in types of osteoporosis where increased resorption is a feature and, hence, it has been employed in postmenopausal osteoporosis. It has been shown that a dose of calcitonin as low as 50 IU three times a week is effective in preventing bone loss and the combination with hormone replacement therapy (HRT) may be additive [43] (Figure 53.4). Calcitonin is effective in the prevention of bone loss, but its efficiency in decreasing osteoporotic fractures is less effective than bisphosphonate [54–56]. It has been shown to stabilize or modestly increase indices of cortical and trabecular bone mass and total body calcium when it is administered to patients with established osteoporosis. However, the increments in bone mass seen are transient and are likely due to reduction in bone resorption with bone formation remaining unaffected until remodeling spaces are filled. The duration and the magnitude of these increases are probably limited by the eventual decline in bone formation, as remodeling equilibrium is re-established.
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Table 53.3 Fracture end-point data from several human clinical trials using salmon-calcitonin Type of CT used Dose
No. of patients (# on CT)
Duration of the study
Fracture Effect on fracture measurements reduction
s-CT (nasal)
50–200 IU/day
208 (156)
2 years
Vertebral
Overgaard [54] Reduction (P 5 0.013) reduction in peripheral fracture (P 5 0.006)
s-CT (IM)
100 IU/day 60 (32) (10 days/month) 100 IU/day 72 (36) (10 days/month) 100–400 IU/day 1255 (944) (three doses)
2 years
Vertebral
2 years
Vertebral
5 years
Vertebral
Reduction of 60% Rico [60] (P 0.025) Reduction of 60% Body [61] (P 0.001) Chestnut [62] Reduction (200 IU)(RR 5 0.67, CI 0.47–0.97) (P 0.05) Reduction (100 IU) (RR 5 0.1, CI 0.01–0.9) Reduction (100 IU (RR 5 0.36, CI 0.1–0.9)
s-CT (IM) s-CT (nasal)
Hip or femoral
Percentage of patients with new vertebral fractures
Arm
35
Placebo
30 25 20 15
*
10
*
*
CalcitoninSalmon – 200 IU
5 0
1
2
3
4
5
Years
Figure 53.5 Effects of intra nasally administered salmon-CT (200 IU per day) on fracture reduction. Cumulative percentages of patients with vertebral fractures are illustrated (*P 0.05) (modified from Chestnut et al., 2000 [52]).
Therefore, realistically, a reduction in the rate of bone loss with maintenance of the existing skeletal mass, rather than a significant sustained increase in bone mass should be considered as the therapeutic goal with calcitonin [57, 58]. Recent studies suggest that long-term use of calcitonin decreases osteoporosis-associated fracture rates by about 40% [59]. Table 53.3 summarizes data from several clinical studies with calcitonin that used fracture reduction as the primary end point. A major drawback with calcitonin use is its high cost. Therefore, it is useful to select patients (i.e. those patients with elevated biochemical markers, patients with recent fractures or bone pain) with high bone turnover and increased rate of bone remodeling who are likely to derive the most benefit from calcitonin. Common subcutaneous dosage used in clinical studies has been 100 IU daily [41, 58],
Reference
but it is likely that lower and less frequent doses may be effective in the prevention of postmenopausal osteoporosis [43]. Smaller doses, such as 20 IU of human calcitonin thrice weekly, have been shown to be effective in preventing postmenopausal bone loss [43, 49]. Furthermore, the combination of estrogen and calcitonin may have an additive effect [49, 64]. FDA approval dose of intranasal S-CT is 200 IU/day. Albeit weak, nasally administered calcitonin can be used for the treatment of osteoporosis [57] (Figure 53.5), as well as for steroid-induced bone loss in children. When calcitonin is administered as a nasal spray, its absorption is low and variable and the bioavailability is low. Therefore, the dose needs to be increased above the recommended injectable dose. Bioavailability may improve with the newer preparations of nasal calcitonin. Immobilization is a situation where calcitionin has potential applicability. Increased osteoclastic activity characterized by hypercalcemia, hypercalciuria and increased bone resorption markers in urine have been shown within weeks of spinal cord injury resulting in paraplegia [65, 66]. This has also been confirmed by quantitative histological methods [67]. Longer periods of immobilization carried out on monkeys have shown a substantial loss of trabecular bone with loss of trabecular architecture. More importantly, once remobilized, these lost trabecular plates were not replaced and the original bone mass was not recovered. Although most of the bone loss is directly due to immobilization, additional contributory neurological and circulatory factors have also been suggested [68]. It is possible that calcitonin could prevent this rapid bone loss (mainly axial trabecular bone), which occurs below the lesion in patients with spinal injury, without substantial inhibition of bone formation.
C h a p t e r 5 3 Calcitonin: History, Physiology, Pathophysiology and Therapeutic Applications l
Hypercalcemia The basis of the plasma calcium lowering action of calcitonin is an acute inhibitory effect on the osteoclasts. However, plasma calcium falls only when bone turnover is high. Calcitonin typically does not lower the serum calcium in normal adults whose bone turnover is not elevated [76]. Hypercalcemia and hypercalcemic crisis due to excessive osteolysis associated with cancers of the breast, lung, kidney or other organs or hematological malignancies such as multiple myeloma, hyperparathyroidism, immobilization or even vitamin D intoxication respond to calcitonin, at least in the short term. A rather rapid reduction in plasma calcium of about 1.0 mmol per liter is observed within 24 hours of commencing calcitonin therapy (Figure 53.6). However, in the absence of additional
8 7 6 5 4 3 2 1 0
Calcitonin None
0
1
A
5
7
14
7
14
Calcitonin None
6 5 4 3 2 1 0
B
3
Number of days 7
Overall feeling better (out of 10)
Calcitonin has been used over the past 40 years for the treatment of complications associated with Paget’s disease of bone [50, 69–74]. The inhibition of osteoclastic activity explains the short-term (acute) effects of calcitonin; long-term responses are thought to be due to the decrease in the number of osteoclasts. In patients with Paget’s disease, a symptomatic response is seen starting 1–2 weeks into therapy and maximized after about 12 weeks [75]. Therapy is usually continued until maximal symptomatic relief is obtained and for at least a further 6 months. If a patient has radiological evidence of an osteolytic lesion in a weight-bearing bone (which may predispose to a fracture), calcitonin could be given (e.g. a dose of 100 IU daily by subcutaneous injection) until complete radiological healing has occurred. Calcitonin in combination with intravenously administered bisphosphonate will expedite the recovery process. If relapses occur, repeat courses of calcitonin can be initiated. If clinical resistance develops, the type of calcitonin used should be changed to another form, preferably human. Improvement of neurological deficits due to Paget’s disease have been described after calcitonin therapy [73]. The use of calcitonin prior to major orthopedic surgery of Pagetic bone reduces blood flow, facilitating the surgery. If a prosthesis is being set into a Pagetic bone, such treatment should be considered for a prolonged period in order to prevent loosening or displacement of the prosthesis [69]. Furthermore, fracture healing in patients with Paget’s disease can also be improved with calcitonin therapy. Immobilization hypercalcemia in Paget’s disease also rapidly responds to calcitonin. Despite this history of proven efficacy of calcitonin in Paget’s disease, bisphosphonates (e.g. pamidronate, alendronate, risedronate, zoledronic acid, etc.) have largely replaced calcitonin as first-line therapy.
Pain score (out of 10)
Paget’s Disease of Bone
661
0
1
3 5 Number of days
Figure 53.6 (A) Comparative calcium lowering effects of calcitonin 200 IU, s.c., administered three times a day, versus prednisolone (40 mg day for 7 days) and the combination of calcitonin plus prednisolone therapy in patients with hypercalcemia of malignancy secondary to myeloma (n 5, in each group). Changes of albumin-corrected serum calcium levels are plotted against the number of days of therapy. Horizontal broken line indicates the upper limit of normal range for serum calcium. Calcitonin has a rapid effect in lowering the plasma calcium, but the effect is short lived. However, the combination therapy had the advantage of rapidly bringing down the raised serum calcium and also maintains it for a longer duration. (From Wimalawansa, 1995, Reproduced with permission from RG Landes Co, Austin) [14]. (B) Demonstration of the comparative calcium lowering effects of calcitonin 200 IU, s.c., three times a day, intravenous bisphosphonate pamidronate (90 mg) and the combination therapy (same doses of the two agents) in patients with hypercalcemia of malignancy secondary to solid tumors (n 9, in each group). Changes of albumin-corrected serum calcium levels are plotted against the number of days of therapy. Horizontal broken line indicates the upper limit of normal range for serum calcium. Calcitonin has a rapid effect in lowering the plasma calcium, but the effect is short lived. The combination therapy from the beginning had the advantage of rapidly bringing down the calcium and maintaining it lower for a longer duration [79].
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Corticosteroids Calcitonin CT + steroid
Serum calcium (mmo/L)
3.4 3.2 3.0
∗
∗ 2.8
∗
∗
∗
2.6
∗
2.4 –3
–1
0
∗
∗ ∗
1
∗
∗
5
3 Days
Serum calcium (mg/dL)
13.0
Calcitonin (CT) Pamidronate CT + Pamidronate
Analgesic Action of Calcitonin
12.0
Figure 53.7 (A) Effects of nasally-administered salmon calcitonin in reduction of pain following acute vertebral crush fractures (n 12 11.0 per group; *P 0.05); (B) overall feeling/well being of patients following the use of nasally administered salmon calcitonin after acute vertebral crush fractures (n 12; *P 0.05). The data presented here are inversely related to relief of pain fol10.0the administration of salmon calcitonin. lowing
1
3
5
7 Days
cytokines and chemical factors. Interestingly, bone pain associated with hormone sensitive tumors (e.g. breast, prostate and thyroid) also shows response, together with some lung tumors secreting ectopic hormones. In addition to the possibility of the effects of calcitonin on -endorphin release, calcitonin may also bind to calcitonin gene-related peptide (CGRP) receptors in the hypothalamus in the central nervous system [85, 86]. CGRP and its receptor distribution in the brain and the dorsal spinal cord [85] ∗ suggests that it may be involved in the processing of pain sensation [87]. In vitro studies have shown that calcitonin could interact with CGRP binding sites in the kidney [88] as well as in the nervous system including hypothalamus ∗ [89, 90]. This suggests that when pharmacological doses 7 of calcitonin are administered, it could occupy neuromodulatory CGRP receptors in the CNS, particularly in the hypothalamic region, which modify the sensory neurotransmission.
9
11
glucocorticoid therapy, the effect may not be maintained beyond 72 hours [77]. Calcitonin is most likely to be effective in cases of hypercalcemia where a generalized increase in bone resorption is a prominent feature, such as primary hyperparathyroidism and some humeral hypercalcemia of malignancy [14, 78]. The calciuric effect of calcitonin may also play a role in reducing the raised plasma calcium [14, 78–79].
Metastatic Bone Pain Calcitonin can be used to control bone pain in patients with skeletal metastatic disease, secondary to malignancy [80]. When injected intrathecally or in the subarachnoid space, s-CT acts as a potent analgesic [81]. It is likely that the main site of action is in the CNS, but the mechanism of its analgesic action is still not understood. The analgesic effect of calcitonin has been postulated to occur through a number of mechanisms. A direct central action [82] and an indirect one through interference with the classical neurotransmitters such as serotonin [83, 84] and prostaglandin (independent of endorphin), and a peripheral action mediated via the inhibition of inflammatory
Most of the literature concerning the analgesic action of s-CT employed the use of the injectable form. The reduction in pain occurs significantly earlier than any demonstrated improvement in skeletal dynamics and, in some instances, no objective improvement in the underlying skeletal condition can be observed. Miacalcin nasal spray is not FDA approved for use as an analgesic agent. To obtain an analgesic effect, one needs to administer 800–1000 IU of intranasal calcitonin (within about a 10-minute period), once daily. Most of the patients on short-term, high dose calci14 tonin therapy experience a decrease in pain, enabling them to decrease or eliminate their opiate analgesics. Similar effects can be obtained with somewhat higher doses of subcutaneously administered calcitonin. There is reasonable evidence for the efficacy of calcitonin as an analgesic in patients with acute vertebral fractures [91, 92]. At doses that are three- to fourfold higher than doses recommended for osteoporosis, calcitonin acutely can reduce pain in patients who have sustained recent osteoporotic fractures (e.g. vertebral crush fracture syndrome). Pain reduction can facilitate early mobilization of these patients; a highly desirable goal. Pain accompanying osteoporosis is not due to bone loss or the osteoporotic process, but occurs only following fractures (or sometimes imminent). Pain in these patients is in part due to surrounding nerve irritation following the fracture, inflammatory reactions and subsequent release of cytokines. Figure 53.7A illustrates the effect of calcitonin on reduction of pain following vertebral compression fractures, in comparison to standard therapy. Figure 53.7B demonstrates the reciprocal feeling of well being following administration of calcitonin. This is most likely a reflection of the rapid relief of pain and, consequently, the ability to move around and, gaining independence.
C h a p t e r 5 3 Calcitonin: History, Physiology, Pathophysiology and Therapeutic Applications l
Intranasal s-CT has been investigated for its analgesic effect in acute back pain due to osteoporosis. In a doubleblind, placebo-controlled study, more than 50% of patients receiving 200 IU daily of s-CT nasal spray demonstrated a ‘good’ response in mobility and functional capacity, while patients receiving placebo nasal spray experienced only a moderate response with respect to the same variables. In addition, intranasal s-CT appears to be more rapid in providing analgesia to postmenopausal osteoporotic women with acute pain than injectable s-CT. A double-blind, placebo controlled study by Pontiroli et al examined the analgesic effect of intranasal s-CT (200 IU daily) versus intramuscular s-CT (100 IU daily), versus placebo in 28 women with painful fractures secondary to postmenopausal osteoporosis for a period of 4 weeks [48]. In the 24 patients who completed the trial, by the second week of treatment with intranasal s-CT, there was a statistically significant reduction in pain score, as measured by a visual analog scale. With intramuscular s-CT, pain scores significantly decreased within the first few days of treatment. However, by week four, the pain scores were not different among the three treatment groups. The analgesic effect of various therapies for osteoporosis will diminish over time. This may be due to either the tolerance or the spontaneous improvement that usually occurs over the study period with most vertebral compressions or wedge fractures.
Adverse Effects of Calcitonin The chronic nature of bone loss in metabolic bone diseases including osteoporosis (either postmenopausal or ageassociated) makes long-term treatment necessary. Agents like calcitonin that have to be given by daily injection are a relative drawback. In addition, a number of short-term adverse effects occur in over 60% of patients after calcitonin injection, including nausea, vomiting, flushing, headache, vertigo and irritation at the site of injection. In some patients, these side effects are severe enough to warrant discontinuation of treatment [93]. Due to the rapidity of high levels achieved in the blood, side effects are greatest following intravenous administration. Side effects are less with intramuscular and least with intranasal administration and subcutaneous injections [51]. Prior administration of an anti-emetic is useful when calcitonin is given intravenously. Nausea and flushing are common, but vomiting is rare. Other rare side effects include diarrhea, diuresis and immunological reactions with nonhuman calcitonin [94, 95]. Calcitonin does not appear to be associated with any serious long-term detrimental side effects in humans [51]. There are no known specific interactions between calcitonin and any other drugs [93]. Side effects associated with nasally administered calcitonin are rhinitis, rhinorrhoea, nasal obstruction, anosmia, dryness and nasal discomfort, sneezing and, more rarely,
663
epistaxis. However, when compared with injection, the incidence of side effects is relatively low with nasallyadministered calcitonin. Nevertheless, a significant number of patients using nasally administered non-human calcitonin (as with the injectable calcitonin preparations) developed neutralizing antibodies with long-term use, which may decrease the efficacy of the therapy. There are no reports of any deaths or long-term side effects attributable to calcitonin usage over 40 years of clinical experience [4, 93]. Overdose has not been reported. Anaphylactic reactions have been reported very rarely in association with calcitonin (non-human calcitonin) therapy (PDR; Committee on Safety of Medicines UK).
References 1. D.H. Copp, K.G. Henze, Parathyroid origin of calcitonin – evidence from perfusion of sheep glands, Endocrinology 75 (1964) 49–55. 2. G.V. Foster, A. Baghdiantz, M.A. Kumar, E. Slack, H.A. Soliman, I. Macintyre, Thyroid origin of calcitonin, Nature 202 (1964) 1303–1305. 3. G.V. Foster, I. Macintyre, A.G. Pearse, Calcitonin production and the mitochondrion-rich cells of the dog thyroid, Nature 203 (1964) 1029–1030. 4. M. Azria, The calcitonin: physiology and pharmacology, S. Karger, Switzerland, 1989. 5. A.G. Pearse, The cytochemistry of the thyroid C cells and their relationship to calcitonin, Proc. R. Soc. Lond. B Biol. Sci. 164 (996) (1966) 478–487. 6. G. Bussolati, A.G. Pearse, Immunofluorescent localization of calcitonin in the ‘C’ cells of pig and dog thyroid, J. Endocrinol. 37 (2) (1967) 205–209. 7. D.H. Copp, D.W. Cockcroft, Y. Kueh, Calcitonin from ultimobranchial glands of dogfish and chickens, Science 158 (803) (1967) 924–925. 8. S.D. Tauber, The ultimobranchial origin of thyrocalcitonin, Proc. Natl. Acad. Sci. USA 58 (4) (1967) 1684–1687. 9. N. Le Douarin, C. Le Lievre, [Demonstration of neural origin of calcitonin cells of ultimobranchial body of chick embryo], C R Acad. Sci. Hebd. Seances Acad. Sci. D 270 (23) (1970) 2857–2860. 10. A.F. Carvalheira, A.G. Pearse, The cytology and cytochemistry of the ‘C’ cells in the thyroid gland of the pig, J. R. Microsc. Soc. 86 (3) (1967) 203–209. 11. A.F. Carvalheira, A.G. Pearse, Comparative cytochemistry of C cell esterases in the mammalian thyroid-parathyroid complex, Histochemie 8 (2) (1967) 175–182. 12. K.L. Becker, K.G. Monaghan, O.L. Silva, Immuno cytochemical localization of calcitonin in Kulchitsky cells of human lung, Arch. Pathol. Lab. Med. 104 (4) (1980) 196–198. 13. H.A. Fritsch, S. Van Noorden, A.G. Pearse, Calcitonin-like immunochemical staining in the alimentary tract of Ciona intestinalis L, Cell Tissue Res. 205 (3) (1980) 439–444. 14. S.J. Wimalawansa, Hypercalcaemia of malignancy: etiology, pathogenesis and clinical management, 1995 Springer, New York, RG Landes Co. Medical Publishers, Austin.
664
Osteoporosis in Men
15. S.J. Culter, Some epidemiologic observations on cancer of the female breast, Int. J. Radiat. Oncol. Biol. Phys. 2 (7-8) (1977) 753–754. 16. M. Ravazzola, L. Orci, S.I. Girgis, F. Galan Galan, I. McIntyre, The lung is the major organ source of calcitonin in the lizard, Cell Biol. Int. Rep. 5 (10) (1981) 937–944. 17. R. Perez Cano, S.I. Girgis, F. Galan Galan, I. MacIntyre, Identification of both human and salmon calcitonin-like molecules in birds suggesting the existence of two calcitonin genes, J. Endocrinol. 92 (3) (1982) 351–355. 18. R. Perez Cano, S.I. Girgis, I. MacIntyre, Further evidence for calcitonin gene duplication: the identification of two different calcitonins in a fish, a reptile and two mammals, Acta Endocrinol. (Copenh) 100 (2) (1982) 256–261. 19. S.I. Girgis, F.G. Galan, T.R. Arnett, et al., Immunoreactive human calcitonin-like molecule in the nervous systems of protochordates and a cyclostome, Myxine. J. Endocrinol. 87 (3) (1980) 375–382. 20. H.A. Fritsch, S. Van Noorden, A.G. Pearse, Gastro-intestinal and neurohormonal peptides in the alimentary tract and cerebral complex of Ciona intestinalis (Ascidiaceae), Cell Tissue Res. 223 (2) (1982) 369–402. 21. H.A. Fritsch, S. Van Noorden, A.G. Pearse, Localization of somatostatin-, substance P- and calcitonin-like immunoreactivity in the neural ganglion of Ciona intestinalis L. (Ascidiaceae), Cell Tissue Res. 202 (2) (1979) 263–274. 22. R. Perez-Cano, F. Galan Galan, S.I. Girgis, T.R. Arnett, I. MacIntyre, A human calcitonin-like molecule in the ultimobranchial body of the amphibia (Rana pipiens), Experientia 37 (10) (1981) 1116–1118. 23. F. Galan Galan, R.M. Rogers, S.I. Girgis, I. MacIntyre, Immunoreactive calcitonin in the central nervous system of the pigeon, Brain Res. 212 (1) (1981) 59–66. 24. L.J. Deftos, D. Burton, B.D. Catherwood, et al., Demonstration by immunoperoxidase histochemistry of calcitonin in the anterior lobe of the rat pituitary, J. Clin. Endocrinol. Metab. 47 (2) (1978) 457–460. 25. L.J. Deftos, D. Burton, H.G. Bone, et al., Immunoreactive calcitonin in the intermediate lobe of the pituitary gland, Life Sci. 23 (7) (1978) 743–748. 26. J.J. Flynn, D.L. Margules, C.W. Cooper, Presence of immunoreactive calcitonin in the hypothalamus and pituitary lobes of rats, Brain Res. Bull. 6 (6) (1981) 547–549. 27. J.W. Jacobs, D. Goltzman, J.F. Habener, Absence of detectable calcitonin synthesis in the pituitary using cloned complementary deoxyribonucleic acid probes, Endocrinology 111 (6) (1982) 2014–2019. 28. S.J. Wimalawansa, Calcitonin: molecular biology, physiology, pathophysiology, and its therapeutic uses, in: A. Pecile, B. Bernard (Eds.) Advances in Bone Regulatory Factors: Morphology, Biochemistry, Physiology and Pharmacology, Plenum Press, 1989, pp. 121–160. 29. N.H. Bell, Effects of glucagon, dibutyryl cyclic 3,5-adenosine monophosphate, and theophylline on calcitonin secretion in vitro, J. Clin. Invest. 49 (7) (1970) 1368–1373. 30. G.C. Nicholson, J.M. Moseley, P.M. Sexton, F.A. Mendelsohn, T.J. Martin, Abundant calcitonin receptors in isolated rat osteoclasts. Biochemical and autoradiographic characterization, J. Clin. Invest. 78 (2) (1986) 355–360.
31. M.B. Ito, H. Schraer, C.V. Gay, The effects of calcitonin, parathyroid hormone and prostaglandin E2 on cyclic AMP levels of isolated osteoclasts, Comp. Biochem. Physiol. A Comp. Physiol. 81 (3) (1985) 653–657. 32. T.J. Chambers, A. Moore, The sensitivity of isolated osteoclasts to morphological transformation by calcitonin, J. Clin. Endocrinol. Metab. 57 (4) (1983) 819–824. 33. G.L. Wong, D.V. Cohn, Target cells in bone for parathormone and calcitonin are different: enrichment for each cell type by sequential digestion of mouse calvaria and selective adhesion to polymeric surfaces, Proc. Natl. Acad. Sci. USA 72 (8) (1975) 3167–3171. 34. T.J. Chambers, J.A. Darby, [Role of calcitonin in bone], Presse Med. 14 (40) (1985) 2061. 35. M. Zaidi, K. Fuller, P.J. Bevis, R.E. GainesDas, T.J. Chambers, I. MacIntyre, Calcitonin gene-related peptide inhibits osteoclastic bone resorption: a comparative study, Calcif. Tissue Int. 40 (3) (1987) 149–154. 36. T.J. Chambers, C.J. Dunn, Pharmacological control of osteoclastic motility, Calcif. Tissue Int. 35 (4-5) (1983) 566–570. 37. T.J. Chambers, J.C. Chambers, J. Symonds, J.A. Darby, The effect of human calcitonin on the cytoplasmic spreading of rat osteoclasts, J. Clin. Endocrinol. Metab. 63 (5) (1986) 1080–1085. 38. H.M. Taggart, C.H. Chesnut III, J.L. Ivey, et al., Deficient calcitonin response to calcium stimulation in postmenopausal osteoporosis? Lancet 1 (8270) (1982) 475–478. 39. R.D. Tiegs, J.J. Body, H.W. Wahner, J. Barta, B.L. Riggs, H. Heath III., Calcitonin secretion in postmenopausal osteoporosis, N. Engl. J. Med. 312 (17) (1985) 1097–1100. 40. D.L. Hurley, R.D. Tiegs, H.W. Wahner, H. Heath III, Axial and appendicular bone mineral density in patients with longterm deficiency or excess of calcitonin, N. Engl. J. Med. 317 (9) (1987) 537–541. 41. H.E. Gruber, J.L. Ivey, D.J. Baylink, et al., Long-term calcitonin therapy in postmenopausal osteoporosis, Metabolism 33 (4) (1984) 295–303. 42. G.F. Mazzuoli, M. Passeri, C. Gennari, et al., Effects of salmon calcitonin in postmenopausal osteoporosis: a controlled doubleblind clinical study, Calcif. Tissue Int. 38 (1) (1986) 3–8. 43. I. MacIntyre, J.C. Stevenson, M.I. Whitehead, S.J. Wimalawansa, L.M. Banks, M.J. Healy, Calcitonin for prevention of postmenopausal bone loss, Lancet 1 (8591) (1988) 900–902. 44. T.J. Chambers, C.J. Magnus, Calcitonin alters behaviour of isolated osteoclasts, J. Pathol. 136 (1) (1982) 27–39. 45. D.M. Kallio, P.R. Garant, C. Minkin, Ultrastructural effects of calcitonin on osteoclasts in tissue culture, J. Ultrastruct. Res. 39 (3) (1972) 205–216. 46. C.J. Hillyard, T.J. Cooke, R.C. Coombes, I.M. Evans, I. Macintyre, Normal plasma calcitonin: circadian variation and response to stimuli, Clin. Endocrinol. (Oxf) 6 (4) (1977) 291–298. 47. R. Seth, P. Motte, A. Kehely, et al., A sensitive and specific two-site enzyme-immunoassay for human calcitonin using monoclonal antibodies, J. Endocrinol. 119 (2) (1988) 351–357. 48. A.E. Pontiroli, E. Pajetta, L. Scaglia, et al., Analgesic effect of intranasal and intramuscular salmon calcitonin in post-menopausal osteoporosis: a double-blind, double-placebo study, Aging (Milano) 6 (6) (1994) 459–463.
C h a p t e r 5 3 Calcitonin: History, Physiology, Pathophysiology and Therapeutic Applications l
49. S.J. Wimalawansa, A. Kehely, L.M. Banks, et al., The effect of percutaneous oestradiol and low dose human calcitonin on postmenopausal bone loss, in: C. Christiansen, J.S. Johansen, B.J. Riis (Eds.), Osteoporosis 1987, Norhaven A/S, Viborg, 1987, pp. 528-32. Proc. Int. Symp. Osteoporosis. 50. A. Angyal, G. Boyd, P.G. Byfield, et al., Calcitonin: chemistry, immuno- and bio-assay effects in man, J. Physiol. 202 (1) (1969) 21P. 51. S.J. Wimalawansa, I. MacIntyre, Calcitonin, in: C.T. Dollery (Ed.), Therapeutic Drugs: A Clinical Pharmacopeia, Churchill Livingstone, Edinburgh, 1991, pp. C18–C22. 52. C.H. Chesnut III, S. Silverman, K. Andriano, et al., A randomized trial of nasal spray salmon calcitonin in postmenopausal women with established osteoporosis: the prevent recurrence of osteoporotic fractures study. PROOF Study Group, Am. J. Med. 109 (4) (2000) 267–276. 53. I. MacIntyre, J.C. Stevenson, et al., Calcitonin for prevention of postmenopausal bone loss, Lancet 1 (8591) (1988) 900–902. 54. K. Overgaard, B.J. Riis, C. Christiansen, J. Podenphant, J.S. Johansen, Nasal calcitonin for treatment of established osteoporosis, Clin. Endocrinol. (Oxf) 30 (4) (1989) 435–442. 55. V. Maresca, Human calcitonin in the management of osteo porosis: a multicentre study, J. Int. Med. Res. 13 (6) (1985) 311–316. 56. J.Y. Reginster, D. Denis, A. Albert, et al., 1-Year controlled randomised trial of prevention of early postmenopausal bone loss by intranasal calcitonin, Lancet 2 (8574) (1987) 1481–1483. 57. R. Civitelli, S. Gonnelli, F. Zacchei, et al., Bone turnover in postmenopausal osteoporosis. Effect of calcitonin treatment, J. Clin. Invest. 82 (4) (1988) 1268–1274. 58. P. Szulc, M. Arlot, M.C. Chapuy, F. Duboeuf, P.J. Meunier, P.D. Delmas, Serum undercarboxylated osteocalcin correlates with hip bone mineral density in elderly women, J. Bone Miner. Res. 9 (10) (1994) 1591–1595. 59. C.H. Chesnut III., Treatment of postmenopausal osteoporosis: some current concepts, Scott. Med. J. 26 (1) (1981) 72–80. 60. H. Rico, et al., Treatment of postmenopausal osteoporosis with calcitonion and caclium. Long term results, in: Osteoporosis, Social and Clnical Aspects. Proc. Second Internaitonal Confer ence, Athens, 1985, pp. 376-380, 1986. Masson. 61. J.J. Body, Calcitonin for prevention and treatment of postmenopausal osteoporosis, Clin. Rheumatol. 14 (Suppl. 3) (1995) 18–21. 62. C.H. Chesnut III., S. Silverman, et al., A randomized trial of nasal spray salmon calcitonin in postmenopausal women with established osteoporosis: the prevent recurrence of osteoporotic fractures study. PROOF Study Group, Am. J. Med. 109 (4) (2000) 267–276. 63. S. Wallach, S.H. Cohn, K.J. Ellis, R. Kohberger, J.F. Aloia, I. Zanzi, Effect of salmon calcitonin on skeletal mass in osteo porosis, Curr. Ther. Res. Clin. Exp. 22 (1977) 556–572. 64. S.J. Wimalawansa, I. Macintyre, Heterogeneity of plasma calcitonin gene-related peptide: partial characterisation of immunoreactive forms, Peptides 9 (2) (1988) 407–410. 65. L. Klein, S. Van Den Noort, J.J. DeJak, Sequential studies of urinary hydroxyproline and serum alkaline phosphatase in acute paraplegia, Med. Serv. J. Can. 22 (7) (1966) 524–533.
665
66. A. Chantraine, Clinical investigation of bone metabolism in spinal cord lesions, Paraplegia 8 (4) (1971) 253–259. 67. P. Minaire, P. Neunier, C. Edouard, J. Bernard, P. Courpron, J. Bourret, Quantitative histological data on disuse osteoporosis: comparison with biological data, Calcif. Tissue Res. 17 (1) (1974) 57–73. 68. A. Chantraine, B. Nusgens, C.M. Lapiere, Bone remodeling during the development of osteoporosis in paraplegia, Calcif. Tissue Int. 38 (6) (1986) 323–327. 69. N.J. Woodhouse, P. Bordier, M. Fisher, et al., Human calcitonin in the treatment of Paget’s bone disease, Lancet 1 (7710) (1971) 1139–1143. 70. N.J. Woodhouse, G.F. Joplin, I. MacIntyre, F.H. Doyle, Radiological regression in Paget’s disease treated by human calcitonin, Lancet 2 (7785) (1972) 992–994. 71. N.J. Woodhouse, S.M. Mohamedally, F. Saed-Nejad, T.J. Martin, Development and significance of antibodies to salmon calcitonin in patients with Paget’s disease on longterm treatment, Br. Med. J. 2 (6092) (1977) 927–929. 72. R. Maier, M. Brugger, H. Bruckner, B. Kamber, B. Riniker, W. Rittel, Analogues of human calcitonin. V. Influence of basic amino acids in positions 11, 17 and 24 on hypocalcaemic activity in the rat, Acta Endocrinol. (Copenh) 85 (1) (1977) 102–108. 73. F.R. Singer, R.S. Fredericks, C. Minkin, Salmon calcitonin therapy for Paget’s disease of bone. The problem of acquired clinical resistance, Arthritis Rheum. 23 (10) (1980) 1148–1154. 74. J.M. Zanelli, E. Lane, T. Kimura, S. Sakakibara, Biological activities of synthetic human parathyroid hormone (PTH) 1-84 relative to natural bovine 1-84 PTH in two different in vivo bioassay systems, Endocrinology 117 (5) (1985) 1962–1967. 75. P.B. Greenberg, F.H. Doyle, M.T. Fisher, et al., Treatment of Paget’s disease of bone with synthetic human calcitonin: biochemical and roentgenologic changes, Am. J. Med. 56 (6) (1974) 867–870. 76. F.R. Singer, N.J. Woodhouse, D.K. Parkinson, G.F. Joplin, Some acute effects of administered porcine calcitonin in man, Clin. Sci. 37 (1) (1969) 181–190. 77. G.R. Mundy, T.J. Martin, The hypercalcemia of malignancy: pathogenesis and management, Metabolism 31 (12) (1982) 1247–1277. 78. S.J. Wimalawansa, Optimal frequency of administration of pamidronate in patients with hypercalcaemia of malignancy, Clin. Endocrinol. (Oxf) 41 (5) (1994) 591–595. 79. S.J. Wimalawansa, Combined therapies with calcitonin and corticosteroids, or bisphosphonate, for treatment of hypercalcemia of malignancy, J. Bone Miner. Metab. 15 (1997) 160–164. 80. C.E. Fiore, M. Lunetta, J.A. Kanis, Long-term effects of histamine H2-receptor antagonists on serum parathyroid hormone in chronic renal failure, Clin. Endocrinol. (Oxf) 23 (3) (1985) 277–282. 81. F. Fraioli, A. Fabbri, L. Gnessi, C. Moretti, C. Santoro, M. Felici, Subarachnoid injection of salmon calcitonin induces analgesia in man, Eur. J. Pharmacol. 78 (3) (1982) 381–382. 82. A. Fabbri, C. Santoro, C. Moretti, et al., The analgesic effect of calcitonin in humans: studies on the role of opioid peptides, Int. J. Clin. Pharmacol. Ther. Toxicol. 19 (11) (1981) 509–511.
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Osteoporosis in Men
83. G. Clementi, A. Prato, G. Conforto, U. Scapagnini, Role of serotonin in the analgesic activity of calcitonin, Eur. J. Pharmacol. 98 (3-4) (1984) 449–451. 84. G. Clementi, M. Amico-Roxas, E. Rapisarda, et al., The analgesic activity of calcitonin and the central serotonergic system, Eur. J. Pharmacol. 108 (1) (1985) 71–75. 85. S.J. Wimalawansa, P.C. Emson, I. MacIntyre, Regional distribution of calcitonin gene-related peptide and its specific binding sites in rats with particular reference to the nervous system, Neuroendocrinology 46 (2) (1987) 131–136. 86. S.J. Wimalawansa, Calcitonin gene-related peptide and its receptors: molecular genetics, physiology, pathophysiology, and therapeutic potentials, Endocr. Rev. 17 (5) (1996 Oct) 533–585. 87. M.G. Rosenfeld, J.J. Mermod, S.G. Amara, et al., Production of a novel neuropeptide encoded by the calcitonin gene via tissuespecific RNA processing, Nature 304 (5922) (1983) 129–135. 88. A. Wohlwend, K. Malmstrom, H. Henke, H. Murer, J.D. Vassalli, J.A. Fischer, Calcitonin and calcitonin generelated peptide interact with the same receptor in cultured LLC-PK1 kidney cells, Biochem. Biophys. Res. Commun. 131 (2) (1985) 537–542. 89. S.J. Wimalawansa, H.R. Morris, I. MacIntyre, Both alphaand beta-calcitonin gene-related peptides are present in
90.
91.
92.
93.
94.
95.
plasma, cerebrospinal fluid and spinal cord in man, J. Mol. Endocrinol. 3 (3) (1989) 247–252. S.J. Wimalawansa, Amylin, calcitonin gene-related peptide, calcitonin, and adrenomedullin: a peptide superfamily, Crit. Rev. Neurobiol. 11 (2-3) (1997) 167–239. G.P. Lyritis, N. Tsakalakos, B. Magiasis, T. Karachalios, A. Yiatzides, M. Tsekoura, Analgesic effect of salmon calcitonin in osteoporotic vertebral fractures: a double-blind placebo-controlled clinical study, Calcif. Tissue Int. 49 (6) (1991) 369–372. C. Gennari, D. Agnusdei, A. Camporeale, Use of calcitonin in the treatment of bone pain associated with osteoporosis, Calcif. Tissue Int. 49 (Suppl. 2) (1991) S9–S13. S.J. Wimalawansa, Long- and short-term side effects and safety of calcitonin in man: a prospective study, Calcif. Tissue Int. 52 (2) (1993) 90–93. F.R. Singer, J.P. Aldred, R.M. Neer, S.M. Krane, J.T. Potts Jr, K.J. Bloch, An evaluation of antibodies and clinical resistance to salmon calcitonin, J. Clin. Invest. 51 (9) (1972) 2331–2338. W.J. Dube, R.S. Goldsmith, S.B. Arnaud, C.D. Arnaud, Development of antibodies to porcine calcitonin during treatment of Paget’s disease of bone, Mayo Clin. Proc. 48 (1) (1973) 43–46.
Chapter
54
Treatment of Male Osteoporosis with Bisphosphonates Andrea Giusti and Socrates E. Papapoulos Department of Endocrinology & Metabolic Diseases, Leiden University Medical Center, Leiden, The Netherlands
Introduction
responsible for the action of BPs on bone resorption and probably also for their affinity for bone mineral. Oral BPs are poorly absorbed from the intestine (less than 1%) with no difference between genders [4]. The intestinal absorption decreases further in the presence of food or calcium which bind them. BPs are eliminated rapidly from the circulation. About 50% of the dose is taken up by the skeleton, primarily at active remodeling sites, while the rest is excreted unmetabolized in urine. The amount of BP taken up by the skeleton depends on its affinity for bone mineral, on the prevalent rate of bone turnover and on renal function [5]. The capacity of the skeleton to retain BPs is large and saturation of binding sites is unlikely even if these are given for a very long time. After exerting their action on the bone surface, they are embedded in bone, where they remain for a long time and are biologically inactive. The elimination of BPs from the body is multiphasic with a very long terminal phase of elimination [6, 7]. BPs decrease the rate of bone resorption and turnover to a level that remains constant during the whole period of treatment without any evidence of a progressive decrease of bone turnover [8, 9]. At the tissue level, BPs are liberated from the bone mineral during bone resorption, are taken up by the osteoclasts, probably by fluid-phase endocytosis, and inhibit their activity by different intracellular actions [10]. BPs without a nitrogen atom in their molecule (e.g. etidronate, clodronate, tiludronate) incorporate into ATP and generate metabolites which induce osteoclast apoptosis. Nitrogen-containing BPs (N-BPs) (e.g. alendronate, ibandronate, pamidronate, risedronate, zoledronate) induce changes in the cytoskeleton (loss of raffled border, disruption of actin rings, altered vescicular trafficking), leading to inactivation and potentially apoptosis of osteoclasts. This action is mainly the result of inhibition of farnesyl pyrophosphate synthase (FPPS), an
Bisphosphonates (BPs) are widely used in the treatment of postmenopausal osteoporosis. They decrease the rate of bone resorption and turnover, they increase bone mineral density (BMD), they preserve or improve structural and material properties of bone and thereby decrease the risk of fractures [1]. In contrast to the wealth of data of the efficacy of BPs in the management of postmenopausal osteoporosis, information regarding their efficacy in male osteoporosis is relatively limited. However, a number of studies help to position BPs in the pharmacological therapy of male osteoporosis. In assessing available evidence, two main questions need to be answered. First, do men respond differently from women to BPs? Second, is there any direct evidence for their efficacy in men with osteoporosis? In this chapter, we address these questions and we review the data supporting the use of BPs in the management of male osteoporosis.
Pharmacology of bisphosphonates The pharmacology of BPs and its relevance to the treatment of osteoporosis has been the subject of recent reviews [2, 3]. In brief, BPs are synthetic analogs of inorganic pyrophosphate in which the oxygen atom that connects the two phosphates is replaced by a carbon. This substitution renders the molecule stable and resistant to biological degradation. BPs have two additional side-chains (R1 and R2) attached to the carbon atom. A hydroxyl substitution at R1 enhances the affinity of BPs for calcium crystals, while a nitrogen atom at R2 increases their anti-resorptive potency and determines their mechanism of action. The whole molecule is, however,
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enzyme of the mevalonate biosynthetic pathway. There is a close relationship between the degree of inhibition of FPPS and the anti-resorptive potency of N-BPs. Bisphosphonates, being non-hormonal treatments that do not interfere with targets other than bone, are not expected to have gender-specific actions, as also supported by numerous animal studies. Moreover, in clinical indications of BP therapy other than osteoporosis, no gender-specific responses have been identified and they are approved for the treatment of both men and women. Examples include Paget’s disease of bone, malignancy-associated hypercalcemia, multiple myeloma and metastatic bone disease. However, the pathophysiology of these bone disorders is the same in men and women which may not be the case in osteoporosis. It can, therefore, be argued that differences in the pathophysiolgy of osteoporosis in men and women may affect their response to BPs. This has been examined in studies which included both women and men treated with BPs.
Do men respond differently to bisphosphonates? Primary Osteoporosis In early exploratory studies of women and men with primary osteoporosis treated with daily oral pamidronate, increases in external calcium balance and BMD were reported without any difference between the two genders [11]. Ho et al. treated men and women with primary and secondary osteoporosis with alendronate 10 mg/d and compared the changes in BMD after one year to those of a control group of women and men who received only calcium supplements [12]. Compared to controls, alendronate treatment significantly increased BMD of the lumbar spine in all patients by 5.4% to 7.0% and the increases in BMD were comparable in men and women with primary and secondary osteoporosis. In assessing BMD responses to treatments in men and women, it is important to note that percent changes can sometimes be misleading because of the generally higher baseline BMD of men and it may be better to compare absolute changes. This was illustrated in a 3-year placebo-controlled study of men and women with primary osteoporosis treated with daily oral pamidronate [13]. After 3 years, spine BMD increased in pamidronatetreated women by 10.1% and by 5.9% in men. However, the absolute increase was 0.047 g/cm² and 0.040 g/cm², in women and men, respectively. In this study, pamidronate decreased the incidence of vertebral fractures by 67% after 3 years with a similar response in men and women. In a larger study, Iwamoto et al treated 60 men (15 with secondary osteoporosis) and 318 women with postmenopausal osteoporosis with alendronate 5 mg/d [14]. Increases in spine BMD were higher in women than in men after 1 year (7.8% versus 5.6%). However, baseline urine collagen type
I cross-linked N-telopeptide (NTx) was significantly higher in the women and it has been previously established that patients with higher rates of bone turnover show greater increases in BMD with anti-resorptive treatments [15]. In a large, randomized, placebo-controlled trial, Lyles et al examined the efficacy of yearly infusions of zoledronate 5 mg, given within 90 days after surgical repair of a hip fracture, to reduce the risk of clinical fractures in men and women [16]. Compared to placebo, zoledronate decreased significantly the rates of new clinical fractures by 35%, including new clinical vertebral and non-vertebral fractures. Of the 2127 patients included in this study, 24% were men. Zoledronate treatment increased total hip BMD by 7.06% in men compared to an increase of 6.11% in women after 3 years and decreased the incidence of clinical fractures by 15% (not significant). No treatment-by-gender interaction was observed indicating a lack of association between treatment and gender with respect to fracture risk reduction and the non-significant result should be attributed to the small number of male patients [17]. Taken together, these studies indicate that, despite differences in the pathophysiology of male and postmenopausal osteoporosis, the response of both genders to BPs is comparable.
Glucocorticoid-Induced Osteoporosis The largest evidence supporting the lack of gender differences in the response to BPs has been obtained in the pivotal trials of glucocorticoid-induced osteoporosis (GIOP). In these studies, men comprised between 29% and 46% of the total number of patients. A meta-analysis of the antifracture efficacy of BPs (alendronate, risedronate, etidronate) in patients with GIOP showed a significant reduction in the risk of vertebral fractures (RR 0.46; 95% CI 0.28, 0.77), which is similar to estimates in postmenopausal osteoporosis [18]. For non-vertebral fractures, the pooled data for BPs showed no significant effect (RR 0.77; 95% CI 0.39, 1.51). The point estimate was, however, comparable to that obtained in postmenopausal osteoporosis and the lack of significance should be probably attributed to the total number of patients included in these analyses (500 in GIOP versus 14 551 in postmenopausal osteoporosis). Responses of the two genders to individual BPs in different trials were also very similar. Oral alendronate, at different daily doses, was tested against placebo in a 48-week, double-blind, randomized-controlled trial (RCT) in men and women taking glucocorticoids (daily dose 7.5 mg prednisone equivalent) [19]. The study, which originally included 477 patients (141 men), was extended for 12-months in 208 subjects (Table 54.1) [20]. After 12 and 24 months, alendronate increased significantly BMD compared to baseline and to placebo. The effect of alendronate on BMD was similar in both genders and, after 2 years, men showed an even significantly higher increase in
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Table 54.1 Bisphosphonates in glucocorticoid-induced osteoporosis Adachi et al 2001[20]a
Cohen et al Reid et al 1999 [21]b 2000 [22]
Active medication
ALN oral 2.5/10, 5 or 10 mg daily
RIS oral 2.5 or 5 mg daily
Control
Placebo
No of patients (men) Supplements
Glucocorticoid dose GCs duration Study type Study duration Mean age (years) VF assessment method Lost to follow up Prevalent VFs New VFs
New NVFs
Ringe et al 2003 [23]
Adachi et al 1997 [24]
Campbell et al 2004 [25]c
Reid et al 2009[26]d
RIS oral IBN iv 2.5 or 5 mg 2 mg every 3 months daily
ETD oral 400 mg for 2 weeks every 3 months
ETD oral 400 mg for 2 weeks every 3 months
ZOL iv 5 mg yearly
Placebo
Placebo
Alpha-D 1 ug
Placebo
Placebo
208 (66)
224 (77)
290 (109)
115 (53)
141 (54)
352 (201)
RIS oral 5 mg daily 833 (265)
Calcium 800–1000 mg Vitamin D 250–500 IU 7.5 mg pred. eq. 4, 4–12, 12 months Prevention – treatment 2 years 54
Calcium 500 mg
Calcium 500 mg
Calcium 500 mg
Calcium 500 mg
7.5 mg pred. eq. 90 days
Calcium 1000 mg Vitamin D 500 IU 7.5 mg pred. eq. 6 months
7.5 mg pred. eq. 2 years
Any
Any (inhaled included) 1 year
Calcium 1000 mg Vitamin D 400–1200 IU 7.5 mg pred. eq. 3, 3 months
Prevention
Treatment
Treatment
Prevention
1 year 57– 62
1 year 59
3 years 64
1 year 61
Prevention – treatment 5 years 60
Prevention – treatment 1 year 53, 57
100 days
Quantitative and Quantitative Quantitative Quantitative and Semiquantitative Quantitative and Semiquantitative semiquantitative semiquantitative semiquantitative 20% 32% 22% 23% 17% 31% 7%
Active Control P-value Active Control P-value
13%
30%
34%
90%
47%
30%
NR
0.7% 6.8% 0.026 5.4% 9.8% NS
5.7% 17.3% NS 3.9% 5.2% NS
5% 15% 0.042 NR NR NR
8.6% 22.8% 0.043 22.4% 28.1% NS
9% 15% NS NR NR NR
9.5% 14.4% NS 8.3% 7.8% NS
1.2% 0.7% NS NR NR
a
Second year extension of the study by Saag et al (1998) [19]. Fracture incidence is compared between RIS 5 mg and controls. c In the study by Campbell et al [25] new non-vertebral fractures include symptomatic vertebral fractures. d The study compared two active treatment: zoledronate versus risedronate; mean age was 53 for the treatment subgroup and 57 for the prevention subgroup; Prevalent VFs at baseline were not reported, overall prevalence of fractures at baseline was 14%. No: number; ALN: alendronate; RIS: risedronate; IBN: ibandronate; ETD: etidronate; ZOL: zoledronate; iv: intravenous; Alpha-D: alfacalcidiol; GCs: glucocorticoids; VF: vertebral fracture; NVF: non-vertebral fracture; NS: not significant; pred. eq.: prednisone equivalent; NR: not reported. b
lumbar spine BMD compared to women. During the first year of the study, there was no difference in the rate of new fractures between aledronate- and placebo-treated patients. However, at the end of the study extension, a significantly smaller number of patients in the alendronate group experienced a new vertebral fracture compared to those in the placebo group (see Table 54.1). Results of subsequent studies confirmed the efficacy of alendronate in the prevention and treatment of GIOP in men and women, both when alendronate was compared to placebo or to an active vitamin D metabolite [27, 28].
The efficay of risedronate in the management of GIOP was examined in two randomized, placebo-controlled trials that included both men and women (see Table 54.1) [21, 22, 29, 30]. Cohen et al assessed the efficacy of risedronate (2.5 mg or 5 mg daily) versus placebo in preventing bone loss in a 12-month, double-blind, RCT that included 224 men and women starting glucocorticoids (7.5 mg prednisone equivalent) [21]. Risedronate prevented bone loss at all skeletal sites and there were no differences between men and women. A non-significant trend for reduction in the incidence of vertebral fractures was observed in the
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Osteoporosis in Men
subgroup treated with risedronate 5 mg/d (see Table 54.1). In the other study, Reid et al evaluated the efficacy, safety and tolerability of risedronate (2.5 mg or 5 mg daily) versus placebo in 290 patients (109 men) who had been receiving high doses of oral glucocorticoids (7.5 mg prednisone equivalent) for at least 6 months [22]. After 12 months, risedronate 5 mg/d increased significantly BMD at the femoral neck, total hip and lumbar spine compared to baseline and to placebo. The treatment benefit on BMD was similar in the two genders. In addition, the combined risedronate doses (2.5 mg and 5 mg) reduced the incidence of new vertebral fractures by 70% (see Table 54.1). Ringe et al. examined the therapeutic efficacy of intravenous injections of ibandronate (2 mg every 3 months) against alfacalcidol in a 3-year, open-label, RCT in men (n 53) and women (n 62) with established GIOP (T-score 2.5) [23]. Compared to alfacalcidol, ibandronate treatment induced significantly larger increases in spine and femoral neck BMD. Although this study was not powered for a fracture outcome, ibandronate treatment reduced the risk of new vertebral fractures by 62% (see Table 54.1). There was no difference between the two treatments in the rate of new non-vertebral fractures. The efficacy of zoledronate in GIOP was examined in a 12-month double-blind, double-dummy, active-controlled RCT of 265 men and 568 women (see Table 54.1). A single intravenous infusion of zoledronate 5 mg was compared to oral risedronate 5 mg/d. All patients received calcium 1000 mg/d and vitamin D 400–1200 IU/d. A single intravenous infusion of zoledronate provided greater increases in BMD and more rapid and substantial decreases in bone turnover compared to daily risedronate [26]. Cyclic etidronate (400 mg/day for 14 days, followed by calcium 500 mg/day without vitamin D supplementation) had a positive effect on lumbar spine BMD compared to placebo, both in prevention and treatment studies of men and women receiving glucocorticoids (see Table 54.1) [24, 25, 28]. However, changes of femoral neck BMD were generally not significant and no reduction in the rate of new fractures has been reported, probably due to the weaker action of this bisphosphonate.
Other Causes of Secondary Osteoporosis Both intravenous and oral BPs have shown protective effects on BMD in transplant recipients (Tables 54.2 and 54.3). Compared to placebo, different dosing regimens of intravenous pamidronate, zoledronate and ibandronate prevented bone loss at the hip and lumbar spine, after kidney, lung, liver, heart and bone marrow transplantation in RCTs that included men and women [55]. Oral bisphosphonates (alendronate and risedronate) showed a similar efficacy profile in heart, liver, kidney and bone marrow transplant recipients [55]. In a randomized trial of alendronate (10 mg daily) and calcitriol (0.25 g twice daily) in patients after
cardiac transplantation, both regimens reduced bone loss at the spine and femoral neck compared with a reference group who received only calcium and vitamin D, with no difference between the two active treatments [37]. Similarly, Tauchmanovà et al found that treatment with risedronate 5 mg daily for 12 months increased BMD significantly at the lumbar spine and prevented further bone loss at the femoral neck in long-term survivors after allogeneic stem cell transplantation [36]. HIV-infected men and women have increased risk for osteoporosis and osteoporotic fractures [56, 57]. A number of small RCTs have recently supported a potential benefit of BPs in the treatment of human immunodeficiency virus- (HIV-) associated osteoporosis [56]. McComsey et al reported a significant increase in BMD of the spine, femoral neck and total hip compared to baseline and to placebo with weekly alendronate in HIV-infected patients with osteoporosis receiving highly active anti-retroviral therapy (HAART), with no differences between men and women [58]. Similar benefits have been demonstrated with zoledronate (4 mg or 5 mg once yearly) in two studies conducted in men with HIV receiving antiretroviral therapy [59, 60]. Thalassemia major is characterized by increased bone resorption, low BMD and subsequent high fracture risk [61]. Alendronate and zoledronate reduced bone turnover and improved BMD in small studies of men and women with thalassemia-induced osteoporosis [61]. These data underscore the similar responses of men and women with GIOP and other causes of secondary osteoporosis to BPs and justify the approval of some of them for the treatment of GIOP of both genders in several countries.
Bisphosphonates in men with primary osteoporosis There are only a few clinical trials of BPs in men with primary osteoporosis (Table 54.4). All included relatively small numbers of patients and none of them was specifically designed to assess anti-fracture efficacy. Results, however, were consistent with those of clinical trials of BPs in women with postmenopausal osteoporosis.
Alendronate In the most comprehensive RCT with alendronate, Orwoll et al randomized 241 men with primary osteoporosis to receive alendronate 10 mg or placebo daily [62]. After 2 years, alendronate-treated men demonstrated significantly higher increases in BMD of the spine and the femoral neck compared to placebo. The BMD response to alendronate was independent of age, smoking status, baseline serum free testosterone and estradiol concentrations. The mean
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671
l
Table 54.2 RCTs of bisphosphonates for prevention of bone loss following lung, liver, heart and bone marrow transplantation Sample size Time from (number of transplantation men)
Duration (years)
Treatment regimen
Aris et al. 2000 Lung [31]
1–12 months
34 (18)
2
PAM 30 mg iv q Ca 1 g Vit. D 3 months 800 IU Ca 1 g Vit. D 800 IU
BMD: significant increase at LS and TH versus control Fracture: no difference
Bianda et al 2000 [32]
Within 2 weeks
26 (24)
1.5
PAM 0.5 mg/kg CT 200 U/d for iv q 3 months 3 months Ca 1 g Ca 1 g Calcitriol 0.5 g/d
BMD: at 12 months lower decrease at LS and FN versus control, no differences at 18 months
References
Transplant type
Heart
Control regimen
Main results
Hommann et al Liver and 2002 [33] multivisceral
First 36 postoperative day
1
IBN 2 mg iv q 3 Ca 1 g Vit. D months 1000 IU Ca 1 g Vit. D 1000 IU
BMD: decrease at LS and FN in control, stable in IBD group
Ninkovic et al 2002 [34]
Liver
Time of transplant
99 (50)
1
PAM 60 mg iv once before transplantation
BMD: decrease at FN, no loss at LS, no difference versus control Fracture: no difference
Ippoliti et al 2003 [35]
Heart
After 6 months
64 (56)
1
CLO 1600 mg/d Ca 2 g oral Ca 2 g
Tauchmanovà et al 2003 [36]
Stem cell
At least 6 months 34 (16)
1
RIS 5 mg/d oral Ca 1 g Vit. D BMD: significant increase at LS and Ca 1 g Vit. D 800 IU FN versus control 800 IU
Shane et al 2004 [37]
Heart
30 days
149 (122)
1
ALN 10 mg/d oral Ca 945 mg Vit. D 1000 IU
Kananen et al 2005 [38]
Stem cell
Time of transplant
72 (36)
1
PAM 60 mg iv 6 Ca 1 g Vit. D infusions 800 IU E/T Ca 1 g Vit. D 800 IU E/T
BMD: lower decrease at LS (stable) and TH versus control Fracture: no difference
Crawford et al 2006 [39]
Liver
Within 7 days
62 (49)
1
ZOL 4 mg iv 5 infusions Ca 600 mg Vit. D 1000 IU
BMD: lower decrease at TH and FN versus control, no difference LS
Time of transplant
116 (64)
2
PAM 90 mg iv Ca 1 g monthly (1 yr) Calcitriol Ca 0.25 g/d 1 g Calcitriol 0.25 g/d
Grigg et al 2006 Stem cell [40]
No treatment
Calcitriol 0.5 g/d oral Ca 945 mg Vit. D 1000 IU
Ca 600 mg Vit. D 1000 IU
BMD: significant increase at LS versus control Fracture: CLO 0% versus control 9.3%
BMD: decrease at LS and TH in both groups Fracture: no difference
BMD: significant increase at LS and lower decrease at FN and TH versus control at 12 months (Continued)
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Osteoporosis in Men Table 54.2
(Continued)
Transplant type
Sample size Time from (number of transplantation men)
Duration (years)
Treatment regimen
Control regimen
Atamaz et al 2006 [41]
Liver
Within 1 months 98 (70)
2
ALN 70 mg weekly Ca 1 g Calcitriol 0.5 g/d
Ca BMD: significant 1 g Calcitriol increase at LS, 0.5 g/d FN and TH versus control Fracture: no difference
Monegal et al 2008 [42]
Liver
Within 7–12 days 79 (61)
1
PAM 90 mg iv 2 infusions Ca 1 g 25OHD
Ca 1 g 25OHD 16 000 IU twice monthly
References
Main results
BMD: significant increase at LS versus control, decrease at FN in both Fracture: no difference
PAM: pamidronate; IBN: ibandronate; RIS: risedronate; ALN: alendronate; ZOL: zoledronate; CT: calcitonin; CLO: clodronate; iv: intravenous; yr: year; Ca: calcium; Vit. D: vitamin D; 25OHD: 25 hydroxy vitamin D; E/T: estrogen or testosterone replacement therapy; BMD: bone mineral density; LS: lumbar spine; TH: total hip; FN: femoral neck.
percent changes of bone turnover markers and BMD were very similar to those previously reported in postmenopausal women with osteoporosis treated with alendronate (Figure 54.1) [66, 67]. Although the trial was not powered for a fracture outcome, alendronate treatment was associated with a significant reduction of the risk of new vertebral fractures assessed morphometrically (placebo 7.1%, alendronate 0.8%; OR 0.10; 95% CI: 0.00, 0.88) (see Table 54.4). In addition, alendronate-treated men lost significantly less height (placebo 2.4 mm, alendronate 0.6 mm, P 0.02). Alendronate treatment decreased the incidence of new non-vertebral fractures by 22.6% after 2 years (placebo 5.3%, alendronate 4.1%), but this decrease was not statistically significant. Ringe et al. examined the efficacy of alendronate 10 mg/ d against alfacalcidol 1 g/d in a 3-year open label clinical trial of 134 men with primary osteoporosis [63]. After 3 years, patients treated with alendronate demonstrated significantly higher increases in BMD of the spine, femoral neck and total hip compared to those receiving alfacalcidiol. Alendronate-treated patients experienced a significantly lower incidence of new vertebral fractures (alendronate 10.3%, alfacalcidol 24.2%; OR 0.36; 95% CI: 0.14, 0.94) and lost less height (alendronate 7.1 mm, alfacalcidol 13.1 mm, P 0.05) (see Table 54.4). There was no difference in the incidence of non-vertebral fractures between the two groups (alendronate 8.7%, alfacalcidol 12.1%). In a systematic review of clinical trials of alendronate in male osteoporosis, Sawka et al pooled the results of these trials incorporating prior information of anti-fracture efficacy from meta-analysis of women [70]. The odds ratios (95% CI) of incident fractures in men treated with alendronate was 0.44 (0.23, 0.83) for vertebral fractures and
0.60 (0.29, 1.44) for non-vertebral fractures. The authors concluded that alendronate decreases the risk of vertebral fractures in men at risk. There is, however, insufficient evidence of a statistically significant reduction of non-vertebral fractures, but the paucity of male trials limit the statistical power to detect such an effect.
Risedronate In a 2-year, open label study of 316 men with primary (59%) or secondary osteoporosis, Ringe et al compared the efficacy of risedronate 5 mg/d with calcium 1000 mg/d and vitamin D 800 IU/d against calcium and vitamin D alone or alfacalcidol 1 g/d and calcium 500 mg/d (in patients with prevalent fractures) on BMD and fracture risk [64]. Patients were at high fracture risk as evidenced by the low BMD (mean spine T-score 3.30) and the presence of prevalent vertebral fractures in 51% of them. Risedronate increased significantly BMD of the spine, femoral neck and total hip after 2 years and the effect was similar to that previously reported in women with postmenopausal osteoporosis treated with this BP (see Figure 54.1) [68,69]. In addition, risedronate treatment decreased significantly the risk of vertebral fractures by 61% and that of nonvertebral fractures by 45% after 2 years (see Table 54.4). Unfortunately, there was no separate analysis of the incidence of fractures in primary and secondary osteoporosis and no details of the type and adjudication of non-vertebral fractures were reported. The skeletal effects of risedronate 35 mg once weekly were evaluated in a 2-year, double-blind, placebocontrolled study of 284 men with primary osteoporosis [65]. Compared to placebo, risedronate significantly
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l
Table 54.3 RCTs using bisphosphonates for prevention of bone loss following kidney transplantation References
Time since transplantation
Sample size Treatment (number of men) Duration(years) regimen
Control regimen
Main results
Grotz et al 1998 [43]
At least 6 months 46 (29)
1
CLO 800 mg/d oral Ca 500 mg
Ca 500 mg
BMD: increase at LS with no difference versus control
Fan et al 2000 [44]
Time of transplant 26 (26)
1
PAM 0.5 mg/kg iv pre-op and at 1 month
No treatment
BMD: no loss at LS and FN versus control
Giannini et al 2001 [45]
At least 18 months 40 (27)
1
ALN 10 mg/d oral Ca 500 mg Ca 500 mg Calcitriol 0.5 g/d Calcitriol 0.5 g/d
BMD: significant increase at LS, FN and TH versus control
Grotz et al 2001 [46]
Time of transplant 80 (58)
1
IBN 1 mg iv preop 2 mg iv q 3 months
BMD: no loss at LS and FN versus control Spinal deformity (5%) less frequent in IBD (P .047)
Coco et al 2003 [47]
Time of transplant 72 (41)
1
PAM 60 mg iv Ca Calcitriol pre-op 30 mg at month 1,2,3 and 6 Ca Calcitriol
BMD: lower decrease at LS versus control, no difference at the hip Fracture: no difference
Haas et al 2003 [48]
Within 2 weeks
20 (12)
0.5
ZOL 4 mg iv immediately after and at 3 months Ca 1 g
BMD: significant increase at LS, no loss at FN and TH versus control
Jeffery et al 2003 [49]
At least 1 year
117 (71)
1
ALN 10 mg/d oral Ca Calcitriol Ca 0.25 g/d
BMD: increase at LS and FN, no difference versus control
El-Agroudy et al 2005 [50]
Within 1 week
60 (60)
1
ALN 5 mg/d oral Ca 500 mg
Ca 500 mg
BMD: significant increase at LS and FN versus control
Nayak et al 2007 [51]
At stabilization renal function
50
0.5
ALN 35 mg weekly oral Ca 1 g Vit. D
Ca 1 g Vit. D
BMD: no changes versus baseline in ALN, decrease in control
Torregrosa et al 2007 [52]
12–36 months
84 (42)
1
RIS 35 mg weekly Ca 2.5 g Vit. D oral 800 IU Ca 2.5 g Vit. D 800 IU
No treatment
Ca 1 g
BMD: significant increase at LS versus control, no difference FN and TH Fracture: no difference (Continued)
674
Osteoporosis in Men Table 54.3 (Continued)
References
Time since transplantation
Sample size Duration(years) Treatment (number of men) regimen
Control regimen
Main results
Lan et al 2008 [53]
At least 1 year
46 (19)
0.5
ALN 70 mg weekly Ca 800 mg oral Calcitriol 0.25 g Ca 800 mg Calcitriol 0.25 g
BMD: significant increase at FN versus control
Trabulus et al 2008 [54]
1–179 months
50 (32)
1
ALN 10 mg/d oral Ca 1 g - Alpha-D Ca 1 g 0.5 g/d – Alpha-D
BMD: significant higher increase at LS and FN in Alpha-D ALN versus Alpha-D and ALN alone
PAM: pamidronate; IBN: ibandronate; RIS: risedronate; ALN: alendronate; ZOL: zoledronate; CT: calcitonin; CLO: clodronate; iv, intravenous; Ca: calcium; Vit. D: vitamin D; Alpha-D: alfacalcidiol; BMD: bone mineral density; LS: lumbar spine; TH: total hip; FN: femoral neck; pre-op: preoperatively.
Table 54.4 Bisphosphonates in men with primary osteoporosis Orwoll et al 2000 [62]
Ringe et al 2004 [63]
Bisphosphonate
ALN oral 10 mg daily ALN oral 10 mg daily
Control
Placebo daily
Number of patients Supplements
241 134 Calcium 500 mg Calcium 500 mg Vitamin D 400–450 IU
Study duration Mean age (years SD) VF assessment method Patients lost to follow up (%) Prevalent VFs (%)
2 years 63 13
3 years 53 11
Quantitative and semiquantitative 15% 53% 0.8% 7.1% 0.017 4.1% 5.3% NS
New VFs
New NVFs
Active Control P-value Active Control P-value
Ringe et al 2009 [64]a
Boonen et al 2008 [65]
RIS oral 5 mg daily
RIS oral 35 mg weekly
Calcium and Vitamin D daily or Alfa-D 1 g daily 316 Calcium 1000 mg Vitamin D 800 IU or Calcium 500 mg 2 years 57 10
Placebo daily
Quantitative and semiquantitative 12%
Semiquantitative
Semiquantitative
5%
9%
54% 10.3% 24.2% 0.04 8.7% 12.1% NS
51% 9.2% 23.6% 0.003 11.8% 22.3% 0.032
35% 1.1% 0.0% NS 4.7% 6.5% NS
Alfa-D 1 g daily
284 Calcium 1000 mg Vitamin D 400–500 IU 2 years 61 11
a Mixed population: 186 men with primary osteoporosis and 130 with secondary osteoporosis. ALN: alendronate; RIS: risedronate; Alpha-D: alfacalcidiol; SD: standard deviation; VF: vertebral fracture; NVF: non-vertebral fracture; NS: not significant.
increased BMD of the spine and hip. The decreases of bone turnover markers and increases of BMD were similar to those seen in women with postmenopausal osteoporosis (see Figure 54.1). Very few clinical fractures (vertebral and non-vertebral) were reported during the trial and there were no differences between the two treatment groups (see Table 54.4).
These findings indicate that alendronate and risedronate, given daily in adequate doses, increase BMD and decrease the risk of new vertebral fractures in men with primary osteoporosis. Moreover, BMD changes and incidence of vertebral fractures are very similar in men and women with osteoporosis, as illustrated in Figures 54.1 and 54.2, for studies selected according to the prevalence of fractures
C h a p t e r 5 4 Treatment of Male Osteoporosis with Bisphosphonates l
12%
Control Bisphosphonate
10%
LS-BMD % Changes after 2 years
675
8% 6% 4% 2% 0% –2%
Men Orwoll 2000
Men Ringe 2004
Women Liberman 1995
Alendronate (10 mg daily)
Women Bone 2000
Men Ringe 2009
Women Harris 1999
Women Reginster 2000
Risedronate (5 mg daily)
Figure 54.1 Percent changes of lumbar spine bone mineral density (LS-BMD) in specifically designed clinical trials of men and women with osteoporosis after 2 years of treatment. Men: Orwoll et al 2000 [62]; Ringe et al 2004 [63]; Ringe et al 2009 [64]. Women: Liberman et al 1995 [66]; Bone et al 2000 [67]; Harris et al 1999 [68]; Reginster et al 2000 [69]. Open bars, daily oral placebo, in [63] alfacalcidol; closed bars, daily oral bisphosphonate.
at baseline, dose of BP used and duration of treatment. Evidence for a significant effect on non-vertebral fractures is still insufficient. This is most likely due to the small numbers of patients included in the clinical trials as the point estimates of fracture reduction were always in favor of BP treatment and similar to those obtained in clinical trials in women, however, with large confidence intervals. Efficacy of intermittent BP administration has not yet been reported in men with primary osteoporosis.
Bisphosphonates in men with secondary osteoporosis Except for the clinical trials of BPs in men and women with secondary osteoporosis already discussed, there are few studies of secondary osteoporosis with specific relevance to men.
Androgen Deprivation Therapy Androgen deprivation therapy (ADT), such as orchidectomy or gonadotropin-releasing hormone (GnRH) agonist therapy (with or without anti-androgen), is increasingly used in the treatment of men with locally advanced prostate cancer. Because of the significant and rapid decrease of BMD and increase in fracture risk associated with ADT,
interventions to prevent skeletal morbidity in these patients are needed [72, 73]. Two intravenous (pamidronate, zoledronate) and one oral N-BP (alendronate) were shown to prevent ADT-induced bone loss in men with non-metastatic prostate cancer [73]. It is important to note that the BP regimens used in the treatment of these patients should be different from those used for the decrease of skeletal morbidity in patients with prostate cancer metastatic to the skeleton. Initial studies assessed dosing regimens lying between those used in metastatic disease and in osteoporosis. For example, Smith et al evaluated the effect of zoledronate (4 mg every 3 months) on BMD in men receiving initial ADT for non-metastatic prostate cancer [74]. After 1 year, zoledronate-treated men showed a significant increase of BMD at the sites examined compared to baseline and to the placebo group. The study was not powered to assess a fracture outcome. These findings were confirmed by two subsequent studies using zoledronate with the same intermittent regimen [73]. More recently, Michaelson et al demonstrated that a less frequent dosing of zoledronate (4 mg once yearly) is also able to prevent bone loss in men without osteoporosis receiving GnRH agonists [75]. Although most evidence supporting the use of BPs for ADT-related bone loss are derived from studies with intravenous N-BPs, a recent 2-year, double-blind, partial crossover RCT demonstrated a benefit of alendronate 70 mg once-weekly [76]. Greenspan et al reported that, among men with non-metastatic prostate cancer receiving ADT,
676
Osteoporosis in Men 30%
Control Bisphosphonate
Patients with new VFs (%)
25% 20% 15% 10% 5% 0% Men Ringe 2004
Women Black 1996
Alendronate (3 years)
Men Ringe 2009
Women Harris 1999
Women Reginster 2000
Risedronate (2 years)
Figure 54.2 Incidence of vertebral fractures (VFs) in specifically designed clinical trials of men and women with osteoporosis treated with daily oral placebo (open bars) or bisphosphonate (closed bars). Men: Ringe et al 2004 [63]; Ringe et al 2009 [64]. Women: Black et al 1996 [71]; Harris et al 1999 [68]; Reginster et al 2000 [69]. Studies are paired according to the prevalence of fractures at baseline, to the dose of BP used and to the duration of the trials (3 years for alendronate studies, 2 years for risedronate studies). Note: Ringe et al [63] compared alendronate with alfacalcidol
alendronate decreases bone turnover and improves BMD. A second year of alendronate therapy provided additional skeletal benefit, while discontinuation resulted in increased bone turnover and bone loss. These results are encouraging and, although further studies are needed to establish anti-fracture efficacy, the evidence indicates that these patients can be effectively treated with BP dosing regimens used in the treatment of primary osteoporosis.
men with Parkinson’s disease over two years of treatment [79]. Finally, Zehnder et al showed that alendronate 10 mg/d prevents bone loss in paraplegic men with complete motor lesions after spinal cord injury [80]. It should be also noted that oral N-BPs have been shown to maintain or improve BMD in men with a variety of other pathologic conditions associated with osteoporosis, such as hyperthyroidism, hyperparathyroidism, non-steroid-treated rheumatoid arthritis, androgen-repleted hypogonadism, bone marrow mastocytosis and inflammatory bowel disease.
Immobilization and Neurologic Disorders Neurologic diseases (Parkinson’s disease and amyotrophic lateral sclerosis) and immobilization states (e.g. paralysis caused by trauma or stroke) can cause substantial bone loss and increase in the risk of fractures [77]. BPs have not been systematically evaluated in the therapy of these conditions. However, a number of recent studies in men support the potential benefit of BPs in the management of bone loss associated with immobilization [78–80]. In an 18-month, double-blind, placebo-controlled RCT of Japanese men after a stroke, risedronate 2.5 mg/d significantly decreased urinary deoxypyridinoline and increased BMD compared to placebo [78]. These changes were associated with an impressive decrease in the risk of hip fractures by 80%. In a subsequent study of identical size and design, the same authors reported that risedronate 2.5 mg/d increased BMD and decreased the risk of hip fracture in
Special issues related to treatment of male osteoporosis with bps A number of issues requiring further attention have been identified during treatment of osteoporotic women with BPs [1]. These include a potential excessive decrease of bone remodeling with treatment and the resolution of the effect following treatment discontinuation and hence treatment length. Controlled studies in men have not been extended beyond 3 years and none of them addressed these specific issues. This is also true for potential adverse effects of BP treatment that have been reported in women, such as osteonecrosis of the jaw, atypical fractures of the femur and atrial fibrillation. Although there is no reason to expect
C h a p t e r 5 4 Treatment of Male Osteoporosis with Bisphosphonates l
differences between men and women, evidence for that is currently lacking. On the other hand, the rate of specific adverse effects related to the use of N-BPs, such as gastrointestinal toxicity associated with the oral, particularly daily use and symptoms related to an acute phase reaction, mainly after first exposure to intravenous N-BPs, appears to be similar in men and women.
Conclusions Current evidence supports the use of N-BPs in men with primary and secondary osteoporosis. The majority of data have been obtained with the use of alendronate and risedronate which decreased bone turnover, increased BMD and decreased the risk of vertebral fractures in men with primary and glucocorticoid-induced osteoporosis. Although an effect of these BPs on the rate of non-vertebral fractures remains to be established, all studies showed percent reductions similar to those achieved in osteoporotic women, but no significance due to the small sample sizes and the wide confidence intervals of the estimations. Of the BPs given intermittently, most of the available data have been obtained in studies with yearly infusions of zoledronate. The efficacy of zoledronate in men with hip fractures and its superiority to risedronate in GIOP strongly suggest that this BP will also be efficacious in the treatment of male osteoporosis. Issues in the management of male osteoporosis with BPs that need to be addressed include the optimal selection of patients for treatment, the safety and efficacy of long-term therapy and the use of BPs in combination with other antiosteoporotic drugs.
References 1. S.E. Papapoulos, Bisphosphonates for postmenopausal osteoporosis, in: C.J. Rosen (Ed.), Primer on the Metabolic Bone Diseases and Disorders of Mineral metabolism, seventh edn., American Society for Bone and Mineral Research, Washington, DC, 2008, pp. 237–241. 2. S.E. Papapoulos, Bisphosphonates: how do they work? Best Pract. Res. Clin. Endocrinol. Metab. 22 (2008) 831–847. 3. R.G.G. Russell, N.B. Watts, F.H. Ebetino, M.J. Rogers, Mechanisms of action of bisphosphonates: similarities and differences and their potential influence on clinical efficacy, Osteoporos. Int. 19 (2008) 733–759. 4. B.J. Gertz, S.D. Holland, W.F. Kline, et al., Studies of the oral bioavailability of alendronate, Clin. Pharmacol. Ther. 58 (1995) 288–298. 5. S.C. Cremers, S.E. Papapoulos, H. Gelderblom, et al., Skeletal retention of bisphosphonate (pamidronate) and its relation to the rate of bone resorption in patients with breast cancer and bone metastases, J. Bone Miner. Res. 20 (2005) 1543–1547. 6. S.A. Khan, J.A. Kanis, S. Vasikaran, et al., Elimination and biochemical responses to intravenous alendronate in postmenopausal osteoporosis, J. Bone Miner. Res. 12 (1997) 1700–1707.
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7. S.E. Papapoulos, S.C. Cremers, Prolonged bisphosphonate release after treatment in children, N. Engl. J. Med. 356 (2007) 1075–1076. 8. H.G. Bone, D. Hosking, J.P. Devogelaer, et al., Alendronate Phase III Osteoporosis Treatment Study Group. Ten years’ experience with alendronate for osteoporosis in postmenopausal women, N. Engl. J. Med. 350 (2004) 1189–1199. 9. S. Papapoulos, P. Makras, Selection of antiresorptive or anabolic treatments for postmenopausal osteoporosis, Nat. Clin. Pract. Endocrinol. Metab. 4 (2008) 514–523. 10. A.J. Roelofs, K. Thompson, S. Gordon, M.J. Rogers, Molecular mechanisms of action of bisphosphonates: current status, Clin. Cancer Res. 12 (2006) 6222s–6230s. 11. R. Valkema, F.J. Vismans, S.E. Papapoulos, E.K. Pauwels, O.L. Bijvoet, Maintained improvement in calcium balance and bone mineral content in patients with osteoporosis treated with the bisphosphonate APD, Bone Miner. 5 (1989) 183–192. 12. Y.V. Ho, A.G. Frauman, W. Thomson, E. Seeman, Effects of alendronate on bone density in men with primary and secondary osteoporosis, Osteoporos. Int. 11 (2000) 98–101. 13. C. Brumsen, S.E. Papapoulos, P. Lips, et al., Daily oral pamidronate in women and men with osteoporosis: a 3-year randomized placebo-controlled clinical trial with a 2-year open extension, J. Bone Miner. Res. 17 (2002) 1057–1064. 14. J. Iwamoto, T. Takeda, Y. Sato, M. Uzawa, Comparison of the effect of alendronate on lumbar bone mineral density and bone turnover in men and postmenopausal women with osteo porosis, Clin. Rheumatol. 26 (2007) 161–167. 15. S. Gonnelli, C. Cepollaro, C. Pondrelli, et al., Bone turnover and the response to alendronate treatment in postmenopausal osteoporosis, Calcif. Tissue Int. 65 (1999) 359–364. 16. K.W. Lyles, C.S. Colón-Emeric, J.S. Magaziner, et al., HORIZON Recurrent Fracture Trial. Zoledronic acid and clinical fractures and mortality after hip fracture, N. Engl. J. Med. 357 (2007) 1799–1809. 17. S. Boonen, J. Magaziner, K. Lyles, et al., Effect of onceyearly i.v. zoledronic acid in men after hip fracture: results from the HORIZON-Recurrent Fracture Trial, Osteoporos. Int. 20 (Suppl 1) (2009) S84. 18. J.A. Kanis, M. Stevenson, E.V. McCloskey, S. Davis, M. Lloyd-Jones, Glucocorticoid-induced osteoporosis: a systematic review and cost-utility analysis, Health Technol. Assess. 11 (2007) 1–231. 19. K.G. Saag, R. Emkey, T.J. Schnitzer, et al., Alendronate for the prevention and treatment of glucocorticoid-induced osteo porosis. Glucocorticoid-Induced Osteoporosis Intervention Study Group, N. Engl. J. Med. 339 (1998) 292–299. 20. J.D. Adachi, K.G. Saag, P.D. Delmas, et al., Two-year effects of alendronate on bone mineral density and vertebral fracture in patients receiving glucocorticoids: a randomized, doubleblind, placebo-controlled extension trial, Arthritis Rheum. 44 (2001) 202–211. 21. S. Cohen, R.M. Levy, M. Keller, et al., Risedronate therapy prevents corticosteroid-induced bone loss: a twelve-month, multicenter, randomized, double-blind, placebo-controlled, parallel-group study, Arthritis Rheum. 42 (1999) 2309–2318. 22. D.M. Reid, R.A. Hughes, R.F. Laan, et al., Efficacy and safety of daily risedronate in the treatment of corticosteroidinduced osteoporosis in men and women: a randomized trial.
678
23.
24.
25.
26.
27.
28.
29.
30.
31.
32.
33.
34.
35.
36.
37.
Osteoporosis in Men
European Corticosteroid-Induced Osteoporosis Treatment Study, J. Bone Miner. Res. 15 (2000) 1006–1013. J.D. Ringe, A. Dorst, H. Faber, K. Ibach, F. Sorenson, Inter mittent intravenous ibandronate injections reduce vertebral fracture risk in corticosteroid-induced osteoporosis: results from a long-term comparative study, Osteoporos. Int. 14 (2003) 801–807. J.D. Adachi, W.G. Bensen, J. Brown, et al., Intermittent etidronate therapy to prevent corticosteroid-induced osteoporosis, N. Engl. J. Med. 337 (1997) 382–387. I.A. Campbell, J.G. Douglas, R.M. Francis, R.J. Prescott, D.M. Reid, Research Committee of the British Thoracic Society. Five year study of etidronate and/or calcium as prevention and treatment for osteoporosis and fractures in patients with asthma receiving long term oral and/or inhaled glucocorticoids., Thorax 59 (2004) 761–768. D.M. Reid, J.P. Devogelaer, K. Saag, et al., HORIZON investigators. Zoledronic acid and risedronate in the prevention and treatment of glucocorticoid-induced osteoporosis (HORIZON): a multicentre, double-blind, double-dummy, randomised controlled trial, Lancet 373 (2009) 1253–1263. R.N. De Nijs, J.W. Jacobs, W.F. Lems, et al., STOP Investi gators. Alendronate or alfacalcidol in glucocorticoid-induced osteoporosis, N. Engl. J. Med. 355 (2006) 675–684. J.P. Devogelaer, S. Goemaere, S. Boonen, et al., Evidencebased guidelines for the prevention and treatment of glucocorticoid-induced osteoporosis: a consensus document of the Belgian Bone Club, Osteoporos. Int. 17 (2006) 8–19. D.M. Reid, S. Adami, J.P. Devogelaer, A.A. Chines, Risedronate increases bone density and reduces vertebral fracture risk within one year in men on corticosteroid therapy, Calcif. Tissue Int. 69 (2001) 242–247. S. Wallach, S. Cohen, D.M. Reid, et al., Effects of risedronate treatment on bone density and vertebral fracture in patients on corticosteroid therapy, Calcif. Tissue Int. 67 (2000) 277–285. R.M. Aris, G.E. Lester, J.B. Renner, et al., Efficacy of pamidronate for osteoporosis in patients with cystic fibrosis following lung transplantation, Am. J. Respir. Crit. Care Med. 162 (2000) 941–946. T. Bianda, A. Linka, G. Junga, et al., Prevention of osteoporosis in heart transplant recipients: a comparison of calcitriol with calcitonin and pamidronate, Calcif. Tissue Int. 67 (2000) 116–121. M. Hommann, K. Abendroth, G. Lehmann, et al., Effect of transplantation on bone: osteoporosis after liver and multivisceral transplantation, Transplant. Proc. 34 (2002) 2296–2298. M. Ninkovic, S. Love, B.D. Tom, P.W. Bearcroft, G.J. Alexander, J.E. Compston, Lack of effect of intravenous pamidronate on fracture incidence and bone mineral density after orthotopic liver transplantation, J. Hepatol. 37 (2002) 93–100. G. Ippoliti, C. Pellegrini, C. Campana, et al., Clodronate treatment of established bone loss in cardiac recipients: a randomized study, Transplantation 75 (2003) 330–334. L. Tauchmanovà, C. Selleri, M. Esposito, et al., Beneficial treatment with risedronate in long-term survivors after allogeneic stem cell transplantation for hematological malignancies, Osteoporos. Int. 14 (2003) 1013–1019. E. Shane, V. Addesso, P.B. Namerow, et al., Alendronate versus calcitriol for the prevention of bone loss after cardiac transplantation, N. Engl. J. Med. 350 (2004) 767–776.
38. K. Kananen, L. Volin, K. Laitinen, H. Alfthan, T. Ruutu, M.J. Välimäki, Prevention of bone loss after allogeneic stem cell transplantation by calcium, vitamin D, and sex hormone replacement with or without pamidronate, J. Clin. Endocrinol. Metab. 90 (2005) 3877–3885. 39. B.A. Crawford, C. Kam, J. Pavlovic, et al., Zoledronic acid prevents bone loss after liver transplantation: a randomized, double-blind, placebo-controlled trial, Ann. Intern. Med. 144 (2006) 239–248. 40. A.P. Grigg, P. Shuttleworth, J. Reynolds, et al., Pamidronate reduces bone loss after allogeneic stem cell transplantation, J. Clin. Endocrinol. Metab. 91 (2006) 3835–3843. 41. F. Atamaz, S. Hepguler, M. Akyildiz, Z. Karasu, M. Kilic, Effects of alendronate on bone mineral density and bone metabolic markers in patients with liver transplantation, Osteoporos. Int. 17 (2006) 942–949. 42. A. Monegal, N. Guañabens, M.J. Suárez, et al., Pamidronate in the prevention of bone loss after liver transplantation: a randomized controlled trial, Transpl. Int. 22 (2009) 198–206. 43. W.H. Grotz, L.C. Rump, A. Niessen, et al., Treatment of osteopenia and osteoporosis after kidney transplantation, Transplantation 66 (1998) 1004–1008. 44. S.L. Fan, M.K. Almond, E. Ball, K. Evans, J. Cunningham, Pamidronate therapy as prevention of bone loss following renal transplantation, Kidney Int. 57 (2000) 684–690. 45. S. Giannini, A. D’Angelo, G. Carraro, et al., Alendronate prevents further bone loss in renal transplant recipients, J. Bone Miner. Res. 16 (2001) 2111–2117. 46. W. Grotz, C. Nagel, D. Poeschel, et al., Effect of ibandronate on bone loss and renal function after kidney transplantation, J. Am. Soc. Nephrol. 12 (2001) 1530–1537. 47. M. Coco, D. Glicklich, M.C. Faugere, et al., Prevention of bone loss in renal transplant recipients: a prospective, randomized trial of intravenous pamidronate, J. Am. Soc. Nephrol. 14 (2003) 2669–2676. 48. M. Haas, Z. Leko-Mohr, P. Roschger, et al., Zoledronic acid to prevent bone loss in the first 6 months after renal transplantation, Kidney Int. 63 (2003) 1130–1136. 49. J.R. Jeffery, W.D. Leslie, M.E. Karpinski, P.W. Nickerson, D.N. Rush, Prevalence and treatment of decreased bone density in renal transplant recipients: a randomized prospective trial of calcitriol versus alendronate, Transplantation 76 (2003) 1498–1502. 50. A.E. El-Agroudy, A.A. El-Husseini, M. El-Sayed, T. Mohsen, M.A. Ghoneim, A prospective randomized study for prevention of postrenal transplantation bone loss, Kidney Int. 67 (2005) 2039–2045. 51. B. Nayak, S. Guleria, M. Varma, et al., Effect of bisphosphonates on bone mineral density after renal transplantation as assessed by bone mineral densitometry, Transplant. Proc. 39 (2007) 750–752. 52. J.V. Torregrosa, D. Fuster, S. Pedroso, et al., Weekly risedronate in kidney transplant patients with osteopenia, Transpl. Int. 20 (2007) 708–711. 53. G. Lan, L. Peng, X. Xie, F. Peng, Y. Wang, S. Yu, Alendronate is effective to treat bone loss in renal transplantation recipients, Transplant. Proc. 40 (2008) 3496–3498. 54. S. Trabulus, M.R. Altiparmak, S. Apaydin, K. Serdengecti, M. Sariyar, Treatment of renal transplant recipients with low bone mineral density: a randomized prospective trial of
C h a p t e r 5 4 Treatment of Male Osteoporosis with Bisphosphonates l
55. 56. 57.
58.
59.
60.
61.
62.
63.
64.
65.
66.
67.
alendronate, alfacalcidol, and alendronate combined with alfacalcidol, Transplant. Proc. 40 (2008) 160–166. E. Stein, P. Ebeling, E. Shane, Post-transplantation osteoporosis, Endocrinol. Metab. Clin. N. Am. 36 (2007) 937–963. V. Amorosa, P. Tebas, Bone disease and HIV infection, Clin. Infect. Dis. 42 (2006) 108–114. V.A. Triant, T.T. Brown, H. Lee, S.K. Grinspoon, Fracture prevalence among human immunodeficiency virus (HIV)infected versus non-HIV-infected patients in a large US healthcare system, J. Clin. Endocrinol. Metab. 93 (2008) 3499–3504. G.A. McComsey, M.A. Kendall, P. Tebas, et al., Alendronate with calcium and vitamin D supplementation is safe and effective for the treatment of decreased bone mineral density in HIV, AIDS 21 (2007) 2473–2482. M.J. Bolland, A.B. Grey, A.M. Horne, et al., Annual zoledronate increases bone density in highly active antiretroviral therapy-treated human immunodeficiency virus-infected men: a randomized controlled trial, J. Clin. Endocrinol. Metab. 92 (2007) 1283–1288. J. Huang, L. Meixner, S. Fernandez, J.A. McCutchan, A double-blinded, randomized controlled trial of zoledronate therapy for HIV-associated osteopenia and osteoporosis, AIDS 23 (2009) 51–57. A. Gaudio, N. Morabito, A. Xourafa, et al., Bisphosphonates in the treatment of thalassemia-associated osteoporosis, J. Endocrinol. Invest. 31 (2008) 181–184. E. Orwoll, M. Ettinger, S. Weiss, et al., Alendronate for the treatment of osteoporosis in men, N. Engl. J. Med. 343 (2000) 604–610. J.D. Ringe, A. Dorst, H. Faber, K. Ibach, Alendronate treatment of established primary osteoporosis in men: 3-year results of a prospective, comparative, two-arm study, Rheumatol. Int. 24 (2004) 110–113. J.D. Ringe, P. Farahmand, H. Faber, A. Dorst, Sustained efficacy of risedronate in men with primary and secondary osteoporosis: results of a 2-year study, Rheumatol. Int. 29 (2009) 311–315. S. Boonen, E. Orwoll, D. Wenderoth, K. Stoner, R. Eusebio, P. Delmas, Once-weekly risedronate in men with osteoporosis: results of a 2-year, placebo-controlled, double-blind, multicenter study, J. Bone Miner. Res. 24 (2009) 719–725. U.A. Liberman, S.R. Weiss, J. Bröll, et al., Effect of oral alendronate on bone mineral density and the incidence of fractures in postmenopausal osteoporosis. The Alendronate Phase III Osteoporosis Treatment Study Group, N. Engl. J. Med. 333 (1995) 1437–1443. H.G. Bone, S.L. Greenspan, C. McKeever, et al., Alendronate and estrogen effects in postmenopausal women with low bone mineral density. Alendronate/Estrogen Study Group, J. Clin. Endocrinol. Metab. 85 (2000) 720–726.
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68. S.T. Harris, N.B. Watts, H.K. Genant, et al., Effects of risedronate treatment on vertebral and nonvertebral fractures in women with postmenopausal osteoporosis: a randomized controlled trial. Vertebral Efficacy with Risedronate Therapy (VERT) Study Group, J. Am. Med. Assoc. 282 (1999) 1344–1352. 69. J. Reginster, H.W. Minne, O.H. Sorensen, et al., Randomized trial of the effects of risedronate on vertebral fractures in women with established postmenopausal osteoporosis. Vertebral Efficacy with Risedronate Therapy (VERT) Study Group, Osteoporos. Int. 11 (2000) 83–91. 70. A.M. Sawka, A. Papaioannou, J.D. Adachi, A. Gafni, D.A. Hanley, L. Thabane, Does alendronate reduce the risk of fracture in men? A meta-analysis incorporating prior knowledge of anti-fracture efficacy in women, BMC Musculoskelet. Disord. 6 (2005) 39–46. 71. D.M. Black, S.R. Cummings, D.B. Karpf, et al., Randomised trial of effect of alendronate on risk of fracture in women with existing vertebral fractures. Fracture Intervention Trial Research Group, Lancet 348 (1996) 1535–1541. 72. B. Abrahamsen, M.F. Nielsen, P. Eskildsen, J.T. Andersen, S. Walter, K. Brixen, Fracture risk in Danish men with prostate cancer: a nationwide register study, BJU Int. 100 (2007) 749–754. 73. CS. Higano, Androgen-deprivation-therapy-induced fractures in men with nonmetastatic prostate cancer: what do we really know? Nat. Clin. Pract. Urol. 5 (2008) 24–34. 74. M.R. Smith, J. Eastham, D.M. Gleason, D. Shasha, S. Tchekmedyian, N. Zinner, Randomized controlled trial of zoledronic acid to prevent bone loss in men receiving androgen deprivation therapy for nonmetastatic prostate cancer, J. Urol. 169 (2003) 2008–2012. 75. M.D. Michaelson, D.S. Kaufman, et al., Randomized controlled trial of annual zoledronic acid to prevent gonadotropinreleasing hormone agonist-induced bone loss in men with prostate cancer, J. Clin. Oncol. 25 (2007) 1038–1042. 76. S.L. Greenspan, J.B. Nelson, D.L. Trump, et al., Skeletal health after continuation, withdrawal, or delay of alendronate in men with prostate cancer undergoing androgen-deprivation therapy, J. Clin. Oncol. 26 (2008) 4426–4434. 77. S. Epstein, A.M. Inzerillo, J. Caminis, M. Zaidi, Disorders associated with acute rapid and severe bone loss, J. Bone Miner. Res. 18 (2003) 2083–2094. 78. Y. Sato, J. Iwamoto, T. Kanoko, K. Satoh, Risedronate sodium therapy for prevention of hip fracture in men 65 years or older after stroke, Arch. Intern. Med. 165 (2005) 1743–1748. 79. Y. Sato, Y. Honda, J. Iwamoto, Risedronate, and ergocalciferol prevent hip fracture in elderly men with Parkinson disease, Neurology 68 (2007) 911–915. 80. Y. Zehnder, S. Risi, D. Michel, et al., Prevention of bone loss in paraplegics over 2 years with alendronate, J. Bone Miner. Res. 19 (2004) 1067–1074.
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55
Treatment of Male Osteoporosis with Parathyroid Hormone Monica Girotra1, Felicia Cosman2,3 and John P. Bilezikian3 1
Memorial Sloan-Kettering Cancer Center; Joan and Sanford I. Weill Medical College of Cornell University, New York, USA Regional Bone Center Helen Hayes Hospital, West Haverstraw, New York, USA 3 Department of Medicine, Division of Endocrinology, Metabolic Bone Diseases Unit, College of Physicians and Surgeons, Columbia University, New York, USA 2
Introduction
dosage, to animals and human subjects. In both men and women, teriparatide initially causes a rapid increase in bone formation markers followed thereafter by an increase in bone resorption markers [9]. These bone marker data are supported by findings from tetracycline-labeled iliac crest bone biopsies in postmenopausal women which show that PTH increases bone formation rates on cancellous, endocortical and periosteal surfaces [10]. The precise cellular mechanisms underlying this response to intermittent PTH are likely multifactorial. PTH directly stimulates several cellular processes in the osteoblast [11, 12]. Recent data also suggest that PTH may influence osteocyte production of sclerostin, an important regulator of the anabolic Wnt pathway [13]. By lowering sclerostin, the Wnt pathway is relieved of this constraint and thus stimulated. The genes in target cells affected by exposure to intermittent PTH include insulin-like growth factor I (IGF-I), amphiregulin, 1-alpha hydroxylase, Runx2, TGF-beta, receptor activator of NFkappaB ligand (RANKL) and macrophage colony stimulating factor (MCSF) among others [12, 14–17]. The net effect is recruitment of osteoblast progenitor cells as well as direct stimulation of mature osteoblasts. These early actions are primarily growth-based or a ‘modeling’ effect. Ultimately, PTH influences the entire bone remodeling cycle with stimulation of osteoclast cells. When the osteoclast is stimulated, the classic bone remodeling system is involved. The early actions of PTH on bone modeling (primarily bone formation) and the subsequent actions of PTH on bone remodeling (bone turnover) has led to the concept of the ‘anabolic window’. The anabolic window describes the time period between the actions of PTH to stimulate bone modeling and bone remodeling and is believed to be the time when PTH is maximally anabolic [18, 19] (Figure 55.1).
The availability of parathyroid hormone (PTH) as an anabolic skeletal agent has broadened our treatment options for osteoporosis. By directly stimulating bone formation, PTH improves bone mass and bone microarchitecture, including trabecular connectivity and cortical thickness. It therefore has the potential to reconstruct the skeleton, an endpoint not shared by anti-resorptive therapies. There are two forms of PTH that are currently available: human recombinant PTH(134), known as teriparatide, and the full length molecule PTH(1-84). Only teriparatide is available in the USA. Approximately 40–60% of men with osteoporosis do not have an identifiable cause and are considered to have idiopathic osteoporosis. Histomorphometric studies suggest that these men often have low bone turnover which would suggest a defect in bone formation [1–3]. Therefore, PTH may be particularly suitable for these men by virtue of its actions to stimulate activities associated with osteoblast function [4, 5].
Anabolic actions of parathyroid hormone In primary hyperparathyroidism (PHPT), continuous secretion of excess parathyroid hormone causes bone loss, particularly at cortical sites. In typical mild forms of PHPT, preferential bone loss at the distal third radius illustrates the catabolic action of PTH at cortical sites [6, 7]. However, even in PHPT, there is evidence for relative protection of cancellous bone [8]. The anabolic properties of PTH are more clearly seen when it is given intermittently, in low Osteoporosis in Men
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PTH as an Anabolic Agent for Bone: A Kinetic Model Bone formation markers
Bone formation markers
Index of Bone Tumover
Peak Bone resorption markers “Anabolic Window”
Months
Figure 55.1 The anabolic window. Based on the difference in kinetics between bone formation and bone resorption markers during PTH treatment, an ‘anabolic window’ is formed during which PTH acts maximally anabolic.
Both reduced bone mineral density and deterioration of bone quality contribute to reduced bone strength in osteoporosis. Among the indices of bone quality, microarchitecture is paramount. When microarchitectural elements, such as trabecular number, spacing and connectivity, deteriorate, bone strength declines and fracture risk increases [20]. The positive effects of PTH(1-84) and teriparatide on bone microarchitecture are most apparent in the cancellous skeleton [20–23]. Histomorphometric analysis of bone biopsies show significant increases in cancellous bone volume, in trabecular number and in trabecular connectivity after postmenopausal women with osteoporosis are treated with PTH(1-84) or teriparatide [21–23]. Although it is likely that similar observations would be made in men treated in this way, such biopsy data are not available. Major increases in bone mineral density (BMD) of the lumbar spine are typically seen when men and women are treated with teriparatide, most likely due to the fact that the anabolic properties of PTH are most evident in cancellous bone. Typically, the distal third radius, a site of primarily cortical bone, does not show improvements in BMD. While declines in BMD at the distal third radius are often a point of concern, in the context of PTH therapy, other factors mitigate against this concern. The reduction in bone density occurs on the inner endosteal surface, where mechanical effects tend to be minimized. In addition, other beneficial effects of teriparatide on cortical bone may overcome any reduction in BMD that may occur [24]. One possibility is the disposition of PTH to stimulate periosteal bone apposition, an effect that could well counteract any reduction in bone density on the endosteal surface. If this were to occur,
BMD would still decline initially, because new periosteal bone is not as well mineralized as the resorbed, mature endosteal bone. Over time, cortical thickness increases with continued periosteal apposition [24]. The effect of PTH to increase periosteal bone has another effect, namely to increase cross-sectional area, a geometrical change that should, by itself, strengthen bone [25]. Microarchitectural features are improved at cortical as well as cancellous sites. The net effect of PTH at both cancellous and cortical sites is an improvement in overall bone strength [26]. In studies of postmenopausal women, finite element analysis of quantitative computed tomography (QCT) scans, a surrogate measure of bone strength, showed PTH(1-84) and teriparatide are associated with an increase in vertebral bone strength, a site of predominantly cancellous bone, and also with femoral bone strength, a site of both cortical and cancellous bone [27, 28]. This increase in bone strength at both cancellous and cortical sites following PTH therapy is further supported by the reduction in fracture risk seen at both vertebral and non-vertebral sites in postmenopausal women following treatment with teriparatide [29]. These actions of PTH on different skeletal sites and compartments are believed to occur in men as well as in postmenopausal women, but more studies are needed to confirm this impression.
Indications for teriparatide use Teriparatide is approved by the US Food and Drug Administration (FDA) for men and postmenopausal women with osteoporosis who are at high risk for fracture. The definition of ‘high risk for fracture’ is somewhat vague, but with factors that are known to confer high risk, one can define this term operationally. Useful treatment guidelines have been offered to help select patients for teriparatide therapy [30]. Individuals who have already sustained an osteoporotic fracture are among the highest risk group because their likelihood of sustaining another fracture is very high [31]. The T-score alone can also confer high risk, especially if the T-score is very low (i.e. 3.0). Age is another key factor because, for any T-score, the older the individual, the higher the fracture risk. Other possible indications for teriparatide [or PTH(1-84)] include bisphosphonate intolerance, fractures during anti-resorptive treatment or significantly reduced bone density while receiving anti-resorptive therapy. Treatment with teriparatide in the USA is approved for up to 24 months at 20 g/day while, in Europe and other countries, teriparatide and PTH(1-84) are approved for 18 months. While more widespread use of teriparatide could be argued on the basis of its actions to improve bone quality directly, limitations are due to the need for daily injections, cost and, to a lesser extent, rat osteosarcoma findings (see below).
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Teriparatide in male osteoporosis Teriparatide is the form of PTH that has been investigated in men with osteoporosis. In the first randomized, controlled trial of teriparatide in men, Kurland et al studied 23 men with idiopathic osteoporosis [19]. In a double-blind, placebo-controlled design, subjects were given 400 IU/day of teriparatide (equivalent to 25 g/day) or placebo for 18 months. There was a highly significant 13.5% increase in lumbar spine bone density. Femoral neck BMD significantly improved, but more slowly and to a lesser extent in comparison to the lumbar spine (by 2.9% at 18 months). There was no change in cortical bone density as measured at the distal radius. Bone turnover markers increased rapidly in teriparatide-treated men, with bone formation markers rising and peaking earlier than bone resorption markers. The actions and sequence of change in these bone turnover markers are identical to observations in women, illustrating that the concept of the anabolic window is valid for men as well. In a larger, randomized placebo-controlled clinical trial, Orwoll et al studied 437 men with idiopathic osteoporosis or osteoporosis due to hypogonadism [32]. Subjects were randomized to one of three treatment groups: subcutaneous injections of placebo, 20 or 40 g of teriparatide. In this short 11-month study, BMD significantly increased in the teriparatide groups by 5.9% (20 g) and 9% (40 g) at the lumbar spine and by 1.5% (20 g) and 2.9% (40 g) at the femoral neck. There was no change in BMD at the cortical distal third radius in the teriparatide groups. Improvements in BMD were independent of gonadal status, age, baseline BMD, body mass index, smoking or alcohol intake. Total body bone mineral content increased in the treated groups, supporting the concept that teriparatide truly increases bone mass and does not merely redistribute cortical bone to cancellous sites. The magnitude and time course of the rise in bone density over this 11-month study tracked virtually identically with the longer course of teriparatide therapy in postmenopausal women [29]. Fracture incidence in men could not be assessed due to the short duration of this clinical trial [32]. However, fractures were evaluated in a follow-up observational period of 30 months [33]. From the original cohort, 279 men had lateral thoracic and lumbar spine x-rays 18 months after PTH was discontinued. In the teriparatide treatment groups (20 and 40 g), vertebral fracture risk was reduced by 51% (P 0.07). A significant reduction of 83% in the combined treatment groups as compared to placebo was seen when only moderate or severe vertebral fractures were considered (6.8 versus 1.1%; P 0.02). While a certain percentage of subjects in all groups in this observational trial received anti-resorptive therapy after teriparatide was discontinued, the placebo group used anti-resorptive treatment more frequently than those who were given either dose of teriparatide (36% versus 25%), an argument against the idea
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that anti-resorptive therapy was an important determinant in the long-term observation of teriparatide-associated fracture risk reduction in men. In the pivotal clinical trial of teriparatide for postmenopausal women, fracture data were reported during the 21month randomized, clinical trial [29]. The risk for one or more new vertebral fractures was markedly reduced by 65 and 69% at the 20 and 40 g teriparatide doses, respectively. Among women who had new vertebral fractures, mean loss of height was significantly less in the 20 and 40 g groups (0.2 and 0.3 cm) as compared to placebo (1.1 cm; P 0.002). This smaller height reduction among those who fractured on teriparatide suggests that the vertebral fractures may have not been as complete or as severe while on the drug as compared to those that occurred on placebo. New non-vertebral fractures decreased by 35% and 40% at the respective 20 and 40 g doses. When fragility fractures (considered to be only half of all fractures that occurred in this trial) were analyzed separately from total fracture incidence, the risk reduction in new non-vertebral fractures was greater at 53% and 54%, respectively. In an observational cohort from this trial, fracture reduction was sustained for up to 30 months after teriparatide was discontinued [33]. However, many women in the original and treatment groups received bisphosphonate therapy during this followup period as was also seen with the trial by Orwoll et al in men [32, 33]. Although one should not directly apply these data to men, the results are consistent with the more limited studies available for teriparatide in the treatment of male osteoporosis [32]. Data have recently become available on the use of teriparatide in glucocorticoid-induced osteoporosis (GIO). GIO, one of the most common secondary causes of osteoporosis, is a distinct clinical entity. It is characterized primarily by a reduction in bone formation, although bone resorption is transiently increased. In GIO, a secondary increase in PTH is no longer considered to be of major pathophysiologic significance [34]. In fact, the histomorphometric features of GIO are quite different from those that are observed with PTH administration or with primary hyperparathyroidism, a disorder of PTH excess. Thus, there is a rationale for considering PTH as a treatment for GIO. Saag et al compared, in a headto-head trial, teriparatide and alendronate in 428 women and men with osteoporosis (aged 22 to 89 years, approximately 20% men) in an 18-month randomized, double-blind, controlled trial [36]. All subjects had received glucocorticoids for at least 3 months (prednisone equivalent, 5 mg daily or more) and had lumbar spine or total hip T-score of either 2.0, or 1.0 plus at least one fragility fracture during glucocorticoid treatment. Equal numbers of subjects (n 214) received either daily teriparatide (20 g) or alendronate (10 mg). In both groups combined, 115 patients (26.9%) had radiologic evidence of prior vertebral fractures and 182 patients (42.5%) had radiologic evidence of prior non-vertebral fractures. Although in these and other respects,
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the two groups were well matched, the subjects, on the whole, had lower BMD and more prevalent fractures than in other clinical trials of GIO [36–41]. At 18 months, BMD at the lumbar spine increased to a significantly greater extent in the teriparatide group than in the alendronate group (7.2% versus 3.4%). A significant difference in lumbar spine BMD between the groups was reached by as early as 6 months. For the subgroup of men, the difference between teriparatide (7.3%) versus alendronate (3.7%) was also significant [42]. At 12 months, BMD at the total hip had increased significantly more in the teriparatide group. For men, at the hip, there was also a difference between teriparatide (4.9%) versus alendronate (3.2%) but statistical significance was not achieved. The most important finding of the study was fewer new vertebral fractures in the teriparatide group than in the alendronate group (0.6% versus 6.1%; P 0.01). When the study was extended for an additional 18 months, the difference in vertebral fractures between teriparatide and alendronate continued to be significant (1.7% versus 7.7%; P 0.01) [43]. There was no difference in the incidence of non-vertebral fractures between the two groups (5.6% teriparatide versus 3.7% alendronate, P 0.36). These data argue rather convincingly for a role for teriparatide in the treatment of GIO in men and women.
Combination or sequential therapy with PTH and an antiresorptive agent Finkelstein et al studied the effects of teriparatide, alendronate, or both in men with osteoporosis [42]. The rationale for this study was apparent in that this kind of combination therapy might take advantage of the two different mechanisms of action of PTH and bisphosphonates. However, both this study and a similar study in postmenopausal women have provided evidence to the contrary. The cohort consisting of 83 men with a lumbar spine or femoral neck T score of 2.0 was randomly assigned to receive alendronate (10 mg daily; 28 men), teriparatide (40 g subcutaneously daily; 27 men) or both (28 men). Note the dose of teriparatide in this study was twice the approved dose. At 30 months, lumbar spine BMD increased significantly more in men treated with teriparatide alone than in the other groups (18.1% teriparatide, 14.8% teriparatide alendron ate, 7.9% alendronate). Femoral neck BMD also increased significantly more in the teriparatide group than in the alendronate group or the combination-therapy group (9.7% teriparatide, 6.2% teriparatide alendronate, 3.2% alendronate). Quantitative computed tomography (QCT) was also used to measure trabecular bone mineral density at the lumbar spine. Trabecular BMD at the spine increased by 48% in the alendronate group as compared to 17% in the combination group and 3% in the alendronate group (P 0.005
for all comparisons). Bone marker data suggest that this kind of combination therapy is associated with an impairment of teriparatide’s ability to stimulate bone formation. Black et al also studied combination therapy in postmenopausal women with PTH(1-84) plus alendronate versus each agent alone [45]. With dual energy x-ray absorptiometry (DXA) outcomes, combination therapy did not have additive effects on spine BMD though it did increase total hip and wrist BMD more than PTH(1-84) monotherapy. However, by QCT measurement of trabecular bone in the spine, combination therapy produced a substantially smaller BMD increase than PTH(1-84) monotherapy. Bone turnover levels suggested a dominant effect of the anti-resorptive agent rather than PTH in this study. The observations of Finkelstein et al in men and those of Black et al in postmenopausal women led to the idea that combination therapy with teriparatide and a less ‘powerful’ anti-resorptive might be associated with benefits. To this end, Deal et al utilized raloxifene in combination with teriparatide in a short 6-month clinical trial of postmenopausal women [46]. Raloxifene reduced bone resorption markers stimulated by teriparatide alone but did not affect the extent to which bone formation markers were stimulated by teriparatide alone. These observations would be expected to increase the ‘anabolic window’ for teriparatide. Accordingly, at the total hip, BMD was significantly greater in those treated with teriparatide and raloxifene, as compared to teriparatide alone, but there was no difference between the two groups at the lumbar spine or femoral neck. This short, proof-of-concept study suggests that combination therapy with teriparatide does have potential if the right combination is selected. This model can be further developed as PTH effects on bone formation could depend partly on its ability to increase bone resorption, explaining why combination therapy with alendronate does not appear to lead to better results than PTH alone. Even though the actions of PTH appear to be directed initially at bone formation, they may rely upon a certain level of activity of the bone remodeling cycle in which there is a pool of committed osteoblasts. If bone resorption is impaired, for example in the presence of a powerful anti-resorptive, PTH may be less effective since it cannot recruit a pool of accessible osteoblasts. This is consistent with the concept that some of the increase in bone mass requires the release of IGF-I and other growth factors from the skeleton by osteoclast action. Perhaps the reason why a less potent anti-resorptive like raloxifene or estrogen does not inhibit skeletal responsiveness to PTH, when used together, is because bone resorption is not reduced to the same degree as with alendronate, thus still providing a pool of available osteoblasts. Finally, it should be noted that these trials have focused on indices, such as BMD and bone turnover markers, and not on fracture data. Whether combining PTH with an anti-resorptive drug is more efficacious in preventing fragility fractures remains to be seen.
C h a p t e r 5 5 Treatment of Male Osteoporosis with Parathyroid Hormone l
Anti-resorptive use prior to PTH therapy Many patients who are being considered for teriparatide or PTH(1-84) therapy have received bisphosphonates or other anti-resorptives in the past. In Europe, the percentage of patients who have first been treated with a bisphosphonate approaches 100%. While examining the studies described above using PTH in combination with an anti-resorptive, one might be concerned that previous anti-resorptive treatment could blunt the subsequent anabolic response to PTH. With regard to studies specifically addressing this question in men, data are lacking. However, in postmenopausal women, there are recent observations that suggest that it may be the extent to which bone turnover is reduced by an anti-resorptive that determines the subsequent bone marker and densitometric response to PTH. For example, some studies in women have shown that previous alendronate use can be associated with a blunting of the subsequent response to PTH, while previous treatment with estrogen, raloxifene or even risedronate does not seem to have this effect [47–50]. It should be noted that not all studies have shown a suppressive effect of alendronate on the subsequent actions of teriparatide. These observations may be related to the degree of suppression of bone turnover by the particular anti-resorptive agent. This concept was directly tested in a trial in which prior risedronate use was compared with prior alendronate use followed by teriparatide in postmenopausal women [50]. As expected, patients who received alendronate had significantly lower bone turnover markers than did those who received risedronate before teriparatide use. When the bisphosphosphonate was discontinued, followed almost immediately by teriparatide for 12 months, the group that had previously been treated with risedronate showed a greater increase in bone formation and bone resorption markers and a much greater increase in BMD as determined by QCT than those who had previously been treated with alendronate. The data are consistent with studies by Kurland et al in men, showing that the baseline bone turnover level in subjects not previously treated with any therapy for osteoporosis is directly related to the rapidity of the teriparatide effect [9, 51]. As noted above, this may seem counterintuitive, since PTH stimulates bone formation and might be expected to have a greater effect in low bone turnover states. This again may reflect the need for active osteoblasts, primed osteoblasts or progenitor osteoblast cells that are more receptive to PTH effects in a state of higher bone turnover. Similarly, it may relate to the observations of Lindsay et al in which modeling-based effects of teriparatide are dependent upon a certain level of bone resorption [52]. Effects of teriparatide in patients previously treated with alendronate or raloxifene might be different in patients who continue the anti-resorptive agent while taking teriparatide versus those who stop the anti-resorptive medication when
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starting teriparatide. In a randomized trial, while bone turnover markers increased more dramatically in the latter group (anti-resorptive stopped), BMD increased more prominently in the former group (continued anti-resorptive) in both the spine and hip [53].
Consequences of discontinuing PTH therapy PTH treatment is approved in the USA and in other countries for a limited period of time, typically 18–24 months. Concerns exist regarding the consequences of discontinuing therapy after this relatively short period of time. These relate to the concept that new bone matrix is not fully mineralized following PTH treatment. This new bone matrix could be at risk for resorption if consolidation therapy with an anti-resorptive is not initiated [54]. This concept has been supported in men by observations from the followup study of teriparatide treatment in idiopathic or hypogonadal osteoporosis [33]. During post-therapy follow up of these men, lumbar spine and hip BMD tended to decline in those who received prior teriparatide treatment with no subsequent osteoporosis drug therapy. However, BMD remained significantly higher than baseline in teriparatidetreated men except at 42 months when total hip BMD for the 20 g group did not significantly differ from baseline. In those who received bisphosphonate therapy following teriparatide, spine and hip BMD increased above both baseline and end of treatment period values. These data are similar to prospective randomized controlled data in postmenopausal women [55] and indicate that anti-resorptives help maintain bone density after teriparatide is discontinued. In studies of postmenopausal women, bone turnover markers fell both in those treated with placebo or alendronate in the post-PTH period [56]. The decrease in bone turnover after PTH is stopped without further treatment is most likely based upon a different mechanism than the decrease in bone turnover when alendronate follows PTH. With alendronate treatment, bone turnover markers likely decrease after PTH because bone resorption falls more quickly than bone formation. This difference in temporal sequence could result in a post-PTH ‘window’ during which bone formation is favored. One could consider this as an extended anabolic window. Alternately, when PTH is stopped without further anti-resorptive therapy, bone formation may fall more rapidly than bone resorption as PTH had been primarily stimulating bone formation. Under these conditions, rapid bone resorption can continue as bone formation decreases and BMD will decline in this setting. A depiction of this concept is shown in Figure 55.2. Additional studies are needed in both men and women to address specifically fracture outcomes after using an anti-resorptive following PTH [56]. However, based on current data, it is recommended to follow
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Future considerations
Kinetics After PTH Withdrawal Without Antiresorptive
BMD Anabolic Window Extended
Formation
Resorption Time
Resorption
% change
% change
With Antiresorptive
BMD Formation Time
Figure 55.2 Changes in bone density and markers of bone turnover after PTH. After therapy with PTH is discontinued, bone markers decline whether or not anti-resorptive therapy is instituted. The graph illustrates the concept that when PTH is stopped without anti-resorptive therapy, bone formation markers fall more quickly, resulting in a decline in bone density. When PTH is followed by anti-resorptive therapy, bone resorption markers fall more rapidly leading to an increase in bone density.
PTH therapy with an anti-resorptive in order to maintain the increases in bone mass acquired during PTH treatment.
Safety of PTH Overall, PTH is well tolerated in both men and women [57, 58]. Clinical trials with teriparatide show no major risk of hypercalcemia at the FDA-approved dosage of 20 g daily [57–59]. Postmarketing experience with teriparatide suggests that the incidence of verified hypercalcemia is even lower than initially reported [60]. If oral calcium intake is lowered by 500 mg/day when teriparatide is started, hypercalcemia is even less likely to occur. Teriparatide is contraindicated in children and in those with hypercalcemia, Paget’s disease of bone, skeletal metastases or skeletal malignancies, or a history of radiation therapy to the skeleton or to soft tissues in which a skeletal port is exposed [61, 62]. In addition, caution should be used in patients with a history of malignancy or renal insufficiency [62, 63]. Osteosarcoma has been described in rats given very high doses of teriparatide or PTH(1-84) for prolonged periods of time [64–66]. One woman was reported to develop an unclear soft tissue malignancy which was later reported pathologically as an osteosarcoma [67]. Without other reports showing osteosarcoma among other teriparatide users, the incidence would appear to be rare. With over 1 million patients world-wide who have been treated with teriparatide, the number of cases of osteosarcoma is even lower than one would expect at random since the annual incidence of osteosarcoma is approximately 1 in 250 000 in adults [68].
In the future, PTH may be tailored for easier and more targeted delivery. For example, a transdermal form is currently under investigation, with 6-month data showing similar spine and superior hip BMD effects compared to teriparatide [69]. PTHrP, parathyroid hormone-related protein, is also being investigated. In a small sample of postmenopausal women, subcutaneous PTHrP resulted in a 4.7% increase in lumbar spine BMD following only 3 months of treatment [70]. Also, a novel PTH-collagen binding domain fusion protein was shown to have prolonged actions as an anabolic agent in mice when administered twice weekly [71]. Cosman et al have described using a cyclical 3-month course of teriparatide against a backdrop of continued alendronate use [72]. Cyclic administration of teriparatide was associated with similar densitometric gains as seen with regular, uninterrupted teriparatide use, despite the fact that only 60% of the total teriparatide dose was utilized in the cyclic group. Of additional interest was the finding that, with sequential 3-month cycles of teriparatide, bone formation markers that fell rapidly when teriparatide was stopped, increased to a similar degree with each cycle of teriparatide. Markers of bone resorption showed smaller increases with successive cycles. This observation supports another way in which the anabolic window could be expanded with teriparatide. The cyclic approach is currently being tested in treatment naïve women. Cosman et al have also shown that, during long-term alendronate therapy, a rechallenge with PTH after being off PTH for 12 months increases bone formation, bone resorption and BMD to a similar extent as during the first course of PTH treatment [73]. These data suggest that a future therapeutic model could be a second course of PTH given 12 months after a first course of therapy in those who remain at high fracture risk. Finally, oral calcilytic molecules that antagonize the parathyroid cell calcium receptor, thereby stimulating the endogenous release of PTH are being studied [74]. This could represent a novel mchanism to deliver intermittently endogenous PTH.
Conclusions Anabolic skeletal agents are changing our approach to osteoporosis treatment. Teriparatide, the first available form of PTH with the most data in men, has emerged as an effective anabolic treatment. This agent increases bone turnover and bone density. In addition, PTH significantly improves skeletal microarchitecture and other bone qualities that contribute to bone strength. These positive effects on several different aspects of bone can accomplish a central goal of therapy, namely to improve the underlying abnormalities that cause skeletal fragility. Although the data for men
C h a p t e r 5 5 Treatment of Male Osteoporosis with Parathyroid Hormone l
are not as complete as those available in women, they are nevertheless similar and suggest a similar profile of efficacy and safety.
References 1. C.J. Rosen, J.P. Bilezikian, Anabolic therapy for osteoporosis, J. Clin. Endocrinol. Metab. 86 (2001) 957–964. 2. E.S. Kurland, C.J. Rosen, F. Cosman, et al., Insulin-like growth factor-1 in men with idiopathic osteoporosis, J. Clin. Endocrinol. Metab. 82 (1997) 2799. 3. E. Hills, C.R. Dunstan, S.Y. Wong, R.A. Evans, Bone histology in young adult osteoporosis, J. Clin. Pathol. 42 (1989) 391. 4. P.R. Ebeling, Clinical practice. Osteoporosis in men, N. Engl. J. Med. 358 (14) (2008) 1474–1482. 5. C.J. Rosen, J.P. Bilezikian, Anabolic therapy for osteoporosis, J. Clin. Endocrinol. Metab. 86 (2001) 957–964. 6. F. Albright, J.C. Aub, W. Bauer, Hyperparathyroidism: a common and polymorphic condition as illustrated by seventeen proven cases from one clinic, J. Am. Med. Assoc. 102 (1934) 1276–1287. 7. F. Albright, E.C. Reifenstein, The parathyroid glands and metabolic bone disease, Williams & Wilkins, Baltimore, 1948. 8. D.W. Dempster, M. Parisien, S.J. Silverberg, et al., On the mechanism of cancellous bone preservation in postmenopausal women with mild primary hyperparathyroidism, J. Clin. Endocrinol. Metab. 84 (5) (1999) 1562–1566. 9. E.S. Kurland, F. Cosman, D.J. McMahon, C.J. Rosen, R. Lindsay, J.P. Bilezikian, Parathyroid hormone as a therapy for idiopathic osteoporosis in men: effects on bone mineral density and bone markers, J. Clin. Endocrinol. Metab. 85 (9) (2000) 3069–3076. 10. R. Lindsay, H. Zhou, F. Cosman, et al., Effects of a onemonth treatment with PTH(1-34) on bone formation on cancellous, endocortical, and periosteal surfaces of the human ilium, J. Bone Miner. Res. 22 (2007) 495. 11. S.M. Krane, Identifying genes that regulate bone remodeling as potential therapeutic targets, J. Exp. Med. 201 (2005) 841. 12. C.J. Rosen, The cellular and clinical parameters of anabolic therapy for osteoporosis, Crit. Rev. Eukaryot. Gene. Expr. 13 (2003) 25. 13. T. Bellido, A.A. Ali, I. Gubrij, et al., Chronic elevation of parathyroid hormone in mice reduces expression of sclerostin by osteocytes: a novel mechanism for hormonal control of osteoblastogenesis, Endocrinology 146 (2005) 4577–4583. 14. A.W. Partridge, S. Liu, S. Kim, et al., Transmembrane domain helix packing stabilizes integrin alphaIIbeta3 in the low affinity state, J. Biol. Chem. 280 (2005) 7294–7300. 15. E.C. Buxton, W. Yao, N.E. Lane, Changes in serum receptor activator of nuclear factor-kappaB ligand, osteoprotegerin, and interleukin-6 levels in patients with glucocorticoidinduced osteoporosis treated with human parathyroid hormone (1-34), J. Clin. Endocrinol. Metab. 89 (2004) 3332. 16. H. Sowa, H. Kaji, M.F. Iu, et al., Parathyroid hormone-Smad3 axis exerts anti-apoptotic action and augments anabolic action of transforming growth factor beta in osteoblasts, J. Biol. Chem. 278 (2003) 522–540.
687
17. V. Krishnan, T.L. Moore, Y.L. Ma, et al., Parathyroid hormone bone anabolic action requires cbfa1/runx2-dependent signaling, Mol. Endocrinol. 17 (2003) 423. 18. M. Rubin, J. Bilezikian, The anabolic effects of parathyroid hormone therapy, Clin. Geriatr. Med. 9 (2002) 415–432. 19. E.S. Kurland, F. Cosman, D.J. McMahon, C.J. Rosen, R. Lindsay, J.P. Bilezikian, Parathyroid hormone as a therapy for idiopathic osteoporosis in men: effects on bone mineral density and bone markers, J. Clin. Endocrinol. Metab. 85 (2000) 3069–3076. 20. D.W. Dempster, F. Cosman, E.S. Kurland, et al., Effects of daily treatment with parathyroid hormone on bone microarchitecture and turnover in patients with osteoporosis: a paired biopsy study, J. Bone Miner. Res. 16 (10) (2001) 1846–1853. 21. Y. Jiang, J.J. Zhao, B.H. Mitlak, O. Wang, H.K. Genant, E.F. Eriksen, Recombinant human parathyroid hormone (134) [teriparatide] improves both cortical and cancellous bone structure, J. Bone Miner. Res. 18 (11) (2003) 1932–1941. 22. R. Recker, S. Bare, M. Miller, M. Newman, J. Fox, Treatment of osteoporotic women with parathyroid hormone 184 for 18 months improves cancellous bone formation and structure; a bone biopsy study, Bone Min. Res. 19 (Suppl. 1) (2004) S97. 23. R.R. Recker, S.P. Bare, S.Y. Smith, et al., Cancellous and cortical bone architecture and turnover at the iliac crest of postmenopausal osteoporotic women treated with parathyroid hormone 1-84, Bone 44 (1) (2009) 113–119. 24. D.B. Burr, T. Hirano, C.H. Turner, C. Hotchkiss, R. Brommage, J.M. Hock, Intermittently administered human parathyroid hormone(134) treatment increases intracortical bone turnover and porosity without reducing bone strength in the humerus of ovariectomized cynomolgus monkeys, J. Bone Miner. Res. 16 (1) (2001) 157–165. 25. A.M. Parfitt, Parathyroid hormone and periosteal bone expansion, J. Bone Miner. Res. 17 (10) (2002) 1741–1743. 26. J.R. Zanchetta, C.E. Bogado, J.L. Ferretti, et al., Effects of teriparatide [recombinant human parathyroid hormone (134)] on cortical bone in postmenopausal women with osteoporosis, J. Bone Miner. Res. 18 (3) (2003) 539–543. 27. T.M. Keaveny, D.W. Donley, P.F. Hoffmann, B.H. Mitlak, E.V. Glass, J.A. San Martin, Effects of teriparatide and alendronate on vertebral strength as assessed by finite element modeling of QCT scans in women with osteoporosis, J. Bone Miner. Res. 22 (1) (2007) 149–157. 28. T.M. Keaveny, P.F. Hoffmann, M. Singh, et al., Femoral bone strength and its relation to cortical and trabecular changes after treatment with PTH, alendronate, and their combination as assessed by finite element analysis of quantitative CT scans, J. Bone Miner. Res. 23 (12) (2008) 1974–1982. 29. R.M. Neer, C.D. Arnaud, J.R. Zanchetta, et al., Effect of parathyroid hormone (134) on fractures and bone mineral density in postmenopausal women with osteoporosis, N. Engl. J. Med. 344 (19) (2001) 1434–1441. 30. A.B. Hodsman, D.C. Bauer, D. Dempster, et al., Parathyroid hormone and teriparatide for the treatment of osteoporosis: a review of the evidence and suggested guidelines for its use, Endocr. Rev. 26 (2005) 688–703. 31. R. Lindsay, S.L. Silverman, C. Cooper, et al., Risk of new vertebral fracture in the year following a fracture, J. Am. Med. Assoc. 285 (2001) 3203. 32. E.S. Orwoll, W.H. Scheele, S. Paul, et al., The effect of teriparatide [human parathyroid hormone (134)] therapy on bone
688
33.
34.
35.
36.
37.
38.
39.
40.
41.
42.
4 3. 44.
45.
46.
47.
48.
Osteoporosis in Men
density in men with osteoporosis, J. Bone Miner. Res. 18 (1) (2003) 917. J.M. Kaufman, E. Orwoll, S. Goemaere, et al., Teriparatide effects on vertebral fractures and bone mineral density in men with osteoporosis: treatment and discontinuation of therapy, Osteoporos. Int. 16 (5) (2005) 510–516. R. Prince, A. Sipos, A. Hossain, et al., Sustained nonvertebral fragility fracture risk reduction after discontinuation of teriparatide treatment, J. Bone Miner. Res. 20 (9) (2005) 1507–1513. M.R. Rubin, J.P. Bilezikian, Clinical review 151: the role of parathyroid hormone in the pathogenesis of glucocorticoid-induced osteoporosis: a re-examination of the evidence, J. Clin. Endocrinol. Metab. 87 (9) (2002) 4033–4041. K.G. Saag, E. Shane, S. Boonen, et al., Teriparatide or alendronate in glucocorticoid-induced osteoporosis, N. Engl. J. Med. 357 (20) (2007) 2028–2039. R.N. de Nijs, J.W. Jacobs, W.F. Lems, et al., Alendronate or alfacalcidol in glucocorticoid-induced osteoporosis, N. Engl. J. Med. 355 (2006) 675–684. D.M. Reid, S. Adami, J.P. Devogelaer, A.A. Chines, Risedronate increases bone density and reduces vertebral fracture risk within one year in men on corticosteroid therapy, Calcif. Tissue Int. 69 (2001) 242–247. K.G. Saag, R. Emkey, T.J. Schnitzer, et al., Alendronate for the prevention and treatment of glucocorticoid-induced osteo porosis, N. Engl. J. Med. 339 (1998) 292–299. S. Cohen, R.M. Levy, M. Keller, et al., Risedronate therapy prevents corticosteroid-induced bone loss: a twelve-month, multicenter, randomized, double-blind, placebo-controlled, parallel-group study, Arthritis Rheum. 42 (1999) 2309–2318. D.M. Reid, R.A. Hughes, R.F. Laan, et al., Efficacy and safety of daily risedronate in the treatment of corticosteroid-induced osteoporosis in men and women: a randomized trial, J. Bone Miner. Res. 15 (2000) 1006–1013. J.S. Finkelstein, A. Hayes, J.L. Hunzelman, J.J. Wyland, H. Lee, R.M. Neer, The effects of parathyroid hormone, alendronate, or both in men with osteoporosis, N. Engl. J. Med. 349 (13) (2003) 1216–1226. K. Saag, et al., European Calcified Tissue Res (2008) (abs). K.G. Saag, J.R. Zanchetta, J.P. Devogelaer, et al., Teriparatide versus alendronate for treatment of glucocorticoid-induced osteoporosis: 36-month results. 30th Annual Meeting of the American Society of Bone and Mineral Research, (2008) Abstract 1171. D.M. Black, S.L. Greenspan, K.E. Ensrud, et al., The effects of parathyroid hormone and alendronate alone or in combination in postmenopausal osteoporosis, N. Engl. J. Med. 349 (13) (2003) 1207–1215. C. Deal, M. Omizo, E.N. Schwartz, et al., Combination teriparatide and raloxifene therapy for postmenopausal osteoporosis: results from a 6-month double-blind placebo-controlled trial, J. Bone Miner. Res. 20 (11) (2005) 1905–1911. B. Ettinger, J. San Martin, G. Crans, I. Pavo, Differential effects of teriparatide on BMD after treatment with raloxifene or alendronate, J. Bone Miner. Res. 19 (5) (2004) 745–751. E. Roe, S. Sanchez, G. del Puerto, et al., Parathyroid hormone 134 (hPTH 134) and estrogen produce dramatic bone density increases in postmenopausal osteoporosisresults from
49.
50.
51.
52.
53.
54.
55.
56.
57.
58.
59.
60.
61.
62.
a placebo-controlled randomized trial, J. Bone Miner. Res. 14 (Suppl. 1) (1999) S137. F. Cosman, J. Nieves, L. Woelfert, et al., Parathyroid hormone added to established hormone therapy: effects on vertebral fracture and maintenance of bone mass after parathyroid hormone withdrawal, J. Bone Miner. Res. 16 (5) (2001) 925–931. P.D. Miller, P.D. Delmas, R. Lindsay, et al., Open-label Study to Determine How Prior Therapy with Alendronate or Risedronate in Postmenopausal Women with Osteoporosis Influences the Clinical Effectiveness of Teriparatide Investigators. Early responsiveness of women with osteoporosis to teriparatide after therapy with alendronate or risedronate, J. Clin. Endocrinol. Metab. 93 (10) (2008) 3785–3793. P. Delmas, A. Licata, G. Crans, et al., Fracture risk reduction during treatment with teriparatide is independent of pretreatment bone turnover, J. Bone Miner. Res. 19 (Suppl. 1) (2004) 1170. R. Lindsay, F. Cosman, H. Zhou, et al., A novel tetracycline labeling schedule for longitudinal evaluation of the shortterm effects of anabolic therapy with a single iliac crest bone biopsy: early actions of teriparatide, J. Bone Miner. Res. 21 (3) (2006) 366–373. F. Cosman, R.A. Wermers, C. Recknor, et al., Efficacy of adding teriparatide versus switching to teriparatide in postmenopausal women with osteoporosis previously treated with raloxifene or alendronate, J. Bone Miner. Res. 22 (Suppl.) (2007) S89. B.M. Misof, P. Roschger, F. Cosman, et al., Effects of intermittent parathyroid hormone administration on bone mineralization density in iliac crest biopsies from patients with osteoporosis: a paired study before and after treatment, J. Clin. Endocrinol. Metab. 88 (3) (2003) 1150–1156. D.M. Black, J.P. Bilezikian, K.E. Ensrud, et al., One year of alendronate after one year of parathyroid hormone (184) for osteoporosis, N. Engl. J. Med. 353 (6) (2005) 555–565. R. Prince, A. Sipos, A. Hossain, et al., Sustained nonvertebral fragility fracture risk reduction after discontinuation of teriparatide treatment, J. Bone Miner. Res. 20 (9) (2005) 1507–1513. E.S. Orwoll, W.H. Scheele, S. Paul, et al., The effect of teriparatide [human parathyroid hormone (1-34)] therapy on bone density in men with osteoporosis, J. Bone Miner. Res. 18 (1) (2003) 9–17. A.H. Tashjian Jr., R.F. Gagel, Teriparatide [human PTH(134)]: 2.5 years of experience on the use and safety of the drug for the treatment of osteoporosis, J. Bone Miner. Res. 21 (2006) 3543–3565. R.M. Neer, C.D. Arnaud, J.R. Zanchetta, et al., Effect of para thyroid hormone (134) on fractures and bone mineral density in postmenopausal women with osteoporosis, N. Engl. J. Med. 344 (19) (2001) 1434–1441. K.D. Harper, J.H. Krege, R. Marcus, B.H. Mitlak, Comments on initial experience with teriparatide in the United States, Curr. Med. Res. Opin. 22 (2006) 1927. E. Canalis, A. Giustina, J.P. Bilezikian, Mechanisms of anabolic therapies for osteoporosis, N. Engl. J. Med. 357 (9) (2007) 905–916. Eli Lilly, Forteo [package insert]. Indianapolis, IN: December 2002.
C h a p t e r 5 5 Treatment of Male Osteoporosis with Parathyroid Hormone l
63. A. Farooki, M. Fornier, M. Girotra, Anabolic therapies for osteoporosis, N. Engl. J. Med. 357 (23) (2007) 2410–2411. 64. J.L. Vahle, G.G. Long, G. Sandusky, M. Westmore, Y.L. Ma, M. Sato, Bone neoplasms in F344 rats given teriparatide [rhPTH(134)] are dependent on duration of treatment and dose, Toxicol. Pathol. 32 (4) (2004) 426–438. 65. J. Jolette, C.E. Wilker, S.Y. Smith, et al., Defining a noncarcinogenic dose of recombinant human parathyroid hormone 1-84 in a 2-year study in Fischer 344 rats, Toxicol. Pathol. 34 (7) (2006) 929–940. 66. C. Jimenez, Y. Yang, H.W. Kim, et al., Primary hyperparathyroidism and osteosarcoma: examination of a large cohort identifies three cases of fibroblastic osteosarcoma, J. Bone Miner. Res. 20 (9) (2005) 1562–1568. 67. K.D. Harper, J.H. Krege, R. Marcus, B.H. Mitlak, Osteosarcoma and teriparatide? J. Bone Miner. Res. 22 (2007) 334. 68. Surveillance Research Program National Cancer Institute SEER*Stat Software, version 6.1.4. Available at www.seer. cancer.gov/seerstat. 69. F. Cosman, N.E. Lane, M. Bolognese, et al., Rapid pulse transdermal delivery of PTH(1-34) (ZP-PTH) is effective in increasing bone mineral density of lumbar spine and hip in postmenopausal women with osteoporosis, Osteoporos. Int. 20 (Suppl. 2) (2009) S228.
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70. M.J. Horwitz, M.B. Tedesco, C. Gundberg, A. Garcia-Ocana, A.F. Stewart, Short-term, high-dose parathyroid hormonerelated protein as a skeletal anabolic agent for the treatment of postmenopausal osteoporosis, J. Clin. Endocrinol. Metab. 88 (2) (2003) 569–575. 71. T. Ponnapakkam, O. Matsushita, J. Sakon, R.C. Gensure, Weekly administration of a novel parathyroid hormonecollagen binding domain fusion protein increases bone mineral density by more than 15 percent in normal mice, J. Bone Miner. Res. 22 (Suppl. 1) (2007) S64. 72. F. Cosman, J. Nieves, M. Zion, et al., Daily and cyclic parathyroid hormone in women receiving alendronate, N. Engl. J. Med. 353 (2005) 5665–5675. 73. F. Cosman, J.W. Nieves, M. Zion, N. Barbuto, R. Lindsay, Retreatment with teriparatide one year after the first teriparatide course in patients on continued long-term alendronate, J. Bone Miner. Res. 24 (6) (2009) 1110–1115. 74. D. Ethgen, J. Phillips, C. Baidoo, et al., Dose-dependent increases in endogenous parathyroid hormone concentrations after administration of a calcium-sensing receptor antagonist to normal volunteers: potential for an oral bone forming agent, J. Bone Miner. Res. 22 (Suppl. 1) (2008) S38.
Chapter
56
Testosterone Therapy for Osteoporosis in Men Kishore M. Lakshman1, Shalender Bhasin1 and Andre B. Araujo2 1
Section of Endocrinology, Diabetes and Nutrition, Division of Endocrinology & Metabolism, Boston University School of Medicine, Boston Medical Center, Boston, Massachusetts, USA 2 New England Research Institutes, Inc., Watertown, Massachusetts, USA
Introduction
population, will cause the annual number of OFs to double or triple by 2040 [10, 11]. Approximately 20% of hip fracture patients die within one year [12, 13]. Excess risk of death associated with hip fracture persists even with adjustment for pre-fracture health status [14, 15]. Risk of death following a fracture is considerably higher among men [14,16]. OF is associated with disability [17, 18] and reduced quality of life [19, 20]. The epidemiology of osteoporosis in men is described in great detail in Chapters 28–32.
Androgens are naturally occurring or synthetic compounds that stimulate development and maintenance of masculine characteristics. Androgens originate in the testes (testosterone, dihydrotestosterone (DHT)), adrenal gland (androstenediol, androstenedione, androsterone, dehydroepiandrosterone, dihydrotestosterone), prostate (dihydrotestosterone) and hair follicles (dihydrotestosterone). To date, most evidence points to the primary importance of testosterone as the androgen that is most strongly associated with musculoskeletal health. For instance, despite indirect evidence from epidemiologic studies to support the possibility that blockage of the conversion of testosterone to DHT by 5-alpha reductase inhibitors may be associated with increased fracture risk [1], clinical trial data do not support this [2–4]. Therefore, this chapter focuses primarily on the role testosterone therapy might have in preserving musculoskeletal health.
Markers of fracture risk Fractures occur when the loads applied to bone exceed their load-bearing capacity [21]. Applied loads are determined by many factors including fall kinematics, height and weight, muscle strength, coordination and body composition [21]. Load-bearing capacity is determined by the material properties of the bone (quality) as well as the amount (mass) and arrangement (geometry) of bone tissue [21, 22]. Therefore, in a broad sense, OF has two principal determinants: events that apply extreme force to bone (i.e. falls) and weakness of bone material itself. Therefore, to understand how testosterone might be used as a therapeutic option for reducing fracture risk in men, it is critical to consider both factors that influence fall risk (e.g. body composition and physical function) and those that influence bone strength/quality (e.g. the bone’s tissue density, material arrangement and microstructure). Likewise, it is critical to consider patients who might be at risk of fracture due to either high fall risk or reduced bone strength. Aging is attended by substantial changes in bone and body composition, such as decreases in bone mineral density (BMD) [23–25], decreases in bone quality (e.g. trabecular
The magnitude of the problem While most research on osteoporosis has focused on women, osteoporosis and associated fractures are not rare among men. Estimated lifetime osteoporotic fracture (OF) risk from age 50 years onwards is 13% in men, compared to 40% in women [5]. Risks that a 65-year-old person will sustain a hip fracture by 90 years are as follows: white women (16.3%), white men (5.5%), black women (5.3%) and black men (2.6%) [6]. Between 1–2 million men suffer from osteoporosis [7]. The portion of annual health-care costs due to OF in men has grown from 20% in 1995 to 25% (or $4 bil) in 2007 [8]. The exponential increase in OF risk with age [9], coupled with the rapid aging of the US Osteoporosis in Men
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number and connectivity, cortical thickness) [26] and loss of muscle [27, 28]. Decreases in BMD and loss of muscle mass and function have been linked with adverse outcomes such as falls, OF and disability [29–33]. In the following two sections, we outline how testosterone might influence muscle and bone, with a greater focus on associations between testosterone and bone outcomes.
Mechanisms by which testosterone influences muscle and bone Testosterone deficiency is thought to contribute to fracture risk in older men [34]. There are several potential mechanisms, including both direct and indirect effects of testosterone on muscle and bone. The mechanisms by which hormones influence body composition and, by extension, strength and physical performance, are only partly understood. Possible biological mechanisms include the effects of testosterone on regulation of mesenchymal stem cell differentiation [35, 36] and muscle protein synthesis [37, 38] through androgen receptor-mediated pathways [36]. Testo sterone could also indirectly affect body composition through its effects on adiponectin, leptin or inflammatory pathways [39–42]. Testosterone may also directly affect bone tissue. Androgen receptors have been identified on bone cells of both the osteoblastic and osteoclastic lineages as well as chondrocytes [43, 44]. Androgens decrease the number of bone remodeling cycles by modifying the genesis of osteoblasts and osteoclasts from their respective progenitor cells. They exert pro-apoptotic effects on osteoclasts and anti-apoptotic effects on osteoblasts and osteocytes. Testosterone also modulates the effects induced by other hormones and cytokines involved in bone metabolism [45]. It is well established that osteoblasts regulate osteoclast formation through expression of members of the tumor necrosis factor (TNF) superfamily, namely the receptor activator of NF-B ligand (RANKL)/receptor activator of NF-B (RANK)/osteoprotegerin (OPG) system [46]. RANKL/RANK regulates osteoclast activation, formation and survival in both in normal bone remodeling and in pathological states, whereas OPG is a decoy receptor for RANKL that prevents its binding to RANK and protects bone from excessive resorption [47]. Testosterone appears to upregulate OPG production as evidenced by its positive association with OPG concentrations in crosssectional studies in healthy men [48]. Testosterone also directly inhibits shedding of RANKL by osteoblasts [49]. Additionally, testosterone appears indirectly to limit bone resorption by inhibiting the expression of interleukins 1 and 6 [50, 51], cytokines that induce bone resorption by promoting osteoclast activation and differentiation. Detailed treatments of how testosterone and other androgens affect
muscle and bone metabolism are discussed in detail in Chapters 25–27.
Studies on the association between testosterone and muscle and bone in men General Observations from Epidemiologic Studies Observational studies have shown correlations between endogenous testosterone levels and muscle mass, muscle strength, physical function and falls [29, 52–57]. In addition, endogenous testosterone levels have been correlated with bone outcomes including bone turnover markers, BMD and hip structural geometry [58–68], although these findings are by no means universal [69–72]. The limited data on endogenous testosterone levels and fracture are somewhat less consistent, with positive findings in some studies [66, 73–77] but not others [33, 78–80]. The relative contributions of testosterone and estradiol to fracture risk in men are the subject of debate [34, 81–83], although consensus is that estradiol levels are more strongly associated with fracture risk and BMD than testosterone [84]. Nonetheless, the role of testosterone seems critical given that estrogen levels in men are derived primarily from peripheral conversion of circulating testosterone by the enzyme CYP19 aromatase.
Effects of Testosterone On Muscle Interventional studies show that testosterone administration increases skeletal muscle mass, maximal voluntary strength and power in eugonadal young and older men, androgendeficient men, older men with low or low normal testosterone levels and in men with many chronic illnesses, such as that associated with chronic obstructive pulmonary disease (COPD), end-stage renal disease and human immuno deficiency virus- (HIV-) associated weight loss [85]. The effects of testosterone administration on skeletal muscle mass and muscle strength are related to the administered dose [86, 87] and the circulating testosterone concentrations [29, 52, 54, 56, 57]. Testosterone therapy in older men with low or low-normal testosterone levels improves selfreported physical function, as assessed by physical function domain of SF-36 [88]. However, the first generation of randomized trials has not shown improvements in performancebased measures of physical function [89–93]. It is possible that the inclusion of men without functional limitations and the use of measures of physical function susceptible to ceiling effects may have limited the ability to detect changes in physical function. Furthermore, many trials had a small sample size and did not have sufficient statistical power to detect clinically meaningful changes in physical function measures. Most trials included men with low normal
C h a p t e r 5 6 Testosterone Therapy for Osteoporosis in Men l
testosterone levels and used relatively small doses of testosterone which did not raise testosterone concentrations robustly into the mid normal range for healthy young men. Thus, it is not surprising that the men receiving testosterone therapy had small or no demonstrable increments in serum concentrations during testosterone therapy.
Effects of Testosterone On Bone Outcomes In Special Patient Populations Idiopathic hypogonadotropic hypogonadism Androgen-deficient men have lower BMD than eugonadal controls [94] and hypogonadal men receiving testosterone therapy [95]. Men with idiopathic hypogonadotropic hypogonadism – regardless of whether they have fused or open epiphyses – have significantly reduced cortical as well as trabecular bone density [96, 97] and bone density increases during gonadal steroid replacement, particularly among patients with open epiphyses [97] suggesting that testosterone therapy should be initiated prior to epiphyseal closure for maximum skeletal benefit. Androgen deprivation for prostate cancer Lowering of testosterone levels of patients with prostate cancer by surgical orchiectomy or by a pharmacological inhibitor, such as a gonadotrpoin releasing hormone (GnRH) agonist, is associated with rapid and marked reduction in BMD and risk of hip, spine and distal forearm osteoporotic fractures is increased [98–102]. Similar decreases in BMD have been reported in men receiving GnRH agonist therapy for benign prostatic hypertrophy [103]. Androgen receptor mutations The important role of androgens in maintenance of bone mass is further supported by observations that men with androgen insensitivity syndrome, due to mutations of the androgen receptor gene, have lower BMD than healthy, 46, XY men [104–107]. Many patients with complete or severe androgen insensitivity are raised as women, undergo gonadectomy and receive estrogen therapy, which complicates the interpretation of data from studies of these patients. In general, even among women with androgen insensitivity syndrome who are receiving estrogen therapy, moderate deficits in spine and hip BMD have been reported [106, 107]. When BMD data are corrected for body and bone size, the deficits in both spine and proximal femur BMD are even more pronounced [106]. Thus, the bone deficits in androgen insensitivity syndrome result from inherited defects in androgen action and estrogen deficiency that develops after gonadectomy. 5-alpha reductase mutations and men on 5-alpha reductase inhibitors
The role of 5-alpha reduction of testosterone to DHT in mediating testosterone’s effects on bone is poorly understood.
693
Patients with mutations of 5-alpha reductase type 2 have been reported to have normal BMD [107]; these individuals have low circulating levels of DHT. Treatment of adult men with the 5-alpha reductase inhibitor, finasteride, does not affect BMD [2–4]. However, finasteride is a weak inhibitor of the type 2 isoform of 5-alpha reductase and does not affect type 1 5-alpha reductase. Thus, although DHT levels are lower in finasteride-treated men than in healthy untreated controls, they are still in the low normal range in many treated men. More recent studies using dutasteride, which is a potent inhibitor of both type 1 and type 2 5-alpha reductase isoforms, also have not shown significant reduction in BMD in men treated with dutasteride [2, 108]. Taken together, these data suggest that testosterone effects on the bone do not require its obligatory conversion to DHT.
Interventional Trials of the Effect of Testosterone On Bone Outcomes The effects of testosterone on bone outcomes have been studied in several groups of men in intervention trials: healthy hypogonadal elderly and middle-aged men, peri pubertal males with idiopathic hypogonadotropic hypogonadism and men with chronic illness or men receiving glucocorticoids (Table 56.1). Open label trials of testosterone therapy in hypogonadal men have shown improvements in BMD, although the BMD is not normalized to levels seen in healthy eugonadal men [95, 119, 126, 127]. Testosterone therapy generally decreases markers of bone turnover. Testosterone therapy of men with idiopathic hypogonadotropic hypogonadism, who have prepubertal onset of androgen deficiency, increases both cortical and trabecular bone density; the increments in cortical and trabecular bone density are greater in men with immature skeletons than in those with mature skeletons [97]. A number of randomized placebo-controlled trials of testosterone therapy on bone outcomes have been conducted. Two separate meta-analyses of testosterone trials in older men or in men receiving glucocorticoids have shown significantly greater increases in vertebral BMD in testosteronetreated men than in those receiving placebo [128, 129]. In general, trials that used intramuscular testosterone showed greater increment in vertebral BMD than those using transdermal testosterone [129]. Changes in femoral neck bone density were not significantly different between testosterone and placebo-treated men. In studies that measured bone markers, testosterone therapy was associated with a greater reduction in bone resorption markers than placebo [128]. However, there was considerable heterogeneity among the trials that were included in these meta-analyses, which limited the precision of the inferences [129]. The trials differed in the age of subjects, baseline testosterone levels, the type and dose of testosterone formulation and treatment duration. Some trials included healthy older men while others included men receiving glucocorticoids
Table 56.1 Testosterone trials involving BMD as an outcome stratified by patient population studied Reference
Patient details
No. Entry T level
Mean age
Blinding
73 y
Control group
Regimen
Duration
Results
Double-blind Placebo
Scrotal testosterone patch (Testoderm 60 cm2 patch) or placebo patch daily
36 months
The mean BMD of the L spine increased (P 0.001) in both the placebo-treated (2.5 0.6%) and testosterone-treated (4.2 0.8%) groups, but the mean changes did not differ between the groups. However, linear regression analysis demonstrated that the lower the pretreatment serum testosterone concentration, the greater the effect of testosterone treatment on lumbar spine bone density from 0 to 36 months (P 0.02) The testosterone group had a 0.3% gain in femoral neck BMD, whereas the control group lost 1.6% over 12 months (P 0.015). No significant changes were seen in markers of bone turnover in either group Outcome: mean percent increase from baseline SEM T-only: Increase in L spine BMD of 10.2 1.4%* Increase in hip BMD of 2.7 0.7% # T F: Increase in L spine BMD of 9.3 1.4%* Increase in hip BMD 2.2 0.7% # *vs 1.3 1.4% for placebo (P 0.001) # vs 0.2 0.7% for placebo, (P or 0.02) Both T groups had similar increments in BMD and none of the three groups had a change in femoral neck BMD Men in both treatment groups had an increase in BMD at the femoral neck. Women who received DHEA had an increase in BMD at the ultradistal radius
Older men with normal or low-normal testosterone levels Snyder et al 1999 [109]
Elderly (65 y) men with low testosterone levels on 3 occasions
Kenny et al 2001 [88]
Elderly (65 y) with 67 low testosterone levels
TT 4.44 nmol/L
76 y
Double-blind Placebo
Transdermal testosterone (5 mg /day) or placebo patch. All men received 500 mg supplemental calcium and 400 IU vitamin D
12 months
Amory et al 2004 [110]
Elderly (65 y) men with low testosterone levels on 2 occasions
70
TT 12.1 nmol/L
71 y
Double-blind Placebo
TE, 200 mg IM every 2 weeks with placebo pills daily (T-only); TE, 200 mg every 2 wk with 5 mg finasteride daily (T F); or placebo injections and pills (placebo)
36 months
Nair et al 2006 Elderly (65 y) with [91] low testosterone and DHEA
87
BT 3.6 nmol/L 66–68 y Double-blind Placebo
2 years
Basurto et al 2008 [111]
48
TT 11.1 nmol/L
29 received DHEA (75 mg per day orally), 27 received testosterone (5 mg transdermal T per day), and 31 received placebo IM injections of TE every 3 weeks
Middle aged/elderly (60 y) with low testosterone levels
108 TT 16.5 nmol/L
63 y
Double-blind Placebo
12 months
Testosterone treated group exhibited a significant (P 0.05) increment (from 1.198 0.153 to 1.240 0.141 g/cm2) in lumbar BMD in parallel with a significant (P 0.001) increment (from 301 32 to 471 107 ng/dL) in testosterone concentrations, whereas no significant change occurred in femoral neck BMD
Table 56.1 Continued Reference EmmelotVonk et al 2008 [90]
Mean age
Blinding
Control group
Patient details
No. Entry T level
Regimen
Middle aged/elderly (60–80 y) with low testosterone levels
237 TT 13.7 nmol/ 67 y L
Double-blind Placebo
80
TT 10.4 nmol/L
53 y
Open
35
Not applicable (only 4 patients with TT 9 nmol/L)
61 y
Double-blind Placebo
IM injections of TE 250 mg
Duration
80 mg of testosterone 6 months undecanoate or placebo twice daily orally
Results No change in BMD of L spine or hip
Adult men with hypogonadism Katznelson et al 1996 [94]
36 adult men with acquired hypogonadism (age, 22–69 yr; median, 58 yr), including 29 men with central hypogonadism and 7 men with primary hypogonadism, and 44 age-matched eugonadal controls Hall et al 1996 35 male patients, [112] aged 34–79 yr, with definite rheumatoid arthritis (RA)
Eugonadal IM injections of TE men 100 mg/week
18 months
Spinal BMD and trabecular BMD increased by 5 1% (P 0.001) and 14 3% (P 0.001), respectively. Radial BMD did not change. Markers of bone formation and resorption decreased significantly over 18 months
9 months
There was no significant effect of treatment on disease activity overall, 5 patients receiving testosterone underwent a ‘flare’. Differences in mean BMD following testosterone or placebo were non-significant (spine: 1.2% vs 1.1%; femur: 0.3% vs 0.3%). There was no suggestion of a positive effect of testosterone on disease activity in men with RA The most significant increase in BMD was seen during the first year of testosterone treatment in previously untreated patients, when BMD increased from 95.2 5.9 to 120.0 6.1 mg/cm3 hydroxyapatite (mean SE). Long-term testosterone treatment maintained BMD in the age-dependent reference range in all 72 hypogonadal men, independent of the type of hypogonadism. Transdermal testosterone patches applied to the scrotum were as effective in normalizing BMD as IM testosterone enanthate injections A significant increase in trabecular and cortical BMD (P 0.001) was documented in the course of replacement therapy in all patients regardless of the type of hypogonadism and age of patients
Behre et al 1997 [113]
72 hypogonadal patients (37 men with primary and 35 men with secondary hypogonadism)
72
Not applicable, all patients hypogonadal
35 y
Open
None
Up to 16 yrs IM injections of TE 250 mg every 3 weeks in 52 patients. Scrotal T patches (Testoderm) at a daily dose of 4–6 mg/day in 11 patients. Oral TU with a daily dose of 120 mg/day in 2 patients. 7 patients desiring fertility received hCG or pulsatile GnRH.
Leifke et al 1998 [114]
32 men aged 18–74 32 years, with IHH (n 6), pituitary insufficiency (n 5), Klinefelter syndrome (n 12) or other forms of primary hypogonadism (n 9)
TT 12 nmol/L
33–35 y Open
None
IM injections of TE 250 mg
1–7 years, 3.2 1.7 (mean SE) years
(Continued)
Table 56.1 Continued Reference Behre et al 1999 [115]
Snyder et al 2000 [92]
De Rosa et al 2001 [116]
Howell et al 2001 [117]
Patient details
No. Entry T level
Mean age
Blinding
Control group
11 hypogonadal [primary (n 4) and secondary (n 7) hypogonadism] aged 35.9 9.8 years (mean SD) 18 hypogonadal men (testosterone: 78 77 ng/dL; 2.7 2.7 nmol/Lb)
11
Not applicable, all patients hypogonadal
36 y
Open
18
TT 8.7 nmol/L
51 y
30 12 patients (aged 29.3 1.4 yr) affected by idiopathic hypogonadotropic hypogonadism (IHH), in 8 patients (29.6 2.6 yr) affected by Klinefelter’s syndrome (KS).10 healthy men (30.6 1.7 yr) matched according to age and BMI served as controls 35 men, mean age 35 40.9 years, with mild Leydig cell dysfunction, defined by a raised LH level (LH or 8 IU/l) and a testosterone level in the lower half of the normal range or frankly subnormal (testosterone 20 nmol/l), following treatment with cytotoxic chemotherapy for malignancy
TT 3.5 nmol/L
TT 20 nmol/L
Regimen
Duration
Results
None
Daily transscrotal T patches (Testoderm)
7–10 yrs
Bone density measured by QCT increased slightly from 113.6 5.4 to 129.7 9.3 mg/cm3 during the observation period (P 0.028)
Open
None
Scrotal testosterone patch (Testoderm 60 cm2 patch) daily
3 years
29–30 y
Open
Eugonadal men
TE 250 mg IM every 3 weeks
41 y
Single-blind
Placebo
Transdermal testosterone (Andropatch 2.5 mg patches, 1–2 patches per day)
BMD of the L spine (L2–4) increased by 7.7 7.6% (P 0.001) and that of the femoral trochanter increased by 4.0 5.4% (P 0.02); both reached maximum values by 24 months 76.4 10 and Spinal BMD in IHH was significantly 70.1 12.3 lower than in controls (0.804 0.04 vs months 1.080 0.01 g/cm2; P 0.001), while (mean SD), there was no difference in neck BMD respectively (0.850 0.01 vs 0.948 0.02 g/cm2). Neither spinal (0.978 0.05 g/cm2) nor neck (0.892 0.03 g/cm2) BMD in KS were significantly different from controls. In IHH there were significant increases in bone formation and in bone resorption markers compared to controls, while such differences were not present in KS
12 months
There was no significant change in BMD at the hip, spine or forearm and no change in fat or lean body mass
Table 56.1 Continued Patient details
No. Entry T level
Mean age
Blinding
Control group
Christmas et al 2002 [118]
72 healthy, elderly (65 years) men
72
TT 16.3 nmol/l
70 y
Double-blind
Placebo
Schubert et al 2003 [119]
53 hypogonadal men (20 with primary and 33 with secondary hypogonadism)
53
TT 3.6 nmol/L
32–36 y
Open
None
Wang et al 2004 [120]
227 hypogonadal men
227
TT 10.4 nmol/L 51 y
Open
None
1% testosterone gel containing 50 or 100 mg T or two T patches (delivering 5 mg T/day) transdermally for 90 days. At day 91, depending on the serum T concentration, the T gel dose was adjusted upward or downward to 75 mg T/day until day 180. No dose adjustment in the T patch group
Reference
Regimen
Duration
6 months Recombinant human GH (0.02 mg/kg SC 3 times a week) plus placebo sex steroid (‘GH’ group), sex steroid (100 mg TE IM every 2 weeks) plus placebo GH (‘HRT’ group for women, ‘T’ group for men), GH plus sex steroid(s) [‘GH HRT(Estraderm 100 g plus Provera 10 mg)]’” for women, ‘GH T’ for men), or placebo GH plus placebo sex steroid(s) (‘placebo’ group) Mesterolone 100 mg PO daily, 6 months testosterone undecanoate 160 mg p.o. daily, TE 250 mg IM every 21 days, or a single subcutaneous implantation of 1200 mg crystalline testosterone
6 months
Results In men, GH T led to a small decrease in BMD at the proximal radius; there were no other significant effects of hormone administration on BMD at the end of 6 months. In women, administration of HRT and GH HRT, but not GH, increased BMD at the lumbar spine, femoral neck and distal radius
In men with primary hypogonadism, the BMD increased dose dependently (crystalline testosterone 7.0 1.3%, testosterone enanthate 4.8 0.2%, testosterone undecanoate 3.4 2.5%, mesterolone 0.8 1.6%) after 6 months of therapy. Only secondary hypogonadal men treated with testosterone enanthate experienced an increase of the BMD BMD increased significantly both in the hip (1.1 0.3%) and spine (2.2 0.5%) only in the T gel 100 mg/ day group (P 0.0001). Bone resorption markers decreased significantly only in the T gel 100 mg/day group and serum bone formation markers increased significantly, but only transiently during the first 90 days in all treatment groups
Peripubertal men with idiopathic hypogonadotropic hypogonadism and unfused epiphyses Finkelstein et al 1989 [97]
21 men with isolated GnRH deficiency; 15 men had used epiphyses and 6 men had open epiphyses
21
Not applicable, all patients eugonadal
19–53 y
Open
None
IM TE (3 patients), HCG (8 23.7 1.1 patients) or pulsatile GnRH (10 (mean SE) patients) in doses titrated to months maintain serum T levels within the normal adult male range
Arisaka et al 1995 [121]
12 adolescent patients (15–21 years) with hypogonadotropic hypogonadism
12
TT 2.8 nmol/L
18 y
Open
Untreated
Group 1 (n 6) given T treatment for 2 consecutive years, and group 2 (n 6) without T treatment for the first year and then with T treatment for the second year. Both groups had age-matched normal controls
1–2 years
Cortical BMD increased 0.03 0.01 g/ cm2 in men with fused epiphyses and 0.08 0.02 g/cm2 in men with open epiphyses (P 0.05). Trabecular BMD increased from 96 13 to 109 12 mg/ cm3 (P 0.01) in men with open epiphyses, but did not change in their counterparts Bone density in group 1 increased significantly during the 2-year T treatment period, but did not increase in group 2 during the first year without T treatment, although an increase was observed during the subsequent year with T treatment. Osteocalcin showed an increase in response to T treatment in both groups
(Continued)
Table 56.1 Continued Reference
Patient details
No. Entry T level
Mean age
Blinding
Control group
23 eugonadal men, aged 34–73 years, with established osteoporotic vertebral crush fractures 23 eugonadal men, aged 34–73 years, with established osteoporotic vertebral crush fractures
23
TT 12 nmol/L
58 y
Open
23
TT 12 nmol/L
58 y
54 eugonadal men with 89 AIDS wasting (weight 90% IBW or weight loss 10% from preillness baseline). Baseline bone turnover and BMD were compared with those in 35 age-matched healthy non-HIV-infected control subjects
Not applicable, all patients eugonadal
Regimen
Duration
Results
None
250 mg testosterone esters (Sustanon 250®) every 2 weeks
6 months
Open
None
250 mg testosterone esters (Sustanon 250®) every 2 weeks
6 months
36–38 y
Double-blind
Self (cross-over design)
TE (200 mg/week, IM) or placebo plus progressive resistance training (3 times/ week) or no training in a 2 2 factorial study design
3 months
Mean bone mineral density at the lumbar spine increased from 0.799 g/cm2 to 0.839 g/cm2 during treatment (P 0. 001), a rise of 5% in 6 months. BMD at the hip did not change All bone markers decreased, indicating that treatment suppressed bone turnover. Although serum osteocalcin levels fell only slightly, there were large reductions in urinary deoxypyridinoline and N-telopeptide (P 0.05), which were correlated with the increase in spinal BMD L spine and total hip BMD are reduced in eugonadal men with AIDS wasting. Biochemical markers of bone turnover suggest that bone formation and bone resorption are uncoupled in these men. Testosterone administration, but not resistance training, over 3 months increases lumbar spine BMD in eugonadal men with AIDS wasting. (2.4 1.3 vs. 1.3 1.0%, testosterone vs. placebo; P 0.02)
Glucocorticoid therapy with 12 months testosterone esters (30 mg of proprionate, 60 mg of phenylprionate, 60 mg of isocaproate and 100 mg of decanoate) or to act as control. After a washout period for those men who were receiving testosterone, the groups were then crossed over and studied for an additional 12 months IM injections of testosterone 12 months 200 mg/day or nandrolone 200 mg/day or placebo
Eugonadal men with osteoporosis Anderson et al 1996 [122]
Anderson et al 1997 [123]
Fairfield et al 2001 [124]
Men receiving glucocorticoid therapy Reid et al 1996 [125]
15 asthmatic men who were receiving longterm glucocorticoid treatment
15
Not applicable
61 y
Open
Self (cross-over design)
Crawford et al 2003 [85]
51 mean receiving a mean daily dose of prednisone of 12.6 2.2 mg
51
Not applicable
60 y
Double-blind
Placebo
BMD in the L spine increased 5.0% 1.4% (P .005) during testosterone supplementation, but it did not change during the control period. The changes were accompanied by a decrease in the indexes of bone turnover
Lumbar spine BMD increased significantly only in men treated with testosterone (4.7 1.1%, P 0.01). There was no significant change in hip or total body BMD
GH: Growth hormone; TE: testosterone enanthate; BMD: bone mineral density; L spine: lumbar spine; IM: intramuscular; TT: total testosterone; BT: bioavailable testosterone; DHEA: dehydroepiandrosterone.
C h a p t e r 5 6 Testosterone Therapy for Osteoporosis in Men l
for bronchial asthma or COPD. Both meta-analyses were in agreement that BMD at hip and peripheral sites was not influenced by testosterone therapy.
Recent Studies of Testosterone Effects On Bone Microstructure The majority of studies of testosterone in association with bone outcomes highlighted above have focused on BMD as assessed by dual energy x-ray absorptiometry (DXA). Several observations highlight the limitations of relying on BMD as a proxy for fracture risk. First, significant differences in trabecular connectivity have been observed in subjects matched for bone volume [130]. Second, studies [131–133] have shown that most fracture patients do not meet the World Health Organization (WHO) criterion for osteoporosis, i.e. BMD T-score 2.5 [134]. Finally, large reductions in fracture risk observed in intervention studies do not correspond with minor changes observed in BMD [135–137]. These observations suggest that other features of bone strength are relevant to fracture risk. Furthermore, several studies demonstrate that structural parameters assessed by high-resolution CT or MRI can contribute additional information regarding mechanical strength of bone beyond bone mass or density [138, 139]. Several studies have examined bone structural parameters (e.g. cortical and trabecular BMD, bone microarchitecture) in association with hypogonadism and endogenous testosterone levels as well as exogenous testosterone administration. An early study by Leifke and colleagues [114] showed that trabecular and cortical BMD assessed by quantitative computed tomography increased 30% and 9%, respectively, among 32 patients treated with testosterone over a period of 3 years. Snyder and colleagues have published a series of investigations in which 10 hypogonadal and 10 race- and age-matched eugonadal men were assessed with the highresolution magnetic resonance microimaging (MRI)-based virtual bone biopsy of the distal tibia [140, 141]. In the first publication by Benito et al [140], hypogonadal men were shown to have 36% lower surface/curve ratio (this ratio is higher when architecture is more intact) and 36% higher topological erosion index (this index is higher when architectural deterioration is greater) than eugonadal subjects. In contrast, mean BMD was not significantly different between the two groups, with differences ranging from 6% lower (femoral neck) to 16% lower (lumbar spine) among hypogonadal men. In a second publication, Benito et al [141] showed that, after 24 months of testosterone treatment in hypogonadal men, BMD of the spine increased 7.4% (P 0.001) and BMD of the total hip increased 3.8% (P 0.008). In addition, MRI-based assessments of microarchitecture improved significantly. The surface-tocurve ratio increased 11% (P 0.004) and the topological erosion index decreased 7.5% (P 0.004). In a third publication, Zhang and colleagues [142] performed microfinite
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element (FE) analyses from a subvolume of each MR image from these patients, showing that 24 months of testosterone treatment of hypogonadal men improves estimated elastic moduli of tibial trabecular bone by increasing trabecular plate thickness. Khosla and colleagues [143] have assessed the relationships between the trabecular microstructural parameters and sex steroids in young, middle-aged and elderly men (n 269) and women (n 205) using a technology that non-invasively assesses microstructure at the wrist: highresolution three-dimensional peripheral QCT. Overall, associations between bioavailable testosterone and trabecular parameters (bone volume/tissue volume (BV/TV), trabecular number (TbN), trabecular thickness (TbTh) and trabecular separation (TbSp)) were weak. No significant age-adjusted associations were observed in young (20–39 years) or elderly (60 years) men. In middle-aged men (40–59 years), a significant age-adjusted correlation was noted between bioavailable testosterone and TbTh (r 0.28). In contrast to these observations, bioavailable estradiol was an important predictor of trabecular microstructure in middle-aged and elderly men. Taken together, these studies together provide support for the notion that frank hypogonadism is associated with decreased microstructural integrity of the trabecular architecture and that testosterone replacement improves it. Differences in findings between studies could be due to differences in site of measurement. In addition, based on the relative weakness of the associations between trabecular parameters and testosterone levels in the population studies of Khosla, coupled with the significant associations observed in the Leifke and Snyder studies of hypogonadal patients, it could be speculated that divergent findings between studies are due to differences in the baseline levels of testosterone in the study samples. This points to the possibility that there is a threshold effect of testosterone levels on bone micro architecture that should be tested in future studies.
Diagnosis of hypogonadism/ androgen deficiency Hypogonadism refers to failure of both Leydig and germ cell function. In contrast, androgen deficiency is a clinical syndrome complex that comprises symptoms and signs in conjunction with biochemical evidence of testosterone deficiency. The diagnosis of androgen deficiency thus includes clinical history and examination as well as measurement of serum testosterone levels. Several professional societies have published guidelines for the diagnosis and treatment of androgen deficiency: the International Society for the Study of Aging Male (ISSAM) in 2002 [144], American Association of Clinical Endocrinologists in 2002 (AACE) [145], the
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Endocrine Society in 2006 [146] and the 2008 consensus statement of the International Society of Andrology (ISA), ISSAM, European Association of Urology (EAU), European Academy of Andrology, (EAA) and the American Society of Andrology (ASA) [147]. According to these current guidelines, diagnosis of androgen deficiency should be made only in men with consistent symptoms and signs and unequivocally low serum testosterone levels. The diagnostic evaluation of men with androgen deficiency proceeds in three steps. The first step includes evaluation of general health, life style, eating patterns, exercise levels and the use of recreational drugs such as alcohol, marijuana, opiates and cocaine, and exclusion of systemic illnesses or medications that might affect testicular function. The second step is the measurement of total testosterone level, preferably in the morning, using a reliable assay. If the total testosterone level is low, this should be confirmed by repeating the measurement of morning total testosterone and, in some patients (e.g. obese men), by measurement or calculation of free or bioavailable testosterone level. The third step in the diagnostic evaluation is to determine whether androgen deficiency is the result of a primary testicular dysfunction or secondary to a hypothalamic or pituitary disorder. This is best accomplished by measurement of serum luteinizing hormone (LH) and follicle stimulating hormone (FSH) levels; elevated LH and FSH levels in association with low testosterone levels indicate primary testicular failure, while low or inappropriately normal LH and FSH in association with low testosterone levels indicate either a hypothalamic–pituitary defect or a dual defect. Several complexities render the operationalization of these guidelines into clinical practice difficult. First, the signs and symptoms of androgen deficiency in men are non-specific and vary with the age of onset of androgen deficiency, its severity and duration, associated co-morbid illnesses, genetic variations in androgen sensitivity and previous testosterone therapy [146, 148, 149]. Second, the measurements of serum testosterone levels by commercially available platform-based immunoassays have been fraught with problems. A number of publications have shown that the commonly used commercial testosterone platform-based immunoassays have suboptimal sensitivity and lack accuracy in the low range. An Expert Panel of the Endocrine Society [150] found the that: (f)or T less than 150 ng/dl (5.2 nmol/liter), the (platformbased immunoassay) values were neither analytically nor clinically useful. For higher T concentrations, the values have some utility, but the discrepancies among methods are unacceptable. Furthermore, population-based reference ranges for testosterone levels that might guide the partitioning of men and women into healthy and diseased are not available for any assay. Gas or liquid chromatography tandem mass spectrometry, widely considered reference methods
for the measurement of testosterone levels, are emerging as the methods of choice for total testosterone levels because of their high throughput, accuracy and greater sensitivity. There is considerable variation in testosterone levels; some of this variation is due to biologic factors, such as the pulsatile, diurnal, seasonal and circannual rhythms of testosterone secretion, age, body mass index, smoking and alcohol intake and genetic factors that contribute to variations in sex hormone binding globulin (SHBG). There also is substantial contribution from assay variation. Consequently, a substantial fraction of men who have low testosterone levels may have normal levels when tested again [151, 152]. Thus, the diagnosis of androgen deficiency should not be made based on a single low testosterone value; low values should be confirmed by repeating the testosterone measurements, preferably in the morning. The lower the initial testosterone value, the lesser is the risk of misclassification. The assays for the measurement of free or bioavailable testosterone are also fraught with problems. Most of the circulating testosterone is bound to sex hormone-binding globulin and to albumin; only 0.5–3% of circulating testosterone is unbound or ‘free’ and can be measured by equilibrium dialysis. Bioavailable testosterone denotes unbound testosterone plus testosterone bound loosely to albumin; this term emerged from research that suggested that, in addition to unbound testosterone, albumin-bound testosterone is also dissociable and bioavailable in some tissues. Bioavailable testosterone is measured by the ammonium sulfate precipitation method, but numerous methodological difficulties in performing these assays dissuaded the Endocrine Society’s Expert Panel from recommending its use in clinical practice. Free testosterone can be measured by the equilibrium dialysis method and is generally viewed as the reference method for the measurement of free testosterone levels, even though it also has some methodological problems. The tracer analog methods are inexpensive and convenient but are affected by the SHBG concentrations, inaccurate and do not provide a true index of ‘free’ testosterone. The experts agree that tracer analog methods should not be used for the measurement of free testosterone levels. Free and bioavailable testosterone concentrations can be calculated from total testosterone and SHBG concentrations using the law of mass action equations [153, 154]. The calculation depends on the measurement of total testosterone, SHBG and albumin and the use of the known equilibrium dissociation constants for SHBG and albumin. The calculated free testosterone concentrations correlate well with those measured by equilibrium dialysis, but there are some differences between the free testosterone concentrations measured by equilibrium dialysis and calculated by applying the law of mass action equations. These discrepancies between the calculated and measured free testosterone concentrations suggest that the assumptions that underlie the law of mass action equations, such as the binding constants, need further refinement. The Endocrine Society’s Expert Panel expressed
C h a p t e r 5 6 Testosterone Therapy for Osteoporosis in Men l
the opinion that calculation of free testosterone concentration from reliably measured total testosterone and SHBG using the law of mass action equations provides the best approach for the estimation of free testosterone concentration [150]. Although bioavailable testosterone can also be calculated, it is a multiple of calculated free testosterone value and, therefore, it does not provide any additional information than that derived from the calculated free testosterone value. The Expert Panel of the Endocrine Society recommends against screening asymptomatic men for androgen deficiency in the general population. However, the Expert Panel suggested that case finding using the measurement of testosterone level may be indicated in men seeking medical care for certain clinical disorders (Table 56.2) in whom the prevalence of testosterone deficiency and possibly, related consequences is high.
Epidemiology of androgen deficiency and co-prevalence with osteoporosis A large and growing number of cross-sectional and longitudinal studies are in agreement that serum total and free testosterone levels decline with advancing age [155,156]. The decline in free testosterone is greater than the decline in total testosterone level because of the age-related increase in SHBG concentration. The age-related decline in testosterone levels has been associated with the risk of type 2 diabetes, heart disease, osteoporosis, decreased muscle mass and strength, fall propensity and fracture risk and mortality. These inferences are limited by the weakness of the associations, heterogeneity of populations and inconsistency of results across studies. The lack of data from large randomized placebo-controlled trials to determine the benefits of testosterone therapy on health outcomes – mobility, sexual function, cognition, vitality, quality of life and fracture risk – and the uncertainty about the risks of prostate and cardiovascular disease during long-term testosterone therapy preclude a general recommendation for administering testosterone therapy for all older men with low testosterone levels. The Endocrine Table 56.2 Conditions associated a high prevalence of low testosterone levels and possible related consequences Sellar mass, radiation to the sellar region or other diseases of the sellar region Treatment with medications that affect testosterone production or metabolism, such as glucocorticoids, ketoconazole and opioids HIV-associated weight loss End-stage renal disease and maintenance hemodialysis Moderate to severe chronic obstructive lung disease Infertility Osteoporosis or low trauma fracture, especially in a young man Type 2 diabetes mellitus
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Society Expert Panel suggested that testosterone therapy might be considered in older men with very low testosterone levels (less than 200 ng/dL) on two or more occasions, who have distressing symptoms of androgen deficiency. The absolute risk of osteoporosis in hypogonadal men (whether asymptomatic or symptomatic) is not known. In the Osteoporotic Fractures in Men Study (MrOS), prevalence of osteoporosis in elderly men with low testosterone was 12.3% [60]. Among middle-aged and older men with low testosterone levels in the Boston Area Community Health/ Bone (BACH/Bone) Survey, symptomatic men had lower BMD in the hip and peripheral sites than men who were not symptomatic [69]. Unpublished BACH/Bone data show that the prevalence of osteopenia was considerably higher among men with symptomatic androgen deficiency (60%) compared to those without (30%). Findings from these studies suggest that baseline BMD measurement should be considered in men who present with androgen deficiency, particularly if other risk factors for osteoporosis are present, as was suggested by the Endocrine Society Expert Panel. Testosterone therapy is currently not approved for the treatment of osteoporosis. Head-to-head trials of testosterone compared with bisphosphonates (the standard of care for men with osteoporosis) have not been done. Therefore, we do not know whether men with osteoporosis who also have low testosterone levels should receive a therapeutic agent currently approved for osteoporosis, such as a bisphosphonate, or whether these men should be treated with testosterone alone before adding a more specific therapy for osteoporosis. In men diagnosed with androgen deficiency, especially those with a history of low trauma fracture, measurement of BMD at baseline and a follow-up BMD after one or two years of testosterone therapy seems justified.
Testosterone preparations Testosterone replacement modalities have been in existence for over six decades and have evolved remarkably since then. Currently available preparations available for clinical use include oral, buccal, injectable, implantable and transdermal testosterone (Table 56.3).
Intramuscular Testosterone The most widely used testosterone substitution therapy is the intramuscular injection of testosterone esters. Testosterone enanthate remains the most commonly prescribed ester. The advantages include their effectiveness in correcting symptoms [89,157], flexibility of dosing and relatively lower cost. However, serum testosterone levels rise into the high normal or supraphysiological range immediately following administration and gradually return to the hypogonadal range within 2 weeks [158,159]. This can manifest as fluctuations in mood, energy and sexual function. Testosterone
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Osteoporosis in Men Table 56.3 Testosterone formulations currently in the market
Formulation
Route of delivery
Dose
Testosterone injectables Testosterone enanthate (Delatestryl® 200 mg, Testoviron® 250 mg) or Testosterone cypionate (Depo-Testosterone®) Testosterone undecanoate (Nebido®)a Chinese testosterone undecanoate preparation
Intramuscular
100 mg every week or 200 mg every 2 weeks
Intramuscular Intramuscular
1000 mg in 4 ml every 12 weeks 1000 mg in 8 ml every 12 weeks
Oral
40–80 mg orally 2 or 3 times a day with meals
Topical Topical
5–10 mg/day One scrotal patch every day
Topical
5–10 g/day
Buccal
30 mg b.i.d.
800 mg (4 pellets, 200 mg each)
Every 4–6 months
Oral testosterone Testosterone undecanoate (Andriol®)a Transdermal testosterone Patches Androderm® Scrotal testosterone patch (Testoderm®) Gels Androgel®, Testogel®, Testim® Buccal, bioadhesive testosterone Striant® Testosterone pellets Tesopel® a
Not approved for use in the USA
undecanoate is a longer-acting ester that maintains serum testosterone levels within the normal range without major fluctuations and its longer half-life allows for administration every 3 months after an initial loading dose in a 6-week interval [160–162]. However, this formulation is currently not approved for use in the USA. Early studies of the effect of intramuscular testosterone esters in hypogonadal men showed improvement in BMD in the forearm and lumbar spine, with the increase in spine BMD being greater in men with open epiphyses [97,121,163,164]. Leifke et al [114] showed that intramuscular testosterone improved spine BMD independently of age and type of hypogonadism. More recent studies of intramuscular testosterone replacement in hypogonadal men have shown significant increases in spinal [116] and trabecular but not radial BMD [94].
Transdermal Testosterone The skin easily absorbs steroids and the scrotal skin in particular shows the highest rate of steroid absorption [165]. Transdermal patches for application to both scrotal and non-scrotal skin have been developed, although the scrotal patch is no longer marketed. The non-scrotal patch contains permeation enhancers to maximize transdermal drug transport and, when applied to the skin of upper arms, abdomen or back, provides physiologic serum testosterone concentrations. The non-genital patch must be renewed every 24 hours and has been shown to reverse the signs and symptoms of hypogonadism [115,166]. A significant drawback of this delivery system is skin irritation leading to a high rate of discontinuation [167].
Testosterone gel is applied to non-genital skin every 24 hours and maintains serum testosterone levels in the physiological range in a dose-dependent manner [168]. The advantages of testosterone gel over the patch are a lower incidence of skin irritation, the ease of application and the invisibility of the dried gel. A potential concern related to the use of the gel is the transfer of the drug to women or children who come in close contact. This risk can be reduced by washing hands after gel application and keeping the area of gel application covered with clothing. Testosterone gels are more expensive than the patch and injectable esters. The DHT to testosterone ratio after application of the testosterone gel is higher than that observed in healthy men or in men receiving testosterone esters, presumably due to the 5alpha reduction of testosterone in the skin. Transdermal (scrotal patch) testosterone is as effective as intramuscular testosterone in normalizing BMD in hypogonadal men [113]. In separate studies of androgen replacement in hypogonadal men via testosterone gel [169] and scrotal patch [92], BMD increased significantly in both the hip and spine in both groups.
Oral Testosterone Unesterified oral testosterone is rapidly absorbed from the gastrointestinal tract and metabolized by the liver to inactive products; 17-alpha-alkyl substitutions render testosterone less susceptible to presystemic metabolism. However, synthetic 17-alpha alkylated derivatives, such as 17--methyltestosterone and fluoxymesterone are potentially hepatotoxic and should not be used in clinical practice.
C h a p t e r 5 6 Testosterone Therapy for Osteoporosis in Men l
Testosterone undecanoate, when administered orally in oleic acid, is absorbed from the gastrointestinal tract through the lymphatic system and reaches the circulation via the thoracic duct [170]. The greater oral bioavailability lies in its ability to bypass the hepatic first-pass metabolism. The formulation, however, needs to be taken frequently and, even with three times-a-day dosing, serum testosterone peaks are short lived, resulting in high fluctuations [171]. Oral testosterone undecanoate is currently not approved for use in the USA.
Buccal Bioadhesive Testosterone Administration of testosterone via the buccal mucosa aids in its mucosal absorption to the systemic circulation. The bioadhesive buccal system adheres to the buccal mucosa and maintains serum testosterone levels in the normal range. It is associated with gum-related side effects (bad taste, local discomfort and irritation) that may lead to poor compliance. Long-term studies investigating their effects on BMD are lacking.
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and thickness, blood flow and other poorly understood factors. Some of the perceived differences in the frequency of erythrocytosis and in the observed anabolic effects on the muscle and bone between injectable testosterone esters and transdermal formulations are likely related to differences in the circulating testosterone levels. Therefore, it is not surprising that meta-analyses of randomized controlled trials of testosterone in men with HIV-associated weight loss also have shown greater gains in fat-free mass in subjects treated with testosterone esters than in those treated with other testosterone formulations [175]. In a separate meta-analysis, Isidori et al [128] showed that testosterone replacement improved BMD significantly at the lumbar spine, but not the femoral neck when compared to placebo. The study revealed a significant effect of treatment preparation used, with the highest increases in BMD found with testosterone esters, likely due to the higher amount of testosterone delivered by the intramuscular esters. Additionally, there was a consistent significant reduction in bone resorption markers but no change in bone formation markers, suggesting that this is the primary mechanism of bone remodeling mediated by testosterone.
Subdermal Testosterone Pellets An implantable pellet system results in physiological testosterone levels for 4–6 months. However, it requires a surgical skin incision with potential risks of bruising, infection, fibrosis and spontaneous extrusion of the pellet [172, 173]. Due to their long duration of action, pellets should be used preferably by men in whom the beneficial effects and tolerance for testosterone has been studied by treatment with shorter-acting preparations. Regular and adequate longterm subcutaneous testosterone pellet implants in hypogonadal men have been shown to result in adult BMD within the normal range expected for an age and gender-matched population [174].
Comparisons of Different Modes of Administration The effects of testosterone therapy vary with the administered dose, the circulating serum testosterone concentrations and possibly genetic factors. With the commonly used dose regimens, the amount of testosterone delivered into the systemic circulation is substantially greater with the injectable testosterone esters than with the transdermal formulations. Therefore, the steady state average testosterone concentrations are substantially higher with testosterone esters than with transdermal formulations. For instance, a regimen of 100 mg of testosterone enanthate weekly provides a nominal delivery of 10 mg of testosterone daily; in contrast, the FDA approved starting regimen of 5 g 1% testosterone gel provides a nominal delivery of only 5 mg testosterone daily. Furthermore, testosterone absorption from the trandermal gel is affected by the site of gel application, skin quality
Strategies to minimize risk of adverse effects Baseline evaluation of hypogonadal men should include screening for conditions in which testosterone therapy is associated with increased risk of adverse effects. Testo sterone administration is contraindicated in men with prostate cancer or breast cancer. Testosterone therapy should not be administered to men with a palpable prostate nodule or induration, or prostate-specific antigen (PSA) greater than 3 ng/mL without a urological evaluation. As testosterone therapy would be expected to raise hematocrit, patients with baseline hematocrit 50% [146, 147] or hyperviscosity should not be treated with testosterone therapy. Testosterone therapy should be administered carefully to men with benign prostatic hypertrophy and mild to moderate lower urinary tract symptoms. Men with severe lower urinary tract symptoms (IPSS symptom score 19) should undergo urological evaluation before consideration of testosterone therapy. Middle-aged and older men are at high risk of harboring a subclinical prostate cancer. Therefore, baseline assessment of prostate cancer risk is necessary in middle-aged and older men before instituting testosterone therapy. Age, race, family history of prostate cancer and prostate specific antigen (PSA) level – the major determinants of prostate cancer risk – should be factored in this risk assessment. Men with baseline PSA greater than 3 ng/mL or family history of prostate cancer should not be treated with testosterone without a urologic evaluation.
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Testosterone administration can cause salt and water retention and exacerbate edema in men with uncontrolled severe heart failure. Therefore, testosterone should not be administered in men with class III or IV congestive heart failure. Testosterone has been reported both to improve and exacerbate obstructive sleep apnea thus, obstructive sleep apnea is not an absolute contraindication for testosterone therapy. However, men with moderate or severe obstructive sleep apnea should be evaluated by a sleep specialist for consideration of bi-level positive airway pressure (BIPAP) before testosterone therapy is instituted.
Testosterone administration and monitoring The initial therapeutic regimens for various testosterone formulations, based on recommendation of the Endocrine Society Expert Panel, are shown in Table 56.3. The goal of testosterone therapy should be to restore serum testosterone levels to the mid-normal range (Figure 56.1). For men receiving testosterone cypionate or enanthate, serum testosterone levels should be measured midway between injections, typically 7 days after intramuscular injection. If serum testosterone level is greater than 700 ng/dL (24.5 nmol/liter), the dose should be reduced. If testosterone level is less than 350 ng/dL (12.3 nmol/liter), the dose should be increased. In men receiving the transdermal testosterone gel, assess testosterone level after patient has been on treatment for 1–2 weeks, ideally between 2 and 6 hours after gel application. In men prescribed a transdermal patch, testosterone levels should be assessed 4–12 h after application of the patch. For the buccal patch, testosterone levels should be measured immediately before application of fresh system.
Monitoring during androgen replacement is the collective responsibility of the patient and the physician. Since testosterone replacement is usually for life, the physician should emphasize the need for periodic evaluations and the patient must comply with them.
Symptomatic Relief Initial monitoring for symptom relief (improvement in libido, sexual function, energy and well-being) should be performed 3 months after initiation of therapy. Failure to benefit from therapy within a reasonable time interval (3–6 months) should result in investigation for other causes of symptoms [147]. Changes in BMD take longer to manifest and should be monitored as below.
BMD Obtain a baseline BMD of the lumbar spine, femoral neck and hip in all hypogonadal men. BMD should be repeated after 1–2 years of testosterone therapy to assess for interval changes in bone mass [146, 147].
Hematocrit Erythrocytosis is the most frequent adverse effect of testosterone therapy in clinical trials. Hematocrit should be measured at baseline, repeated at 3 months and then annually. The Endocrine Society specifies a hematocrit cut-off of 54%, above which testosterone therapy should be discontinued. If hematocrit rises above this level, testosterone therapy should be stopped until hematocrit decreases to a safe level. The patient should be evaluated for hypoxia and sleep apnea and therapy should be restarted at a reduced dose. A therapeutic phlebotomy at periodic intervals may be required in some cases.
Testosterone Concentration
Prostate Mid-normal range
T tr
T trajectory in the presence of T therapy
ajec
tory
Hypogonadal range
Severely hypogonadal range
T tr
ajec
tory
in th
e ab
sen
ce o
fracture risk increased
fTt
hera
py
Age
Figure 56.1 Conceptual model for testosterone therapy and its role in slowing or reversing declines in circulating testosterone levels and its hypothetical relationship to fracture risk.
Digital examination of the prostate and PSA measurement should be performed before initiating treatment, at 3 months, 12 months and annually thereafter depending upon the regional practice pattern. A major issue during monitoring of testosterone therapy relates to the rise of PSA. The issue here is what magnitude can be attributed to testosterone therapy and assay variability. A key question is: what magnitude of PSA increment should lead to urologic evaluation for consideration of prostate biopsy? Serum PSA levels are lower in androgen-deficient men and testosterone therapy increases serum PSA, although the testosterone-induced increment in PSA levels is small. In a meta-analysis of testosterone trials, the average PSA increment in healthy, young hypogonadal men was 0.3 ng/mL and in older men 0.44 ng/mL. Increments greater than 1 ng/mL are unusual in healthy androgen-deficient men given
C h a p t e r 5 6 Testosterone Therapy for Osteoporosis in Men l
testosterone therapy. The 90% confidence interval of PSA change between samples drawn 3–6 months apart in men assigned to the placebo arm of the finesteride trial [176] was 1.4 ng/mL. These considerations led the Endocrine Society Expert Panel to recommend that increments of 1.4 ng/mL or greater above baseline in any one-year period should warrant urologic evaluation and consideration of prostate biopsy. If longitudinal PSA data are available for more than 2 years, PSA velocity can be calculated to assess risk of prostate cancer. Based on the data published by Carter, PSA velocity of more than 0.4 ng/ml/year, using the PSA level after 6 months of testosterone administration as the reference, requires further urological evaluation [177]. PSA velocity should be used only if there are longitudinal PSA data for more than 2 years.
Other Since the risk of liver toxicity from testosterone has been limited almost exclusively to alkylated oral forms of testosterone, monitoring of liver function tests is not necessary during testosterone therapy. Both the ISSAM and AACE recommend that a fasting lipid profile be obtained prior to initiation of treatment and at regular intervals (no longer than 1 year) during treatment. Plasma lipids and other general health maintenance should be performed as dictated by patient’s age and local medical practice. The patient should be evaluated for formulation-specific adverse events at each visit. For instance, in men using buccal testosterone tablets, inquire about alterations in taste and examine gums and oral mucosa for irritation. The men receiving injectable testosterone esters should be asked about fluctuations in mood or libido. Also, hematocrit should be measured to detect excessive erythrocytosis, especially in older patients. Patients and physicians should monitor for signs of skin reaction at the site of patch or gel application. Patients who are using testosterone gel should be advised to cover the application site with clothing and wash the skin before having skin-to-skin contact, because gels leave a residue of testosterone on the skin that can be transferred to a woman or child who comes in close contact.
Use of testosterone therapy in men at risk for osteoporosis and fracture Men with HIV/AIDS There is a high prevalence of osteopenia and osteoporosis in HIV-infected men [178,179]. Several factors predispose to low BMD in HIV-infected patients. Cross-sectional surveys [180–182] report a high prevalence of low testosterone levels in HIV-infected men, even in those receiving anti-retroviral therapy. Low testosterone levels in these men have
705
been correlated with weight loss [183], loss of muscle mass and exercise capacity [184] and wasting, each of which is a risk factor for low BMD. Several studies have shown that testosterone therapy in HIV-infected men is associated with significant gains in body weight and lean body mass [185–191]. However, there is a paucity of studies evaluating the effects of testosterone therapy on bone remodeling and BMD changes in HIV-infected men. One study [124] showed that intramuscular testosterone enanthate, when given over a 3-month period to eugonadal HIV-infected men with wasting, increased lumbar spine BMD. While studies suggest that gains in lean body mass and body weight occur regardless of the route of administration of testosterone and its analogs, there is evidence that lean body mass gains are higher in HIV-infected men who received intramuscular testosterone [175]. Based on available evidence, the Endocrine Society Task Force suggests that clinicians consider short-term (3- to 6-month) testosterone therapy as an adjunctive therapy in HIV-infected men with low testosterone levels and weight loss to promote weight maintenance and gains in lean body mass and muscle strength. Additionally, appropriate counseling for safe sex practices should be provided.
Other Patient Populations Glucocorticoids suppress testosterone production by their effects at all levels of the hypothalamic–pituitary–testicular axis; not surprisingly, glucocorticoid-treated men have a high prevalence of low testosterone levels. Testosterone deficiency and changes in muscle and bone mass usually occur with the administration of more than 5–7.5 mg/d of prednisone or its equivalent [85,192]. Placebo-controlled trials of testosterone therapy in men receiving glucocorticoid treatment for bronchial asthma or chronic obstructive pulmonary disease have shown a greater gain in lean body mass and a greater decrease in fat mass than placebo and have reported significant increase in lumbar but not femoral BMD [85, 125]. Based on available evidence, which is undoubtedly very weak, the Endocrine Society Expert Panel suggested that clinicians offer short-term testosterone therapy to men receiving high doses of glucocorticoids who have low testosterone levels, to promote preservation of lean body mass and BMD. Other chronic disease states that are associated with hypogonadism are end-stage renal disease, chronic opioid use, chronic obstructive pulmonary disease and type 2 diabetes. Screening for testosterone deficiency is recommended but there are few data on the prevalence of reduced muscle mass and low BMD in these patient groups. The role of testosterone therapy in eugonadal men for the palliative treatment of severe secondary weight loss and presumably BMD loss, associated with chronic diseases such as HIV/AIDS, cancer, burns, postoperative recovery,
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end-stage renal disease and hepatic failure is controversial. While testosterone therapy appears to have a favorable effect on muscle catabolism, there are no formal guidelines for its use in these groups due to lack of evidence regarding the long-term benefits and risks.
Selective androgen receptor modulators (SARMs) Selective androgen receptor modulators (SARMs) are a class of androgen receptor ligands that bind androgen receptor and display tissue-selective activation of androgenic signaling [35,193,194]. Steroidal SARMs that are based on modification of the testosterone molecule have been around for over 60 years, but the last decade has witnessed the discovery of a number of non-steroidal SARMs that do not serve as substrates for CYP19 aromatase or 5alpha reductase, act as full agonists in muscle and bone and as partial agonists in prostate. The first generation nonsteroidal SARMs that are being developed for treatment of frailty, functional limitations associated with aging, cancer cachexia and osteoporosis, fall into a number of structural categories: aryl-propionamide, bicyclic hydantoin, quinolinones, tetrahydroquinoline analogs, benizimidazole, imidazolopyrazole, indole and pyrazoline derivaties, azasteroidal derivatives and aniline, diaryl aniline and bezoxazepinones derivatives. The precise molecular mechanisms of tissue selectivity of SARMs are not fully understood, but unique interactions of SARM ligands with androgen receptor result in specific conformational change in the androgen receptor protein, recruitment of a unique repertoire of co-regulator proteins thus contributing to their tissue-specific transcriptional regulation of gene expression. SARMs do not undergo aromatization or 5-alpha reduction and this may also contribute to their prostate-sparing effect. Preclinical studies of first generation SARMs in animal models have shown anabolic effects on skeletal muscle mass and bone mass and density and varying degree of tissue selectivity with respect to the prostate [193–196]. Early phase I and II trials have reported modest increments in fatfree mass and significant reductions in high density lipoprotein (HDL) cholesterol and SHBG. While SARMs show considerable appeal as anabolic agents for the treatment of osteoporosis as well as functional limitations associated with aging, long-term human studies containing large samples are required to prove their efficacy as well as resolve existing safety concerns.
Acknowledgments This work was supported by Award Numbers R01AG020727 and P30AG031679 from the National Institute on Aging. The content is solely the responsibility of the authors and does
not necessarily represent the official views of the National Institute on Aging or the National Institutes of Health.
References 1. S.J. Jacobsen, T.C. Cheetham, R. Haque, J.M. Shi, R.K. Loo, Association between 5-alpha reductase inhibition and risk of hip fracture, J. Am. Med. Assoc. 300 (14) (2008) 1660–1664. 2. J.K. Amory, B.D. Anawalt, A.M. Matsumoto, et al., The effect of 5alpha-reductase inhibition with dutasteride and finasteride on bone mineral density, serum lipoproteins, hemoglobin, prostate specific antigen and sexual function in healthy young men, J. Urol. 179 (6) (2008) 2333–2338. 3. A.M. Matsumoto, L. Tenover, M. McClung, et al., The long-term effect of specific type II 5alpha-reductase inhibition with finasteride on bone mineral density in men: results of a 4-year placebo controlled trial, J. Urol. 167 (5) (2002) 2105–2108. 4. H. Matzkin, J. Chen, Y. Weisman, et al., Prolonged treatment with finasteride (a 5 alpha-reductase inhibitor) does not affect bone density and metabolism, Clin. Endocrinol. (Oxf.) 37 (5) (1992) 432–436. 5. L.J. Melton 3rd, E.A. Chrischilles, C. Cooper, A.W. Lane, B.L. Riggs, Perspective. How many women have osteoporosis? J. Bone Miner. Res. 7 (9) (1992) 1005–1010. 6. J.A. Barrett, J.A. Baron, M.R. Karagas, M.L. Beach, Fracture risk in the US Medicare population, J. Clin. Epidemiol. 52 (3) (1999) 243–249. 7. A.C. Looker, E.S. Orwoll, C.C. Johnston, et al., Prevalence of low femoral bone density in older U.S. adults from NHANES III, J. Bone Miner. Res. 12 (11) (1997) 1761–1768. 8. R. Burge, B. Dawson-Hughes, D.H. Solomon, J.B. Wong, A. King, A. Tosteson, Incidence and economic burden of osteo porosis-related fractures in the United States, 2005–2025, J. Bone Miner. Res. 22 (3) (2007) 465–475. 9. L.J. Melton 3rd, Epidemiology of hip fractures: implications of the exponential increase with age, Bone 18 (Suppl. 3) (1996) 121S–125S. 10. B. Gullberg, O. Johnell, J.A. Kanis, World-wide projections for hip fracture, Osteoporos. Int. 7 (5) (1997) 407–413. 11. E.L. Schneider, J.M. Guralnik, The aging of America. Impact on health care costs, J. Am. Med. Assoc. 263 (17) (1990) 2335–2340. 12. J.R. Center, T.V. Nguyen, D. Schneider, P.N. Sambrook, J.A. Eisman, Mortality after all major types of osteoporotic fracture in men and women: an observational study, Lancet 353 (9156) (1999) 878–882. 13. C. Cooper, E.J. Atkinson, S.J. Jacobsen, W.M. O’Fallon, L.J. Melton III, Population-based study of survival after osteoporotic fractures, Am. J. Epidemiol. 137 (9) (1993) 1001–1005. 14. S.J. Jacobsen, J. Goldberg, T.P. Miles, J.A. Brody, W. Stiers, A.A. Rimm, Race and sex differences in mortality following fracture of the hip, Am. J. Public Health 82 (8) (1992) 1147–1150. 15. A.N. Tosteson, D.J. Gottlieb, D.C. Radley, E.S. Fisher, L.J. Melton 3rd, Excess mortality following hip fracture: the role of underlying health status, Osteoporos. Int. 18 (11) (2007) 1463–1472.
C h a p t e r 5 6 Testosterone Therapy for Osteoporosis in Men l
16. E.S. Fisher, J.A. Baron, D.J. Malenka, et al., Hip fracture incidence and mortality in New England, Epidemiology 2 (2) (1991) 116–122. 17. K.S. Markides, C.A. Stroup-Benham, J.S. Goodwin, L.C. Perkowski, M. Lichtenstein, L.A. Ray, The effect of medical conditions on the functional limitations of MexicanAmerican elderly, Ann. Epidemiol. 6 (5) (1996) 386–391. 18. M.C. Nevitt, B. Ettinger, D.M. Black, et al., The association of radiographically detected vertebral fractures with back pain and function: a prospective study, Ann. Intern. Med. 128 (10) (1998) 793–800. 19. S.E. Hall, J.A. Williams, J.A. Senior, P.R. Goldswain, R.A. Criddle, Hip fracture outcomes: quality of life and functional status in older adults living in the community, Aust. N. Z. J. Med. 30 (3) (2000) 327–332. 20. R. Norton, M. Butler, E. Robinson, T. Lee-Joe, A.J. Campbell, Declines in physical functioning attributable to hip fracture among older people: a follow-up study of casecontrol participants, Disabil. Rehabi. 22 (8) (2000) 345–351. 21. M.L. Bouxsein, E.R. Myers, W.C. Hayes, Biomechanics of age-related fractures, in: R. Marcus, D. Feldman, J.L. Kelsey (Eds.), Osteoporosis, Academic Press, San Diego, 1996. 22. E. Seeman, P.D. Delmas, Bone quality – the material and structural basis of bone strength and fragility, N. Engl. J. Med. 354 (21) (2006) 2250–2261. 23. A.B. Araujo, T.G. Travison, S.S. Harris, M.F. Holick, A.K. Turner, J.B. McKinlay, Race/ethnic differences in bone mineral density in men, Osteoporos. Int. 18 (7) (2007) 943–953. 24. A.C. Looker, H.W. Wahner, W.L. Dunn, et al., Updated data on proximal femur bone mineral levels of US adults, Osteoporos. Int. 8 (5) (1998) 468–489. 25. L.M. Marshall, J.M. Zmuda, B.K. Chan, et al., Race and ethnic variation in proximal femur structure and BMD among older men, J. Bone Miner. Res. 23 (1) (2008) 121–130. 26. B.L. Riggs, L.J. Melton, R.A. Robb, et al., A populationbased assessment of rates of bone loss at multiple skeletal sites: evidence for substantial trabecular bone loss in young adult women and men, J. Bone Miner. Res. 23 (2) (2008) 205–214. 27. R.N. Baumgartner, Body composition in healthy aging, Ann. NY Acad. Sci. 904 (2000) 437–448. 28. R. Roubenoff, V.A. Hughes, Sarcopenia: current concepts, J. Gerontol. A. Biol. Sci. Med. Sci. 55 (12) (2000) M716–M724. 29. R.N. Baumgartner, D.L. Waters, D. Gallagher, J.E. Morley, P.J. Garry, Predictors of skeletal muscle mass in elderly men and women, Mech. Ageing Dev. 107 (2) (1999) 123–136. 30. J.M. Kinney, Nutritional frailty, sarcopenia and falls in the elderly, Curr. Opin. Clin. Nutr. Metab. Care 7 (1) (2004) 15–20. 31. J.E. Morley, R.N. Baumgartner, R. Roubenoff, J. Mayer, K.S. Nair, Sarcopenia, J. Lab. Clin. Med. 137 (4) (2001) 231–243. 32. H.K. Kamel, Sarcopenia and aging, Nutr. Rev. 61 (5 Pt 1) (2003) 157–167. 33. J.R. Center, T.V. Nguyen, P.N. Sambrook, J.A. Eisman, Hormonal and biochemical parameters and osteoporotic fractures in elderly men, J. Bone Miner. Res. 15 (7) (2000) 1405–1411. 34. B.L. Riggs, S. Khosla, L.J. Melton 3rd, Sex steroids and the construction and conservation of the adult skeleton, Endocr. Rev. 23 (3) (2002) 279–302.
707
35. S. Bhasin, O.M. Calof, T.W. Storer, et al., Drug insight: Testosterone and selective androgen receptor modulators as anabolic therapies for chronic illness and aging, Nat. Clin. Pract. Endocrinol. Metab. 2 (3) (2006) 146–159. 36. R. Singh, J.N. Artaza, W.E. Taylor, et al., Testosterone inhibits adipogenic differentiation in 3T3-L1 cells: nuclear translocation of androgen receptor complex with beta-catenin and T-cell factor 4 may bypass canonical Wnt signaling to down-regulate adipogenic transcription factors, Endocrinology 147 (1) (2006) 141–154. 37. I.G. Brodsky, P. Balagopal, K.S. Nair, Effects of testosterone replacement on muscle mass and muscle protein synthesis in hypogonadal men – a clinical research center study, J. Clin. Endocrinol. Metab. 81 (10) (1996) 3469–3475. 38. A.A. Ferrando, M. Sheffield-Moore, et al., Testosterone administration to older men improves muscle function: molecular and physiological mechanisms, Am. J. Physiol. Endocrinol. Metab. 282 (3) (2002) E601–E607. 39. M. Cesari, B.W. Penninx, M. Pahor, et al., Inflammatory markers and physical performance in older persons: the InCHIANTI study, J. Gerontol. A. Biol. Sci. Med. Sci. 59 (3) (2004) 242–248. 40. D. Kapoor, S. Clarke, R. Stanworth, K.S. Channer, T.H. Jones, The effect of testosterone replacement therapy on adipocytokines and C-reactive protein in hypogonadal men with type 2 diabetes, Eur. J. Endocrinol. 156 (5) (2007) 595–602. 41. M. Maggio, S. Basaria, A. Ble, et al., Correlation between testosterone and the inflammatory marker soluble interleukin6 receptor in older men, J. Clin. Endocrinol. Metab. 91 (1) (2006) 345–347. 42. S.T. Page, K.L. Herbst, J.K. Amory, et al., Testosterone administration suppresses adiponectin levels in men, J. Androl. 26 (1) (2005) 85–92. 43. D.S. Colvard, E.F. Eriksen, P.E. Keeting, et al., Identification of androgen receptors in normal human osteoblast-like cells, Proc. Natl. Acad. Sci. USA 86 (3) (1989) 854–857. 44. L. Pederson, M. Kremer, J. Judd, et al., Androgens regulate bone resorption activity of isolated osteoclasts in vitro, Proc. Natl. Acad. Sci. USA 96 (2) (1999) 505–510. 45. Q. Chen, H. Kaji, T. Sugimoto, K. Chihara, Testosterone inhibits osteoclast formation stimulated by parathyroid hormone through androgen receptor, FEBS Lett. 491 (1-2) (2001) 91–93. 46. S. Khosla, Minireview: the OPG/RANKL/RANK system, Endocrinology 142 (12) (2001) 5050–5055. 47. B.F. Boyce, L. Xing, Functions of RANKL/RANK/OPG in bone modeling and remodeling, Arch. Biochem. Biophys. 473 (2) (2008) 139–146. 48. P. Szulc, L.C. Hofbauer, A.E. Heufelder, S. Roth, P.D. Delmas, Osteoprotegerin serum levels in men: correlation with age, estrogen, and testosterone status, J. Clin. Endocrinol. Metab. 86 (7) (2001) 3162–3165. 49. D.M. Huber, A.C. Bendixen, P. Pathrose, et al., Androgens suppress osteoclast formation induced by RANKL and macrophage-colony stimulating factor, Endocrinology 142 (9) (2001) 3800–3808. 50. L.C. Hofbauer, R.M. Ten, S. Khosla, The anti-androgen hydroxyflutamide and androgens inhibit interleukin-6 production by an androgen-responsive human osteoblastic cell line, J. Bone Miner. Res. 14 (8) (1999) 1330–1337.
708
Osteoporosis in Men
51. C.C. Pilbeam, L.G. Raisz, Effects of androgens on parathyroid hormone and interleukin-1-stimulated prostaglandin production in cultured neonatal mouse calvariae, J. Bone Miner. Res. 5 (11) (1990) 1183–1188. 52. A.B. Araujo, T.G. Travison, S. Bhasin, et al., Association between testosterone and estradiol and age-related decline in physical function in a diverse sample of men, J. Am. Geriatr. Soc. 56 (11) (2008) 2000–2008. 53. E. Orwoll, L.C. Lambert, L.M. Marshall, et al., Endogenous testosterone levels, physical performance, and fall risk in older men, Arch. Intern. Med. 166 (19) (2006) 2124–2131. 54. L.A. Schaap, S.M. Pluijm, J.H. Smit, et al., The association of sex hormone levels with poor mobility, low muscle strength and incidence of falls among older men and women, Clin. Endocrinol. (Oxf.) 63 (2) (2005) 152–160. 55. L.A. Schaap, S.M. Pluijm, D.J. Deeg, et al., Low testosterone levels and decline in physical performance and muscle strength in older men: findings from two prospective cohort studies, Clin. Endocrinol. (Oxf.) 68 (1) (2008) 42–50. 56. P. Szulc, B. Claustrat, F. Marchand, P.D. Delmas, Increased risk of falls and increased bone resorption in elderly men with partial androgen deficiency: the MINOS study, J. Clin. Endocrinol. Metab. 88 (11) (2003) 5240–5247. 57. T.A. Roy, M.R. Blackman, S.M. Harman, J.D. Tobin, M. Schrager, E.J. Metter, Interrelationships of serum testosterone and free testosterone index with FFM and strength in aging men, Am. J. Physiol. Endocrinol. Metab. 283 (2) (2002) E284–E294. 58. J.R. Center, T.V. Nguyen, P.N. Sambrook, J.A. Eisman, Hormonal and biochemical parameters in the determination of osteoporosis in elderly men, J. Clin. Endocrinol. Metab. 84 (10) (1999) 3626–3635. 59. J.R. Center, D. Bliuc, T.V. Nguyen, J.A. Eisman, Risk of subsequent fracture after low-trauma fracture in men and women, J. Am. Med. Assoc. 297 (4) (2007) 387–394. 60. H.A. Fink, S.K. Ewing, K.E. Ensrud, et al., Association of testosterone and estradiol deficiency with osteoporosis and rapid bone loss in older men, J. Clin. Endocrinol. Metab. 91 (10) (2006) 3908–3915. 61. G.A. Greendale, S. Edelstein, E. Barrett-Connor, Endogenous sex steroids and bone mineral density in older women and men: the Rancho Bernardo Study, J. Bone Miner. Res. 12 (11) (1997) 1833–1843. 62. S. Khosla, L.J. Melton III, E.J. Atkinson, W.M. O’Fallon, G. G. Klee, B.L. Riggs, Relationship of serum sex steroid levels and bone turnover markers with bone mineral density in men and women: a key role for bioavailable estrogen, J. Clin. Endocrinol. Metab. 83 (7) (1998) 2266–2274. 63. S. Khosla, L.J. Melton III, E.J. Atkinson, W.M. O’Fallon, Relationship of serum sex steroid levels to longitudinal changes in bone density in young versus elderly men, J. Clin. Endocrinol. Metab. 86 (8) (2001) 3555–3561. 64. S. Khosla, L.J. Melton III, R.A. Robb, et al., Relationship of volumetric BMD and structural parameters at different skeletal sites to sex steroid levels in men, J. Bone Miner. Res. 20 (5) (2005) 730–740. 65. M. Lorentzon, C. Swanson, N. Andersson, D. Mellstrom, C. Ohlsson, Free testosterone is a positive, whereas free estradiol is a negative, predictor of cortical bone size in young Swedish men: the GOOD study, J. Bone Miner. Res. 20 (8) (2005) 1334–1341.
66. D. Mellstrom, O. Johnell, O. Ljunggren, et al., Free testosterone is an independent predictor of BMD and prevalent fractures in elderly men: MrOS Sweden, J. Bone Miner. Res. 21 (4) (2006) 529–535. 67. P. Szulc, F. Munoz, B. Claustrat, et al., Bioavailable estradiol may be an important determinant of osteoporosis in men: the MINOS study, J. Clin. Endocrinol. Metab. 86 (1) (2001) 192–199. 68. P. Szulc, K. Uusi-Rasi, B. Claustrat, F. Marchand, T.J. Beck, P.D. Delmas, Role of sex steroids in the regulation of bone morphology in men, The MINOS study, Osteoporos. Int. 15 (11) (2004) 909–917. 69. A.B. Araujo, T.G. Travison, B.Z. Leder, J.B. McKinlay, Correlations between serum testosterone, estradiol, and sex hormone-binding globulin and bone mineral density in a diverse sample of men, J. Clin. Endocrinol. Metab. 93 (6) (2008) 2135–2141. 70. A. Bjornerem, N. Emaus, G.K. Berntsen, et al., Circulating sex steroids, sex hormone-binding globulin, and longitudinal changes in forearm bone mineral density in postmenopausal women and men: the Tromso study, Calcif. Tissue Int. 81 (2) (2007) 65–72. 71. L. Gennari, D. Merlotti, G. Martini, et al., Longitudinal association between sex hormone levels, bone loss, and bone turnover in elderly men, J. Clin. Endocrinol. Metab. 88 (11) (2003) 5327–5333. 72. I. Van Pottelbergh, S. Goemaere, J.M. Kaufman, Bioavailable estradiol and an aromatase gene polymorphism are determinants of bone mineral density changes in men over 70 years of age, J. Clin. Endocrinol. Metab. 88 (7) (2003) 3075–3081. 73. S. Amin, Y. Zhang, D.T. Felson, et al., Estradiol, testosterone, and the risk for hip fractures in elderly men from the Framingham Study, Am. J. Med. 119 (5) (2006) 426–433. 74. E. Barrett-Connor, J.E. Mueller, D.G. von Muhlen, G.A. Laughlin, D.L. Schneider, D.J. Sartoris, Low levels of estradiol are associated with vertebral fractures in older men, but not women: the Rancho Bernardo Study, J. Clin. Endocrinol. Metab. 85 (1) (2000) 219–223. 75. N.O. Kuchuk, N.M. van Schoor, S.M. Pluijm, J.H. Smit, W. de Ronde, P. Lips, The association of sex hormone levels with quantitative ultrasound, bone mineral density, bone turnover and osteoporotic fractures in older men and women, Clin. Endocrinol. (Oxf.) 67 (2) (2007) 295–303. 76. C. Meier, T.V. Nguyen, D.J. Handelsman, et al., Endogenous sex hormones and incident fracture risk in older men: the Dubbo Osteoporosis Epidemiology Study, Arch. Intern. Med. 168 (1) (2008) 47–54. 77. H.L. Stanley, B.P. Schmitt, R.M. Poses, W.P. Deiss, Does hypogonadism contribute to the occurrence of a minimal trauma hip fracture in elderly men?, J. Am. Geriatr. Soc. 39 (8) (1991) 766–771. 78. A. Bjornerem, L.A. Ahmed, R.M. Joakimsen, et al., A prospective study of sex steroids, sex hormone-binding globulin, and non-vertebral fractures in women and men: the Tromso Study, Eur. J. Endocrinol. 157 (1) (2007) 119–125. 79. H.W. Goderie-Plomp, M. van der Klift, W. de Ronde, A. Hofman, F.H. de Jong, H.A. Pols, Endogenous sex hormones, sex hormone-binding globulin, and the risk of incident vertebral fractures in elderly men and women: the Rotterdam Study, J. Clin. Endocrinol. Metab. 89 (7) (2004) 3261–3269.
C h a p t e r 5 6 Testosterone Therapy for Osteoporosis in Men l
80. D. Mellstrom, L. Vandenput, H. Mallmin, et al., Older men with low serum estradiol and high serum SHBG have an increased risk of fractures, J. Bone Miner. Res. 23 (10) (2008) 1552–1560. 81. A. Falahati-Nini, B.L. Riggs, E.J. Atkinson, W.M. O’Fallon, R. Eastell, S. Khosla, Relative contributions of testosterone and estrogen in regulating bone resorption and formation in normal elderly men, J. Clin. Invest. 106 (12) (2000) 1553–1560. 82. D. Vanderschueren, K. Venken, J. Ophoff, R. Bouillon, S. Boonen. Clinical review: sex steroids and the periosteum – reconsidering the roles of androgens and estrogens in periosteal expansion, J. Clin. Endocrinol. Metab. 91 (2) (2006) 378–382. 83. K. Venken, K. De Gendt, S. Boonen, et al., Relative impact of androgen and estrogen receptor activation in the effects of androgens on trabecular and cortical bone in growing male mice: a study in the androgen receptor knockout mouse model, J. Bone Miner. Res. 21 (4) (2006) 576–585. 84. S. Khosla, Oestrogen, bones and men: when testosterone just isn’t enough, Clin. Endocrinol. (Oxf.) 56 (3) (2002) 291–293. 85. B.A. Crawford, P.Y. Liu, M.T. Kean, J.F. Bleasel, D.J. Handelsman, Randomized placebo-controlled trial of androgen effects on muscle and bone in men requiring longterm systemic glucocorticoid treatment, J. Clin. Endocrinol. Metab. 88 (7) (2003) 3167–3176. 86. T.W. Storer, L. Magliano, L. Woodhouse, et al., Testosterone dose-dependently increases maximal voluntary strength and leg power, but does not affect fatigability or specific tension, J. Clin. Endocrinol. Metab. 88 (4) (2003) 1478–1485. 87. T.W. Storer, L. Woodhouse, L. Magliano, et al., Changes in muscle mass, muscle strength, and power but not physical function are related to testosterone dose in healthy older men, J. Am. Geriatr. Soc. 56 (11) (2008) 1991–1999. 88. A.M. Kenny, K.M. Prestwood, C.A. Gruman, K.M. Marcello, L.G. Raisz, Effects of transdermal testosterone on bone and muscle in older men with low bioavailable testosterone levels, J. Gerontol. A. Biol. Sci. Med. Sci. 56 (5) (2001) M266–M272. 89. S. Bhasin, L. Woodhouse, R. Casaburi, et al., Older men are as responsive as young men to the anabolic effects of graded doses of testosterone on the skeletal muscle, J. Clin. Endocrinol. Metab. 90 (2) (2005) 678–688. 90. M.H. Emmelot-Vonk, H.J. Verhaar, H.R. Nakhai Pour, et al., Effect of testosterone supplementation on functional mobility, cognition, and other parameters in older men: a randomized controlled trial, J. Am. Med. Assoc. 299 (1) (2008) 39–52. 91. K.S. Nair, R.A. Rizza, P. O’Brien, et al., DHEA in elderly women and DHEA or testosterone in elderly men, N. Engl. J. Med. 355 (16) (2006) 1647–1659. 92. P.J. Snyder, H. Peachey, J.A. Berlin, et al., Effects of testosterone replacement in hypogonadal men, J. Clin. Endocrinol. Metab. 85 (8) (2000) 2670–2677. 93. P.J. Snyder, H. Peachey, P. Hannoush, et al., Effect of testosterone treatment on body composition and muscle strength in men over 65 years of age, J. Clin. Endocrinol. Metab. 84 (8) (1999) 2647–2653. 94. L. Katznelson, J.S. Finkelstein, D.A. Schoenfeld, D.I. Rosenthal, E.J. Anderson, A. Klibanski, Increase in bone density and lean body mass during testosterone administration
95.
96.
97.
98. 99.
100.
101.
102.
103.
104.
105.
106.
107.
108.
109.
709
in men with acquired hypogonadism, J. Clin. Endocrinol. Metab. 81 (12) (1996) 4358–4365. M. Zitzmann, M. Brune, V. Vieth, E. Nieschlag, Monitoring bone density in hypogonadal men by quantitative phalangeal ultrasound, Bone 31 (3) (2002) 422–429. J.S. Finkelstein, A. Klibanski, R.M. Neer, S.L. Greenspan, D.I. Rosenthal, W.F. Crowley Jr., Osteoporosis in men with idiopathic hypogonadotropic hypogonadism, Ann. Intern. Med. 106 (3) (1987) 354–361. J. Finkelstein, A. Klibanski, R. Neer, et al., Increases in bone density during treatment of men with idiopathic hypogonadotropic hypogonadism, J. Clin. Endocrinol. Metab. 69 (1989) 776–783. H.W. Daniell, Osteoporosis after orchiectomy for prostate cancer, J. Urol. 157 (2) (1997) 439–444. H.W. Daniell, S.R. Dunn, D.W. Ferguson, G. Lomas, Z. Niazi, P.T. Stratte, Progressive osteoporosis during androgen deprivation therapy for prostate cancer, J. Urol. 163 (1) (2000) 181–186. S.L. Greenspan, P. Coates, S.M. Sereika, J.B. Nelson, D.L. Trump, N.M. Resnick, Bone loss after initiation of androgen deprivation therapy in patients with prostate cancer, J. Clin. Endocrinol. Metab. 90 (12) (2005) 6410–6417. L.J. Melton 3rd, K.I. Alothman, S. Khosla, S.J. Achenbach, A.L. Oberg, H. Zincke, Fracture risk following bilateral orchiectomy, J. Urol. 169 (5) (2003) 1747–1750. J.J. Stepan, M. Lachman, J. Zverina, V. Pacovsky, D.J. Baylink, Castrated men exhibit bone loss: effect of calcitonin treatment on biochemical indices of bone remodeling, J. Clin. Endocrinol. Metab. 69 (3) (1989) 523–527. D. Goldray, Y. Weisman, N. Jaccard, C. Merdler, J. Chen, H. Matzkin, Decreased bone density in elderly men treated with the gonadotropin-releasing hormone agonist decapeptyl (D-Trp6-GnRH), J. Clin. Endocrinol. Metab. 76 (2) (1993) 288–290. S. Bertelloni, G.I. Baroncelli, G. Federico, M. Cappa, R. Lala, G. Saggese, Altered bone mineral density in patients with complete androgen insensitivity syndrome, Horm. Res. 50 (6) (1998) 309–314. D.L. Danilovic, P.H. Correa, E.M. Costa, K.F. Melo, B.B. Mendonca, I.J. Arnhold, Height and bone mineral density in androgen insensitivity syndrome with mutations in the androgen receptor gene, Osteoporos. Int. 18 (3) (2007) 369–374. R. Marcus, D. Leary, D.L. Schneider, E. Shane, M. Favus, C.A. Quigley, The contribution of testosterone to skeletal development and maintenance: lessons from the androgen insensitivity syndrome, J. Clin. Endocrinol. Metab. 85 (3) (2000) 1032–1037. V. Sobel, B. Schwartz, Y.S. Zhu, J.J. Cordero, J. ImperatoMcGinley, Bone mineral density in the complete androgen insensitivity and 5alpha-reductase-2 deficiency syndromes, J. Clin. Endocrinol. Metab. 91 (8) (2006) 3017–3023. G.L. Andriole, R. Kirby, Safety and tolerability of the dual 5alpha-reductase inhibitor dutasteride in the treatment of benign prostatic hyperplasia, Eur. Urol. 44 (1) (2003) 82–88. P.J. Snyder, H. Peachey, P. Hannoush, et al., Effect of testosterone treatment on bone mineral density in men over 65 years of age, J. Clin. Endocrinol. Metab. 84 (6) (1999) 1966–1972.
710
Osteoporosis in Men
110. J.K. Amory, N.B. Watts, K.A. Easley, et al., Exogenous testosterone or testosterone with finasteride increases bone mineral density in older men with low serum testosterone, J. Clin. Endocrinol. Metab. 89 (2) (2004) 503–510. 111. L. Basurto, A. Zarate, R. Gomez, C. Vargas, R. Saucedo, R. Galvan, Effect of testosterone therapy on lumbar spine and hip mineral density in elderly men, Aging Male 11 (3) (2008) 140–145. 112. G.M. Hall, J.P. Larbre, T.D. Spector, L.A. Perry, J.A. Da Silva, A randomized trial of testosterone therapy in males with rheumatoid arthritis, Br. J. Rheumatol. 35 (6) (1996) 568–573. 113. H.M. Behre, S. Kliesch, E. Leifke, T.M. Link, E. Nieschlag, Long-term effect of testosterone therapy on bone mineral density in hypogonadal men, J. Clin. Endocrinol. Metab. 82 (8) (1997) 2386–2390. 114. E. Leifke, H.C. Korner, T.M. Link, H.M. Behre, P.E. Peters, E. Nieschlag, Effects of testosterone replacement therapy on cortical and trabecular bone mineral density, vertebral body area and paraspinal muscle area in hypogonadal men, Eur. J. Endocrinol. 138 (1) (1998) 51–58. 115. H.M. Behre, S. von Eckardstein, S. Kliesch, E. Nieschlag, Long-term substitution therapy of hypogonadal men with transscrotal testosterone over 7–10 years, Clin. Endocrinol. (Oxf.) 50 (5) (1999) 629–635. 116. M. De Rosa, L. Paesano, V. Nuzzo, et al., Bone mineral density and bone markers in hypogonadotropic and hypergonadotropic hypogonadal men after prolonged testosterone treatment, J. Endocrinol. Invest. 24 (4) (2001) 246–252. 117. S.J. Howell, J.A. Radford, J.E. Adams, E.M. Smets, R. Warburton, S.M. Shalet, Randomized placebo-controlled trial of testosterone replacement in men with mild Leydig cell insufficiency following cytotoxic chemotherapy, Clin. Endocrinol. (Oxf.) 55 (3) (2001) 315–324. 118. C. Christmas, K.G. O’Connor, S.M. Harman, et al., Growth hormone and sex steroid effects on bone metabolism and bone mineral density in healthy aged women and men, J. Gerontol. A. Biol. Sci. Med. Sci. 57 (1) (2002) M12–M18. 119. M. Schubert, C. Bullmann, T. Minnemann, C. Reiners, W. Krone, F. Jockenhovel, Osteoporosis in male hypogonadism: responses to androgen substitution differ among men with primary and secondary hypogonadism, Horm. Res. 60 (1) (2003) 21–28. 120. C. Wang, G. Cunningham, A. Dobs, et al., Long-term testosterone gel (AndroGel) treatment maintains beneficial effects on sexual function and mood, lean and fat mass, and bone mineral density in hypogonadal men, J. Clin. Endocrinol. Metab. 89 (5) (2004) 2085–2098. 121. O. Arisaka, M. Arisaka, Y. Nakayama, S. Fujiwara, K. Yabuta, Effect of testosterone on bone density and bone metabolism in adolescent male hypogonadism, Metabolism 44 (4) (1995) 419–423. 122. F.H. Anderson, R.M. Francis, K. Faulkner, Androgen supplementation in eugonadal men with osteoporosis – effects of 6 months of treatment on bone mineral density and cardiovascular risk factors, Bone 18 (2) (1996) 171–177. 123. F.H. Anderson, R.M. Francis, R.T. Peaston, H.J. Wastell, Androgen supplementation in eugonadal men with osteo porosis: effects of six months’ treatment on markers of bone
124.
125.
126.
127.
128.
129.
130. 131.
132.
133.
134.
135.
136.
137.
138.
formation and resorption, J. Bone Miner. Res. 12 (3) (1997) 472–478. W.P. Fairfield, J.S. Finkelstein, A. Klibanski, S.K. Grinspoon, Osteopenia in eugonadal men with acquired immune deficiency syndrome wasting syndrome, J. Clin. Endocrinol. Metab. 86 (5) (2001) 2020–2026. I.R. Reid, D.J. Wattie, M.C. Evans, J.P. Stapleton, Testosterone therapy in glucocorticoid-treated men, Arch. Intern. Med. 156 (11) (1996) 1173–1177. T. Diamond, D. Stiel, S. Posen, Effects of testosterone and venesection on spinal and peripheral bone mineral in six hypogonadal men with hemochromatosis, J. Bone Miner. Res. 6 (1) (1991) 39–43. J.S. Finkelstein, R.M. Neer, B.M. Biller, J.D. Crawford, A. Klibanski, Osteopenia in men with a history of delayed puberty, N. Engl. J. Med. 326 (9) (1992) 600–604. A.M. Isidori, E. Giannetta, E.A. Greco, et al., Effects of testosterone on body composition, bone metabolism and serum lipid profile in middle-aged men: a meta-analysis, Clin. Endocrinol. (Oxf.) 63 (3) (2005) 280–293. M.J. Tracz, K. Sideras, E.R. Bolona, et al., Testosterone use in men and its effects on bone health. A systematic review and meta-analysis of randomized placebo-controlled trials, J. Clin. Endocrinol. Metab. 91 (6) (2006) 2011–2016. R.R. Recker, Architecture and vertebral fracture, Calcif. Tissue Int. 53 (Suppl. 1) (1993) S139–S142. S.C. Schuit, M. van der Klift, A.E. Weel, et al., Fracture incidence and association with bone mineral density in elderly men and women: the Rotterdam Study, Bone 34 (1) (2004) 195–202. E.S. Siris, S.K. Brenneman, P.D. Miller, et al., Predictive value of low BMD for 1-year fracture outcomes is similar for postmenopausal women ages 50-64 and 65 and older: results from the National Osteoporosis Risk Assessment (NORA), J. Bone Miner. Res. 19 (8) (2004) 1215–1220. K.L. Stone, D.G. Seeley, L.Y. Lui, et al., BMD at multiple sites and risk of fracture of multiple types: long-term results from the Study of Osteoporotic Fractures, J. Bone Miner. Res. 18 (11) (2003) 1947–1954. World Health Organization, WHO Technical Report Series 843: Assessment of Fracture Risk and its Application to Screening for Postmenopausal Osteoporosis: Report of a WHO Study Group, World Health Organization, Geneva, 1994. P.D. Delmas, E. Seeman, Changes in bone mineral density explain little of the reduction in vertebral or nonvertebral fracture risk with anti-resorptive therapy, Bone 34 (4) (2004) 599–604. S.R. Cummings, D.B. Karpf, F. Harris, et al., Improvement in spine bone density and reduction in risk of vertebral fractures during treatment with antiresorptive drugs, Am. J. Med. 112 (4) (2002) 281–289. S. Sarkar, B.H. Mitlak, M. Wong, J.L. Stock, D.M. Black, K.D. Harper, Relationships between bone mineral density and incident vertebral fracture risk with raloxifene therapy, J. Bone Miner. Res. 17 (1) (2002) 1–10. S. Majumdar, M. Kothari, P. Augat, et al., High-resolution magnetic resonance imaging: three-dimensional trabecular bone architecture and biomechanical properties, Bone 22 (5) (1998) 445–454.
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139. D. Ulrich, B. van Rietbergen, A. Laib, P. Ruegsegger, The ability of three-dimensional structural indices to reflect mechanical aspects of trabecular bone, Bone 25 (1) (1999) 55–60. 140. M. Benito, B. Gomberg, F.W. Wehrli, et al., Deterioration of trabecular architecture in hypogonadal men, J. Clin. Endocrinol. Metab. 88 (4) (2003) 1497–1502. 141. M. Benito, B. Vasilic, F.W. Wehrli, et al., Effect of testosterone replacement on trabecular architecture in hypogonadal men, J. Bone Miner. Res. 20 (10) (2005) 1785–1791. 142. X.H. Zhang, X.S. Liu, B. Vasilic, et al., In vivo microMRIbased finite element and morphological analyses of tibial trabecular bone in eugonadal and hypogonadal men before and after testosterone treatment, J. Bone Miner. Res. 23 (9) (2008) 1426–1434. 143. S. Khosla, L.J. Melton 3rd, S.J. Achenbach, A.L. Oberg, B.L. Riggs, Hormonal and biochemical determinants of trabecular microstructure at the ultradistal radius in women and men, J. Clin. Endocrinol. Metab. 91 (3) (2006) 885–891. 144. A. Morales, B. Lunenfeld, Investigation, treatment and monitoring of late-onset hypogonadism in males. Official recommendations of ISSAM. International Society for the Study of the Aging Male, Aging Male 5 (2) (2002) 74–86. 145. S.M. Petak, H.R. Nankin, R.F. Spark, R.S. Swerdloff, L.J. Rodriguez-Rigau, American Association of Clinical Endocrinologists Medical Guidelines for clinical practice for the evaluation and treatment of hypogonadism in adult male patients – 2002 update, Endocr. Pract. 8 (6) (2002) 440–456. 146. S. Bhasin, G.R. Cunningham, F.J. Hayes, et al., Testosterone therapy in adult men with androgen deficiency syndromes: an endocrine society clinical practice guideline, J. Clin. Endocrinol. Metab. 91 (6) (2006) 1995–2010. 147. C. Wang, E. Nieschlag, R. Swerdloff, et al., Investigation, treatment and monitoring of late-onset hypogonadism in males: ISA, ISSAM, EAU, EAA and ASA recommendations, Eur. J. Endocrinol. 159 (5) (2008) 507–514. 148. M. Zitzmann, S. Faber, E. Nieschlag, Association of specific symptoms and metabolic risks with serum testosterone in older men, J. Clin. Endocrinol. Metab. 91 (11) (2006) 4335–4343. 149. S. Kelleher, A.J. Conway, DJ. Handelsman, Blood testosterone threshold for androgen deficiency symptoms, J. Clin. Endocrinol. Metab. 89 (8) (2004) 3813–3817. 150. W. Rosner, R.J. Auchus, R. Azziz, P.M. Sluss, H. Raff, Utility, limitations, and pitfalls in measuring testosterone: an Endocrine Society position statement, J. Clin. Endocrinol. Metab. 92 (2) (2007) 405–413. 151. D.J. Brambilla, A.M. Matsumoto, A.B. Araujo, J.B. McKinlay, The effect of diurnal variation on clinical measurement of serum testosterone and other sex hormone levels in men, J. Clin. Endocrinol. Metab. 94 (3) (2009) 907–913. 152. D.J. Brambilla, A.B. O’Donnell, A.M. Matsumoto, J.B. McKinlay, Intraindividual variation in levels of serum testosterone and other reproductive and adrenal hormones in men, Clin. Endocrinol. (Oxf.) 67 (6) (2007) 853–862. 153. A. Vermeulen, L. Verdonck, J.M. Kaufman, A critical evaluation of simple methods for the estimation of free testosterone in serum, J. Clin. Endocrinol. Metab. 84 (10) (1999) 3666–3672. 154. R. Södergard, T. Backstrom, V. Shanbhag, H. Carstensen, Calculation of free and bound fractions of testosterone and
155.
156.
157.
158.
159.
160.
161.
162.
163.
164. 165.
166.
167.
168.
169.
711
estradiol-17 beta to human plasma proteins at body temperature, J. Steroid. Biochem. 16 (6) (1982) 801–810. H.A. Feldman, C. Longcope, C.A. Derby, et al., Age trends in the level of serum testosterone and other hormones in middleaged men: longitudinal results from the Massachusetts male aging study, J. Clin. Endocrinol. Metab. 87 (2) (2002) 589–598. S.M. Harman, E.J. Metter, J.D. Tobin, J. Pearson, M.R. Blackman, Longitudinal effects of aging on serum total and free testosterone levels in healthy men. Baltimore Longitudinal Study of Aging, J. Clin. Endocrinol. Metab. 86 (2) (2001) 724–731. S. Bhasin, L. Woodhouse, R. Casaburi, et al., Testosterone dose-response relationships in healthy young men, Am. J. Physiol. Endocrinol. Metab. 281 (6) (2001) E1172–E1181. E. Nieschlag, H.J. Cuppers, W. Wiegelmann, E.J. Wickings. Bioavailability and LH-suppressing effect of different testosterone preparations in normal and hypogonadal men, Horm. Res. 7 (3) (1976) 138–145. P.J. Snyder, D.A. Lawrence, Treatment of male hypogonadism with testosterone enanthate, J. Clin. Endocrinol. Metab. 51 (6) (1980) 1335–1339. C.J. Partsch, G.F. Weinbauer, R. Fang, E. Nieschlag, Injectable testosterone undecanoate has more favourable pharmacokinetics and pharmacodynamics than testosterone enanthate, Eur. J. Endocrinol. 132 (4) (1995) 514–519. M. Schubert, T. Minnemann, D. Hubler, et al., Intramuscular testosterone undecanoate: pharmacokinetic aspects of a novel testosterone formulation during long-term treatment of men with hypogonadism, J. Clin. Endocrinol. Metab. 89 (11) (2004) 5429–5434. T. Minnemann, M. Schubert, S. Freude, et al., Comparison of a new long-acting testosterone undecanoate formulation vs testosterone enanthate for intramuscular androgen therapy in male hypogonadism, J. Endocrinol. Invest. 31 (8) (2008) 718–723. J.P. Devogelaer, S. De Cooman, C. Nagant de Deuxchaisnes, Low bone mass in hypogonadal males. Effect of testosterone substitution therapy, a densitometric study, Maturitas 15 (1) (1992) 17–23. R.M. Francis, The effects of testosterone on osteoporosis in men, Clin. Endocrinol. (Oxf.) 50 (4) (1999) 411–414. R.J. Feldmann, H.I. Maibach, Regional variation in percutaneous penetration of 14C cortisol in man, J. Invest. Dermatol. 48 (2) (1967) 181–183. A.S. Dobs, A.W. Meikle, S. Arver, S.W. Sanders, K.E. Caramelli, N.A. Mazer, Pharmacokinetics efficacy, and safety of a permeation-enhanced testosterone transdermal system in comparison with bi-weekly injections of testosterone enanthate for the treatment of hypogonadal men, J. Clin. Endocrinol. Metab. 84 (10) (1999) 3469–3478. W.P. Jordan Jr., Allergy and topical irritation associated with transdermal testosterone administration: a comparison of scrotal and nonscrotal transdermal systems, Am. J. Contact. Dermatol. 8 (2) (1997) 108–113. R.S. Swerdloff, C. Wang, G. Cunningham, et al., Long-term pharmacokinetics of transdermal testosterone gel in hypogonadal men, J. Clin. Endocrinol. Metab. 85 (12) (2000) 4500–4510. C. Wang, R.S. Swerdloff, A. Iranmanesh, et al., Effects of transdermal testosterone gel on bone turnover markers and
712
170.
171.
172.
173.
174.
175.
176.
177. 178.
179.
180.
181.
182.
Osteoporosis in Men bone mineral density in hypogonadal men, Clin. Endocrinol. (Oxf.) 54 (6) (2001) 739–750. A. Coert, J. Geelen, J. de Visser, J. van der Vies, The pharmacology and metabolism of testosterone undecanoate (TU), a new orally active androgen, Acta Endocrinol. (Copenh.) 79 (4) (1975) 789–800. T. Schurmeyer, E.J. Wickings, C.W. Freischem, E. Nieschlag, Saliva and serum testosterone following oral testosterone undecanoate administration in normal and hypogonadal men, Acta Endocrinol. (Copenh.) 102 (3) (1983) 456–462. D.J. Handelsman, M.A. Mackey, C. Howe, L. Turner, A.J. Conway, An analysis of testosterone implants for androgen replacement therapy, Clin. Endocrinol. (Oxf.) 47 (3) (1997) 311–316. S. Kelleher, L. Turner, C. Howe, A.J. Conway, D.J. Handelsman, Extrusion of testosterone pellets: a randomized controlled clinical study, Clin. Endocrinol. (Oxf.) 51 (4) (1999) 469–471. M.R. Zacharin, J. Pua, S. Kanumakala, Bone mineral density outcomes following long-term treatment with subcutaneous testosterone pellet implants in male hypogonadism, Clin. Endocrinol. (Oxf.) 58 (6) (2003) 691–695. A. Kong, P. Edmonds, Testosterone therapy in HIV wasting syndrome: systematic review and meta-analysis, Lancet Infect. Dis. 2 (11) (2002) 692–699. G.J. Gormley, E. Stoner, R.C. Bruskewitz, et al., The effect of finasteride in men with benign prostatic hyperplasia. The Finasteride Study Group, N. Engl. J. Med. 327 (17) (1992) 1185–1191. H.B. Carter, PSA variability versus velocity, Urology 49 (1997) 305. C. Cazanave, M. Dupon, V. Lavignolle-Aurillac, et al., Reduced bone mineral density in HIV-infected patients: prevalence and associated factors, AIDS 22 (3) (2008) 395–402. H. Knobel, A. Guelar, G. Vallecillo, X. Nogues, A. Diez, Osteopenia in HIV-infected patients: is it the disease or is it the treatment?, AIDS 15 (6) (2001) 807–808. S. Arver, I. Sinha-Hikim, G. Beall, M. Guerrero, R. Shen, S. Bhasin, Serum dihydrotestosterone and testosterone concentrations in human immunodeficiency virus-infected men with and without weight loss, J. Androl. 20 (5) (1999) 611–618. P. Rietschel, C. Corcoran, T. Stanley, N. Basgoz, A. Klibanski, S. Grinspoon, Prevalence of hypogonadism among men with weight loss related to human immunodeficiency virus infection who were receiving highly active antiretroviral therapy, Clin. Infect. Dis. 31 (5) (2000) 1240–1244. A.S. Dobs, W.L. Few 3rd, M.R. Blackman, S.M. Harman, D.R. Hoover, N.M. Graham, Serum hormones in men with human immunodeficiency virus-associated wasting, J. Clin. Endocrinol. Metab. 81 (11) (1996) 4108–4112.
183. G.O. Coodley, M.O. Loveless, H.D. Nelson, M.K. Coodley, Endocrine function in the HIV wasting syndrome, J. Acquir. Immune. Defic. Syndr. 7 (1) (1994) 46–51. 184. S. Grinspoon, C. Corcoran, K. Lee, B. Burrows, J. Hubbard, L. Katznelson, et al., Loss of lean body and muscle mass correlates with androgen levels in hypogonadal men with acquired immunodeficiency syndrome and wasting, J. Clin. Endocrinol. Metab. 81 (11) (1996) 4051–4058. 185. J.R. Berger, L. Pall, C.D. Hall, D.M. Simpson, P.S. Berry, R. Dudley, Oxandrolone in AIDS-wasting myopathy, AIDS. 10 (14) (1996) 1657–1662. 186. S. Bhasin, T.W. Storer, N. Asbel-Sethi, et al., Effects of testosterone replacement with a nongenital, transdermal system, Androderm, in human immunodeficiency virus-infected men with low testosterone levels, J. Clin. Endocrinol. Metab. 83 (9) (1998) 3155–3162. 187. S. Bhasin, T.W. Storer, M. Javanbakht, et al., Testosterone replacement and resistance exercise in HIV-infected men with weight loss and low testosterone levels, J. Am. Med. Assoc. 283 (6) (2000) 763–770. 188. S. Grinspoon, C. Corcoran, K. Parlman, et al., Effects of testosterone and progressive resistance training in eugonadal men with AIDS wasting. A randomized, controlled trial, Ann. Intern. Med. 133 (5) (2000) 348–355. 189. S. Grinspoon, C. Corcoran, T. Stanley, L. Katznelson, A. Klibanski, Effects of androgen administration on the growth hormone-insulin-like growth factor I axis in men with acquired immunodeficiency syndrome wasting, J. Clin. Endocrinol. Metab. 83 (12) (1998) 4251–4256. 190. J. Gold, H.A. High, Y. Li, et al., Safety and efficacy of nandrolone decanoate for treatment of wasting in patients with HIV infection, AIDS 10 (7) (1996) 745–752. 191. S. Bhasin, R.A. Parker, F. Sattler, et al., Effects of testosterone supplementation on whole body and regional fat mass and distribution in human immunodeficiency virus-infected men with abdominal obesity, J. Clin. Endocrinol. Metab. 92 (3) (2007) 1049–1057. 192. T.P. van Staa, H.G. Leufkens, C. Cooper, Does a fracture at one site predict later fractures at other sites? A British cohort study, Osteoporos. Int. 13 (8) (2002) 624–629. 193. S. Bhasin, R. Jasuja, Selective androgen receptor modulators, Curr. Opinion. Nutr. Metab. (2009) In press. 194. R. Narayanan, M.L. Mohler, C.E. Bohl, D.D. Miller, J.T. Dalton, Selective androgen receptor modulators in preclinical and clinical development, Nucl. Recept. Signal. 6 (2008) e010. 195. J.T. Dalton, A. Mukherjee, Z. Zhu, L. Kirkovsky, D.D. Miller, Discovery of nonsteroidal androgens, Biochem. Biophys. Res. Commun. 244 (1) (1998) 1–4. 196. J.N. Miner, W. Chang, M.S. Chapman, et al., An orally active selective androgen receptor modulator is efficacious on bone, muscle, and sex function with reduced impact on prostate, Endocrinology 148 (1) (2007) 363–373.
Chapter
57
Future Therapies: Strontium, SERMs, SARMs and New Therapies on the Horizon Mahmoud Tabbal and Ghada El-Hajj Fuleihan Calcium Metabolism and Osteoporosis Program, American University of Beirut Medical Center, Beirut, Lebanon
Introduction
diseases. The development of bisphosphonates, SERMs, parathyroid hormone (PTH) and strontium have stemmed from astute observations on their beneficial effect on bone. Conversely, mouse genetics studies have unraveled the genetic basis of rare inherited skeletal syndromes. These investigations have shed light on key genes and pathways regulating osteoclast and osteoblast formation, differentiation and function and simultaneously paved the way for new drug development [9, 11–13]. Two prominent signaling pathways, the receptor activator of the nuclear factor kappa B (RANK)/RANK ligand (RANKL) pathway and the Wnt canonical signaling pathway, are important targets for drug development through the use of ligands specific to RANKL or to the Wnt-lipoprotein receptor related protein (LRP) 5/6-frizzeled (Fzd) receptor complex (Wnt-LRP5/6-Fzd). In this chapter we will review strontium, SERMs, SARMs and other new therapies on the horizon.
Although one-third to one-half of men with osteoporosis may have secondary osteoporosis [1], an important proportion have idiopathic disease and would be expected to respond to therapies approved for use in postmenopausal osteoporosis. Indeed, the evidence from trials conducted in men using bisphosphonates and teriparatide confirms an anti-fracture efficacy that is comparable to that reported in women. Sex steroids play a pivotal role in skeletal health in young men and, although declining sex steroid levels contribute to agerelated bone loss, the relative importance of estrogen and androgens is not fully elucidated. It may vary by skeletal envelope and life stage and may be modulated by genetic, environmental, hormonal and enzymatic influences [2–6]. These observations have led to interest in developing selective estrogen receptor modulators (SERMs) and selective androgen receptor modulators (SARMs) for the treatment of osteoporosis in men. Osteoporosis therapies affect bone remodeling, maintain or increase bone mass and decrease fracture risk, either through anti-catabolic or through anabolic effects [7]. Due to the coupling of resorption and formation, the changes in resorption or formation in response to the above therapies are usually in the same direction, resulting in initial increments in bone mass that ultimately plateau [7]. Although anti-catabolic therapies have substantially improved care for osteoporosis over the last decade, the idea that anabolic agents that reconstruct the osteoporotic skeleton has great conceptual appeal [8–10]. The last two decades have witnessed quantum leaps of progress in our understanding of bone biology and in gaining insight into pathophysiology of metabolic bone Osteoporosis in Men
Strontium Strontium is an alkaline earth element originally discovered in lead mines in Strontian, Scotland, in the late 1700s [14]. It is present in trace quantities in water and food and is poorly absorbed, actively concentrated in areas of active osteogenesis by ionic substitution at the surfaces of crystals embedded within the bone matrix and is excreted largely through renal pathways. Strontium was used for the treatment of osteoporosis in the 1950s and was also used for the treatment of painful bone metastatic disease, as the -emitting strontium-89 isotope. It fell out of favor, however, due to mineralization defects possibly explained by 713
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dietary factors and formulation issues [14]. Over the last decade, strontium has been developed in a different formulation, strontium ranelate. Strontium ranelate is available for the treatment of osteoporosis worldwide, with a major exception being the USA where the Food and Drug Administration (FDA) has not received an application for its review. Its safety and efficacy in men are being investigated in an ongoing trial entitled ‘The efficacy and safety of strontium ranelate in the treatment of male osteoporosis a randomized controlled trial’ – The MALEO study. The trial randomizes 221 Caucasian males with osteoporosis from 15 countries, aged more than 65 years, to 2 g of strontium ranelate versus placebo over 2 years. The primary outcome is lumbar spine bone mineral density (BMD) and secondary outcomes are BMD at the hip and bone markers. The anticipated end date for this study is October 15, 2009, principal analysis for the one year data is expected in 2010 and 2-year analyses in 2011 (http://www.controlled-trials. com/ISRCTN49960746/strontiumranelate).
Preclinical Studies Effect of strontium ranelate on Bone Remodeling in Cell Lines and Animal Studies Strontium ranelate increases the proliferation and differentiation of osteoblastic cells in a dose-dependent fashion, an effect mediated, at least in part, through the cyclo-oxygenase 2-prostaglandin E2 pathway [15]. At a concentration of 1 mM, strontium ranelate (S12911) increased the replication of pre-osteoblastic cells, increased bone formation rate (BFR) by 20–35% and stimulated the synthesis of collagen and non-collagenous proteins by 35% [16]. Whether administered during the phase of osteoblast proliferation (day 1–5) or differentiation (day 5–22) in primary osteoblast cell cultures from murine calvariae, strontium ranelate significantly increased bone nodule numbers [17]. Strontium induced an osteocyte phenotype at a dose of 5 mM or greater and significantly increased in vitro mineralization [18]. It was also shown to upregulate osteoprotegerin (OPG), thus promoting inhibition of osteoblast-induced osteoclastogenesis through inhibition of the RANK/RANKL system [18]. The impact of strontium ranelate on replication of cells from the osteo blastic lineage may occur through two distinct mechanisms, one involving a calcium-sensing receptor (CaSR)-mediated stimulation of mitogenic signals and another through the regulation of a putative autocrine growth factor [19, 20]. Strontium ranelate was also shown to inhibit the differentiation, but not the numbers, of osteoclasts [17, 21], to decrease markers of osteoclast function and to reduce bone resorbing activity and bone resorption pits [19, 21, 22]. Strontium ranelate treatment was also associated with a disruption of the osteoclast actin-containing sealing zone that is essential for bone resorption [17]. In addition to its effects on the OPG/ RANKL pathway described above, the inhibitory effect of strontium ranelate on osteoclastogenesis is also mediated, in
part, through the CaSR, with stimulation of a phospholipase C-dependent signaling pathway and enhancement of nuclear translocation of nuclear factor of activated T cells B (NF-B), leading to apoptosis of mature osteoclasts [23]. This strontiuminduced apoptosis, unlike that elicited by calcium, depends on protein kinase C II (PKCII) activation and not inositol 1,4,5-triphosphate action. Strontium ranelate-induced osteoclast apoptosis may thus potentiate calcium-induced osteoclast apoptosis through an additive mechanism [23]. The strontium ranelate-induced dissociation between bone formation and resorption was also demonstrated in intact animal models, including rats, mice and monkeys, as well as in ovariectomized or immobilized rats [24]. Administration of strontium ranelate to ovariectomized rats, at doses of 77, 154 or 308 mg/kg/day for 2 months, reduced, but did not abolish, bone loss at the tibial metaphysis, so that trabecular volume loss was only partially prevented. Similarly, at comparable doses, strontium ranelate was able to reduce bone resorption and long bone loss that was induced by hind limb immobilization in rats, but it did not prevent or reverse decrements in parameters of bone formation induced by immobilization, such as reductions in osteoblast surfaces, mineral apposition rate (MAR) and BFR [25]. Similarly, in adult monkeys, administration of strontium ranelate for 6 months at doses of 100, 275 and 750 mg/kg decreased osteoclast surface (OcS) and number by five- to sixfold, without any change in bone formation parameters [26]. Finally, in ovariectomized rats, strontium ranelate administration for 90 days, at doses of 25 or 150 mg/kg/day, did not increase bone formation at either trabecular or periosteal surfaces and did not inhibit trabecular bone resorption. In that study, no improvements in bone strength could be demonstrated [27]. Bone Distribution of Strontium and Effects on Bone Morphology and Bone Material Properties Strontium ranelate given to 30 monkeys for 52 weeks at doses of 200–1250 mg/kg/day was detected in bone mineral substance of both old and new cortical and cancellous bone, but the content was 1.6 times higher in new bone as compared to old bone [28]. Ten weeks after withdrawal, strontium content decreased by 50% but did so only in new bone tissue. Preservation of crystal characteristics suggests that strontium linked to bone mineral substance is probably adsorbed or exchanged onto the surface of the crystals. The effect of strontium ranelate on bone morphology was investigated in detail by Ammann et al in female rats given 0, 225, 450 or 900 mg/kg/day of strontium ranelate for 2 years. Parallel experiments were conducted in intact female and male rats using 625 mg/kg/day of strontium ranelate. Bone mineral content (BMC) and BMD increased in both series of experiments [29]. There was a significant increase in vertebral body volume by 6.4% in the group receiving 900 mg/kg/day, an increase in the mid-shaft femur
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diameter by 2.4% and 4.3% at the doses of 450 mg/kg/day and 900 mg/kg/day respectively, and an increase in ash weight of the L4 vertebral body from 5% to 31% in a dosedependent manner. A significant increase in maximal load of 18% and total energy of 40% was noted in males as compared to a non-significant increase in the female group. By bone histomorphometry, there was an increase in trabecular bone volume (BV) by 27–41% with a significant increase in trabecular number by 9–31% and trabecular thickness by 11–21%. At the cortical bone level, bone mass significantly increased, as evidenced by an increase in cortical area with no change in cortical porosity. Periosteal perimeter increased by 1.8–5% with a stable endocortical bone perimeter indicating inhibition of endocortical resorption with increased periosteal bone formation. However, the increase in cortical thickness of 5–10% was not statistically significant [29]. The histomorphometry nomenclature committee of the American Society of Bone and Mineral Research had recommended the use of trabecular number, thickness and spacing to evaluate bone architecture, but the assumptions and methods used to derive these structural indices are not rigorously determined and thus their limitations [30]. In summary, the net effect of strontium in animal models was a modest decrease in bone resorption and no substantial effect on bone formation [24–27]. It is important to note that the substantial positive effects of strontium on bone mass, BV, morphology and bone material properties demonstrated in the study of Ammann et al may be explained by the large doses used that by far exceed those administered in the clinical trials.
Clinical Aspects of Strontium Ranelate in Human Subjects In the mid-1990s, two dose-ranging clinical trials involving more than 500 women over a 2-year period were launched. Strontium ranelate increased adjusted BMD of the lumbar spine in a dose-dependent manner [14]. This led to two large fracture reduction trials, the Spinal Osteoporosis Therapeutic Intervention (SOTI, n 1649) trial investigating the effect of strontium ranelate on the risk of vertebral fractures and the Treatment of Peripheral Osteoporosis (TROPOS, n 5091) trial investigating its effects on the risk of non-vertebral fractures in older postmenopausal women with established osteoporosis. Both studies were preceded by a short run-in period of 2–24 weeks designed to normalize the calcium/vitamin D status. The main efficacy end point, reduction in fractures, as defined above for each trial, was assessed at 3 years. Extended 4-year data are now available from SOTI and 5-year data from TROPOS [31]. The SOTI study demonstrated a 6.8% increase in BMD, adjusted for strontium content, at 3 years and a 40–50% reduction in the rate of morphometric and symptomatic vertebral fractures at 1 and 3 years in the strontium ranelate group as compared with the placebo group. The number needed to
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treat (NNT) over 3 years to prevent one vertebral fracture was nine [14]. Data available on 1445 patients followed up for 4 years revealed a 33% decrease in vertebral fracture risk [31]. The TROPOS study showed a significant increase in hip BMD, by 8% at the femoral neck and 10% at the total hip, and a 16% reduction in the risk of non-vertebral fractures at 3 years. TROPOS confirmed the efficacy of strontium ranelate in reducing vertebral fracture risk. Whereas it did not reduce hip fracture risk in the overall group, post-hoc analyses in a high risk subgroup, that is women older than 74 years with a femoral neck BMD T-score 3, demonstrated a 36% reduction in hip fracture [31]. Of the original TROPOS cohort, 53% of subjects continued in the study and, in that subset, the efficacy of strontium ranelate in reducing non-vertebral fractures and reducing hip fractures in the high risk subgroup was sustained [31]. The 3-year changes in femoral neck and total proximal femur BMD, but not spine BMD, explained 76% and 74% of the reduction in vertebral fractures observed during strontium therapy. Each percentage point increase in femoral neck and total proximal femur BMD was associated with a 3% (confidence interval (CI), 1–5%) and 2% (CI, 1–4%) reduction in risk of a new vertebral fracture, respectively [31]. This is in sharp contrast to other approved osteoporosis therapies, where BMD changes only account for 4–37% of their anti-fracture efficacy. Pre-determined subset analyses from the pooled data from SOTI and TROPOS to assess the efficacy of strontium ranelate according to risk factors revealed that age, family history of osteoporosis, baseline body mass index and heavy smoking were not predictors of the anti-fracture efficacy of strontium ranelate [31]. Bone Remodeling, Histomorphometry and Micro-CT in Clinical Trials The changes in markers of bone formation and bone resorption in clinical trials were quite variable and modest at best. In the SOTI trial, strontium resulted in an increase in bone-specific alkaline phosphatase (BSAP) with a treatment effect of only 8%. There was a biphasic response in the serum telopeptide of type I collagen, with an initial decrease in the first year and then an increase to above baseline values afterwards, the strontium-treated group remaining lower than placebo with a difference of 12%. Markers were not reported in the TROPOS trial. Histomorphometric and micro-CT analyses were performed on 141 non-paired transiliac bone biopsies obtained from 133 postmenopausal osteoporotic women, 49 biopsies after 1–5 years of 2 g/ day strontium ranelate and 92 biopsies at baseline or after 1–5 years of placebo [32]. In the strontium ranelate-treated group, the authors report that osteoblast surfaces were significantly higher (38% versus control, P 0.047) and that MAR was higher in cancellous bone (9% versus control, P 0.019) and only marginally higher in cortical bone (10%, P 0.056), as compared to placebo. Means
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of multiple 2-dimensional (2-D) analyses of 3-year biopsies, reported as three-dimensional (3-D) analysis [33] with treatment (20 biopsies) and placebo (21 biopsies) using micro-CT were also reported in that study. Compared to placebo, measurements in the strontium ranelate group showed higher cortical thickness (18%, P 0.008) and trabecular number (14%, P 0.05) and lower structural model index (an estimate of the proportions of plate-like and rod-like structures, 22%, P 0.01) and trabecular separation (16%, P 0.04), but no change in connectivity, density or cortical porosity. No significant increase in cancellous BV or trabecular thickness could be demonstrated and measurements of wall thickness were not reported. Because the comparison was based on unpaired biopsies, the observed differences may also partially reflect age-related decrements in the variables of interest in the placebo group, as opposed to an exclusive treatment effect on such parameters. It is difficult to reconcile the data from animal and human studies with regards to results pertaining to bone remodeling, static and dynamic indices of bone histomorphometry and that derived from micro-CT analyses and biomechanical testing. To date, the exact mechanism for fracture reduction with strontium ranelate therapy is still unclear.
Safety of Strontium Ranelate In the SOTI trial, the most common adverse events within the first 3 months only were nausea and diarrhea (6.1% versus 3.6% in the placebo group). In the TROPOS trial, nausea (7.2% versus 4.4% in placebo), diarrhea (6.7% versus 5.0% in placebo), headache (3.4 versus 2.4% in placebo) and dermatitis and eczema (5.5% versus 4.1% in placebo) were reported more commonly in the strontium ranelate group, but again only during the first 3 months of treatment. A small decrease in mean serum total calcium (0.24 mg/dl) and intact serum PTH (4 pg/ml) levels and a small increase in serum phosphate (0.30 mg/dl) was observed in both SOTI and TROPOS, consistent with activation of the CaSR. Although the median serum level of strontium ranelate in the SOTI trial of 0.12 mmol/L is below the reported concentration (at least 0.4 mmol/ L) that is known to activate the CaSR in vitro, such levels may have been reached in the trial in view of the fact that neither the timing of the blood collection (peak or trough levels) nor the spread of the values above the median were specified. In the pooled database of the SOTI and TROPOS populations, only nausea and diarrhea had an incidence higher than 2%. There was a small but transient rise in serum creatine phosphokinase concentrations and a slight increase in the annual incidence of venous thromboembolism (0.9% in strontium versus 0.6% in placebo). Isolated, but very serious, cases of hypersensitivity syndrome or drug rash with eosinophilia and systemic symptoms (DRESS) have been reported in the post-marketing surveillance period. The syndrome is
defined by the presence of skin reactions, fever and systemic findings, hypereosinophilia, hepatic abnormalities and renal impairment. The syndrome typically occurs 2–6 weeks after initiating therapy and usually resolves upon discontinuation. It is estimated that the syndrome is rare (16/570 000 patient-years) and its mechanism is not clearly elucidated. Because of the potential fatal outcome linked to this syndrome, treatment with strontium ranelate should be stopped immediately if such symptoms or signs of this adverse event appear. In view of its renal excretion, the drug should not be used in patients with creatinine clearances below 30 ml/min.
Selective estrogen receptor modulators (SERMS) The effects of sex steroids on the male skeleton have been extensively reviewed in Section 6. In summary, cancellous bone mass and integrity are maintained by androgens and estrogens in both genders and across the life cycle. Sex steroids induce these positive effects, which can be additive, through their respective receptors. The estrogen receptor (ER) has two receptor isoforms ER and ER; the concentration of ER is higher in developing cortical bone whereas that of ER is higher in cancellous bone [34]. The androgen receptor (AR) is present in nearly all bone cells and testosterone has a major impact on skeletal growth and maintenance through a dual action on either the AR or the ER, in the latter case after aromatization to estrogen. For longitudinal bone growth, ER is the crucial pathway, whereas for periosteal growth, activation of both the AR and ER appears to be relevant. The beneficial effect of sex steroids on bone could occur through different pathways. These include binding to their respective receptors on osteoblasts followed by genomic and non-genomic signaling, modulation of the Wnt--catenin pathway, interaction with the growth hormone/insulin-like growth factor I (IGF-I) axis, mechanical loading from their action on muscle or anti-resorptive effect [35]. Two experiments of nature underscore the positive effect of estrogen on skeletal health in men. Bone mass in men with homozygous null mutations in the ER and in those with aromatase deficiency is reduced and, in the latter case, it increased with estrogen replacement [5]. Estrogen is a major determinant of volumetric BMD (vBMD) in men and low estrogen levels with a threshold effect at estradiol levels approximately 16 pg/ml (59 pM), is associated with agerelated bone loss and fractures [5].
Tissue Specificity of SERMs Estrogen is also a key modulator of many processes including differentiation, homeostasis and reproduction.
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Therefore, its long-term use as a replacement therapy to preserve skeletal health in men, as in women, is not possible due to its adverse effects on other target organs. The pleiotropic biological effects of estrogen on different target organs, through its receptor isoforms, have led to the concept of selective modulation of the receptor by diverse synthesized ER ligands leading to tissue specific effects. In most tissues, ER is usually an activator of estrogen function and ER inhibits the stimulatory activity of ER by forming a heterodimer with it [34]. The mechanisms for the tissue specificity of SERMs include differential expression of the two ER isoforms in target organs, diverse conformational changes in the 3-D structure of the ligand-ER upon its binding to the receptor and the resulting diverse expression and binding of various co-activators and co-repressors to the ER depending on the above conformational changes [34, 36]. Because tissue specificity of individual SERMS confers a unique profile of clinical effects, the safety and efficacy of each has to be independently established in clinical trials, prior to its approval for clinical use. The prototype of a SERM that was designed to address several of a postmenopausal woman’s health needs is raloxifene, a compound that has positive effects on the skeleton, a protective effect on the breast and lacks any adverse effects on the uterus [37]. Five categories of non-steroidal SERMS are in clinical use or various phases of development [36] (Figure 57.1). These include triphenylethylenes (tamoxifen, toremifene and ospemifene), chloroethylenes (clomiphene), naphthalenes (lasofoxifene), benzothiophenes (raloxifene and arzoxifene), indoles (bazedoxifene and pipendoxifene, the latter is also known as ERA 923) [36]. To date, tamoxifen, raloxifene and toremifene are the approved SERMS for clinical use in postmenopausal women. Tamoxifen, at the dose of 20 mg, is indicated for the prevention and the treatment of ER positive breast cancer, including metastatic breast cancer in men and women. Toremifene citrate, at the dose of 80 mg, is also approved for the treatment of estrogen positive breast cancer, whereas raloxifene, at the daily dose of 60 mg, is the only SERM to date that is approved for the prevention and treatment of postmenopausal osteoporosis. Another indication for raloxifene use is a decrease in the risk of invasive breast cancer in postmenopausal women with osteoporosis and in postmenopausal women at high risk of breast cancer. There are four trials with lasofoxifene registered on ClinicalTrials.gov, all of which have been completed. Lasofoxifene, at the dose of 0.5 mg, is under regulatory review by the FDA for the indication of treatment of osteoporosis in postmenopausal women at increased risk of fractures. SERMs that have entered fullscale clinical development are bazedoxifene, arzoxifene, ospemifene and pipendoxifene in women. There are 21 trials for bazedoxifene registered on ClinicalTrials.gov, nine for the management of menopause, eight for osteoporosis, one for breast cancer, one for vaginal atrophy and two are
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conducted in healthy women. Twelve trials are registered for arzoxifene, six for breast cancer, one for ovarian cancer, one for endometrial cancer and four for osteoporosis. While the pivotal trial that included vertebral fracture risk reduction and breast cancer risk reduction as primary endpoints did achieve the endpoints, there was no effect of treatment on non-vertebral fractures, and the company has decided not to submit the compound for regulatory review. Four trials are registered for ospemifene; all are to treat vaginal atrophy. There is one trial registered for pipendoxifene (ERA 923) for the treatment of metastatic breast cancer. The development of various SERMS over the last two decades has provided a major therapeutic advance in the management of women’s health issues [34, 36]. The protective effect of estrogen on the male skeleton and the expression of ER in the prostate have led to investigations to assess the usefulness of SERMs in addressing the health needs of aging men, akin to the paradigm of SERMs in women. The two SERMs that have clinical data in men are raloxifene and toremifene.
Preclinical Studies In an osteoblastic cell line, raloxifene downregulated bone resorbing cytokines such as interleukin-6 (IL-6), IL-1 and IL-1, similar to estrogen and by suppressing the RANKLOPG pathway [38]. Raloxifene was also shown to upregulate Fas ligand production in osteoblasts through ER leading to pre-osteoclast apoptosis [39]. In rats, raloxifene prevented orchidectomy-induced bone loss and maintained ash mineral content and thickness [40, 41] and, in the same animal model, improved parameters of bone structural integrity such as three-point bending and maximal load failure [42]. Raloxifene had no feminizing effect in the same animal model and it did not affect testicular sperm production or reproductive performance, but resulted in a decrease in prostate weight by 30% [43]. Similarly, lasofoxifene was also shown to prevent age-related and orchidectomy-induced bone loss in rats and to preserve bone strength [44, 45].
Clinical Trials In two studies conducted in middle-aged (6 months study) and elderly men (6 weeks cross-over study), raloxifene at 60 mg/day decreased markers of bone resorption only in the subset of subjects with low estradiol levels [46, 47]. These findings suggest that its efficacy would only be established in patients with hypogonadism as was demonstrated in men on anti-androgen therapy. The effect of raloxifene on serum sex steroid and gonadotropin levels varied widely between studies, findings that again could in part be explained by the baseline levels of androgen and estrogen prior to treatment initiation. Indeed, raloxifene had no effect on sex steroids and resulted in a very mild increase in follicle stimulating hormone (FSH) in the 6-month study of elderly men [46].
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CH3
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Figure 57.1 Chemical structure of native estrogen (17-beta estradiol) and non-steroidal selective estrogen receptor modulators (SERMs) in use or clinical development. *Agents approved for clinical use. Lasofoxifene, arzofoxifene, bazedoxifene and pipendoxifene are in pre-registration stage.
C h a p t e r 5 7 Future Therapies: Strontium, SERMs, SARMs and New Therapies on the Horizon l
It caused a 20% increase in testosterone with no change in gonadotropins in the one-month study of young men with hyperlipidemia [48]. In contrast, in a study of healthy middle-aged men, raloxifene administration for 6 weeks resulted in modest increments in circulating serum total and bioavailable estradiol and testosterone of 10–12%. Logistic regression analyses revealed that these increments were only observed in the subset with baseline levels below the threshold of 100 pM for estradiol and 19 pM for testosterone [49]. Finally, elderly men given raloxifene for 3 months had a 20– 30% increase in serum gonadotropin levels and a 16–20% increase in total and free sex steroid levels [47]. In contrast to the well established effect of raloxifene on lipoprotein levels in women, decreasing low-density lipoprotein (LDL) by 12%, apolipoprotein B by 9% and Lp(a) lipoprotein by 7% [34], the results in men are not consistent. Whereas no effect was noted in elderly men, a 4–5% decrease in total cholesterol was reported in the studies of healthy elderly men and hyperlipidemic young men [46, 47, 49]. Clinical Trials in Men on Anti-androgen Therapies for Prostate Cancer Gonadotropin-releasing hormone (GnRH) agonists are the mainstay therapy of metastatic prostate cancer, often used in non-metastatic disease and have been shown to improve survival in men with locally advanced disease [50]. Consequences of such therapy include hypogonadism, loss of libido, vasomotor flushes, osteoporosis, increased fat mass and decreased lean mass. Therefore, the anabolic effect of SERMs on bone and their neutral or suppressive effect on prostate growth makes them attractive therapies to reverse some of the above mentioned side effects. Indeed, ER receptors are present in the prostate and raloxifene was shown to reduce prostate size in an androgen responsive human prostate cancer cell line through an androgen independent pathway [51]. In an open-label study, 48 men with non-metastatic prostate cancer and very low testeosterone and estradiol levels on GnRH therapy were given raloxifene or no therapy for one year. Treatment resulted in a 34% decrease in amino-terminal propectide of type I collagen and a significant increase in bone density at the hip, the between group differences varied between 2% and 4% [52]. There were no differences in serum lipid levels between the two groups. Toremifene is being developed for the treatment of complications resulting from androgen deprivation therapy in patients with prostate cancer. In a 6-month randomized study of 46 men, toremifene significantly increased bone mass and reduced hot flushes [53]. In a completed phase III fracture prevention study, 1392 men receiving androgen deprivation therapy were randomized to receive placebo or toremifene 80 mg/day for 24 months. An interim preplanned analysis on the first 192 men revealed significant increments in BMD at the spine and hip with between group differences of 1.5–2.3% [54]. Results on fracture
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reduction are not published yet, but were presented in April 2008 at the annual meeting of the American Academy of Cancer Research and a summary of the presented data are available in the press release by GTx, Inc. http://phx.corporate-ir.net/phoenix.zhtml?c 148196& p irol-newsArticle&ID 1111644&highlight . In a modified intent-to-treat analysis which included all patients with at least one follow-up X-ray, toremifene citrate resulted in a 53% reduction in new morphometric vertebral fractures at 2 years (fracture rate in the placebo group was 3.6%). In contrast to the raloxifene study of patients with prostate cancer, toremifene citrate 80 mg resulted in significant decrements in total cholesterol, LDL and triglycerides and an increase in high-density lipoprotein (HDL), compared to placebo. Significant improvements in gynecomastia were noted with toremifene compared to placebo [55].
Adverse Events In the raloxifene trials, women had a higher incidence of flulike syndrome, leg cramps, peripheral edema and hot flushes. Raloxifene increased blood coagulation indices in the direction of enhanced clotting [34]. In the Raloxifene Use for The Heart (RUTH) trial, raloxifene increased the relative risk of venous thrombosis by 1.44 and the relative risk of fatal stroke by 1.49. The absolute risk increments were 1.2/1000 and 0.7/1000 woman-years, respectively [34]. Raloxifene was usually well tolerated by men. Men on raloxifene tended to have hot flushes, but there were no reports of decreased libido, erection or breast tenderness [46, 47, 49]. One case of pulmonary embolism was reported in one man participating in the prostate cancer study. Workup of that man revealed that he had a concomitant increase in homocysteine levels [52]. The number of study participants in the male raloxifene trials was small, thus limiting information on safety. The press release of the toremifene fracture trial in men with prostate cancer reported an increase in venous thromboembolic events (VTEs), with an incidence of 2.4% in the treatment group as compared with 1.02% in the placebo group. Most VTEs occurred within the first year and the majority occurred in men greater than 80 years of age, those with a history of VTEs or with recent surgical procedure and immobilization.
Selective androgen receptor modulators (SARMS) Whereas treatment of severe androgen deficiency with androgens is beneficial to bone, less clear is their benefit to partially androgen-deficient elderly men. Furthermore, potential adverse events may limit such use. Indeed, the AR is ubiquitously expressed in many tissues including bone, skeletal muscle, prostate, liver, central nervous
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Osteoporosis in Men Table 57.1 Desired profile of activity of new selective androgen receptor modulators (SARMs): male application Tissue/parameter
Prostate/sex accessory tissues Libido Inhibition of gonadotropins Hair growth Bone growth Muscle mass/strength Fat-free mass Lipids/cardiovascular risk factors Blood pressure/fluid retention Erythropoiesis Liver function (enzyme elevation) Breast (gynecomastia)
Indications Hypogonadism
Selected indicationsa
Stimulatory, but less than DHT Stimulatory Present Stimulatory Stimulatory Stimulatory Increase Neutral Neutral Weakly stimulatory Neutral Neutral
Weak or neutral Stimulatory/neutral Absent/reduced Neutral Stimulatory Stimulatory Increase Neutral/beneficial Neutral Stimulatory Neutral Neutral
Reproduced from Negro-Vilar A. Selective androgen receptor modulators (SARMs): a novel approach to androgen therapy for the millennium. J Clin Endocrinol Metabol 1999;84:3459-62 [57], with permission from the Endocrine Society. a Selected indications may include glucocorticoids-induced osteoporosis, androgen replacement in elderly men, HIV-wasting, cancer cachexia, certain anemias, muscular dystrophies and male contraception. DHT: dihydrotestoterone.
system, skin, adrenal gland and epidydimis [56]. The concept of developing SARMs to address the health needs of men was stimulated by the paradigm of developing SERMs to address women’s health needs [37, 57].
Tissue Specificity of SARMs Since the first report in 1998, the field of SARMs has grown tremendously, with the development of compounds that attempt to combine agonistic effects on muscle and bone, while maintaining neutral or antagonistic effects on prostate and liver [56–59]. The desired activity of a SARM is detailed in Table 57.1. The dual anabolic effect of SARMs on muscle and bone renders them particularly advantageous for the treatment of aging and steroid-induced osteoporosis. Indeed, an increase in muscle mass would be expected to exert a positive effect on bone mass, reduce the risk of falls and further decrease fracture risk. Other potential applications for SARMs include their use in muscle wasting syndromes, human immunodeficiency virus and cancerassociated cachexia, anemia, benign prostate hypertrophy, prostate cancer and male contraception (without adversely affecting libido). Tissue selectivity would also allow the use of SARMs in women [57]. The above different potential clinical applications of SARMs necessitate different tissue-selectivity profiles. Several mechanisms mediate the effect of testosterone on target organs, namely a direct effect on the AR, an indirect effect on that receptor after conversion to dihydrotestosterone by the 5-reductase enzyme or an effect on the ER after conversion to estrogen by the aromatase enzyme. This multiplicity of mechanisms provides opportunities to achieve tissue selectivity of AR ligands. Plausible mechanisms for
tissue selectivity of SARMs include resistance to the 5reductase or aromatase enzymes, differential recruitment of co-activator and co-repressor complexes in target tissues and the use of diverse intracellular signaling cascades by the same ligand in different tissues [57, 59]. Tissue-specific expression of the 5-reductase, the lack of interaction of SARMs with the 5-reductase and their resistance to aromatase action, accounts for the observed tissue selectivity of several anabolic SARMs in development [56, 59]. SARMs are non-steroidal androgens that belong to the following major structural classes of compounds: quinolinone analogs, aryl propionamide analogs, hydantoin analogs, indoles and the tetrahydroquinoline analogs. A full update on SARMs in preclinical and clinical development is provided in recent reviews of the topic [56, 59]. To date no SARM has been approved for clinical use, however, a few compounds with demonstrated tissue selectivity have been entered in clinical trials (Figure 57.2).
Preclinical Studies with SARMs Several animal studies have established the proof of concept that SARMs can have tissue specificity. Tissue specificity of an oral androgen modulator in an animal model was first demonstrated in 2003, with propionamide compounds S-1 and S-4 [60], followed by a tetrahydroquinoline SARM S-40503 [61] and then a quinolinone SARM- LGD2226 [62]. These compounds have strong anabolic activity in skeletal muscle and bone and only a partial agonist activity on prostatic tissue. Propionamides The tissue selectivity of the propionamides S-1 and S-4 was tested in an animal model of castrated Sprague-Dawley rats
C h a p t e r 5 7 Future Therapies: Strontium, SERMs, SARMs and New Therapies on the Horizon l
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Figure 57.2 Chemical structure of testosterone and non-steroidal selective androgen receptor modulators (SARMs) in clinical development.
and compared to that of testosterone propionate. After 14 days, the animals were sacrificed and their organs weighed. Compounds S-1 and S-4 stimulated anabolic organs (levator ani muscle) more than androgenic organs (seminal vesicles and prostate). Both compounds were less androgenic than testosterone propionate, but had a comparable or superior anabolic activity, with no effect on levels of FSH [60]. The tissue selectivity of compound S-1 was further verified and compared to that of hydroxyflutamide (an anti-androgen) and finasteride (a 5-reductase inhibitor), drugs used to treat benign prostate hyperptrophy, in intact male rats. Compound S-1 selectively decreased the weight of the prostate, with similar efficacy to finasteride, without affecting levator ani weight [63]. Similarly, tissue selectivity of S-4 was subsequently validated in castrated male rats and compared to that of vehicle or dihydrotestosterone. The anabolic effect of S-4 on bone and muscle was comparable if not superior to that of dihydrotestosterone, with minimal effect on the prostate [64]. In an ovariectomy-induced model of accelerated bone loss, S-4 was also shown to maintain whole body, trabecular and cortical bone mass, increase bone strength and decrease body fat [65]. An aryl propionamide, S-23, given concomitantly with estrogen to maintain sexual behavior, was shown to lower serum levels
of gonadotropins and abolish spermatogenesis and pregnancy in mating trials in the intact animal. It also reduced fat mass and increased bone and lean mass and could thus be a useful drug for male contraception [66]. Tetrahydroquinolines The bone anabolic activity of the tetrahydroquinoline SARM, S-40503, was tested over 4 weeks in a model of orchidectomized rats and compared to dihydrotestosterone. It resulted in an increase in femoral neck BMD and in the weight of the levator ani muscle, but it did not increase prostate weight, in contrast to dihydrotestosterone. The reduced androgenic activity of S-40503 was further confirmed by demonstration of a neutral effect on the prostate of normal animals [61]. The bone anabolic effect of S-40503 was further established by demonstration of an increase in MAR, an index of bone formation, and improved biomechanical strength of femoral cortical bone in ovariectomized rats [61]. Quinolinones A SARM quinolinone, LGD2226, was shown to have an anabolic effect on muscle and bone, with reduced impact on prostate growth and on the hypothalamic–pituitary axis,
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compared to dihydrotestosterone. The mating behavior of rats was intact and biomechanical testing revealed enhanced bone strength compared to sham animals [62]. The development of LGD2226 was later discontinued, but another quinolinone, LGD2941, with improved bioavailability compared to LGD2226, maintained a favorable muscle and bone profile and entered the clinical development phase. The quinolinone, LGD3303, was also recently shown to exert a potent activity on the levator ani muscle, but only a partially agonist activity on the prostate, despite achieving higher tissue concentrations in the prostate compared to the muscle [67]. Indoles In an intact animal model, an indole SARM, JNJ-26146900, was shown to reduce prostate weight, similarly to the androgen antagonist bicalutamide and, in a mouse xenograft model of prostate cancer, it reduced testosterone-induced prostate growth. The compound also prevented orchidectomy-induced loss of muscle and bone mass and improved material properties of bone as assessed by BV, trabecular connectivity and number [68]. Similarly, JNJ-37654032 was shown to selectively stimulate growth of the levator ani muscle, without stimulating prostate growth, while reducing FSH levels, in an orchidectomized rat model. Conversely, in the intact rats, the compound reduced prostate growth, size of the testes, without having any inhibitory effect on muscle [69]. Hydantoins A hydantoin SARM, BMS-564929, was more potent than testosterone in stimulating the growth of the levator ani muscle, but not prostate growth, in castrated rats [70].
SARMs in Clinical Development Many chemically distinct SARM templates have been reported, fewer have demonstrated in vivo tissue selectivity and only a handful described in preclinical studies above, have further advanced to the clinical trials stage (see Figure 57.2) [59]. Propionamides are the furthest ahead in SARM drug development. These include compound S-4 that has entered phase I trials, the propionamide, MK-2866, known as Ostarine™, that is being developed for the indications of sarcopenia and cancer cachexia. It was shown in a phase IIa study to significantly improve functional performance, as assessed by the stair climb test, in elderly men and women, by increasing lean body mass by 1.4 kg, at 3 months, with the 3 mg/day dose. The drug had no effects on prostate-specific antigen in men and hair growth in women, lipid levels decreased, as did indices of insulin resistance and there was no difference in adverse events between Ostarine™ and placebo [59]. An additional phase IIb study in muscle wasting associated with cancer cachexia was launched in 2008. Of the quinolinone SARMs, LGD2941 has completed phase
I trial for the indication of frailty and osteoporosis and, of the family of hydantoins SARMs, PS178990, previously known as BMS-564929, has also entered phase I trial for the indication of age-related functional decline. Finally, GSK-971086, a compound with undisclosed chemical structure, is in phase I dose-ranging trial in healthy men (www.ClinicalTrials.gov, NCT00540553).
New therapies on the horizon Anti-Catabolic Therapies Many of the drugs in development are still targeting the osteoclast, as displayed in Figure 57.3. Only compounds that are in the most advanced stages of clinical development will be reviewed in detail (Table 57.2). The potential concern with such class of drugs is that they may inhibit needed, as well as unneeded, bone resorption, thus impairing physiologic repair of bone microdamage.
Inhibitor of Receptor Nuclear Activator of Nuclear Factor Kappa B Ligand (NF-B or RANKL) Pathway NF-B or RANKL, a cytokine member of the tumor necrosis factor receptor family produced by osteoblasts, binds to its receptor RANK on osteoclasts to regulate osteoclastogenesis. RANKL is a major regulator of osteoclast proliferation, differentiation and survival [71]. OPG is a decoy receptor for RANKL that is also secreted by osteoblasts. OPG deficiency in animals and humans is associated with osteoporosis, whereas disruptions in the RANKL pathway result in osteopetrosis in mice and, therefore, the RANK/ RANKL/OPG pathway provides an opportunity for antiresorptive drug development. Whereas the development of recombinant OPG was halted because of immunogenicity, that of a high affinity human monoclonal immunoglobulin G2 antibody to RANKL, denosumab, previously known as AMG 162, has reached completion of a large phase III trial. Preclinical Studies The effect of denosumab is primate specific, therefore, its activity in preclinical studies was mostly tested in monkeys and in genetically engineered mice that express a chimeric human/murine form of RANKL [72]. In that model, denosumab at doses of 1–5 mg/kg delivered once to twice weekly resulted in a substantial suppression of serum tartarate-resistant acid phosphatase-5b (TRACP-5b) and serum osteoclacin levels, reflecting the normal coupling between bone formation and resorption. In the young mice, it was associated with a 95% reduction in OcS/bone surface (BS) and a twofold increase in BV/total volume (TV). In adult
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Calcitonin receptors
JNK Carbonic anhydrase II HCO3
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3
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Figure 57.3 Some current anti-resorptive drug development targets (highlighted as 1 to 7) indicated in the osteoclast. Targeting RANKL or its signaling (1 and 2) inhibits osteoclast formation and activity. Drug approaches through any of pathways 4 to 7 might inhibit bone resorption without an accompanying inhibition of bone formation. Reproduced from Martin TJ, Ng KW. New agents for the treatment of osteoporosis. BoneKEy-Osteovision 2007;4(11):287-98 [10], with permission from the International Bone and Mineral Society.
Table 57.2 New osteoporosis drugs in clinical development Mode of Signaling pathway action
Category
Cell target
Compound
Stage of development
Company
Anti-catabolic Inhibition of RANKL
RANKL antibody
Osteoclast
Denosumab
Phase III
Amgen Inc
Cathepsin K inhibitor Integrin antagonist
Osteoclast
Odanacatib
Phase III
Merck & Co., Inc
Osteoclast
MK0429 (also known as L-000845704) PTHrP 1-36
Phase II
Merck & Co., Inc
Phase II
Osteotrophin LLC
AXT914
Phase I
Novartis International AG
MK5442 Sclerostin ab
Phase IIb Phase I**
Merck & Co., Inc Amgen Inc
Inhibition of cathepsin K Inhibition of integrin binding to bone matrix Anabolic
Stimulation of PTHrP osteoblastogenesis* Antagonism of calcium- Calcilytic sensing-receptor, increase endogenous PTH
Osteoblast
Stimulation of Wnt/catenin pathway
Osteoblast
Sclerostin antibody
CaSR on parathyroid gland
PTHrP: PTH-related protein; CaSR: Calcium sensing receptor; ab: antibody. *Signaling pathway similar to PTH, see text. ** Phase II in planning.
mice, it was associated with a markedly lower OcS, osteoblast surface and significantly greater trabecular BV than controls. It also resulted in significant reductions in trabecular mineralizing surface (MS), MAR and BFR [72]. The powerful suppression of bone formation by denosumab
did not seem to deleteriously affect bone quality, as assessed by improved trabecular microarchitecture. Indeed, on micro-CT analyses, denosumab treatment was associated with significantly greater cortical vBMD, trabecular vBMD, trabecular BV fraction and trabecular thickness.
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Improvements in bone strength parameters were evaluated in the same animal model of fracture healing [73]. Male human RANKL knock-in mice that express a chimeric form of RANKL were randomized to receive denosumab 10 mg/kg bi-weekly, alendronate 0.1 mg/kg, or control. TRACP-5b decreased significantly in the denosumab group to almost undetectable level versus a 25% reduction in the alendronate group. Mechanical testing showed improved mechanical properties of fractured femora in both treatment groups and micro-CT analyses revealed that callus tissues from the denosumab-treated animals had greater percent BV and BMD than the alendronate treated animals; the latter had greater increments in these parameters than placebo [73]. Clinical Studies Pharmacokinetic studies revealed that denosumab has a rapid onset of action within 12 hours, with a long circulating half-life allowing for a dosing frequency of every 6 months [71]. It is not retained in bone and its effects are reversible upon treatment discontinuation. In a phase II dose-ranging trial, denosumab was compared to alendronate or placebo in 412 postmenopausal women with low BMD, with a T-score at the spine of 1.8 to 4.0 or at the femoral neck/total hip T-scores of 1.8 to 3.5. Patients were randomized to receive denosumab subcutaneously at doses of 6, 14 or 30 mg every 3 months, 14, 60, 100 or 210 mg every 6 months, placebo or alendronate 70 mg per week [74]. Denosumab therapy for one year increased BMD at the lumbar spine by 4.6%, at the total hip by 1.9–3.6% and at the third radius by 0.4–1.3%. Compared to denosumab, alendronate therapy resulted in comparable increments at the lumbar spine, lower increments at the hip and decrements at the forearm. Near maximal reduction in mean serum levels of C-telopeptide cross- links (CTx) (by 88%) was noted at 3 days after administration of denosumab and the duration of suppression was dose dependent [74]. In a planned 2-year extension of that trial, denosumab treatment was associated with similar or greater increments in BMD than alendronate at all four skeletal sites, with the exception of the 14 mg every 6-month dose. Serum CTx and urinary N-telopeptide cross-links (uNTx/Cr) demonstrated continuous suppression. The most substantial increments in BMD occurred at denosumab doses of 30 mg given every 3 months and 60 mg given every 6 months [75]. In another comparative phase III trial, 1189 postmenopausal women, with a T-score less than 2.0 at the lumbar spine or total hip, were randomized to receive subcutaneous denosumab 60 mg every 6 months or alendronate 70 mg/week. At 12 months, denosumab resulted in greater increments in BMD at all skeletal sites compared with alendronate and a greater suppression of bone remodeling markers [76]. Denosumab administration to 332 postmenopausal women with osteopenia over 2 years resulted in a mean BMD increment of 6.5% at the spine, 3.4% at the hip and in increments in total vBMD at the distal forearm, compared to decrements
in the placebo group. The increment at the spine was rapid and observed as early as one month post-therapy. Hip structural analyses revealed that the hip cross-sectional moment of inertia, section modulus and average cortical thickness all increased compared to placebo, but there was no significant effect on cortical outer diameter. The results were more significant in the subset of women who were more than 5 years postmenopausal. The bone resorption marker CTX decreased by 89% at 1 month and the bone formation marker procollagen I N-terminal propeptide declined more gradually, by 32% at 1 month and by 65–76% from 6 to 24 months [77]. The safety and efficacy of denosumab in reducing fracture risk was evaluated in a phase III trial that enrolled 7868 women with osteoporosis, aged 60–90 years and a mean T-score between 4 and 2.5 at the spine or total hip [78]. The primary endpoint was new vertebral fracture and the secondary endpoints were hip and non-vertebral fractures. Denosumab therapy reduced the risk of morphometric vertebral fractures by 68%, of hip fractures by 40% and of non-vertebral fractures by 20% [78]. Denosumab, at doses of 180 mg every 6 months for 12 months, was also shown to decrease bone erosion by magnetic resonance imaging in patients with rheumatoid arthritis and to effectively decrease bone remodeling markers in patients with multiple myeloma or with cancer and bone metastases [71, 79, 80]. On-going Trials in Men Denosumab is being compared in a non-inferiority trial to zoledronic acid in the treatment of bone metastases in 1700 men with refractory prostate cancer. The primary outcome is time-to-first skeletal-related event and estimated completion time is July 2009 (ClinicalTrials.gov: NCT00321620). The efficacy of denosumab in the treatment of bone loss in subjects undergoing androgen-deprivation therapy for non-metastatic prostate cancer is also being evaluated in a 2-year study in 1468 patients. The primary endpoint is lumbar spine BMD and secondary endpoints are BMD at other sites, the estimated completion date is May 2010 (ClinicalTrials.gov: NCT00089674). Finally, the long-term safety and tolerability of denosumab in the treatment of bone loss in 800 patients undergoing androgen-deprivation therapy for non-metastatic prostate cancer will be evaluated in an open label, single arm, 3-year extension study of a currently ongoing 2-year study using denosumab at 60 mg subcutaneously for 2 years. The estimated study completion date is September 2012 (ClinicalTrials.gov: NCT00838201). Adverse Events Most trials did not detect any difference in the overall proportion of subjects experiencing adverse events in the denosumab group compared to placebo or alendronate
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[71, 74, 76]. In one study, sore throat and rash were more common in the denosumab treated group compared to placebo and a trend for increased infections necessitating hospital admission was noted; nine patients in the placebo versus 18 patients in the denosumab group (5.5% versus. 11% respectively, P 0.07) [77]. In another study, an increased incidence of hypertension and urinary tract infection was noted in the denosumab group compared to placebo and that group registered six cases of adverse events with hospitalization due to infection [75]. In the fracture trial, which included the largest number of subjects with the longest follow up, there were no significant differences in the total incidence of adverse events, serious adverse events or study discontinuation due to adverse events between the denosumab group and placebo. Denosumab therapy did not increase the risk of cancer, infections, cardiovascular disease or delay fracture healing [78]. The long-term safety of denosumab, as is the case with any new therapy, awaits extended observations that will become available in the post-marketing period of that drug.
Cathepsin K Inhibitors Cathepsin K, a cysteine protease and member of a family of 12 cathepsin enzymes, is most heavily expressed in osteoclasts and is a key mediator in the degradation of type I collagen during bone resorption [10, 81]. Following tight attachment to the BS, osteoclasts secrete protons into a sealed extracellular compartment, creating an acidic pH (about 4–5) that removes the bone mineral and exposes the underlying matrix that is then degraded by cathepsin K. This collagenase is localized in lysosomal vesicles at the ruffled border, fuses with the cell membrane and is released into the acidified sealed resorption space beneath active osteoclasts (see Figure 57.1). An autosomal recessive disorder, pycnodysostosis, resulting from mutations in the cathepsin K gene, is characterized by short stature, dense bones and non-traumatic fractures [10, 81]. Targeted mutations in the cathepsin K gene result in mice with higher bone mass, both in cortical and trabecular bone, thicker cortices and preserved bone quality compared to wild type mice [82]. Conversely, overexpression of cathepsin K leads to transgenic mice with reduced trabecular volume, due to accelerated bone turnover [81]. The above observations made cathepsin K a target molecule for osteoporosis drug development. Because cathepsin K inhibitors do not affect the interaction between osteoblasts and osteoclasts, they cause limited inhibition of bone formation, an advantage compared to other anticatabolic drugs such as bisphosphonates. Cathepsin K is also expressed in synovial fibroblasts, in macrophages of rheumatoid arthritis joints and in breast and prostate cancer. Cathepsin K inhibitors could therefore be useful in the management of rheumatologic disorders and in prevention and treatment of metastatic bone disease [81]. Several antibodies
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against cathepsin K, balicatib, relacatib and odanacatib have been developed. Odanacatib appears to be the most selective antibody to cathepsin K, whereas balicatib and relacatib have a greater effect on other cathepsins (e.g. cathepsin B, L and S). Evaluation of the above three cathepsin K inhibitors in whole cell assays revealed the selectivity of odanacatib. In dermal fibroblast culture, odanacatib was shown to result in minimal intracellular collagen accumulation compared to the other two antibodies [83]. These observations explain the development of skin rashes and the rare incidence of morphea-like skin changes that resulted in the suspension of all cathepsin K inhibitor trials, with the exception of those investigating odanacatib. Preclinical Studies Odanacatib, at doses of 6 and 30 mg/kg orally for 21 months, fully protected rhesus monkeys from ovariectomyinduced bone loss, without affecting bone formation at the lower dose [84]. Similarly, administration of odanacatib to ovarietcomized rabbits for 7 months, prevented bone loss to a similar extent as alendronate, without suppressing bone formation, and biomechanical testing confirmed preserved bone integrity [85]. In the odanacatib group, BV/TV was higher compared to placebo and BFR tended to be higher compared to the alendronate group. Bone mineralization surface/BS tended to be lower in the alendronate group, but remained unchanged in the odanacatib group. Clinical Studies Three hundred and ninety-nine postmenopausal women, mean age 64.2 7.8 years with low BMD T-scores between 2.0 and 3.5 at the lumbar spine, total hip, femoral neck or hip trochanter, were randomized to receive odanacatib, at doses of 3, 10, 25 or 50 mg weekly or placebo over 2 years (1 year dose-ranging plus 1-year extension) [86]. At 24 months, the 50 mg dose resulted in an increase in lumbar spine and total hip BMD by 5.5% and 3.2%, respectively, compared to placebo. At this dose, uNTx/Cr and BSAP decreased by 52% and 13%, respectively, whereas uNTx/Cr decreased by 5% and BSAP increased by 3% with placebo. These findings are consistent with the mechanism of action of odanacatib decreasing bone resorption without affecting bone formation. Rash was reported in 4.8% of those in the 50 mg group and in 7.9% of those in the placebo group. Two phase III trials with odanacatib are registered on ClinicalTrials.gov. One is to test the safety and treatment effect of 50 mg of odanacatib with vitamin D, versus placebo with vitamin D, over 24 months in 180 postmenopausal women with low BMD (NCT00729183, estimated study completion date May 2011). The other is to examine the effects of odanacatib on fractures in 20 000 postmenopausal women with osteoporosis (NCT00529373, estimated study completion date May 2011).
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Integrin Antagonists The initiation of osteoclastic bone resorption requires close contact between the osteoclast and BS, a process mediated by 3 integrin (vitronectin receptor), a product of osteoclasts (see Figure 57.3) [11, 13, 81]. This attachment protein plays a rate-limiting role in osteoclast activity. The interaction between integrin and matrix proteins occurs through a peptide Arg-Gly-Asp (RGD) sequence, the disruption of which interferes with osteoclastic resorption. Indeed, treatment of rats with echistatin or kistrin, which bind with high affinity to v3 integrin or with small molecules that mimic the RGD sequence recognized by the integrin, inhibits bone resorption stimulated by PTH or estrogen deficiency [11, 81]. In vitro and animal studies have shown that RGD mimetic compounds that neutralize the activity of integrin interfere with osteoclast attachment to BS and decrease bone resorption in a dose-dependent manner in the murine model [11, 81]. One such compound, L-000845704 also known as MK0429, was investigated using doses of 100 mg/day, 400 mg/ day and 200 mg/twice a day, in a 12-month, randomized, double-blind, placebo-controlled study, in 227 women with a mean age of 63 years and low BMD. Treatment was associated with significant increments at the lumbar spine BMD at all doses and increments at the hip only with the 200 mg bid dose. All doses decreased the bone resorption marker uNTx/Cr equally by 42% and bone formation marker BSAP by 20–30% [87]. Adverse events that may have been related to treatment included hot flushes, insomnia and night sweats, appetite decrease, headaches, dermatitis, pruritus, rash and urticaria. The relationship of these adverse events to the study drug needs to be assessed in future studies, however, commitment to further development of MK-0429 is unclear since there are no registered phase III trials for this compound (ClinicalTrials.gov: NCT00533650, NCT00302471). The integrin receptor is also expressed in budding blood vessels and leukocytes and one integrin antagonist compound was shown to prevent the establishment of bone tumor deposits in nude rats undergoing intra-tibial engraftment of human breast cancer or melanoma cells [81].
Other Anti-Catabolic Drugs Candidate drugs that may also inhibit bone resorption without affecting bone formation include those that target chloride channels such as the ClCN7 channel, vacuolar H()-ATPase and c-src (see Figure 57.3) [10, 11]. Preclinical and limited clinical studies using such drugs are briefly described in other reviews, but it is unclear whether commitment to the development of any of those drugs has been made [10, 11].
Anabolic Therapies Anabolic therapies target the osteoblast and its regulators to increase bone mass and improve bone quality and strength (Figure 57.4). Bone morphogenic and Wnt proteins play a
key role in osteoblastogenesis and bone formation, but do so through different signaling pathways in the osteoblast [88]. Another important regulator of osteoblast function is IGF-I [88, 89]. The first prototype of an exclusive anabolic drug is human recombinant PTH 1-34 (teriparatide) or human recombinant PTH 1-84 (which has been discussed in detail in Chapter 55). The exact signaling pathway that accounts for the anabolic effect of PTH on bone is not known. Possibilities include a direct anti-apoptotic effect on the osteoblasts and indirect effects through the modulation of skeletal growth factors such as IGF-I or growth factor antagonists (sclerostin, see below) [88, 89]. Some of the limitations of teriparatide use include its daily administration subcutaneously and its cost, thus leading to investigations of similar molecules with variations on the amino-acid length or with fusion to the Fc fragment of IgG to ensure longer half-lives and with alternative delivery systems (inhalational, nasal spray, oral or patches; see Chapter 55 for full details). More importantly, given the finite duration of approved use for PTH of 18–24 months, there is an unmet need for additional anabolic drugs.
PTH-Related Peptide (PTHrP) PTHrP is an endogenous peptide with high sequence homology to native PTH in the amino-terminal of the molecule that binds to the shared PTH/PTHrP receptor and leads to very similar effects to PTH. In vitro and in vivo studies reveal that PTHrP has anabolic effects on bone [11]. Advantages of PTHrP include its tolerability at large doses, rapid and large increments in bone mass and a possible pure anabolic effect [90]. Administration of PTHrP at a dose of 6.56 g/kg/day subcutaneous over 3 months to 16 postmenopausal women increased lumbar spine bone density by 4.7% and increased serum osteocalcin level without increasing bone resorption markers [90]. In a follow-up dose escalation study, PTHrP administered as a single dose varying between 570 and 1946 g (that is up 100 times the PTH 1-34 dose) to 22 healthy subjects was well tolerated. The highest calcium reached was 10.6 mg/dL at the highest dose [91]. In a phase II comparative trial, 105 postmenopausal women with osteoporosis will be randomized to a standard dose of PTH 1-34 or one of two doses of PTHrP 1-36. The purpose of the study is to demonstrate that PTHrP 1-36 stimulates bone formation to the same extent or greater degree as PTH (1-34) but with less resorption (ClinicalTrials.gov: NCT00853723). Whether PTHrP 1-36 will be superior to PTH as a therapy for osteoporosis remains to be established.
Calcium-Sensing Receptor (CaSR) Antagonists/Calcilytics Short-term antagonists of the CaSRs would stimulate endogenous PTH release in pulses, thus possibly mimicking
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l
Basal conditions
A
LRP5 and LRP6
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B
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C
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LRP5 and LRP6 Wnt
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LRP5 and LRP6 Axin APC GSK3β Cytoplasm
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Dishevelled Axin
β-Catenin
APC GSK3β
Proteasome
GSK3β
β-Catenin Proteasome
TCF-4 LEF-1 β-Catenin Nucleus
Transcription Gene expression
Figure 57.4 The canonical Wnt--catenin signaling pathway used in osteoblasts. (A) shows that under basal conditions, -catenin is phosphorylated by glycogen synthase kinase 3 (GSK-3), axin and adenomatous polyposis coli (APC) tumor-suppressor protein and degraded in the proteasome. (B) shows that after Wnt binding to its receptor (frizzled) and co-receptors (low-density lipoprotein receptorrelated proteins 5 and 6 [LRP5 and LRP6]), disheveled, an intracellularprotein, is induced to degrade GSK-3. In addition, the cytoplasmic tails of LRP5 and LRP6 bind and anchor axin. These two events lead to the stabilization of -catenin and its translocation to the nucleus, where it binds to T-cell factor 4 (TCF-4) or lymphoid enhancer binding factor 1 (LEF-1) to regulate transcription. (C) shows that the extracellular Wnt antagonists prevent Wnt signaling. Dickkopf-1 (Dkk-1) in association with Kremen and sclerostin bind LRP5 and LRP6. Soluble frizzled-related protein 1 (sFRP-1) binds Wnt and prevents its interaction with frizzled. Reproduced from Canalis et al Mechanisms of anabolic therapies for osteoporosis. N Engl J Med 2007;357(9):905–16 [88], with permission from the Massachusetts Medical Society. (See color plate section).
the anabolic skeletal effects of teriparatide [11]. Ronacaleret is a calcilytic that was reported to increase bone formation markers, but trials using that drug were discontinued after the planned interim analysis of a phase II trial showed that it did not increase lumbar spine BMD at 6 months [13]. Another compound, ATF936, was shown to have a favorable pharmacokinetic profile and is currently under investigation (ClinicalTrials.gov: NCT00417261).
Wnt--Catenin Signaling Pathway The Wnt proteins belong to a large family of ligands that regulate embryonic induction, control cell polarity and specify cell fate [92]. Wnt proteins can activate cellular processes through three pathways: the -catenin, Ca2 and planar polarity pathway [8]. In bone cells, the canonical pathway is used and is illustrated in Figure 57.4. This pathway uses a receptor complex at the cell surface that consists of Fzd receptors and LRP5 or 6, homologous members
of the LDL receptor family. Under basal conditions, -catenin is phosphorylated by glycogen synthetase kinase 3 (GSK3), axin and adenomatous polyposis coli (APC) tumor-suppressor protein and subsequently degraded in the proteasome (see Figure 57.4(A). Binding of Wnt to the Fzd receptor-LRP5/6 complex results in stabilization of -catenin which translocates into the nucleus and regulates gene expression (see Figure 57.4B4). Natural antagonists of the Wnt pathway that interfere with the binding of Wnt to its receptors-co-receptors include sclerostin and Dickkopf-1 (Dkk-1), products of the osteoblast and osteocyte (see Figure 57.4C4). Mutations of the Wnt co-receptors illustrate the critical role of the Wnt--catenin pathway in bone remodeling. Loss-of-function mutations in the Wnt co-receptor LRP5 in human subjects leads to the osteoporosis pseudoglioma (OPPG) syndrome, whereas gain-of-function mutations lead to the high bone mass trait [89]. LRP5 deletions and gain-of-function mutations in mice reproduce the phenotypes described above in humans [89]. The
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Wnt-LRP5/6-Fzd signaling pathway is therefore a promising target for osteoporosis drug development. Candidates include those that block endogenous antagonists such as sclerostin and Dkk-1, those that activate GSK-3 or stimulate LRP5/6, activin inhibitors and osteoblast proteasome inhibitors. Sclerostin and Dkk-1 are in part restricted to bone and these antibodies would therefore activate Wnt signaling without deleterious effects in other organs. Sclerostin antibody is the compound that is furthest along in drug development. Sclerostin Antibody Genetic and phenotypic study of sclerosteosis led to the discovery of the protein sclerostin that is encoded for by the SOST gene. Mutations in the SOST gene lead to skeletal dysplasias with high bone mass, such as occurs in sclerosteosis and van Buchem’s syndrome [10, 88]. Sclerosteosis is an autosomal recessive sclerosing bone disease characterized by thickening of the skeleton and skull, enlargement of the jaw, entrapment of cranial nerves with facial palsy, hearing loss and loss of smell [93]. Heterozygous carriers were shown to have a high BMD, without any of the bone complications described in the homozygotes [93]. Targeted deletions of the sclerostin gene in mice result in a high bone mass phenotype characterized by increments in BMD and in BV at cortical and trabecular sites, as shown in micro-CT analyses [94]. Histomorphometry showed increased BFRs at the endosteal and periosteal surfaces of the distal femur and mechanical testing revealed increased strength of the lumbar vertebrae and femur [94]. The treatment of ovariectomized rats with sclerostin antibody for 2 weeks resulted in a rapid rise in BMD at the lumbar vertebrae and femur-tibia, which normalized to the levels of sham mice at 3 weeks. After 5 weeks of therapy, BMD was 26% higher in lumbar vertebrae and 17% higher in tibia-femur compared to baseline, whereas it was unchanged in the sham ovariectomized rats [95]. Micro-CT analyses of the distal femur revealed restoration of trabecular vBMD and of BV/TV to sham control levels, due to a 57% increase in trabecular thickness. An increase in trabecular thickness was also documented by histomorphometric analyses of the proximal tibia and dynamic indices revealed substantial increments in MS/BS by 472%, MAR by 72% and BFR/BS by 967%. Similarly, there were substantial increments in dynamic indices of bone formation at the lumbar vertebrae with increment in MS/BS of 270%, MAR of 26% and BFR/BS of 380%. Finally, histomorphometric analyses of the femoral mid-shaft revealed significant increments in bone formation at periosteal and endocortical surfaces and increments in bone formation indices paralleling those noted at the vertebrae. These changes were reflected in increments in bone strength in the lumbar vertebrae and the femoral mid-shaft [95]. Reversibility of the sclerostin antibody effect on BMD several weeks after treatment discontinuation and the lack of any blunting of its anabolic effect was demonstrated in ovariectomized rat models.
In a phase I trial, 48 healthy postmenopausal women were randomized to receive a single subcutaneous dose of 0.1, 0.3, 1, 3, 5 or 10 mg/kg of sclerostin monoclonal antibody versus placebo. Dose related increments in the bone formation markers procollagen type I N-terminal propeptide (PINP), osteocalcin and BSAP, were demonstrated by 21 days, with a mean percentage change from baseline of 60–100%, at the dose of 3 mg/kg. A trend of dose-related decrease in serum C-Tx was also observed [96].
Conclusion Substantial advances in our understanding of key pathways regulating bone remodeling have allowed a significant expansion in therapeutic options to treat osteoporosis. Strontium, an interesting earth element with clear antifracture efficacy at the vertebral and non-vertebral sites in women, is being tested in men. The proof-of-concept raloxifene trial led to the development of additional SERMs and SARMs, aiming at further refining tissue specificity to address the varied health needs of men and women. Advantages of other new anti-resorptive drugs include the powerful but reversible effects of denosumab on bone remodeling and its long half-life allowing infrequent dosing intervals and the lack of suppression of bone formation with drugs such as cathepsin K inhibitors. The rapid expansion of anabolic drugs aiming at restoring bone integrity includes ones that mimic the effect of PTH on osteoblastogenesis such as PTHrP, calcilytics or molecules that targets the Wnt-catenin pathway, such as sclerostin. Recent data on the neuroendocrine regulation of bone and the common links between bone/mineral and fat/fuel metabolism further widen the horizon as to yet additional novel therapeutic options. Regulatory authorities still require placebo-controlled trials to establish the efficacy of new therapies, a requirement that creates conflicts with ethical considerations randomizing high risk patients to placebo, despite the availability of efficacious therapies. The alternative would be to study a substantially larger number of subjects at lower risk for fractures, a prohibitive alternative in dire economic times. Advances in science and technology have greatly expanded the horizons of osteoporosis drug development. Reconciliation of ethical, regulatory, societal, demographic and economic considerations constitute formidable challenges that will ultimately determine the fate of drug development in general, and osteoporosis drug development in particular, over the coming decade.
Acknowledgments The authors would like to acknowledge Ms Aida Farha, Ms Tala Ghalayini and Mr Ghassan Baliki for PubMed
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searches and article retrieval and Ms Rola El-Rassi for manuscript preparation. The authors thank Drs Jim Dalton (GTx, Inc), Willard Dere (Amgen Inc), Lorraine Fitzpatrick (GlaxoSmithKline), Bruce Mitlak (Eli Lilly and Company), Art Santora (Merck & Co., Inc) and Nicholas Sauter (Novartis International AG) for information provided regarding drugs in development. Special thanks to Drs Edward Brown, Juliet Compston, Edward Nemeth, Michael Parfitt and Andrew Stewart for helpful discussions and comments.
Glossary of abbreviations 3-D three dimensional AR androgen receptor BFR bone formation rate BMC bone mineral content BMD bone mineral density BS bone surface BSAP bone-specific alkaline phosphatase BV bone volume CaSR calcium-sensing receptor C-Tx C-telopeptide cross-links Dkk-1 Dickkopf-1 ER estrogen receptor FDA Food and Drug Administration FSH follicle stimulating hormone Fzd frizzled GnRH gonadotropin releasing hormone GSK3 glycogen synthetase kinase 3 HDL high-density lipoprotein IGF-1 insulin-like growth factor-1 LDL low-density lipoprotein LPR 5/6 lipoprotein receptor related protein 5/6 MAR mineral apposition rate MS mineralizing surface NF-B nuclear factor kappa B OcS osteoclast surface OPG osteoprotegerin PKC protein kinase C PTH parathyroid hormone PTHrP PTH related protein RANK receptor activator of the nuclear factor kappa b RANKL RANK ligand RGD Arg-Gly-Asp SARM Selective Androgen Receptor Modulator SERM Selective Estrogen Receptor Modulator SOTI Spinal Osteoporosis Therapeutic Intervention trial TRACP-5b tartarate-resistant acid phosphatase-5b TROPOS TReatment Of Peripheral OSteoporosis trial TV total volume uNTx/Cr urinary N-telopeptide cross-links/creatinine vBMD volumetric BMD VTE venous thromboembolic event
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References 1. S. Amin, D.T. Felson, Osteoporosis in men, Rheum. Dis. Clin. North Am. 27 (1) (2001) 19–47. 2. B.Z. Leder, K.M. LeBlanc, D.A. Schoenfeld, R. Eastell, J.S. Finkelstein, Differential effects of androgens and estrogens on bone turnover in normal men, J. Clin. Endocrinol. Metab. 88 (1) (2003) 204–210. 3. A. Falahati-Nini, B.L. Riggs, E.J. Atkinson, W.M. O’Fallon, R. Eastell, S. Khosla, Relative contributions of testosterone and estrogen in regulating bone resorption and formation in normal elderly men, J. Clin. Invest. 106 (12) (2000) 1553–1560. 4. D. Mellstrom, L. Vadneput, H. Mallmin, et al., Older men with low serum estradiol and high serum SHBG have an increased risk of fractures, J. Bone Miner. Res. 23 (2008) 1552–1560. 5. L. Gennari, S. Khosla, J.P. Bilezekian, Estrogen and fracture risk in men. Commentary, J. Bone Miner. Res. 23 (2008) 1548–1551. 6. S. Amin, Y. Zhang, D.T. Felson, et al., Estradiol, testosterone, and the risk for hip fractures in elderly men from the Framingham Study, Am. J. Med. 119 (2006) 426–433. 7. B.L. Riggs, A.M. Parfitt, Drugs used to treat osteoporosis: the critical need for a uniform nomenclature based on their action on bone remodeling, J. Bone Miner. Res. 20 (2) (2005) 177–184. 8. A. Chan, R.L. van Bezooijen, C.W.G.M. Lowik, A new paradigm in the treatment of osteoporosis: Wnt pathway proteins and their antagonists, Curr. Opin. Investig. Drugs 8 (4) (2007) 293–298. 9. S. Khosla, J.J. Westendorf, M.J. Oursler, Building bone to reverse osteoporosis and repair fractures, J. Clin. Invest. 118 (2) (2008) 421–428. 10. J. Martin, K.W. Ng, New agents for the treatment of osteo porosis, BoneKEy-Osteovision 4 (11) (2007) 287–298. 11. A. Grey, Emerging pharmacologic therapies for osteoporosis, Expert Opin. Emerg. Drugs 12 (3) (2007) 493–508. 12. C. Deal, Potential new drug targets for osteoporosis, Nat. Clin. Pract. Rheumatol. 5 (1) (2009) 20–27. 13. E.M. Lewiecki, Emerging drugs for postmenopausal osteo porosis, Expert Opin. Emerg. Drugs 14 (1) (2009) 129–144. 14. G. El-Hajj Fuleihan, Strontium ranelate – a novel therapy for osteoporosis or a permutation of the same? N. Engl. J. Med. 350 (5) (2004) 504–506. 15. S. Choudhary, P. Halbout, C. Alander, L. Raisz, C. Pilbeam, Strontium ranelate promotes osteoblastic differentiation and mineralization of murine bone marrow stromal cells: involvement of prostaglandins, J. Bone Miner. Res. 22 (7) (2007) 1002–1010. 16. E. Canalis, M. Hott, P. Deloffre, Y. Tsouderos, P.J. Marie, The divalent strontium salt S12911 enhances bone cell replication and bone formation in vitro, Bone 18 (6) (1996) 517–523. 17. E. Bonnelye, A. Chabadel, F. Saltel, P. Jurdic, Dual effect of strontium ranelate: stimulation of osteoblast differentiation and inhibition of osteoclast formation and resorption in vitro, Bone 42 (1) (2008) 129–138. 18. G.J. Atkins, K.J. Welldon, P. Halbout, D.M. Findlay, Strontium ranelate treatment of human primary osteoblasts promotes an osteocyte-like phenotype while eliciting an osteoprotegerin response, Osteoporos. Int. 20 (4) (2009) 653–664. 19. P.J. Marie, Strontium ranelate: new insights into its dual mode of action, Bone 40 (2007) S5–S8.
730
Osteoporosis in Men
20. J. Caverzasio, Strontium ranelate promotes osteoblastic cell replication through at least two different mechanisms, Bone 42 (6) (2008) 1131–1136. 21. R. Baron, Y. Tsouderos, In vitro effects of S12911-2 on osteo clast function and bone marrow macrophage differentiation, Eur. J. Pharmacol. 450 (1) (2002) 11–17. 22. N. Takahashi, T. Sasaki, Y. Tsouderos, T. Suda, S 12911-2 inhibits osteoclastic bone resorption in vitro, J. Bone Miner. Res. 18 (6) (2003) 1082–1087. 23. A.S. Hurtel-Lemaire, R. Mentaverri, A. Caudrillier, et al., The calcium-sensing receptor is involved in strontium ranelateinduced osteoclast apoptosis, New insights into the associated signaling pathways, J. Biol. Chem. 284 (1) (2009) 575–584. 24. P.J. Marie, Strontium ranelate: a physiological approach for optimizing bone formation and resorption, Bone 38 (2006) S10–S14. 25. M. Hott, P. Deloffre, Y. Tsouderos, P.J. Marie, S12911-2 reduces bone loss induced by short-term immobilization in rats, Bone 33 (1) (2003) 115–123. 26. J. Buehler, P. Chappuis, J.L. Saffar, Y. Tsouderos, A. Vignery, Strontium ranelate inhibits bone resorption while maintaining bone formation in alveolar bone in monkeys (Macaca fascicularis), Bone 29 (2) (2001) 176–179. 27. R.K. Fuchs, M. Allen, K.W. Condon, et al., Strontium ranelate does not stimulate bone formation in ovariectomized rats, Osteoporos. Int. 19 (2008) 1331–1341. 28. D. Farlay, G. Boivin, G. Panczer, A. Lalande, P.J. Meunier, Longterm strontium ranelate administration in monkeys preserves characteristics of bone mineral crystals and degree of mineralization of bone, J. Bone Miner. Res. 20 (9) (2005) 1569–1578. 29. P. Ammann, V. Shen, B. Robin, Y. Mauras, J.P. Bonjour, R. Rizzoli, Strontium ranelate improves bone resistance by increasing bone mass and improving architecture in intact female rats, J. Bone Miner. Res. 19 (12) (2004) 2012–2020. 30. A.M. Parfitt, M.K. Drezner, F.H. Glorieux, et al., Bone histomorphometry: standardization of nomenclature, symbols and units, J. Bone Miner. Res. 2 (6) (1987) 595–610 Report of the ASBMR Histomorphometry Nomenclature Committee. 31. C. Roux, Strontium ranelate: short- and long-term benefits for post-menopausal women with osteoporosis, Rheumatology (Oxf) 47 (Suppl. 4) (2008) iv. 20-22. 32. M.E. Arlot, Y. Jiang, H.K. Genant, et al., Histomorphometric and microCT analysis of bone biopsies from postmenopausal osteoporotic women treated with strontium ranelate, J. Bone Miner. Res. 23 (2) (2008) 215–222. 33. M. Parfitt, Effects of strontium ranelate – results important but presentation muddled, IBMS BoneKEy 5 (3) (2008) 108–113. 34. B.L. Riggs, L.C. Hartmann, Selective estrogen-receptor modulators – mechanisms of action and application to clinical practice, N. Engl. J. Med. 348 (7) (2003) 618–629. 35. D. Vanderschueren, J. Gaytant, S. Boonen, K. Venken, Androgens and bone, Curr. Opin. Endocrinol. Diabetes Obes. 15 (3) (2008) 250–254. 36. W. Shelly, M.W. Draper, V. Krishnan, M. Wong, R.B. Jaffe, Selective estrogen receptor modulators: an update on recent clinical findings, Obstet. Gynecol. Surv. 63 (3) (2008) 163–181. 37. G. El-Hajj Fuleihan, Tissue-specific estrogens – the promise for the future, N. Engl. J. Med. 337 (1997) 1686–1687 Editorial. 38. J. Cheung, Y.T. Mak, S. Papaioannou, B.A. Evans, I. Fogelman, G. Hampson, Interleukin-6 (IL-6), IL-1, receptor activator of nuclear factor kappaB ligand (RANKL) and
39.
40. 41.
42.
43.
44.
45.
46.
47.
48.
49.
50.
51.
52.
53.
osteoprotegerin production by human osteoblastic cells: comparison of the effects of 17-beta oestradiol and raloxifene, J. Endocrinol. 177 (3) (2003) 423–433. S.A. Krum, G.A. Miranda-Carboni, P.V. Hauschka, et al., Estrogen protects bone by inducing Fas ligand in osteoblasts to regulate osteoclast survival, EMBO J. 27 (3) (2008) 535–545. P.D. Broulík, K. Broulíková, Raloxifen prevents bone loss in castrated male mice, Physiol. Res. 56 (4) (2007) 443–447. Y. Onoe, C. Miyaura, M. Ito, H. Ohta, S. Nozawa, T. Suda, Comparative effects of estrogen and raloxifene on B lymphopoiesis and bone loss induced by sex steroid deficiency in mice, J. Bone Miner. Res. 15 (3) (2000) 541–549. E.K. Stürmer, D. Seidlová-Wuttke, S. Sehmisch, et al., Stand ardized bending and breaking test for the normal and osteoporotic metaphyseal tibias of the rat: effect of estradiol, testosterone, and raloxifene, J. Bone Miner. Res. 21 (1) (2006) 89–96. J.A. Hoyt, L.F. Fisher, D.K. Swisher, R.A. Byrd, P.C. Francis, The selective estrogen receptor modulator, raloxifene: reproductive assessments in adult male rats, Reprod. Toxicol. 12 (3) (1998) 223–232. H.Z. Ke, H. Qi, D.T. Crawford, K.L. Chidsey-Frink, H.A. Simmons, D.D. Thompson, Lasofoxifene (CP-336,156), a selective estrogen receptor modulator, prevents bone loss induced by aging and orchidectomy in the adult rat, Endocrinology 141 (4) (2000) 1338–1344. H.Z. Ke, H. Qi, K.L. Chidsey-Frink, D.T. Crawford, D.D. Thompson, Lasofoxifene (CP-336,156) protects against the age-related changes in bone mass, bone strength, and total serum cholesterol in intact aged male rats, J. Bone Miner. Res. 16 (4) (2001) 765–773. P.M. Doran, B.L. Riggs, E.J. Atkinson, S. Khosla, Effects of raloxifene, a selective estrogen receptor modulator, on bone turnover markers and serum sex steroid and lipid levels in elderly men, J. Bone Miner. Res. 16 (11) (2001) 2118–2125. E.J. Duschek, L.J. Gooren, C. Netelenbos, Effects of raloxifene on gonadotrophins, sex hormones, bone turnover and lipids in healthy elderly men, Eur. J. Endocrinol. 150 (4) (2004) 539–546. A. Blum, L. Hathaway, R. Mincemoyer, et al., Hormonal, lipoprotein, and vascular effects of the selective estrogen receptor modulator raloxifene in hypercholesterolemic men, Am. J. Cardiol. 85 (12) (2000) 1491–1494. B. Uebelhart, F. Herrmann, I. Pavo, M.W. Draper, R. Rizzoli, Raloxifene treatment is associated with increased serum estradiol and decreased bone remodeling in healthy middleaged men with low sex hormone levels, J. Bone Miner. Res. 19 (9) (2004) 1518–1524. M.R. Smith, Androgen deprivation therapy for prostate cancer: new concepts and concerns, Curr. Opin. Endocrinol. Diabetes Obes. 14 (3) (2007) 247–254. I.Y. Kim, D.H. Seong, B.C. Kim, et al., Raloxifene, a selective estrogen receptor modulator, induces apoptosis in androgen-responsive human prostate cancer cell line LNCaP through an androgen-independent pathway, Cancer Res. 62 (13) (2002) 3649–3653. M.R. Smith, M.A. Fallon, H. Lee, J.S. Finkelstein, Raloxifene to prevent gonadotropin-releasing hormone agonist-induced bone loss in men with prostate cancer: a randomized controlled trial, J. Clin. Endocrinol. Metab. 89 (8) (2004) 3841–3846. M.S. Steiner, A. Patterson, R. Israeli, K.G. Barnette, R. Boger, D. Price, Toremifene citrate versus placebo for
C h a p t e r 5 7 Future Therapies: Strontium, SERMs, SARMs and New Therapies on the Horizon l
54.
55.
56.
57.
58.
59.
60.
61.
62.
63.
64.
65.
66.
67.
treatment of bone loss and other complications of androgen deprivation therapy in patients with prostate cancer, J. Clin. Oncol. 22 (Suppl. 14) (2004) 4597. M.R. Smith, S.B. Malkowicz, F. Chu, et al., Toremifene increases bone mineral density in men receiving androgen deprivation therapy for prostate cancer: interim analysis of a multicenter phase 3 clinical study, J. Urol. 179 (1) (2008) 152–155. M.R. Smith, S.B. Malkowicz, F. Chu, et al., Toremifene improves lipid profiles in men receiving androgen-deprivation therapy for prostate cancer: interim analysis of a multicenter phase III study, J. Clin. Oncol. 26 (11) (2008) 1824–1829. W. Gao, J.T. Dalton, Expanding the therapeutic use of androgens via selective androgen receptor modulators (SARMs), Drug Discov. Today 12 (5-6) (2007) 241–248. A. Negro-Vilar, Selective androgen receptor modulators (SARMs): a novel approach to androgen therapy for the new millennium, J. Clin. Endocrinol. Metab. 84 (10) (1999) 3459–3462. W. Gao, J. Kim, J.T. Dalton, Pharmacokinetics and pharmacodynamics of nonsteroidal androgen receptor ligands, Pharm. Res. 23 (8) (2006) 1641–1658. R. Narayanan, M.L. Mohler, C.E. Bohl, D.D. Miller, J.T. Dalton, Selective androgen receptor modulators in preclinical and clinical development, Nucl. Recept. Signal. 6 (2008) e010. D. Yin, W. Gao, J.D. Kearbey, et al., Pharmacodynamics of selective androgen receptor modulators, J. Pharmacol. Exp. Ther. 304 (3) (2003) 1334–1340. K. Hanada, K. Furuya, N. Yamamoto, et al., Bone anabolic effects of S-40503, a novel nonsteroidal selective androgen receptor modulator (SARM), in rat models of osteoporosis, Biol. Pharm. Bull. 26 (11) (2003) 1563–1569. J.N. Miner, W. Chang, M.S. Chapman, et al., An orally active selective androgen receptor modulator is efficacious on bone, muscle, and sex function with reduced impact on prostate, Endocrinology 148 (1) (2007) 363–373. W. Gao, J.D. Kearbey, V.A. Nair, et al., Comparison of the pharmacological effects of a novel selective androgen receptor modulator, the 5alpha-reductase inhibitor finasteride, and the antiandrogen hydroxyflutamide in intact rats: new approach for benign prostate hyperplasia, Endocrinology 145 (12) (2004) 5420–5428. W. Gao, P.J. Reiser, C.C. Coss, et al., Selective androgen receptor modulator treatment improves muscle strength and body composition and prevents bone loss in orchidectomized rats, Endocrinology 146 (11) (2005) 4887–4897. J.D. Kearbey, W. Gao, R. Narayanan, et al., Selective androgen receptor modulator (SARM) treatment prevents bone loss and reduces body fat in ovariectomized rats, Pharm. Res. 24 (2) (2007) 328–335. A. Jones, J. Chen, D.J. Hwang, D.D. Miller, J.T. Dalton, Preclinical characterization of a (S)-N-(4-cyano-3-trifluoro methyl-phenyl)-3-(3-fluoro, 4-chlorophenoxy)-2-hydroxy2-methyl-propanamide: a selective androgen receptor modulator for hormonal male contraception, Endocrinology 150 (1) (2009) 385–395. E.G. Vajda, F.J. López, P. Rix, et al., Pharmacokinetics and pharmacodynamics of LGD-3303 [9-chloro-2-ethyl-1-methyl3-(2,2,2-trifluoroethyl)-3H-pyrrolo-[3,2-f]quinolin-7(6H)-one], an orally available nonsteroidal-selective androgen receptor modulator, J. Pharmacol. Exp. Ther. 328 (2) (2009) 663–670.
731
68. G. Allan, M.T. Lai, T. Sbriscia, et al., A selective androgen receptor modulator that reduces prostate tumor size and prevents orchidectomy-induced bone loss in rats, J. Steroid Biochem. Mol. Biol. 103 (1) (2007) 76–83. 69. G. Allan, T. Sbriscia, O. Linton, et al., A selective androgen receptor modulator with minimal prostate hypertrophic activity restores lean body mass in aged orchidectomized male rats, J. Steroid Biochem. Mol. Biol. 110 (3-5) (2008) 207–213. 70. J. Ostrowski, J.E. Kuhns, J.A. Lupisella, et al., Pharmacological and x-ray structural characterization of a novel selective androgen receptor modulator: potent hyperanabolic stimulation of skeletal muscle with hypostimulation of prostate in rats, Endocrinology 148 (1) (2007) 4–12. 71. A.E. Kearns, S. Khosla, P.J. Kostenuik, Receptor activator of nuclear factor kappaB ligand and osteoprotegerin regulation of bone remodeling in health and disease, Endocr. Rev. 29 (2) (2008) 155–192. 72. P. Kostenuik, H. Nguyen, J. McCabe, et al., Denosumab, a fully human monoclonal antibody to RANKL, inhibits bone resorption and increases bone density in knock-in mice that express chimeric (murine/human) RANKL, J. Bone Miner. Res. 24 (2009) 182–195. 73. L.C. Gerstenfeld, D.J. Sacks, M. Pelis, et al., Comparison of effects of the bisphosphonate alendronate versus the RANKL inhibitor denosumab on murine fracture healing, J. Bone Miner. Res. 24 (2009) 196–208. 74. M.R. McClung, E.M. Lewiecki, S.B. Cohen, et al., Denosumab in postmenopausal women with low bone mineral density, N. Engl. J. Med. 354 (8) (2006) 821–831. 75. E.M. Lewiecki, P.D. Miller, M.R. McClung, et al., Two-year treatment with denosumab (AMG 162) in a randomized phase 2 study of postmenopausal women with low BMD, J. Bone Miner. Res. 22 (12) (2007) 1832–1841. 76. J.P. Brown, R.L. Prince, C. Deal, et al., Comparison of the effect of denosumab and alendronate on BMD and biochemical markers of bone turnover in postmenopausal women with low bone mass: a randomized, blinded, phase 3 trial, J. Bone Miner. Res. 24 (1) (2009) 153–161. 77. H.G. Bone, M.A. Bolognese, C.K. Yuen, et al., Effects of denosumab on bone mineral density and bone turnover in postmenopausal women, J. Clin. Endocrinol. Metab. 93 (6) (2008) 2149–2157. 78. S.R. Cummings, M.R. McClung, C. Christiansen, et al., A phase III study of the effects of denosumab on vertebral, nonvertebral, and hip fracture in women with osteoporosis: results from the FREEDOM trial, J. Bone Miner. Res. 23 (Suppl.) (2008) S80. 79. G.K. Ellis, H.G. Bone, R. Chlebowski, et al., Randomized trial of denosumab in patients receiving adjuvant aromatase inhibitors for nonmetastatic breast cancer, J. Clin. Oncol. 26 (30) (2008) 4875–4882. 80. K. Fizazi, A. Lipton, X. Mariette, et al., Randomized phase II trial of denosumab in patients with bone metastases from prostate cancer, breast cancer, or other neoplasms after intravenous bisphosphonates, J. Clin. Oncol. 27 (10) (2009 Apr 1) 1534–1536. 81. S.B. Rodan, L.T. Duong, Cathepsin K – A new molecular target for osteoporosis, IBMS BoneKEy 5 (1) (2008) 16–24. 82. B. Pennypacker, M. Shea, Q. Liu, et al., Bone density, strength, and formation in adult cathepsin K (/) mice, Bone 44 (2) (2009) 199–207.
732
Osteoporosis in Men
83. J.Y. Gauthier, N. Chauret, W. Cromlish, et al., The discovery of odanacatib (MK-0822), a selective inhibitor of cathepsin K, Bioorg. Med. Chem. Lett. 18 (3) (2008) 923–928. 84. T. Cusick, B. Pennypacker, D. Kimmel, Effects of odanacatib on bone mass and turnover in estrogen deficient adult rhesus monkeys, J. Bone Miner. Res. 23 (Suppl.) (2008) S148. 85. B.L. Pennypacker, T.E. Cusick, D.B. Kimmel, Bone effects of odanacatib in adult overiectomized rabbits, J. Bone Miner. Res. 23 (Suppl.) (2008) S148. 86. M. McClung, H. Bone, F. Cosman, et al., A randomized, doubleblind, placebo-controlled study of Odanacatib (MK-822) in the treatment of postmenopausal women with low bone mineral density: 24-month results, J. Bone Miner. Res. 23 (Suppl.) (2008) S82. 87. M.G. Murphy, K. Cerchio, S.A. Stoch, K. Gottesdiener, M. Wu, R. Recker, L-000845704 Study Group. Effect of L-000845704, an alphaVbeta3 integrin antagonist, on markers of bone turnover and bone mineral density in postmenopausal osteoporotic women, J. Clin. Endocrinol. Metab. 90 (4) (2005) 2022–2028. 88. E. Canalis, A. Giustina, J.P. Bilezikian, Mechanisms of anabolic therapies for osteoporosis, N. Engl. J. Med. 357 (9) (2007) 905–916. 89. J.P. Bilezikian, T. Matsumoto, T. Bellido, et al., Targeting bone remodeling for the treatment of osteoporosis: summary of the proceedings of an ASBMR workshop, J. Bone Miner. Res. 24 (3) (2009) 373–385.
90. M.J. Horwitz, M.B. Tedesco, C. Gundberg, A. Garcia-Ocana, A.F. Stewart, Short-term, high-dose parathyroid hormonerelated protein as a skeletal anabolic agent for the treatment of postmenopausal osteoporosis, J. Clin. Endocrinol. Metab. 88 (2) (2003) 569–575. 91. M.J. Horwitz, M.B. Tedesco, S.M. Sereika, et al., Safety and tolerability of subcutaneous PTHrP(1-36) in healthy human volunteers: a dose escalation study, Osteoporos. Int. 17 (2) (2006) 225–230. 92. J. Caverzasio, Non-canonical Wnt signaling: what is its role in bone? IBMS BoneKEy 6 (3) (2009) 107–115. 93. J. Gardner, R. van Bezooijen, B. Mervis, et al., Bone mineral density in sclerosteosis; affected individuals and gene carriers, J. Clin. Endocrinol. Metab. 90 (2005) 6392–6395. 94. X. Li, M.S. Ominsky, Q.T. Niu, et al., Targeted deletion of the sclerostin gene in mice results in increased bone formation and bone strength, J. Bone Miner. Res. 23 (6) (2008) 860–869. 95. X. Li, M.S. Ominsky, K.S. Warmington, et al., Sclerostin antibody treatment increases bone formation, bone mass and bone strength in a rat model of postmenopausal osteo porosis, J. Bone Miner. Res. (2008 Dec 2) doi:10.1359/ JBMR.081206. 96. D. Padhi, B. Stouch, G. Jang, et al., Anti-sclerostin antibody increases markers of bone formation in healthy postmenopausal women, J. Bone Miner. Res. 22 (Suppl. 1) (2007) S37. 1. 2. 3. 4. 5. 6. 7. 8. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 25. 26. 27. 28. 29. 30. 31. 32. 33. 34.
Index
A ADT, see Androgen deprivation therapy Aging adipogenesis in bone marrow, 5 androgen deficiency androgen replacement effects, 328, 430 partial deficiency in elderly, 428–429 skeletal changes, 321 bone cell changes, 185 bone composition changes, 9–10 bone loss assessment, 207–208, 210 body mass index effects, 215 cortical versus trabecular bone, 212–213 ethnic differences, 213–215 overview, 171–173 quantitative computed tomography studies, 210–212 screening, 208–210, 216–217 vitamin supplement studies, 215–216 bone remodeling aging effects, 169–171, 578 marker changes, 179–181 overview, 167–169 bone shape changes, 199–200 bone size and geometry determinants challenges for study, 202–203 estrogen and receptors, 198–199 ethnicity, 195–196 genetics, 195 growth hormone/insulin-like growth factor axis, 197 mechanical load, 196–197 nutrition, 196 sex steroids and periosteal expansion, 199 testosterone, 197–198 bone structure changes, 578 bone turnover marker response to interventions, 182 female bone changes, 577–578 fracture risk, 181, 363 mechanisms of bone width expansion cohort effect, 200 mechanical compensation of endosteal bone loss, 200–201 mechanical load lifelong reaction, 201 neoteny, 201 potential for mechanical protection and response, 201
mineral metabolism effects calcitonin, 190 growth hormone/insulin-like growth factor axis, 190 parathyroid hormone, 187–188 sex steroids, 190 vitamin D, 185–187 muscle effects of testosterone replacement therapy, 337–338 osteogenesis reduction, 5 periosteal bone formation in adulthood, 173–174 radial bone growth, 194–195 sarcopenia and age-associated functional decline, 642–643 sex differences in bone loss and fracture rates, 174 sex hormone-binding globulin changes, 424–425 AIS, see Androgen insensitivity syndrome Alcohol use alcoholism bone turnover marker effects, 30 histomorphometry of bone in alcoholism, 581–582 bone effects bone mineral density, 437–438 confounding studies, 439–440 overview, 436–437 epidemiology, 435–436 ethanol physiology, 435 fall and fracture risk, 438–439 moderation and beneficial effects, 436 Alendronate, see Bisphosphonates ALOX15, see 15-Lipoxygenase Anabolic steroids, abuse by athletes, 497 Androgen, see also Dihydroxytestosterone; Testosterone abuse, 497 aging skeletal changes, 321 animal models of altered responsiveness, 307–309 animal studies of bone effects, 306 bone mineral density in disturbances androgen deprivation therapy, 324 androgen insensitivity syndrome, 324–326 delayed puberty, 326 idiopathic hypogonadotropic hypogonadism, 324 Klinefelter syndrome, 324
733
5-reductase inhibitors, 326–327 castration effects on bone mass, 309–311 deficiency aging and bone health effects partial deficiency in elderly, 428–429 androgen replacement effects, 430 diagnosis, 699–701 epidemiology, 701 hypogonadism and, 427–428 osteoporosis comorbidity, 701 post-pubertal onset, 426–427 prepubertal onset, 425–426 estrogen action comparison, 298 female studies of bone effects, 311 metabolism, 295–298 precursors, 297–298 puberty skeletal changes, 319–321 replacement therapy effects, see also Testosterone replacement therapy aging, 328 dehydroepiandrosterone, 328–329 idiopathic hypogonadotropic hypogonadism, 327–328 normal men, 329 selective androgen receptor modulators see Selective androgen receptor modulators skeletal development role bone growth, 306 epiphyseal function, 306–307 periosteum, 309 synthetic androgens, 298 Androgen deprivation therapy (ADT) bisphosphonate therapy, 595, 675–676 bone mineral density, 324 bone turnover marker effects, 30–31 selective estrogen receptor modulator therapy, 719 testosterone therapy, 693 Androgen insensitivity syndrome (AIS) androgen replacement therapy, 327–328, 693 bone growth effects, 114–115 bone mineral density, 324–326 Androgen receptor bone cell signaling, 298–299 expression osteoblast, 299–301 regulation, 301–303 knockout mice, 277, 284, 307 transgenic mice, 307–309
734
Index
Andropause, testosterone replacement therapy, 596–597 Anorexia nervosa, bone growth effects, 125–126 Aromatase deficiency effects, 297 functional overview, 296–297, 424 gene mutation effects on bone mass, 151 gene polymorphism effects on bone mass, 154 Ash fraction, bone mechanical properties, 58 Athletes bone loading measurement, 491–492 terminology, 491 bone mineral density, 497–500 nutritional and environmental determinants of skeletal health, 494–496 skeletal mass determinants, 492–494 steroid abuse, 497 stress fractures, 500–501 Azathioprine, bone effects, 444
B Bisphosphonates androgen deprivation therapy, 595, 675–676 bone turnover marker response, 34 chronic kidney disease and osteoporosis treatment, 457–461 cost-effectiveness, 619–621 fibrous dysplasia management, 516 glucocorticoid-induced osteoporosis management, 418, 668–670 hypercalciuria management, 485 hyperparathyroidism management, 474–475 immobilized patient use, 676 overview of benefits, 595 parathyroid hormone combination therapy, 684 use prior to parathyroid hormone therapy, 685 pharmacology, 667–668 primary osteoporosis management alendronate, 670, 674–675 overview, 668, 675 special considerations for men, 676 transplantation osteoporosis management, 670–674 BMD, see Bone mineral density BMI, see Body mass index BMP2, see Bone morphogenetic protein 2 Body mass index (BMI), bone loss effects in aging, 215 Bone aging effects, see Aging cells, 3–4 composition aging effects, 10–11 enzymes, 9–10 extracellular matrix, 6 GLA proteins, 6–7 matricellular proteins, 8 minerals, 5–6 SIBLING proteins, 7–8 small leucine-rich proteoglycans, 8–9 heterogeneity, 3 histomorphometry, see Histomorphometry, bone
mechanical properties, see Mechanical properties, bone remodeling, see Remodeling, bone turnover markers, 25–36 Bone biopsy, see Histomorphometry, bone Bone histomorphometry, see Histomorphometry, bone Bone marrow transplantation osteoporosis prevention bisphosphonates, 448–449 calcitonin, 449 testosterone, 449 vitamin D, 449 skeletal effects, 447 skeletal evaluation of candidates, 447–448 Bone mineral density (BMD), see also Peak bone mass aging changes, 207–208 androgen disturbances androgen deprivation therapy, 324 androgen insensitivity syndrome, 324–326 delayed puberty, 326 idiopathic hypogonadotropic hypogonadism, 324 Klinefelter syndrome, 324 5-reductase inhibitors, 326–327 androgen effects, 321–323 assessment dual-energy X-ray absorptiometry, 70–71 quantitative computed tomography, 72 athletes, 497–500 bone turnover marker correlations, 31, 36 calcium supplementation effects, 237–238 childhood and adolescence, 107–109 fracture limitations in prediction, 69–70 risk, 356, 363–364 gender-specific heritability, 150 glucocorticoid-induced osteoporosis diagnosis, 417 hyperparathyroidism evaluation, 470 idiopathic osteoporosis diagnosis, 406 limitations in fracture prediction, 69–70 measurement, see Computed tomography; Dual-energy X-ray absorptiometry; Quantitative ultrasound oxidative stress and control of bone mass, 274–275 protein nutrition effects, 257 reference ranges, 207–208 T-scores fracture risks, 592–593 osteoporosis diagnosis absolute risk, 606–607 limitations, 610 normative reference ranges, 607–610 overview, 605 risk gradient, 606 testosterone therapy monitoring, 704 Bone morphogenetic protein 2 (BMP2), gene polymorphisms and bone mass, 153 Bone remodeling, see Remodeling, bone Bone scintigraphy, vertebral fracture, 569 Bone sialoprotein (BSP) bone turnover marker, 26 functional overview, 8
Brittleness, bone mechanical properties, 53–54 Bruck syndrome, features, 510 BSP, see Bone sialoprotein
C Calcitonin adverse effects, 663 aging effects on mineral metabolism, 190 analgesic action, 663 biological effects, 656 bone turnover marker response, 34 distribution, 653 efficacy loss plateau phenomenon, 658 resistance primary, 658 secondary, 658–659 indications hypercalcemia, 661 metastatic bone pain, 662 osteoporosis, 659–660 Paget’s disease of bone, 661 overview of benefits in osteoporosis, 595 pharmacology, 656–657 physiological role, 654–656 preparations, 657–658 release, 654 structure, 653–654 synthesis, 653 Calcium, see also Hypercalciuria athlete intake, 495–496 balance, 43, 48–49, 483 bone strength role, 237 circulating levels, 42 diet and bone growth effects, 122–123 dietary reference intakes, 236 dietary sources, 236 gastrointestinal absorption, 235 intracellular metabolism, 47 laboratory evaluation, 593 nutritional therapy, 630 overview of benefits in osteoporosis, 597–598 physiological loss, 236 regulation intestinal, 42–43 renal, 43–44, 235 serum, 44 skeletal, 44, 235–236 supplementation effects bone mineral density, 237–238 children, 239–240 fracture, 238–239 threshold effect, 236–237 total body stores, 41–42 Calcium-sensing receptor (CaSR), antagonist therapy cinacalcet for hyperparathyroidism management, 475–476 overview, 726–727 Cancellous bone density (CBD), puberty changes, 98–99, 101 Cardiac transplantation bone loss and fracture rate, 445–446 mineral metabolism and bone turnover, 446 skeletal status before transplantation, 445 CaSR, see Calcium-sensing receptor
Index Cathepsin K bone turnover marker, 27 inhibitor therapy clinical studies, 725 preclinical studies, 725 rationale, 725 CBD, see Cancellous bone density Celiac disease, bone growth effects, 126 Chondrocyte functional overview, 3–4 vitamin D regulation, 245–246 Chronic kidney disease (CKD) bone histomorphometry, 456–457 bone turnover marker monitoring, 455–456 osteoporosis diagnosis stage, 1–3, 453–454 stage 5–5D, 454 osteoporosis treatment, 457–461 renal bone disease and fragility fracture, 454 Cinacalcet, hyperparathyroidism management, 475–476 CKD, see Chronic kidney disease Collagen, synthesis disorders, 506–512 Collagen type I, see also Osteogenesis imperfecta gene defect effects on bone mass, 151, 157, 506 postttranslational modifications, 28–29 telopeptides as bone turnover markers, 25, 181 Computed tomography (CT) bone architecture assessment micro computed tomography, 76–77, 551–554 volumetric imaging of spine and hip, 72–73 finite element analysis, 558–560 multidetector row computed tomography, 547–551 principles, 71–72 quantitative computed tomography bone loss in aging studies, 210–212 bone mineral density assessment, 72 children and adolescents, 97 finite element modeling, 75 high-resolution peripheral quantitative computed tomography, 554–556 osteoporosis diagnosis and monitoring, 548–551 physical activity and bone adaptation assessment, 133 volumetric analysis, 73–75 vertebral fracture, 569 Corticosteroid-induced osteoporosis, see Glucocorticoid-induced osteoporosis Cost analysis, see Fracture Cost-effectiveness, osteoporosis interventions bone densitometry role, 625 disutility, 624–625 elderly men at high risk of fracture absolute 10-year fracture risk, 620–621 low bone mineral density, 618–620 fracture reduction benefit after therapy cessation, 624 glucocorticoid-induced fracture, 621–622 good health economic modeling study characteristics, 614–615 non-vertebral fracture, 623–624
noncompliance impact, 624–625 overview, 613–614 societal willingness to pay for quality-adjusted life years, 623 study examples, 617–618 Crescent sign, bone mechanical properties, 64 Crohn’s disease, bone growth effects, 126 CT, see Computed tomography Cyclosporine A, bone effects, 444
D Dairy products bone health studies, 256–257 diet and bone growth effects, 124 Dehydroepiandrosterone (DHEA) effects on bone health, 328–329 secretion and action, 423–424 Delayed puberty, see Puberty Denosumab adverse events, 724–725 clinical studies, 724 preclinical studies, 722–724 rationale, 722 Dentin matrix protein 1 (DMP1), functional overview, 7–8 Dentin phosphophoryn, functional overview, 8 Dentin sialoprotein (DSP), functional overview, 8 Depression, osteoporotic fracture, 397 Development, see Puberty; Skeletal growth DHEA, see Dehydroepiandrosterone DHT, see Dihydroxytestosterone Dickkopfs-1 (Dkk1), bone turnover marker, 27–28 Dihydroxytestosterone (DHT) bone effects, 295–296 female studies of bone effects, 311 osteoblast effects, 303–304 osteoclast effects, 305 Disutility, fracture prevention, 624–625 Dkk1, see Dickkopfs-1 DMP1, see Dentin matrix protein 1 DSP, see Dentin sialoprotein Dual-energy X-ray absorptiometry (DXA) bone architecture assessment, 70 bone mineral density change monitoring, 535 children and adolescents, 97 diagnostics osteopenia, 531 osteoporosis, 531–534, 591–592 exercise monitoring, 640 fracture risk assessment, 534–535 hip strength analysis, 70–71 indications, 535–537 interpretation, 526–527 normative databases, 529–531, 537, 591 physical activity and bone adaptation assessment, 133 pitfalls, 527–529 principles, 525–526 quantitative ultrasound for prediction of test need, 542–543 sites for measurement, 527 vertebral fracture, 536–537, 567, 569 DXA, see Dual-energy X-ray absorptiometry
735
E Economic analysis, see Cost-effectiveness, osteoporosis interventions; Fracture EDS, see Ehlers-Danlos syndrome Ehlers-Danlos syndrome (EDS) classification, 510–511 clinical features, 510–511 gene mutations, 511–512 osteoporosis association, 512 Elderly, see Aging ESR1, gene mutation effects on bone mass, 151, 153 ESR2, gene polymorphism effects on bone mass, 153–154 Estrogen aging effects on mineral metabolism, 190, 198–199 androgen action comparison, 298 bone cell effects osteoblast differentiation, 272–273 osteoblastogenesis, 271–272 survival, 273–274 osteoclast apoptosis induction, 274 osteoclastogenesis, 270–271 osteocyte survival, 273–274 clinical studies in men bone growth, 289–290 bone maintenance, 290–291 fractures, 291–292 17-estradiol and bone turnover markers, 30 laboratory evaluation, 593–594 overview of benefits in osteoporosis, 596 oxidative stress and control of bone mass, 274–275 periosteal expansion role, 111–113 periosteum regulation, 276 receptors defect effects on bone mass, 151, 153–154 knockout mice, 277, 284 signaling osteoblast, 275–276 osteocyte, 275 rodent studies in males bone growth, 283–284 bone maintenance, 285 selective estrogen receptor modulators, see Selective estrogen receptor modulators skeletal growth effects, 90, 106–107 Ethanol, see Alcohol use Ethnicity bone remodeling differences in aging, 213–215 bone size and geometry determinants, 195–196 Exercise, see Physical activity
F Falls physical activity exercise response, 645–646 injury risk, 646 performance and risk of fracture, falls, and disability, 641–644
736
Index
Falls (Continued) risk alcohol use, 438–439 observational studies, 376–377 physical function relationship, 381 randomized trials, 377 vitamin D in prevention, 631 Fatigue, bone mechanical properties, 63–65 FD, see Fibrous dysplasia FEA, see Finite element analysis FEM, see Finite element modeling Fiber, nutritional therapy, 632 Fibrillin, gene mutations and disease, 513–514 Fibrous dysplasia (FD) clinical manifestations, 515 gene mutations, 515–516 Finite element analysis (FEA), image-based bone analysis, 558–560 Finite element modeling (FEM), 75–76 FIT, see Fracture Intervention Trial FK506, see Tacrolimus Folate, nutritional therapy, 632 Fracture, see also Vertebral fracture alcohol use and risk, 438–439 athletes and stress fractures, 500–501 bone mineral density fracture risk, 356, 363–364 limitations in prediction, 69–70 T-scores and fracture risks, 592–593 bone turnover marker correlations, 31–33 calcium supplementation effects, 238–239 cost-effectiveness of interventions, see Cost-effectiveness, osteoporosis interventions economic impact of osteoporotic fractures attributable cost excess costs, 391 incremental costs, 391 overview, 387–388 direct costs, 386 hip fracture, 389–390 indirect costs, 386 overview, 385–386 projected costs, 391–392 sex differences, 385 total cost Australia, 390–391 Europe, 389–390 Middle East, 391 North America, 388–389 overview, 386–387 vertebral fracture, 390 epidemiology distal forearm fracture, 355 hip fracture, 353–354 osteoporotic fractures, 352, 361 overall incidence in men, 351 proximal humerus fracture, 355 sex differences in rates, 174, 351–352, 361 vertebral fracture, 354–355 estrogen levels and risks in men, 291–292 morbidity hip fracture, 396 vertebral fracture, 395–396 wrist fracture, 395
mortality hip fracture, 398–399 second fracture, 399 vertebral fracture, 399 muscle, testosterone, and risk modification, 342 osteoporosis evaluation of men with increased fracture risk, 589–590 osteoporotic fracture epidemiology in men, 691 physical activity exercise response, 377–378, 645–646 injury risk, 646 performance and risk of fracture, falls, and disability, 641–644 prognosis in men distal forearm fracture, 362–363 hip fracture, 362 vertebral fracture, 362 protein intake effects, 257–258 protein nutrition and risk, 257–258 psychosocial consequences depression, 397 health-related quality of life, 397–398 social role loss, 397 renal bone disease and fragility fracture, 454 risk assessment dual-energy X-ray absorptiometry, 534–535 quantitative ultrasound, 541–542 risk factors aging, 363 overview, 691–692 personal history, 364 smoking, 364 risk prognosis, 365–369 vertebral fracture assessment with dual-energy X-ray absorptiometry, 536–637 Fracture Intervention Trial (FIT), 618–619 Fracture toughness, bone mechanical properties, 63
G GIO, see Glucocorticoid-induced osteoporosis Glomerular filtration rate reduction, see Chronic kidney disease Glucocorticoid-induced osteoporosis (GIO) cost-effectiveness of interventions, 621–622 diagnosis, 417–418 epidemiology, 415 histomorphometry of bone, 580–581 pathophysiology, 415–417 transplantation osteoporosis, 553–554 treatment, 418–419, 668–670 GR, see Growth hormone Greulich-Pyle atlas, skeletal maturity assessment, 95–96 Growth hormone (GH) aging effects on mineral metabolism, 190, 197 androgen modulation in muscle, 341–342 bone turnover marker response to therapy, 35 glucocorticoid-induced osteoporosis management, 419 histomorphometry of bone deficiency, 583 periosteal expansion role, 111–113 skeletal growth effects, 89–90, 106–107 skeletal mass determination, 493–494
H Health-related quality of life (HRQOL), osteoporotic fracture, 397–398 Hematocrit, testosterone therapy monitoring, 704 Hemochromatosis, see Hereditary hemochromatosis Hereditary hemochromatosis (HH), features and osteoporosis, 517–518 HH, see Hereditary hemochromatosis High-resolution peripheral quantitative computed tomography, see Computed tomography Hip strength analysis (HSA), technique, 70–71 Histomorphometry, bone biopsy indications in male osteoporosis, 584 chronic kidney disease, 456–457 hypercalciuria, 483 micro magnetic resonance imaging, 555, 557–558 osteoporosis in males alcoholism, 581–582 glucocorticoid-induced osteoporosis, 580–581 growth hormone deficiency, 583 hematologic disease, 583 hyperparathyroidism, 582 hyperthyroidism, 582–583 hypogonadism, 581 hypothyroidism, 582–583 liver disease, 583 osteogenesis imperfecta, 583 osteomalacia, 582 osteopetrosis, 583–584 primary osteoporosis, 578–580 pycnodysostosis, 583–584 prospects, 584–585 strontium ranelate effects, 715–716 HIV, see Human immunodeficiency virus Homocystinuria, features and osteoporosis, 518 Hooke’s law, bone mechanical properties, 56 HRQOL, see Health-related quality of life HSA, see Hip strength analysis Human immunodeficiency virus (HIV) bisphosphonate management of osteoporosis, 670 testosterone therapy, 338–339, 705 Hypercalcemia, calcitonin management, 661 Hypercalciuria bone mass, 479–480 bone mineral density relationship with urinary calcium, 481–482 bone pathogenesis histomorphometry, 483 macroscopic structure, 482–483 calcium metabolism assessment balance, 483 biochemical tests, 483 intestinal transport, 483–484 renal transport, 484 definition, 480 dietary factors, 484–486 systemic disorders, 479 treatment bisphosphonates, 485 nutrition, 486 potassium bicarbonate, 485 thiazide diuretics, 485 vitamin D levels in serum, 480–481
Index Hyperparathyroidism, see Primary hyperparathyroidism Hyperthyroidism, histomorphometry of bone, 582–583 Hypophosphatasia, features, 514–515 Hypothyroidism, histomorphometry of bone, 582–583
I ICER, see Incremental cost-effectiveness ratio Idiopathic hypogonadotropic hypogonadism (IHH) androgen deficiency diagnosis, 699–701 epidemiology, 701 osteoporosis comorbidity, 701 bone mineral density, 324 testosterone therapy, 693 Idiopathic osteoporosis clinical presentation, 408 diagnosis age, 406 bone mineral density, 406 fragility fracture, 406–407 overview, 405–406 secondary cause exclusion, 407–408 genetics, 409–410 pathophysiology, 409–410 prospects for study, 411 skeletal phenotype, 408–409 treatment, 410–411 IGF-I, see Insulin-like growth factor-I IGFBP2, see Insulin-like growth factor-binding protein 2 Immobilization, bone turnover marker effects, 30 Incremental cost-effectiveness ratio (ICER), 614 Insulin-like growth factor-I (IGF-I) aging effects on mineral metabolism, 190, 197 gene defect effects on bone mass, 157 glucocorticoid-induced osteoporosis management, 419 idiopathic osteoporosis levels, 410 periosteal expansion role, 111–113 protein nutrition effects, 258–259 skeletal growth effects, 89–90, 106–107 skeletal mass determination, 493–494 Insulin-like growth factor-binding protein 2 (IGFBP2), knockout mice, 159 Integrins, antagonist therapy, 726
K Kallman syndrome, bone growth effects, 114 Kidney disease, see Chronic kidney disease Kidney transplantation bone loss and fracture rate, 444–445 mineral metabolism and bone turnover, 445 skeletal status before transplantation, 444 Klinefelter syndrome bone growth effects, 114 bone mineral density, 324
L Liver transplantation bone loss and fracture rate, 446 mineral metabolism and bone turnover, 446 skeletal status before transplantation, 446
LRP5, gene defect effects on bone mass, 151, 155–157, 409–410 Lung transplantation bone loss and fracture rate, 447 skeletal status before transplantation, 447 Lysyl-hydroxylase (PLOD) Bruck syndrome and PLOD2, 510 Ehlers-Danlos syndrome and PLOD1, 511
M Magnesium balance, 46, 49 circulating levels, 45–46 diet and bone growth effects, 122, 124 intracellular metabolism, 47 regulation, 46 total body stores, 42 Magnetic resonance imaging (MRI) bone histomorphometry with micro magnetic resonance imaging, 555, 557–558 vertebral fracture, 569 Male Osteoporosis Self-Assessment Screening Tool (MOST), 209 Marfan syndrome (MFS) clinical features, 512–513 diagnostic criteria, 513 gene mutations, 513–514 osteoporosis, 514 Mass spectrometry, bone turnover marker discovery, 29 Matrix extracellular phosphoglycoprotein (MEPE), functional overview, 8 Matrix-gla protein (MGP), functional overview, 7–8 Mechanical properties, bone anatomical structural effect cancellous tissue in simple compression and tension, 56–57 cortical tissue in simple compression and tension, 57–58 long bone in bending, 52–56 vertebrae in compression, 56 bone loading measurement, 491–492 terminology, 491 collagenous matrix function, 60–61 damage repair dependence, 65 fatigue, 63–65 fracture toughness, 63 hierarchy concept, 51 microstructure effects cancellous bone, 61–62 cortical bone, 62 strain rate, 62–63 ultrastructure studies demineralization, 58 deproteinization, 58 drying, 59 mineral crystal model, 61 overview, 58 synthesis of experiments, 59–60 Menkes’ disease, features and osteoporosis, 516 Menopause, bone loss, 171–172 MEPE, see Matrix extracellular phosphoglycoprotein Mesenchymal stem cell, androgen effects, 341
737
Metastatic bone pain, calcitonin management, 662 MFS, see Marfan syndrome MGP, see Matrix-gla protein Micro computed tomography, see Computed tomography Micro magnetic resonance imaging, see Magnetic resonance imaging Milk, see Dairy products Modulus of rupture, bone mechanical properties, 55 MOST, see Male Osteoporosis Self-Assessment Screening Tool Mouse strains gene defect effects on bone mass, 158–160 sex-specific skeletal traits, 158–159 MRI, see Magnetic resonance imaging Multidetector row computed tomography, see Computed tomography Muscle androgen effects dose-response relationships, 336–337, 342 epidemiological studies, 335–336 fracture risk modification, 342 gonadal suppression studies, 336 interactive effects with resistance training, 337 mechanisms of action, 340–342 reaction time, 340 selective androgen receptor modulators, 343 testosterone replacement therapy aging, 337–338 chronic illness, 338–339 failure analysis, 339–340 quality of life, 340 exercise muscle-bone unit, 640–641 prescription and strength response, 645 strength changes in aging lower extremities, 380 muscle mass decline, 380–381 physical function and fall risk, 381 upper extremities, 379–380 testosterone effects epidemiologic studies, 692–693 mechanisms, 692 Mycophenolate mofetil, bone effects, 444
N Nutrition, see also Specific nutrients bone size and geometry determination in aging, 196 skeletal growth role assessment, 119–120 dairy products, 124 diseases anorexia nervosa, 125–126 celiac disease, 126 Crohn’s disease, 126 obesity, 126 ulcerative colitis, 126 exercise-diet interactions, 125 micronutrients calcium, 122–123 magnesium, 122, 124 phosphorous, 124
738
Index
Nutrition (Continued) vitamin D, 122 mineral absorption enhancers and inhibitors, 124–125 relative role, 210–121 salt intake, 124 therapy calcium, 630 fiber, 632 folate, 632 hypercalciuria management, 486 macronutrients, 629 vitamin D calcium combination, 630 fall prevention, 631 fracture prevention, 631 vitamin K, 632
O Obesity, bone growth effects, 126 Occipital horn syndrome, features and osteoporosis, 516–517 OI, see Osteogenesis imperfecta OPG, see Osteoprotegerin Ossification, endochondral, 5 OST, see Osteoporosis Self-Assessment Screening Tool Osteoblast aging effects, 185 androgen receptor expression localization, 299–301 regulation, 301–303 bone remodeling, 18–19 functional overview, 3–4 regulators as bone turnover markers, 27–28 sex steroid effects androgens, 303–305 differentiation, 272–273 osteoblastogenesis, 271–272 survival, 273–274 vitamin D regulation, 245 Osteocalcin, functional overview, 6 Osteoclast aging effects, 185 functional overview, 4 regulators as bone turnover markers, 27–28 sex steroid effects androgen effects, 305–306 apoptosis induction, 274 estrogen receptor signaling, 275–276 osteoclastogenesis, 270–271 vitamin D regulation, 245 Osteocyte aging effects, 185 estrogen receptor signaling, 275 functional overview, 3–4 sex steroid effects on survival, 273–274 Osteogenesis imperfecta (OI) diagnosis, 506 histomorphometry of bone, 583 type I, 507–508 type II, 508 type III, 508 type IV, 509 type V, 509 type VI, 509–510
type VII, 510 type VIII, 510 Osteomalacia, histomorphometry of bone, 582 Osteonectin, functional overview, 8 Osteopenia, diagnosis with dual-energy X-ray absorptiometry, 531 Osteopetrosis, histomorphometry of bone, 583–584 Osteopontin bone turnover marker, 26 functional overview, 7 Osteoporosis Self-Assessment Screening Tool (OST), 208–209 Osteoporosis, see also Glucocorticoid-induced osteoporosis; Idiopathic osteoporosis; Transplantation osteoporosis diagnostic criteria for men absolute risk, 606–607 limitations, 610 normative reference ranges, 607–610 risk gradient, 606 evaluation of men with increased fracture risk, 589–590 fracture, see Fracture susceptibility genes, see Susceptibility genes, osteoporosis Osteoprotegerin (OPG) bone turnover marker, 27 gene defect effects on bone mass, 157–158
P Paget’s disease of bone, calcitonin management, 661 Parathyroid gland imaging, 470–471 removal, 471–473 Parathyroid hormone (PTH), see also Primary hyperparathyroidism; Teriparatide aging effects on mineral metabolism, 187–188 anabolic actions, 681–682 bone turnover marker response to therapy, 35 calcium balance, 48 discontinuation consequences, 685–686 idiopathic osteoporosis management, 410–411 phosphorous balance, 49 prospects for therapy, 686 receptor defect effects on bone mass, 155 renal regulation calcium, 43–44 phosphorous, 45 safety, 686 vitamin D and expression, 245 Parathyroid hormone-related peptide (PTHrP), therapy, 726 PBM, see Peak bone mass Peak bone mass (PBM) heritability, 149–150 timing, 100 Periostin, bone turnover marker, 26 Peroxisome proliferator-activated receptors (PPARs), activity in athletes, 494 Phosphate balance, 45, 49 circulating levels, 44 diet and bone growth effects, 124 hyperparathyroidism management, 474
hypophosphatasia features, 514–515 intracellular metabolism, 47 regulation, 45 total body stores, 42 PHPT, see Primary hyperparathyroidism Physical activity bone turnover marker effects, 30 exercise prescription for osteoporosis bipedal locomotion, 639 bone mineral density monitoring, 640 bone strength response, 644–645 bone strength versus fall risk, 638–639 goals, 635–636 muscle strength response, 645 one-leg standing, 639 physics, anatomy, and physiology, 636–638 pitfalls in assessing interventions, 636 prospects, 647–648 recommendations, 646–647 tensegrity, 639–640 overview of benefits in osteoporosis, 598 Physical activity, see also Athletes assessment, 375–376 bone adaptation assessment, 133 mechanisms, 132 overview, 131 bone health studies cross-sectional studies, 134–135 intervention studies, 136–142 muscle-bone unit, 640–641 prospective observational studies, 135–136 diet interactions, 125 fall risk observational studies, 376–377 randomized trials, 377 fracture risk, 377–378 persistence of bone health benefits, 142–143 physical function assessment, 378–379 fall risk, 381 fracture risk, 381–382 physical performance and risk, 381–382 prospects for study, 143–144 recommendations in older adults, 375 risk of fracture, falls, and disability exercise response, 645–646 injury risk, 646 performance effects, 641–644 sarcopenia and age-associated functional decline, 642–653 skeletal growth influences, 133–134 strength, see Muscle testosterone interactive effects with resistance training, 337 types and bone strength promotion, 133 PLOD, see Lysyl-hydroxylase Potassium bicarbonate, hypercalciuria management, 485 PPARs, see Peroxisome proliferator-activated receptors Primary hyperparathyroidism (PHPT) bone mineral density evaluation, 470 clinical manifestations, 465, 469 diagnosis, 469–470 epidemiology, 465–467
Index etiology, 467 histomorphometry of bone, 582 medical management, 474–476 natural history of mild disease, 471 parathyroid imaging, 470–471 pathology, 467 signs and symptoms, 467–469 surgical management clinical course after surgery, 473 removal, 471–473 Prostate cancer, see also Androgen deprivation therapy bone turnover marker effects metastasis, 30 androgen deprivation therapy, 30–31 Prostate-specific antigen (PSA), testosterone therapy monitoring, 704–705 Protein, dietary bone effects bone mineral density, 257 dairy products, 256–257 fracture risk, 257–258 growth, 255–256 metabolism, 258–260 overview, 255 hypercalciuria effects, 485 insufficiency correction effects, 260–261 nutritional therapy, 629 PSA, see Prostate-specific antigen PTH, see Parathyroid hormone PTHrP, see Parathyroid hormone-related peptide Puberty androgens and skeletal changes, 319–321 bone measurement techniques, 96–98 bone mineral density in delayed puberty, 326 peak bone mass, 100 radial bone growth, 193 skeletal changes density, 98–99 longitudinal growth, 98 size, 99 skeletal maturation, 95–96 Pycnodysostosis, histomorphometry of bone, 583–584 Pyridoxine, bone loss effects in aging, 215
Q QALY, see Quality-adjusted life year QTL, see Quantitative trait loci Quality-adjusted life year (QALY) cost-effectiveness of osteoporosis interventions elderly men at high risk of fracture absolute 10-year fracture risk, 621 low bone mineral density, 619–620 glucocorticoid-induced fracture, 622 societal willingness to pay, 623 overview, 614 Quantitative computed tomography, see Computed tomography Quantitative trait loci (QTL), linkage studies of male osteoporosis, 152 Quantitative ultrasound (QUS) dual-energy X-ray absorptiometry need prediction, 542–543 fracture risk prediction, 541–542
principles, 541 therapy monitoring, 543–544 QUS, see Quantitative ultrasound
R Race, see Ethnicity Raloxifene, see Selective estrogen receptor modulators Ramamycin, see Sirolimus RANK ligand bone turnover marker, 27 inhibitor therapy adverse events, 724–725 clinical studies, 724 preclinical studies, 722–724 rationale, 722 5-Reductase inhibitors and bone mineral density, 326–327 testosterone therapy for deficiency, 693 15-Lipoxygenase (ALOX15), gene defect effects on bone mass, 157–158 Remodeling, bone aging effects, 169–171, 578 mechanism activation, 15 formation, 18–20 overview, 15–16 resorption, 15, 17 reversal, 17–18 overview, 167–169 physiological functions, 20–21 regional variation in skeleton, 21–22 skeletal growth, 89 strontium ranelate effects, 714–716 Renal disease, see Chronic kidney disease Rett syndrome, features and osteoporosis, 518–519
S Salt, diet and bone growth effects, 124 Sarcopenia, age-associated functional decline, 642–643 SARMs, see Selective androgen receptor modulators Sclerostin antibody therapy, 728 gene mutation effects on bone mass, 152 osteocyte production, 4 Selective androgen receptor modulators (SARMs) development, 722 muscle effects, 343 overview, 706, 719 preclinical studies hydantoins, 722 indoles, 722 propionamides, 720–721 quinolines, 721–722 tetrahydroquinolines, 721 tissue specificity, 720 types and structures, 721 Selective estrogen receptor modulators (SERMs) clinical trials, 717, 719 preclinical trials, 717 safety, 719
739
tissue specificity, 716–717 types and structures, 718 SERMs, see Selective estrogen receptor modulators Sex hormone-binding globulin (SHBG) aging effects, 424–425 assay, 700–701 levels and bone health, 323 SHBG, see Sex hormone-binding globulin SIBLING proteins, functional overview, 7–8 Singh Index, 70 Sirolimus, bone effects, 444 Skeletal growth, see also Puberty bone mass acquisition in childhood and adolescence, 107–109 bone remodeling, 89 bone structure, 86–88 genetic syndrome effects, 114–115 hormonal regulation, 89–90, 105–107 later influences on fragility, 88–89 nutrition role assessment, 119–120 dairy products, 124 diseases anorexia nervosa, 125–126 celiac disease, 126 Crohn’s disease, 126 obesity, 126 ulcerative colitis, 126 exercise-diet interactions, 125 micronutrients calcium, 122–123 magnesium, 122, 124 phosphorous, 124 vitamin D, 122 mineral absorption enhancers and inhibitors, 124–125 relative role, 210–121 salt intake, 124 periosteal expansion assessment, 109–110 genetic factors, 113 regulation, 110–113 physical activity influences, 133–134 radial bone growth, 193 stature, 85–86 Skeletal maturity, assessment, 95–96 SLRPs, see Small leucine-rich proteoglycans Small leucine-rich proteoglycans (SLRPs), functional overview, 8–9 Smoking bone turnover marker effects, 30 fracture risk, 364 Social role, loss in osteoporotic fracture, 397 Strain rate, bone mechanical properties, 62–63 Strain, bone mechanical properties, 53–55 Stress, bone mechanical properties, 53–55 Strontium ranelate clinical studies bone mineral density, 715 bone remodeling, 715 histomorphometry, 715–716 overview of benefits in osteoporosis, 596 safety, 716 development, 713–714 preclinical studies
740
Index
bone distribution and morphology, 714–716 bone remodeling, 714 Susceptibility genes, osteoporosis identification animal studies, 158–160 association studies, 153–158 linkage studies, 151–153 overview, 150–151 monogenetic disorders of low bone mass, 151–152 Swyer syndrome, bone growth effects, 115
T Tacrolimus (FK506), bone effects, 444 Tamoxifen, see Selective estrogen receptor modulators Tanner-Whitehouse system, skeletal maturity assessment, 96 Tartrate-resistant acid phosphatase (TRACP), isoenzyme 5 as bone turnover marker, 26–27 T cell, bone resorption regulation, 276–277 Tensegrity, skeletal strength, 639–640 Teriparatide, see also Parathyroid hormone bisphosphonates combination therapy, 684 use prior to parathyroid hormone therapy, 685 dosing, 692 glucocorticoid-induced osteoporosis management, 418–419 osteoporosis management, 683–684 overview of benefits in osteoporosis, 595 Testosterone, see also Androgen aging effects on mineral metabolism, 190, 199 alcohol use effects, 437 bone cell effects mechanisms, 692 osteoblast differentiation, 272–273 osteoblastogenesis, 271–272 survival, 273–274 osteoclast apoptosis induction, 274 osteoclastogenesis, 270–271 osteocyte survival, 273–274 castration effects on bone mass, 309–311 sex steroid replacement effects, 311–312 deficiency adverse effect minimization, 703–704 diagnosis, 699–701 epidemiology, 701 osteoporosis comorbidity, 701 female studies of bone effects, 311 laboratory evaluation, 593–594 metabolism, 295–298 muscle effects dose-response relationships, 336–337, 342 epidemiological studies, 335–336 fracture risk modification, 342 gonadal suppression studies, 336 interactive effects with resistance training, 337 mechanisms of action, 340–342 reaction time, 340
selective androgen receptor modulators, 343 testosterone replacement therapy aging, 337–338 chronic illness, 338–339 failure analysis, 339–340 quality of life, 340 muscle effects epidemiologic studies, 692–693 mechanisms, 692 periosteal expansion role, 111–113 periosteum regulation, 276, 309 secretion and action, 423–424 selective androgen receptor modulators, see Selective androgen receptor modulators skeletal growth effects, 90, 106–107 Testosterone replacement therapy (TRT) andropause, 596–597 bone outcomes androgen deprivation therapy, 693 androgen insensitivity syndrome, 693 human immunodeficiency virus, 705 idiopathic hypogonadotropic hypogonadism, 693 interventional trials, 693–699 microstructure effects, 699 5-reductase deficiency, 693 bone turnover marker response, 33–34 castration studies, 311–312 controversies, 597 glucocorticoid-induced osteoporosis, 418 hypogonadal adults, 596 metabolic bone disease, 597 monitoring symptomatic relief, 704 bone mineral density, 704 hematocrit, 704 prostate-specific antigen, 704–705 muscle effects aging, 337–338 chronic illness, 338–339 failure analysis, 339–340 quality of life, 340 preparations buccal, 703 comparison, 703 intramuscular, 701–702 oral, 702–703 subdermal, 703 transdermal, 702 Thalassemia, bisphosphonate management of osteoporosis, 670 Thiazide diuretics hypercalciuria management, 485 overview of benefits in osteoporosis, 595–596 Three-point bending test, bone mechanical properties, 54–56 TNF-, see Tumor necrosis factor- Toughness, bone mechanical properties, 53–54 TRACP, see Tartrate-resistant acid phosphatase Transplantation osteoporosis bisphosphonate management, 670–674 bone marrow transplantation, skeletal effects, 448 cardiac transplantation
bone loss and fracture rate, 445–446 mineral metabolism and bone turnover, 446 skeletal status before transplantation, 445 immunosuppressive drugs and skeletal effects azathioprine, 444 cyclosporine A, 444 glucocorticoids, 553–544 mycophenolate mofetil, 444 sirolimus, 444 tacrolimus, 444 kidney transplantation bone loss and fracture rate, 444–445 mineral metabolism and bone turnover, 445 skeletal status before transplantation, 444 liver transplantation bone loss and fracture rate, 446 mineral metabolism and bone turnover, 446 skeletal status before transplantation, 446 lung transplantation bone loss and fracture rate, 447 skeletal status before transplantation, 447 prevention bisphosphonates, 448–449 calcitonin, 449 testosterone, 449 vitamin D, 449 skeletal evaluation of candidates, 447–448 TRT, see Testosterone replacement therapy Tumor necrosis factor- (TNF-), protein nutrition effects, 260
U Ulcerative colitis, bone growth effects, 126 Ultrasonography, see Quantitative ultrasound
V Vertebral fracture deformity versus fracture, 567 diagnosis algorithm-based quantitative assessment, 571–572 challenges, 565–566 describing, 573 incident vertebral fracture, 572 prospects for study, 573 qualitative approach, 569 quantitative vertebral morphometry, 569–571 semiquantitative morphometry, 571 economic impact of osteoporotic fracture, 390 epidemiology, 354–355 imaging bone scintigraphy, 569 computed tomography, 569 dual-energy X-ray absorptiometry, 567, 569 indications, 572–573 magnetic resonance imaging, 569 plain radiography, 567–568 mortality, 399 prognosis in men, 362 relevance in men, 566 Vertebral fracture assessment (VFA), dual-energy X-ray absorptiometry, 536–637 VFA, see Vertebral fracture assessment Vitamin C, bone loss effects in aging, 215–216
Index Vitamin D aging effects on mineral metabolism, 185–187 athlete intake, 495–496 deficiency bone turnover markers, 30 rickets, 243, 246 diet and bone growth effects, 122 functions calcium absorption, 244–245 calcium renal handling, 245 chondrocyte regulation, 245–246 osteoblast regulation, 245 osteoclast regulation, 245 parathyroid hormone expression, 245 glucocorticoid-induced osteoporosis management, 418 hypercalciuria and levels in serum, 480–481 laboratory evaluation, 593 nutritional therapy
calcium combination, 630 fall prevention, 631 fracture prevention, 631 overview of benefits in osteoporosis, 597–598 receptor overview, 244 defect effects on bone mass, 154–155 status evaluation hard endpoints, 247–249 surrogate endpoints bone mineral density and turnover markers, 247 calcium absorption, 247 parathyroid hormone level, 246–247 vitamin D concentration, 246 supplement definition, 249–250 overview of surveys, 249–250 selection and treatments, 249
741
supplementation effects with calcium bone mineral density, 237–238 children, 239–240 fracture, 238–239 synthesis and metabolism, 243–244 Vitamin K, nutritional therapy, 632
W Wilson disease, features and osteoporosis, 517 Wnt androgen effects in muscle, 341 signaling pathway therapeutic targeting, 727–728
Y Young’s modulus, bone mechanical properties, 53–55