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Osteoporosis in Men
This Page Intentionally Left Blank
Osteoporosis
in Men
The Effects of Gender
on Skeletal Health
Edited by
Eric S. Orwoll
Oregon Health Sciences University
Portland VA Medical Center
Portland, Oregon
ACADEMIC PRESS
San Diego London Boston New York
Sydney Tokyo Toronto
Front cover photograph:
Histological section of the vertebral body edge
from an 82-year-old woman. For more details, see Figure 4 (color insert)
in Chapter 16.
This book is printed on acid-free paper. (~)
Copyright ~3 1999 by ACADEMIC PRESS
All Rights Reserved.
No part of this publication may be reproduced or transmitted in any form or by any
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Permissions Department, Harcourt Brace & Company, 6277 Sea Harbor Drive,
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Academic Press
a division o['Harcourt Brace & Company
525 B Street, Suite 1900, San Diego, California 92101-4495, USA

Gender
3
IV. Effects
of
Race 4
V. Effects
of
Geography
6
VI.
Secular Trends
7
VII. Public Health Implications
8
References
9
Chapter
2
Economic Impact
of
Fractures
Anna
N.
A.
Tosteson
I.
Introduction
15
11.
Economic Evaluation

A. RadiologicaluMorphometric 34
B. RadiologicaluDensitometric 34
C. Clinical 35
V. Social and Economic Factors 36
A. Occupation 37
B. Diet 38
C. Exercise 39
D. Leisure Activities 39
VI. Falls 39
VII. Consequencs of Osteoporotic Vertebral and Femoral Fracture
VIII. Intervention 42
A. Pain Control 42
B. Surgery 43
C. Reduction of Falls Risk 43
D. Reduction of Forces Acting at the Impact Site 44
IX. Future Trends 44
References 45
41
Contents
vii
Chapter 4
Outcomes and the Personal Impact of Osteoporosis
Deborah T. Gold
I. Introduction 51
A. Osteoporosis and Men: What We Know 52
B. Osteoporosis: Its Social/Emotional Impact and Quality
of Life 55
II. Men and Osteoporosis-Where Do We Start to Understand
Outcomes? 58
A. Focus Groups 58

Skeleton 88
B. Growth in Size, Mass, and Volumetric Density of the
Appendicular Skeleton 91
C. Delayed Puberty 93
III. Changes in Bone Size, Mass, and Volumetric Density during
Aging 94
A. Trabecular and Cortical Bone Loss 94
B. Relative Contributions of Peak Bone Mass and Bone Loss to Bone
Mass in Old Age 98
C. Hip Axis Length 99
IV. Comparing Men with and without Fractures 100
A. Reduced Bone Size 100
B. Less Bone in the Bone~Reduced Accrual and Excessive Bone
Loss 101
C. Histomorphometry and Reduced Bone Formation 102
D. Cellular Evidence of Reduced Bone Formation 103
V. Summary 105
VI. Questions 106
References 107
Chapter 7
Aging and Changes in Cortical Mass and Structure
R. Bruce Martin
I. Introduction 111
II. Basic Mechanical Considerations in Diaphyseal Modeling 112
III. The Mechanical Role of Remodeling 114
IV. Gender Differences in Modeling during Puberty 114
V. Animal Studies of the Effects of Sex Hormones on Modeling 116
VI. Male Hypogonadism 118
VII. Remodeling, Fatigue Damage, and Mechanical Properties in the
Aging Skeleton 119

IX. Maintaining Bone Mass Exercise Prescription 148
X. Conclusions 149
References 150
137
132
Chapter 9
Insulin-like Growth Factors and Bone: Implications for the
Pathogenesis and Treatment of Osteoporosis
Clifford J. Rosen
I. Introduction 157
II. Physiology of the IGFs 158
A. IGF-I and IGF-II Structure and Function 158
B. The Skeletal IGF Regulatory System 160
C. Regulation of Serum and Skeletal IGFs 162
III. IGFs and Their Role in Acquisition and Maintenance of Adult
Bone Mass 167
A. Acquisition of Peak Bone MassmRole of the IGFs 167
x Contents
B. IGF-I and Maintenance of Bone Density
IV. Summary 172
References 173
168
Chapter I 0
Age-Related Changes in Mineral Metabolism
Bernard P. Halloran and Daniel D. Bikle
I. Introduction 179
II. Regulation of Mineral Metabolism 180
III. Human Aging 180
A. Aging and Disease 180
B. The Basis of Aging: Cell Senescence 181

Receptor 212
III. Effects of Androgens on the Proliferation and Differentiation of
Osteoblastic Cells 217
IV. Interaction with Other Factors to Modulate Bone Formation and
Resorption 218
V. Direct Effects of Androgens on Other Cell Types in Bone
in Vitro 222
VI. Metabolism of Androgens in Bone Aromatase and 5oL-Reductase
Activities 223
VII. Androgen Effects on Bone: Animal Studies 227
A. Effects on Epiphyseal Function and Bone Growth during Skeletal
Development 227
B. Effects on Bone Mass in Growing Male Animals 228
C. Mature Male Animals 230
D. Androgens in the Female Animal 235
E. Effects of Replacement Sex Steroids after Castration 236
F. Gender Specificity in the Actions of Sex Steroids 238
G. The Animal Model of Androgen Resistance 238
VIII. Summary 239
References 240
Chapter 13
Androgens and Bone: Clinical Aspects
Eric S.
Orwoll
I. Introduction 247
II. Puberty 248
Ill. Estrogens versus Androgens in Puberty 251
IV. Age-Related Declines in Androgen Levels in Adult Men: Contribution
to Bone Loss 252
V. Estrogens in Adult Men 254

B. Maintenance of Bone Mass 283
IV. Effects of Estrogen on Human Bone Metabolism and Calcium
Homeostasis 286
A. Bone Loss Patterns over Life 286
B. Accelerated Phase of Bone Loss in Women 286
C. Continuous Phase of Bone Loss 287
D. Gender Comparison and the Role of Estrogen in Bone
Metabolism in Males 288
V. Summary 290
References 291
Chapter 15
Age-Related Changes in Bone Remodeling
Torben Sceiniche and Erik F. Eriksen
I. Introduction
299
A. Variation in Bone Remodeling 300
B. Bone Loss due to Remodeling 302
II. Bone Mass and Structure 303
III. Age-Related Changes in Bone Turnover (Activation Frequency)
and Differences between Men and Women 305
Contents
xiii
A. Bone Remodeling in Healthy Men 305
B. Bone Remodeling in Healthy Women 307
C. Bone Remodeling in Healthy Men Compared with Healthy
Women 309
D. Age-Related Changes in the Amount of Bone Resorbed
(Resorption Depth) and Reformed (Wall Thickness) during the
Remodeling Cycle: Differences between Men and Women 309
IV. Conclusion 311

xiv Contents
C. Upper Limb Fractures 341
IV. Risk Factors for Fractures 341
A. Bone Mineral Density 341
B. Fractures Attributable to Osteoporosis
C. Falls and Fall-Related Factors 343
V. Bone Mineral Density in Men 344
A. Age-Related Change in BMD 344
B. Body Size 345
C. Physical Activity 346
D. Dietary Calcium Intake 347
E. Smoking 347
F. Alcohol 348
G. Genetic Factors 349
H. Candidate Genes 350
VI. Summary and Future Directions 352
A. Summary 352
B. Future Directions 353
References 354
342
Chapter 18
Risk Factors for Fractures in Men
Jane A. Cauley and Joseph M. Zmuda
I. Introduction 363
A. Prospective Cohort Studies of Fracture in Men
B. Risk Factors for Hip Fracture 364
C. Risk Factors for Vertebral Fracture 378
D. Risk Factors for Osteoporotic Fracture 384
E. Risk Factors for Wrist Fractures 385
II. Summary and Future Directions 386

B. Fractures 419
III. Pathophysiology 420
A. Osteoblasts 420
B. Osteoclasts 421
C. Intestinal and Renal Handling of Calcium and Phosphate
D. Vitamin D and Parathyroid Hormone 422
E. Sex Hormones 422
IV. Patient Evaluation 423
V. Management 425
A. Calcium Supplementation 426
B. Bisphosphonates 426
C. Vitamin D and Its Metabolites 427
D. Fluoride 428
E. Calcitonin 429
F. Testosterone Supplementation 429
VI. Research Directions 431
References 431
421
Chapter 2 I
Alcohol
Robert F. Klein
I. Introduction 437
II. Alcohol-Induced Osteoporotic Fractures
III. Alcohol-Induced Osteopenia 439
438
xvi Contents
A. Limitations of Current Studies 442
IV. Potential Mechanisms of Alcohol-Induced Bone Disease
A. Effect of Alcohol on Adult Bone 443
B. Effect of Alcohol on Growing Bone 445

Chapter 23
Secondary Causes of Osteoporosis
Peter R. Ebeling
I. Glucocorticoid-Induced Osteoporosis
483
Contents
xvii
II. Pulmonary Disease and Immunosuppressive Drugs 485
III. Hypogonadism 486
IV. Alcohol and Osteomalacia 489
V. Tobacco 490
VI. GastrointestinalDisease 491
VII. Hypercalciuria 493
VIII. Anticonvulsants 493
IX. Pernicious Anemia 494
X. Thyrotoxicosis and Thyroidectomy 494
XI. Hyperparathyroidism 494
XII. Immobilization 495
XIII. OsteogenesisImperfecta 495
XIV. Homocystinuria 495
XV. Neoplastic Disease (Multiple Myeloma, Lymphoma) 496
XVI. Ankylosing Spondylitis and Rheumatoid Arthritis 496
XVII. Systemic Mastocytosis 497
References 499
Chapter 24
The Assessment of Bone Mass in Men
Philip D. Ross, Antonio Lombardi, and Debra Freedholm
I. Introduction 505
II. Clinical Interpretation of BMD 506
III. Techniques for Measuring Bone Mineral Density 507

VII. Falls 539
VIII. Discussion of Diagnostic Measures of Particular Interest 539
A. Biochemical Markers of Mineral Metabolism 539
B. Biochemical Markers of Bone Remodeling 540
C. Histomorphometric Characterization 545
D. Growth Factors and Cytokine Measures 545
IX. Summary 546
References 547
Chapter 26
The Prevention and Therapy of Osteoporosis in Men
Eric S. Orwoll
I. Introduction 553
II. Prevention 554
A. Conditions Associated with Osteoporosis
AMajor Concern 554
B. Exercise 555
C. Calcium/Vitamin D 555
III. Therapy 557
A. Androgens 557
B. Calcitonin 558
C. Bisphosphonates 559
D. Thiazide Diuretics 562
E. Fluoride 563
F. Emerging Therapies 563
IV. Summary 565
References 566
Index 571
Contributors
Numbers in parentheses indicate the pages on which the authors' contributions begin.
Frazer Anderson (29) Department of Geriatric Medicine, Southampton Gen-

les, Los Angeles, California 90027
Deborah T. Gold (51) Departments of Psychiatry and Behavioral Sciences,
Sociology, and Psychology, Duke Aging Center, Duke University Medical
Center, Durham, North Carolina 27710
Bernard P. Halloran (179) Department of Medicine, University of Califor-
nia, San Francisco; and Division of Endocrinology, Veterans Affairs Med-
ical Center, San Francisco, California 94121
Sundeep Khosla (275) Endocrine Research Unit, Division of Endocrinology
and Metabolism, Mayo Clinic and Mayo Foundation, Rochester, Min-
nesota 55905
Robert F. Klein (437) Oregon Health Sciences University, Portland VA Med-
ical Center, Portland, Oregon 97201
Etah S. Kurland (395) College of Physicians and Surgeons, Columbia Uni-
versity, New York, New York 10032
Antonio Lombardi (505) Merck & Co., Inc., Rahway, New Jersey 07065
Robert Marcus (129) Stanford University School of Medicine, Veterans Af-
fairs Medical Center, Palo Alto, California 94304
R. Bruce Martin (111) Orthopaedic Research Laboratories, University of
California at Davis Medical Center, Sacramento, California 95817
L. Joseph Melton III (1) Mayo Clinic and Mayo Foundation, Rochester,
Minnesota 55905
Lis Mosekilde (313) Department of Cell Biology, Institute of Anatomy, Uni-
versity of Aarhus, DK-8000 Aarhus, Denmark
Tuan V. Nguyen (335) Wright State University School of Medicine, Yellow
Springs, Ohio 45387
Eric S. Orwoll (211,247, 527, 553) Bone and Mineral Unit, Department of
Medicine, Oregon Health Sciences University, Portland VA Medical Cen-
ter, Portland, Oregon 97207
Ian R. Reid (417) Department of Medicine, University of Auckland, Auck-
land, New Zealand

The recognition that osteoporosis is a huge public health problem came
recently, but it rapidly stimulated the emergence of a major new province in
biology and medicine. Professional meetings devoted to bone metabolism
and metabolic bone disorders have blossomed, new journals have emerged,
and the pioneering careers of dedicated early investigators have inspired the
vigor of a new generation of scientists. All this research interest is already
yielding substantial benefit for patients as new diagnostic methods and effec-
tive preventative and therapeutic approaches promise to dramatically reduce
the personal and economic burden of osteoporosis. Even as the care of osteo-
porosis is becoming a routine part of clinical medicine, there is eminent
promise of even more impressive breakthroughs.
Clearly, postmenopausal women bear the brunt of osteoporosis. That
demographic has driven research, and the foundations of knowledge of os-
teoporosis are to be found in studies of older women. Every effort directed
toward that part of the problem has been welcome and appropriate, but it is
now starkly apparent to clinicians that little information exists to direct the
evaluation and therapy of men with osteoporosis. In response to that reali-
zation, and because its study may provide a broader scientific insight, emi-
nent investigators have turned their attention to the issue. A rapid expansion
in the understanding of osteoporosis in men has begun, and this volume is
devoted to that knowledge.
The goal for the volume was twofoldmto summarize the current state
of the art and to identify directions for needed research. Of special impor-
tance was an attempt to examine bone biology and osteoporosis in men in
light of how they differ from similar events in women. It may be through
that prism that accomplishments in this area can be most remarkable.
xxiii
xxiv Preface
Though much remains to be done, the insights presented here should
help to form the foundation for subsequent basic and clinical investigation