Osteoporosis (eBook)

Front Cover 1
Osteoporosis 4
Copyright Page 5
Contents 6
Contributors 20
Preface 26
Part I: Introduction 28
Chapter 1: The Bone Organ System: Form and Function 30
I. Introduction 30
II. Composition and Organization of Bone 30
III. Cellular Components of Bone 38
IV. Bone Homeostasis 41
V. Bone Mechanics 44
VI. Summary 49
References 49
Chapter 2: The Nature of Osteoporosis 54
I. Defining Osteoporosis 54
II. Material and Structural Basis of Skeletal Fragility 55
III. Conclusions 60
References 60
Chapter 3: The Economics of Osteoporosis 64
I. Introduction 64
II. Cost of Illness Studies: Characterizing the Magnitude of the Health Problem 64
III. Cost-Effectiveness Analyses: Identifying Efficient Osteoporosis Care Strategies 67
IV. Future Research Directions 70
Acknowledgments 70
References 70
Chapter 4: Reflections on Osteoporosis 74
I. Introduction 74
II. Definition 74
III. Diagnosis 76
IV. Fragility Fractures 77
V. Bone Density and Fracture Risk 77
VI. Pathogenesis 78
VII. Prevention 90
VIII. Treatment 91
IX. Conclusions 92
References 92
Chapter 5: Skeletal Heterogeneity and the Purposes of Bone Remodeling: Implications for the Understanding of Osteoporosis 98
I. Introduction 98
II. Skeletal Heterogeneity 99
III. The Purposes of Bone Remodeling 101
IV. Implications for Understanding Osteoporosis 106
References 112
Part II: Basic Science of Bone Biology 118
Chapter 6: Osteoblast Biology 120
I. Overview 120
II. Embryonic Development of the Osteoblast Phenotype: Lessons for Bone Formation in the Postnatal Skeleton 120
III. Development Sequence of Osteoblast Phenotype Development 127
IV. Phenotype Properties of Osteogenic Lineage Cells 133
V. Molecular Mechanisms Mediating Progression of Osteoblast Growth and Differentiation 143
VI. Conclusion 155
Acknowledgments 156
References 156
Chapter 7: Osteoclast Biology 178
I. Introduction 178
II. Key Osteoclast Differentiation Pathways 178
III. The Fully Differentiated Osteoclast: Mechanisms of Bone Degradation 181
IV. Bone Resorption Coordinated by Intermediate Proteins 184
V. Osteoclast Death 185
VI. Mechanistic Approaches to Modification of Osteoclastic Activity In Vivo 185
VII. Regulation of Osteoclastic Differentiation and Activity In Vivo 187
VIII. Interaction of Hormonal and Local Signals with Osteoclast Activity 188
IX. Diseases with Altered Bone Resorption 189
References 190
Chapter 8: Osteocytes 196
I. Introduction 196
II. Osteocyte Ontogeny 196
III. Osteoid-Osteocytes 197
IV. Osteocyte Selective Genes/Proteins and their Potential Functions 198
V. Morphology of Osteocytes: Lacunocanalicular System and Dendrite Formation 199
VI. Osteocyte Cell Models 201
VII. Mechanisms and Response of Osteocytes to Mechanical Forces 201
VIII. Osteocyte Signals for Bone Formation 204
IX. Osteocyte Signals for Bone Resorption 205
X. Osteocyte Apoptosis 206
XI. Osteocyte Modification of their Microenvironment 206
XII. Osteocyte Density 207
XIII. Role of Gap Junctions and Hemichannels in Osteocyte Communication 207
XIV. Osteocytes in the Embryonic and the Adult Skeleton 208
XV. The Implications of Osteocyte Biology for Bone Disease 209
XVI. Conclusions 210
Acknowledgment 210
References 210
Chapter 9: The Regulatory Role of Matrix Proteins in Mineralization of Bone 218
I. Introduction 218
II. Collageneous Proteins 220
III. Intermediate Cartilage Matrix 222
IV. Bone-Enriched Matrix Proteins 228
V. The Mineralization of Bone Matrix 246
Acknowledgments 249
References 249
Chapter 10: Development of the Skeleton 268
I. Introduction 268
II. Patterning the Skeleton 268
III. Endochondral Bone Formation 277
IV. Intramembranous Bone Formation 288
References 290
Chapter 11: Mouse Genetics as a Tool to Study Bone Development and Physiology 298
I. Introduction: Historical Perspective and Significance 298
II. Introduction To Mouse Skeletal Physiology 299
III. Inbred Strains of Mice 300
IV. Recombinant Inbred strains 302
V. Congenic Strains 303
VI. Recombinant Congenic Strains 306
VII. Summary 307
References 307
Chapter 12: Parathyroid Hormone and Parathyroid Hormone-Related Protein 310
I. Introduction 310
II. Secretion of Parathyroid Hormone 310
III. Metabolism of Parathyroid Hormone 311
IV. Bone Resorbing Action of Parathyroid Hormone 312
V. Effects of Parathyroid Hormone on Bone Formation 313
VI. Renal Actions of Parathyroid Hormone 315
VII. Parathyroid Hormone-Related Protein as a Mediator of Malignancy-Associated Hypercalcemia 316
VIII. Physiological Roles of Parathyroid Hormone-Related Protein 316
IX. Mechanism of Action of Parathyroid Hormone and Parathyroid Hormone-Related Protein 321
Acknowledgments 327
References 327
Chapter 13: Vitamin D: Biology, Action, and Clinical Implications 344
I. Introduction 344
II. Vitamin D Synthesis and Metabolism 345
III. Pathways of Activation and Inactivation of Vitamin D 353
IV. Mechanism of 1,25(OH)2 D Action 358
V. Nongenomic Actions of Vitamin D 368
VI. Physiology: Regulation of Serum Calcium 369
VII. Genetic Disorders 371
VIII. 1,25(OH)2 D3 Analogs with Decreased Calcemic Activity 373
IX. Actions of Vitamin D in Classical Target Organs to Regulate Mineral Homeostasis 375
X. Actions of 1,25(OH)2D in Nonclassical Target Organs 381
XI. Vitamin D and Osteoporosis 387
References 388
Chapter 14: Regulation of Bone Cell Function by Estrogens 410
I. Introduction 410
II. What is an Estrogen? 410
III. Estrogen Receptors 410
IV. ERalpha and ERbeta Knockout Mice (ERKO and ßERKO) 419
V. Estrogens and Bone 419
VI. Estrogen Receptors in Bone Cells 420
VII. Estrogenic Responses in Bone Cells 425
VII. Estrogen-Related Receptor-alpha and Osteopontin Gene Expression 437
IX. Nongenomic Actions of Estrogens in Bone Cells 437
X. Conclusion 438
References 439
Chapter 15 Androgens and Skeletal Biology: Basic Mechanisms 452
I. Introduction 452
II. Androgens and the Role of Androgen Metabolism 452
III. Cellular Biology of the Androgen Receptor in the Skeleton 455
IV. The Consequences of Androgen Action in Bone Cells 460
V. The Skeletal Effects of Androgen: Animal Studies 464
VI. Animal Models of Altered Androgen Responsiveness 467
VII. Effects on the Periosteum: The Role of Androgen Receptor versus Aromatization of Testosterone 468
VIII. Summary 469
References 470
Chapter 16: Phosphatonins 478
I. Introduction 478
II. Phosphorus Homeostasis 478
III. Phosphatonins 481
IV. Fibroblast Growth Factor 23 481
V. Secreted Frizzled-Related Protein 4 487
VI. Matrix Extracellular Phosphoglycoprotein 487
VII. Fibroblast Growth Factor 7 488
VIII. Summary 489
References 489
Chapter 17: Wnt Signaling in Bone 494
I. Wnts 494
II. The Wnt/beta-Catenin Signaling Pathway 495
III. Other Wnt Pathways 500
IV. Mutations in Wnt Pathway Components and Altered Bone Mass 502
V. Wnt Signaling and Bone Cell Function 504
VI. Wnt Signaling and the Bone Response to Mechanical Loading 507
VII. Conclusions and Future Directions 508
References 509
Chapter 18: Cytokines and Bone Remodeling 518
I. Introduction 518
II. Evidence for a Role of Cytokines in Osteoclastic Bone Resorption 519
III. The Osteoclast as a Cell Source of Cytokines Involved in Osteoclastic Resorption 520
IV. The Osteoblast as a Cell Source of Cytokines Involved in Osteoclastic Resorption 520
V. Rank Ligand and Its Signaling Receptor, RANK 521
VI. Osteoprotegerin 524
VII. Macrophage–Colony-Stimulating Factor and Its Receptor, C-fms 525
VIII. Vascular Endothelial Growth Factor 527
IX. Tumor Necrosis Factor 527
X. Interleukin-6 (IL-6) 528
XI. Interleukin-15 (IL-15), Interleukin-17 (IL-17), and Interleukin-1 8 (IL-18) 529
XII. Bone Morphogenetic Proteins 530
XIII. Hedgehog (Hh) Signaling Molecules 536
XIV. Sclerostin 538
XV. Parathyroid Hormone-Related Peptide (Pthrp) 538
XVI. Neuronal Regulation of Bone Remodeling 539
XVII. Conclusion 542
References 542
Chapter 19: Skeletal Growth Factors 556
I. Introduction 556
II. Platelet-Derived Growth Factor 556
III. Vascular Endothelial Growth Factor 558
IV. Fibroblast Growth Factor 559
V. Transforming Growth Factor Beta 560
VI. Bone Morphogenetic Protein 561
VII. Insulin-Like Growth Factor 562
VIII. Insulin-Like Growth Factor Binding Proteins 564
IX. Hepatocyte Growth Factor 565
Acknowledgments 565
References 565
Chapter 20: Intercellular Communication during Bone Remodeling 574
I. Introduction 574
II. Sequence of Cellular Events in Bone Remodeling 575
III. Cell Interactions Early in Remodeling 575
IV. Interaction of Osteoblast Lineage Cells with Osteoclasts 576
V. Factors Proposed to Mediate the Coupling of Bone Formation to Resorption 577
VI. Osteoclast Products in the Coupling Process 579
VII. Similarities between Bone Remodeling and Inflammation 580
VIII. Bone Mass Homeostasis 581
IX. The Role of Mechanical Function (Strain) in the Coupling of Bone Resorption to Bone Formation 581
X. Integrated View of the Coupling of Bone Resorption and Bone Formation 582
References 583
Part III: Structure and Biomechanics 588
Chapter 21: Skeletal Development: Mechanical Consequences of Growth, Aging, and Disease 590
I. Developmental Mechanics in Skeletogenesis 590
II. Mechanical Regulation of Bone Biology 591
III. Mechanobiologic Self-Design of Bones 593
IV. Adaptational Mechanics in Aging and Disease 604
References 605
Chapter 22: Inhibition of Osteoporosis by Biophysical Intervention 608
I. Introduction 608
II. Bone’s Sensitivity to Mechanical Signals 609
III. Structural Demands on the Skeleton 609
IV. Regulation of Bone Morphology by Biophysical Stimuli 612
V. Osteogenic Potential of Low-Magnitude, High-Frequency Signals 616
VI. Regulating the Bone Cell Response Mechanical Signals 618
VII. Biophysical Stimuli in the Clinic 620
VIII. Summary 623
Acknowledgments 623
References 623
Chapter 23: Biomechanics of Age-Related Fractures 628
I. Introduction 628
II. Biomechanics of Bone: Basic Concepts and Age-Related Changes 629
III. Biomechanics of Hip Fractures 636
IV. Biomechanics of Vertebral Fractures 641
V. Summary and Clinical Implications 643
References 645
Chapter 24: Bone Quality 652
I. Introduction 652
II. Chapter Objective 654
III. The Brooklyn Bridge: A Paradigm for Understanding Bone Quality 654
IV. Factors Impacting Bone Quality 656
V. Conclusions 662
Acknowledgements 663
References 663
Part IV: Epidemiology and Risk Factors 670
Chapter 25: Epidemiologic Methods in of Osteoporosis 672
I. Introduction 672
II. Descriptive and Analytic Studies 672
III. Study Designs 673
IV. Some Useful Epidemiologic Concepts 681
V. Some Frequently Used Statistics 682
VI. Criteria for Deciding Whether an Association is Causal 683
VII. Sample Size Considerations 684
VIII. Measurement Error 685
IX. Conclusions 690
Acknowledgments 691
References 691
Chapter 26: Race, Ethnicity and Osteoporosis 694
I. Introduction 694
II. Background and Defi nitions 694
III. Ethnoepidemiology of Osteoporosis 695
IV. Ethnic Influences on Risk for Osteoporosis 699
V. Summary 707
References 707
Chapter 27: The Study of Osteoporotic Fractures: Major Findings and Contributions 716
I. Overview 716
II. Summary of Key Findings 716
III. What is a Vertebral Fracture? 722
IV. Ethnic Differences in Osteoporosis 724
V. Sleep Disturbance and Risk of Falls and Fractures 724
VI. Consequences of Fracture: Mortality 725
VII. Breast Cancer 726
VIII. Hip Osteoarthritis 726
IX. SOF Online 727
X. Summary 727
SOF Research Group 727
Acknowledgments 728
References 728
Chapter 28: Bone Mineral Acquisition In Utero and during Infancy and Childhood 732
I. Introduction 732
II. Quantitative Assessment of Bone Health in Infants and Children 732
III. Bone Acquisition In Utero 737
IV. Bone Acquisition in the Preterm Infant 749
V. Bone Acquisition in Term Infants and Children 750
References 761
Chapter 29: Bone Acquisition in Adolescence 770
I. Introduction 770
II. Bone Development 770
III. Mechanical Factors 775
IV. Nonmechanical Factors 778
V. Summary 781
References 781
Chapter 30: Genetic Determinants of Osteoporosis 786
I. Introduction 786
II. Finding Risk Gene Variants for Complex Traits 792
III. Osteoporosis Risk Gene Variants 808
IV. Applications and Prospects 818
References 820
Chapter 31: Nutrition and Risk for Osteoporosis 826
I. Introduction 826
II. Problems in the Investigation of Nutritional Effects on Bone 829
III. The Notion of a Nutrient Requirement 832
IV. The Natural Intake of Calcium and Vitamin D 832
V. Calcium 834
VI. Vitamin D 848
VII. Protein 850
VIII. Vitamin K 851
IX. Other Essential Nutrients 852
X. Conclusion 855
References 856
Chapter 32: Physical Activity in Prevention of Osteoporosis and Associated Fractures 864
I. Introduction 864
II. Bone Adaptation to Physical Loading 864
III. Physical Activity and Bone 870
IV. Prevention of Falls and Fall-Related Fractures by Physical Activity 877
V. Conclusions and Recommendations 879
References 879
Chapter 33: Premenopausal Reproductive and Hormonal Characteristics and the Risk for Osteoporosis 888
I. Introduction 888
II. Pregnancy 888
III. Age at First Pregnancy 891
IV. Parity and Nulliparity 891
V. Lactation 892
VI. Ovarian Activity or Menstrual Cycle Characteristics and Bone Mass 895
VII. Dysfunctional Ovulation 897
VIII. Oral Contraceptive Use 899
IX. Progestin-Injectable Contraceptives 900
X. Oophorectomy 903
XI. Summary and Implications 904
References 904
Chapter 34: Nonskeletal Risk Factors for Osteoporosis and Fractures 914
I. Physical Characteristics 914
II. Anthropometric Variables 915
III. Lifestyle Factors 919
References 924
Chapter 35: Falls as Risk Factors for Fracture 938
I. Introduction 938
II. Risk Factors for Falls 938
III. Risk Factors for Injurious Falls 940
IV. Falls Prevention Strategies 943
V. Summary and Implications 944
References 945
Chapter 36: Assessment of Fracture Risk 950
I. Introduction 950
II. Definition of Osteoporotic Fracture 950
III. Epidemiology of Osteoporotic Fracture 952
IV. Synthesis of Risk Factors and Risk Assessment Models 971
V. Summary and Future Directions 975
References 977
Chapter 37: Outcomes of Osteoporotic Fractures 986
I. Introduction 986
II. Definitions of Functional Outcomes Related to Fracture 986
III. Osteoporosis-Relevant Quality of Life Assessments 986
IV. Outcomes of Wrist Fractures 987
V. Outcomes of Vertebral Fractures 988
VI. Outcomes of Hip Fractures 995
VII. Conclusions 997
References 997
Part V: Pathophysiology 1000
Chapter 38: Local and Systemic Factors in the Pathogenesis of Osteoporosis 1002
I. Introduction 1002
II. Role of Systemic Hormones 1002
III. Local Factors 1003
IV. Cytokines 1004
V. Prostaglandins 1004
VI. Growth Factors 1005
VII. Colony-Stimulating Factors 1005
VIII. Further Considerations of Interactions of Systemic Hormones and Local Mediators 1005
IX. Conclusions 1006
References 1006
Chapter 39: Animal Models for Osteoporosis 1012
I. Introduction 1012
II. Goals of Animal Models for Osteoporosis 1012
III. Specifi c Animal Models 1013
IV. Evaluation of the Osteopenic Skeleton Animal Models 1022
V. Fracture Repair 1029
VI. Summary 1029
References 1030
Chapter 40: Estrogen, Bone Homeostasis, and Osteoporosis 1038
I. Introduction 1038
II. Secretion and Metabolism of Sex Steroids 1038
III. Direct Effects of Sex Steroids on Bone 1039
IV. Indirect Effects of Sex Steroids on Bone 1043
V. Age- and Sex-Specific Skeletal Changes 1043
VI. Hormonal Determinants of Skeletal Growth and Maturation 1046
VII. Hormonal Determinants of Age-Related Bone Loss in Women 1046
VIII. Hormonal Determinants of Age-Related Bone Loss in Men 1050
IX. The Conundrum of Trabecular Bone Loss in Hormone-Sufficient Young Adults 1054
X. Estrogen Deficiency and Age-Related Osteoporosis 1054
XI. Other Factors Contributing to Osteoporosis 1058
XII. Summary and Conclusions 1059
References 1059
Chapter 41: Postmenopausal Osteoporosis: How the Hormonal Changes of Menopause Cause Bone Loss 1068
I. Steroid Biosynthesis and Menopause 1068
II. Mechanism of Action of Estrogen in Bone 1068
III. Mechanisms of Estrogen Regulation of T Cell TNF Production 1072
IV. T Cell Thymic Output and Bone Loss 1075
V. From Animal Models to Human Disease 1076
VI. Conclusions 1076
References 1077
Chapter 42: Osteoporosis in Men: Epidemiology, Pathophysiology, and Clinical Characterization 1082
I. Fractures in Men 1082
II. The Major Determinants of Bone Health in Men 1086
III. Osteoporosis 1093
IV. The Evaluation of Osteoporosis in Men 1099
V. Therapy 1103
References 1107
Chapter 43: Osteoporosis in Childhood and Adolescence 1122
I. Introduction 1122
II. Principles of Bone Development 1122
III. Definition and Diagnosis of Osteoporosis in Children and Adolescents 1124
IV. Pathogenesis and Treatment of Specific Disorders 1128
V. Summary and Future Directions 1150
References 1150
Chapter 44: Glucocorticoid-Induced Osteporosis 1162
I. Introduction 1162
II. Epidemiology of Glucocorticoid-Induced Osteoporosis 1162
III. The Pathogenesis and Molecular Basis of Glucocorticoid Action on Bone Metabolism and Development 1168
IV. Other Musculoskeletal Effects of Glucocorticoids 1173
V. Treatment Options and Fracture Risk Reduction 1174
VI. Management of Glucocorticoid-Induced Osteoporosis in Children 1183
References 1183
Chapter 45: Adult Scoliosis, Degenerative Disease, and BMD: A Subsegmental Analytic Approach 1194
I. Introduction 1194
II. The Biomechanics of Scoliosis 1194
III. The Use of Dual-Energy X-Ray Absorptiometry to Characterize Physiological Changes in the Spine 1195
IV. Postmenopausal Scoliosis Measured by Subsegmental Analysis 1197
V. Conclusions 1200
Appendix 1201
References 1202
Chapter 46: Mechanisms of Immobilization-Induced Bone Loss 1204
I. Transduction of Mechanical Loading 1204
II. Sensing Strain, Fluid Shear Stress, and Compression 1204
III. Bone Responsiveness to Loss of Weight Bearing 1207
IV. Animal and in Vitro Models 1208
References 1210
Chapter 47: Leptin-Dependent Regulation of Bone Mass 1214
I. Introduction 1214
II. Regulation of Bone Formation by Leptin 1214
III. Regulation of Bone Resorption by Leptin 1217
IV. Summary and Perspectives 1218
References 1219
Chapter 48: Thyroid Hormone and the Skeleton 1222
I. Introduction 1222
II. Thyroid Hormone and Skeletal Growth and Maturation 1222
III. Thyroid Hormone and Mineral Metabolism 1222
IV. Thyroid Hormone and Skeletal Metabolism 1223
V. Bone Mass and Fracture Risk in Thyroid Disease 1223
VI. Prevention of Thyroid Hormone-Induced Bone Loss 1225
References 1225
Chapter 49: Osteoporosis in Gastrointestinal, Pancreatic, and Hepatic Diseases 1230
I. Physiologic Considerations 1230
II. Gastrointestinal Diseases 1232
III. Hepatic Diseases 1238
IV. Bone Disease Complicating Therapy 1243
References 1246
Chapter 50: The Skeletal Actions of Parathyroid Hormone in Primary Hyperparathyroidism and in Osteoporosis 1254
I. Introduction 1254
II. Parathyroid Hormone, Primary Hyperparathyroidism, and the Skeleton 1254
III. Parathyroid Hormone and Osteoporosis 1262
IV. Summary 1267
Acknowledgment 1267
References 1267
Chapter 51: Osteogenesis Imperfecta and Other Defects of Bone Development as Occasional Causes of Adult Osteoporosis 1274
I. Scope of the Problem 1274
II. Osteogenesis imperfecta as a Cause of Adult Osteoporosis 1274
III. Histology of Bone and Bone Histomorphometry in Osteogenesis Imperfecta 1286
IV. Osteoporosis in the Heritable Disorders of Connective Tissue 1294
V. Osteoporosis in Inherited Hematologic Disorders 1298
VI. Osteoporosis in Inherited Hepatic Disease 1300
References 1300
Chapter 52: Osteoporosis Associated with Illnesses and Medications 1310
I. Introduction 1310
II. Metabolic Disorders 1310
III. Medications 1321
References 1331
Chapter 53: Transplantation Osteoporosis 1342
I. Immunosuppression and Osteoporosis 1342
II. Immunosuppressive Agents and Utilization of Preclinical Studies Describing Mechanisms of Action 1342
III. Clinical Studies Supporting the Role of Calcineurin Inhibitors in Bone Loss after Transplantation 1346
IV. Other Immune-Modifying Drugs 1346
V. Summary of Immunosuppressant Agents 1348
VI. Clinical Impact of Transplantation on Bone 1348
VII. Evaluation of Candidates for Transplantation 1352
VIII. Management of Transplantation Osteoporosis 1353
IX. Newer Therapeutic Options 1356
References 1357
Chapter 54: Osteoporosis Associated with Cancer Therapy 1364
I. Introduction 1364
II. Breast Cancer 1364
III. Prostate Cancer 1375
IV. Multiple Myeloma and Monoclonal Gammopathy of Undetermined Significance 1382
V. Hematopoietic Stem Cell Transplantation and Bone Loss 1384
VI. Skeletal Complications of Radiation Therapy 1387
VII. Childhood Cancer 1388
VIII. Thyroid Cancer 1390
IX. Osteonecrosis of the Jaw 1391
X. Conclusion 1391
References 1391
Chapter 55: Osteoporosis Associated with Pregnancy 1402
I. Introduction 1402
II. Calcium Homeostasis 1402
III. Osteoporosis Associated with Pregnancy 1404
IV. Osteoporosis Associated with Heparin Therapy during Pregnancy 1407
V. Osteoporosis Associated with Magnesium Sulfate Therapy during Pregnancy 1408
VI. Paradoxical Bone Mineralization in Twin-to-Twin Transfusion Syndrome 1408
Acknowledgment 1408
References 1409
Chapter 56: Osteoporosis Associated with Rheumatologic Disorders 1414
I. Introduction 1414
II. Rheumatoid Arthritis 1414
III. Juvenile Rheumatoid Arthritis 1419
IV. Seronegative Spondyloarthropathies 1419
V. Systemic Lupus Erythematosus 1421
Acknowledgments 1422
References 1422
Chapter 57: Oral Bone Loss and Systemic Osteopenia: Potential Treatment and Risks 1426
I. Introduction 1426
II. Diagnosis 1428
III. Risk Factors for Intraoral Bone Loss 1431
IV. Patterns of Progression of Oral Bone Loss 1433
V. Oral Bone Loss and Systemic Osteopenia: Are They Related? 1435
VI. Treatment 1436
VII. Summary 1438
References 1438
Chapter 58: Localized Osteoporosis 1444
I. Introduction 1444
II. Mechanical Stress and Normal Bone Architecture 1445
III. Localized Osteoporosis: Generalizations 1446
IV. Localized Osteoporosis and Fracture 1447
V. Internal Fixation Devices 1448
VI. Inflammatory Disease-Associated Localized Osteoporosis 1449
VII. Reflex Sympathetic Dystrophy 1450
VIII. Transient Osteoporosis of the Hip 1450
IX. Total Hip Replacement 1451
X. Prosthetic Design 1453
XI. Immobilization Osteoporosis: Animal Studies of Localized Bone Loss 1453
XII. Aging 1454
XIII. Hormones and Drugs 1455
XIV. Local Cellular Mechanisms 1455
XV. Summary 1457
References 1457
Part VI: Evaluation and Management 1462
Chapter 59: Evaluation of the Patient with Osteoporosis or at Risk for Osteoporosis 1464
I. Introduction 1464
II. The Decision to Measure 1464
III. What BMD to Measure? 1467
IV. The Evaluation of the Patient with Low BMD 1468
V. Summary and Conclusions 1472
References 1472
Chapter 60: Who Should Be Screened: Who Should Be Treated? 1476
I. Introduction 1476
II. Who Should Be Treated? 1476
III. Who to Test? 1481
IV. Summary 1483
References 1483
Chapter 61: Radiology of Osteoporosis 1488
I. Principal Radiographic Findings in Osteopenia and Osteoporosis 1488
II. Diseases Characterized by Generalized Osteopenia 1491
III. Regional Osteoporosis 1507
References 1515
Chapter 62: Clinical Use of Bone Densitometry 1520
I. Densitometry Techniques 1520
II. Basic Principles of Densitometry 1526
III. Performing Densitometry Measurements with DXA 1528
IV. Monitoring the DXA Scanner 1534
V. Uses of Bone Densitometry 1537
VI. Conclusions 1542
References 1543
Chapter 63: Biochemical Markers of Bone Turnover in Osteoporosis 1546
I. Biochemical Markers of Bone Formation 1547
II. Biochemical Markers of Bone Resorption 1548
III. Clinical Use of Bone Turnover Markers in Postmenopausal Osteoporosis 1553
IV. Bone Turnover Markers in Men 1562
V. Conclusion: what we know and what we need to know 1563
References 1563
Chapter 64: The Conundrum of Compliance and Persistence with Oral Bisphosphonates for Postmenopausal Osteoporosis 1574
I. Introduction 1574
II. Compliance and Persistence with Prescription Medications for Chronic Diseases 1574
III. Osteoporosis 1575
IV. Problems with Research in Compliance and Persistence 1577
V. Improving Compliance and Persistence with Bisphosphonate Therapies 1578
VI. Conclusion 1579
Acknowledgment 1579
References 1579
Chapter 65: An Orthopedic Perspective of Osteoporosis 1582
I. Introduction 1582
II. Biomechanics 1582
III. Specific Injuries 1582
IV. Prevention of Fracture 1598
References 1599
Chapter 66: Lessons from Bone Histomorphometry on the Mechanism of Action of Osteoporosis Drugs 1602
I. Introduction 1602
II. Anticatabolic Therapies 1602
III. Anabolic Therapies 1611
References 1617
Part VII: Pharmacology and Therapeutics 1622
Chapter 67: Design Considerations for Clinical Investigations of Osteoporosis 1624
I. Background: Inference from Phenomena Subject to Variation 1624
II. Types of Investigational Designs 1625
III. Principal Types of Bias with Various Designs 1626
IV. When Controlled Trials and Observational Studies Disagree 1633
V. Design Alternatives 1634
VI. Design Issues of Special Relevance to Investigation of Bone 1635
VII. Ethics of the Placebo 1644
VIII. Burden of Proof and the Null Hypothesis 1645
References 1646
Chapter 68: Regulatory Considerations for the Design and Conduct of Osteoporosis Registration Trials 1648
I. Introduction 1648
II. History of Osteoporosis Guidances 1648
III. FDA and EMEA Guidance Documents 1651
IV. New and Future Initiatives 1653
V. Conclusion 1654
References 1654
Chapter 69: Evidence-Based Osteoporosis Care 1656
I. Introduction 1656
II. Hierarchy of Evidence 1656
III. Critical Appraisal of the Literature 1658
IV. Interpreting and Translating the Evidence into Practice 1662
V. Summary 1672
References 1673
Chapter 70: The Role of Calcium in the Treatment of Osteoporosis 1678
I. Introduction 1678
II. Intestinal Calcium Absorption 1678
III. Calcium and Bone Growth 1679
IV. Calcium and Bone Remodeling 1681
V. Calcium and Fracture Risk 1681
References 1683
Chapter 71: Vitamin D and its Metabolites and Analogs in the Management of Osteoporosis 1686
I. Introduction 1686
II. Vitamin D in the Pathogenesis of Osteoporosis 1687
III. Animal Models 1688
IV. Postmenopausal Osteoporosis 1689
V. Other Osteoporoses 1706
VI. Conclusions 1707
References 1707
Chapter 72: Estrogen Therapy: Prevention and Treatment of Osteoporosis 1714
I. Introduction and Historical Perspective 1714
II. Endogenous Estrogen 1715
III. Trends in Estrogen use 1716
IV. Observational Studies on Fracture Prevention 1716
V. Effects of Hormonal Therapy on Bone Mineral Density and Markers of Bone Remodeling 1717
VI. Randomized Clinical Trials of Hormone Therapy with Fracture Outcomes 1718
VII. Effects of Hormone Therapy on Other Disease Outcomes 1721
VIII. Dose, Regimen, and Type of Estrogen 1722
IX. Discontinuation and Extinction of the Effect of Hormone Therapy 1722
X. Estrogen with Calcium 1724
XI. Summary 1726
XII. Conclusion 1726
References 1726
Chapter 73: Estrogen Analogues: Selective Estrogen Receptor Modulators Phytoestrogens 1732
I. Introduction 1732
II. Classifi cation and Chemical Structure of SERMS and Phytoestrogens 1732
III. Cellular Mechanism of Action of SERMS and Phytoestrogens 1735
IV. Animal Data 1739
V. Clinical Application of SERMS and Phytoestrogens 1740
References 1746
Chapter 74: Bisphosphonates: Pharmacology and Use in the Treatment of Osteoporosis 1752
I. Introduction and History 1752
II. Pharmacokinetics and Pharmacodynamics 1753
III. Treatment of Postmenopausal Osteoporosis: Efficacy 1755
IV. Other Forms of Osteoporosis 1760
V. Bisphosphonate Safety 1760
VI. Conclusions 1763
References 1763
Chapter 75: Calcitonin in Osteoporosis 1770
I. Introduction 1770
II. Clinical Efficacy in Postmenopausal Osteoporosis 1770
III. Clinical Efficacy in Other Forms of Osteoporosis 1776
IV. Clinical Pharmacology 1779
V. Therapeutic Regimens and Safety 1782
VI. Analgesic Effect 1785
VII. Therapeutic Indications 1786
Acknowledgments 1787
References 1787
Chapter 76: Strontium Ranelate 1794
I. The Need for New Therapies for Fracture Prevention 1794
II. Strontium Ranelate 1795
III. Strontium Ranelate and Vertebral Fracture Risk Reduction 1795
IV. Strontium Ranelate and Hip and Other Non-Vertebral Fracture Risk Reduction 1796
V. Strontium Ranelate in Women over 80 Years of Age 1797
VI. Cost-Effectiveness of Strontium Ranelate Tgerapy 1798
VII. Mechanisms of Action 1799
VIII. Strontium Ranelate and the Cellular Machinery of Bone Modeling and Remodeling 1800
IX. Bone Formation and Resorption In Vitro and In Vitro 1800
X. Conclusion 1806
Acknowledgment 1806
References 1806
Chapter 77: Androgens 1810
I. Introduction 1810
II. Androgens 1810
III. Effects of Testosterone on Bone in Men 1811
IV. Effects of Testosterone on Bone in Women 1817
References 1818
Chapter 78: Treatment with PTH Peptides 1820
I. Introduction 1820
II. Candidates for Anabolic Therapy 1820
III. Postmenopausal Osteoporosis 1820
IV. PTH treatment of Men 1830
V. PTH in Special Populations 1830
VI. Persistence of Effect 1831
VII. Rechallenge with PTH 1831
VIII. Pharmacokinetics of PTH Administration 1831
IX. Mode of Action 1832
X. PTH Peptides Under Development 1834
XI. Conclusion 1834
References 1834
Chapter 79: Growth Hormone and Insulin-Like Growth Factors: Potential Applications and Limitations in the Management of Osteoporosis 1836
I. Introduction 1836
II. Physiology of Growth Hormone-Releasing Hormone (GHRH)—GH-IGF-I 1837
III. The Role of GH/IGF-I in Skeletal Physiology 1842
IV. Pathophysiology of Osteoporosis: Role of GH/IGFS 1844
V. Growth Hormone Therapy for Osteoporosis 1847
VI. IGF-I for the Treatment of Osteoporosis 1852
VII. Summary 1855
Acknowledgments 1856
References 1856
Chapter 80: New Approaches to Osteoporosis Therapeutics 1864
I. Introduction 1864
II. Bone Resorption Inhibitors 1864
III. Anabolic Agents 1887
IV. Summary 1909
References 1911
Index 1924