Marcus and Feldman’s Osteoporosis

Fifth Edition

Edited by

David W. Dempster

Department of Pathology and Cell Biology, Columbia University, New York, NY, United States

Helen Hayes Hospital, Regional Bone Center, West Haverstraw, NY, United States

Jane A. Cauley

Department of Epidemiology, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, United States

Mary L. Bouxsein

Center for Advanced Orthopaedic Studies, Beth Israel Deaconess Medical Center, Boston, MA, United States

Department of Orthopedic Surgery, Harvard Medical School, Boston, MA, United States

Felicia Cosman

Department of Medicine, Columbia University, New York, NY, United States

Table of Contents

Cover image

Title page

Copyright

List of contributors

Foreword

Part I: Introduction

Chapter 1. The nature of osteoporosis

Abstract

1.1 Defining osteoporosis

1.2 Material and structural basis of skeletal fragility

1.3 Role of bone matrix properties

1.4 Summary

References

Further reading

Chapter 2. The bone organ system: form and function

Abstract

2.1 Introduction

2.2 Composition and organization of bone

2.3 Cellular components of bone

2.4 Bone homeostasis

2.5 Basic bone mechanics

2.6 Summary

References

Part II: Developmental, cellular and molecular biology of bone

Chapter 3. Development of the skeleton

Abstract

3.1 Overview

3.2 Patterning the skeleton

3.3 Endochondral bone development

3.4 Intramembranous bone formation

References

Chapter 4. The skeletal stem cell

Abstract

4.1 Introduction

4.2 Defining skeletal stem cells

4.3 Migration of skeletal stem cells

4.4 Kinetics of skeletal cell turnover

4.5 Potential use of skeletal stem cells as therapy

4.6 Interactions with the hematopoietic system

4.7 Conclusion

References

Chapter 5. Osteoclast biology

Abstract

5.1 Introduction

5.2 Regulation of osteoclast formation

5.3 Osteoclast function

5.4 Conclusion

Financial support

Potential conflicts of interest

References

Chapter 6. Osteoblast biology: developmental origin and interactive nature of osteoblasts

Abstract

6.1 Developmental origin of osteoblasts

6.2 Interactive nature of osteoblasts

References

Chapter 7. Osteocytes

Abstract

7.1 Introduction

7.2 Osteocyte ontogeny

7.3 Osteoid–osteocytes

7.4 Osteocyte-selective genes/proteins and their potential functions

7.5 Morphology of osteocytes: lacunocanalicular system and dendrite formation

7.6 Osteocyte cell models

7.7 Mechanisms and response of osteocytes to mechanical forces

7.8 Osteocyte signals for bone formation

7.9 Osteocyte signals for bone resorption

7.10 Osteocyte apoptosis and autophagy

7.11 Osteocyte modification of their microenvironment

7.12 Osteocyte regulation of phosphate metabolism

7.13 Osteocyte communication with muscle

7.14 Role of gap junctions and hemichannels in osteocyte communication

7.15 Osteocytes in the embryonic and the adult skeleton with aging

7.16 The implications of osteocyte biology for bone disease

7.17 Conclusion

Acknowledgment

References

Chapter 8. The regulatory role of matrix proteins in mineralization of bone

Abstract

8.1 Introduction

8.2 Collagenous proteins

8.3 Intermediate cartilage matrix

8.4 Bone-enriched matrix proteins

8.5 The mineralization of bone matrix

Acknowledgments

References

Part III: Skeletal hormones and regulatory factors

Chapter 9. Parathyroid hormone and parathyroid hormone–related protein

Abstract

9.1 Introduction

9.2 Synthesis and secretion of parathyroid hormone

9.3 Metabolism of parathyroid hormone

9.4 Bone-resorbing action of parathyroid hormone

9.5 Effects of parathyroid hormone on bone formation

9.6 Renal actions of parathyroid hormone

9.7 Parathyroid hormone–related protein as a mediator of humoral hypercalcemia of malignancy

9.8 Physiological roles of parathyroid hormone–related protein

9.9 Mechanism of action of parathyroid hormone and parathyroid hormone–related protein

Acknowledgment

References

Chapter 10. Phosphatonins

Abstract

10.1 Introduction

10.2 Phosphorus homeostasis

10.3 Phosphatonins

10.4 Fibroblast growth factor 23

10.5 Secreted frizzled-related protein 4

10.6 Matrix extracellular phosphoglycoprotein

10.7 Fibroblast growth factor 7

10.8 Summary

References

Chapter 11. Skeletal growth factors

Abstract

Abbreviations

11.1 Introduction

11.2 Platelet-derived growth factor

11.3 Vascular endothelial growth factor

11.4 Fibroblast growth factor

11.5 Transforming growth factor beta

11.6 Bone morphogenetic proteins

11.7 Insulin-like growth factor

11.8 Insulin-like growth factor binding proteins

11.9 Hepatocyte growth factor

Acknowledgments

References

Chapter 12. WNT signaling in skeletal homeostasis and diseases

Abstract

12.1 Introduction

12.2 WNT signaling

12.3 WNT signaling in skeletal development, homeostasis, and diseases

12.4 WNT signaling interacts with other pathways in bone mass regulation

12.5 WNT signaling and mechanical loading

12.6 Targeting the WNT pathway for therapeutic intervention

12.7 Conclusion

References

Part IV: Biomechanics and mechanobiology

Chapter 13. The mechanical behavior of bone

Abstract

13.1 Introduction

13.2 Introduction to bone mechanics

13.3 Role of bone composition and microstructure on bone mechanical properties

13.4 Mechanical behavior of whole bone

13.5 Age-related changes in bone mechanics that contribute to fracture

13.6 Summary

References

Chapter 14. Cellular and molecular mechanotransduction in bone

Abstract

14.1 Introduction

14.2 Bone mechanotransduction

14.3 Forms of mechanical stimulation—tissue mechanics

14.4 Electromagnetic fields

14.5 Deformation or strain

14.6 Fluid flow due to loading

14.7 Vibration

14.8 Damage

14.9 Cellular and pericellular mechanics

14.10 Electromagnetic fields

14.11 Direct cellular deformation

14.12 Fluid flow

14.13 Models of pericellular flow

14.14 Pressure

14.15 Vibration

14.16 Damage

14.17 Mechanosensing mechanisms

14.18 Molecular dynamics

14.19 Cytoskeleton

14.20 Integrins and adhesion-associated proteins

14.21 Membrane channels

14.22 Plasma membrane dynamics and mechanotransduction

14.23 Mechanosome

14.24 Primary cilia

14.25 Mechanically activated intracellular signaling pathways

14.26 Intracellular calcium signaling

14.27 G protein–mediated signaling

14.28 Kinase signaling

14.29 Cell–cell pathways that are activated or mediate effects of mechanical stimuli

14.30 Gap junctions

14.31 Nitric oxide

14.32 Eicosanoid signaling

14.33 C-X-C motif chemokine 12

14.34 Nucleotide signaling

14.35 Other mechanisms

14.36 Effects of aging on bone mechanotransduction

14.37 Conclusion and implications for osteoporosis

References

Chapter 15. Adaptation of skeletal structure to mechanical loading

Abstract

15.1 Introduction and background

15.2 Diaphyseal cortical bone

15.3 Cancellous bone

15.4 Toward a more mechanistic understanding of functional adaptation in bone

15.5 Conclusion

References

Chapter 16. Biomechanics of hip and vertebral fractures

Abstract

16.1 Introduction

16.2 Biomechanics of hip fractures

16.3 Biomechanics of vertebral fractures

16.4 Summary and clinical implications

Abbreviations

References

Part V: Epidemiology of osteoporosis

Chapter 17. Epidemiologic methods in studies of osteoporosis

Abstract

17.1 Introduction

17.2 Descriptive and analytic studies

17.3 Study designs in analytical epidemiologic studies

17.4 Some useful epidemiologic concepts

17.5 Frequently used statistics

17.6 Criteria for deciding whether an association matters

17.7 Sample size considerations

17.8 Measurement error

17.9 Fracture risk prediction models

17.10 Discrepant results between studies examining similar research questions

17.11 Summary

Acknowledgments

References

Chapter 18. Genetics of osteoporosis

Abstract

18.1 Introduction

18.2 Finding risk gene variants for complex traits

18.3 Identifying osteoporosis risk gene variants

18.4 Applications and prospects

Acknowledgment

References

Chapter 19. Race, ethnicity, and osteoporosis

Abstract

19.1 Introduction

19.2 Background and definitions

19.3 Ethnoepidemiology of osteoporosis

19.4 Ethnic differences in US hip fractures

19.5 Hip fracture rate by immigration status

19.6 Ethnic differences in other fractures

19.7 Ethnic patterns in bone strength measures

19.8 Risk factors for fracture

19.9 Ethnic differences in bone turnover

19.10 Ethnic differences in bone geometry

19.11 Ethnic differences in composite indices of bone strength

19.12 Vitamin D deficiency

19.13 Absolute versus relative risk of fracture by ethnicity

19.14 Mortality and disability after osteoporotic fracture

19.15 Future projections

19.16 Disparities in screening, diagnosis, and treatment of osteoporosis between ethnic and racial groups

19.17 Summary

References

Chapter 20. Geographic variability in the incidence of hip and vertebral fractures

Abstract

20.1 Introduction

20.2 Background on hip fracture incidence

20.3 Methodology

20.4 Crude hip fracture incidence rates

20.5 Age-standardized hip fracture incidence rates

20.6 Secular trends in hip fracture rates

20.7 Limitations of studies on hip fractures

20.8 Vertebral fractures

20.9 Predictors of fracture variability

20.10 Conclusion

Acknowledgments

References

Appendix: Age-standardized yearly rates of hip fractures by continent, country, gender, and age-group in order

Chapter 21. Nutrition and osteoporosis

Abstract

21.1 Introduction

21.2 Calcium, vitamin D, and dairy intake

21.3 Other nutrients and bone health

21.4 Rationale for dietary patterns

References

Chapter 22. Physical activity, exercise, and skeletal health

Abstract

22.1 Physical activity across the life span for osteoporosis and fracture prevention

22.2 Imaging bone strength

22.3 Physical activity, exercise, and measurement of bone loading stimulus

22.4 Bone strength adaptation to exercise in growing bone—systematic reviews

22.5 Bone strength adaptation to exercise in growing bone—recent interventions

22.6 Maturity, sex- and site-specific adaptation—observational evidence

22.7 Maintenance of bone benefits from physical activity during childhood and youth

22.8 Skeletal adaptation to physical activity in older age

22.9 Recommendations

References

Chapter 23. Reproductive and hormonal factors and the risk for osteoporosis

Abstract

23.1 Introduction

23.2 Pregnancy

23.3 Age at first pregnancy

23.4 Parity and nulliparity

23.5 Lactation

23.6 Ovarian activity or menstrual cycle characteristics and bone mass

23.7 Dysfunctional ovulation

23.8 Oral contraceptive use

23.9 Progestin-injectable contraceptives

23.10 Oophorectomy

23.11 Summary and implications

References

Further reading

Chapter 24. Clinical and epidemiological studies: skeletal changes across menopause

Abstract

24.1 Introduction

24.2 Methodological issues in studying menopause

24.3 Pathophysiology of skeletal changes at menopause

24.4 Changes in bone density across menopause

24.5 Bone structure/size changes

24.6 Study of Women’s Health Across the Nation

24.7 Bone turnover

24.8 Mechanisms underlying bone loss at menopause

24.9 Fracture risk across the menopausal transition

24.10 Identification of women at high risk of fracture

24.11 Summary

References

Chapter 25. Osteoporosis in men: what is similar and what is different?

Abstract

25.1 Introduction

25.2 Epidemiology

25.3 Why are osteoporosis and fractures less common in men?

25.4 Diagnosis and treatment of osteoporosis in men

Acknowledgment

References

Chapter 26. Falls as risk factors for fracture

Abstract

26.1 Introduction

26.2 Risk factors for falls

26.3 Risk factors for injurious falls

26.4 Falls-prevention strategies

26.5 Methodologic approaches to analyzing falls

26.6 Summary and implications

References

Chapter 27. Impact of physical characteristics and lifestyle factors on bone density and fractures

Abstract

27.1 Physical characteristics

27.2 Anthropometric variables

27.3 Lifestyle factors

References

Chapter 28. Imminent fracture risk and disability post fracture

Abstract

28.1 Introduction

28.2 Imminent fracture risk

28.3 Disability and quality of life following osteoporotic fracture

28.4 Risk of mortality following osteoporotic fractures

28.5 Conclusion

References

Chapter 29. Economics of osteoporosis

Abstract

29.1 Introduction

29.2 Economic landscape

29.3 Economic impact of osteoporosis fracture prevention strategies

29.4 Conclusion

References

Part VI: General pathophysiology of osteoporosis

Chapter 30. Skeletal heterogeneity and the purposes of bone remodeling: Implications for the understanding of osteoporosis

Abstract

30.1 Introduction

30.2 Skeletal heterogeneity

30.3 Remodeling and turnover

30.4 Relationship to marrow composition

30.5 The purposes of bone remodeling

30.6 The life history of a basic multicellular unit

30.7 Fatigue damage and mechanical competence

30.8 Metabolic functions of remodeling

30.9 Implications for understanding osteoporosis

30.10 Pathogenesis of fractures

30.11 Prevention of fractures

References

Chapter 31. On the evolution and contemporary roles of bone remodeling

Abstract

31.1 Introduction

31.2 The basics of bone remodeling

31.3 Skeletal involvement in managing metabolic imperatives: roles and consequences

31.4 The biological imperative of lightness

31.5 The biological imperative of calcium homeostasis

31.6 Calcium, remodeling, and skeletal structure

31.7 Effects of pharmacologically modified remodeling on calcium and bone mass

31.8 Effects of dietary calcium on bone mass and strength

31.9 An evolutionary theory on the origin of continuous bone remodeling

31.10 Bone remodeling and reproduction

31.11 Lactational and postmenopausal bone loss as antagonistic pleiotropies

31.12 Bone remodeling, skeletal microcracks, and fatigue damage

31.13 Effects of remodeling inhibition on bone strength

31.14 The partnership of bone remodeling and modeling

31.15 Summary

References

Chapter 32. Estrogen deficiency and the pathogenesis of osteoporosis

Abstract

32.1 Introduction

32.2 Age- and sex-specific skeletal changes

32.3 Secretion and metabolism of sex steroids

32.4 Direct effects of sex steroids on bone

32.5 Indirect effects of sex steroids on bone

32.6 Hormonal determinants of skeletal growth and maturation

32.7 Hormonal determinants of age-related bone loss in women

32.8 Hormonal determinants of age-related bone loss in men

32.9 The conundrum of trabecular bone loss in hormone-sufficient young adults

32.10 Other factors contributing to osteoporosis

References

Chapter 33. Cytokines and the pathogenesis of osteoporosis

Abstract

33.1 Receptor activator of nuclear factor-κB ligand, receptor activator of nuclear factor-κB, and osteoprotegerin

33.2 Colony-stimulating factor-1

33.3 Additional colony stimulating factors

33.4 Interleukin-1

33.5 Tumor necrosis factor

33.6 Additional tumor necrosis factor superfamily members

33.7 Interleukin-6

33.8 Additional interleukin-6 family members

33.9 Interleukin-7

33.10 Interleukin-8 and other chemokines

33.11 Interleukin-10

33.12 Interleukin-12, interleukin-23, interleukin-27, and interleukin-35

33.13 Interleukin-15

33.14 Interleukin-17 and interleukin-25

33.15 Interleukin-18, interleukin-33, and interleukin-37

33.16 Interferons

33.17 Additional cytokines

References

Chapter 34. Bone and fat

Abstract

34.1 Introduction

34.2 Bone and fat—epidemiological studies

34.3 Physiology of adipose tissue and energy expenditure

34.4 Adipocytic and osteoblastic differentiation

34.5 The central role of peroxisome proliferator–activated receptor-gamma

34.6 Peroxisome proliferator–activated receptor gamma and the skeleton

34.7 Hormonal factors that regulate bone and energy metabolism

34.8 Drug-induced changes in bone and fat

34.9 Second-generation antipsychotics

34.10 Selective serotonin reuptake inhibitors

References

Chapter 35. Bone, muscle, and sarcopenia

Abstract

35.1 Skeletal muscle anatomy and physiology: an overview

35.2 Muscle–bone interactions

35.3 Sarcopenia, osteopenia, and related conditions

35.4 Sarcopenia assessment tools

35.5 Management of osteosarcopenia

35.6 Conclusion

References

Chapter 36. Bone mineral acquisition in utero and during infancy and childhood

Abstract

36.1 Introduction

36.2 Bone acquisition in utero

36.3 Bone acquisition in the preterm infant

36.4 Bone acquisition in term infants and children

36.5 Conclusion

Acknowledgments

References

Chapter 37. Osteoporosis in childhood and adolescence

Abstract

37.1 Introduction

37.2 Definition and diagnosis of osteoporosis in children and adolescents

37.3 Etiology of osteoporosis in children and adolescents

37.4 Treatment of osteoporosis

37.5 Summary and future directions

References

Chapter 38. Osteoporosis in premenopausal women, pregnancy, and lactation

Abstract

38.1 Introduction

38.2 Overview of osteoporosis in premenopausal women

38.3 Evaluation of premenopausal women with low-trauma fracture and/or low bone mineral density

38.4 Treatment approach for premenopausal women with low-trauma fractures or low bone mineral density

38.5 Summary

References

Chapter 39. Bone and the microbiome

Abstract

39.1 Introduction

39.2 The gut microbiota could be considered as an additional organ

39.3 Experimental animal studies

39.4 Effects of probiotics on bone mass in rodents

39.5 Effects of prebiotics on bone in rodents

39.6 Mechanisms for gut microbiota to affect adult bone homeostasis

39.7 Human studies

39.8 Summary and conclusion

References

Part VII: Impact of comorbidity and medications on skeletal health

Chapter 40. Immobilization osteoporosis

Abstract

40.1 Introduction

40.2 Animal studies

40.3 Human studies

40.4 Summary

References

Chapter 41. Osteoporosis in neurological disorders: Parkinson’s disease, stroke, and multiple sclerosis

Abstract

41.1 Introduction

41.2 Parkinson’s disease

41.3 Stroke

41.4 Multiple sclerosis

41.5 Osteoporosis in neurological disorders—the future

References

Further reading

Chapter 42. Effects on the skeleton from medications used to treat nonskeletal disorders

Abstract

42.1 Introduction

42.2 Medications that reduce sex steroids

42.3 Antidiabetic agents

42.4 Acid-suppressive medications

42.5 Antiepilepsy drugs

42.6 Selective serotonin receptor uptake inhibitors

42.7 Heparin and oral anticoagulants

42.8 Drugs that may protect against osteoporosis

References

Chapter 43. Osteoporosis associated with gastrointestinal disorders: celiac and inflammatory bowel diseases

Abstract

43.1 Celiac disease

43.2 Inflammatory bowel diseases

43.3 Treatment modalities of decreased bone health/osteoporosis in inflammatory bowel disease

References

Chapter 44. Osteoporosis associated with eating disorders

Abstract

44.1 Introduction to eating disorders

44.2 Assessment of bone outcomes in eating disorders, including the use of novel techniques

44.3 Factors related to the development of low bone density in patients with eating disorders

44.4 Recommendations for the management of low bone density in eating disorders

44.5 Conclusion

References

Chapter 45. Glucocorticoid-induced osteoporosis and Cushing’s syndrome

Abstract

45.1 Introduction

45.2 Epidemiology of glucocorticoid-induced osteoporosis

45.3 The pathogenesis and molecular basis of glucocorticoid action on bone metabolism and development

45.4 Other musculoskeletal effects of glucocorticoids

45.5 Effects of Cushing’s syndrome on bone

45.6 Treatment options and fracture risk reduction

45.7 Management of glucocorticoid-induced osteoporosis in children

45.8 Conclusion

Acknowledgments

References

Chapter 46. Thyroid hormone, thyroid medication, and the skeleton

Abstract

46.1 Introduction

46.2 Systemic regulation of thyroid hormone action

46.3 Cellular transport and metabolism of thyroid hormone

46.4 Thyroid hormone receptors

46.5 Thyroid hormone action in bone

46.6 Action of thyroid-stimulating hormone receptor in bone

46.7 Studies in genetically modified mice

46.8 Effects of thyroid signaling mutations on the human skeleton

46.9 Skeletal effects of normal variation in thyroid status

46.10 Skeletal consequences of hypothyroidism

46.11 Skeletal consequences of hyperthyroidism

46.12 Conclusion

46.13 Author short biographies

Acknowledgments

References

Chapter 47. The skeletal actions of parathyroid hormone in primary hyperparathyroidism

Abstract

47.1 Introduction

47.2 Parathyroid hormone, primary hyperparathyroidism, and the skeleton

47.3 Primary hyperparathyroidism in the differential diagnosis of osteoporosis

47.4 Summary

Acknowledgment

References

Chapter 48. Osteogenesis imperfecta and other defects of bone development as occasional causes of adult osteoporosis

Abstract

48.1 Scope of the problem

48.2 Osteogenesis imperfecta as a cause of adult osteoporosis

48.3 Type I collagen and osteogenesis imperfecta

48.4 Clinical overview of osteogenesis imperfecta

48.5 Type IV osteogenesis imperfecta (OMIM 166,220)

48.6 Recessive forms of osteogenesis imperfecta

48.7 Genotype expression in osteogenesis imperfecta

48.8 The pathophysiology of osteogenesis imperfecta

48.9 Organ involvement in osteogenesis imperfecta

48.10 Osteoporosis in the heritable disorders of connective tissue

References

Chapter 49. Human immunodeficiency virus and osteoporosis

Abstract

49.1 Aging and human immunodeficiency virus

49.2 Human immunodeficiency virus medicine 101

49.3 Epidemiology of low bone mineral density in human immunodeficiency virus

49.4 Etiology of low bone mineral density in human immunodeficiency virus

49.5 Vitamin D deficiency

49.6 Children and adolescents

49.7 Nonskeletal risk factors for fracture

49.8 Screening considerations in persons living with human immunodeficiency virus

49.9 Treatment considerations

49.10 Conclusion

References

Chapter 50. Diabetes, diabetic medications, and risk of fracture

Abstract

50.1 Introduction

50.2 Fractures, bone turnover, bone morphology, and bone strength in diabetes mellitus

50.3 Bone metabolism in diabetes: from obesity and insulin resistance to insulin deficiency

50.4 Diabetes mellitus and bone health: pathways to skeletal fragility

50.5 Effect of diabetes therapies on bone metabolism

50.6 Clinical management: prevention, prediction, and treatment

50.7 Conclusion

References

Chapter 51. Skeletal health after bariatric surgery

Abstract

51.1 Introduction

51.2 Overview of bariatric operations

51.3 Bone outcomes after bariatric surgery

51.4 Potential mechanisms for postoperative bone changes

51.5 Clinical implications and management

References

Chapter 52. Osteoporosis in organ transplant patients

Abstract

52.1 The bone remodeling system

52.2 Skeletal effects of immunosuppressive drugs

52.3 Effects of vitamin D on immunity and graft rejection

52.4 Effect of transplantation on bone and mineral metabolism

52.5 Prevention and treatment of transplantation osteoporosis

52.6 Summary and conclusion

References

Chapter 53. Osteoporosis associated with rheumatologic disorders

Abstract

53.1 Introduction

53.2 Rheumatoid arthritis

53.3 Focal subchondral and marginal bone erosions

53.4 Generalized bone loss

53.5 Juvenile idiopathic arthritis

53.6 Glucocorticoids in children

53.7 Osteoporosis treatment in children

53.8 Seronegative spondyloarthropathies

53.9 Systemic lupus erythematosus

References

Chapter 54. Osteoporosis associated with chronic kidney disease

Abstract

54.1 Introduction

54.2 Grades of chronic kidney disease

54.3 Epidemiology

54.4 Pathophysiology

54.5 Skeletal manifestations of chronic kidney disease

54.6 Extraskeletal calcifications

54.7 Treatment of bone disease

54.8 Summary

References

Chapter 55. Relationship between periodontal disease, tooth loss, and osteoporosis

Abstract

55.1 Introduction

55.2 Periodontal disease and tooth loss prevalence

55.3 Clinical measures of periodontal disease

55.4 Osteoporosis characterization in studies of periodontal disease and tooth loss

55.5 Mechanisms by which osteoporosis and periodontal disease may be associated

55.6 Risk factors for periodontal disease

55.7 Studies of the association between periodontal disease and osteoporosis

55.8 Summary

References

Chapter 56. Impact of breast cancer and its treatment on bone loss and fracture risk—pathophysiology and management

Abstract

56.1 Introduction

56.2 Conclusion and future directions

Conflicts of interest

References

Further reading

Chapter 57. Management of bone health in men with prostate cancer

Abstract

57.1 Bone health management in prostate cancer

57.2 Nonpharmacologic therapies

57.3 Future directions and gaps in care

57.4 Conclusion and recommendations

References

Chapter 58. Impact of MGUS and myeloma on skeletal health

Abstract

58.1 Introduction

58.2 Skeletal effects of monoclonal gammopathy of undetermined significance

58.3 Skeletal effects of multiple myeloma

58.4 Summary

Acknowledgments

Conflicts of interest

References

Chapter 59. Renal stone disease, hypercalciuria, and osteoporosis: use of thiazides and alkali for osteoporosis

Abstract

59.1 Background

59.2 Hypercalciuria: definitions and determinants

59.3 Epidemiology

59.4 Pathophysiologic mechanisms contributing to hypercalciuria and osteoporosis in urinary stone disease

59.5 Therapeutic effects of thiazide on the bone

59.6 Mechanism(s) of action of thiazides on bone metabolism—in vivo and in vitro

59.7 Alkali therapy for hypercalciuric stone formers and nonstone-forming population

59.8 Approach to the patient

59.9 Management of hypercalciuric patients

59.10 Conclusion

Acknowledgments

References

Chapter 60. Sleep disorders and osteoporosis

Abstract

60.1 Introduction

60.2 Normal sleep and circadian rhythms

60.3 Physiologic relationships between sleep/circadian systems and bone metabolism

60.4 Skeletal response to shift work and sleep duration changes

60.5 Obstructive sleep apnea and bone

60.6 Melatonin and bone

60.7 Chronotherapy

60.8 Future directions

60.9 Conclusion

Acknowledgment

References

Part VIII: Diagnosis and evaluation

Chapter 61. Evaluation of the osteoporosis patient

Abstract

61.1 Introduction

61.2 Medical history

61.3 Physical examination

61.4 Laboratory studies

61.5 Imaging

61.6 Invasive procedures

61.7 Treatment decisions

61.8 Conclusion

Disclosure

References

Chapter 62. Who should be screened for osteoporosis?

Abstract

62.1 Introduction

62.2 Bone mineral density testing

62.3 Formal risk assessment tools

62.4 Who should be screened?

62.5 Younger postmenopausal women aged 50–64 years

62.6 Men

62.7 When to stop screening?

62.8 How often to screen?

62.9 Guideline statements

62.10 Summary

References

Chapter 63. Vertebral fracture identification

Abstract

63.1 Insufficiency fracture

63.2 Means of identifying vertebral fracture

63.3 Imaging criteria for identification of vertebral fracture

63.4 Vertebral fracture location, determinants, and prevalence

63.5 Grading vertebral fracture severity on radiography

63.6 Identifying acute vertebral fracture with magnetic resonance imaging

63.7 Differentiating osteoporotic from metastatic fracture on magnetic resonance imaging

63.8 Identifying osteoporotic vertebral fractures in children

63.9 Opportunistic vertebral fracture detection

63.10 Conclusion

References

Chapter 64. Noninvasive imaging techniques and fracture risk assessment

Abstract

64.1 Introduction

64.2 Dual-energy X-ray absorptiometry

64.3 Contribution of bone microstructure to fracture risk

64.4 Alternative and noninvasive techniques for fracture risk assessment

64.5 Conclusion

References

Chapter 65. Biochemical markers of bone turnover in osteoporosis

Abstract

65.1 Biochemical markers of bone formation

65.2 Biochemical markers of bone resorption

65.3 Analytical and preanalytical variability

65.4 Preanalytical variability in clinical practice

65.5 Clinical use of bone markers in postmenopausal osteoporosis

65.6 Bone turnover markers in men

65.7 Bone markers—clinical studies versus clinical practice

65.8 Conclusion: what we know, what we need to learn

References

Chapter 66. A comparison of fracture risk assessment tools

Abstract

66.1 Introduction

66.2 Validated fracture risk assessment tools

66.3 Special considerations in using fracture risk assessment tools

66.4 Algorithms using fracture risk assessment tools

66.5 Future directions in fracture risk assessment tools

Conflicts of interest

Financial support and sponsorship

References

Part IX: Patient management

Chapter 67. Orthopedic aspects of osteoporosis

Abstract

67.1 Engaging the orthopedic specialist

67.2 Geriatric fracture care and care treatment pathways

67.3 Orthopedic hardware and fragile bone

67.4 Lower extremity fractures

67.5 Upper extremity fractures

67.6 Pelvis and sacral fractures

67.7 Spine fractures and elective spine surgery

67.8 Periprosthetic fractures

References

Chapter 68. Fall prevention interventions

Abstract

68.1 Epidemiology of falls and fall-related injuries in older people

68.2 Risk factors for falls

68.3 Fall risk screening and assessment

68.4 Fall prevention strategies

68.5 Successful single fall prevention strategies

68.6 Multifactorial fall prevention strategies

68.7 Summary

References

Further reading

Chapter 69. Exercise and other physical therapy interventions in the management of osteoporosis

Abstract

69.1 Exercise for the prevention of falls, fall-related injuries, and fractures

69.2 Effect of exercise on bone mineral density

69.3 Exercise, sarcopenia, and physical function

69.4 Exercise, fear of movement, and safety concerns

69.5 Tailoring physical activity

69.6 Language

69.7 Resources and exercise professionals

69.8 Summary: exercise recommendations for people with osteoporosis

69.9 Tips about prescribing exercise components

69.10 Physical therapy assessment and treatment

69.11 Summary: physical therapy plan for people with osteoporosis

References

Chapter 70. Calcium and vitamin D in the management of osteoporosis

Abstract

70.1 Introduction

70.2 Bone remodeling, osteoporosis, and calcium

70.3 Interplay of calcium and vitamin D

70.4 Impact of calcium and vitamin D on bone mineral density

70.5 Dietary recommendations and sources for calcium and vitamin D

70.6 Calcium and vitamin D supplementation for treatment of osteoporosis

70.7 Safety

70.8 Conclusion

Acknowledgments

References

Chapter 71. Nutrients beyond calcium and vitamin D to treat osteoporosis

Abstract

71.1 Introduction

71.2 Phytoestrogens

71.3 Dehydroepiandrosterone

71.4 Antioxidants

71.5 Bicarbonates

71.6 B vitamins and homocysteine

71.7 Minerals

71.8 Conclusion

References

Chapter 72. Condition still critical: compliance and persistence with osteoporosis medications

Abstract

72.1 Introduction

72.2 A brief history of osteoporosis pharmaceutical treatments

72.3 Side effects of osteoporosis medications: their effect on adherence

72.4 A turning point in adherence: serious side effects of osteoporosis medications

72.5 Can we change pessimism and apathy about osteoporosis and its medications?

72.6 What now? A fundamental change in public perceptions of osteoporosis and treatment

72.7 Conclusion

References

Part X: Pharmacotherapeutics

Chapter 73. Estrogen and estrogen analogs for prevention and treatment of osteoporosis

Abstract

73.1 Background

73.2 Estrogen receptors in the bone

73.3 Estrogen and combined hormone therapy

73.4 Selective estrogen receptor modulators

73.5 Special population considerations

73.6 Conclusion

Conflict of interest

References

Chapter 74. Bisphosphonates pharmacology and use in the treatment of osteoporosis

Abstract

74.1 Introduction and history

74.2 Pharmacokinetics and pharmacodynamics

74.3 Treatment of postmenopausal osteoporosis: efficacy

74.4 Bisphosphonate efficacy beyond 3 years

74.5 Bisphosphonate safety

74.6 Gastrointestinal adverse effects and esophageal cancer

74.7 Musculoskeletal side effects

74.8 Acute phase reaction

74.9 Atrial fibrillation

74.10 Renal safety

74.11 Bisphosphonate drug holidays

74.12 Summary

References

Chapter 75. Denosumab for the treatment of osteoporosis

Abstract

75.1 Denosumab

75.2 Efficacy

75.3 Use of denosumab with bone-forming agents

75.4 Safety and tolerability

75.5 Withdrawal of therapy

75.6 Adherence to denosumab therapy

75.7 Denosumab in other populations

75.8 Summary

References

Chapter 76. Teriparatide and abaloparatide treatment for osteoporosis

Abstract

76.1 Introduction

76.2 Teriparatide monotherapy in postmenopausal women with osteoporosis

76.3 Abaloparatide treatment for osteoporosis

76.4 Abaloparatide Comparator Trial in Vertebral Endpoints extension study

76.5 Clinical issues

76.6 Which patients are appropriate for teriparatide and abaloparatide treatment?

76.7 Conclusion

References

Chapter 77. Calcitonin in osteoporosis

Abstract

77.1 Introduction

77.2 Clinical pharmacology

77.3 Clinical efficacy in postmenopausal osteoporosis

77.4 Clinical efficacy in other forms of osteoporosis

77.5 Therapeutic regimens

77.6 Analgesic effect

77.7 Safety

Acknowledgments

References

Chapter 78. Androgens

Abstract

78.1 Introduction

78.2 Endogenous androgens

78.3 Effects of testosterone on bone in men

78.4 Effects of testosterone on bone in women

78.5 Effects of cross hormone therapy in transgender people

References

Chapter 79. Long-term bisphosphonate treatment: continuation and interruption

Abstract

Abbreviations

79.1 Introduction: osteoporosis as a chronic disease

79.2 Long-term bisphosphonate studies

79.3 Bisphosphonate interruption (holiday)

79.4 Guidance for patients on long-term bisphosphonate therapy

79.5 Suggested approaches to long-term treatment

79.6 Conclusion

Acknowledgment

References

Chapter 80. Romosozumab for the treatment of postmenopausal osteoporosis

Abstract

80.1 Introduction

80.2 Early clinical studies

80.3 Pivotal fracture trials: FRAME

80.4 Pivotal fracture trials: ARCH

80.5 Other phase 3 studies: STRUCTURE

80.6 Other phase 3 studies: BRIDGE

80.7 Conclusion

References

Chapter 81. Lessons from bone histomorphometry on the mechanisms of action of osteoporosis drugs

Abstract

81.1 Introduction

81.2 Anticatabolic therapies

81.3 Anabolic therapies

References

Part XI: New directions

Chapter 82. Long-term treatment strategies and goal-directed therapy

Abstract

82.1 Introduction

82.2 Hormone therapy and selective estrogen modulators

82.3 Bisphosphonates

82.4 Denosumab

82.5 Anabolic therapies

82.6 Summary of treatment strategies by level of risk

82.7 Conclusion: goal-directed therapy

References

Index

Copyright

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List of contributors

Bo Abrahamsen,     Holbæk Hospital and University of Southern Denmark, Odense, Denmark

Robert A. Adler

McGuire Veterans Affairs Medical Center and Virginia Commonwealth University School of Medicine, Richmond, VA, United States

Endocrinology and Metabolism Section, McGuire Veterans Affairs Medical Center, Richmond, VA, United States

Endocrine Division, Virginia Commonwealth University School of Medicine, Richmond, VA, United States

Sara Ajjour,     Calcium Metabolism and Osteoporosis Program, Faculty of Medicine – American University of Beirut Medical Center, Beirut, Lebanon

Mohammad Mehdi Alemi,     Department of Orthopedic Surgery, Center for Advanced Orthopaedic Studies, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, United States

Dennis E. Anderson,     Department of Orthopedic Surgery, Center for Advanced Orthopaedic Studies, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, United States

Timothy R. Arnett,     Department of Cell and Developmental Biology, University College London, London, United Kingdom

Mariam A. Assaad,     American University of Beirut Medical Center, Beirut, Lebanon

Ghada T. Ballane,     Calcium Metabolism and Osteoporosis Program, Faculty of Medicine – American University of Beirut Medical Center, Beirut, Lebanon

Roland Baron

Division of Bone and Mineral Research, Harvard School of Dental Medicine, Boston, MA, United States

Endocrine Unit, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States

J.H. Duncan Bassett,     Molecular Endocrinology Laboratory, Department of Metabolism, Digestion and Reproduction, Imperial College London, London, United Kingdom

Douglas C. Bauer

Department of Medicine, University of California, San Francisco, CA, United States

Department of Epidemiology & Biostatistics, University of California, San Francisco, CA, United States

William A. Bauman

Department of Veterans Affairs Rehabilitation Research & Development Service, National Center for the Medical Consequences of Spinal Cord Injury and the Internal Medicine Service, James J. Peters Veterans Affairs Medical Center, Bronx, NY, United States

Departments of Medicine and Rehabilitation & Human Performance, The Icahn School of Medicine at Mount Sinai, New York, NY, United States

Kristen M. Beavers,     Department of Health and Exercise Science, Wake Forest University, Winston-Salem, NC, United States

Sarah D. Berry

Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA, United States

Hebrew SeniorLife, Hinda and Arthur Marcus Institute for Aging Research, Harvard Medical School, Boston, MA, United States

John P. Bilezikian,     Metabolic Bone Diseases Unit, Department of Medicine, College of Physicians and Surgeons, Columbia University, New York, NY, United States

Emmanuel Biver,     Division of Bone Diseases, Geneva University Hospitals and Faculty of Medicine, University of Geneva, Geneva, Switzerland

Dana Bliuc

Osteoporosis and Bone Biology Program, Garvan Institute of Medical Research, Sydney, Australia

Faculty of Medicine, UNSW, Sydney, Australia

Lynda F. Bonewald,     Indiana Center for Musculoskeletal Health, Departments of Anatomy and Cell Biology and Orthopaedic Surgery, Indiana School of Medicine, Indianapolis, IN, United States

Adele L. Boskey,     Department of Orthopaedic Surgery, Hospital for Special Surgery, New York, New York, United States

Mary L. Bouxsein

Department of Orthopedic Surgery, Center for Advanced Orthopaedic Studies, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, United States

Center for Advanced Orthopaedic Studies, Beth Israel Deaconess Medical Center, Boston, MA, United States

Department of Orthopedic Surgery, Harvard Medical School, Boston, MA, United States

Nathalie Bravenboer

Department of Clinical Chemistry, Research Institute Amsterdam Movement Sciences Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands

Section Endocrinology, Department of Internal Medicine, Centre for Bone Quality LUMC, Leiden, The Netherlands

Todd T. Brown,     Division of Endocrinology, Diabetes, and Metabolism, Johns Hopkins University, Baltimore, MD, United States

Susan V. Bukata,     University of California Los Angeles, Los Angeles, CA, United States

Katelyn Burkhart,     Department of Orthopedic Surgery, Center for Advanced Orthopaedic Studies, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, United States

Ernesto Canalis,     Department of Orthopaedic Surgery and Medicine, UConn Health, Farmington, CT, United States

Christopher Cardozo

Department of Veterans Affairs Rehabilitation Research & Development Service, National Center for the Medical Consequences of Spinal Cord Injury and the Internal Medicine Service, James J. Peters Veterans Affairs Medical Center, Bronx, NY, United States

Departments of Medicine and Rehabilitation & Human Performance, The Icahn School of Medicine at Mount Sinai, New York, NY, United States

Alesha B. Castillo

Department of Orthopaedic Surgery, NYU Grossman School of Medicine, New York, NY, United States

Department of Biomedical Engineering, Tandon School of Engineering, New York University, Brooklyn, NY, United States

Department of Veterans Affairs, New York Harbor Healthcare System, Manhattan, New York, NY, United States

Jane A. Cauley,     Department of Epidemiology, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA, United States

Jacqueline R. Center

Osteoporosis and Bone Biology Program, Garvan Institute of Medical Research, Sydney, Australia

Clinical School, St Vincent’s Hospital, Sydney, Australia

Faculty of Medicine, UNSW, Sydney, Australia

Julia C. Chen,     Department of Biomedical Engineering, Columbia University, New York, NY, United States

Roberto Civitelli,     Department of Internal Medicine, Washington University in St. Louis, St. Louis, MO, United States

Adi Cohen,     Division of Endocrinology, Department of Medicine, Columbia University Irving Medical Center, New York, NY, United States

Felicia Cosman,     Department of Medicine, Columbia University College of Physicians and Surgeons, New York, NY, United States

Carolyn J. Crandall,     Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, United States

Brooke M. Crawford,     University of California Los Angeles, Los Angeles, CA, United States

Natalie E. Cusano,     Division of Endocrinology, Department of Medicine, Bone Metabolism Program, Lenox Hill Hospital, New York, NY, United States

Francisco J.A. de Paula,     Department of Internal Medicine, University of São Paulo, Ribeirão Preto, Brazil

Kim Delbaere

Falls, Balance and Injury Research Centre, Neuroscience Research Australia, Randwick, NSW, Australia

School of Public Health and Community Medicine, University of New South Wales, Kensington, NSW, Australia

David W. Dempster

Regional Bone Center, Helen Hayes Hospital, West Haverstraw, NY, United States

College of Physicians and Surgeons, Columbia University, New York, NY, United States

Department of Clinical Pathology and Cell Biology, College of Physicians and Surgeons of Columbia University, New York, NY, United States

Dima L. Diab,     Cincinnati VA Medical Center, University of Cincinnati Bone Health and Osteoporosis Center, Cincinnati, OH, United States

Ingrid Dick-de-Paula,     Department of Internal Medicine, University of São Paulo, Ribeirão Preto, Brazil

Linda A. DiMeglio,     Department of Pediatrics, Division of Pediatric Endocrinology/Diabetology and Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN, United States

Matthew T. Drake,     Department of Endocrinology, Mayo Clinic, Rochester, MN, United States

Alanna M.K. Dubrovsky,     University of California, Davis, Sacramento, CA, United States

Luca D’Onofrio,     Department of Experimental Medicine, Sapienza University of Rome, Rome, Italy

Richard Eastell,     Department of Oncology and Metabolism, University of Sheffield, Sheffield, United Kingdom

Grahame J. Elder

Osteoporosis and Bone Biology Division, Garvan Institute of Medical Research, Darlinghurst, NSW, Australia

University of Notre Dame, Sydney, NSW, Australia

University of Sydney, NSW, Australia

Ghada A. El-Hajj Fuleihan

American University of Beirut Medical Center, Beirut, Lebanon

Calcium Metabolism and Osteoporosis Program, WHO Collaborating Center for Metabolic Bone Diseases, American University of Beirut, Beirut, Lebanon

Kristine E. Ensrud

Department of Medicine and Division of Epidemiology and Community Health, University of Minnesota, Minneapolis, MN, United States

Center for Care Delivery & Outcomes Research, Minneapolis VA Health Care System, Minneapolis, MN, United States

Serge Ferrari,     Service of Bone Diseases, Department of Medicine, Geneva University Hospital, Geneva, Switzerland

Bernard Freudenthal,     Molecular Endocrinology Laboratory, Department of Metabolism, Digestion and Reproduction, Imperial College London, London, United Kingdom

Harry K. Genant,     Medicine and Orthopaedic Surgery, University of California, San Francisco, CA, United States

Louis C. Gerstenfeld,     Department of Orthopaedic Surgery, Boston University School of Medicine, Boston, MA, United States

Lora Giangregorio,     Professor and Schlegel Research Chair in Mobility and Aging, Department of Kinesiology, University of Waterloo, Waterloo, ON, Canada

Evelien Gielen

Centre for Metabolic Bone Diseases, University Hospitals Leuven, Leuven, Belgium

Gerontology and Geriatrics Section, Department of Public Health and Primary Care, KU Leuven, Leuven, Belgium

Deborah T. Gold,     Duke University Medical Center, Durham, NC, United States

Steven R. Goldring,     Hospital for Special Surgery, New York, NY, United States

Catherine M. Gordon,     Division of Adolescent/Young Adult Medicine and Endocrinology, Boston Children’s Hospital, Harvard Medical School, Boston, MA, United States

Francesca Gori,     Division of Bone and Mineral Research, Harvard School of Dental Medicine, Boston, MA, United States

Gail A. Greendale,     Division of Geriatrics, David Geffen School of Medicine at UCLA, Los Angeles, CA, United States

James F. Griffith,     Department of Imaging & Interventional Radiology, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong

Peyman Hadji

Frankfurter Center of Bone Health, Frankfurt am Main, Germany

Philipps-University of Marburg, Marburg, Germany

Christopher J. Hernandez

Nancy E & Peter C Meinig School of Biomedical Engineering, Cornell University, Ithaca, NY, United States

Sibley School of Mechanical & Aerospace Engineering, Cornell University, Ithaca, NY, United States

Jonathan Hoggatt

Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA, United States

Department of Stem Cells and Regenerative Biology, Harvard University, Cambridge, MA, United States

Harvard Stem Cell Institute, Cambridge, MA, United States

Denise K. Houston,     Section of Gerontology and Geriatric Medicine, Department of Internal Medicine, Wake Forest School of Medicine, Winston-Salem, NC, United States

Amira I. Hussein,     Department of Mechanical Engineering, Boston University, Boston, MA, United States

Christopher R. Jacobs,     Department of Biomedical Engineering, Columbia University, New York, NY, United States

Xuezhi Jiang

Department of Obstetrics and Gynecology, The Reading Hospital of Tower Health, Reading, PA, United States

Department of Obstetrics and Gynecology, Sidney Kimmel Medical College of Thomas Jefferson University, Philadelphia, PA, United States

James D. Johnston,     Department of Mechanical Engineering, College of Engineering, University of Saskatchewan, Saskatoon, SK, Canada

Risa Kagan

Department of Obstetrics, Gynecology and Reproductive Sciences, UCSF, San Francisco, CA, United States

Obstetrics, Gynecology, and Reproductive Sciences, UCSF, Sutter East Bay Medical Foundation, Berkeley, CA, United States

Lamya Karim,     Department of Bioengineering, University of Massachusetts Dartmouth, Dartmouth, MA, United States

Carrie Karvonen-Gutierrez,     Department of Epidemiology, University of Michigan, Ann Arbor, MI, United States

Wendy B. Katzman,     Professor Emeritus, Department of Physical Therapy and Rehabilitation Science, University of California San Francisco, San Francisco, CA, United States

Masanobu Kawai,     Osaka Medical Center and Research Institute for Maternal and Child Health, Izumi, Japan

Sundeep Khosla,     Division of Endocrinology and Metabolism and Kogod Center on Aging, Department of Internal Medicine, Mayo Clinic, Rochester, MN, United States

Douglas P. Kiel

Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA, United States

Hebrew SeniorLife, Hinda and Arthur Marcus Institute for Aging Research, Harvard Medical School, Boston, MA, United States

Saija A. Kontulainen,     College of Kinesiology, University of Saskatchewan, Saskatoon, SK, Canada

Paul Kostenuik

Phylon Pharma Services, Newbury Park, CA, United States

University of Michigan School of Dentistry (Adjunct), Ann Arbor, MI, United States

Alexandra Krez,     Endocrinology and Metabolic Bone Disease Service, Hospital for Special Surgery, New York, NY, United States

Henry Kronenberg,     Endocrine Unit, Massachusetts General Hospital and Harvard Medical School, Boston, MA, United States

Rajiv Kumar

Division of Endocrinology, Diabetes, Metabolism, and Nutrition, Mayo Clinic, Rochester, MN, United States

Department of Internal Medicine, Mayo Clinic, Rochester, MN, United States

Division of Nephrology, Mayo Clinic, Rochester, MN, United States

Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN, United States

Nancy E. Lane,     University of California, Davis, Sacramento, CA, United States

Lisa Langsetmo,     Epidemiology and Community Health, University of Minnesota, Minneapolis, MN, United States

Michaël R. Laurent

Centre for Metabolic Bone Diseases, University Hospitals Leuven, Leuven, Belgium

Imelda Hospital, Bonheiden, Belgium

L. Lawenius,     Centre for Bone and Arthritis Research, Department of Internal Medicine and Clinical Nutrition, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden

Sergey Leikin,     Section on Physical Biochemistry, National Institute of Child Health and Development, National Institutes of Health, Department of Health and Human Services, Bethesda, MD, United States

William D. Leslie,     University of Manitoba, Winnipeg, MB, Canada

E. Michael Lewiecki,     New Mexico Clinical Research & Osteoporosis Center, Albuquerque, NM, United States

Minghao Liu,     Division of Endocrinology, Department of Medicine, Columbia University Irving Medical Center, New York, NY, United States

Yi Liu,     Department of Medicine, Beth Israel Lahey Health, Burlington, MA, United States

Stephen R. Lord

Falls, Balance and Injury Research Centre, Neuroscience Research Australia, Randwick, NSW, Australia

School of Public Health and Community Medicine, University of New South Wales, Kensington, NSW, Australia

Joseph Lorenzo,     Departments of Medicine and Orthopaedic Surgery, UConn Health, Farmington, CT, United States

Nina S. Ma,     Section of Endocrinology, Children’s Hospital Colorado and Department of Pediatrics, University of Colorado School of Medicine, Aurora, CO, United States

Naim M. Maalouf,     Department of Internal Medicine, Charles and Jane Pak Center for Mineral Metabolism and Clinical Research, University of Texas Southwestern Medical Center, Dallas, TX, United States

Robert Marcus,     Department of Medicine, Stanford University, Stanford, CA, United States

Michael R. McClung

Oregon Osteoporosis Center, Portland, OR, United States

Mary MacKillop Center for Health Research, Australian Catholic University, Melbourne, VIC, Australia

Marcela Moraes Mendes,     School of Biosciences and Medicine, University of Surrey, Guildford, United Kingdom

Paul D. Miller,     Colorado Center for Bone Research, Lakewood, CO, United States

Madhusmita Misra,     Division of Pediatric Endocrinology, MassGeneral Hospital for Children, Boston, MA, United States

Mahshid Mohseni,     Department of Internal Medicine, Washington University in St. Louis, St. Louis, MO, United States

Elise F. Morgan,     Department of Mechanical Engineering, Boston University, Boston, MA, United States

Suzanne N. Morin,     McGill University, Montreal, QC, Canada

Mona Al Mukaddam,     University of Pennsylvania School of Medicine, Philadelphia, PA, United States

Chris J.J. Mulder,     Department of Gastroenterology, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands

Nandini Nair,     Division of Endocrinology, Department of Medicine, Columbia University Irving Medical Center, New York, NY, United States

Nicola Napoli,     Area of Endocrinology & Diabetes, University Campus Bio-Medico of Rome, Rome, Italy

Nat Nasomyont,     Division of Endocrinology, Cincinnati Children’s Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, OH, United States

Dorothy A. Nelson,     Oakland University, Rochester, MI, United States

Jeri W. Nieves,     Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, NY, United States

Robert Nissenson,     Research Scientist, VA Medical Center, San Francisco and Professor of Medicine and Physiology, University of California, San Francisco, United States

Claes Ohlsson,     Centre for Bone and Arthritis Research, Department of Internal Medicine and Clinical Nutrition, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden

Christina V. Oleson,     Department of Physical Medicine and Rehabilitation, Case Western Reserve University, Cleveland, OH, United States

Laura Ortinau

Department of Molecular Human Genetics, Baylor College of Medicine, Houston, TX, United States

Center for Skeletal Biology, Baylor College of Medicine, Houston, TX, United States

Eric Orwoll,     Bone and Mineral Research Unit, Oregon Health and Science University, Portland, OR, United States

Susan M. Ott,     University of Washington, Seattle, WA, United States

Roberto Pacifici,     Division of Endocrinology, Metabolism, and Lipids, Emory University School of Medicine, Atlanta, GA, United States

Andrea Palermo,     Area of Endocrinology & Diabetes, University Campus Bio-Medico of Rome, Rome, Italy

A.M. Parfitt,     Division of Endocrinology, University of Arkansas for Medical Sciences, Little Rock, AR, United States

Dongsu Park

Department of Molecular Human Genetics, Baylor College of Medicine, Houston, TX, United States

Center for Skeletal Biology, Baylor College of Medicine, Houston, TX, United States

Sylvain Provot,     Lariboisière Hospital, INSERM Unit 1132, University of Paris, Paris, France

Sonia Bhandari Randhawa,     Department of Obstetrics and Gynecology, The Reading Hospital of Tower Health, Reading, PA, United States

John F. Randolph Jr.

Obstetrics and Gynecology and Epidemiology, University of Michigan, Ann Arbor, MI, United States

Reproductive Endocrinology and Infertility, University of Michigan, Ann Arbor, MI, United States

Fernando Rivadeneira,     Department of Internal Medicine, Erasmus University Medical Center, Rotterdam, The Netherlands

Pamela Gehron Robey,     Skeletal Biology Section, National Institute of Dental Research, National Institutes of Health, Department of Health and Human Services, Bethesda, MD, United States

Lauren Robinson,     Section of Eating Disorders, Psychological Medicine, Institute of Psychiatry, Psychology, and Neuroscience, King’s College London, London, United Kingdom

Tara Rogers-Soeder,     VA Northern California Healthcare System, Mather, CA, United States

G. David Roodman

Kenneth Wiseman Professor of Medicine, Department of Medicine, Division of Hematology Oncology, Indiana University School of Medicine, Indianapolis, IN, United States

Roudebush VA Medical Center, Indianapolis, IN, United States

Clifford J. Rosen,     Center for Clinical and Translational Research, Maine Medical Center Research Institute, Scarborough, ME, United States

Kenneth G. Saag,     Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, United States

Shivani Sahni,     Marcus Institute for Aging Research, Hebrew SeniorLife, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, United States

Khashayar Sakhaee,     Department of Internal Medicine, Charles and Jane Pak Center for Mineral Metabolism and Clinical Research, University of Texas Southwestern Medical Center, Dallas, TX, United States

David T. Scadden

Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA, United States

Department of Stem Cells and Regenerative Biology, Harvard University, Cambridge, MA, United States

Harvard Stem Cell Institute, Cambridge, MA, United States

Anne L. Schafer

Department of Medicine, University of California, San Francisco, CA, United States

Endocrine Research Unit, San Francisco Veterans Affairs Health Care System, San Francisco, CA, United States

Department of Epidemiology and Biostatistics, University of California, San Francisco, CA, United States

Ernestina Schipani,     Departments of Orthopaedic Surgery, Medicine and Cell and Developmental Biology, University of Michigan School of Medicine, Ann Arbor, MI, United States

Monica C. Serra,     Division of Geriatrics, Gerontology & Palliative Medicine and the Sam & Ann Barshop Institute for Longevity & Aging Studies, Department of Medicine, UT Health San Antonio and the San Antonio Geriatric Research Education and Clinical Center, South Texas Veterans Health Care System, San Antonio, TX, United States

Jay R. Shapiro,     Bone and Osteogenesis Imperfecta Department, The Kennedy Krieger Institute, Johns Hopkins University School of Medicine, Baltimore, MD, United States

Catherine Sherrington

School of Public Health, University of Sydney, Sydney, NSW, Australia

Institute for Musculoskeletal Health, Sydney Local Health District, Sydney, NSW, Australia

James M. Shikany,     Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, United States

Shonni J. Silverberg,     Metabolic Bone Diseases Unit, Department of Medicine, College of Physicians and Surgeons, Columbia University, New York, NY, United States

Andrea J. Singer,     Departments of Medicine and Obstetrics and Gynecology, MedStar Georgetown University Hospital and Georgetown University Medical Center, Washington, DC, United States

K. Sjögren,     Centre for Bone and Arthritis Research, Department of Internal Medicine and Clinical Nutrition, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden

Peter J. Snyder,     University of Pennsylvania School of Medicine, Philadelphia, PA, United States

Emily M. Stein,     Endocrinology and Metabolic Bone Disease Service, Hospital for Special Surgery, New York, NY, United States

Christine M. Swanson,     Division of Endocrinology, Metabolism and Diabetes, University of Colorado Anschutz Medical Campus, Aurora, CO, United States

Pawel Szulc,     INSERM UMR 1033, University of Lyon, Edouard Herriot Hospital, Lyon, France

Pamela Taxel,     UConn Health, Department of Medicine, Division of Endocrinology and Metabolism, Farmington, CT, United States

Peter J. Tebben

Division of Endocrinology, Diabetes, Metabolism, and Nutrition, Mayo Clinic, Rochester, MN, United States

Department of Internal Medicine, Mayo Clinic, Rochester, MN, United States

Department of Pediatrics, Mayo Clinic, Rochester, MN, United States

Sarah E. Twardowski,     Department of Epidemiology and Environmental Health, School of Public Health and Health Professions, University of Buffalo, Buffalo, NY, United States

André G. Uitterlinden,     Department of Internal Medicine, Erasmus University Medical Center, Rotterdam, The Netherlands

Rachana Vaidya,     Department of Bioengineering, University of Massachusetts Dartmouth, Dartmouth, MA, United States

Cristianna Vallera,     University of California Los Angeles, Los Angeles, CA, United States

Adriaan A. van Bodegraven

Department of Gastroenterology, Geriatrics, Internal and Intensive Care Medicine (Co-MIK), Zuyderland MC, Sittard-Geleen, The Netherlands

Department of Gastroenterology, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands

Bram C.J. van der Eerden,     Laboratory for Calcium and Bone Metabolism, Department of Internal Medicine, Erasmus University Medical Center, Rotterdam, The Netherlands

Marjolein C.H. van der Meulen

Nancy E & Peter C Meinig School of Biomedical Engineering, Cornell University, Ithaca, NY, United States

Sibley School of Mechanical & Aerospace Engineering, Cornell University, Ithaca, NY, United States

Biomechanics & Biomaterials, Hospital for Special Surgery, New York, NY, United States

André J. van Wijnen

Department of Orthopedic Surgery, Mayo Clinic College of Medicine, Mayo Clinic, Rochester, MN, United States

Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, Mayo Clinic, Rochester, MN, United States

Dirk Vanderschueren,     Clinical and Experimental Endocrinology, Department of Chronic Diseases and Metabolism (CHROMETA), University of Leuven, Leuven, Belgium

Jean Wactawski-Wende,     Department of Epidemiology and Environmental Health, School of Public Health and Health Professions, University of Buffalo, Buffalo, NY, United States

Laura Watts,     Molecular Endocrinology Laboratory, Department of Metabolism, Digestion and Reproduction, Imperial College London, London, United Kingdom

Nelson B. Watts,     Director, Mercy Health Osteoporosis and Bone Health Services, Suite 212; Cincinnati, OH, United States

Ashley A. Weaver,     Department of Biomedical Engineering, Wake Forest School of Medicine, Winston-Salem, NC, United States

Robert S. Weinstein,     University of Arkansas for Medical Sciences, Little Rock, AR, United States

Graham R. Williams,     Molecular Endocrinology Laboratory, Department of Metabolism, Digestion and Reproduction, Imperial College London, London, United Kingdom

Joy Wu,     Division of Endocrinology, Stanford University School of Medicine, Stanford, CA, United States

Karin C. Wu

Department of Medicine, University of California, San Francisco, CA, United States

Endocrine Research Unit, San Francisco Veterans Affairs Health Care System, San Francisco, CA, United States

Michael T. Yin,     Division of Infectious Diseases, Columbia University, New York, NY, United States

Elaine W. Yu,     Department of Medicine, Endocrine Unit, Harvard Medical School, Massachusetts General Hospital, Boston, MA, United States

Hua Zhou,     Regional Bone Center, Helen Hayes Hospital, West Haverstraw, NY, United States

Foreword

We are pleased to have been invited by the current editorial team to be drawn from retirement to introduce the Fifth Edition of Osteoporosis. Once again, 7 years have passed since its last iteration. During this interval, understanding of basic mechanisms of bone biology has progressed impressively, as has recognition and insight into clinical entities associated with bone loss and fracture. This new edition greatly expands coverage of these disorders. For example, diabetes mellitus and celiac disease, which were discussed previously in a single composite chapter, have now reached a level of understanding and detail that justifies their treatment as stand-alone chapters. Other individual new chapters include the microbiome, neurologic disease, eating disorders, bariatric surgery, hypercalciuric renal stone disease, and sleep disorders.

In contrast to progress in the basic understanding of disease mechanisms, therapeutic advances have been relatively slow. One of the best prospects for registration of a new antiresorptive molecule, odanacatib, failed to acquire FDA approval due to adverse side effects, and only two new anabolic agents, abaloparatide and romosozumab, have been approved. These two drugs are very well covered in excellent chapters. However, it appears that the loss of odanacatib as well as the great expense of conducting registration level clinical trials in osteoporosis may have put a damper on pharmaceutical company interest in bringing forth new agents. Consequently, as shown by the current chapters on therapeutics, much research now focuses on additional detail for established drugs: treatment schedules, the use of drug holidays to limit side effects, drug sequencing to improve overall long-term efficacy, developing effective combination therapies, and optimizing goal directed therapies.

Consistent with a policy that the editors of Osteoporosis have followed since the earliest editions, there has been a significant turnover of authors for the Fifth Edition. We think this policy of bringing in new voices is a healthy form of remodeling that keeps the book fresh and timely. It also unfortunately partly reflects the passing of some authors from the scene. Since the last edition, several of our distinguished authors have died. These include Robert Heaney, Adele Boskey, Michael Parfitt, B.E.C. Nordin, and Christopher Jacobs, as well as others in the osteoporosis field. Having known and worked with many of these individuals for numerous years and through several editions of Osteoporosis, we are saddened to record these passings.

We gratefully thank Ms. Tari Broderick for her patient and skillful efforts on our behalf in helping to guide the publication of multiple editions of this book. Tari worked with us at Academic Press and then at Elsevier in the production of Osteoporosis over its entire publication history and she has just retired.

We congratulate the current Editors for putting together a splendid volume. We wish the readers many hours of excellent reading.

Robert Marcus, M.D.

David Feldman, M.D.

Stanford University, January 2020

Volume 1

Contents

Outline

Part I Introduction

Part II Developmental, cellular and molecular biology of bone

Part III Skeletal hormones and regulatory factors

Part IV Biomechanics and mechanobiology

Part V Epidemiology of osteoporosis

Part VI General pathophysiology of osteoporosis

Part I

Introduction

Outline

Chapter 1 The nature of osteoporosis

Chapter 2 The bone organ system: form and function

Chapter 1

The nature of osteoporosis

David W. Dempster¹,², Robert Marcus³ and Mary L. Bouxsein⁴,    ¹1Department of Clinical Pathology and Cell Biology, College of Physicians and Surgeons of Columbia University, New York, NY, United States,    ²2Regional Bone Center, Helen Hayes Hospital, West Haverstraw, NY, United States,    ³3Department of Medicine, Stanford University, Stanford, CA, United States,    ⁴4Department of Orthopaedic Surgery, Beth Israel Deaconess Medical Center and Endocrine Division, Massachusetts General Hospital, Harvard Medical School, Boston, MA, United States

Abstract

Two decades ago, in 2000, the National Institutes of Health (NIH) held a Consensus Development Panel on Osteoporosis that defined osteoporosis as a skeletal disorder characterized by compromised bone strength predisposing a person to an increased risk of fracture. Bone strength primarily reflects the integration of bone density and bone quality. The incorporation of compromised bone strength in the definition was an important contribution. However, bone strength cannot be measured noninvasively. Moreover, the term bone quality was vague but also important as it acknowledged that factors other than bone mineral density (BMD) contributed to bone strength. Bones are hierarchical in structure and each level of the hierarchy—from ultrastructure of the extracellular matrix to the gross anatomy of the bone—contributes to their mechanical properties. The NIH definition of osteoporosis spurred investigators to understand better the non-BMD factors that contribute to bone strength. These factors include the material properties of bone matrix (both organic and inorganic), the microarchitecture of both cancellous and cortical bone, the rate of bone turnover, and the accumulation of microdamage. This introductory chapter will briefly review current knowledge on the role that these factors play in determining bone strength and its impairment in osteoporosis.

Keywords

Osteoporosis; bone mineral density (BMD); fragility; trabecular microarchitecture; matrix mineralization; bone quality

1.1 Defining osteoporosis

This chapter introduces the topic of osteoporosis from the perspective of the bone. Its purpose is to consider the definition of osteoporosis and to discuss the nature of osteoporotic bone, including the characteristics that affect its ability to resist fracture. Osteoporosis is a condition of generalized skeletal fragility in which bone strength is sufficiently weak that fractures occur with minimal trauma, often no more than is applied by routine daily activity. Albright and Reifenstein [1] proposed in 1948 that primary osteoporosis consists of two separate entities, one related to menopausal estrogen loss and the other to aging. This concept was elaborated upon by Riggs et al. [2] who suggested the terms Type I osteoporosis, to signify a loss of trabecular bone after menopause, and Type II osteoporosis, to represent a loss of cortical and trabecular bone in men and women as the end result of age-related bone loss. By this formulation the Type I disorder directly results from lack of endogenous estrogen, while Type II osteoporosis reflects the composite influences of long-term remodeling inefficiency, inadequacy of dietary calcium and vitamin D, along with altered intestinal mineral absorption, renal mineral handling, and parathyroid hormone (PTH) secretion. Although there may be heuristic value to defining subsets of patients in this manner, the model suffers by not accounting for the complex and multifactorial nature of a disease that defies rigid categorization.

Bone mass at any time in adult life reflects the peak investment in bone mineral at skeletal maturity minus that which has been subsequently lost. A woman who experienced interruption of menses, extended bed rest, eating disorder, or systemic illness during her adolescent growth years might enter adult life having failed to achieve the bone mass that would have been predicted from her genetic or constitutional profile. Also, some women might achieve their genetically determined peak bone mass, but the genetic factors might predict a low peak bone mass level. In both the cases, even with a normal rate of subsequent bone loss, her skeleton would still be in jeopardy simply due to the deficit in peak bone mass. Thus it seems most appropriate to consider osteoporosis the consequence of a stochastic process, that is, multiple genetic, physical, hormonal, and nutritional factors acting alone or in concert to diminish skeletal integrity.

Historical artifacts show that characteristic deformities of vertebral osteoporosis were recognized in antiquity [3], although broad awareness of this condition has come about only during the past four decades. Unfortunately, because traditional radiographic techniques cannot distinguish osteoporosis until it is severe, confirmation of the diagnosis remained problematic until the 1980s, with introduction of single-photon absorptiometry and then dual-photon absorptiometry, initially, and followed by then dual-energy X-ray absorptiometry (DXA) that allowed quantitative assessment of bone mineral density (BMD). Prior to these BMD assessment technologies, diagnosis was by necessity clinical, requiring a history of one or more low-trauma fractures. Although highly specific, such a grossly insensitive diagnostic criterion offered no assistance to physicians who hope to identify and treat affected individuals who have not yet sustained a fracture.

The introduction of accurate noninvasive bone mass measurements afforded the opportunity to estimate a person’s fracture risk and to make an early diagnosis of osteoporosis. Briefly stated, large prospective studies showed that a reduction in BMD of one standard deviation from the mean value for a young, normal reference population confers a two- to threefold increase in long-term fracture risk [4–9]. In a manner similar to that by which serum cholesterol concentration predicts risk for myocardial infarction or blood pressure predicts risk for stroke, BMD measurements can successfully identify subjects at increased risk of fracture and can help physicians select those individuals who will derive greatest benefit for initiation of therapy.

Several factors limit the ability of BMD measurements to predict an individual’s fracture risk with great accuracy. BMD is clearly related to body weight, yet routine clinical bone mass assessments may not be weight-adjusted. Various features of bone geometry that affect bone strength and fracture risk are not generally considered in the clinical interpretation of bone mass measurements, including bone size as well as the spatial distribution of bone mass. Moreover, bone mass determinations cannot distinguish individuals with low mass and intact microarchitecture from those with equal mass who have trabecular disruption and cortical porosity [10]. Other factors, including age, bone turnover rate, and falling risk, are independent risk factors for fracture, at least in older subjects [11], and cannot be assessed by BMD measurement.

In 1994 a group of senior investigators in this field offered a working definition of osteoporosis based exclusively on bone mass [12]. The reasoning behind this proposal, made on behalf of the World Health Organization (WHO), was that the clinical significance of osteoporosis lies exclusively in the occurrence of fracture, that BMD measurements predict long-term fracture risk, and that selection of rigorous diagnostic criteria would minimize the number of patients who are incorrectly diagnosed. The authors suggested that osteoporosis be diagnosed as a BMD value of 2.5 standard deviations below the average for healthy young adult women. Using this value, approximately 30% of postmenopausal women would be designated as osteoporotic, which gives a realistic projection of lifetime fracture rates. In addition, Kanis et al. [12] proposed that BMD values of 1–2.5 standard deviations below the young adult men be designated as osteopenic. Such values identify individuals at increased risk for fracture, but for whom a diagnosis of osteoporosis would not be justified since it would mislabel far more individuals than would actually be expected ever to fracture. Of course, it would still be possible to make a clinical diagnosis of osteoporosis based on a prior fragility fracture.

This approach has proven useful for clinical management but has several limitations. The applicability of this criterion to young people prior to the completion of peak bone acquisition would be inappropriate. The BMD measurement is itself subject to several confounding factors, including bone size