E-grāmata: Osteoporosis

Contributors		xix
Preface		xxv
Part I Introduction
The Bone Organ System: Form and Function
Elise F. Morgan
George L. Barnes
Thomas A. Einhorn
Introduction		3	(1)
Composition and Organization of Bone		3	(8)
Cellular Components of Bone		11	(3)
Bone Homeostasis		14	(3)
Bone Mechanics		17	(5)
Summary		22	(5)
The Nature of Osteoporosis
Robert Marcus
Mary L. Bouxsein
Defining Osteoporosis		27	(1)
Material and Structural Basis of Skeletal Fragility		28	(5)
Conclusions		33	(4)
The Economics of Osteoporosis
Anna N.A. Tosteson
David J. Vanness
Introduction		37	(1)
Cost of Illness Studies: Characterizing the Magnitude of the Health Problem		37	(3)
Cost-Effectiveness Analyses: Identifying Efficient Osteoporosis Care Strategies		40	(3)
Future Research Directions		43	(4)
Reflections on Osteoporosis
B. E. Christopher Nordin
Introduction		47	(1)
Definition		47	(2)
Diagnosis		49	(1)
Fragility Fractures		50	(1)
Bone Density and Fracture Risk		50	(1)
Pathogenesis		51	(12)
Prevention		63	(1)
Treatment		64	(1)
Conclusions		65	(6)
Skeletal Heterogeneity and the Purposes of Bone Remodeling: Implications for the Understanding of Osteoporosis
A. M. Parfitt
Introduction		71	(1)
Skeletal Heterogeneity		72	(2)
The Purposes of Bone Remodeling		74	(5)
Implications for Understanding Osteoporosis		79	(14)
Part II Basic Science of Bone Biology
Osteoblast Biology
Jane B. Lian
Gary S. Stein
Overview		93	(1)
Embryonic Development of the Osteoblast Phenotype: Lessons for Bone Formation in the Postnatal Skeleton		93	(7)
Development Sequence of Osteoblast Phenotype Development		100	(6)
Phenotype Properties of Osteogenic Lineage Cells		106	(10)
Molecular Mechanisms Mediating Progression of Osteoblast Growth and Differentiation		116	(12)
Conclusion		128	(23)
Osteoclast Biology
Harry C. Blair
Scott Simonet
David L. Lacey
Mone Zaidi
Introduction		151	(1)
Key Osteoclast Differentiation Pathways		151	(3)
The Fully Differentiated Osteoclast: Mechanisms of Bone Degradation		154	(3)
Bone Resorption Coordinated by Intermediate Proteins		157	(1)
Osteoclast Death		158	(1)
Mechanistic Approaches to Modification of Osteoclastic Activity In Vivo		158	(2)
Regulation of Osteoclastic Differentiation and Activity In Vivo		160	(1)
Interaction of Hormonal and Local Signals with Osteoclast Activity		161	(1)
Diseases with Altered Bone Resorption		162	(7)
Osteocytes
Lynda F. Bonewald
Introduction		169	(1)
Osteocyte Ontogeny		169	(1)
Osteoid-Osteocytes		170	(1)
Osteocyte Selective Genes/Proteins and their Potential Functions		171	(1)
Morphology of Osteocytes: Lacunocanalicular System and Dendrite Formation		172	(2)
Osteocyte Cell Models		174	(1)
Mechanisms and Response of Osteocytes to Mechanical Forces		174	(3)
Osteocyte Signals for Bone Formation		177	(1)
Osteocyte Signals for Bone Resorption		178	(1)
Osteocyte Apoptosis		179	(1)
Osteocyte Modification of their Microenvironment		179	(1)
Osteocyte Density		180	(1)
Role of Gap Junctions and Hemichannels in Osteocyte Communication		180	(1)
Osteocytes in the Embryonic and the Adult Skeleton		181	(1)
The Implications of Osteocyte Biology for Bone Disease		182	(1)
Conclusions		183	(8)
The Regulatory Role of Matrix Proteins in Mineralization of Bone
Wei Zhu
Pamela Gehron Robey
Adele L. Boskey
Introduction		191	(2)
Collageneous Proteins		193	(2)
Intermediate Cartilage Matrix		195	(6)
Bone-Enriched Matrix Proteins		201	(18)
The Mineralization of Bone Matrix		219	(22)
Development of the Skeleton
Sylvain Provot
Ernestina Schipani
Joy Wu
Henry Kronenberg
Introduction		241	(1)
Patterning the Skeleton		241	(9)
Endochondral Bone Formation		250	(11)
Intramembranous Bone Formation		261	(10)
Mouse Genetics as a Tool to Study Bone Development and Physiology
Clifford J. Rosen
Wesley G. Beamer
Introduction: Historical Perspective and Significance		271	(1)
Introduction To Mouse Skeletal Physiology		272	(1)
Inbred Strains of Mice		273	(2)
Recombinant Inbred strains		275	(1)
Congenic Strains		276	(3)
Recombinant Congenic Strains		279	(1)
Summary		280	(3)
Parathyroid Hormone and Parathyroid Hormone-Related Protein
Robert A. Nissenson
Introduction		283	(1)
Secretion of Parathyroid Hormone		283	(1)
Metabolism of Parathyroid Hormone		284	(1)
Bone Resorbing Action of Parathyroid Hormone		285	(1)
Effects of Parathyroid Hormone on Bone Formation		286	(2)
Renal Actions of Parathyroid Hormone		288	(1)
Parathyroid Hormone-Related Protein as a Mediator of Malignancy-Associated Hypercalcemia		289	(1)
Physiological Roles of Parathyroid Hormone-Related Protein		289	(5)
Mechanism of Action of Parathyroid Hormone and Parathyroid Hormone-Related Protein		294	(23)
Vitamin D: Biology, Action, and Clinical Implications
David Feldman
Peter J. Malloy
Aruna V. Krishnan
Eva Balint
Introduction		317	(1)
Vitamin D Synthesis and Metabolism		318	(8)
Pathways of Activation and Inactivation of Vitamin D		326	(5)
Mechanism of 1,25(OH)2D Action		331	(10)
Nongenomic Actions of Vitamin D		341	(1)
Physiology: Regulation of Serum Calcium		342	(2)
Genetic Disorders		344	(2)
1,25(OH)2D3 Analogs with Decreased Calcemic Activity		346	(2)
Actions of Vitamin D in Classical Target Organs to Regulate Mineral Homeostasis		348	(6)
Actions of 1,25(OH)2D in Nonclassical Target Organs		354	(6)
Vitamin D and Osteoporosis		360	(23)
Regulation of Bone Cell Function by Estrogens
Barry S. Komm
Boris Cheskis
Peter V.N. Bodine
Introduction		383	(1)
What is an Estrogen?		383	(1)
Estrogen Receptors		383	(9)
Erα and ERβ Knockout Mice (ERKO and βERKO)		392	(1)
Estrogens and Bone		392	(1)
Estrogen Receptors in Bone Cells		393	(5)
Estrogenic Responses in Bone Cells		398	(12)
Estrogen-Related Receptor-α and Osteopontin Gene Expression		410	(1)
Nongenomic Actions of Estrogens in Bone Cells		410	(1)
Conclusion		411	(14)
Androgens and Skeletal Biology: Basic Mechanisms
Kristine M. Wiren
Introduction		425	(1)
Androgens and the Role of Androgen Metabolism		425	(3)
Cellular Biology of the Androgen Receptor in the Skeleton		428	(5)
The Consequences of Androgen Action in Bone Cells		433	(4)
The Skeletal Effects of Androgen: Animal Studies		437	(3)
Animal Models of Altered Androgen Responsiveness		440	(1)
Effects on the Periosteum: The Role of Androgen Receptor versus Aromatization of Testosterone		441	(1)
Summary		442	(9)
Phosphatonins
Peter J. Tebben
Theresa J. Berndt
Rajiv Kumar
Introduction		451	(1)
Phosphorus Homeostasis		451	(3)
Phosphatonins		454	(1)
Fibroblast Growth Factor 23		454	(6)
Secreted Frizzled-Related Protein 4		460	(1)
Matrix Extracellular Phosphoglycoprotein		460	(1)
Fibroblast Growth Factor 7		461	(1)
Summary		462	(5)
Wnt Signaling in Bone
Mark L. Johnson
Robert R. Recker
Wnts		467	(1)
The Wnt/β-Catenin Signaling Pathway		468	(5)
Other Wnt Pathways		473	(2)
Mutations in Wnt Pathway Components and Altered Bone Mass		475	(2)
Wnt Signaling and Bone Cell Function		477	(3)
Wnt Signaling and the Bone Response to Mechanical Loading		480	(1)
Conclusions and Future Directions		481	(10)
Cytokines and Bone Remodeling
Gregory R. Mundy
Babatunde Oyajobi
Gloria Gutierrez
Julie Sterling
Susan Padalecki
Florent Elefteriou
Ming Zhao
Introduction		491	(1)
Evidence for a Role of Cytokines in Osteoclastic Bone Resorption		492	(1)
The Osteoclast as a Cell Source of Cytokines Involved in Osteoclastic Resorption		493	(1)
The Osteoblast as a Cell Source of Cytokines Involved in Osteoclastic Resorption		493	(1)
Rank Ligand and Its Signaling Receptor, Rank		494	(3)
Osteoprotegerin		497	(1)
Macrophage-Colony-Stimulating Factor and Its Receptor, C-fms		498	(2)
Vascular Endothelial Growth Factor		500	(1)
Tumor Necrosis Factor		500	(1)
Interleukin-6 (IL-6)		501	(1)
Interleukin-15 (IL-15), Interleukin-17 (IL-17), and Interleukin-18 (IL-18)		502	(1)
Bone Morphogenetic Proteins		503	(6)
Hedgehog (Hh) Signaling Molecules		509	(2)
Sclerostin		511	(1)
Parathyroid Hormone-Related Peptide (Pthrp)		511	(1)
Neuronal Regulation of Bone Remodeling		512	(3)
Conclusion		515	(14)
Skeletal Growth Factors
Ernesto Canalis
Introduction		529	(1)
Platelet-Derived Growth Factor		529	(2)
Vascular Endothelial Growth Factor		531	(1)
Fibroblast Growth Factor		532	(1)
Transforming Growth Factor Beta		533	(1)
Bone Morphogenetic Protein		534	(1)
Insulin-Like Growth Factor		535	(2)
Insulin-Like Growth Factor Binding Proteins		537	(1)
Hepatocyte Growth Factor		538	(9)
Intercellular Communication during Bone Remodeling
T. John Martin
Gideon A. Rodan
Introduction		547	(1)
Sequence of Cellular Events in Bone Remodeling		548	(1)
Cell Interactions Early in Remodeling		548	(1)
Interaction of Osteoblast Lineage Cells with Osteoclasts		549	(1)
Factors Proposed to Mediate the Coupling of Bone Formation to Resorption		550	(2)
Osteoclast Products in the Coupling Process		552	(1)
Similarities between Bone Remodeling and Inflammation		553	(1)
Bone Mass Homeostasis		554	(1)
The Role of Mechanical Function (Strain) in the Coupling of Bone Resorption to Bone Formation		554	(1)
Integrated View of the Coupling of Bone Resorption and Bone Formation		555	(8)
Part III Structure and Biomechanics
Skeletal Development: Mechanical Consequences of Growth, Aging, and Disease
Marjolein C.H. Van Der Meulen
Dennis R. Carter
Gary S. Beaupre
Developmental Mechanics in Skeletogenesis		563	(1)
Mechanical Regulation of Bone Biology		564	(2)
Mechanobiologic Self-Design of Bones		566	(11)
Adaptational Mechanics in Aging and Disease		577	(4)
Inhibition of Osteoporosis by Biophysical Intervention
Clinton Rubin
Stefan Judex
Janet Rubin
Yi-Xian Qin
Introduction		581	(1)
Bone's Sensitivity to Mechanical Signals		582	(1)
Structural Demands on the Skeleton		582	(3)
Regulation of Bone Morphology by Biophysical Stimuli		585	(4)
Osteogenic Potential of Low-Magnitude, High-Frequency Signals		589	(2)
Regulating the Bone Cell Response to Mechanical Signals		591	(2)
Biophysical Stimuli in the Clinic		593	(3)
Summary		596	(5)
Biomechanics of Age-Related Fractures
Mary L. Bouxsein
Introduction		601	(1)
Biomechanics of Bone: Basic Concepts and Age-Related Changes		602	(7)
Biomechanics of Hip Fractures		609	(5)
Biomechanics of Vertebral Fractures		614	(2)
Summary and Clinical Implications		616	(9)
Bone Quality
J. Christopher Fritton
Mitchell B. Schaffler
Introduction		625	(2)
Chapter Objective		627	(1)
The Brooklyn Bridge: A Paradigm for Understanding Bone Quality		627	(2)
Factors Impacting Bone Quality		629	(6)
Conclusions		635	(10)
Part IV Epidemiology and Risk Factors
Epidemiologic Methods in Studies of Osteoporosis
MaryFran Sowers
Carrie A. Karvonen-Gutierrez
Introduction		645	(1)
Descriptive and Analytic Studies		645	(1)
Study Designs		646	(8)
Some Useful Epidemiologic Concepts		654	(1)
Some Frequently Used Statistics		655	(1)
Criteria for Deciding Whether an Association is Causal		656	(1)
Sample Size Considerations		657	(1)
Measurement Error		658	(5)
Conclusions		663	(4)
Race, Ethnicity and Osteoporosis
Dorothy A. Nelson
John M. Pettifor
Shane A. Norris
Introduction		667	(1)
Background and Definitions		667	(1)
Ethnoepidemiology of Osteoporosis		668	(4)
Ethnic Influences on Risk for Osteoporosis		672	(8)
Summary		680	(9)
The Study of Osteoporotic Fractures: Major Findings and Contributions
Jane A. Cauley
Kristine E. Ensrud
Teresa A. Hillier
Marc Hochberg
Katie L. Stone
Steven R. Cummings
Overview		689	(1)
Summary of Key Findings		689	(6)
What is a Vertebral Fracture?		695	(2)
Ethnic Differences in Osteoporosis		697	(1)
Sleep Disturbance and Risk of Falls and Fractures		697	(1)
Consequences of Fracture: Mortality		698	(1)
Breast Cancer		699	(1)
Hip Osteoarthritis		699	(1)
SOF Online		700	(1)
Summary		700	(5)
Bone Mineral Acquisition In Utero and during Infancy and Childhood
Jon M. Burnham
Mary B. Leonard
Introduction		705	(1)
Quantitative Assessment of Bone Health in Infants and Children		705	(5)
Bone Acquisition In Utero		710	(12)
Bone Acquisition in the Preterm Infant		722	(1)
Bone Acquisition in Term Infants and Children		723	(20)
Bone Acquisition in Adolescence
Moira A. Petit
Heather M. MacDonald
Heather A. McKay
Tom Lloyd
Introduction		743	(1)
Bone Development		743	(5)
Mechanical Factors		748	(3)
Nonmechanical Factors		751	(3)
Summary		754	(5)
Genetic Determinants of Osteoporosis
Andre G. Uitterlinden
Fernando Rivadeneira
Hans P. T. M. Van Leeuwen
Joyce B. J. Van Meurs
Huibert A. P. Pols
Introduction		759	(6)
Finding Risk Gene Variants for Complex Traits		765	(16)
Osteoporosis Risk Gene Variants		781	(10)
Applications and Prospects		791	(8)
Nutrition and Risk for Osteoporosis
Robert P. Heaney
Introduction		799	(3)
Problems in the Investigation of Nutritional Effects on Bone		802	(3)
The Notion of a Nutrient Requirement		805	(1)
The Natural Intake of Calcium and Vitamin D		805	(2)
Calcium		807	(14)
Vitamin D		821	(2)
Protein		823	(1)
Vitamin K		824	(1)
Other Essential Nutrients		825	(3)
Conclusion		828	(9)
Physical Activity in Prevention of Osteoporosis and Associated Fractures
Kirsti Uusi-Rasi
Pekka Kannus
Harri Sievanen
Introduction		837	(1)
Bone Adaptation to Physical Loading		837	(6)
Physical Activity and Bone		843	(7)
Prevention of Falls and Fall-Related Fractures by Physical Activity		850	(2)
Conclusions and Recommendations		852	(9)
Premenopausal Reproductive and Hormonal Characteristics and the Risk for Osteoporosis
MaryFran Sowers
Introduction		861	(1)
Pregnancy		861	(3)
Age at First Pregnancy		864	(1)
Parity and Nulliparity		864	(1)
Lactation		865	(3)
Ovarian Activity or Menstrual Cycle Characteristics and Bone Mass		868	(2)
Dysfunctional Ovulation		870	(2)
Oral Contraceptive Use		872	(1)
Progestin-Injectable Contraceptives		873	(3)
Oophorectomy		876	(1)
Summary and Implications		877	(10)
Nonskeletal Risk Factors for Osteoporosis and Fractures
Jeri W. Nieves
Physical Characteristics		887	(1)
Anthropometric Variables		888	(4)
Lifestyle Factors		892	(19)
Falls as Risk Factors for Fracture
Sarah D. Berry
Douglas P. Kiel
Introduction		911	(1)
Risk Factors for Falls		911	(2)
Risk Factors for Injurious Falls		913	(3)
Falls Prevention Strategies		916	(1)
Summary and Implications		917	(6)
Assessment of Fracture Risk
Nguyen Dinh Nguyen
Tuan V. Nguyen
Introduction		923	(1)
Definition of Osteoporotic Fracture		923	(2)
Epidemiology of Osteoporotic Fracture		925	(19)
Synthesis of Risk Factors and Risk Assessment Models		944	(4)
Summary and Future Directions		948	(11)
Outcomes of Osteoporotic Fractures
Gail A. Greendale
Elizabeth Barrett-Connor
Introduction		959	(1)
Definitions of Functional Outcomes Related to Fracture		959	(1)
Osteoporosis-Relevant Quality of Life Assessments		959	(1)
Outcomes of Wrist Fractures		960	(1)
Outcomes of Vertebral Fractures		961	(7)
Outcomes of Hip Fractures		968	(2)
Conclusions		970	(5)
Part V Pathophysiology
Local and Systemic Factors in the Pathogenesis of Osteoporosis
Lawrence G. Raisz
Introduction		975	(1)
Role of Systemic Hormones		975	(1)
Local Factors		976	(1)
Cytokines		977	(1)
Prostaglandins		977	(1)
Growth Factors		978	(1)
Colony-Stimulating Factors		978	(1)
Further Considerations of Interactions of Systemic Hormones and Local Mediators		978	(1)
Conclusions		979	(6)
Animal Models for Osteoporosis
Urszula T. Iwaniec
Russell T. Turner
Introduction		985	(1)
Goals of Animal Models for Osteoporosis		985	(1)
Specific Animal Models		986	(9)
Evaluation of the Osteopenic Skeleton in Animal Models		995	(7)
Fracture Repair		1002	(1)
Summary		1002	(9)
Estrogen, Bone Homeostasis, and Osteoporosis
B. Lawrence Riggs
Sundeep Khosla
L. Joseph Melton III
Introduction		1011	(1)
Secretion and Metabolism of Sex Steroids		1011	(1)
Direct Effects of Sex Steroids on Bone		1012	(4)
Indirect Effects of Sex Steroids on Bone		1016	(1)
Age- and Sex-Specific Skeletal Changes		1016	(3)
Hormonal Determinants of Skeletal Growth and Maturation		1019	(1)
Hormonal Determinants of Age-Related Bone Loss in Women		1019	(4)
Hormonal Determinants of Age-Related Bone Loss in Men		1023	(4)
The Conundrum of Trabecular Bone Loss in Hormone-Sufficient Young Adults		1027	(1)
Estrogen Deficiency and Age-Related Osteoporosis		1027	(4)
Other Factors Contributing to Osteoporosis		1031	(1)
Summary and Conclusions		1032	(9)
Postmenopausal Osteoporosis: How the Hormonal Changes of Menopause Cause Bone Loss
Roberto Pacifici
Steroid Biosynthesis and Menopause		1041	(1)
Mechanism of Action of Estrogen in Bone		1041	(4)
Mechanisms of Estrogen Regulation of T Cell TNF Production		1045	(3)
T Cell Thymic Output and Bone Loss		1048	(1)
From Animal Models to Human Disease		1049	(1)
Conclusions		1049	(6)
Osteoporosis in Men: Epidemiology, Pathophysiology, and Clinical Characterization
Eric S. Orwoll
Robert F. Klein
Fractures in Men		1055	(4)
The Major Determinants of Bone Health in Men		1059	(7)
Osteoporosis		1066	(6)
The Evaluation of Osteoporosis in Men		1072	(4)
Therapy		1076	(19)
Osteoporosis in Childhood and Adolescence
Leanne Ward
Laura K. Bachrach
Introduction		1095	(1)
Principles of Bone Development		1095	(2)
Definition and Diagnosis of Osteoporosis in Children and Adolescents		1097	(4)
Pathogenesis and Treatment of Specific Disorders		1101	(22)
Summary and Future Directions		1123	(12)
Glucocorticoid-Induced Osteoporosis
Robert A. Adler
Jeffrey Curtis
Robert S. Weinstein
Kenneth G. Saag
Introduction		1135	(1)
Epidemiology of Glucocorticoid-Induced Osteoporosis		1135	(6)
The Pathogenesis and Molecular Basis of Glucocorticoid Action on Bone Metabolism and Development		1141	(5)
Other Musculoskeletal Effects of Glucocorticoids		1146	(1)
Treatment Options and Fracture Risk Reduction		1147	(9)
Management of Glucocorticoid-Induced Osteoporosis in Children		1156	(11)
Adult Scoliosis, Degenerative Disease, and BMD: A Subsegmental Analytic Approach
Alan L. Burshell
Eric A. Nauman
Introduction		1167	(1)
The Biomechanics of Scoliosis		1167	(1)
The Use of Dual-Energy X-Ray Absorptiometry to Characterize Physiological Changes in the Spine		1168	(2)
Postmenopausal Scoliosis Measured by Subsegmental Analysis		1170	(3)
Conclusions		1173	(4)
Mechanisms of Immobilization-Induced Bone Loss
Bernard Halloran
Daniel D. Bikle
Transduction of Mechanical Loading		1177	(1)
Sensing Strain, Fluid Shear Stress, and Compression		1177	(3)
Bone Responsiveness to Loss of Weight Bearing		1180	(1)
Animal and in Vitro Models		1181	(6)
Leptin-Dependent Regulation of Bone Mass
Gerard Karsenty
Introduction		1187	(1)
Regulation of Bone Formation by Leptin		1187	(3)
Regulation of Bone Resorption by Leptin		1190	(1)
Summary and Perspectives		1191	(4)
Thyroid Hormone and the Skeleton
Daniel Baran
Introduction		1195	(1)
Thyroid Hormone and Skeletal Growth and Maturation		1195	(1)
Thyroid Hormone and Mineral Metabolism		1195	(1)
Thyroid Hormone and Skeletal Metabolism		1196	(1)
Bone Mass and Fracture Risk in Thyroid Disease		1196	(2)
Prevention of Thyroid Hormone-Induced Bone Loss		1198	(5)
Osteoporosis in Gastrointestinal, Pancreatic, and Hepatic Diseases
Daniel D. Bikle
Physiologic Considerations		1203	(2)
Gastrointestinal Diseases		1205	(6)
Hepatic Diseases		1211	(5)
Bone Disease Complicating Therapy		1216	(11)
The Skeletal Actions of Parathyroid Hormone in Primary Hyperparathyroidism and in Osteoporosis
John P. Bilezikian
Lorraine A. Fitzpatrick
Shonni J. Silverberg
Introduction		1227	(1)
Parathyroid Hormone, Primary Hyperparathyroidism, and the Skeleton		1227	(8)
Parathyroid Hormone and Osteoporosis		1235	(5)
Summary		1240	(7)
Osteogenesis Imperfecta and Other Defects of Bone Development as Occasional Causes of Adult Osteoporosis
Jay R. Shapiro
Scope of the Problem		1247	(1)
Osteogenesis imperfecta as a Cause of Adult Osteoporosis		1247	(12)
Histology of Bone and Bone Histomorphometry in Osteogenesis Imperfecta		1259	(8)
Osteoporosis in the Heritable Disorders of Connective Tissue		1267	(4)
Osteoporosis in Inherited Hematologic Disorders		1271	(2)
Osteoporosis in Inherited Hepatic Disease		1273	(10)
Osteoporosis Associated with Illnesses and Medications
Hyesoo Lowe
Elizabeth Shane
Introduction		1283	(1)
Metabolic Disorders		1283	(11)
Medications		1294	(21)
Transplantation Osteoporosis
Sol Epstein
Immunosuppression and Osteoporosis		1315	(1)
Immunosuppressive Agents and Utilization of Preclinical Studies Describing Mechanisms of Action		1315	(4)
Clinical Studies Supporting the Role of Calcineurin Inhibitors in Bone Loss after Transplantation		1319	(1)
Other Immune-Modifying Drugs		1319	(2)
Summary of Immunosuppressant Agents		1321	(1)
Clinical Impact of Transplantation on Bone		1321	(4)
Evaluation of Candidates for Transplantation		1325	(1)
Management of Transplantation Osteoporosis		1326	(3)
Newer Therapeutic Options		1329	(8)
Osteoporosis Associated with Cancer Therapy
Ailleen Heras-Herzig
Wende M. Kozlow
Sue A. Brown
Theresa A. Guise
Introduction		1337	(1)
Breast Cancer		1337	(11)
Prostate Cancer		1348	(7)
Multiple Myeloma and Monoclonal Gammopathy of Undetermined Significance		1355	(2)
Hematopoietic Stem Cell Transplantation and Bone Loss		1357	(3)
Skeletal Complications of Radiation Therapy		1360	(1)
Childhood Cancer		1361	(2)
Thyroid Cancer		1363	(1)
Osteonecrosis of the Jaw		1364	(1)
Conclusion		1364	(11)
Osteoporosis Associated with Pregnancy
Rachel B. Wagman
Robert Marcus
Introduction		1375	(1)
Calcium Homeostasis		1375	(2)
Osteoporosis Associated with Pregnancy		1377	(3)
Osteoporosis Associated with Heparin Therapy during Pregnancy		1380	(1)
Osteoporosis Associated with Magnesium Sulfate Therapy during Pregnancy		1381	(1)
Paradoxical Bone Mineralization in Twin-to-Twin Transfusion Syndrome		1381	(6)
Osteoporosis Associated with Rheumatologic Disorders
Steven R. Goldring
Introduction		1387	(1)
Rheumatoid Arthritis		1387	(5)
Juvenile Rheumatoid Arthritis		1392	(1)
Seronegative Spondyloarthropathies		1392	(2)
Systemic Lupus Erythematosus		1394	(5)
Oral Bone Loss and Systemic Osteopenia: Potential Treatment and Risks
Marjorie K. Jeffcoat
Introduction		1399	(2)
Diagnosis		1401	(3)
Risk Factors for Intraoral Bone Loss		1404	(2)
Patterns of Progression of Oral Bone Loss		1406	(2)
Oral Bone Loss and Systemic Osteopenia: Are They Related?		1408	(1)
Treatment		1409	(2)
Summary		1411	(6)
Localized Osteoporosis
D.J. Schurman
W.J. Maloney
R.L. Smith
Introduction		1417	(1)
Mechanical Stress and Normal Bone Architecture		1418	(1)
Localized Osteoporosis: Generalizations		1419	(1)
Localized Osteoporosis and Fracture		1420	(1)
Internal Fixation Devices		1421	(1)
Inflammatory Disease-Associated Localized Osteoporosis		1422	(1)
Reflex Sympathetic Dystrophy		1423	(1)
Transient Osteoporosis of the Hip		1423	(1)
Total Hip Replacement		1424	(2)
Prosthetic Design		1426	(1)
Immobilization Osteoporosis: Animal Studies of Localized Bone Loss		1426	(1)
Aging		1427	(1)
Hormones and Drugs		1428	(1)
Local Cellular Mechanisms		1428	(2)
Summary		1430	(7)
Part VI Evaluation and Management
Evaluation of the Patient with Osteoporosis or at Risk for Osteoporosis
Rekha Nugaram
Aysegul Atmaca
Michael Kleerekoper
Introduction		1437	(1)
The Decision to Measure BMD		1437	(3)
What BMD to Measure?		1440	(1)
The Evaluation of the Patient with Low BMD		1441	(4)
Summary and Conclusions		1445	(4)
Who Should Be Screened: Who Should Be Treated?
Michael R. McClung
Introduction		1449	(1)
Who Should Be Treated?		1449	(5)
Who to Test?		1454	(2)
Summary		1456	(5)
Radiology of Osteoporosis
Michael Jergas
Harry K. Genant
Principal Radiographic Findings in Osteopenia and Osteoporosis		1461	(3)
Diseases Characterized by Generalized Osteopenia		1464	(16)
Regional Osteoporosis		1480	(13)
Clinical Use of Bone Densitometry
Kenneth G. Faulkner
Paul D. Miller
Densitometry Techniques		1493	(6)
Basic Principles of Densitometry		1499	(2)
Performing Densitometry Measurements with DXA		1501	(6)
Monitoring the DXA Scanner		1507	(3)
Uses of Bone Densitometry		1510	(5)
Conclusions		1515	(5)
Biochemical Markers of Bone Turnover in Osteoporosis
Pawel Szulc
Pierre D. Delmas
Biochemical Markers of Bone Formation		1520	(1)
Biochemical Markers of Bone Resorption		1521	(5)
Clinical Use of Bone Turnover Markers in Postmenopausal Osteoporosis		1526	(9)
Bone Turnover Markers in Men		1535	(1)
Conclusion: what we know and what we need to know		1536	(11)
The Conundrum of Compliance and Persistence with Oral Bisphosphonates for Postmenopausal Osteoporosis
Deborah T. Gold
Samantha Solimeo
Introduction		1547	(1)
Compliance and Persistence with Prescription Medications for Chronic Diseases		1547	(1)
Osteoporosis		1548	(2)
Problems with Research in Compliance and Persistence		1550	(1)
Improving Compliance and Persistence with Bisphosphonate Therapies		1551	(1)
Conclusion		1552	(3)
An Orthopedic Perspective of Osteoporosis
Charles Reitman
Kenneth Mathis
Michael H. Heggeness
Introduction		1555	(1)
Biomechanics		1555	(1)
Specific Injuries		1555	(16)
Prevention of Fracture		1571	(4)
Lessons from Bone Histomorphometry on the Mechanism of Action of Osteoporosis Drugs
Hua Zhou
David W. Dempster
Introduction		1575	(1)
Anticatabolic Therapies		1575	(9)
Anabolic Therapies		1584	(13)
Part VII Pharmacology and Therapeutics
Design Considerations for Clinical Investigations of Osteoporosis
Robert P. Heaney
Background: Inference from Phenomena Subject to Variation		1597	(1)
Types of Investigational Designs		1598	(1)
Principal Types of Bias with Various Designs		1599	(7)
When Controlled Trials and Observational Studies Disagree		1606	(1)
Design Alternatives		1607	(1)
Design Issues of Special Relevance to Investigation of Bone		1608	(9)
Ethics of the Placebo		1617	(1)
Burden of Proof and the Null Hypothesis		1618	(3)
Regulatory Considerations for the Design and Conduct of Osteoporosis Registration Trials
Bruce H. Mitlak
Introduction		1621	(1)
History of Osteoporosis Guidances		1621	(3)
FDA and EMEA Guidance Documents		1624	(2)
New and Future Initiatives		1626	(1)
Conclusion		1627	(2)
Evidence-Based Osteoporosis Care
Kurt A. Kennel
Brian A. Swiglo
Victor M. Montori
Introduction		1629	(1)
Hierarchy of Evidence		1629	(2)
Critical Appraisal of the Literature		1631	(4)
Interpreting and Translating the Evidence into Practice		1635	(10)
Summary		1645	(6)
The Role of Calcium in the Treatment of Osteoporosis
Rene Rizzoli
Introduction		1651	(1)
Intestinal Calcium Absorption		1651	(1)
Calcium and Bone Growth		1652	(2)
Calcium and Bone Remodeling		1654	(1)
Calcium and Fracture Risk		1654	(5)
Vitamin D and its Metabolites and Analogs in the Management of Osteoporosis
Roger Bouillon
Ian R. Reid
Introduction		1659	(1)
Vitamin D in the Pathogenesis of Osteoporosis		1660	(1)
Animal Models		1661	(1)
Postmenopausal Osteoporosis		1662	(17)
Other Osteoporoses		1679	(1)
Conclusions		1680	(7)
Estrogen Therapy: Prevention and Treatment of Osteoporosis
Joan A. McGowan
Marcia L. Stefanick
Introduction and Historical Perspective		1687	(1)
Endogenous Estrogen		1688	(1)
Trends in Estrogen use		1689	(1)
Observational Studies on Fracture Prevention		1689	(1)
Effects of Hormonal Therapy on Bone Mineral Density and Markers of Bone Remodeling		1690	(1)
Randomized Clinical Trials of Hormone Therapy with Fracture Outcomes		1691	(3)
Effects of Hormone Therapy on Other Disease Outcomes		1694	(1)
Dose, Regimen, and Type of Estrogen		1695	(1)
Discontinuation and Extinction of the Effect of Hormone Therapy		1695	(2)
Estrogen with Calcium		1697	(2)
Summary		1699	(1)
Conclusion		1699	(6)
Estrogen Analogues: Selective Estrogen Receptor Modulators and Phytoestrogens
Richard Prince
Douglas B. Muchmore
Ethel S. Siris
Introduction		1705	(1)
Classification and Chemical Structure of Serms and Phytoestrogens		1705	(3)
Cellular Mechanism of Action of Serms and Phytoestrogens		1708	(4)
Animal Data		1712	(1)
Clinical Application of Serms and Phytoestrogens		1713	(12)
Bisphosphonates: Pharmacology and Use in the Treatment of Osteoporosis
Paul D. Miller
Introduction and History		1725	(1)
Pharmacokinetics and Pharmacodynamics		1726	(2)
Treatment of Postmenopausal Osteoporosis: Efficacy		1728	(5)
Other Forms of Osteoporosis		1733	(1)
Bisphosphonate Safety		1733	(3)
Conclusions		1736	(7)
Calcitonin in Osteoporosis
Roberto Civitelli
Introduction		1743	(1)
Clinical Efficacy in Postmenopausal Osteoporosis		1743	(1)
Clinical Efficacy in Other Forms of Osteoporosis		1744	(8)
Clinical Pharmacology		1752	(3)
Therapeutic Regimens and Safety		1755	(3)
Analgesic Effect		1758	(1)
Therapeutic Indications		1759	(8)
Strontium Ranelate
Ego Seeman
The Need for New Therapies for Fracture Prevention		1767	(1)
Strontium Ranelate		1768	(1)
Strontium Ranelate and Vertebral Fracture Risk Reduction		1768	(1)
Strontium Ranelate and Hip and Other Non-Vertebral Fracture Risk Reduction		1769	(1)
Strontium Ranelate in Women over 80 Years of Age		1770	(1)
Cost-Effectiveness of Strontium Ranelate Therapy		1771	(1)
Mechanisms of Action		1772	(1)
Strontium Ranelate and the Cellular Machinery of Bone Modeling and Remodeling		1773	(1)
Bone Formation and Resorption In Vitro and In Vitro		1773	(6)
Conclusion		1779	(4)
Androgens
Peter J. Snyder
Introduction		1783	(1)
Androgens		1783	(1)
Effects of Testosterone on Bone in Men		1784	(6)
Effects of Testosterone on Bone in Women		1790	(3)
Treatment with PTH Peptides
Felicia Cosman
Robert Lindsay
Introduction		1793	(1)
Candidates for Anabolic Therapy		1793	(1)
Postmenopausal Osteoporosis		1793	(10)
PTH treatment of Men		1803	(1)
Pth in Special Populations		1803	(1)
Persistence of Effect		1804	(1)
Rechallenge with PTH		1804	(1)
Pharmacokineticsofpth Administration		1804	(1)
Mode of Action		1805	(2)
PTH Peptides Under Development		1807	(1)
Conclusion		1807	(2)
Growth Hormone and Insulin-Like Growth Factors: Potential Applications and Limitations in the Management of Osteoporosis
Clifford J. Rosen
Tim Niu
Introduction		1809	(1)
Physiology of Growth Hormone-Releasing Hormone (GHRH)---GH-IGF-I		1810	(5)
The Role of GH/IGF-I in Skeletal Physiology		1815	(2)
Pathophysiology of Osteoporosis: Role of GH/IGFS		1817	(3)
Growth Hormone Therapy for Osteoporosis		1820	(5)
IGF-I for the Treatment of Osteoporosis		1825	(3)
Summary		1828	(9)
New Approaches to Osteoporosis Therapeutics
Rivka Dresner-Pollak
S. Aubrey Stock
Michael Rosenblatt
Introduction		1837	(1)
Bone Resorption Inhibitors		1837	(23)
Anabolic Agents		1860	(22)
Summary		1882	(15)
Index		1897

Dr. Marcus is Professor-Emeritus, Stanford University, where he served on the full-time medical faculty for almost 25 years, before joining the Emeritus faculty in 2001. At Stanford, he was located at the Veterans Affairs Medical Center, Palo Alto California, where he served as Director of the Aging Study Unit of the Geriatrics Research, Education, & Clinical Center from 1982-2001. Dr. Marcus enjoyed a long career as a clinical investigator in the fields of bone and mineral metabolism and osteoporosis medicine. His own research interests included diagnosis and therapy of primary hyperpara-thyroidism, interactions of the parathyroid-vitamin D axis with estrogen, age-related changes in the growth hormone-IGF axis, effects of growth hormone replacement for older men and women, metabolic and musculoskeletal effects of resistance exercise in older men and women, adolescent bone acquisition, and osteoporosis therapeutics. Dr. Marcus laboratory was a study site for many of the pivotal clinical trials in the osteoporosis field. These include the NIH Post-menopausal Estrogen/Progestin Interventions Trial (PEPI), Mercks Fracture Intervention Trial (FIT), Lillys Multiple Outcomes of Raloxifene Intervention (MORE), and Lillys registration trial of recombinant PTH(1-34) in the treatment of postmenopausal women with osteoporosis. In 2001. Dr. Marcus joined the US Affiliate of Eli Lilly & Company to support Lillys program in Osteoporosis and Skeletal Medicine. From 2003 until his retirement from Lilly in 2008, Dr. Marcus was the lead physician for the Forteo team at Lilly. He has published more than 150 research papers, editorials, and reviews. Dr. Marcus served as President of the American Society for Bone & Mineral Research in 2000-2001. Dr. Rosen is Professor and Senior Scientists at The Jackson Laboratory, Bar Harbor, Maine, where his group studies the role of insulin-like growth factors on bone and the genetics of osteoporosis in inbred strains of mice. In 2007 he joined the Maine Medical Center Research Institute in Scarborough, Maine. He is also the former Director of the Maine Center for Osteoporosis Research and Education, St. Joseph Hospital, Bangor.Dr. Rosen is a Past President of the American Society of Bone and Mineral Research (ASBMR). He served five years as the First Editor in Chief of the Journal of Clinical Densitometry, the official journal for the International Society of Clinical Densitometry, and currently serves as Associate Editor of the Journal of Bone and Mineral Research. His publications exceed 270 manuscripts published in a wide spectrum of clinical and basic science journals.