Physiology and Pharmacology of Bone

1 Calcium Homeostasis.- A. Introduction and Scope.- B. Concepts of Homeostasis.- C. Extracellular Fluid Free Calcium: The Controlled Variable.- D. Parathyroid Hormone: The Controlling Variable.- I. Afferent Loop: Effects of Calcium on PTH Secretion.- II. Efferent Loop: Effects of PTH on Free Calcium.- III. Short-Term Regulation as a Function of Parathyroid Status.- E. Other Calciotropic Hormones.- I. Calcitriol.- II. Calcitonin.- F. External Balance and Turnover of Calcium.- I. Dietary Intake and Intestinal Absorption.- II. Renal Excretion.- III. Role of Intestine and Kidney in Calcium Homeostasis.- G. Bone and Bone Mineral in Relation to Calcium Homeostasis.- I. Aspects of Bone Remodeling.- II. Role of Bone Remodeling in Calcium Homeostasis.- III. Quiescent Bone Surfaces.- IV. Circulation of Bone, Macro and Micro.- V. Bone Mineral: Composition and Structure.- VI. Movement of Calcium Ions in and out of Bone.- VII. Blood-Bone Equilibrium and Its Homeostatic Function.- VIII. Blood-Bone Equilibrium: Physiochemical and Cellular Mechanism.- H. Integration of Skeletal and Mineral Homeostasis.- References.- 2 Bone Remodeling and Bone Structure.- A. Introduction.- B. Bone Macro- and Microanatomy.- I. Cortical Bone.- II. Cancellous Bone.- C. Bone Remodeling.- I. Quantum Concept of Bone Remodeling.- II. Coupling Phenomenon.- D. Evaluation of Bone Remodeling and Structure.- I. Surface Area Estimates.- E. Evaluation of Bone Resorption.- I. Cortical Bone.- II. Cancellous Bone.- F. Evaluation of Bone Formation.- I. Cortical Bone.- II. Cancellous Bone.- G. Bone Balance.- I. Cortical Bone.- II. Cancellous Bone.- III. Calculation of Activation Frequency.- IV. Calculation of Tissue Level Indices of Turnover.- H. Indices Pertaining to Cancellous Bone Structure.- I. Trabecular Bone Volume.- II. Marrow Space Star Volume.- I. The Bone Resorption Sequence.- I. Cancellous Bone.- II. Cortical Bone.- J. The Bone Formation Sequence.- I. Cancellous Bone.- II. Cortical Bone.- III. The Bone Structural Unit.- K. Bone Remodeling and Bone Loss.- L. Reversible Bone Loss.- I. Cancellous Bone.- II. Cortical Bone.- M. Irreversible Bone Loss.- I. Cortical Bone.- II. Cancellous Bone.- III. Bone Turnover and Bone Loss.- N. Implications for Bone Mass Measurements.- O. Physiological Ageing Processes in Bone: Differences Between Females and Males.- I. Bone Loss in Cortical Bone.- II. Bone Loss in Cancellous Bone.- P. Relationship Between Bone Structure and Bone Strength.- I. Cancellous Bone.- Q. Bone Remodeling in Metabolic Bone Disease.- I. High and Low Turnover Bone Disease.- II. Bone Remodeling in Osteoporosis.- R. Final Remarks and Future Perspectives.- References.- 3 Biology of the Osteoclast.- A. Introduction.- B. Main Morphological Features of the Osteoclast.- C. Structure-Function Relationship.- D. Motility, Attachment, and Establishment of the Bone-Resorbing Compartment.- I. Cytoskeletal Organization.- II. Attachment Apparatus.- 1. Clear Zone.- 2. Podosomes and the Sealing Zone.- 3. Role of Integrins.- 4. Regulation of Bone Resorption and the Attachment Apparatus.- E. Proteins Destined for Export: Biosynthetic and Secretory Functions of the Osteoclast.- I. Lysosomal Enzymes.- II. Nature and Specificity of the Secreted Enzymes.- III. Generation of Oxygen-Derived Free Radicals and Synthesis and Secretion of Other Proteins by the Osteoclast.- F. Cytosolic and Membrane Proteins: Membrane Composition and Ion Transport.- I. Apical Membrane and the Process of Acidification.- II. Role of the Basolateral Membrane and Ion Channels in Acidification, Intracellular pH, and Membrane Potential Regulation.- III. Handling and Regulatory Role of Calcium.- G. Conclusion.- References.- 4 Osteoblasts: Differentiation and Function.- A. Introduction.- B. Mature Members of the Osteoblast Lineage: Definitions.- C. Origin of Osteoblasts.- D. Osteoblast Lineage.- E. Protein Products of Osteoblasts.- F. Factors That Influence Osteoblast Differentiation.- G. Model of Osteoblast Differentiation.- H. Osteoblast Proliferation.- I. Hormone Receptors and Responses of Osteoblasts.- J. Role of Osteoblasts in Intercellular Communication.- I. Osteoclast Activation.- II. Osteoclast Formation.- III. Coupling of Resorption to Formation.- K. Proteinase Production by Osteoblasts.- L. Conclusion.- References.- 5 Cytokines of Bone.- A. Introduction.- B. Nature of the Osteotropic Cytokines.- C. Cell Source of the Osteotropic Cytokines.- D. Interactions Between Systemic Factors and Cytokines.- E. Interactions Between Cytokines.- F. Diseases Associated with Abnormal Cytokine Production.- G. Interleukin-1.- H. Interleukin-1 Receptor Antagonist.- I. Tumor Necrosis Factor and Lymphotoxin.- J. Interleukin-6.- K. Gamma-Interferon.- L. ß2-Microglobulin.- M. Osteoclastpoietic Factor.- N. Colony-Stimulating Factors.- O. Leukemia-Inhibitory Factor (Differentiation-Inducing Factor).- P. Prostaglandins and Other Arachidonic Acid Metabolites.- Q. Transforming Growth Factor ß.- R. Bone Morphogenetic Proteins.- S. Other Bone-Derived Growth Factors.- References.- 6 Hormonal Factors Which Regulate Bone Resorption.- A. Introduction.- B. Parathyroid Hormone.- I. Effects of PTH on Bone Resorption.- II. Effects of PTH on Bone Formation.- III. Signal Transduction Mechanisms for PTH in Bone Cells.- IV. Effects of PTH on Bone Turnover.- V. Effects of PTH on Calcium Homeostasis.- C. 1,25-Dihydroxyvitamin D.- I. Vitamin D Receptor.- II. Effects of 1,25-Dihydroxyvitamin D on Osteoclasts.- III. Effects of Vitamin D Metabolites on Cells of the Osteoblast Lineage.- D. Calcitonin.- E. Amylin.- F. Cortisol.- G. Thyroid Hormones.- H. Estrogens.- References.- 7 Factors That Regulate Bone Formation.- A. Introduction.- B. Platelet-Derived Growth Factor.- C. Heparin-Binding Growth Factors.- D. Insulin-Like Growth Factors and Their Binding Proteins.- E. Transforming Growth Factor Beta.- References.- 8 Mineralization.- A. Introduction.- B. Direct Cellular Control of Mineralization Through Matrix Vesicles.- C. Mechanism of Matrix Vesicle Calcification.- I. Role of Alkaline Phosphatase.- II. Role of Lipids.- III. Constitutive Proteins of Matrix Vesicles.- IV. Biphasic Hypothesis of Mineralization-Crystal Initiation Phase.- V. Biphasic Hypothesis of Mineralization-Crystal Growth Phase.- D. Indirect Cellular Control of Mineralization.- I. Effect of Bone Morphogens on the Calcification Mechanism.- II. Role of Growth Factors in Mineralization.- III. Hormones That Affect Calcification.- IV. Pathological Calcification.- V. Vitamin D.- E. Cellular Regulation of the Composition and Mineralizing Potential of Matrix.- I. Collagen.- II. Proteoglycans and Noncollagenous Proteins of Matrix.- III. Control of Angiogenesis.- IV. Cellular Regulation of the Ionic Milieu at Calcification Sites.- V. Control of pH.- References.- 9 Pathogenesis of Osteoporosis.- A. Introduction.- B. Primary Osteoporosis.- I. Calcium-Regulating Hormones.- 1. Parathyroid Hormone.- 2. 1,25-Dihydroxyvitamin D.- 3. Calcitonin.- II. Systemic Hormones.- 1. Sex Hormones.- 2. Other Systemic Hormones.- III. Local Factors.- 1. Interleukins.- 2. Prostaglandins.- 3. Growth Factors.- IV. Calcium and Other Nutrients.- V. Physical Activity and Life-style.- VI. Alternative Hypotheses.- C. Secondary Osteoporosis.- I. Glucocorticoid-Induced Osteoporosis.- II. Hyperparathyroidism.- III. Hyperthyroidism.- IV. Hypogonadism.- V. Nutritional and Gastrointestinal Disorders.- VI. Renal Disease.- VII. Multiple Myeloma and Other Hematologic Disorders.- VIII. Mast Cells and Heparin.- IX. Osteogenesis Imperfecta.- X. Miscellaneous Therapeutic Agents.- D. Conclusion.- References.- 10 Vitamin D Metabolism.- A. Overview.- B. Dermal Production of Vitamin D3 and Dietary Sources of Vitamin D.- I. Substrate and Chemistry.- II. Ultraviolet Light and Skin Pigmentation.- III. Dietary Sources of Vitamin D.- C. Serum Vitamin D Binding Protein.- I. Ethnic Differences.- II. Binding Affinities and Function.- D. Hepatic 25-Hydroxylation.- I. Microsomal 25-Hydroxylase.- II. Vitamin D Catabolism.- III. 25-Hydroxyvitamin D Bioactivity.- E. Renal 1-Hydroxylation.- I. Proximal Tubule Mitochondrial P450.- II. Regulation of Renal 1-Hydroxylation.- III. Pathophysiology of Renal 1-Hydroxylation.- F. Extrarenal 1-Hydroxylation.- I. Physiological Extrarenal 1-Hydroxylation.- II. Pathological Extrarenal 1-Hydroxylation.- G. Renal and Target Tissue 24-Hydroxylation.- I. Renal 24-Hydroxylation.- II. Target Tissue 24-Hydroxylation.- III. Catabolic Versus Unique Functions of 24,25-Dihydroxyvitamin D.- H. Vitamin D Catabolism.- I. Target Tissues.- I. Bone and Calcium Related.- II. Hematopoietic Cells.- III. Skin and Skin Appendages.- IV. Reproduction and Endocrine Glands.- V. Other Tissues.- J. Vitamin D Receptor.- I. Functional Role.- II. End Organ Resistance.- III. Molecular Biology.- IV. Vitamin D Response Element in Responsive Genes.- K. Genomic and Nongenomic Effects.- L. Summary.- References.- 11 Bisphosphonates: Mechanisms of Action and Clinical Use.- A. Introduction.- B. Chemistry and General Characteristics.- C. Synthesis.- D. Methods of Determination.- E. History of the Development for Use in Bone Disease.- F. Mode of Action.- I. Physicochemical Effects.- II. Effect on Calcification In Vivo.- III. Inhibition of Bone Resorption.- 1. Assessment of Activity.- 2. Activity of Various Bisphosphonates.- 3. Mechanisms of Action of Bone Resorption Inhibition.- 4. Other Effects In Vivo.- G. Pharmacokinetics.- H. Animal Toxicology.- I. Drug Interactions.- J. Clinical Use.- I. Ectopic Calcification and Ossification.- 1. Soft Tissue Calcification.- 2. Urolithiasis.- 3. Dental Calculus.- 4. Fibrodysplasia Ossificans Progressiva.- 5. Other Heterotopic Ossifications.- II. Diseases with Increased Bone Resorption.- 1. Paget’s Disease.- 2. Hypercalcemia of Malignancy and Tumoral Bone Destruction.- 3. Hyperparathyroidism and Other Causes of Hypercalcemia.- 4. Osteoporosis.- III. Other Indications.- K. Adverse Events.- L. Contraindications.- M. Future Prospects.- References.- 12 Paget’s Disease.- A. Introduction.- B. Nature of the Underlying Disease Process.- C. Epidemiology.- D. Direct Studies on the Etiology of Paget’s Disease.- E. Possible Role of Canine Distemper Virus.- F. Properties of the Osteoclast That Might Make It Particularly Susceptible to Persistent Infection with an RNA Virus.- G. Clinical Features.- I. Bones Affected and Extent.- II. Symptoms and Signs.- 1. Features Due to Long-standing Excessive Bony Remodelling.- 2. Features Due to Secondary Arthritis.- 3. Features Due to Pressure on Surrounding Structures.- 4. Neoplasia.- H. Histopathology.- I. Clinical Assessment and Investigation.- J. Treatment of Paget’s Disease.- I. Bisphosphonates (Diphosphonates).- II. Probable Mode of Action of Bisphosphonates in Paget’s Disease.- III. Future Work.- References.- 13 Hyperparathyroid and Hypoparathyroid Bone Disease.- A. Introduction.- B. Parathyroid Hormone Function: Calcium Homeostasis.- C. Classification of Parathyroid Disease.- D. Primary Hyperparathyroidism.- I. Incidence.- II. Diagnosis.- III. Pathogenesis.- IV. Nonskeletal Signs.- V. Skeletal Signs.- 1. Radiology.- 2. Histology.- 3. Bone Mass and Fracture.- VI. Human Parathyroid Hormone.- E. Secondary Hyperparathyroidism.- I. Renal Failure.- 1. Diagnosis.- 2. Pathogenesis.- 3. Skeletal Signs.- II. Vitamin D Deficient Osteomalacia/Rickets.- 1. Pathogenesis and Diagnosis.- 2. Skeletal Signs.- III. Ageing.- 1. Diagnosis and Pathogenesis.- IV. Others.- F. Tertiary Hyperparathyroidism.- G. Hypoparathyroidism.- I. Diagnosis and Pathogenesis.- 1. Nonskeletal Signs.- 2. Skeletal Signs.- References.- 14 Skeletal Responses to Physical Loading.- A. Introduction.- B. Influences on Bone Form.- C. Hierarchy of Functional Control.- D. Nature of the Loading-Related Stimulus.- E. Experimental Studies: In Vivo.- F. Experimental Studies: In Vitro.- G. Loading of Bone Cell Cultures.- H. Implications of Experiments In Vivo.- I. Implications of Experiments In Vitro.- I. Organ Culture.- J. Discussion.- K. Summary.- References.- 15 Parathyroid Hormone: Biosynthesis, Secretion, Chemistry, and Action.- A. Physiologic Actions.- I. Actions in Bone.- 1. Effects upon Osteoclasts.- 2. Effects upon Osteoblasts.- II. Actions in Kidney.- 1. Calcium Reabsorption.- 2. Phosphate Reabsorption.- 3. Other Renal Effects.- B. Biosynthesis and Secretion of PTH.- I. Parathyroid Hormone Biosynthesis.- II. Parathyroid Hormone Gene.- III. Parathyroid Hormone Secretion.- 1. Physiology.- 2. Cellular Mechanisms.- C. Structural Basis of PTH Function.- I. Parathyroid Hormone Binding and Activation Domains.- II. Evolutionary Lessons: Rat and Chicken PTH.- III. Three-Dimensional Structure of PTH.- IV. Lessons from the Structure and Activity of PTHrP.- V. Structure-Activity Relationships for Middle and Carboxyl Regions of PTH.- D. Parathyroid Hormone Receptors.- E. Second Messengers in PTH Action.- I. Cyclic AMP.- II. Other Second Messengers.- III. Physiologic Roles of Different Second Messengers in PTH Action.- IV. Second Messengers in PTH Regulation of Renal Phosphate Transport.- V. Modulation of PTH Signal Transduction.- F. Conclusion.- References.- 16 Calcitonin Gene Products: Molecular Biology, Chemistry, and Actions.- A. Introduction.- B. Calcitonin/CGRP Genes.- I. Structure of DNA.- II. Regulation of Transcription.- III. Tissue-Specific Expression of Messenger RNA.- C. Calcitonin Gene Products.- I. Biosynthesis.- II. Structure and Tissue Distribution.- III. Regulation of Release.- IV. Metabolism.- D. Biological Action.- I. Calcitonin Receptor and Targets.- 1. Receptors.- 2. Biological Targets.- II. Calcitonin Gene-Related Peptide Receptors and Targets.- 1. Receptors.- 2. Biological Targets.- III. Other Gene Products.- E. Clinical Implications.- I. Calcitonin.- II. Calcitonin Gene-Related Peptide.- F. Conclusions.- References.- 17 Parathyroid Hormone-Related Protein: Molecular Biology, Chemistry, and Actions.- A. Introduction.- B. Molecular Biology.- I. Isolation and Cloning.- II. Chromosomal Localization.- III. Genomic Structure.- IV. Regulation of Gene.- V. Recombinant PTHrP.- C. Chemistry.- I. Structure-Activity Relationships.- II. Tertiary Structure.- III. Immunology.- IV. Molecular Processing.- V. Structural Conservation.- D. Actions.- I. Second Messengers and Receptors.- II. Postreceptor Events.- III. Actions on Bone.- IV. Actions on Kidney.- E. Physiological Functions.- I. Parathyroid Hormone Related Protein as an Oncofetal Hormone.- II. Paracrine Agent in Smooth Muscle Relaxation.- III. Parathyroid Hormone Related Protein in Lactating Breast.- IV. Location in Epithelia.- V. Endocrine and Paracrine Roles.- References.- 18 Pathophysiology of Skeletal Complications of Cancer.- A. Introduction.- B. Frequency of the Skeleton as a Site for Malignant Disease.- C. Cancers Which Involve the Skeleton.- D. Favored Skeletal Sites of Malignancy.- E. Complications of the Metastatic Process.- F. Pathophysiology of the Metastatic Process.- I. Properties of Tumor Cells Which Favor Metastasis.- II. Tumor Cell Invasion at the Primary Site.- 1. Adhesion.- 2. Secretion of Enzymes.- 3. Cell Motility.- III. Tumor Cells in the Bloodstream.- IV. Tumor Cell Arrest at the Metastatic Site.- V. Growth Regulatory Factors at Metastatic Sites.- G. Potential Mechanisms for the Metastatic Process in Bone.- I. Chemotactic Factors.- II. Growth Regulatory Factors.- III. Calcium.- IV. Proteolytic Enzymes.- H. Factors Which May Be Involved in Osteolysis.- I. Parathyroid Hormone Related Protein.- II. Transforming Growth Factor a.- III. Transforming Growth Factor ?.- IV. Prostaglandins of the E Series.- V. Parathyroid Hormone.- VI. Vitamin D Sterols.- VII. Platelet-Derived Growth Factor.- VIII. Procathepsin D.- IX. Bone-Resorbing Cytokines.- I. Factors Involved in Osteoblastic Effects.- I. Transforming Growth Factor ?2.- II. Fibroblast Growth Factor.- III. Plasminogen Activator Sequence.- References.- 19 The Proteins of Bone.- A. Introduction.- B. Collagen.- I. Structure and Synthesis of Bone Collagen.- 1. Structure of Collagens.- 2. Type I Collagen Synthesis and Secretion.- II. Disorders of Collagen Synthesis: Osteogenesis Imperfecta.- III. Markers of Collagen Metabolism.- 1. Markers of Type I Collagen Synthesis: Propeptides.- 2. Markers of Collagen Degradation.- C. Gamma-carboxyglutamic Acid Containing Proteins of Bone.- I. Gamma-Carboxy glutamic Acid (GLA).- II. Osteocalcin.- 1. Structure, Biosynthesis, and Tissular Distribution.- 2. Functional Role.- 3. Circulating Osteocalcin.- III. Matrix GLA-Protein.- D. Proteoglycans.- I. Biglycan and Decorin.- 1. Structure.- 2. Distribution.- 3. Properties and Potential Role.- II. CS-PGIII.- III. Other Proteoglycans.- E. SPARC/Osteonectin.- I. Structure.- II. Binding to Hydroxyapatite and to Other Proteins.- III. Tissular Distribution.- IV. Biological Properties and Potential Role.- V. Circulating SPARC/Osteonectin.- F. Bone RGD-Containing Proteins.- I. Bone Sialoproteins.- 1. Osteopontin.- 2. Bone Sialoprotein II.- II. Thrombospondin.- III. Fibronectin.- G. Other Proteins in Bone.- I. Proteases and Protease Inhibitors.- II. Plasma Proteins.- H. Conclusion.- References.- 20 Bone Morphogenetic Proteins.- A. Introduction.- B. Biochemistry and Molecular Biology of the BMPs.- I. In Vivo Assay System.- II. Discovery of Multiple Related Proteins.- 1. Purification from Bone.- 2. Bone Morphogenetic Protein Family.- 3. Recombinant Expression.- 4. Expression of BMPs in Other Tissues.- 5. Chromosomal Localization of the BMP Genes.- C. Activities of Individual BMP Molecules.- I. In Vivo Activities.- II. In Vitro Activities.- III. Bone Morphogenetic Proteins in Embryogenesis.- D. Clinical Utility of BMPs.- I. Clinical Indications.- II. Animal Studies.- 1. Bone-Derived Extracts.- 2. Recombinant Human BMPs.- III. Human Studies with Bone Extracts.- E. Summary.- References.