Bone Regulators and Osteoporosis Therapy

Preface
Contents
The Cells of Bone and Their Interactions
1 Osteoclasts
2 The Osteoblast Lineage and Matrix-Producing Osteoblasts
3 Osteocytes
4 The Process of Bone Mineralization: Control by Osteoblasts and Osteocytes
5 Chondrocytes
6 Osteogenesis and Bone Modeling
7 Bone Remodeling
8 Coupling Factors: Signals Between Osteoclasts and the Osteoblast Lineage
9 RANKL/OPG as an Example of Signals from the Osteoblast Lineage to Osteoclasts
10 Signals Within the Osteoblast Lineage Regulate Bone Formation
11 Interactions Between Bone Cells and Other Cells and Tissues in and Beyond Bone
References
PTH and PTHrP Actions on Bone
1 Introduction
2 Receptors and Second Messenger Systems for PTH and PTHrP
3 Expression and Actions of PTHR in Bone
3.1 Effects of PTH and PTHrP on Bone Cells
3.1.1 Molecular Mechanisms of Action in Osteoblasts
3.1.2 Adaptor Proteins
4 Conclusion
References
Vitamin D and Bone
1 The Vitamin D Endocrine System: Metabolism and Molecular Mechanism of Action
2 Effect of Vitamin D on Calcium Homeostasis
2.1 Intestine
2.2 Kidney
2.3 Bone
2.3.1 1,25(OH)2D3 and Bone Metabolism During a Positive Calcium Balance
Stage-Dependent Inactivation of Vdr Expression in Osteoblast-Lineage Cells Points to a Minor Role of Osteoblastic Vdr Expressi...
Vdr Signaling in Growth Plate Chondrocytes Transiently Regulates Bone and Phosphate Homeostasis
Stage-Specific Deletion of Osteoclastic Vdr Expression Does Not Manifestly Affect Bone Homeostasis
2.3.2 1,25(OH)2D3 and Bone Metabolism During a Negative Calcium Balance
3 Vitamin D and Bone Health
4 Conclusion
References
Gonadal Hormones and Bone
1 Overview of the Effects of Estrogens and Androgens on Bone
1.1 Postmenopausal Osteoporosis
1.2 Male Osteoporosis
2 Gonadal Hormones and Bone Cells
2.1 Estrogen Receptors and Bone Cells
2.2 Effects of Estrogens on Osteoblasts, Osteocytes, and Bone Formation
2.3 Effects of Estrogens on Osteoclasts and Bone Resorption
2.4 Effects of Androgens on Bone Cells
3 Genetic Effects of Gonadal Hormones
3.1 Genetic Effects of Estrogens and Androgens
3.2 The Role of Gonadal Hormones on Osteoblastic Gene Expression
3.2.1 Estrogen-Regulated Genes via ERα in Osteoblasts (Table 1)
3.2.2 Estrogen-Regulated Genes via ERβ in Osteoblasts
3.2.3 Androgen-Regulated Genes via AR in Osteoblasts (Table 2)
3.3 The Effects of Gonadal Hormones on Osteoclastic Gene Expression
3.3.1 Estrogen-Regulated Genes in Osteoclasts (Table 3)
3.3.2 Androgen-Regulated Genes in Osteoclasts (Table 4)
4 Pharmacologic Approach to Estrogen and Androgen Deficiency on Bone
4.1 Overview of Osteoporosis Treatment in Elderly Patients with Gonadal Hormone Deficiency
4.2 Selective Androgen Receptor Modulators (SARMs)
4.3 Estrogen Replacement Therapy and the Women´s Health Initiative
4.4 Selective Estrogen Receptor Modulators (SERMs)
References
Thyroid Hormones, Glucocorticoids, Insulin, and Bone
1 Thyroid Hormones and Bone
1.1 Cellular and Nuclear Actions of Thyroid Hormones
1.2 Thyroid Hormone Resistance Syndromes
1.3 Bone Disease in Thyroid Dysfunction Syndromes
1.3.1 Hyperthyroidism
1.3.2 Hypothyroidism
2 Glucocorticoids and Bone
2.1 Introduction
2.2 Subcellular Actions
2.3 Cellular and In Vitro Effects of Corticosteroids
2.3.1 Osteoblasts
2.3.2 Osteoclasts
2.3.3 Osteocytes
2.4 Animal Studies and Tissue-Level Effects
2.5 Clinical Data
2.5.1 Endogenous Hypercortisolism
2.5.2 Autonomous Cortisol Secretion
2.5.3 Endogenous Differences in GC Metabolism
2.5.4 Exogenous Glucocorticoid Excess
3 Insulin and Bone
3.1 The Relationship Between Glucose and Bone Metabolism at the Cellular Level
3.2 The Relationship Between Glucose and Bone Metabolism at Clinical Level
References
Growth Factors, Carrier Materials, and Bone Repair
1 Introduction
2 Bone Healing, Growth Factors, and Bone Grafts
2.1 The Bone Healing Cascade
2.2 Grafts for Surgical Augmentation of Bony Healing
3 Growth Factors Involved in Bone Regeneration
3.1 BMP-2
3.2 BMP-7
3.3 BMP-6
3.4 FGFs
3.5 PDGF
3.6 Other Growth Factors with Clinical Potential
3.7 Combination Growth Factor Delivery for Bone Regeneration
3.8 Spatiotemporal Growth Factor Delivery Considerations
4 Scaffolds for Bone Regeneration
4.1 Metals
4.2 Ceramics
4.3 Polymers
4.4 Composites
4.5 Bioactive Components and Delivery
5 Conclusion
References
Prostaglandins and Bone
1 Introduction
2 PGE2 Production
3 PGE2 Receptors
4 Bone Remodeling and PGE2
5 Skeletal Phenotypes of Mice with COX-2 Deficiency
6 COX-2 and PTH: A Special Relationship
7 Effects of NSAIDS on Bone
8 Summary
References
Cytokines and Bone: Osteoimmunology
1 Receptor Activator of Nuclear Factor-κB Ligand (RANKL), Receptor Activator of Nuclear Factor-κB (RANK), and Osteoprotegerin ...
2 Colony-Stimulating Factor-1 (CSF-1)
3 Additional Colony Stimulating Factors
4 Interleukin-1 (IL-1)
5 Tumor Necrosis Factor (TNF)
6 Additional TNF Superfamily Members
6.1 Fas-Ligand (FasL)
6.2 TNF-Related Apoptosis-Inducing Ligand (TRAIL)
6.3 CD40 Ligand (CD40L)
7 Interleukin-6 (IL-6)
8 Additional Interleukin-6 Family Members
8.1 Interleukin-11 (IL-11)
8.2 Leukemia Inhibitory Factor (LIF)
8.3 Oncostatin M (OSM)
9 Interleukin-7 (IL-7)
10 Interleukin-10 (IL-10)
11 Interleukin 12 (IL-12), Interleukin 23 (IL-23), Interleukin 27 (IL-27), and Interleukin 35 (IL-35)
12 Interleukin 15 (IL-15)
13 Interleukin 17 (IL-17) and Interleukin 25 (IL-25)
14 Interleukin 18 (IL-18), Interleukin 33 (IL-33), and Interleukin 37 (IL-37)
15 Interferons (INF)
16 Additional Cytokines
References
Chemokines and Bone
1 Overview of Bone Remodeling
2 Osteoimmunology
3 Chemokines and Chemokine Receptors
References
Calcium and Bone
1 Introduction
2 Calcium Distribution
3 Calcium Homeostasis
4 Intestinal Calcium Absorption
5 Vitamin D Metabolism
6 Dietary Calcium Requirement
6.1 Calcium Balance Studies
6.2 Bone Balance Studies
6.3 Determining Requirement: Calcium or Bone Balance?
7 Studies of Calcium Supplementation
7.1 Biochemical Effects
7.2 BMD Effects
7.3 Fracture Effects
8 Calcium Intake in Children
9 Non-bone Effects of Calcium
9.1 Gastrointestinal
9.2 Renal Calculi
9.3 Cardiovascular Disease
10 Conclusions
References
FGF23 and Bone and Mineral Metabolism
1 Phosphate Metabolism and Rickets/Osteomalacia
2 Discovery and Cloning of FGF23
3 Actions of FGF23 in the Kidney
4 FGF Receptors
5 A Receptor for FGF23
6 Regulation of FGF23 Production
7 FGF23 and Hypophosphatemic Diseases
7.1 XLH
7.2 ADHR
7.3 Autosomal Recessive Hypophosphatemic Rickets (ARHR) 1, 2
7.4 Hypophosphatemic Disease with Dental Anomalies and Ectopic Calcification
7.5 Osteoglophonic Dysplasia, Jansen-Type Metaphyseal Chondrodysplasia, and McCune-Albright Syndrome/Fibrous Dysplasia
7.6 Other Genetic Hypophosphatemic Diseases
7.7 TIO
7.8 Intravenous Iron Administration
7.9 Other FGF23-Related Hypophosphatemic Diseases
8 Treatment of FGF23-Related Hypophosphatemic Diseases
9 FGF23 and Hyperphosphatemic Tumoral Calcinosis
10 FGF23 and Chronic Kidney Disease-Mineral and Bone Disorder (CKD-MBD)
11 Klotho-Independent Actions of FGF23
12 Concluding Remarks
References
The Central Regulation of Bone Mass: Genetic Evidence and Molecular Bases
1 Introduction: Why Should Bone Have a Coordinating Role?
2 Leptin Is a Negative Regulator of Bone Mass Accrual
2.1 Bone Mass Increases in the Absence of Leptin Signaling
2.2 Leptin Action on Bone Mass Accrual Is Independent of its Effect on Body Weight
3 Mechanism of the Regulation of Bone Remodeling by Leptin
3.1 Leptin Regulates Bone Remodeling by a Central Mechanism
3.2 Leptin Regulates the Bone Through a Serotonin Relay
3.3 Leptin Regulation of Bone Mass Accrual Is Mediated by Serotonin Signaling to VMH Neurons Via the Htr2c Receptor
4 Establishing the Efferent Mediators of the Central Regulation of Bone Remodeling by Leptin
4.1 Sympathetic Tone Mediates Regulation of Bone Formation and Resorption by Leptin
4.2 A Second Potential Leptin Mediator: Leptin Regulation of Cart Expression in the Hypothalamus Affects Bone Resorption
5 Leptin Actions on Bone Remodeling as Related to Human Bone Biology
References
Genetics of Skeletal Disorders
1 Introduction
2 Genetics of Bone and Mineral Disorders
2.1 Inheritance
2.2 Genetic Heterogeneity
2.3 Molecular Insights from Monogenic Disorders and Polygenic Traits
2.4 Genes and Pathways as Therapeutic Targets
3 Approach to the Patient with Genetic Bone and Mineral Disease
3.1 Clinical Approach
3.2 Medical History and Physical Examination
3.3 Family History and Mode of Disease Inheritance
4 Overview of Genetic Tests
4.1 Clinical Value of Genetic Testing
4.2 Pretest Considerations
4.3 Detection of Chromosomal Abnormalities, Copy Number Variations (CNVs), and Mutations Causing Disease
4.3.1 Karyotype
4.3.2 Fluorescence In Situ Hybridization (FISH)
4.3.3 Multiplex Ligation-Dependent Probe Amplification (MLPA)
4.3.4 Array-Based Screening
4.3.5 DNA Sequence Analysis
4.4 Assessment of Variant Pathogenicity
4.5 Special Circumstances for Genetic Testing
4.5.1 Genetic Tests for Mosaicism
4.5.2 Genetic Tests for Prenatal Diagnosis
4.6 Informed Consent and Ethical Considerations
5 Conclusions
References
Pathogenesis of Osteoporosis
1 Introduction to Bone Turnover: Cells and Regulators
2 Increased Osteoclastogenesis and Osteoclast Activity in Osteoporosis
3 Regulation of RANK Signaling and Bone Resorption
4 Decreased Osteoblastogenesis and Bone Formation in Osteoporosis
5 Osteocytes: Bone Endocrine Cells as Emerging Regulators in the Pathogenesis of Osteoporosis
6 Marrow Fat and Osteoporosis: Marrow Fat Infiltration and Compromised Bone Remodeling
7 Conclusions
References
Structural and Metabolic Assessment of Bone
1 Introduction
2 Noninvasive Measurement of Bone Mineral Density
2.1 Radiographs
2.2 Absorptiometry
2.3 Fracture Risk Assessment Tool (FRAX)
2.4 Trabecular Bone Score (TBS)
2.5 Quantitative Ultrasound
2.6 Quantitative Computed Tomography (QCT) and Peripheral QCT (pQCT)
2.7 High-Resolution Peripheral QCT (HRpQCT)
2.8 Magnetic Resonance Imaging (MRI)
3 Invasive Techniques to Measure Structure: Bone Biopsy
3.1 Impact Microindentation
4 Metabolic Assessment of Bone
4.1 Metabolic Assessment: Laboratory Assessment of Systemic Factors Causing Bone Loss
4.2 Metabolic Assessment of Bone: Invasive Techniques
4.3 Noninvasive Assessment of Bone Formation and Resorption
4.4 Bone Formation Markers
4.5 Bone Resorption Markers
4.6 Potential of Serum Sclerostin
5 Conclusions
References
Osteoporosis Therapeutics 2020
1 Introduction
2 Osteoporosis Therapeutics: Clinical Outcomes, Effects on Bone Tissue, and Material Quality
2.1 Background of Osteoporosis and the Influence of Osteoporosis Therapeutics on Bone Tissue/Material Quality
2.2 Effects of Antiresorptive Agents
2.2.1 Raloxifene and Hormone Replacement Therapy (HRT)
2.2.2 Bisphosphonates
2.2.3 Denosumab
2.3 Effects of Anabolic Agents
2.3.1 Teriparatide and Abaloparatide
2.3.2 Romosozumab
3 Management of Osteoporosis 2020
3.1 Review of Osteoporosis Guidelines
3.2 Glucocorticoid-Induced Osteoporosis (GIOP)
3.3 Osteoporosis Therapeutics After Fracture
3.4 Osteonecrosis of the Jaw (ONJ)
3.5 Atypical Femoral Fractures (AFFs)
3.6 Adherence to Osteoporosis Therapeutics
4 Conclusion
References
Reduced Bone Modeling and Unbalanced Bone Remodeling: Targets for Antiresorptive and Anabolic Therapy
1 Introduction
2 Antiresorptive Therapy
3 Anabolic Therapy
3.1 Primarily Remodeling-Based Anabolic Agents
3.1.1 Teriparatide (PTH 1-34)
3.1.2 Abaloparatide
3.2 Modeling-Based Anabolic Therapy
3.2.1 Romosozumab
4 First-Line Therapy: Antiresorptive, Anabolic, Combined, or Sequential?
4.1 Combining Antiresorptive and Anabolic Agents
4.2 Sequential Therapy
4.2.1 Anabolic to Antiresorptive
4.2.2 Antiresorptive to Anabolic
5 Are We There Yet?
References
New Targets and Emergent Therapies for Osteoporosis
1 Overview
2 Existing Osteoporosis Therapies
3 Historical Failures
4 Improving Existing Osteoporosis Treatments
5 Activating Osteoblasts During Anabolic Therapy
6 Trabecular Bone Expansion with Prolonged Anabolic Therapy
7 The Bone Mechanostat
8 Additional WNT Signaling Targets
9 Understanding Anabolic Signaling Pathways
10 Animal Models
11 Human: Rodent Protein Differences
12 Identifying Novel Osteoporosis Drug Targets and Pathways
13 Targeting Drugs to Bone
14 Evolving Advances in Drug Delivery
15 Summary and Future Prospects
16 Research Resources
References
Drugs Causing Bone Loss
1 Introduction
2 Methods
3 Drugs Causing Bone Loss Ordered by ATC Code, and Thus Organ System
3.1 The Alimentary System
3.1.1 Proton Pump Inhibitors (PPI)
3.1.2 Drugs Against Diabetes
3.1.3 Vitamin A
3.2 Blood
3.2.1 Anticoagulants (Heparin and Vitamin K Antagonists)
3.3 Circulation
3.3.1 Diuretics
3.3.2 Statins
3.4 Dermatology
3.4.1 Topical Corticosteroids
3.5 Sex Steroids
3.5.1 Depot Medroxyprogesterone Acetate (DMPA)
3.5.2 Oral Contraceptives
3.6 Systemic Hormones
3.6.1 Glucocorticoids (Except Budesonide)
3.6.2 Thyroid Hormones
3.7 Infectious Diseases
3.7.1 Antiviral Therapy in Human Immunodeficiency Virus (HIV)
3.8 Chemotherapy
3.8.1 Cytotoxic Drugs
3.8.2 GnRH Agonists (Gonadotropin Releasing Hormone Agonists)
3.8.3 Antiandrogens
3.8.4 Aromatase Inhibitors
3.8.5 Selective Estrogen Receptor Modulators (SERM)
3.9 Muscles and Joints
3.9.1 Non-steroidal Anti-inflammatory Drugs (NSAID)
3.9.2 Paracetamol (Acetaminophen)
3.10 Nervous System
3.10.1 Opioids
3.10.2 Drugs Against Epilepsy
3.10.3 Neuroleptics
3.10.4 Antidepressants
3.10.5 Sedatives
3.11 Respiratory
3.11.1 Inhaled Corticosteroids and Beta Agonists
References
Natural Products as Potential Bone Therapies
1 Introduction
2 Classification of Bone Protective Natural Products
3 Biological Activities and Associated Mechanisms
3.1 Estrogen and Estrogen Receptor (ER) Signalling
3.1.1 Natural Compounds
3.1.2 Herbal Extracts
3.1.3 Chinese Medicine Formula
3.2 Calcium Balance and Vitamin D Metabolism
3.3 Local Regulation of Bone Activities
3.3.1 Osteogenesis
3.3.2 Osteoclastogenesis
3.3.3 Adipogenesis
3.4 Novel Mechanisms: Metabolomics and Gut Microbiota
3.4.1 Metabolomics
3.4.2 Gut Microbiota
4 Conclusions
References