Vitamin D - 3rd Edition - ISBN: 9780123819789, 9780123819796

Vitamin D

3rd Edition

Two-Volume Set

Editors: David Feldman J. Wesley Pike John Adams
Hardcover ISBN: 9780123819789
eBook ISBN: 9780123819796
Imprint: Academic Press
Published Date: 8th June 2011
Page Count: 2144
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Vitamin D, a steroid hormone, has mainly been known for its effects on bone and osteoporosis. The current therapeutic practices expand into such markets as cancer research, pediatrics, nephrology, dermatology, immunology, and genetics. This 3e includes over 100 chapters covering everything from chemistry and metabolism to mechanisms of action, diagnosis and management, new analogs, and emerging therapies. This complete reference works is a must-have resource for anyone working in endocrinology, osteology, bone biology, or cancer research.


Bone specialists, endocrinologists, basic scientists and researchers interested in vitamin D and osteoporosis prevention.

Table of Contents

Preface to the 3rd Edition

Preface to the 2nd Edition

Preface to the 1st Edition




Relevant Lab Values in Adults and Children

Criteria for Vitamin D Deficiency: 25(OH)D Serum Levels

Approximate normal ranges for serum values in adults

Approximate normal ranges for serum values in children

Useful equivalencies of different units

Volume I

Section I: Chemistry, Metabolism, Circulation

Chapter 1. Historical Overview of Vitamin D

Discovery of the Vitamins

Discovery that Vitamin D is not a Vitamin

Isolation and Identification of Nutritional Forms of Vitamin D

Discovery of the Physiological Functions of Vitamin D

Discovery of the Hormonal Form of Vitamin D



Chapter 2. Photobiology of Vitamin D


Historical Perspective

Photobiology of Vitamin D

Role of Sunlight and Dietary Vitamin D in Bone Health, Overall Health, and Well-Being

Sunlight, Vitamin D, and Skin Cancer




Chapter 3. The Activating Enzymes of Vitamin D Metabolism (25- and 1α-Hydroxylases)


General Information Regarding Vitamin D Hydroxylases

Vitamin D3-25-Hydroxylases

25-Hydroxyvitamin D-1α-Hydroxylase

Additional Topics


Chapter 4. CYP24A1: Structure, Function, and Physiological Role


CYP24A1-Catalyzed Pathways

Structure–Function Relationships

Putative CYP24A1 Involvement in Nonclassical Systems



Chapter 5. The Vitamin D Binding Protein DBP


Vitamin D Binding Protein: Protein and Gene Structure

Functions of DBP

Conclusions and Perspectives


Chapter 6. Industrial Aspects of Vitamin D

History of Vitamin D Leading to Commercialization

Manufacture of the Provitamins

Irradiation of 7-Dehydrocholesterol and Ergosterol

Metabolite Manufacture


Dietary Requirements

Economic Aspects

Storage and Shipping


Section II: Mechanisms of Action

Chapter 7. The Vitamin D Receptor: Biochemical, Molecular, Biological, and Genomic Era Investigations


Vitamin D Biology

Discovery of the Vitamin D Receptor

VDR Research: The Biochemical Era

VDR Research: The Molecular Biological Era

VDR Research: The Genomic Era

VDR Chromosomal Gene: Structure and Molecular Regulation

Concluding Comments



Chapter 8. Nuclear Vitamin D Receptor: Natural Ligands, Molecular Structure–Function, and Transcriptional Control of Vital Genes

Ligands, Gene Targets, and Biological Actions of VDR

VDR as a Member of the Nuclear Receptor Superfamily

Molecular Structure–Function of VDR

Mechanisms of VDR-Mediated Control of Gene Expression

VDR-Mediated Control of Vital Genes in Healthful Aging and Disease Prevention

Conclusions and Perspectives



Chapter 9. Structural Basis for Ligand Activity in VDR


Crystal Structure of hVDRΔ Bound to 1,25(OH)2D3

Crystal Structure of zVDR Wild-Type LBD Bound to 1,25(OH)2D3

Structure of VDR LBD Complexed to Superagonist Ligands

Structures of VDR Complexed to 2α-Substituted Analogs

Structures of VDR with Nonsteroidal Ligands

Structures of VDR With Analogs that Induce Structural Rearrangements

Structural Basis for Vitamin D Receptor Antagonism

Structure-Based Design of Novel Superagonist Analogs



Chapter 10. Coregulators of VDR-mediated Gene Expression


Coactivators of VDR


Conclusion – Integrated Model of Coregulator Activity


Chapter 11. Target Genes of Vitamin D: Spatio-temporal Interaction of Chromatin, VDR, and Response Elements


Transcriptional Regulation by 1,25(OH)2D3

Genomic VDR-Binding Sites

VDR Target Genes

VDR Target Gene Analysis

Transcriptional Cycling




Chapter 12. Epigenetic Modifications in Vitamin D Receptor-mediated Transrepression


WINAC: a Novel VDR-Associating ATP-Dependent Chromatin Remodeling Complex

E-Box Motif Negative VDRE Mediates 1,25(OH)2D3-Induced Transrepression

Coregulator Switching at E-Box nVDREs in Ligand-Dependent Transrepression by VDR

WINAC Mediates Ligand-Induced Transrepression by VDR

1,25(OH)2D3-Dependent VDR Transrepression Involves CpG Site Methylation in the CYP27B1 Promoter

Cell-Cycle-Independent DNA Demethylation During CYP27B1 Transcriptional Derepression

MBD4 Mediates Active DNA Demethylation

MBD4 is a Downstream Mediator in PTH Signaling-Induced Transcriptional Derepression



Chapter 13. Vitamin D and Wnt/β-Catenin Signaling


WNT Signaling

Antagonism of Wnt/β-Catenin Pathway by 1,25(OH)2D3 in Colon Cancer

Wnt and 1,25(OH)2D3 in the Bone

Wnt and 1,25(OH)2D3 in the Skin



Chapter 14. Vitamin D Response Element-binding Protein


Current View of Steroid/Sterol Hormone Action

New World Primates

New World Primate-Like VItamin D Resistance in Man

Heterogeneous Nuclear Ribonucleoproteins (HNRNPS)

HNRNPS as Multi-Level, Multi-Site, cis-Binding Regulators of Gene Expression

The Estrogen Response Element Binding Protein (ERE-BP) and the Intracellular Estrogen Binding Protein (IEBP)

Compensation for the Dominant-Negative Acting, Response Element-Binding Proteins



Chapter 15. Vitamin D Sterol/VDR Conformational Dynamics and Nongenomic Actions

1α,25(OH)2-Vitamin D3 (1,25(OH)2D3) Regulation of Genomic Versus Nongenomic Signaling

Vitamin D3 Sterol (VDS) Chemistry

1,25(OH)2D3 Mediated Rapid, Nongenomic Responses

The Plasma Membrane Vitamin D Receptor

The VDR Conformational Ensemble Model

VDR Ligand Specificity: Does an Unliganded VDR Ever Exist in Vivo?


Section III: Mineral and Bone Homeostasis

Chapter 16. Genetic and Epigenetic Control of the Regulatory Machinery for Skeletal Development and Bone Formation: Contributions of Vitamin D3

Programs of Bone Formation

Nuclear Organization of the Regulatory Machinery for Bone Formation

Epigenetic Mechanism for Lineage Commitment

Gene Expression within the Three-Dimensional Context of Nuclear Architecture

Chromatin Remodeling Facilitates Bone-Specific and Vitamin-D-Mediated Promoter Accessibility and Integration of Regulatory Activities

Scaffolding of Regulatory Components for Combinatorial Control of Gene Expression

Closing Remarks



Chapter 17. Vitamin D Regulation of Osteoblast Function


Properties of Mature Osteoblasts and Osteocytes

Major Regulatory Functions of Osteoblasts and Osteocytes and Control by the Vitamin D Endocrine System

Effects of 1,25(OH)2D3 on Osteoblast Differentiation

Regulation of Intracellular Signaling Pathways by 1,25(OH)2D3

Summary and Conclusions



Chapter 18. Osteoclasts



Chapter 19. Molecular Mechanisms for Regulation of Intestinal Calcium and Phosphate Absorption by Vitamin D

An Overview of Intestinal Calcium Absorption

Critical Role of VDR in Control of Intestinal CA Absorption

Can High Vitamin D Status Increase Intestinal Calcium Absorption?

An Overview of Intestinal Phosphate Absorption



Chapter 20. The Calbindins: Calbindin-D28K and Calbindin-D9K and the Epithelial Calcium Channels TRPV5 and TRPV6

Introduction and General Considerations, the Calbindins

Localization and Proposed Functional Significance of the Calbindins

Regulation of Calbindin Gene Expression

Epithelial Calcium Channels



Chapter 21. Mineralization




Chapter 22. Vitamin D Regulation of Type I Collagen Expression in Bone


Regulation of Bone Collagen Synthesis

Molecular Mechanisms of Regulation

Conclusions and Perspectives


Chapter 23. Target Genes: Bone Proteins

Vitamin D and Skeletal Homeostasis

Exogenous and Endogenous Sources of 1,25(OH)2D3

Direct Actions of Vitamin D in Bone

Concluding Remarks


Chapter 24. Vitamin D and the Calcium-Sensing Receptor


What is the CASR?

Overview of Roles of CASR and VDR in Maintaining CA2+O Homeostasis

The CASR and VDR in Tissues Participating in CA2+O Homeostasis

The CASR and VDR in Tissues Uninvolved in CA2+O Homeostasis

Polymorphisms of the CASR and VDR and Calcium and Bone Homeostasis

Summary and Perspectives


Chapter 25. Effects of 1,25-Dihydroxyvitamin D3 on Voltage-Sensitive Calcium Channels in Osteoblast Differentiation and Morphology

Systemic and Intracellular Ca2+ Homeostasis

Voltage-Sensitive Calcium Channels

1,25-Dihydroxyvitamin D3 Actions on Voltage-Sensitive Ca2+ Channels

1,25-Dihydroxyvitamin D3-Regulated Osteoblast Differentiation

Influence of 1,25(OH)2D3 on Osteoblast Cell Survival



Section IV: Targets

Chapter 26. Vitamin D and the Kidney


Role of the Kidney in the Metabolism of 25(OH)D

Effects of Vitamin D, 25(OH)D3 and 1,25(OH)2D3 on the Renal Handling of Calcium and Phosphorus

Distribution and Regulation of Vitamin-D-Dependent Proteins in the Kidney



Chapter 27. Vitamin D and the Parathyroids


Parathyroid Hormone Biosynthesis

The Parathyroid Hormone Gene

Development of the Parathyroid and Tissue-Specific Expression of The PTH Gene

Promoter Sequences

Regulation of PTH Gene Expression



Chapter 28. Cartilage

Chondrogenesis, Endochondral Ossification, and Vitamin D

Separate Roles for 24,25(OH)2D3 and 1,25(OH)2D3 in Cartilage

Rapid Actions of Vitamin D and Nongenomic Mechanisms

Physiologic Relevance of Nongenomic Regulation of Matrix Vesicles



Chapter 29. Vitamin D and Oral Health

Introduction: The Dento-Maxillofacial Skeleton

Dental Rare Diseases and Molecular Determinants of Dental Rickets

Experimental Analysis of Dental Pathway in Experimental Models of Vitamin D Bioactivation

Specificity of Oral Bone: Potential Vitamin D Impact in Development, Periodontal Disease, and JAW Osteonecrosis

Conclusions: Facts and Hypothesis


Chapter 30. The Role of Vitamin D and its Receptor in Skin and Hair Follicle Biology


Keratinocyte Differentiation


Barrier Function

Hair Cycle

Keratinocyte Stem Cells

Pathways Important for Keratinocyte Stem Cell Function



Chapter 31. Vitamin D and the Cardiovascular System


Vitamin D and the Vasculature

Vitamin D and the Heart

Clinical Epidemiological Considerations of Vitamin D Deficiency




Chapter 32. Vitamin D: A Neurosteroid Affecting Brain Development and Function; Implications for Neurological and Psychiatric Disorders


Vitamin D Signaling in the Brain

Vitamin D Deficiency, Brain Development, and Function

Vitamin D and Neurological Disorders

Possible Neuroprotective Mechanisms of Vitamin D

Vitamin D and Neuropsychiatric Disorders



Chapter 33. Contributions of Genetically Modified Mouse Models to Understanding the Physiology and Pathophysiology of the 25-Hydroxyvitamin D-1-Alpha Hydroxylase Enzyme (1α(OH)ase) and the Vitamin D Receptor (VDR)


Mouse Models

1,25(OH)2D/VDR System and Skeletal and Mineral Homeostasis

Extraskeletal Actions of 1,25(OH)2D



Section V: Human Physiology

Chapter 34. Vitamin D: Role in the Calcium and Phosphorus Economies


Overview of the Calcium Economy

Overview of the Phosphorus Economy

Calcium and Phosphorus Absorptive Inputs

Physiological Sources of Vitamin D Activity

Optimal Vitamin D Status

Summary and Conclusions


Chapter 35. Fetus, Neonate and Infant

Overview of Calcium Metabolism in the Fetus

Animal Data Relevant to Vitamin D and the Fetus

Human Data Relevant to Vitamin D and the Fetus

Overview of Calcium Metabolism in the Neonate and Infant

Animal Data Relevant to Vitamin D and the Neonate and Infant

Human Data Relevant to Vitamin D and the Neonate and Infant



Chapter 36. Vitamin D Deficiency and Calcium Absorption during Childhood


Premature Infants

Full-Term Infants – Calcium

Vitamin D in Full-Term Infants

Toddlers and Prepubertal Children

Special Issues


Chapter 37. Adolescence and Acquisition of Peak Bone Mass


Pubertal Bone Acquisition

Vitamin D in Children and Adolescents

Vitamin D and Intermediate Endpoints of Vitamin D and Bone Metabolism

Vitamin D and Other Predictors of Calcium Retention

Vitamin D and Bone

Vitamin D and Muscle

Sex and Racial Differences

Vitamin D and Diabetes

Vitamin D, Asthma, and Influenza

Vitamin D Requirements in Adolescents

Summary and Conclusions


Chapter 38. Vitamin D Metabolism in Pregnancy and Lactation


Adaptations in Vitamin D and Calcium Metabolism

Changes in Bone Mineral Content and Density

Low Maternal Vitamin D During Pregnancy

Effect of Low Maternal Vitamin D During Lactation on the Infant

Potential Risk of High Maternal Vitamin D During Pregnancy



Chapter 39. Vitamin D: Relevance in Reproductive Biology and Pathophysiological Implications in Reproductive Dysfunction


Procreative Relevance – Animal Models

Vitamin D – Relevance in Human Reproductive Physiology


Chapter 40. Vitamin D and the Renin-Angiotensin System


The Renin-Angiotensin System

Vitamin D Regulation of the Renin-Angiotensin System

Vitamin D, Blood Pressure and Heart Disease

Vitamin D and Chronic Kidney Disease



Chapter 41. Parathyroid Hormone, Parathyroid Hormone-Related Protein, and Calcitonin

Parathyroid Hormone

Parathyroid-Hormone-Related Protein



Chapter 42. FGF23/Klotho New Regulators of Vitamin D Metabolism


Regulation of Vitamin D Metabolism

PTH–Vitamin D Axis: Key Regulator of Calcium Homeostasis

FGF23 Klotho Bone Kidney Axis: A Pathway Coordinating Phosphate and Vitamin D Homeostasis with Bone Mineralization

Relationship Beween FGF23 and PTH

Role of FGF23 in Phosphate Homeostasis

Hormonal Actions of klotho?

How Knowledge of FGF23 Regulation and Function Changes Concepts, Treatments, and Clinical Practice



Chapter 43. The Role of the Vitamin D Receptor in Bile Acid Homeostasis


Bile Acids in Physiology and Disease

VDR as a Bile Acid Receptor

Regulation of Bile Acid Synthesis by VDR

Evolution of VDR: From Bile Acid Metabolism to Mineral Homeostasis


Chapter 44. Vitamin D and Fat


Vitamin D Metabolism and Mechanism of Action

Vitamin D Deficiency and Adiposity

Vitamin D and Obesity: Clinical Implication


Chapter 45. Extrarenal 1α-Hydroxylase


Vitamin D and Granuloma-Forming Disease: a Historical Perspective

Human Diseases With Extrarenal Overproduction of Active Vitamin D Metabolites

Extrarenal Synthesis of 1,25(OH)2D in Normal Physiology and Cancer

Mechanisms for the Regulation of Extrarenal 1α-Hydroxylase

Diagnosis, Prevention, and Treatment of the Patient with Endogenous Vitamin D Intoxication

Conclusions and Future Prospects


Section VI: Diagnosis and Management

Chapter 46. Approach to the Patient with Metabolic Bone Disease


Diagnostic Evaluation





Chapter 47. Detection of Vitamin D and Its Major Metabolites


Detection of Vitamin D

Detection of 25(OH)D

Detection of 24,25(OH)2D

Detection of 1,25(OH)2D

Clinical Interpretation and Relevance of Antirachitic Sterol Measurements

Stability of 25(OH)D and 1,25(OH)2D in Serum or Plasma

Assessment of Assay Performance


Chapter 48. Bone Histomorphometry


Bone Biopsy


Assessment of Mineralization

Histological Diagnosis of Osteomalacia

Assessment of Bone Turnover

Assessment of Remodeling Balance

Assessment of Bone Structure

Future Developments


Chapter 49. Radiology of Rickets and Osteomalacia

Introduction and Historical Aspects

Vitamin D Deficiency

Renal Osteodystrophy

Renal Tubular Defects and Hypophosphatemia


Differential Diagnoses

Vitamin D Intoxication

Technical Aspects of Imaging



Chapter 50. High-Resolution Imaging Techniques for Bone Quality Assessment


X-ray Computed Tomography (CT)

Magnetic Resonance Imaging (MRI)


Chapter 51. The Role of Vitamin D in Orthopedic Surgery


Impact on Orthopedic Trauma

Impact on Pediatric Orthopedics

Impact on Total Joint Arthroplasty

Impact on Muscle Strength and Rehabilitation

Prevention and Treatment in Orthopedic Patients


Section VII: Nutrition, Sunlight, Genetics and Vitamin D Deficiency

Chapter 52. Worldwide Vitamin D Status


Vitamin D Status in North America (Including Canada and Mexico)

Vitamin D Status in South America

Vitamin D Status in Europe

Vitamin D Status in the Middle East

Vitamin D Status in Asia

Vitamin D Status in Africa

Vitamin D Status in Oceania

Multicenter and Global Studies using a Central Laboratory Facility



Risk Groups




Chapter 53. Sunlight, Vitamin D and Prostate Cancer Epidemiology


Types of Epidemiologic Studies

Subclinical Prostate Cancer is Prevalent and May Dilute Effects in Epidemiologic Studies

Prostate Cancer and the Vitamin D Hypothesis

1,25(OH)2D is Synthesized by Normal Prostate Epithelial Cells and its Synthesis is Reduced in Prostate Cancer Cells

Ecologic Studies of Sunlight and Prostate Cancer

Studies of Prostate Cancer and VDR Polymorphisms

Serological Studies of the Vitamin D Deficiency Hypothesis

Epidemiologic Studies of Sun Exposure and Prostate Cancer

Epidemiologic Studies of Calcium and Prostate Cancer



Chapter 54. Nutrition and Lifestyle Effects on Vitamin D Status


Determinants of Vitamin D Status

Factors Influencing Skin Synthesis Supplying Vitamin D

Nutrient Intake as Determinant of Vitamin D Status

Lifestyle Strategies to Improve Vitamin D Status


Chapter 55. Bone Loss, Vitamin D and Bariatric Surgery: Nutrition and Obesity


Epidemiology of Bariatric Surgery

Indications for Bariatric Surgery

Classification of Bariatric Surgery

Surgical Complications of Bariatric Surgery

Health Benefits of Bariatric Surgery

Medical Complications of Bariatric Surgery

Bone Loss After Gastric Bypass

Vitamin D Status

Calcium Malabsorption after Gastric Bypass Surgery

Evidence of Efficacy of Supplemental Vitamin D




Chapter 56. Genetics of the Vitamin D Endocrine System


Genetic Studies

Candidate Genes

Genome-wide Association Studies

Future Developments


Chapter 57. The Pharmacology of Vitamin D


Overview of the System of Vitamin D Metabolism and its Regulation

Placebo-Controlled Clinical-Trial Justification for an Optimal Serum 25(Oh)D Level

Dosage Considerations

Pharmacokinetic Principles, Volume of Distribution, Turnover and Half-Life as it Pertains to Vitamin D

Vitamin D Toxicity and Safety Issues

The Concept of a Loading Dose

Summary and Conclusions


Chapter 58. How to Define Optimal Vitamin D Status


Vitamin D Status and Bone Health in Adults and The Elderly

Vitamin D and Extra-Skeletal Health

Vitamin D and Human Health: What is The Optimal Vitamin D Status


Volume II

Section VIII: Disorders

Chapter 59. The Hypocalcemic Disorders: Differential Diagnosis and Therapeutic Use of Vitamin D


Differential Diagnosis of Hypocalcemia

Therapy for Hypocalcemia



Chapter 60. Vitamin D Deficiency and Nutritional Rickets in Children


Historical Perspective

The Epidemiology of Vitamin D Deficiency and Nutritional Rickets

Clinical Presentation

Biochemical Abnormalities

Radiologic Changes

The Growth Plate in Rickets

Treatment and Prevention

Dietary Calcium Deficiency

The Pathogenetic Spectrum of Nutritional Rickets



Chapter 61. Vitamin D and Osteoporosis

Effects of Vitamin D on the Skeleton

The Role of Vitamin D Genetic Factors in Osteoporosis and Possible Interactions with Vitamin D Therapy

Primary Fracture Prevention with Vitamin D or Calcium and Vitamin D

Secondary Fracture Prevention with Vitamin D or Calcium and Vitamin D

Effects of Active Vitamin D Analogs on Fractures

Future Directions for Vitamin D in Osteoporosis


Chapter 62. Relevance of Vitamin D Deficiency in Adult Fracture and Fall Prevention

Muscle Effects of Vitamin D

Vitamin D Modulates Fracture Risk in Two Ways: By Increasing Bone Density and Decreasing Falls

Anti-fall and Fracture Efficacy of Vitamin D

Desirable 25(OH)D Status for Optimal Musculoskeletal Health

Dosing Interval of Vitamin D and Musculoskeletal Health

How to Achieve a Serum Concentration of at Least 75 nmol/l for Musculoskeletal Health



Chapter 63. Clinical Disorders of Phosphate Homeostasis


Disorders of Phosphate Homeostasis

Disorders Related to an Altered Phosphate Load

Concluding remarks


Chapter 64. Pseudo-vitamin D Deficiency


Clinical Manifestations

Biochemical Findings

Genetic and Molecular Studies


Evolution of Pddr Under Treatment from Childhood to Adulthood



Chapter 65. Hereditary 1,25-Dihydroxyvitamin-D-Resistant Rickets


The Clinical Features of HVDRR

Mechanism of 1,25(OH)2D Action

Cellular Basis of HVDRR

Molecular Basis for HVDRR

Therapy of HVDRR


Concluding Remarks


Chapter 66. Glucocorticoids and Vitamin D

Mechanisms of GlucocorticoId Osteoporosis

Steroid Receptors and Actions in Bone

Glucocorticoids, Vitamin D, and Inflammation

Effect of Glucocorticoids on Vitamin D Metabolism

Vitamin D as Treatment for Gio



Chapter 67. Drug and Hormone Effects on Vitamin D Metabolism


Hormone Effects on Vitamin D Metabolism

Drug Effects on Vitamin D Metabolism



Chapter 68. Vitamin D and Organ Transplantation


Effects of Vitamin D on Immunity and Graft Rejection

Vitamin D Deficiency Prior to Organ Transplant

Vitamin D Deficiency Following Organ Transplant

Treatment of Post-Transplant Bone Loss with Vitamin D and Analogs



Chapter 69. Vitamin D and Bone Mineral Metabolism in Hepatogastrointestinal Diseases

Physiologic Considerations

Gastrointestinal Diseases

Pancreatic Diseases

Hepatic Diseases

Total Parenteral Nutrition


Chapter 70. Vitamin D and Renal Disease


Renal Maintenance of the Vitamin D Endocrine System

Contribution of the low 25(OH)D and 1,25(OH)2D Levels and Abnormal VDR Actions to Mineral and Skeletal Abnormalities, Renal, and Cardiovascular Damage

Safety and Efficacy of Vitamin D And 1,25(OH)2D Therapy to Improve Outcomes in Chronic Renal Failure

Adequacy of Current Recommendations to Correct Vitamin D Deficiency




Chapter 71. Idiopathic Hypercalciuria and Nephrolithiasis


Idiopathic Hypercalciuria

Genetic Hypercalciuric Rats

Current View of Human Genetic Hypercalciuria

Therapeutics of Idiopathic Hypercalciuria and Effects on Calcium Metabolism

Risk of Stone Formation Using Vitamin D Analogs



Chapter 72. Hypercalcemia Due to Vitamin D Toxicity


Forms of Exogenous Vitamin D Toxicity

Forms of Endogenous Vitamin D Toxicity

Mechanisms of Vitamin D Toxicity

Clinical Manifestations

Diagnosis of Vitamin D Toxicity

Treatment of Vitamin D Toxicity

Summary and Conclusions


Chapter 73. Vitamin D: Cardiovascular Effects and Vascular Calcification


Vitamin D Signaling In Cardiovascular Remodeling And Myocardial Function

Vitamin D Actions In Atherosclerosis And Arteriosclerosis

Vitamin D and Human Cardiovascular Disease: Compelling Epidemiology and Physiology, Emerging but Less Compelling Evidence of Interventional Benefit in 2010

Vitamin D Intoxication and Cardiovascular Calcification: Pharmacological Considerations

The Impact of Calcium, Phosphate, and Vitamin D Excesses on Smooth Muscle Matrix Vesicle Physiology and Vascular Calcification

The FGF23/Klotho/Vitamin D Axis, Nephrocalcinosis, and Cardiovascular Calcification

Vitamin D, Vascular PTH Receptor Signaling and Arteriosclerotic Calcium Accrual: Lessons Learned from Preclinical Models and Patients with End-Stage Renal Disease

Defining Cardiovascular Toxicity Thresholds for Vitamin D: Critical Clues from the Clinical Literature

Vitamin D, The Calcium-Sensing Receptor (Casr), And Cardiovascular Disease

Summary, Conclusions, and Future Directions



Section IX: Analogs

Chapter 74. Alterations in 1,25-Dihydroxyvitamin D3 Structure that Produce Profound Changes in in Vivo Activity


The Non-Calcemic Holy Grail of Vitamin D Analogs

Analogs Directed to Specific Structures




Chapter 75. Mechanisms for the Selective Actions of Vitamin D Analogs


Identification of Selective Vitamin D Analogs

The In VIVO Selectivity of Vitamin D Analogs is Determined by Multiple Protein Interactions

Concluding Remarks


Chapter 76. Analogs of Calcitriol


14-epi Analogs of 1,25(OH)2D3

Decalin Analogs

C- and D-ring Analogs

CF-ring Analogs

E-ring Analogs

Acyclic Analogs

Non-Secosteroidal Compounds



Chapter 77. Analogs for the Treatment of Osteoporosis




Clinical Comparison Between Alfacalcidol and Eldecalcitol




Chapter 78. Non-secosteroidal Ligands and Modulators


Diarylmethane Ligands

C/D-Ring Modified Ligands

Bis- and Tris-Aromatic Triols

Miscellaneous non-Secosteroids



Chapter 79. The Bile Acid Derivatives Lithocholic Acid Acetate and Lithocholic Acid Propionate are Functionally Selective Vitamin D Receptor Ligands

The Vitamin D Receptor is a Dual-Functional Receptor for Vitamin D and Bile Acids

Bile Acids and Nuclear Receptors

Development of Bile Acid Derivatives

X-Ray Crystal Structures of VDR in Complex with LCA Derivatives



Chapter 80. CYP24A1 Regulation in Health and Disease


CYP24A1: Properties, Function and Expression

Regulation of CYP24A1 mRNA Expression and Stability

Dysregulation of CYP24A1 and Role in the Pathogenesis of Human Disease

CYP24A1 Inhibitors

Conclusion and Future Directions


Chapter 81. Calcitriol and Analogs in the Treatment of Chronic Kidney Disease


Analogs of Vitamin D used in CKD

Analogs in Animal Models of Uremia

CKD Stages 3–4


Cardiovascular Disease in CKD and Different Forms of Vitamin D



Section X: Cancer

Chapter 82. The Epidemiology of Vitamin D and Cancer Risk


Overview of Epidemiologic Study Designs for the Study of Vitamin D and Cancer

Studies of 25(OH)D, Predicted 25(OH)D, Vitamin D intake and Cancer Risk by Cancer Site

Studies of Sun Exposure

Randomized Controlled Trials


Summary and Synthesis of The Epidemiology of Vitamin D and Cancer


Chapter 83. Vitamin D: Cancer and Differentiation


Vitamin D and Cancer

Vitamin D Effects on Tumor Cells

Combination Therapy

Resistance and Vitamin D Metabolism

Stimulation of Proliferation



Chapter 84. Vitamin D Effects on Differentiation and Cell Cycle


Induction of Differentiation by 1,25(OH)2D3 and its Analogs

Cell Cycle Consequences of Vitamin-D-Induced Differentiation

Cell-Type Specificity of Inhibition of Cell Proliferation by Vitamin D and Analogs without Evidence of Differentiation




Chapter 85. Vitamin D Actions in Mammary Gland and Breast Cancer


Vitamin D Actions on Breast Cancer Cells in Vitro

Determinants of Breast Cancer Sensitivity to Vitamin D

Vitamin D Metabolites and Analogs: Preclinical and Clinical Trials

Vitamin D and Prevention of Breast Cancer

Summary and Outstanding Research Questions


Chapter 86. Vitamin D and Prostate Cancer


Prostate as a Target for Vitamin D

Vitamin D and Inhibition of Prostate Cancer Growth

Vitamin D Analogs and Prostate Cancer

Mechanisms of the Anti-Cancer Actions of Calcitriol

The Role of Calcitriol in Prostate Cancer Chemoprevention

Calcitriol in Combination with other Agents

Clinical Trials

Summary and Conclusions


Chapter 87. The Vitamin D System and Colorectal Cancer Prevention

Colorectal Cancer Epidemiology and Pathogenesis

Vitamin D and Colorectal Cancer Pathogenesis

Colonic Synthesis of 1,25(OH)2D3

Regulation of CYP27b1 and of CYP24a1 Expression by Nutrition



Chapter 88. Hematological Malignancy


Overview of Hematopoiesis

Effects of Vitamin D Compounds on Normal Hematopoiesis

Effects of Vitamin D Compounds in Leukemic Cells

Vitamin D Analogs Activity Against Leukemic Cells



Chapter 89. Vitamin D and Skin Cancer

Two Sources of Vitamin D: Diet or Sunlight

Vitamin D and Indoor Tanning

UV Exposure Contributes to NMSC and Melanoma Development

Vitamin D and Visceral Cancer Risk and its Potential Role in Reducing Skin Cancer Risk

Role of Vitamin D in Keratinocytes

Role of Vitamin D in Squamous Cell Carcinomas (SCC)

Role of Vitamin D in Basal Cell Carcinomas (BCC)

Role of Vitamin D in Melanomas

Photoprotection and Vitamin D Levels



Chapter 90. The Anti-tumor Effects of Vitamin D in Other Cancers


Thyroid Cancer

Bone and Soft Tissue Sarcomas


Gastro-Esophageal Cancers

Lung Cancers

Hepatocellular Carcinoma (HCC)

Bladder Cancer


Head and Neck

Renal Cell Carcinoma

Pancreatic Cancer



Section XI: Immunity, Inflammation, and Disease

Chapter 91. Vitamin D and Innate Immunity

Introduction and Historical Background

VDR Gene Polymorphisms and Infectious Diseases

Molecular Events Underlying Innate Immune Regulation by Vitamin D

Physiological and Pathophysiological Ramifications of 1,25(OH)2D3-Regulated Camp Expression

Conclusions and Future Directions


Chapter 92. Control of Adaptive Immunity by Vitamin D Receptor Agonists


Vitamin D Receptor Agonists as Immunoregulatory Agents

Dendritic Cells as Targets for Immunoregulation by VDR Agonists

Induction of Tolerogenic Dendritic Cells by VDR Agonists

Modulation of T and B Lymphocytes by VDR Agonists

Vitamin D Deficiency in Autoimmune Diseases

Mechanisms for the Immunomodulatory Effects Of VDR Agonists in Autoimmune Diseases


Chapter 93. The Role of Vitamin D in Innate Immunity: Antimicrobial Activity, Oxidative Stress and Barrier Function

Innate Immunity

Immune Activity of 1,25-Dihydroxyvitamin D

Vitamin D Pathway and Tuberculosis

History of Vitamin D, Sunshine, and Tuberculosis


Chapter 94. Vitamin D and Diabetes


Vitamin D and the Beta Cell

Vitamin D and the Immune System in Type 1 Diabetes

Vitamin D and Genetic Predisposition to Diabetes

Clinical Perspectives


Chapter 95. Vitamin D and Multiple Sclerosis

The Vitamin D–Multiple Sclerosis Hypothesis

Original Evidence Underlying the Vitamin D–Multiple Sclerosis Hypothesis

Multiple Sclerosis Etiology and the Association with Vitamin D

Genetic Evidence Linking Vitamin D and Multiple Sclerosis

Experimental Autoimmune Encephalomyelitis, A Multiple Sclerosis Model

Vitamin D and Prevention of EAE

Mechanisms of EAE Prevention

Vitamin D Amelioration of Established EAE

Mechanisms of EAE Amelioration

Multiple Sclerosis, Pregnancy, and Immune Tolerance

Vitamin D, Estrogen, EAE, and Multiple Sclerosis

Vitamin-D-Based Therapy of Multiple Sclerosis

Conclusions and Future Research Directions



Chapter 96. Vitamin D and Inflammatory Bowel Disease


What is IBD?

Who Gets IBD?

The “Hygiene Hypothesis”

The “Vitamin D Hypothesis”

The Immune Response and IBD

Vitamin D Regulates T Cell Responsiveness

Experimental Models of IBD

Current Treatments for IBD

Vitamin D as a Treatment Option for IBD


Chapter 97. Psoriasis and Other Skin Diseases

Introduction/Historical Overview

Pathogenesis of Psoriasis

The Vitamin D System in Normal and Psoriatic Skin

Physiological and Pharmacological Actions of Vitamin D Analogs in Normal and Psoriatic Skin

Clinical use of Calcitriol in Psoriasis

Vitamin D Analog Therapy in Other Skin Diseases



Section XII: Therapeutic Applications and New Advances

Chapter 98. The Role of Vitamin D in Type 2 Diabetes and Hypertension

Epidemiology and Burden of Type 2 Diabetes and Hypertension

Biologic Plausibility of an Association Between Vitamin D and Type 2 Diabetes and Hypertension

Evidence from Human Studies for a Link Between Vitamin D and Type 2 Diabetes

Evidence from Human Studies for a Link Between Vitamin D and Hypertension

Summary of Evidence from Human Studies on Type 2 Diabetes and Hypertension and Limitations in the Study of Vitamin D

Optimal Intake of Vitamin D in Relation to Type 2 Diabetes and Hypertension



Chapter 99. Vitamin D Receptor Agonists in the Treatment of Benign Prostatic Hyperplasia

Benign Prostatic Hyperplasia: an Introduction

Pathogenesis of BPH

Medical Treatment for BPH

Vitamin D Receptor Agonists Control Prostate Cell Growth

Vitamin D Receptor Agonists and BPH-Related Luts

Vitamin D Receptor Agonists Inhibit Intraprostatic Inflammation

Vitamin D Receptor Agonists Modulate Prostatic Urethra Dysfunction

Concluding Remarks


Chapter 100. Sunlight Protection by Vitamin D Compounds


UV-Induced DNA Damage and Repair

UV-Induced Immune Suppression


Local Production of Vitamin D Metabolites in Skin

Vitamin D Compounds and Photoprotection

Mechanisms of Photoprotection

Perspectives on Future Use of Vitamin D Compounds for Sun Protection


Chapter 101. The Role of Vitamin D in Osteoarthritis and Rheumatic Disease


Hyaline Cartilage in OA

Bone Health and OA

The Synovium

Vitamin D Receptor (VDR) Genotype and OA Progression

Vitamin D Status and OA Progression

Rheumatoid Arthritis

Systemic Lupus Erythematosus (SLE)

Psoriatic Arthritis (PsA)



Chapter 102. Vitamin D and Cardiovascular Disease


Components of Direct Cardiovascular Effects

Components of Indirect Cardiovascular Effects

Cardio- and Cerebrovascular Mortality as Endpoint in Observational and Interventional Studies

Clinical Cardiovascular Outcomes in Observational and Randomized Interventional Studies

Situation in Patients With Chronic Kidney Disease or on Hemodialysis

Summary and Conclusions


Chapter 103. Vitamin D, Childhood Wheezing, Asthma, and Chronic Obstructive Pulmonary Disease


Common Respiratory Disorders

Vitamin D and Respiratory Infection

Vitamin D and Asthma

Vitamin D and COPD

Potential Mechanisms

Future Research on Vitamin D and Respiratory/Allergic Disorders




Chapter 104. Vitamin D and Skeletal Muscle Function



Physical Performance


Muscle Morphology

Molecular Mechanisms of Action

VDR Knockout Mouse Model

VDR Polymorphisms




Chapter 105. The VITamin D and OmegA-3 TriaL (VITAL): Rationale and Design of a Large-Scale Randomized Controlled Trial


Biology of Vitamin D and Proposed Mechanisms for Lowering Cancer and CVD Risk

Current Evidence on Vitamin D and Risk of Cancer and CVD

Rationale for VITAL

Rationale for the Selected Vitamin D Dose in VITAL

Core Aspects of Trial Design

Trial Eligibility

Recruitment, Enrollment, Run-in and Randomization

Characteristics of Participants in VITAL

Detailed Assessment of Dietary and Supplement Intake in VITAL

Blood Collections in VITAL

Follow-up and Enpoint Determination Procedures

Monitoring of Compliance

Trial Monitoring and Safety

Statistical Power

Vital Value: Ancillary Studies and Establishment of a Clinical and Translational Science Center Sub-Cohort

Key Points


Color Plates

Color Plates



No. of pages:
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About the Editor

David Feldman

David Feldman, MD, is Emeritus Professor of Medicine (Active) at Stanford University School of Medicine where he has been on the faculty since 1974. He has been a full professor since 1984 and was chief of the Endocrinology Division for 10 years. His laboratory studies the role of steroid hormone receptors, particularly the vitamin D receptor, and its mechanism of action. His current major research focus is hormone-dependent cancer including breast cancer and prostate cancer and the pathways by which vitamin D inhibits cancer growth. Professor Feldman is actively involved in both basic science approaches to the anti-cancer actions of vitamin D as well as to clinical trials studying the use of vitamin D in breast and prostate cancer. Professor Feldman was recently honored with an award for a Career of Outstanding Contributions to Vitamin D Research. He has authored over 290 medical research articles, reviews, editorials, and book chapters. In addition to being a co-editor of all four editions of OSTEOPOROSIS, he is the editor-in-chief of Vitamin D, just published in its third edition.

Affiliations and Expertise

Emeritus Professor of Medicine, Stanford University School of Medicine, Stanford, California, USA

J. Wesley Pike

Dr. Pike’s laboratory is focused on the molecular mechanisms whereby vitamin D, the sex steroids, and other systemic hormones regulate the production as well as cellular activity of bone-forming osteoblasts and bone-resorbing osteoclasts. A long-term area of interest has been in the actions of vitamin D. His laboratory has shown that these actions are mediated by a specific receptor that is localized to the nucleus of target cells and which functions as a transcription factor following activation by its hormonal vitamin D ligand. This research led to the molecular cloning of this factor and elucidation of its regulation and mechanism of action.

Affiliations and Expertise

Professor, Department of Biochemistry, University of Wisconsin, Madison, USA

John Adams

Affiliations and Expertise

Vice Chair for Research, UCLA-Orthopaedic Hospital Department of Orthopaedic Surgery Director, Orthopaedic Hospital Research Center, University of California, Los Angeles


"In this brief review, it is impossible to cover all the nuances of vitamin D addressed in this book. Interested readers may want to peruse the book chapters to assess relevance to their personal interests. I regard this impressive text as a ‘‘must have’’ in the medical libraries of most hospitals. Clinicians and researchers with an interest in vitamin D may want their own personal copy for ready reference. I highly recommend it and congratulate the authors and editors in providing a much needed reference text on arguably one of the more important nutrients to our species."--American Journal of Human Biology

"In this remarkable compendium, the editors provide a fresh and comprehensive review of a multifaceted and sometimes controversial vitamin D. This third edition is not just an update, but a greatly expanded work organized to authoritatively cover the evidence for new roles of vitamin D in cardiovascular health, immunity, psychiatric disorders, and much more. In more than 100 chapters, experts span the history of vitamin D, update its molecular mechanism and chemistry, provide specifics of clinical use in disorders of the skeleton, and review progress in an array of diseases including diabetes, inflammatory bowel disease, multiple sclerosis, and psoriasis. In this edition one finds new information for a broad audience including internal medicine, nutrition, orthopedics, basic scientists, and teachers. How does one define optimal vitamin D status? How does vitamin D affect innate immunity? What are the epigenetic modifications of the vitamin D receptor that contribute to its function? Are there other natural ligands for the vitamin D receptor? These are a part of the new increased scope of Vitamin D, Third Edition. If you are interested in vitamin D, you should have this book."

—Mark S. Nanes, MD, PhD, Professor of Medicine, Emory University, Atlanta, GA, USA

"The Third Edition of the classic text Vitamin D is a superb summary of an important and topical issue. Its contributors are truly experts in the field and they have managed to comprehensively describe the biochemistry, pharmacology and effects of vitamin D as well as to eloquently weave in the relevant biology of bone, muscle, immunology and other relevant tissues. The 105 readable chapters offer a complete and well balanced mix of basic and clinical topics that provides an opportunity to understand the full breadth of vitamin D action. Each section represents an excellent summary of up-to-date information and, as a whole, this text offers an outstanding resource that will appeal to a broad spectrum of readers – from students to established clinicians and investigators."

—Eric Orwoll, MD, Department of Medicine, Division of Endocrinology, Diabetes, and Clinical Nutrition, Oregon Health and Science University, Portland, OR, USA

"The Third Edition of Vitamin D is well written, comprehensive and balanced. Several of the new chapters, such as Epigenetic Modifications and Wnt/ß-Catenin Signaling, have strayed away from the "traditional" vitamin D but the authors have put these topics very clearly into perspective in ways that will be valuable to those studying vitamin D action. The overall list of authors for this book is a virtual '"who's who" of vitamin D research, and the coverage of the topic is appropriately broad, including those matters in nutrition and epidemiology that have been the subject of much interest in recent years."

—T. Jack Martin, AO MD DSC FRACP FRCPA FAA FRS, John Holt Fellow, Emeritus Professor of Medicine
Bone, Joint & Cancer Unit, St Vincent's Institute, Victoria, Australia

Ratings and Reviews