Vitamin D (eBook)

e9780123819789v1.pdf 1
Front Cover 1
Vitamin D 4
Copyright 5
Contents 6
Preface to the 3rd Edition 10
Preface to the 2nd Edition 12
Preface to the 1st Edition 14
Contributors 16
Introduction 22
Abbreviations 24
Relevant Lab Values in Adults and Children 30
Criteria for Vitamin D Deficiency: 25(OH)D Serum Levels 30
Approximate normal ranges for serum values in adultsaaNormal ranges differ in various laboratories and these values are pro ... 31
Approximate normal ranges for serum values in childrena 31
Useful equivalencies of different units 31
Section I -Chemistry, Metabolism, Circulation 32
Chapter 1 - Historical Overview of Vitamin D 34
Discovery of the Vitamins 34
Discovery that Vitamin D is not a Vitamin 35
Isolation and Identification of Nutritional Forms of Vitamin D 36
Discovery of the Physiological Functions of Vitamin D 36
Discovery of the Hormonal Form of Vitamin D 37
Acknowledgments 40
References 40
Chapter 2 - Photobiology of Vitamin D 44
Introduction 44
Historical Perspective 44
Photobiology of Vitamin D 45
Role of Sunlight and Dietary Vitamin D in Bone Health, Overall Health, and Well-Being 48
Sunlight, Vitamin D, and Skin Cancer 49
Conclusion 51
Acknowledgment 51
References 51
Chapter 3 - The Activating Enzymes of Vitamin D Metabolism (25- and 1a-Hydroxylases) 54
Introduction 54
General Information Regarding Vitamin D Hydroxylases 54
Vitamin D3-25-Hydroxylases 57
25-Hydroxyvitamin D-1a-Hydroxylase 62
Additional Topics 65
References 69
Chapter 4 - CYP24A1: Structure, Function, and Physiological Role 74
Overview 74
CYP24A1-Catalyzed Pathways 74
Structure–Function Relationships 77
Putative CYP24A1 Involvement in Nonclassical Systems 79
Perspectives 82
References 83
Chapter 5 - The Vitamin D Binding Protein DBP 88
Introduction 88
Vitamin D Binding Protein: Protein and Gene Structure 88
Functions of DBP 91
Conclusions and Perspectives 98
References 99
Chapter 6 - Industrial Aspects of Vitamin D 104
History of Vitamin D Leading To Commercialization 104
Manufacture of the Provitamins 105
Irradiation of 7-Dehydrocholesterol and Ergosterol 110
Metabolite Manufacture 114
Analytical 115
Dietary Requirements 118
Economic Aspects 119
Storage and Shipping 121
References 122
Section II -Mechanisms of Action 126
Chapter 7 - The Vitamin D Receptor: Biochemical, Molecular, Biological, and Genomic Era Investigations 128
Introduction 128
Vitamin D Biology 129
Discovery of the Vitamin D Receptor 130
VDR Research: The Biochemical Era 130
VDR Research: The Molecular Biological Era 132
VDR Research: The Genomic Era 141
VDR Chromosomal Gene: Structure and Molecular Regulation 149
Concluding Comments 155
Acknowledgment 156
References 156
Chapter 8 - Nuclear Vitamin D Receptor: Natural Ligands, Molecular Structure–Function, and Transcriptional Control of Vital ... 168
Ligands, Gene Targets, and Biological Actions of Vdr 168
VDR as a Member of the Nuclear Receptor Superfamily 175
Molecular Structure–Function Of VDR 178
Mechanisms of VDR-Mediated Control of Gene Expression 181
VDR-Mediated Control of Vital Genes in Healthful Aging and Disease Prevention 185
Conclusions and Perspectives 188
Acknowledgment 193
References 193
Chapter 9 - Structural Basis for Ligand Activity in VDR 202
Introduction 202
Crystal Structure of hvdr. Bound to 1,25(Oh)2d3 203
Crystal Structure of zVDR Wild-Type LBD Bound to 1,25(OH)2D3 206
Structure of VDR LBD Complexed to Superagonist Ligands 206
Structures of VDR Complexed to 2a-Substituted Analogs 210
Structures of VDR With Nonsteroidal Ligands 212
Structures of VDR With Analogs that Induce Structural Rearrangements 213
Structural Basis for Vitamin D Receptor Antagonism 215
Structure-based Design of Novel Superagonist Analogs 218
Conclusion 219
References 220
Chapter 10 - Coregulators of VDR-mediated Gene Expression 224
Introduction 224
Coactivators of VDR 226
Corepressors 232
Conclusion – Integrated Model of Coregulator Activity 234
References 235
Chapter 11 - Target Genes of Vitamin D: Spatio-temporal Interaction of Chromatin, VDR, and Response Elements 242
Introduction 242
Transcriptional Regulation by 1,25(OH)2D3 244
Genomic VDR-Binding sites 245
VDR Target Genes 249
VDR Target Gene Analysis 250
Transcriptional Cycling 251
Conclusion 253
Acknowledgments 253
References 253
Chapter 12 - Epigenetic Modifications in Vitamin D Receptor-mediated Transrepression 258
Introduction 258
WINAC: A Novel VDR-Associating ATP-Dependent Chromatin Remodeling Complex 258
E-Box Motif Negative VDRE Mediates 1,25(OH)2D3-Induced Transrepression 259
Coregulator Switching at E-Box nVdres in Ligand-Dependent Transrepression by VDR 260
WINAC Mediates Ligand-Induced Transrepression by VDR 260
1,25(OH)2D3-Dependent VDR Transrepression Involves CpG Site Methylation in the CYP27B1 Promoter 261
Cell-Cycle-Independent DNA Demethylation During CYP27B1 Transcriptional Derepression 262
MBD4 Mediates Active DNA Demethylation 263
MBD4 is a Downstream Mediator in PTH Signaling-Induced Transcriptional Derepression 263
Conclusion 264
References 264
Chapter 13 - Vitamin D and Wnt/ß-Catenin Signaling 266
Introduction 266
WNT Signaling 266
Antagonism of Wnt/ß-Catenin Pathway by 1,25(OH)2D3 in Colon Cancer 269
Wnt and 1,25(OH)2D3 in the Bone 273
Wnt and 1,25(OH)2D3 in the Skin 275
Conclusions 276
References 276
Chapter 14 - Vitamin D Response Element-binding Protein 282
Introduction 282
Current View of Steroid/Sterol Hormone Action 282
New World Primates 284
New World Primate-Like VItamin D Resistance in Man 286
Heterogeneous Nuclear Ribonucleoproteins (hnRNPs) 289
hnRNPs as Multi-Level, Multi-Site, cis-Binding Regulators of Gene Expression 293
The Estrogen Response Element Binding Protein (ERE-BP) and the Intracellular Estrogen Binding Protein (IEBP) 295
Compensation for the Dominant-Negative Acting, Response Element-Binding Proteins 296
Conclusion 298
References 298
Chapter 15 - Vitamin D Sterol/VDR Conformational Dynamics and Nongenomic Actions 302
1a,25(OH)2-Vitamin D3 (1,25(OH)2D3) Regulation of Genomic Versus Nongenomic Signaling 302
Vitamin D3 Sterol (VDS) Chemistry 302
1,25(OH)2D3 Mediated Rapid, Nongenomic Responses 308
The Plasma Membrane Vitamin D Receptor 314
The VDR Conformational Ensemble Model 315
VDR Ligand Specificity: Does an Unliganded VDR Ever Exist in Vivo? 322
References 322
Section III -Mineral and Bone Homeostasis 330
Chapter 16 - Genetic and Epigenetic Control of the Regulatory Machinery for Skeletal Development and Bone Formation: Contrib ... 332
Programs of Bone Formation 332
Nuclear Organization of the Regulatory Machinery for Bone Formation 337
Epigenetic Mechanism for Lineage Commitment 340
Gene Expression within the Three-Dimensional Context of Nuclear Architecture 340
Chromatin Remodeling Facilitates Bone-Specific and Vitamin-D-Mediated Promoter Accessibility and Integration of Regulatory ... 342
Scaffolding of Regulatory Components for Combinatorial Control of Gene Expression 344
Closing Remarks 346
Acknowledgments 346
References 346
Chapter 17 - Vitamin D Regulation of Osteoblast Function 352
Introduction 352
Properties of Mature Osteoblasts and Osteocytes 352
Major Regulatory Functions of Osteoblasts and Osteocytes and Control by the Vitamin D Endocrine System 354
Effects of 1,25(OH)2D3 on Osteoblast Differentiation 357
Regulation of Intracellular Signaling Pathways by 1,25(OH)2D3 359
Summary and Conclusions 361
Acknowledgments 361
References 361
Chapter 18 - Osteoclasts 366
Introduction 366
References 373
Chapter 19 - Molecular Mechanisms for Regulation of Intestinal Calcium and Phosphate Absorption by Vitamin D 380
An Overview of Intestinal Calcium Absorption 380
Critical Role of VDR in Control of Intestinal Ca Absorption 382
Can High Vitamin D Status Increase Intestinal Calcium Absorption? 382
An Overview of Intestinal Phosphate Absorption 387
Acknowledgments 389
References 389
Chapter 20 - The Calbindins: Calbindin-D28K and Calbindin-D9K and the Epithelial Calcium Channels TRPV5 and TRPV6 394
Introduction and General Considerations, The Calbindins 394
Localization and Proposed Functional Significance of the Calbindins 395
Regulation of Calbindin Gene Expression 401
Epithelial Calcium Channels 403
Conclusion 404
References 405
Chapter 21 - Mineralization 412
Introduction 412
Conclusions 427
References 427
Chapter 22 - Vitamin D Regulation of Type I Collagen Expression in Bone 434
Introduction 434
Regulation of Bone Collagen Synthesis 435
Molecular Mechanisms of Regulation 436
Conclusions and Perspectives 437
References 438
Chapter 23 - Target Genes: Bone Proteins 442
Vitamin D and Skeletal Homeostasis 442
Exogenous and Endogenous Sources of 1,25(OH)2D3 443
Direct Actions of Vitamin D in Bone 445
Concluding Remarks 450
References 450
Chapter 24 - Vitamin D and the Calcium-Sensing Receptor 456
Introduction 456
What is the CaSR? 456
Overview of Roles of CaSR and VDR in Maintaining Ca2+O Homeostasis 458
The CaSR and VDR in Tissues Participating in Ca2+O Homeostasis 461
The CaSR and VDR in Tissues Uninvolved in Ca2+O Homeostasis 474
Polymorphisms of the CaSR and VDR and Calcium and Bone Homeostasis 477
Summary and Perspectives 478
References 480
Chapter 25 - Effects of 1,25-Dihydroxyvitamin D3 on Voltage-Sensitive Calcium Channels in Osteoblast Differentiation and Mor ... 488
Systemic and Intracellular Ca2+ Homeostasis 488
Voltage-Sensitive Calcium Channels 488
1,25-Dihydroxyvitamin D3 Actions on Voltage-Sensitive Ca2+ Channels 491
1,25-Dihydroxyvitamin D3-Regulated Osteoblast Differentiation 493
Influence of 1,25(OH)2D3 on Osteoblast Cell Survival 494
Acknowledgments 495
References 495
Section IV -Targets 500
Chapter 26 - Vitamin D and the Kidney 502
Introduction 502
Role of the Kidney in the Metabolism of 25(OH)D 503
Effects of vitamin D, 25(OH)D3 and 1,25(OH)2D3 on the Renal Handling of Calcium and Phosphorus 504
Distribution and Regulation of Vitamin-D-Dependent Proteins in the Kidney 506
Conclusion 513
References 513
Chapter 27 - Vitamin D and the Parathyroids 524
Introduction 524
Parathyroid Hormone Biosynthesis 524
The Parathyroid Hormone Gene 524
Development of the Parathyroid and Tissue-Specific Expression of The PTH Gene 525
Promoter Sequences 525
Regulation Of Pth Gene Expression 526
Conclusion 533
References 534
Chapter 28 - Cartilage 538
Chondrogenesis, Endochondral Ossification, and Vitamin D 538
Separate Roles for 24,25(OH)2D3 and 1,25(OH)2D3 in Cartilage 540
Rapid Actions of Vitamin D and Nongenomic Mechanisms 542
Physiologic Relevance of Nongenomic Regulation of Matrix Vesicles 544
Conclusion 546
References 547
Chapter 29 - Vitamin D and Oral Health 552
Introduction: The Dento-Maxillofacial Skeleton 552
Dental Rare Diseases and Molecular Determinants of Dental Rickets 553
Experimental Analysis of Dental Pathway in Experimental Models of Vitamin D Bioactivation 555
Specificity of Oral Bone: Potential Vitamin D Impact in Development, Periodontal Disease, and JAW Osteonecrosis 557
Conclusions: Facts and Hypothesis 560
References 561
Chapter 30 - The Role of Vitamin D and its Receptor in Skin and Hair Follicle Biology 564
Introduction 564
Keratinocyte Differentiation 564
Coactivators 565
Barrier Function 565
Hair Cycle 565
Keratinocyte Stem Cells 567
Pathways Important for Keratinocyte Stem Cell Function 567
Conclusions 568
References 569
Chapter 31 - Vitamin D and the Cardiovascular System 572
Introduction 572
Vitamin D and the Vasculature 572
Vitamin D and the Heart 581
Clinical Epidemiological Considerations of Vitamin D Deficiency 585
Conclusion 588
Acknowledgments 589
References 589
Chapter 32 - Vitamin D: A Neurosteroid Affecting Brain Development and Function Implications for Neurological and Psychiatr ...
Introduction 596
Vitamin D Signaling in the Brain 596
Vitamin D Deficiency, Brain Development, and Function 598
Vitamin D and Neurological Disorders 601
Possible Neuroprotective Mechanisms of Vitamin D 603
Vitamin D and Neuropsychiatric Disorders 604
Conclusions 606
References 608
Chapter 33 - Contributions of Genetically Modified Mouse Models to Understanding the Physiology and Pathophysiology of the 2 ... 614
Introduction 614
Mouse Models 615
1,25(OH)2D/VDR System and Skeletal and Mineral Homeostasis 615
Extraskeletal Actions of 1,25(OH)2D 619
Conclusion 627
References 628
Section V -Human Physiology 636
Chapter 34 -Vitamin D: Role in the Calcium and Phosphorus Economies 638
Introduction 638
Overview of the Calcium Economy 638
Overview of the Phosphorus Economy 643
Calcium and Phosphorus Absorptive Inputs 644
Physiological Sources of Vitamin D Activity 650
Optimal Vitamin D Status 651
Summary and Conclusions 653
References 653
Chapter 35 -Fetus, Neonate and Infant 656
Overview of Calcium Metabolism in the Fetus 656
Animal Data Relevant to Vitamin D and the Fetus 658
Human Data Relevant to Vitamin D and the Fetus 659
Overview of Calcium Metabolism in the Neonate and Infant 663
Animal Data Relevant to Vitamin D and the Neonate and Infant 664
Human Data Relevant to Vitamin D and the Neonate and Infant 666
Conclusions 671
References 671
Chapter 36 -Vitamin D Deficiency and Calcium Absorption during Childhood 678
Introduction 678
Premature Infants 679
Full-Term Infants – Calcium 680
Vitamin D in Full-Term Infants 681
Toddlers and Prepubertal Children 682
Special Issues 683
References 685
Chapter 37 -Adolescence and Acquisition of Peak Bone Mass 688
Introduction 688
Pubertal Bone Acquisition 688
Vitamin D in Children and Adolescents 690
Vitamin D and Intermediate Endpoints of Vitamin D and Bone Metabolism 693
Vitamin D and Other Predictors of Calcium Retention 697
Vitamin D and Bone 698
Vitamin D and Muscle 700
Sex and Racial Differences 700
Vitamin D and Diabetes 702
Vitamin D, Asthma, and Influenza 702
Vitamin D Requirements in Adolescents 702
Summary and Conclusions 703
References 704
Chapter 38 -Vitamin D Metabolism in Pregnancy and Lactation 710
Introduction 710
Adaptations in Vitamin D and Calcium Metabolism 710
Changes in Bone Mineral Content and Density 713
Low Maternal Vitamin D During Pregnancy 715
Effect of Low Maternal Vitamin D During Lactation on the Infant 719
Potential Risk of High Maternal Vitamin D During Pregnancy 720
Conclusions 720
References 720
Chapter 39 -Vitamin D: Relevance in Reproductive Biology and Pathophysiological Implications in Reproductive Dysfunction 726
Introduction 726
Procreative Relevance – Animal Models 726
Vitamin D – Relevance in Human Reproductive Physiology 727
References 734
Chapter 40 -Vitamin D and the Renin-Angiotensin System 738
Introduction 738
The Renin-Angiotensin System 738
Vitamin D Regulation of the Renin-Angiotensin System 742
Vitamin D, Blood Pressure and Heart Disease 746
Vitamin D and Chronic Kidney Disease 747
Conclusion 749
References 750
Chapter 41 -Parathyroid Hormone, Parathyroid Hormone-Related Protein, and Calcitonin 756
Parathyroid Hormone 756
Parathyroid-Hormone-Related Protein 764
Calcitonin 768
References 771
Chapter 42 -FGF23/Klotho New Regulators of Vitamin D Metabolism 778
Introduction 778
Regulation of Vitamin D Metabolism 778
PTH–Vitamin D Axis: Key Regulator of Calcium Homeostasis 779
FGF23 Klotho Bone Kidney Axis: A Pathway Coordinating Phosphate and Vitamin D Homeostasis with Bone Mineralization 780
Relationship Beween FGF23 and PTH 784
Role of FGF23 in Phosphate Homeostasis 784
Hormonal Actions of klotho? 785
How Knowledge of FGF23 Regulation and Function Changes Concepts, Treatments, and Clinical Practice 786
Conclusion 786
References 788
Chapter 43 -The Role of the Vitamin D Receptor in Bile Acid Homeostasis 794
Introduction 794
Bile Acids in Physiology and Disease 794
VDR as a Bile Acid Receptor 795
Regulation of Bile Acid Synthesis by VDR 795
Evolution of VDR: From Bile Acid Metabolism to Mineral Homeostasis 796
References 797
Chapter 44 -Vitamin D and Fat 800
Introduction 800
Vitamin D Metabolism and Mechanism of Action 800
Vitamin D Deficiency and Adiposity 801
Vitamin D and Obesity: Clinical Implication 804
References 805
Chapter 45 -Extrarenal 1a-Hydroxylase 808
Introduction 808
Vitamin D and Granuloma-Forming Disease: a Historical Perspective 808
Human Diseases With Extrarenal Overproduction of Active Vitamin D Metabolites 810
Extrarenal Synthesis of 1,25(OH)2D in Normal Physiology and Cancer 813
Mechanisms for the Regulation of Extrarenal 1a-Hydroxylase 817
Diagnosis, Prevention, and Treatment of the Patient with Endogenous Vitamin D Intoxication 825
Conclusions and Future Prospects 827
References 827
Section VI -Diagnosis and Management 836
Chapter 46 -Approach to the Patient with Metabolic Bone Disease 838
Introduction 838
Diagnostic Evaluation 838
Treatment 849
Conclusion 853
References 853
Chapter 47 -Detection of Vitamin D and Its Major Metabolites 854
Introduction 854
Detection of Vitamin D 856
Detection of 25(OH)D 858
Detection of 24,25(OH)2D 863
Detection of 1,25(OH)2D 864
Clinical Interpretation and Relevance of Antirachitic Sterol Measurements 870
Stability of 25(OH)D and 1,25(OH)2D in Serum or Plasma 872
Assessment of Assay Performance 872
References 873
Chapter 48 -Bone Histomorphometry 876
Introduction 876
Bone Biopsy 876
Histomorphometry 877
Assessment of Mineralization 879
Histological Diagnosis of Osteomalacia 882
Assessment of Bone Turnover 883
Assessment of Remodeling Balance 884
Assessment of Bone Structure 886
Future Developments 888
References 888
Chapter 49 -Radiology of Rickets and Osteomalacia 892
Introduction and Historical Aspects 892
Vitamin D Deficiency 893
Renal Osteodystrophy 900
Renal Tubular Defects and Hypophosphatemia 906
Acidemia 911
Differential Diagnoses 911
Vitamin D Intoxication 911
Technical Aspects of Imaging 911
Conclusions 915
References 915
Chapter 50 -High-Resolution Imaging Techniques for Bone Quality Assessment 922
Introduction 922
X-ray Computed Tomography (CT) 922
Magnetic Resonance Imaging (MRI) 936
References 947
Chapter 51 -The Role of Vitamin D in Orthopedic Surgery 958
Introduction 958
Impact on Orthopedic Trauma 958
Impact on Pediatric Orthopedics 962
Impact on Total Joint Arthroplasty 965
Impact on Muscle Strength and Rehabilitation 966
Prevention and Treatment in Orthopedic Patients 968
References 969
Section VII -Nutrition, Sunlight, Genetics and Vitamin D Deficiency 976
Chapter 52 -Worldwide Vitamin D Status 978
Introduction 978
Vitamin D Status in North America (Including Canada and Mexico) 978
Vitamin D Status in South America 981
Vitamin D Status in Europe 981
Vitamin D Status in the Middle East 985
Vitamin D Status in Asia 986
Vitamin D Status in Africa 986
Vitamin D Status in Oceania 988
Multicenter and Global Studies using a Central Laboratory Facility 988
Ethnicity/Migration 988
Nutrition 990
Risk Groups 990
Implications 990
Conclusions 990
References 991
Chapter 53 -Sunlight, Vitamin D and Prostate Cancer Epidemiology 996
Introduction 996
Types of Epidemiologic Studies 996
Subclinical Prostate Cancer is Prevalent and May Dilute Effects in Epidemiologic Studies 997
Prostate Cancer and the Vitamin D Hypothesis 997
1,25(OH)2D is Synthesized by Normal Prostate Epithelial Cells and its Synthesis is Reduced in Prostate Cancer Cells 998
Ecologic Studies of Sunlight and Prostate Cancer 1000
Studies of Prostate Cancer and VDR Polymorphisms 1000
Serological Studies of the Vitamin D Deficiency Hypothesis 1001
Epidemiologic Studies of Sun Exposure and Prostate Cancer 1003
Epidemiologic Studies of Calcium and Prostate Cancer 1005
Conclusions 1006
References 1006
Chapter 54 -Nutrition and Lifestyle Effects on Vitamin D Status 1010
Introduction 1010
Determinants of Vitamin D Status 1011
Factors Influencing Skin Synthesis Supplying Vitamin D 1014
Nutrient Intake as Determinant of Vitamin D Status 1022
Lifestyle Strategies to Improve Vitamin D Status 1033
References 1035
Chapter 55 -Bone Loss, Vitamin D and Bariatric Surgery: Nutrition and Obesity 1040
Background 1040
Epidemiology of Bariatric Surgery 1040
Indications for Bariatric Surgery 1041
Classification of Bariatric Surgery 1042
Surgical Complications of Bariatric Surgery 1045
Health Benefits of Bariatric Surgery 1046
Medical Complications of Bariatric Surgery 1046
Bone Loss After Gastric Bypass 1047
Vitamin D Status 1049
Calcium Malabsorption after Gastric Bypass Surgery 1050
Evidence of Efficacy of Supplemental Vitamin D 1051
Conclusion 1052
References 1052
Chapter 56 -Genetics of the Vitamin D Endocrine System 1056
Introduction 1056
Genetic Studies 1057
Candidate Genes 1061
Genome-wide Association Studies 1065
Future Developments 1068
References 1068
Chapter 57 -The Pharmacology of Vitamin D 1072
Introduction 1072
Overview of the System of Vitamin D Metabolism and its Regulation 1073
Placebo-Controlled Clinical-Trial Justification for an Optimal Serum 25(Oh)D Level 1079
Dosage Considerations 1081
Pharmacokinetic Principles, Volume of Distribution, Turnover and Half-Life as it Pertains to Vitamin D 1085
Vitamin D Toxicity and Safety Issues 1087
The Concept of a Loading Dose 1089
Summary and Conclusions 1091
References 1092
Chapter 58 -How to Define Optimal Vitamin D Status 1098
Introduction 1098
Vitamin D Status and Bone Health in Adults and The Elderly 1100
Vitamin D and Extra-Skeletal Health 1107
Vitamin D and Human Health: What is The Optimal Vitamin D Status 1113
References 1114
Color Plates 1120
e9780123819789v2 1158
Front Cover 1158
Vitamin D 1161
Copyright 1162
Contents 1163
Preface to the 3rd Edition 1167
Preface to the 2nd Edition 1169
Preface to the 1st Edition 1171
Contributors 1173
Introduction 1179
Abbreviations 1181
Relevant Lab Values in Adults and Children 1187
Criteria for Vitamin D Deficiency: 25(OH)D Serum Levels 1187
Approximate normal ranges for serum values in adultsaaNormal ranges differ in various laboratories and these values are pro ... 1188
Approximate normal ranges for serum values in childrena 1188
Useful equivalencies of different units 1188
Section VIII -Disorders 1189
Chapter 59 -The Hypocalcemic Disorders: Differential Diagnosis and Therapeutic Use of Vitamin D 1191
Physiology 1191
Differential Diagnosis of Hypocalcemia 1194
Therapy for Hypocalcemia 1200
References 1203
Chapter 60 -Vitamin D Deficiency and Nutritional Rickets in Children 1207
Introduction 1207
Historical Perspective 1207
The Epidemiology of Vitamin D Deficiency and Nutritional Rickets 1208
Clinical Presentation 1210
Biochemical Abnormalities 1211
Radiologic Changes 1213
The Growth Plate in Rickets 1214
Treatment and Prevention 1215
Dietary Calcium Deficiency 1217
The Pathogenetic Spectrum of Nutritional Rickets 1220
Conclusions 1221
References 1221
Chapter 61 -Vitamin D and Osteoporosis 1229
Effects of Vitamin D on the Skeleton 1229
The Role of Vitamin D Genetic Factors in Osteoporosis and Possible Interactions with Vitamin D Therapy 1230
Primary Fracture Prevention with Vitamin D or Calcium and Vitamin D 1234
Secondary Fracture Prevention with Vitamin D or Calcium and Vitamin D 1239
Effects of Active Vitamin D Analogs on Fractures 1240
Future Directions for Vitamin D in Osteoporosis 1240
References 1241
Chapter 62 -Relevance of Vitamin D Deficiency in Adult Fracture and Fall Prevention 1245
Muscle Effects of Vitamin D 1245
Vitamin D Modulates Fracture Risk in Two Ways: By Increasing Bone Density and Decreasing Falls 1245
Anti-fall and Fracture Efficacy of Vitamin D 1246
Desirable 25(OH)D Status for Optimal Musculoskeletal Health 1248
Dosing Interval of Vitamin D and Musculoskeletal Health 1248
How to Achieve a Serum Concentration of at Least 75nmol/l for Musculoskeletal Health 1250
Summary 1250
References 1250
Chapter 63 -Clinical Disorders of Phosphate Homeostasis 1255
Introduction 1255
Disorders of Phosphate Homeostasis 1259
Disorders Related to an Altered Phosphate Load 1273
Concluding remarks 1278
REFERENCES 1279
Chapter 64 -Pseudo-vitamin D Deficiency 1287
Introduction 1287
Clinical Manifestations 1287
Biochemical Findings 1289
Genetic and Molecular Studies 1289
Treatment 1291
Evolution of Pddr Under Treatment from Childhood to Adulthood 1292
Conclusion 1294
References 1294
Chapter 65 -Hereditary 1,25-Dihydroxyvitamin-D-Resistant Rickets 1297
Introduction 1297
The Clinical Features of HVDRR 1298
Mechanism of 1,25(OH)2D Action 1301
Cellular Basis of HVDRR 1303
Molecular Basis for HVDRR 1309
Therapy of HVDRR 1319
Alopecia 1323
Concluding Remarks 1324
References 1325
Chapter 66 -Glucocorticoids and Vitamin D 1333
Mechanisms of GlucocorticoId Osteoporosis 1333
Steroid Receptors and Actions in Bone 1334
Glucocorticoids, Vitamin D, and Inflammation 1335
Effect of Glucocorticoids on Vitamin D Metabolism 1336
Vitamin D as Treatment for Gio 1338
Summary 1341
References 1342
Chapter 67 -Drug and Hormone Effects on Vitamin D Metabolism 1345
Introduction 1345
Hormone Effects on Vitamin D Metabolism 1345
Drug Effects on Vitamin D Metabolism 1357
Conclusion 1369
References 1369
Chapter 68 -Vitamin D and Organ Transplantation 1391
Introduction 1391
Effects of Vitamin D on Immunity and Graft Rejection 1391
Vitamin D Deficiency Prior to Organ Transplant 1392
Vitamin D Deficiency Following Organ Transplant 1393
Treatment of Post-Transplant Bone Loss with Vitamin D and Analogs 1394
Conclusions 1396
References 1396
Chapter 69 -Vitamin D and Bone Mineral Metabolism in Hepatogastrointestinal Diseases 1399
Physiologic Considerations 1399
Gastrointestinal Diseases 1402
Pancreatic Diseases 1408
Hepatic Diseases 1409
Total Parenteral Nutrition 1414
References 1415
Chapter 70 -Vitamin D and Renal Disease 1425
Introduction 1425
Renal Maintenance of the Vitamin D Endocrine System 1427
Contribution of the low 25(OH)D and 1,25(OH)2D Levels and Abnormal VDR Actions to Mineral and Skeletal Abnormalities, Renal ... 1437
Safety and Efficacy of Vitamin D And 1,25(OH)2D Therapy to Improve Outcomes in Chronic Renal Failure 1446
Adequacy of Current Recommendations to Correct Vitamin D Deficiency 1447
Summary 1448
References 1449
Chapter 71 -Idiopathic Hypercalciuria and Nephrolithiasis 1459
Introduction 1459
Idiopathic Hypercalciuria 1459
Genetic Hypercalciuric Rats 1469
Current View of Human Genetic Hypercalciuria 1474
Therapeutics of Idiopathic Hypercalciuria and Effects on Calcium Metabolism 1474
Risk of Stone Formation Using Vitamin D Analogs 1475
Summary 1475
References 1476
Chapter 72 -Hypercalcemia Due to Vitamin D Toxicity 1481
Introduction 1481
Forms of Exogenous Vitamin D Toxicity 1481
Forms of Endogenous Vitamin D Toxicity 1485
Mechanisms of Vitamin D Toxicity 1489
Clinical Manifestations 1492
Diagnosis of Vitamin D Toxicity 1493
Treatment of Vitamin D Toxicity 1494
Summary and Conclusions 1495
References 1495
Chapter 73 -Vitamin D: Cardiovascular Effects and Vascular Calcification 1503
Introduction 1503
Vitamin D Signaling In Cardiovascular Remodeling And Myocardial Function 1504
Vitamin D Actions In Atherosclerosis And Arteriosclerosis 1506
Vitamin D And Human Cardiovascular Disease: Compelling Epidemiology And Physiology, Emerging But Less Compelling Evidence O ... 1508
Vitamin D Intoxication And Cardiovascular Calcification: Pharmacological Considerations 1509
The Impact Of Calcium, Phosphate, And Vitamin D Excesses On Smooth Muscle Matrix Vesicle Physiology And Vascular Calcification 1511
The Fgf23/Klotho/Vitamin D Axis, Nephrocalcinosis, And Cardiovascular Calcification 1513
Vitamin D, Vascular Pth Receptor Signaling And Arteriosclerotic Calcium Accrual: Lessons Learned From Preclinical Models An ... 1514
Defining Cardiovascular Toxicity Thresholds For Vitamin D: Critical Clues From The Clinical Literature 1515
Vitamin D, The Calcium-Sensing Receptor (Casr), And Cardiovascular Disease 1516
Summary, Conclusions, And Future Directions 1518
REFERENCES 1519
Section IX -Analogs 1527
Chapter 74 -Alterations in 1,25-Dihydroxyvitamin D3 Structure that Produce Profound Changes in in Vivo Activity 1529
Introduction 1529
The Non-Calcemic Holy Grail of Vitamin D Analogs 1529
Analogs Directed to Specific Structures 1530
Summary 1533
References 1533
Chapter 75 -Mechanisms for the Selective Actions of Vitamin D Analogs 1537
Introduction 1537
Identification of Selective Vitamin D Analogs 1537
The IN VIVO Selectivity of Vitamin D Analogs is Determined by Multiple Protein Interactions 1540
Concluding Remarks 1551
References 1552
Chapter 76 -Analogs of Calcitriol 1561
Introduction 1561
14-epi Analogs of 1,25(OH)2D3 1562
Decalin Analogs 1565
C- and D-ring Analogs 1565
CF-ring Analogs 1577
E-ring Analogs 1578
Acyclic Analogs 1579
Non-Secosteroidal Compounds 1581
Conclusion 1584
References 1585
Chapter 77 -Analogs for the Treatment of Osteoporosis* 1589
Introduction 1589
Alfacalcidol 1589
Eldecalcitol 1592
Clinical Comparison Between Alfacalcidol and Eldecalcitol 1593
Conclusion 1595
References 1595
Chapter 78 -Non-secosteroidal Ligands and Modulators 1597
Introduction 1597
Diarylmethane Ligands 1598
C/D-Ring Modified Ligands 1602
Bis- and Tris-Aromatic Triols 1603
Miscellaneous non-Secosteroids 1605
Perspectives 1607
References 1608
Chapter 79 -The Bile Acid Derivatives Lithocholic Acid Acetate and Lithocholic Acid Propionate are Functionally Selective V ... 1609
The Vitamin D Receptor is a Dual-Functional Receptor for Vitamin D and Bile Acids 1609
Bile Acids and Nuclear Receptors 1611
Development of Bile Acid Derivatives 1614
X-Ray Crystal Structures of VDR in Complex with LCA Derivatives 1617
Perspectives 1620
References 1621
Chapter 80 -CYP24A1 Regulation in Health and Disease 1625
Introduction 1625
CYP24A1: Properties, Function and Expression 1625
Regulation of CYP24A1 mRNA Expression and Stability 1629
Dysregulation of CYP24A1 and Role in the Pathogenesis of Human Disease 1634
CYP24A1 Inhibitors 1639
Conclusion and Future Directions 1643
References 1643
Chapter 81 -Calcitriol and Analogs in the Treatment of Chronic Kidney Disease 1655
Introduction 1655
Analogs of Vitamin D Used in CKD 1656
Analogs in Animal Models of Uremia 1656
CKD Stages 3–4 1659
ESRD 1660
Cardiovascular Disease in CKD and Different Forms of Vitamin D 1663
Conclusions 1663
References 1664
Section X -Cancer 1667
Chapter 82 -The Epidemiology of Vitamin D and Cancer Risk 1669
Introduction 1669
Overview of Epidemiologic Study Designs for the Study of Vitamin D and Cancer 1670
Studies of 25(OH)D, Predicted 25(OH)D, Vitamin D intake and Cancer Risk by Cancer Site 1672
Studies of Sun Exposure 1678
Randomized Controlled Trials 1680
Mortality/Survival 1681
Summary and Synthesis of The Epidemiology of Vitamin D and Cancer 1684
References 1686
Chapter 83 -Vitamin D: Cancer and Differentiation 1691
Introduction 1691
Vitamin D and Cancer 1691
Vitamin D Effects on Tumor Cells 1698
Combination Therapy 1705
Resistance and Vitamin D Metabolism 1706
Stimulation of Proliferation 1708
Conclusions 1709
References 1709
Chapter 84 -Vitamin D Effects on Differentiation and Cell Cycle 1725
Introduction 1725
Induction of Differentiation by 1,25(OH)2D3 and its Analogs 1725
Cell Cycle Consequences of Vitamin-D-Induced Differentiation 1731
Cell-Type Specificity of Inhibition of Cell Proliferation by Vitamin D and Analogs Without Evidence of Differentiation 1742
Conclusions 1743
References 1743
Chapter 85 -Vitamin D Actions in Mammary Gland and Breast Cancer 1757
Introduction 1757
Vitamin D Actions on Breast Cancer Cells in Vitro 1758
Determinants of Breast Cancer Sensitivity to Vitamin D 1762
Vitamin D Metabolites and Analogs: Preclinical and Clinical Trials 1764
Vitamin D and Prevention of Breast Cancer 1765
Summary and Outstanding Research Questions 1768
References 1768
Chapter 86 -Vitamin D and Prostate Cancer 1775
Introduction 1775
Prostate as a Target for Vitamin D 1777
Vitamin D and Inhibition of Prostate Cancer Growth 1778
Vitamin D Analogs and Prostate Cancer 1783
Mechanisms of the Anti-Cancer Actions of Calcitriol 1784
The Role of Calcitriol in Prostate Cancer Chemoprevention 1789
Calcitriol in Combination with other Agents 1791
Clinical Trials 1794
Summary and Conclusions 1796
References 1797
Chapter 87 -The Vitamin D System and Colorectal Cancer Prevention 1811
Colorectal Cancer Epidemiology and Pathogenesis 1811
Vitamin D and Colorectal Cancer Pathogenesis 1813
Colonic Synthesis of 1,25(OH)2D3 1815
Regulation of CYP27b1 and of CYP24a1 Expression by Nutrition 1819
References 1824
Chapter 88 -Hematological Malignancy 1831
Introduction 1831
Overview of Hematopoiesis 1831
Effects of Vitamin D Compounds on Normal Hematopoiesis 1834
Effects of Vitamin D Compounds in Leukemic Cells 1835
Vitamin D Analogs Activity Against Leukemic Cells 1841
Conclusions 1844
References 1844
Chapter 89 -Vitamin D and Skin Cancer 1851
Two Sources of Vitamin D: Diet or Sunlight 1851
Vitamin D and Indoor Tanning 1852
UV Exposure Contributes to NMSC and Melanoma Development 1853
Vitamin D and Visceral Cancer Risk and its Potential Role in Reducing Skin Cancer Risk 1854
Role of Vitamin D in Keratinocytes 1855
Role of Vitamin D in Squamous Cell Carcinomas (SCC) 1855
Role of Vitamin D in Basal Cell Carcinomas (BCC) 1856
Role of Vitamin D in Melanomas 1857
Photoprotection and Vitamin D Levels 1858
Conclusions 1859
References 1859
Chapter 90 -The Anti-tumor Effects of Vitamin D in Other Cancers 1863
Introduction 1863
Thyroid Cancer 1863
Bone and Soft Tissue Sarcomas 1864
Melanoma 1864
Gastro-Esophageal Cancers 1864
Lung Cancers 1864
Hepatocellular Carcinoma (HCC) 1865
Bladder Cancer 1865
Gliomas 1866
Head and Neck 1866
Renal Cell Carcinoma 1867
Pancreatic Cancer 1867
Conclusions 1868
References 1868
Section XI -Immunity, Inflammation, and Disease 1875
Chapter 91 -Vitamin D and Innate Immunity 1877
Introduction and Historical Background 1877
VDR Gene Polymorphisms and Infectious Diseases 1879
Molecular Events Underlying Innate Immune Regulation by Vitamin D 1880
Physiological and Pathophysiological Ramifications of 1,25(OH)2D3-Regulated Camp Expression 1883
Conclusions and Future Directions 1884
References 1884
Chapter 92 -Control of Adaptive Immunity by Vitamin D Receptor Agonists 1889
Introduction 1889
Vitamin D Receptor Agonists as Immunoregulatory Agents 1889
Dendritic Cells as Targets for Immunoregulation by VDR Agonists 1890
Induction of Tolerogenic Dendritic Cells by VDR Agonists 1892
Modulation of T and B Lymphocytes by VDR Agonists 1896
Vitamin D Deficiency in Autoimmune Diseases 1899
Mechanisms For The Immunomodulatory Effects Of Vdr Agonists In Autoimmune Diseases 1899
References 1903
Chapter 93 -The Role of Vitamin D in Innate Immunity: Antimicrobial Activity, Oxidative Stress and Barrier Function 1911
Innate Immunity 1911
Immune Activity of 1,25-Dihydroxyvitamin D 1913
Vitamin D Pathway and Tuberculosis 1916
History of Vitamin D, Sunshine, and Tuberculosis 1918
References 1918
Chapter 94 -Vitamin D and Diabetes 1925
Introduction 1925
Vitamin D and the Beta Cell 1925
Vitamin D and the Immune System in Type 1 Diabetes 1929
Vitamin D and Genetic Predisposition to Diabetes 1935
Clinical Perspectives 1936
References 1937
Chapter 95 -Vitamin D and Multiple Sclerosis 1943
The Vitamin D–Multiple Sclerosis Hypothesis 1943
Original Evidence Underlying the Vitamin D–Multiple Sclerosis Hypothesis 1943
Multiple Sclerosis Etiology and the Association with Vitamin D 1944
Genetic Evidence Linking Vitamin D and Multiple Sclerosis 1950
Experimental Autoimmune Encephalomyelitis, A Multiple Sclerosis Model 1953
Vitamin D and Prevention of EAE 1954
Mechanisms of EAE Prevention 1956
Vitamin D Amelioration of Established EAE 1961
Mechanisms of EAE Amelioration 1961
Multiple Sclerosis, Pregnancy, and Immune Tolerance 1963
Vitamin D, Estrogen, EAE, and Multiple Sclerosis 1963
Vitamin-D-Based Therapy of Multiple Sclerosis 1965
Conclusions and Future Research Directions 1966
References 1968
Chapter 96 -Vitamin D and Inflammatory Bowel Disease 1979
Introduction 1979
What is IBD? 1979
Who Gets IBD? 1980
The “Hygiene Hypothesis” 1981
The “Vitamin D Hypothesis” 1981
The Immune Response and IBD 1982
Vitamin D Regulates T Cell Responsiveness 1983
Experimental Models of IBD 1984
Current Treatments for IBD 1985
Vitamin D as a Treatment Option for IBD 1986
References 1986
Chapter 97 -Psoriasis and Other Skin Diseases 1991
Introduction/Historical Overview 1991
Pathogenesis of Psoriasis 1991
The Vitamin D System in Normal and Psoriatic Skin 1992
Physiological and Pharmacological Actions of Vitamin D Analogs in Normal and Psoriatic Skin 1994
Clinical use of Calcitriol in Psoriasis 1995
Vitamin D Analog Therapy in Other Skin Diseases 1997
Conclusion 2000
References 2000
Section XII -Therapeutic Applications and New Advances 2005
Chapter 98 -The Role of Vitamin D in Type 2 Diabetes and Hypertension 2007
Epidemiology and Burden of Type 2 Diabetes and Hypertension 2007
Biologic Plausibility of an Association Between Vitamin D and Type 2 Diabetes and Hypertension 2008
Evidence from Human Studies for a Link Between Vitamin D and Type 2 Diabetes 2010
Evidence from Human Studies for a Link Between Vitamin D and Hypertension 2021
Summary of Evidence from Human Studies on Type 2 Diabetes and Hypertension and Limitations in the Study of Vitamin D 2023
Optimal Intake of Vitamin D in Relation to Type 2 Diabetes and Hypertension 2024
Conclusions 2024
References 2024
Chapter 99 -Vitamin D Receptor Agonists in the Treatment of Benign Prostatic Hyperplasia 2031
Benign Prostatic Hyperplasia: an Introduction 2031
Pathogenesis of BPH 2031
Medical Treatment for BPH 2033
Vitamin D Receptor Agonists Control Prostate Cell Growth 2033
Vitamin D Receptor Agonists and BPH-Related Luts 2034
Vitamin D Receptor Agonists Inhibit Intraprostatic Inflammation 2035
Vitamin D Receptor Agonists Modulate Prostatic Urethra Dysfunction 2036
Concluding Remarks 2037
References 2038
Chapter 100 -Sunlight Protection by Vitamin D Compounds 2043
Introduction 2043
UV-Induced DNA Damage and Repair 2043
UV-Induced Immune Suppression 2044
Photocarcinogenesis 2044
Local Production of Vitamin D Metabolites in Skin 2045
Vitamin D Compounds and Photoprotection 2045
Mechanisms of Photoprotection 2047
Perspectives on Future Use of Vitamin D Compounds for Sun Protection 2049
References 2050
Chapter 101 -The Role of Vitamin D in Osteoarthritis and Rheumatic Disease 2055
Osteoarthritis 2055
Hyaline Cartilage in OA 2055
Bone Health and OA 2056
The Synovium 2057
Vitamin D Receptor (VDR) Genotype and OA Progression 2058
Vitamin D Status and OA Progression 2058
Rheumatoid Arthritis 2060
Systemic Lupus Erythematosus (SLE) 2062
Psoriatic Arthritis (PsA) 2066
Conclusions 2066
References 2066
Chapter 102 -Vitamin D and Cardiovascular Disease 2073
Introduction 2073
Components of Direct Cardiovascular Effects 2074
Components of Indirect Cardiovascular Effects 2079
Cardio- and Cerebrovascular Mortality as Endpoint in Observational and Interventional Studies 2084
Clinical Cardiovascular Outcomes in Observational and Randomized Interventional Studies 2087
Situation in Patients With Chronic Kidney Disease or on Hemodialysis 2089
Summary and Conclusions 2090
References 2091
Chapter 103 -Vitamin D, Childhood Wheezing, Asthma, and Chronic Obstructive Pulmonary Disease 2099
Introduction 2099
Common Respiratory Disorders 2100
Vitamin D and Respiratory Infection 2102
Vitamin D and Asthma 2106
Vitamin D and COPD 2110
Potential Mechanisms 2111
Future Research on Vitamin D and Respiratory/Allergic Disorders 2114
Summary 2115
References 2116
Chapter 104 -Vitamin D and Skeletal Muscle Function 2123
Introduction 2123
Myopathy 2124
Physical Performance 2125
Falls 2128
Muscle Morphology 2129
Molecular Mechanisms of Action 2130
VDR Knockout Mouse Model 2134
VDR Polymorphisms 2135
PTH 2135
Conclusion 2135
References 2136
Chapter 105 -The VITamin D and OmegA-3 TriaL (VITAL): Rationale and Design of a Large-Scale Randomized Controlled Trial 2143
Introduction 2143
Biology of Vitamin D and Proposed Mechanisms for Lowering Cancer and CVD Risk 2143
Current Evidence on Vitamin D and Risk of Cancer and CVD 2144
Rationale for VITAL 2146
Rationale for the Selected Vitamin D Dose in VITAL 2146
Core Aspects of Trial Design 2147
Trial Eligibility 2148
Recruitment, Enrollment, Run-in and Randomization 2148
Characteristics of Participants in VITAL 2149
Detailed Assessment of Dietary and Supplement Intake in VITAL 2149
Blood Collections in VITAL 2150
Follow-up and Enpoint Determination Procedures 2150
Monitoring of Compliance 2151
Trial Monitoring and Safety 2151
Statistical Power 2152
Vital Value: Ancillary Studies and Establishment of a Clinical and Translational Science Center Sub-Cohort 2152
Key Points 2153
References 2153
Index 2157
Color Plates 2183