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The Nonskeletal Effects of Vitamin D: an Endocrine Society Scientific Statement

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The Nonskeletal Effects of Vitamin D: an Endocrine Society Scientific Statement REVIEW The Nonskeletal Effects of Vitamin D: An Endocrine Society Scientific Statement Clifford J. Rosen, John S. Adams, Daniel D. Bikle, Dennis M. Black, Marie B. Demay, JoAnn E. Manson, M. Hassan Murad, and Christopher S. Kovacs Tufts University School of Medicine (C.J.R.), Boston, Massachusetts 02111; UCLA-Orthopaedic Hospital Department of Orthopedic Surgery (J.S.A.), University of California, Los Angeles, California 90095; University of California (D.D.B.), San Francisco, California 94121; Department of Epidemiology and Biostatistics (D.M.B.), University of California, San Francisco, California 94143; Endocrine Unit (M.B.D.), Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114; Harvard Medical School (J.E.M.), Brigham and Women’s Hospital, Boston, Massachusetts 02215; College of Medicine (M.H.M.), Mayo Clinic, Rochester, Minnesota 55905; and Memorial University of Newfoundland (C.S.K.), St. John’s, Newfoundland and Labrador, Canada A1B 3V6 Significant controversy has emerged over the last decade concerning the effects of vitamin D on skeletal and nonskeletal tissues. The demonstration that the vitamin D receptor is expressed in virtually all cells of the body and the growing body of observational data supporting a relationship of serum 25-hydroxyvitamin D to chronic metabolic, cardiovascular, and neoplastic diseases have led to widespread utilization of vitamin D supplemen- tation for the prevention and treatment of numerous disorders. In this paper, we review both the basic and clinical aspects of vitamin D in relation to nonskeletal organ systems. We begin by focusing on the molecular aspects of vitamin D, primarily by examining the structure and function of the vitamin D receptor. This is followed by a systematic review according to tissue type of the inherent biological plausibility, the strength of the observational data, and the levels of evidence that support or refute an association between vitamin D levels or supplementation and maternal/child health as well as various disease states. Although observational studies support a strong case for an association between vitamin D and musculoskeletal, cardiovascular, neoplastic, and metabolic disorders, there remains a paucity of large-scale and long-term randomized clinical trials. Thus, at this time, more studies are needed to definitively conclude that vitamin D can offer preventive and therapeutic benefits across a wide range of physiological states and chronic nonskeletal disorders. (Endocrine Reviews 33: 456–492, 2012) I. Introduction F. Conclusions II. Distribution, Structure, and Function of the Vitamin D IV. Vitamin D and Its Relationship to Obesity and Diabetes Receptor Mellitus A. Background A. Introduction B. VDR distribution B. Observational studies of the relationship of vitamin C. VDR structure D to obesity and the metabolic syndrome C. Randomized trials of vitamin D in obesity, type 2 D. Role of coactivators and corepressors diabetes mellitus E. Plasticity of the VDRE D. Conclusions F. Nongenomic actions of vitamin D V. Vitamin D for the Prevention of Falls and Improvement III. Vitamin D and the Skin in Quality of Life A. Introduction A. Introduction B. Proliferation, differentiation, barrier function of B. Observational studies of vitamin D and falls skin C. Randomized trials of vitamin D on falls C. Coactivators and corepressors of vitamin D in skin D. Effects of vitamin D supplementation on pain and D. Hair follicle phenotype, 1,25-(OH)2D indepen- quality of life dence, molecular interactors, and targets E. Translational studies and clinical trials of vitamin Abbreviations: BMI, Body mass index; CI, confidence interval; CV, cardiovascular; CVD, CV disease; 1,25D-MARRSBP, 1,25-(OH)2D membrane-associated rapid response steroid- D and skin binding protein; DRIP, VDR-interacting protein; HAT, histone acetyl transferase; HR, hazard ratio; IFN-␥, interferon-␥; LBD, ligand-binding domain; LEF1, lymphoid enhancer-binding ISSN Print 0163-769X ISSN Online 1945-7189 factor-1; LPS, lipopolysaccharide; mTB, Mycobacterium tuberculosis; NR, nuclear receptor; Printed in U.S.A. NOD, nonobese diabetic; 1,25-(OH)2D, 1,25-dihydroxyvitamin D; 25(OH)D, 25-hydroxyvi- Copyright © 2012 by The Endocrine Society tamin D; OR, odds ratio; PRR, pattern recognition receptor; RCT, randomized clinical trial; doi: 10.1210/er.2012-1000 Received January 5, 2012. Accepted April 18, 2012. RR, relative risk; RXR, retinoid X receptor; SRC, steroid receptor coactivator; TLR, Toll-like re- First Published Online May 17, 2012 ceptor; UCP, uncoupling protein; VDR, vitamin D receptor; VDRE, vitamin D response element. 456 edrv.endojournals.org Endocrine Reviews, June 2012, 33(3):456–492 Endocrine Reviews, June 2012, 33(3):456–492 edrv.endojournals.org 457 E. Conclusions because this molecule represents the final common path- VI. Vitamin D and Cancer way through which vitamin D works on nonskeletal tis- A. Introduction B. Total cancer and cancer mortality: research sues. We next critically evaluate the literature for each findings organ system, beginning with the biological plausibility of C. Vitamin D and the risk of site-specific cancers an association, followed by utilization of the available D. Other site-specific cancers evidence from observational studies and randomized tri- E. Conclusions VII. Vitamin D and Cardiovascular Disease als, to delineate the strength of associations between se- A. Introduction rum 25-hydroxyvitamin D [25(OH)D] and/or dose of vi- B. Studies of hypertension and lipids tamin D supplementation and tissue-specific outcomes. C. Studies of other CVD endpoints Several reviews of the skeletal effects of vitamin D have VIII. Vitamin D and Immune Function A. Introduction recently been published, including The Endocrine Soci- B. Clinical observations and trials ety’s Clinical Practice Guideline on vitamin D deficiency C. Conclusions and the complete Institute of Medicine (IOM) Report on IX. Vitamin D, the Placenta, and Maternal/Fetal Health A. Introduction Calcium and Vitamin D (1–3). It is important to note that B. Biological plausibility after the publication of these two summaries, our work C. Animal data took on additional significance, particularly in relation to D. Observational and association studies nonskeletal effects of vitamin D, as the controversy sur- E. Randomized interventional trials F. Conclusions rounding the definition of a target serum level of 25(OH)D X. Summary and Future Direction reached new heights. Importantly, this Scientific State- ment represents the first comprehensive evaluation of both the basic and clinical evidence related to the effects of I. Introduction vitamin D on nonskeletal tissues. he 100th anniversary of the identification of a factor T whose deficiency was linked to the development of rickets, and was later found to be cholecalciferol, is ap- II. Distribution, Structure, and Function of the proaching. Painstaking work by a number of laboratories Vitamin D Receptor over the last nine decades convincingly demonstrated that A. Background cholecalciferol not only was essential for skeletal health Vitamin D is a steroid hormone, and the active metab- but also was a hormone mediating nonclassical tissue ef- olite, 1,25-(OH) D, is the ligand for a transcription factor fects across a wide range of homeostatic functions. The 2 and intracellular receptor called the “vitamin D receptor.” physiology of vitamin D from its synthesis in the skin to its The VDR is widely distributed across many tissues. In- active form, 1,25-dihydroxyvitamin D [1,25-(OH)2D], was fully defined by the mid-1970s (Fig. 1, A and B). How- deed, cells lacking the VDR are the exception rather than ever, the cloning of the vitamin D receptor (VDR) did not the rule, and this widespread distribution underlies the occur until 1987, and its subsequent identification in vir- potential myriad of physiological actions for vitamin D. tually all tissues spurred further basic and clinical studies Not surprisingly, most if not all effects of 1,25-(OH)2D are and led to a much greater appreciation of the physiological mediated by the VDR acting primarily by regulating the role of vitamin D (Fig. 2). At the same time, interest in expression of genes whose promoters contain specific vitamin D as a therapeutic modality for the prevention of DNA sequences known as vitamin D response elements chronic diseases grew exponentially. Indeed, in a 2-month (VDRE). The VDR works in partnership with other tran- span during the summer of 2011, there were more than scription factors, the best-studied of which is the retinoid 500 publications centered on vitamin D, most of which X receptor (RXR), and a number of coactivators and core- were related to its relationship to nonskeletal tissues. pressors that provide context, tissue, and target gene speci- However, the results from those studies, as well as others, are confounded and difficult to interpret. In this Scientific ficity. However, some actions of 1,25-(OH)2D are more im- Statement we seek to outline the evidence that defines the mediate and may be mediated by a membrane-bound effects of vitamin D on epidermal, neuromuscular, car- VDR that has been less well characterized than the nu- diovascular (CV), metabolic, immunological, maternal/ clear VDR. Our understanding of the mechanism by fetal, and neoplastic tissues. Before reviewing the evidence which VDR regulates gene expression has increased enor- in these areas, we first present an overview of the VDR mously over the past few years. 458 Rosen et al. Nonskeletal Effects of Vitamin D Endocrine Reviews, June 2012, 33(3):456–492 Figure 1. Figure 1. A, Production of vitamin D from the skin via ultraviolet radiation (290–330 nm) in a nonenzymatic manner. B, The synthesis of vitamin D metabolites including the inactive form, 24,25-dihydroxyvitamin D, and the active form, 1,25-(OH)2D. This process is controlled at several levels, including the liver, kidney, and peripheral tissues, and is regulated by systemic hormones including PTH, 1,25-(OH)2D, and FGF23. Calcium and phosphorus are also major modulators of 1␣-hydroxylase and 24,25-hydroxylase activity through their effects on PTH and FGF23.
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