The nonskeletal effects of vitamin D: an Endocrine Society scientific statement

Abstract

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 supplementation 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.

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 1α-hydroxylase and 24,25-hydroxylase activity through their effects on PTH and FGF23. FGF 23, Fibroblast growth factor 23.

Figure 2.

Model of the VDR. The N-terminal region is short relative to other steroid hormone receptors. This region is followed by two zinc fingers, which constitute the principal DNA-binding domain. NLS are found within and just C-terminal to the DNA-binding domain. The LBD makes up the bulk of the C-terminal half of the molecule, with the AF-2 domain occupying the most C-terminal region. The AF-2 domain is largely responsible for binding to coactivators such as the SRC family and DRIP in the presence of ligand. Regions on the second zinc finger and within the LBD facilitate heterodimerization with RXR. Corepressor binding is less well characterized but appears to overlap that of coactivators in helices 3 and 5, a region blocked by helix 12 in the presence of ligand. NLS, Nuclear localization signals.

Figure 3.

Impact of vitamin D on the human innate (upper panel) and adaptive immune response (lower panel). When activated by mitogen or specific antigen, macrophages, dendritic cells, and lymphocytes express the VDR, thereby becoming targets for the active vitamin D metabolite, 1,25-(OH)₂D. Macrophages and dendritic cells can also express the CYP27B1-hydroxylase that synthesizes 1,25-(OH)₂D from substrate 25(OH)D, the major circulating metabolite of vitamin D and acknowledged best indicator of the amount of vitamin D entering the host via cutaneous synthesis or that ingested in the diet. Operating in an intracrine mode, 1,25-(OH)₂D promotes microbial killing in the macrophage, whereas it inhibits maturation and the antigen-presenting capacity of the dendritic cell. If 1,25-(OH)₂D escapes the confines of the macrophage or dendritic cell in sufficient amount, it can act on VDR-expressing lymphocytes recruited to the local inflammatory microenvironment. The major bioaction of 1,25-(OH)₂D acting through the VDR in lymphocytes is to inhibit their proliferation and differentiation to maturity; this antiproliferative effect is more profound on the classes of helper than suppressor cells, leading to generalized suppression of the adaptive immune response. 1,25D, 1,25-dihydroxyvitamin D; 25D, 25-hydroxyvitamin D.