Vitamin D metabolism and extraskeletal outcomes: an update

Abstract

Vitamin D deficiency is a general health problem affecting individuals at all stages of life and on different continents. The musculoskeletal effects of vitamin D are well known. Its deficiency causes rickets, osteomalacia, and secondary hyperparathyroidism and increases the risk of fractures. Clinical and experimental evidence suggests that vitamin D performs multiple extraskeletal functions. Several tissues unrelated to calcium and phosphate metabolism express vitamin D receptor (VDR) and are directly or indirectly influenced by 1,25(OH)₂D (calcitriol). Some also express the enzyme 1 alpha-hydroxylase (CYP27B1) and produce 1,25(OH)₂D, inducing autocrine or paracrine effects. Among the pleiotropic effects of vitamin D are the regulation of cell proliferation and differentiation, hormone secretion, and immune function. In this review, we outline vitamin D physiology and the outcomes of recent large RCTs on its potential extraskeletal effects. Those studies exhibit a need for continued clinical analysis to elucidate whether vitamin D status can influence extraskeletal health. Longer longitudinal follow-up and standardized assays are crucial to better assess potential outcomes.

Keywords: Vitamin D; randomized controlled trial; vitamin D/metabolism; vitamin D/physiology; vitamin D/therapeutic use.

Figure 1. Basic physiology of vitamin D action. Solar radiation converts 7-dehydrocholesterol (7-DHC) into pre-vitamin D (pre-vit D₃) and thermo-isomerize it to vitamin D3 (VitD₃). Some foods are a source of vitamin D2 and D3 in smaller amounts. Vitamin D (VD) is transported through the plasma by vitamin D binding protein (VDBP), and undergoes two hydroxylations; in the liver, it is converted by the enzyme 25-hydroxylase into 25-hydroxyvitamin D (25OHD), and in the kidneys, the enzyme 1 alpha-hydroxylase converts it into 1,25-dihydroxyvitamin D (1,25(OH)₂D), the active form of vitamin D. When binding to the vitamin D receptor (VDR), it undergoes heterodimerization with the retinoic acid receptor (RXR) in the cell nucleus. This heterodimer binds to the vitamin D responsive element (VDRE), culminating in the regulation and expression of several genes. Among its roles, it inhibits PTH synthesis and stimulates the gene expression of FGF-23. This representation was partly generated using Servier Medical Art, provided by Servier, licensed under a Creative Commons Attribution 3.0 unported license.

Figure 2. Model for Secondary Regulation of Fibroblast Growth Factor-23 by 1,25(OH)₂D/VDR. (Amended from Haussler et al., 2021) (18). [This representation was generated using Servier Medical Art, provided by Servier, licensed under a Creative Commons Attribution 3.0 unported license (https://creativecommons.org/licenses/by/3.0/)].