Vitamin D metabolism and extraskeletal outcomes: an update

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.