Skeletal and Extraskeletal Actions of Vitamin D: Current Evidence and Outstanding Questions

Abstract

The etiology of endemic rickets was discovered a century ago. Vitamin D is the precursor of 25-hydroxyvitamin D and other metabolites, including 1,25(OH)2D, the ligand for the vitamin D receptor (VDR). The effects of the vitamin D endocrine system on bone and its growth plate are primarily indirect and mediated by its effect on intestinal calcium transport and serum calcium and phosphate homeostasis. Rickets and osteomalacia can be prevented by daily supplements of 400 IU of vitamin D. Vitamin D deficiency (serum 25-hydroxyvitamin D <50 nmol/L) accelerates bone turnover, bone loss, and osteoporotic fractures. These risks can be reduced by 800 IU of vitamin D together with an appropriate calcium intake, given to institutionalized or vitamin D-deficient elderly subjects. VDR and vitamin D metabolic enzymes are widely expressed. Numerous genetic, molecular, cellular, and animal studies strongly suggest that vitamin D signaling has many extraskeletal effects. These include regulation of cell proliferation, immune and muscle function, skin differentiation, and reproduction, as well as vascular and metabolic properties. From observational studies in human subjects, poor vitamin D status is associated with nearly all diseases predicted by these extraskeletal actions. Results of randomized controlled trials and Mendelian randomization studies are supportive of vitamin D supplementation in reducing the incidence of some diseases, but, globally, conclusions are mixed. These findings point to a need for continued ongoing and future basic and clinical studies to better define whether vitamin D status can be optimized to improve many aspects of human health. Vitamin D deficiency enhances the risk of osteoporotic fractures and is associated with many diseases. We review what is established and what is plausible regarding the health effects of vitamin D.

Figure 1.

Metabolism and action of vitamin D and its metabolites, with special focus on renal and extrarenal production of 1,25(OH)₂D and the genomic or nongenomic pathways of vitamin D action.

Figure 2.

Radiologic image of nutritional rickets. A radiologic image of a 19-mo-old child with nutritional rickets is shown. The child was born from Indian parents, living in Australia, after a normal pregnancy of 40 wk and received exclusive breastfeeding for 18 mo without vitamin D supplementation. Height and weight were around the 50th percentile. Medical attention was asked because of genu varum and delayed walking. Serum calcium (2.01 mmol/L; 2.10 to 2.65) and phosphate were slightly decreased. Serum 25OHD was <18 nmol/L and alkaline phosphatase and PTH (126 pmol/L; 1.0 to 7.0) levels were high.

Figure 3.

Regulation of keratinocyte differentiation by calcium and 1,25(OH)₂D. Calcium and 1,25(OH)₂D interact to regulate keratinocyte differentiation at multiple steps. 1,25(OH)₂D acts via its nuclear hormone receptor, VDR, to directly regulate gene transcription. Among the genes that it regulates are involucrin and loricrin, which encode major constituents of the cornified envelope (CE) as well as transglutaminase (TG) that crosslinks these proteins and others to form the CE. Although the effects of calcium on gene transcription do not appear to be direct, calcium is likely to act at least in part through protein kinase C, which phosphorylates and so activates transcription factors of the AP-1 family critical for the induction of these genes. Not shown is that 1,25(OH)₂D also induces genes that encode enzymes that produce the long-chain lipids required for “waterproofing” the CE. 1,25(OH)₂D also induces the calcium sensing receptor (CaR) that responds to extracellular calcium by activating phospholipase C (PLC). PLC, by cleaving phosphatidylinositol bisphosphate (PIP₂), releases two important signaling molecules: diacylglycerol (DG) and inositol trisphosphate (IP₃). The latter releases calcium from intracellular stores such as the endoplasmic reticulum (ER) and Golgi through the IP₃ receptor (IP₃R). DG works in conjunction with calcium to activate protein kinase C. 1,25(OH)₂D induces both the β and γ forms of PLC, but calcium is required for their activation. The CaR also activates Src/Fyn, which phosphorylate the catenins, including β-catenin, to enable their binding to and formation of the E-cadherin complex in the membrane. Both calcium and 1,25(OH)₂D are essential for the formation of this complex: 1,25(OH)₂D induces E-cadherin, whereas calcium promotes its translocation to the membrane. Not shown is that α-catenin binds to β-catenin, linking the E-cadherin/catenin complex to the cytoskeleton, critical for cell migration. The E-cadherin/catenin complex also contains two enzymes, phosphatidylinositol phosphate 5 kinase 1α (PIP5K1α) and phosphatidylinositol 3 kinase (PI3K), that sequentially phosphorylate PIP to PIP₂ to PIP₃. PIP₃ is the major activator of PLC-γ1 during keratinocyte differentiation, which in addition to promoting the cleavage of PIP₂ to IP₃ and DG also activates at least one of the calcium channels, TRP3. [Reproduced with permission from Bikle DD. Vitamin D, Calcium. and the Epidermis. In: Feldman D, Wesley Pike J, Bouillon R, et al., eds. Vitamin D. 4th ed. London: Academic Press; 2018:527-544.]

Figure 4.

Vitamin D metabolism and signaling in innate immunity. The figure depicts intracrine production 1,25(OH)₂D from circulating 25OHD in macrophages and DCs, as well as the effects of 1,25(OH)₂D signaling on expression of several classes of proteins implicated in innate immune signaling. See text for details.

Figure 5.

Vitamin D metabolism and signaling in the acquired immune system. In antigen-presenting cells (including DCs), 1,25(OH)₂D₃ inhibits the surface expression of major histocompatibility complex II (MHC-II)–complexed antigen and of costimulatory molecules, in addition to production of the cytokines IL-12 and IL-23, thereby indirectly shifting the polarization of T cells from a Th1 and Th17 phenotype toward a Th2 phenotype. Additionally, 1,25(OH)₂D₃ directly affects T cell responses by inhibiting the production of Th1 cytokines (IL-2 and IFN-γ) and Th17 cytokines (IL-17 and IL-21), as well as by stimulating Th2 cytokine production (IL-4). Moreover, 1,25(OH)₂D₃ favors Treg cell development via modulation of DCs and by directly targeting T cells. Finally, 1,25(OH)₂D₃ blocks plasma-cell differentiation, IgG and IgM production, and B cell proliferation.