Vitamin D and bone health: from physiological function to disease association

Vitamin D (VD) is a pleiotropic secosteroid hormone with well-established roles in calcium homeostasis, bone metabolism, and emerging functions in immune regulation, inflammation, and chronic disease modulation. In this paper, we provide a comprehensive summary of the current research on the significance of VD for bone health, with emphasis on its mechanism of action and its clinical significance in bone health. This review starts with an overview of VD metabolism, with emphasis on the enzyme transformation of vitamin D3 (VD3) and vitamin D2 (VD2) into the active 1,25-dihydroxyvitamin D (1α,25(OH)₂D) and their genomic and non-genomic signaling pathways through the Vitamin D receptor (VDR). Then, we discuss how VDR polymorphisms affect disease susceptibility and the dual role of VD in promoting innate immunity as well as inhibiting over-adaptive immunity. Our main focus is placed on VD’s involvement in bone destruction diseases, including osteoarthritis (OA), osteoporosis (OP), rheumatoid arthritis (RA), and bone tuberculosis. For OA, there is conflicting evidence on whether VD supplementation reduces cartilage degradation or pain. In OP, vitamin D deficiency aggravates bone loss, but the effectiveness of supplementation is dependent on baseline and calcium supplementation. For RA, the immunomodulatory effects of VD may decrease the activity of the disease, whereas in tuberculosis, VD increases the clearance of macrophage-mediated mycobacterial clearance, although the clinical study data are still inconclusive. This review underscores VD as a critical mediator of bone-immune crosstalk while calling for rigorous translational research to clarify its therapeutic potential across diverse diseases.