Vitamin D and Health Outcomes: State-of-the-Art Review of Triangulated Evidence and Ongoing Controversies
Abstract
PURPOSE OF REVIEW: Vitamin D is a pleiotropic hormone with an established role in skeletal integrity and broader actions in immune regulation, inflammation, cellular proliferation, and energy homeostasis. Despite decades of research, its extra-skeletal effects remain controversial, largely due to discordant findings across observational studies, Mendelian randomization studies (MRS), and randomized controlled trials (RCTs). Unlike many prior reviews, this state-of-the-art review synthesizes triangulated evidence across these study designs to clarify outcome-specific causal relationships and ongoing controversies. RECENT FINDINGS: Triangulated evidence provides strong and consistent support for a causal role of vitamin D in skeletal health, particularly in the prevention and treatment of rickets and osteomalacia, and in fracture risk reduction among vitamin D–deficient and older populations. For selected extra-skeletal outcomes, modest and threshold-dependent benefits are observed, including reductions in cancer mortality, protection against autoimmune disorders, most convincingly multiple sclerosis, and decreased risk of acute respiratory infections, including COVID-19, primarily in individuals with low baseline 25(OH)D concentrations. In contrast, associations with cardiovascular disease, metabolic disorders, obesity, and most neuropsychiatric outcomes are not consistently supported by genetic or interventional evidence, suggesting limited or non-causal effects. Across…
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