Vitamin D and Health: Establishing Causal Relationships Through Observational Evidence and Hill's Criteria in a...

Vitamin D has been linked to beneficial effects across more than 100 health outcomes, generating substantial interest in its extraskeletal functions. However, because nutrients differ fundamentally from pharmaceuticals in biology and mechanisms of action, conventional pharmaceutical-style randomized controlled trials (RCTs) are often inappropriate for evaluating nutrient efficacy. Instead, well-designed observational studies that have assessed serum 25-hydroxyvitamin D [25(OH)D] concentrations and correlated them with biologically relevant clinical outcomes provide evidence of effectiveness and establish causality. Since vitamin D primarily acts as a preventive agent for chronic diseases, the strongest evidence is derived from large, long-term, ecological and prospective cohort studies. In contrast, many RCTs have failed to demonstrate significant benefits because of methodological limitations, including enrollment of vitamin D-sufficient participants, inadequate dosing regimens, vitamin D supplementation in control groups, short intervention periods, and analyses based on assigned dose rather than serum 25(OH)D concentrations achieved, which determine biological responses. Early ecological studies demonstrated inverse associations between solar ultraviolet B doses and the risks of cancer, cardiovascular disease (CVD), and infectious diseases. These findings have been consistently supported by numerous prospective larger cohort studies linking higher serum 25(OH)D concentrations with improved health outcomes. Observational studies also offer important advantages, including being large and covering diverse populations, wide variations in vitamin D status, longer follow-up, and adjustment for multiple confounding factors. When interpreted within a biological framework using Bradford Hill's criteria for causality-including consistency, strength and temporality of associations, dose-response relationships, biological plausibility, mechanistic evidence, coherence, and experimental support-the accumulated evidence strongly supports causal relationships that vitamin D sufficiency reduces risks of several diseases. This narrative review critically evaluates the evidence for cancer, CVD, blood pressure, COVID-19, type 1 and type 2 diabetes, periodontal disease, multiple sclerosis, and dementia. For these diseases, the authors concluded that the evidence satisfies Hill's criteria for causality and aligns with current understanding of vitamin D biology and nutrient-health relationships.