Comparing the Evidence from Observational Studies and Randomized Controlled Trials for Nonskeletal Health Effects of Vitamin D

Although observational studies of health outcomes generally suggest beneficial effects with, or following, higher serum 25-hydroxyvitamin D [25(OH)D] concentrations, randomized controlled trials (RCTs) have generally not supported those findings. Here we review results from observational studies and RCTs regarding how vitamin D status affects several nonskeletal health outcomes, including Alzheimer’s disease and dementia, autoimmune diseases, cancers, cardiovascular disease, COVID-19, major depressive disorder, type 2 diabetes, arterial hypertension, all-cause mortality, respiratory tract infections, and pregnancy outcomes. We also consider relevant findings from ecological, Mendelian randomization, and mechanistic studies. Although clear discrepancies exist between findings of observational studies and RCTs on vitamin D and human health benefits these findings should be interpreted cautiously. Bias and confounding are seen in observational studies and vitamin D RCTs have several limitations, largely due to being designed like RCTs of therapeutic drugs, thereby neglecting vitamin D’s being a nutrient with a unique metabolism that requires specific consideration in trial design. Thus, RCTs of vitamin D can fail for several reasons: few participants’ having low baseline 25(OH)D concentrations, relatively small vitamin D doses, participants’ having other sources of vitamin D, and results being analyzed without consideration of achieved 25(OH)D concentrations. Vitamin D status and its relevance for health outcomes can usefully be examined using Hill’s criteria for causality in a biological system from results of observational and other types of studies before further RCTs are considered and those findings would be useful in developing medical and public health policy, as they were for nonsmoking policies. A promising approach for future RCT design is adjustable vitamin D supplementation based on interval serum 25(OH)D concentrations to achieve target 25(OH)D levels suggested by findings from observational studies.