Vitamin D deficiency /insufficiency is widely recognized as a global health problem that is likely to be involved in pathogenesis or progression of many acute and chronic health disorders. Its relation to skeletal health has been clearly demonstrated and thoroughly examined. This review aims to highlight the continuous debate about the relation between vitamin D and extra-skeletal health and whether it is a causality or just an association. Overall, the available evidence does not meet the criteria for establishing cause-and-effect relationships because of the limitations of observational studies to corroborate the causality due to many potential confounders. Moreover, the causal relationship couldn't be established in randomized studies or in many meta-analyses. This may reflect the fact that vitamin D level reduction is just a biomarker of ill health. The inflammatory processes involved in the disease occurrence and the functional limitations of the diseases would have a role in reducing serum 25-hydroxy vitamin D "25 (OH) D" level, which would explain why low vitamin D is reported in a wide range of disorders. This may underscore the possibility of harm instead of benefit of vitamin D supplementation when its exact role is not fully established, thus many guidelines and interest groups are still hesitant toward recommending replacement in extra-skeletal disease. Future directions entails the need for a large well-designed randomized control trials (RCTs) to resolve the active debate on the benefits of vitamin D replacement for extra-skeletal disease, and not only that, future studies should establish specific, clinically relevant effects of vitamin D repletion, provide cut-values for optimal serum levels of 25 (OH) D, and appropriate doses for non-skeletal health benefits.
Keywords: Cancer; Diabetes; Vitamin D; cardiovascular disease; immune system.