Despite thousands of vitamin D studies published, including hundreds of reviews and meta-analyses, it is still uncertain if supplementation with vitamin D will have positive health effects, except for the skeleton. This cannot be answered by doing more observational studies as it is impossible to control for confounding factors and reverse causality. The only way to firmly prove positive vitamin D effects is by doing the properly designed randomized controlled trials (RCTs). However, it has been difficult to show the expected positive effects by vitamin D supplementation in RCTs, which may indicate that the effects, if present must be small. On the other hand, results from Mendelian randomization studies have shown promising results at least for mortality and multiple sclerosis. In the near future, results from several large RCTs with hard endpoints will be available. If these show positive results, the main question on vitamin D and health is answered. If they turn out negative, they will be criticized for having included subjects without vitamin D deficiency, and some studies might not have used an optimal dosing regimen. New and better-designed RCTs will then be needed, but will be very hard to perform.
Keywords: Mendelian randomization; Observational trials; Randomized controlled trials; Reverse causality; Vitamin D.
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