Why did we end up having so few vitamin D answers and what can we do about it? A provocative and narrative review

In spite of numerous vitamin D publications, including thousands of RCTs, meta-analyses, review papers and editorials, we still do not have answers to the most basic vitamin D questions. The recommendations for vitamin D intake are based on a few and questionable studies, and according to the latest Endocrine Society Guidelines from 2024, there is no clinical trial evidence for establishing serum 25-hydroxyvitamin D (25OHD) thresholds to define vitamin D deficiency. Furthermore, large and impressive vitamin D RCTs, some with more than 20,000 participants, have failed to show significant effects on disease prevention. However, there are indications that vitamin D may have a small preventive effect on type 2 diabetes and auto-immune diseases, and vitamin D may also improve cancer survival. In general, the RCTs have been under-powered, and most subjects included were already vitamin D sufficient. The time for new vitamin D mega trials is probably over, and in the future, we have to design our RCTs smarter. One should mainly include subjects with low serum 25OHD levels, use individual dosing to reach a preset 25OHD level [treat-to-target), use realistic power calculations, and we should use similar study designs to facilitate individual patient data meta-analyses. We must be willing to realize that we have failed, we must be willing to change, and we must be willing to pull our forces together. A vitamin D consensus conference is highly needed. We cannot accept that in 2025 we do not know what is a sufficient serum 25OHD level.