Objective Rickets and osteomalacia are rare diseases caused by vitamin D deficiency. The US Institute of Medicine considers that there is a risk of vitamin D deficiency with serum 25(OH)vitamin D<30 nmol/L, and potential risk between 30–50 nmol/L, relying on evidence from surrogate markers, e.g. parathyroid hormone suppression, unmineralised bone on biopsy. 25(OH)D shows considerable analytical variability, is not the bioactive metabolite, and is expensive to measure. Academic enthusiasm for, media coverage of, and public interest in, vitamin D supplementation to prevent a wide range of diseases, with some claims that serum 25(OH)D≥75 nmol/L is optimal, have led to marked increases in requests to measure 25(OH)D (119% increase in NE Scotland over 4 y). We investigated whether clinical endpoints from randomised controlled trials (RCTs) supported supplementation for diseases other than rickets and osteomalacia.

Method In December 2015, we searched Pubmed, recent systematic reviews, and trial registries for RCTs of vitamin D with surrogate or clinical endpoints in adults. We examined whether vitamin D affected a range of clinical endpoints according to baseline 25(OH)D status, whether mean/median baseline 25(OH)D in RCTs changed over time, and whether ongoing trials will evaluate clinical endpoints from vitamin D supplementation in populations at risk of deficiency.

Results We found 547 RCTs of vitamin D supplementation, with 137 reporting clinical endpoints, and 118 reporting baseline 25(OH)D. Mean/median baseline 25(OH)D was <25, 25–49,≥50 nmol/L in 12 (10%), 62 (53%), and 44 (38%) of RCTs, respectively. No effect was evident for nonskeletal outcomes in the full dataset. Of 12, mostly small, RCTs in populations with 25(OH)D<25 nmol 8 had neutral results and 4 showed benefit (3 primary endpoints, 1 secondary endpoint). Trials reporting subgroup analyses for 25(OH)D<20–32 nmol/L recapitulated the main analyses in all 7 trials, with only 1 trial showing benefit. Baseline 25(OH)D increased over time, and large (≥1000) ongoing trials are likely to have baseline 25(OH)D >40–50 nmol/L.

Conclusions The evidence supporting supplementation with vitamin D in populations with 25(OH)D<25 nmol/L is weak for outcomes other than rickets and osteomalacia, and does not suggest benefit above this threshold. Assessing vitamin D status for healthy populations, with little risk of rickets or osteomalacia from very low sunlight exposure, is not clinically useful.