LAUSR

We thank Grant et al. for their interest in our recently published Review on vitamin D supplementation (Bouillon, R. et al. The health effects of vitamin D supplementation: evidence from human studies. Nat. Rev. Endocrinol. 18, 96–110 (2022)1). Considering the well-accepted hierarchy of evidence, our Review dealt with large randomized clinical trials (RCTs) published from 2017 to 2020 and Mendelian randomization studies, and deliberately did not review observational studies. Grant et al., however, use several observational studies and post hoc analyses to argue the benefits of high serum concentrations of 25-hydroxyvitamin D (25OHD) on hypertension, breast cancer or type 2 diabetes mellitus (T2DM) (Grant, W.B. et al. The emerging evidence for non-skeletal health benefits of vitamin D supplementation in adults. Nat. Rev. Endocrinol. https://doi.org/ 10.1038/s41574-022-00646-x (2022)2). The D2d study of individuals with prediabetes concluded that 4,000 IU of vitamin D per day did not decrease the progression of prediabetes into T2DM in the intention to treat analysis3. In their Correspondence, Grant et al. discuss data from a post hoc analysis of this RCT2. We clearly mentioned in our Review that in this same post hoc analysis, a reduction in the progression from prediabetes to T2DM was found in participants with continuously high serum concentrations of 25OHD (>100 nmol/l) throughout the trial1. This interesting observation should guide a follow up trial, however, it is certainly not sufficient to change clinical practice for patients with prediabetes. Grant et al. cite data on breast cancer incidence in three different cohorts of women, concluding that women with the highest serum concentrations of 25OHD had a lower risk of breast cancer than women with the lowest these studies included too few participants with severe vitamin D deficiency to validate the potential extra skeletal benefits of correcting vitamin D deficiency. While awaiting studies dealing with such questions, we suggest to follow the major guidelines, which unanimously recommend correction of vitamin D status in individuals with severe (serum levels of 25OHD <30 nmol/l) or modest (<50 nmol/l) vitamin D deficiency8.