LAUSR

There is considerable discussion of the importance for increased serum 25‐hydroxyvitamin D (S‐25OHD) concentration associated with adequacy for bone health. Accordingly, whether long‐term high S‐25OHD concentration in general positively affects bone mineral density (BMD) is uncertain. We used a Mendelian randomization design to determine the association between genetically increased S‐25OHD concentrations and BMD. Five single‐nucleotide polymorphisms (SNPs) in or near genes encoding enzymes and carrier proteins involved in vitamin D synthesis or metabolism were used as instrumental variables to genetically predict 1 standard deviation increase in S‐25OHD concentration. Summary statistics data for the associations of the S‐25OHD‐associated SNPs with dual‐energy X‐ray absorptiometry (DXA)‐derived femoral neck and lumbar spine BMD were obtained from the Genetic Factors for Osteoporosis (GEFOS) Consortium (32,965 individuals) and ultrasound‐derived heel estimated BMD from the UK Biobank (142,487 individuals). None of the SNPs were associated with BMD at Bonferroni‐corrected significance level, but there was a suggestive association between rs6013897 near CYP24A1 and femoral neck BMD (p = 0.01). In Mendelian randomization analysis, genetically predicted 1 standard deviation increment of S‐25OHD was not associated with higher femoral neck BMD (SD change in BMD 0.02; 95% confidence interval [CI] –0.03 to 0.07; p = 0.37), lumbar spine BMD (SD change in BMD 0.02; 95% CI –0.04 to 0.08; p = 0.49), or estimated BMD (g/cm2 change in BMD –0.03; 95% CI –0.05 to –0.01; p = 0.02). This study does not support a causal association between long‐term elevated S‐25OHD concentrations and higher BMD in generally healthy populations. These results suggest that more emphasis should be placed on the development of evidence‐based cut‐off points for vitamin D inadequacy rather than a general recommendation to increase S‐25OHD. © 2018 American Society for Bone and Mineral Research.