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Abstract Vitamin D deficiency is a candidate risk factor for osteoporosis, characterized by decreased bone mineral density (BMD). We performed this two-sample Mendelian randomization (MR) analysis to investigate the causal effect of vitamin D on BMD. We extracted 143 single-nucleotide polymorphisms from a recent GWAS on 417,580 participants of European ancestry as instrumental variables, and used summary statistics for BMD at forearm (n = 10,805), femoral neck (n = 49,988), lumbar spine (n = 44,731) and total-body of different age-stages (< 15, 15–30, 30–45, 45–60, > 60) (n = 67,358). We explored the direct effect of vitamin D on BMD with an adjusted body mass index (BMI) in a multivariable MR analysis. We found no support for causality of 25-hydroxyvitamin D on BMD at forearm, femoral neck, lumbar spine, and total-body BMD across the lifespan. There was no obvious difference between the total and direct effect of vitamin D on BMD after adjusting for BMI. Our MR analysis provided evidence that genetically determined vitamin D was not causally associated with BMD in the general population. Large-scale randomized controlled trials are warranted to investigate the role of vitamin D supplementation in preventing osteoporosis in the high-risk population.