Circulating Alpha-Tocopherol Levels, Bone Mineral Density, and Fracture: Mendelian Randomization Study

Recent cohort studies indicate a potential role of the antioxidant alpha-tocopherol in reducing bone loss and risk of fractures, especially hip fractures. We performed a Mendelian randomization investigation of the associations of circulating alpha-tocopherol with estimated bone mineral density (eBMD) using heel ultrasound and fractures, identified from hospital records or by self-reports and excluding minor fractures. Circulating alpha-tocopherol was instrumented by three genetic variants associated with alpha-tocopherol levels at p < 5 x 10(-8) in a genome-wide association meta-analysis of 7781 participants of European ancestry. Summary-level data for the genetic associations with eBMD in 426,824 individuals and with fracture (53,184 cases and 373,611 non-cases) were acquired from the UK Biobank. Two of the three genetic variants were strongly associated with eBMD. In inverse-variance weighted analysis, a genetically predicted one-standard-deviation increase of circulating alpha-tocopherol was associated with 0.07 (95% confidence interval, 0.05 to 0.09) g/cm(2) increase in BMD, which corresponds to a >10% higher BMD. Genetically predicted circulating alpha-tocopherol was not associated with odds of any fracture (odds ratio 0.97, 95% confidence interval, 0.91 to 1.05). In conclusion, our results strongly strengthen a causal link between increased circulating alpha-tocopherol and greater BMD. Both an intervention study in those with a low dietary intake of alpha-tocopherol is warranted and a Mendelian randomization study with fragility fractures as an outcome.