B Vitamins and Hip Fracture: Secondary Analyses and Extended Follow-Up of Two Large Randomized Controlled Trials

Abstract

Elevated plasma homocysteine levels are associated with increased risk of fractures in observational studies. However, it is unsettled whether homocysteine-lowering treatment affects fracture risk. The aim of this study was to investigate the effect of an intervention with B vitamins on the risk of hip fracture in a secondary analysis of combined data from two large randomized controlled trials originally designed to study cardiovascular diseases. Both trials had identical design, intervention, and primary objective. Based on a two-by-two factorial design, the intervention consisted of a daily capsule with either (1) folic acid (0.8 mg) plus vitamin B12 (0.4 mg) and vitamin B6 (40 mg); (2) folic acid (0.8 mg) plus vitamin B12 (0.4 mg); (3) vitamin B6 alone (40 mg); or (4) placebo. The participants were followed with respect to hip fracture during the trial or during an extended follow-up (from the trial start for each patient until the end of 2012). No statistically significant association was found between folic acid plus vitamin B12 treatment and the risk of hip fracture, neither during the trial (median 3.3 years; hazard ratio [HR] 0.87; 95% confidence interval [CI], 0.48 to 1.59) nor during the extended follow-up (median 11.1 years; HR 1.08; 95% CI, 0.84 to 1.40). Nor were there significant differences in the risk of hip fracture between groups receiving versus not receiving vitamin B6 during the trial (HR 1.42; 95% CI, 0.78 to 2.61). However, during the extended follow-up, those receiving vitamin B6 showed a significant 42% higher risk of hip fracture (HR 1.42; 95% CI, 1.09 to 1.83) compared to those not receiving vitamin B6. In conclusion, treatment with folic acid plus vitamin B12 was not associated with the risk of hip fracture. Treatment with a high dose of vitamin B6 was associated with a slightly increased risk of hip fracture during the extended follow-up (in-trial plus post-trial follow-up). © 2017 American Society for Bone and Mineral Research.