Homocysteine-Lowering Treatment and the Risk of Fracture: Secondary Analysis of a Randomized Controlled Trial and an Updated Meta-Analysis

High plasma homocysteine is a risk factor for osteoporotic fractures. Several studies have assessed the possible preventive effect of homocysteine-lowering B-vitamin treatment on the risk of fracture with inconclusive results. In the current study, we include new results from the Aspirin Folate Polyp Prevention Study (AFPPS) together with an updated meta-analysis of randomized controlled trials (RCTs). Our objective was to determine whether there is an association between homocysteine-lowering B-vitamin treatment and the risk of fracture. The AFPPS trial was performed between 1994 and 2004 in nine clinical centers in the United States, and 1021 participants were randomized to a daily folic acid dose of 1 mg (n = 516) or placebo (n = 505). The main outcome was fracture of any type. In addition, we analyzed the risk of hip fracture. In the meta-analysis, studies were identified following a search strategy in electronic database and by hand searching. Risk ratio with 95% confidence interval (CI) was chosen for pooled analyses. In the AFPPS, no statistically significant association was found between folic acid treatment and fractures of any type (risk ratio [RR] = 0.95; 95% CI 0.61–1.48) or hip fracture (RR = 0.98; 95% CI 0.25–3.89). In the meta-analysis, six RCTs were included with a total of 36,527 participants. For interventions including folic acid and/or vitamin B12, the pooled RR for treatment was 0.97 (95% CI 0.87–1.09) for fractures of any type (n = 1199) and 1.00 (95% CI 0.81–1.23) for hip fractures (n = 335). In conclusion, no association was found between homocysteine-lowering treatment with B vitamins (folic acid and vitamin B12) and the risk of fracture