Risk of fracture with thiazolidinediones: an updated meta-analysis of randomized clinical trials

Objective: The use of thiazolidinediones (TZDs) has been associated with increased fracture risk. We performed a comprehensive literature review and meta-analysis to estimate the risk of fractures with TZDs

Methods: We searched MEDLINE, Embase and the Cochrane Database, from inception to May 2014. We included all randomized trials that described the risk of fractures or changes in bone mineral density (BMD) with TZDs. We pooled data with odds ratios (ORs) for fractures and the weighted mean difference in BMD. To assess heterogeneity in results of individual studies, we used Cochran's Q statistic and the I(2) statistic.

Results: We included 24,544 participants with 896 fracture cases from 22 randomized controlled trials. Meta-analysis showed that the significantly increased incidence of fracture was found in women (OR=1.94; 95%CI: 1.60-2.35; P<0.001), but not in men (OR=1.02; 95%CI: 0.83-1.27; P=0.83). For women, the fracture risk was similar in rosiglitazone (OR=2.01; 95%CI: 1.61-2.51; P<0.001) and pioglitazone (OR=1.73; 95%CI: 1.18-2.55; P=0.005) treatment and appeared to be similar for participants aged <60years old (OR=1.89; 95%CI: 1.51-2.36; P<0.001) and aged ≥60years old (OR=2.07; 95%CI: 1.51-2.36; P<0.001). There was a non-significant trend towards increased risk of fractures in different cumulative durations of TZD exposure. TZD treatment was also associated with significant changes in BMD among women at the lumbar spine(weighted mean difference: -0.49%, 95%CI: -0.66% to -0.32%; P<0.001), the femoral neck (weighted mean difference: -0.34%, 95%CI: -0.51% to -0.16%; P<0.001) and the hip(weighted mean difference: -0.33%, 95%CI: -0.52% to -0.14%; P<0.001).

Conclusions: Our results suggest that TZD treatment is associated with an increased risk of fractures in women, effects of rosiglitazone and pioglitazone are similar, fracture risk is independent of age and fracture risk has no clear association with duration of TZD exposure.