Long-term use of thiazolidinediones and fractures in type 2 diabetes: a meta-analysis

Background

Rosiglitazone and pioglitazone may increase the incidence of fractures. We aimed to determine systematically the risk of fractures associated with thiazolidinedione therapy and to evaluate the effect of the therapy on bone density.

Methods

We searched MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials (CENTRAL), other trial registries and product information sheets through June 2008. We selected long-term (≥ 1 year) randomized controlled trials involving patients with type 2 diabetes and controlled observational studies that described the risk of fractures or changes in bone density with thiazolidinediones. We calculated pooled odds ratios (ORs) for fractures and the weighted mean difference in bone density.

Results

We analyzed data from 10 randomized controlled trials involving 13 715 participants and from 2 observational studies involving 31 679 participants. Rosiglitazone and pioglitazone were associated with a significantly increased risk of fractures overall in the 10 randomized controlled trials (OR 1.45, 95% confidence interval [CI] 1.18–1.79; p < 0.001). Five randomized controlled trials showed a significantly increased risk of fractures among women (OR 2.23, 95% CI 1.65–3.01; p < 0.001) but not among men (OR 1.00, 95% CI 0.73–1.39; p = 0.98). The 2 observational studies demonstrated an increased risk of fractures associated with rosiglitazone and pioglitazone. Bone mineral density in women exposed to thiazolidinediones was significantly reduced at the lumbar spine (weighted mean difference –1.11%, 95% CI –2.08% to –0.14%; p = 0.02) and hip (weighted mean difference –1.24%, 95%CI –2.34% to –0.67%; p < 0.001) in 2 randomized controlled trials.

Interpretation

Long-term thiazolidinedione use doubles the risk of fractures among women with type 2 diabetes, without a significant increase in risk of fractures among men with type 2 diabetes.Recent systematic reviews have focused on the adverse cardiovascular effects of the thiazolidinediones rosiglitazone and pioglitazone.^1–5 In late 2006, the risk of fractures with the use of rosiglitazone was raised in a footnote of the report of the A Diabetes Outcome and Progression Trial (ADOPT).⁶ The manufacturers of rosiglitazone⁷ and pioglitazone followed this up by issuing warning letters about the risk of fractures.^7–9Women with type 2 diabetes are at an increased risk of nonvertebral fractures,¹⁰ with a near doubling in the risk of hip fractures.¹¹ Any additional risk from thiazolidinedione therapy could have a considerable impact. Our primary objective was to determine systematically the relative and absolute risks of fractures with long-term thiazolidinedione therapy for type 2 diabetes. We also reviewed the effect of thiazolidinedione therapy on bone mineral density to ascertain its biological plausibility.