Rosiglitazone Associated Fractures in Type 2 Diabetes: An Analysis From ADOPT

Abstract Objective: To examine possible factors associated with the increased risk of fractures observed with rosiglitazone in ADOPT (A Diabetes Outcome Progression Trial). Research Design and Methods: Data from the 1840 women and 2511 men randomized in ADOPT to rosiglitazone, metformin or glyburide for a median of 4.0 years were examined with respect to time to first fracture, rates of occurrence and sites of fractures. Results: In men, fracture rates did not differ between treatment groups. In women, at least one fracture was reported with rosiglitazone in 60 patients (9.3% of patients, 2.74/100 patient years [PY]), metformin in 30 (5.1%, 1.54/100 PY) and glyburide in 21 (3.5%, 1.29/100 PY). The cumulative incidence (95% CI) of fractures in women at five years was 15.1% (11.2, 19.1) with rosiglitazone, 7.3% (4.4, 10.1) with metformin and 7.7% (3.7, 11.7) with glyburide, representing hazard ratios of 1.81 (1.17, 2.80) and 2.13 (1.30, 3.51) for rosiglitazone compared to metformin and glyburide, respectively. The increase in fractures with rosiglitazone occurred in pre- and postmenopausal women, and was predominantly in the lower and upper limb. No particular risk factor underlying the increased fractures in female patients who received rosiglitazone therapy was identified. Conclusions: Further investigation into the risk factors and underlying pathophysiology for the increased fracture rate in women taking rosiglitazone is required to relate them to preclinical data and better understand the clinical implications of and possible interventions for these findings.