Effects of TZD Use and Discontinuation on Fracture Rates in ACCORD Bone Study

Context: In trials, thiazolidinediones (TZDs) increase fracture risk in women, but the effects of discontinuation are unknown. Objective: The objective was to investigate the effects of TZD use and discontinuation on fractures in women and men. Design: This was a longitudinal observational cohort study using data from the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial bone ancillary study. Duration of TZD use and discontinuation during ACCORD, assessed every 2–4 months at clinic visits, were modeled as time-varying covariates in proportional hazards models for occurrence of first non-spine fracture. Participants: We studied a total of 6865 participants in ACCORD BONE. Main Outcome Measures: Main outcome measures were centrally adjudicated non-spine fracture. Results: Average age was 62.4 (SD, 6.6) years; average duration of diabetes was 11.1 (SD, 7.8) years. Rosiglitazone was used by 74% and pioglitazone by 13% of participants. During a mean follow-up of 4.8 (SD, 1.5) years, 262 men and 287 women experienced at least one non-spine fracture. The fracture rate was higher in women with 1–2 years of TZD use (hazard ratio [HR] = 2.32; 95% confidence interval [CI], 1.49, 3.62) or >2 years of TZD use (HR = 2.01; 95% CI, 1.35, 2.98), compared with no use. The fracture rate was reduced in women who had discontinued TZD use for 1–2 years (HR = 0.57; 95% CI, 0.35, 0.92) or > 2 years (HR = 0.42; 95% CI, 0.24, 0.74) compared with current users. TZD use and discontinuation were not associated with non-spine fractures in men. Conclusions: TZD use was associated with increased non-spine fractures in women, but not men, with type 2 diabetes. When women discontinued TZD use, the fracture effects were attenuated.