Thiazolidinedione Therapy Gets Complicated

An escalating number of recent publications suggest that the thiazolidinedione (TZD) medications may have a negative effect on the skeleton. The manufacturers of the two currently available TZDs, rosiglitazone and pioglitazone, have both issued letters to health care providers, warning that these medications may cause an increased risk of fracture in women (1,2). TZDs improve insulin sensitivity and are widely prescribed for type 2 diabetes, but we are just beginning to understand their clinical effects on bone. In December 2006, the ADOPT trial reported a higher risk of fractures in diabetic women randomized to rosiglitazone than in women randomized to metformin or glyburide (3). The ADOPT trial followed 4,360 (42% women) participants with a mean age of 57 years for a median of 4 years. The primary outcome was time to monotherapy failure as determined by fasting glucose. An imbalance in fracture rates was identified in a final review of adverse event reports. The proportion of women reporting a fracture was 9.3% for rosiglitazone, 5.1% for metformin, and 3.5% for glyburide, corresponding to an approximate relative risk (RR) of 2.18 (95% CI 1.52–3.13) for rosiglitazone versus the other treatments combined. Among male participants, 89 reported a fracture, distributed similarly across treatments (rosiglitazone 3.9%, metformin 3.4%, and glyburide 3.3%), corresponding to an approximate RR of 1.18 (0.77–1.80), for rosiglitazone versus the other treatments combined. Pioglitazone, the other currently available TZD, may also have negative skeletal effects. In March 2007, Takeda (2) reported increased fracture risk in women, but not men, using pioglitazone, based on an analysis of their clinical trial database, including 24,000 person-years of follow-up. Among women, fracture incidence was 1.9 per 100 person-years for pioglitazone and 1.1 per 100 person-years for those using placebo or another active drug. The incidence for men was not reported but did …