Hospitalised hip fracture risk with rosiglitazone and pioglitazone use compared with other glucose-lowering drugs

Abstract

Aims/hypothesis: Current drug labels for thiazolidinediones (TZDs) warn of increased fractures, predominantly for distal fractures in women. We examined whether exposure to TZDs affects hip fracture in women and men and compared the risk to that found with other drugs used in diabetes.

Methods: Using a nationwide database of prescriptions, hospital admissions and deaths in those with type 2 diabetes in Scotland we calculated TZD exposure among 206,672 individuals. Discrete-time failure analysis was used to model the effect of cumulative drug exposure on hip fracture during 1999-2008.

Results: There were 176 hip fractures among 37,479 exposed individuals. Hip fracture risk increased with cumulative exposure to TZD: OR per year of exposure 1.18 (95% CI 1.09, 1.28; p = 3 × 10(-5)), adjusted for age, sex and calendar month. Hip fracture increased with cumulative exposure in both men (OR 1.20; 95% CI 1.03, 1.41) and women (OR 1.18; 95% CI 1.07, 1.29) and risks were similar for pioglitazone (OR 1.18) and rosiglitazone (OR 1.16). The association was similar when adjusted for exposure to other drugs for diabetes and for other potential confounders. There was no association of hip fracture with cumulative exposure to sulfonylureas, metformin or insulin in this analysis. The 90-day mortality associated with hip fractures was similar in ever-users of TZD (15%) and in never-users (13%).

Conclusions/interpretation: Hip fracture is a severe adverse effect with TZDs, affecting both sexes; labels should be changed to warn of this. The excess mortality is at least as much as expected from the reported association of pioglitazone with bladder cancer.

Fig. 1

Age-standardised rates of hip fracture by cumulative exposure to TZD in women. The error bars indicate the 95% CI for the rates. The x axis shows cumulative years of exposure; the data point at x = 0 is for all unexposed person time-periods, and the other data points are for exposure categories 0 < x ≤ 1, 1 < x ≤ 2, 2 < x ≤ 3, 3 < x ≤ 4 and x > 4 years. The dotted regression line shows the linear effect of cumulative exposure (x) calculated by weighted least squares from the ever-exposed data points as an approximation to the modelling approach described in the Methods. Whereas the data point at x = 0 is the log fracture rate observed for all unexposed person time-periods, the point on the dotted regression line where x = 0 is the estimate from the model of the log fracture rate at the point of starting exposure in those exposed. Thus the difference in height between these two points gives the magnitude of the ever-exposed term and is the sum of any immediate stepwise effect of the drug and any difference in prior risk of fracture in ever vs never exposed. Since an immediate stepwise effect of TZD on hip fracture is unlikely the difference in height suggests that those who become exposed have a lower prior fracture risk than the never exposed

Fig. 2

Age-standardised rates of hip fractures by cumulative exposure to TZD in men. The error bars indicate the 95% CI for the rates. See legend to Fig. 1 for interpretation of this figure