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Discontinuation of TZD Reduces Fracture Rates

Thiazolidinediones (TZDs), rosiglitazone and pioglitazone, have been shown to increase fracture risk in women after a year of TZD use; however, there has been little data available on the effects of the discontinuation of TZD.

This longitudinal observational cohort study used data from an ancillary study of skeletal health within the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial, ACCORD-BONE. The ACCORD trial ran from 2001 to 2009 and had 10,251 type 2 diabetes participants, A1C of 7.5%-11%, with an increased risk of CVD. These subjects were randomly assigned to the intensive or standard glycemic therapy groups. The trial achieved a median A1C of 6.4% and 7.5% in the intensive and standard glycemic therapy groups, respectively. However, the intervention for the intensive group was stopped early and participants were assigned to the standard glycemic group protocol in 2008 due to higher all-cause mortality.

During the participants’ annual visit from 2006 to 2009, they were asked if they had experienced a fracture since their last annual visit. 6,865 participants were included in the ACCORD-BONE trial. Only confirmed nonspine fractures were included in these analyses. Of the two TZDs, rosiglitazone was more widely used (74%) than pioglitazone (13%) in the ACCORD trial. The categorization for TZD use and TZD discontinuation was time-varying in proportional hazard models for occurrence of first non-spine fracture. Participants’ heights were also measured upon visits to observe any changes in height from baseline.

During the mean follow-up of 4.8 years, 5.8% of men and 12.1% of women experienced at least one confirmed nonspine fracture. There was no statistically significant difference on the effect of TZD use or TZD discontinuation on fracture rate in men. When compared with no TZD use, the fracture rate increased in women with:

  • 1-2 years of TZD use (HR = 2.32; 95% CI 1.49, 3.62) or
  • > 2 years of TZD use (HR = 2.01; 95% CI 1.35, 2.98).

Results indicate that fracture rate after discontinuing TZD returns to the same rate as those who never used TZD. Height loss was not statistically significant during TZD use or after TZD discontinuation.

The authors conclude that TZD use in the ACCORD trial for subjects with type 2 diabetes with increased risk of CVD was associated with increased fracture risk in women, but not in men. However, discontinuing TZD was shown to reduce fracture rate, indicating that these fracture effects are reversible.

Practice Pearls:

  • TZD use in the ACCORD trial was associated with increased fracture risk in women, but not men.
  • After the discontinuation of TZD, the patient’s fracture rates return to the same rate as those who never used a TZD.
  • Discontinuation of TZD reduces the patient’s fracture risk, which indicates that the fracture effects are reversible.

Schwartz AV, Chen H, Ambrosius WT, et al. “Effects of TZDs Use and Discontinuation on Fracture Rates in ACCORD Bone Study.” Journal of Clinical Endocrinology & Metabolism, 18 Aug 2015. Web. 02 Sep 2015.