More data linking thiazolidinediones to fractures

Shelley Wood

August 12, 2009

Vancouver, BC - Once again, a large cohort study—this time from British Columbia, Canada—is pointing to an increased fracture risk with thiazolidinediones (TZDs), used in the treatment of type 2 diabetes[1]. The study, which reviewed fracture risk in more than 84 000 patients receiving either rosiglitazone (Avandia, GlaxoSmithKline) or pioglitazone (Actos, Takeda) vs a sulfonylurea, found that both men and women are at increased risk of broken bones when taking a TZD and hints that pioglitazone may be more strongly associated with fracture risk. Two years ago, the FDA requested that a warning on fracture risk be added to the pioglitazone labeling.

The study appears in the August 10/24, 2009 issue of the Archives of Internal Medicine.

"Larger observational studies are needed, and fracture data from clinical trials need to be fully published so that fracture risks can be known with greater certainty," Dr Colin R Dormuth (University of British Columbia, Vancouver) and colleagues write.

Dormuth et al point out that the research linking fractures to TZD use has not been entirely consistent, with some trials (but not all) suggesting different effects for the two commercially available TZDs and others pointing to a different degree of risk according to gender.

In the current study—seemingly the largest prospective cohort study to date—TZD use was associated with a 28% increased risk of peripheral fractures in both men and women, as compared with sulfonylurea treatment. That increased risk was higher with pioglitazone in both women (a statistically significant increased risk of 77%) and men (a 61% increase) than in men or women treated with rosiglitazone. When investigators factored in duration of therapy, the risks associated with TZD use appeared to increase the longer the patient had taken the drug. In a number-needed-to-harm analysis, which took into account a baseline fracture risk associated with any diabetes treatment, Dormuth et al predicted that 86 patients would need to receive a TZD for three years in order to produce one additional peripheral fracture.

"Our findings suggest that both men and women are at increased risk of fracture as a result of exposure to TZDs and that pioglitazone treatment may be more strongly associated with fractures than rosiglitazone treatment," they write. "Prescribers of these medications should therefore not assume that fracture risk is confined to women who take rosiglitazone."

The authors acknowledge the shortcomings of their analysis, emphasizing the need for randomized control trial data and, at the very least, for fracture data from previous studies to be "fully published." Future studies of fracture risk and diabetes drugs must include information on confounding factors, such as body-mass index and physical activity, they add. But in the meantime, they conclude: "There is insufficient clinical-trial evidence to show that treatment with TZDs provides clinical benefits beyond glycemic control, and in the absence of mitigating clinical benefits, mounting evidence of harm should discourage physicians from prescribing those drugs."

The financial disclosures for this paper are listed as "none reported."

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