TZDs may increase risk for fracture in men, women

Men and women who are exposed to thiazolidinediones may be at increased risk for fractures, especially with pioglitazone.

A prospective cohort study examined risk for fractures in 84,339 adults (mean age, 59; 43% women) from British Columbia, Canada, who began treatment with a TZD or sulfonylurea.

Treatment with a TZD was associated with a 28% increased risk for peripheral fractures — the primary outcome — compared with treatment with a sulfonylurea (HR=1.28; 95% CI, 1.10-1.48).

Specifically, pioglitazone (Actos, Takeda) was associated with an increased risk (77%) for peripheral fracture in women (HR=1.76; 95% CI, 1.32-2.38). Previous data demonstrate an increased risk for fractures with rosiglitazone (Avandia, GlaxoSmithKline).

Compared with sulfonylureas, pioglitazone was also associated with more peripheral fractures in men (HR=1.61; 95% CI, 1.18-2.20); however, this association was not reported with rosiglitazone (HR=1.00; 95% CI, 0.75-1.34).

“This study provides further data that treatment with TZDs is associated with an increased risk of fracture compared with treatment with sulfonylureas in women, and it provides new data that pioglitazone exposure might increase the risk of peripheral fractures and all fractures relative to treatment with a sulfonylurea in men,” the researchers concluded. “Prescribers of these medications should therefore not assume that fracture risk is confined to women who take rosiglitazone.”

However, the confidence intervals for pioglitazone and rosiglitazone overlapped, “which prevents us from making a strong conclusion that the two drugs have different fracture risks,” they wrote. – by Katie Kalvaitis

Dormuth CR. Arch Intern Med. 2009;169:1395-1402.

In the current issue of the Archives of Internal Medicine, Dormuth et al report that thiazolidinedione treatment increased fracture rates relative to sulfonylurea treatment. They performed a prospective population-based cohort study of over 84,000 patients from British Columbia who began TZD therapy between 1998 and 2007. The cohort was relatively young, with a mean age of 59 years, and predominantly men (57%). The researchers identified 2,214 fractures through the provincial health registry. The overall HR for appendicular fractures in TZD users was 1.28, with subgroup analysis suggesting that the fracture risk was greater in patients receiving pioglitazone than those receiving rosiglitazone. The authors estimate that 86 patients would have to be treated with a TZD for three years in order to obtain each excess fracture.

These data are consistent with present pathophysiological understanding of the mechanism by which TZDs work. They are differentiating agents that help to drive precursor cells toward the adipocyte lineage. Adipocytes and osteoblasts are derived from a common precursor, so it should not be surprising that promotion of adipocytic differentiation should occur at the expense of osteoblastic differentiation. Indeed, earlier clinical studies have shown decreases in osteoblastic differentiation markers (JCEM. 2007;92:3523, JCEM. 2007;92:1305).

This study has several limitations that the authors appropriately note. The number of events was relatively small, reflecting the relatively young age of the cohort. As a cohort study, cause and effect relationships cannot be inferred. The TZD and sulfonylurea groups were imperfectly matched, differing in age (TZD users were younger) and past use of metformin (TZD users were more likely to have used metformin).

Dormuth and colleagues suggest that additional, larger clinical studies are needed to determine whether TZDs have adverse bone effects of sufficient magnitude to warrant consideration of fracture risk as a significant risk in candidates for TZD therapy. I disagree, believing that more will be learned from laboratory studies and from clinical populations at higher baseline fracture risk. Supposing that the present findings are confirmed, clinicians will still be faced with the problem of how to balance between disparate types of risks. In other words, they will need to practice the art of medicine.

– Robert D. Blank, MD, PhD

Endocrine Today Editorial Board member