WINSTON-SALEM, NC—Long-term use of certain oral diabetes drugs can double the risk of fracture for women with type 2 diabetes and may be particularly risk for elderly, postmenopausal women.

“This study shows that these agents double the risk of fractures in women with type 2 diabetes, who are already at higher risk before taking the therapy.”—Sonal Singh, MD, MPH
The culprit drugs are thiazolidinediones (TZDs). The two currently available are rosiglitazone (GlaxoSmithKline's Avandia™) and pioglitazone (Takeda's Actos™).

In absolute terms, use of TZDs for one year would result in:
  • 1 additional fracture among every 21 elderly, postmenopausal women
  • 1 additional fracture for every 55 younger women
The report, from researchers at Wake Forest University School of Medicine in Winston-Salem, NC, and from the University of East Anglia in Norwich, UK, appears online today on the Web site for the Canadian Medical Association Journal and will appear in the January 6 issue.1

 Diabetes drug fracture effect worse than expected

“We knew going into this study that there was an association between thiazolidinediones and fracture risk, however the magnitude of risk had not been evaluated,” said coauthor Sonal Singh, MD, MPH, of Wake Forest University. “This study shows that these agents double the risk of fractures in women with type 2 diabetes, who are already at higher risk before taking the therapy.”

This conclusion was based on an analysis of nearly 14,000 subjects in 10 previously completed trials that lasted at least one year. All of the studies included participants with impaired glucose tolerance and type 2 diabetes, and all compared the risk of fracture among patients with type 2 diabetes who were taking TZD therapy and patients not taking the therapy.

Overall, the results showed that use of TZDs significantly increased the risk of fractures among patients with type 2 diabetes, and was associated with changes in bone mineral density at the lumbar spine and the hip.

TZDs were not associated with increased fracture risk in men.

Translating research into practice

The researchers warn that this additional risk from TZD therapy could have a major public health impact, since women with type 2 diabetes are already at an increased risk of nonvertebral fractures, with a near doubling in the risk of hip fractures.

The TZDs have also come under fire for possible adverse cardiovascular effects, Dr. Singh said.

Clinicians have been advised to consider the updated 2008 guidelines of the American Diabetes Association and European Association for Study of Diabetes consensus recommendations, which do not consider thiazolidinediones among the well-validated core therapies for type 2 diabetes and uniformly advised against the use of rosiglitazone.

In an editorial that accompanies this study, Loraine L. Lipscombe, MD, wrote, “Given that there are other effective drugs to control glycemia that are associated with fewer adverse events, thiazolidinediones should not be considered appropriate as first-line therapy for type 2 diabetes mellitus. If a patient is unable to take other therapies or if other therapies have failed, there may be a role for  thiazolidinediones in carefully selected patients duly informed of the potential adverse effects. Considering that studies of pioglitazone have not shown the possible higher risk of myocardial infarction seen with rosiglitazone, but rather suggest a reduction in ischemic events,  pioglitazone may be a safer option.” Dr. Lipscombe is at the Institute for Clinical Evaluative Sciences in Toronto, Ontario, Canada.

References
1. Lipscombe LL. Thiazolidinediones: Do harms outweigh benefits? (editorial). Canadian Medical Association Journal. [epub ahead of print] Dec. 10, 2008. Available at:  www.cmaj.ca.