Two common diabetes drugs — rosiglitazone and pioglitazone — are linked to higher fracture rates in women, according to a meta-analysis in CMAJ by a team of researchers from the University of East Anglia in the United Kingdom and Wake Forest University in the United States.

The drugs, called thiazolidinediones, help improve glycemic control and decrease insulin resistance in patients with diabetes. 

The researchers looked at 10 randomized controlled trials of at least one year's duration involving 13 715 diabetes patients taking thiazolidinediones and those not taking the therapy. They found significantly reduced bone density in the lumbar spine and at the hip in women on the drugs.

It appears that long-term thiazolidinedione use doubles the risk of fractures among women with type 2 diabetes, without a significant increase in fracture risk in men. The researchers estimate that a fracture would occur in 1 out of 21 women at high risk of fracture who are taking thiazolidinedione for one year and among low risk women, there would be 1 fracture in every 55 if these drugs are taken for more than a year.

With more than 4 million users of thiazolidinediones in the United States alone in 2006, "the public health impact may be considerable," write Dr. Yoon Loke and coauthors. "If one assumes that half of those users were women and that the baseline risk of fractures is similar to that found in the ADOPT study, an estimated 30 000 excess fractures may have occurred if these women had been prescribed thiazolidinediones rather than metformin for more than a year." 

The researchers call for further investigation into the underlying causes of this apparent sex-specific effect. 

In a related commentary http://www.cmaj.ca/press/081713.pdf, Dr. Lorraine Lipscombe of the Institute for Clinical Evaluative Sciences and the University of Toronto writes that "clinical drug trials are often underpowered to detect unanticipated and rare adverse effects, and a standardized postmarketing surveillance process is needed." She cautions that the net benefit of these drugs is unclear, and there are other effective drugs that can control glycemia with fewer adverse events.