Long-term use of GlaxoSmithKline's Avandia and Takeda's Actos doubles the risk of bone fractures in women with type 2 diabetes, according to a study released on Wednesday.

Scientists already knew the two thiazolidinedione (TZD) drugs for diabetes were associated with fractures, but the magnitude of the risk had not been evaluated.

"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," said Sonal Singh of North Carolina's Wake Forest University School of Medicine.

Singh and colleagues at Wake Forest, working with researchers at Britain's University of East Anglia, based their findings on a pooled analysis of 10 previous clinical studies lasting at least a year involving 14,000 patients.

They concluded that if TZDs were used by diabetic women aged around 70 for a year, one additional fracture would occur among every 21 women. Among younger women, around age 56, use of the drugs would lead to one extra fracture for every 55 women.

The results may add to concerns about the TZD class of drugs, which are already linked to adverse cardiovascular side effects.

Both Avandia, known generically as rosiglitazone, and Actos, or pioglitazone, raise the risks of heart failure and carry strong warnings on their labels.

Avandia has also been linked to heart attack risk, and its sales have plunged since May 2007, hitting Glaxo sales and profits.

Researchers said the underlying cause of the sex-specific effect of TZDs on fractures was unclear, but they suggested the drugs may cause the problem by replacing bone marrow with fat cells.