Long-term use of a class of drugs for type 2 diabetes doubles a woman’s risk of breaking a bone, research suggests.
Thiazolidinediones, including rosiglitazone and pioglitzone, had already been linked to a raised risk of fractures, as well as heart problems. UK and US researchers have quantified the risk, and showed that using the drugs for more than a year thins the bones significantly. It found no increased fracture risk among men.
Two million prescriptions were written for rosigliatzone and pioglitazone in the UK alone last year. The European Medicines Agency carried out a safety review of rosiglitazone and pioglitzone last year, and concluded their benefits outweighed their risks.
But the researchers argued the drugs had relatively modest therapeutic effects, and the regulators should think again.
Lead researcher Dr Yoon Loke, of the University of East Anglia, said: “Women with type 2 diabetes are already at an increased risk of fractures – with a near doubling in the risk of hip fractures – so any additional risk from thiazolidinedione therapy could have a considerable impact on public health.”
Dr Loke said the underlying cause of the effect of thiazolidinediones was unclear, and required further research. One suggestion is that the drugs may cause fractures by replacing bone marrow with fat cells. However, he stressed women should not stop taking the drugs without first taking medical advice.
The latest study, also conducted by researchers at Wake Forest University in North Carolina, examined data from 10 previous trials, involving a total of 13,715 patients. It found that year-long thiazolidinedione use among elderly, postmenopausal women with type 2 diabetes resulted in one extra fracture per 21 women. Among younger women, aged around 56, the figure was one extra fracture per 55 women.
There is no clear evidence that other drugs used to treat type 2 diabetes, such as metformin and sulfonylurea, cause an increased risk of fractures.
Recent research into thiazolidinediones has focused on the drugs’ adverse effects on the heart and cardiovascular system. One study found that they doubled the risk of congestive heart failure, while another found rosiglitazone was associated both with increased heart attacks and a doubling of heart failure.
Dr Victoria King, of the charity Diabetes UK, said: “We really do need further evidence through properly controlled trials before we can conclusively link thiazolidinediones to increased risk of various bone conditions in humans and determine which groups of people may be at greater risk.”
In a statement, the Medicines and Healthcare products Regulatory Authority (MHRA) said fears that thiazolidinediones raised the risk of fractures in women had been raised before, and healthcare professionals notified.
The information leaflet providing with the drug to patients already contains a warning about fracture risk. GlaxoSmithKline, which markets rosiglitazone as Avandia, said the safety and effectiveness of the drug was backed by one of the largest clinical trial programs ever undertaken for any medicine, with 52,000 patients studied.
New findings out of Wake Forest University School of Medicine and the University of East Anglia show that long-term use of a popular class of oral diabetic drugs doubles the risk of fractures in women with type 2 diabetes.
“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 Sonal Singh, M.D., M.P.H., an assistant professor of internal medicine and a co-researcher for the study. “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.”
In absolute terms, Singh said, if thiazolidinediones (TZDs) are used by elderly, postmenopausal women (around 70 years) with type 2 diabetes for one year, one additional fracture would occur among every 21 women. Among younger women (around 56 years), use of the drugs for one year or longer would result in one additional fracture for every 55 women.
For the study, researchers reviewed 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. Nearly 14,000 participants were included in the studies. Data was broken down by gender in five of the studies.
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.
Data from the studies that reported sex-specific results showed that TZDs significantly increased the risk of fractures among women. They were not, however, associated with the same increase of fracture risk in men. The studies also showed a consistent decline in bone mineral density in women exposed to TZD therapy.
“Women with type 2 diabetes are at an increased risk of nonvertebral fractures, with a near doubling in the risk of hip fractures,” the researchers wrote in their findings. “Any additional risk from thiazolidinedione therapy could have considerable impact.”
In 2006, there were nearly 4 million patients in the United States taking TZDs, half of whom were likely women, Singh said.
While the underlying cause for the sex-specific effect of TZDs needs further investigation, researchers suggest that the drugs may cause fractures by replacing bone marrow with fat cells.
The findings appear online on the Web site for the Canadian Medical Association Journal and will appear in the January 6 issue.