Bone risk from diabetes drug

The Daily Mail today reports that regular use of a group of diabetes drugs, “doubles the chances of fractures in female patients,” and could “more than double the risk of heart failure”.

The story is based on research that reviewed and pooled the results of 10 studies in almost 14,000 people with type 2 diabetes. This research found thiazolidinedione drugs, such as Actos and Avandia, increased the risk of fractures in women, but not men.

This review provides relatively robust evidence that there is an increased risk of fractures for women with type 2 diabetes taking these types of drugs. This increased risk will need to be weighed up against the potential benefits of taking these drugs, but only in relation to patient histories.

It is worth noting that some thiazolidinediones already carry warnings about increased risk of fractures, and that National Institute for Health and Clinical Excellence (NICE) guidance already recommends that people with evidence of heart failure or higher risk of fractures, should not be prescribed these drugs.

Women concerned about their use of these drugs should not stop taking them without consulting their doctor first. Their doctor will be able to advise on their specific treatment options.

Where did the story come from?

Dr Yoon Loke and colleagues from the University of East Anglia and Wake Forest University School of Medicine carried out this research. No external funding was received for this study. The study was published in the peer-reviewed Canadian Medical Association Journal .

What kind of scientific study was this?

This was a systematic review looking at the effect of a group of diabetes drugs called thiazolidinediones on bone density and the risk of fractures.

The researchers carried out systematic searches of medical and scientific literature databases, the information sheets provided with the drugs, drug company trial registers, regulatory authority websites, and reference lists of other systematic reviews to identify relevant studies.

The researchers included published and unpublished randomised controlled trials (RCTs) that compared any thiazolidinedione drug with a control treatment. The control treatment could be either a placebo or an active treatment that the thiazolidinedione group also received.

The RCTs had to include people with type 2 diabetes or impaired glucose tolerance (a condition that can develop into type 2 diabetes), and had to follow up participants for at least a year and look at fracture outcomes.

When the researchers looked at the effects on bone density, they included both RCTs and controlled observational studies with any length of follow-up. Two researchers looked at the quality of the trials and decided on which studies to include. They then extracted and pooled relevant data using standard statistical methods.

What were the results of the study?

The researchers identified 10 double blind RCTs that looked at the effect of thiazolidinediones on fractures. Overall, these studies included 13,715 people with impaired glucose tolerance and type 2 diabetes. Participants were followed up for between one and four years.

Overall, about 3% of people in the thiazolidinedione groups had a fracture (185 out of 6,122 people) compared to 2.4% in the control groups (186 out of 7,593 people). This represented an increase of 45% in the odds of having a fracture within the thiazolidinedione group. However, this increase was not significant once the researchers took into account differences between the studies.

The researchers then looked specifically at five studies that reported fractures separately for men and women. In total, 7,001 men and 4,400 women were followed by these studies. The researchers found that there was an increase in fractures with the thiazolidinediones groups among women, but not men.

Almost 6% of women experienced a fracture in the thiazolidinedione group, compared to 3% in the control group. This doubling of risk was statistically significant, even when differences between the studies were taken into account.

Two small RCTs (including 84 people) and two small observational studies (including 243 people) looked at the effects of thiazolidinediones on bone mineral density (BMD). They all found a reduction in BMD with the thiazolidinediones. However, none of these studies were specifically in people with type 2 diabetes.

What interpretations did the researchers draw from these results?

The researchers concluded that, “long-term thiazolidinedione use doubles the risk of fractures among women with type 2 diabetes, without a significant increase in risk of fractures among men with type 2 diabetes”.

They suggest that, “the relatively modest benefits of thiazolidinediones must be balanced against their significant long-term effects on the bone and cardiovascular system. Clinicians should reconsider the use of thiazolidinediones in women with type 2 diabetes.”

What does the NHS Knowledge Service make of this study?

There are a few limitations that need to be taken into account when interpreting the results of this study, some of which the authors acknowledge:

  • None of the included RCTs specifically set out to examine the effect of the thiazolidinediones on fractures. These studies collected this data as part of monitoring of overall adverse events. It is possible that some fractures may have been missed as they were not being specifically looked for.
  • The review was not able to determine whether the increased risk of fractures was related to any specific thiazolidinedione, or whether the risk applied to specific fracture sites, as there was not enough data.
  • There was limited data on BMD and these results should not be seen as conclusive. In addition, not all of the people in these studies had type 2 diabetes, and the results may not be representative of what would be seen in this population.

This review provides relatively robust evidence of an increased risk of fractures in women with type 2 diabetes taking thiazolidinediones. This increase in risk will need to be weighed up against the potential benefits of taking these drugs based on the circumstances and histories of each patient.

It is worth noting that some thiazolidinediones already have warnings about increased risk of fractures on their packaging. NICE already recommends that people with evidence of heart failure or who are at higher risk of fractures should not be prescribed thiazolidinediones.

Women who take these drugs and are concerned about their fracture risk, should not stop taking their medication without consulting their doctor first. They will be able to advise women about their treatment options based on their individual circumstances.

Sir Muir Gray adds...

Because harmful effects are usually much rarer than beneficial effects, single trials may not reveal them. This shows again why systematic reviews are needed.

NHS Attribution