The FDA recently informed physicians of a report issued by GlaxoSmithKline acknowledging that Avandia (rosiglitazone) has been linked to increased fractures in females (1). The report stems from a review of the safety data from ADOPT (A Diabetes Outcome and Progression Trial) (2), which was a recently published randomized trial of 4,360 patients designed to compare glycemic control with rosiglitazone relative to metformin and glyburide monotherapies. In the published study, there were no unexpected adverse events reported, although rosiglitazone was associated with weight gain, increased LDL, edema, and a reduction in the hematocrit. However, further review of the safety data revealed that significantly more female patients in the group randomized to receive rosiglitazone experienced fractures, mostly occurring in the upper arm (humerus), hand, or foot. The incidence of fractures in men was low and similar in all groups.
9.3% of females randomized to the rosiglitazone group experienced a fracture, compared to 5.1% of females in the metformin group and 3.5% of females in the glyburide group. Therefore, females in the rosiglitazone group were twice as likely to experience a fracture compared to those in the other groups, with a number needed to harm of 20. According to GlaxoSmithKline, an interim analysis of fractures in another long-term ongoing rosiglitazone trial designed to assess cardiovascular endpoints in DM2 is consistent with observations from ADOPT, although the safety committee has recommended that this study continue without modification, with final results available in 2009.
Again, it is important to note that most of the fractures occurring in ADOPT were in smaller bones and different from the fractures typically seen in post-menopausal females with osteoporosis (hip or spine). The rate of hip or spine fractures in the ADOPT trial was low, and similar in all groups.
This news of an increased incidence of fracture comes on the heels of reports of two other classes of medications, SSRIs and PPIs, both associated with an increased risk of fractures. Interestingly, antidepressants have also been linked to increased forearm, ankle, and foot fractures, and the mechanism for these fractures appears to be independent of bone mineral density (3). Although the etiology by which these drugs cause fractures remains unclear, perhaps further investigation will ultimately lead to further insight and a better understanding of bone physiology and remodeling, leading to new therapeutic targets. However, until then, given the prevalence of the use of PPIs, SSRIs, and TZDs, the results of these recent studies are very concerning and may have serious public health implications.
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