Nancy A. Melville

October 11, 2013

BALTIMORE — New research suggests that the antiplatelet agent clopidogrel does not add much to the fracture risk in patients who have suffered a stroke, because the stroke itself appears to be the greatest contributor to this risk. The findings were reported at the American Society for Bone and Mineral Research (ASBMR) 2013 Annual Meeting.

"We found a high risk of fracture in stroke patients; however, the contribution of clopidogrel treatment was much less than the contribution of the stroke," said lead researcher Niklas Jørgensen, MD, PhD, head of the Research Center for Aging and Osteoporosis at Copenhagen University Hospital, Glostrup, Denmark.

Dr. Jørgensen and colleagues previously found the risk for fracture to be increased by as much as 50% to 80% in those treated with clopidogrel in a large Danish population study, compared with those who did not receive the agent. The higher risk was associated with longer duration of treatment (J Intern Med. 2012;272:385-303).

In this new analysis, they specifically examined the fracture risk associated with stroke in the same population.

Asked to comment on the findings, Douglas C. Bauer, MD, an associate professor of medicine, epidemiology, and biostatistics at the University of California, San Francisco Medical Center, said it was important to clarify any side effects of clopidogrel, which could have a broad impact because of its extensive use. With more than $9 billion in global sales in 2010 alone, clopidogrel was the second-best selling drug in the world before the patent expired in 2012.

"Clopidogrel is widely used for both stroke and cardiovascular protection, so any increase in fracture risk with use will have important public-health implications," he told Medscape Medical News. He suggested that further research should take a closer look at specific subgroups of patients to get a better understanding of areas of potential risk, such as patients with severe strokes. "One concern is that…clopidogrel might be used in more severe strokes, and those with more severe strokes are known to have a higher fracture risk because of falling."

It will also be important to establish whether there is any association between clopidogrel and fracture in other populations in which the drug is widely employed, such as those who receive it after stent placement, he noted.

Clopidogrel "Does Not Add Much" to Fracture Risk

In the Danish population study, 77,503 patients prescribed clopidogrel between 1996 and 2008 were each matched with 3 control subjects of the same age and gender.

The new analysis specifically assessed the risk for fracture associated with stroke. In the clopidogrel-treatment group, the authors identified 1.2% with prior hemorrhagic stroke, 9.3% with an ischemic stroke, and 7.2% with a transient ischemic attack (TIA), compared with 0.9% hemorrhagic stroke, 2.6% ischemic stroke, and 2.3% TIA among control subjects.

They found a significantly increased risk for fractures in the hemorrhagic-stroke group (hazard ratio [HR], 1.34; P < .001) and ischemic-stroke group (HR, 1.54; P < .001), compared with those who did not have strokes.

Unexpectedly, those with TIA also had an increased risk for fractures (HR, 1.28; P < .001).

"By definition of the disease, the neurological symptoms of transient ischemic stroke should disappear after 24 hours, so it was surprising to see the same increase in fracture risk in those patients as in stroke patients," Dr. Jørgensen said.

Among subjects using clopidogrel, the increase in fracture risk (HR, 1.05; P = .001), was significantly less than the increased risk associated with stroke alone.

"The risk of any fracture in the ischemic- and hemorrhagic- stroke and TIA groups increased between 30% and 50%; however, in the clopidogrel group, we saw a significant but relatively minor increase of just 5%, and the same was true for hip and vertebral fractures," Dr. Jørgensen said.

"What the findings tell us…is that stroke increases the risk of fractures; surprisingly, transient ischemic attack also increases risk of fractures to almost the same extent. However, clopidogrel does not add much to the fracture risk," he concluded.

Dr. Jørgensen and Dr. Bauer have reported no relevant financial relationships.

American Society for Bone and Mineral Research 2013 Annual Meeting. Abstract 1026, presented October 5, 2013.

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