Bisphosphonate link to nonhealing fractures strengthened

Mar 1 2013

By Lynda Williams, Senior medwireNews Reporter

US scientists have identified a safety signal between bisphosphonate use and nonhealing femoral fractures, possibly due to the rare side effect, atypical femur fracture.

The research, published in the Journal of Bone and Joint Surgery, adds to evidence for a causative role and is the first to demonstrate a link between the use of antiresorption agents and nonhealing femoral fractures in the US Food and Drug Agency Adverse Event Reporting System (FAERS) database.

Nevertheless, the investigators say that bisphosphonate use has led to a 30% decrease in hip fracture among older individuals in the USA, with an associated decrease in morbidity and mortality.

"The benefits of bisphosphonates are 100-fold greater than the risk of atypical femoral fractures," they emphasize.

Beatrice Edwards (Northwestern University, Chicago, Illinois) and co-authors identified 362 reports of nonhealing femoral fractures in the FAERS database. The proportional reporting ratio (PRR), for these fractures and bisphosphonate use was 4.51.

Of note, the majority of affected patients had used the commonest agent, alendronate (PRR=3.32).

"It is unlikely that this is due to greater exposure as the proportional reporting ratio takes into account the number of nonhealing femoral fractures reported and total number of reports associated with the drug compared with the number of such fractures reported and total number of reports associated with all other drugs," Edwards et al comment.

The researchers say that comorbidities were rare in the patients, with 7% reporting rheumatoid arthritis and 2% breast cancer. Other medications used included glucocorticoids (10%), etanercept (10%), estrogen (3%), and aromatase inhibitors (<1%).

None of the femoral fractures reported in the FAERS database were atypical, defined as unilateral or bilateral fractures occurring after prodromal thigh pain in the absence of trauma. Radiographs demonstrate cortical thickening of the femur.

However, the researchers' literature review included a case series demonstrating that 26% of atypical femoral fractures were nonhealing, prompting them to suggest: "Some of the nonhealing femoral fractures in the FAERS database could well be atypical femoral fractures."

The researchers therefore call for an international registry to record bisphosphonate-related atypical femoral fracture, and for further research into identification of developing fractures in the clinic and the underlying genetic susceptibility.

"A better understanding of the mechanisms leading to these atypical femoral fractures may enable us to develop prediction rules for this uncommon adverse drug reaction and to stratify and target our care accordingly," they write.

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