Risk-Benefit Profile Still Favors Bisphosphonate for Fractures

The risk of atypical fractures increased with longer duration of bisphosphonate treatment, but the absolute risk remained low, a new study showed.

Looking at nearly 200,000 women ages 50 and older, Dennis Black, PhD, of the University of California San Francisco, and colleagues found 277 atypical femur fractures over a decade of follow-up (1.74 fractures per 10,000 patient-years).

As shown in the team’s study in the New England Journal of Medicine, there were 50 atypical femur fractures among women taking a bisphosphonate for 3 to less than 5 years (n=29,287), nearly a nine-fold increased risk compared with those who took bisphosphonates for less than 3 months (hazard ratio 8.86, 95% CI 2.79-28.20).

And women who were on a bisphosphonate for 8 or more years saw a 43-fold higher risk for incurring an atypical femur fracture (HR 43.51, 95% CI 13.70-138.15), which equated to a total of 95 atypical fractures reported among this group (n=16,893).

Certain clinical factors modified this risk of atypical femur fractures — for example, glucocorticoid use of a year or more (HR 2.28, 95% CI 1.52-3.43 vs no glucocorticoid use), weight per 5-kg increment (HR 1.15, 95% CI 1.11-1.19), and height per 5-cm decrement (HR 1.28, 95% CI 1.15-1.43).

Additionally, Asian women had a higher risk for this type of fracture while on a bisphosphonate compared with white women (HR 4.84, 95% CI 3.57-6.56).

The risk-benefit profile still fell in favor of bisphosphonate use, due to the protection against both osteoporotic and hip fractures, the researchers reported.

“The benefits of bisphosphonates and other osteoporosis treatments, including the reduction of the devastating consequences of hip and other fractures, far, far outweigh the risks of atypical fractures,” Black told MedPage Today.

Putting this into perspective, he explained that in comparison to spine, hip, and other osteoporotic fractures that can be prevented with bisphosphonate treatment — reducing the risk by as much as 70% — atypical fractures are “extremely rare” and the absolute risk is low.

For instance, the results showed that after 3 years of bisphosphonate use, 541 clinical fractures and 149 hip fractures were prevented per 10,000 white patients, while only two bisphosphonate-related atypical fractures occurred.

And although atypical fractures were significantly more common among Asian than white women, Asian women still had a favorable risk-benefit profile with bisphosphonates. Per 10,000, there were 330 clinical fractures and 91 hip fractures prevented among Asian patients after 3 years on bisphosphonates and eight reported atypical fractures. However after 10 years of bisphosphonate treatment in Asian women, this gap narrowed: 831 clinical fractures and 360 hip fractures were prevented, but there was a total of 236 bisphosphonate-associated atypical fractures.

“The benefits far outweigh risks in Caucasians and other race groups that we studied other than Asians, where the balance was more modest,” Black explained. “Clinicians might want to focus osteoporosis treatment in Asian women to those at higher risk of hip and spine fractures — for example, those older than 70 or with very low bone density.”

“Shorter duration of therapy and use of a drug holiday might be particularly valuable in Asian patients,” he added.

Black said it was reassuring that the study found a “rapid” drop in this associated atypical fracture risk after bisphosphonate discontinuation. Overall, the rate of atypical fractures dropped from 4.50 per 10,000 person-years for current users, down to 1.18 per 10,000 person-years during the 3 to 15 months since discontinuing the treatment. And more than 15 months after discontinuation, the rates dropped even further, down to only 0.50 per 10,000 person-years.

This “strongly supports the concept of a drug holiday,” which involves a temporary discontinuation of bisphosphonates after about 5 years of continuous treatment to reverse the heightened atypical fracture risk, Black added.

All 196,129 women in this prospective cohort study were enrolled in the Kaiser Permanente Southern California healthcare system and had received at least one prescription for an oral or intravenous bisphosphonate for osteoporosis. Almost all women (97.5%) in the study were prescribed oral bisphosphonates alone — 95% of whom were prescribed alendronate (Fosamax, Binosto). Less than 2% of the cohort were on both an oral bisphosphonate and zoledronic acid (Reclast), while less than 1% of the cohort was on zoledronic acid alone.