Longer Bisphosphonate Use Ups AFF Risk, but Not All Is Tied to Drug

Marlene Busko

September 21, 2020

In a national study of older Danes who had previously had a fracture and were taking bisphosphonates, the risk of having a serious though rare atypical femoral fracture (AFF) was greater after 3 to 5 years of bisphosphonate use.

The risk quickly dropped after patients stopped taking a bisphosphonate, which suggests that bisphosphonate "holidays" may be useful for some patients, the researchers say. These findings support previous work.

But the study also found that 34% of the AFFs occurred in patients who had not been taking a bisphosphonate. That rate is higher than the 6% to 22% that has been reported by others.

Doug Bauer, MD, from the University of California, San Francisco, presented the new study findings during the virtual American Society of Bone and Mineral Research (ASBMR) 2020 annual meeting.

"We found no clear risk factor that accounts for this increased risk [for AFFs] among those not exposed to bisphosphonates," he said, "but we believe this was a real finding, as our study protocol ensured that the study radiologists were completely blinded to treatments received."

Suzanne N. Morin, MD, who was not involved in this research, pointed out that the reported AFF risks related to bisphosphonate dose and cessation are in keeping with findings of other studies, including a recent large study by Dennis M. Black, MD, and colleagues that was published in The New England Journal of Medicine.

That study found that Asians are at higher risk for AFFs than White persons. Others have reported that specific femur geometry or physique and use of glucocorticoids increase AFF risk, Morin, from the Research Institute of the McGill University Health Center, Montreal, Quebec, Canada, told Medscape Medical News.

The current study suggests that rheumatoid arthritis may be a risk factor, she added.

The fact that the rate of AFFs among patients who had not been exposed to bisphosphonates was higher than previously reported "may be due to differences in the method they used to ascertain the fractures or in medication use," she also speculated.

The clinical implications of research to date are that "the risk of AFF should not dissuade patients and providers from short-term use of bisphosphonates (3 to 5 years)," Bauer told Medscape Medical News. He noted that most patients should not take a bisphosphonate for longer than this unless they have a very high fracture risk.

Similarly, Morin said that clinicians "should consider initiating bisphosphonate in those at high risk for fractures and reevaluate their use after 3 to 6 years, depending on individual's risk profile."

AFF Is Serious but Rare Complication of Bisphosphonate Use

"Since first reported over 10 years ago, it has become clear that AFFs are a rare but serious complication of bisphosphonate therapy," Bauer explained.

However, there is still uncertainty about the magnitude of this risk, including the absolute risk for AFFs among adults who take bisphosphonates and those who do not.

To study this, the researchers analyzed data from national healthcare and pharmacy records and a radiology image database in Denmark.

They identified almost 5000 adults who were aged 50 years or older and who experienced a subtrochanteric and femoral shaft fracture during the period 2010 to 2015.

Two expert radiologists who were blinded to the patients' clinical history or treatment identified AFF on the basis of ASBMR 2014 criteria.

The researchers compared three patient groups:

  • 189 patients with AFF

  • 2397 patients with typical subtrochanteric and femoral shaft fractures (no AFF)

  • 35,946 adults older than age 50 (control persons)

Compared to patients with typical fractures, patients with AFF were younger (aged 71 vs 77), more likely to be women (79% vs 69%), and more likely to have rheumatoid arthritis (12% vs 2.5%).

Compared to patients in the other two groups, those with AFF were more likely to use corticosteroids, proton pump inhibitors, statins, and hormone replacement therapy.

They were also more likely to use bisphosphonates (58%) than patients with typical subtrochanteric and femoral shaft fractures (19%) or control patients (10%).

The bisphosphonates used in Denmark at the time were mostly alendronate (85%) and rarely ibandronate (6%), IV zoledronic acid (5%), etidronate (3%), or risedronate (1%).

34% of Patients With AFFs Had No Bisphosphonate Exposure

In this national cohort of adults older than 50, the absolute rates of AFF per 10,000 person-years were as follows:

  • 0.07 in nonusers of bisphosphonates

  • 1.84 in those with 3 to 5 years of bisphosphonate use

  • 4.63 in those with >7 years of bisphosphonate use

As a comparison, the rate of classic hip fracture was 43.8 per 10,000 person-years.

Compared to no bisphosphonate use, the relative risk for AFF was close to 40 times higher with more than 7 years of use, after adjusting for multiple confounders.

The risk for AFF was also significantly higher among patients with rheumatoid arthritis or hypertension and for those who used proton pump inhibitors.

"Note that age, gender, and previous fracture were not associated with the risk of AFF" after controlling for multiple confounders, Bauer stressed.

The relative risk for AFF fell significantly after it had been withheld from use for more than 1 year.

Among the 189 patients with confirmed AFF, 64 patients (34%) had never taken a bisphosphonate.

Preliminary analysis showed that among patients with AFF, those who had not been exposed to bisphosphonates were younger, more likely to be male, and less likely to have had a previous fracture, rheumatoid arthritis, or to have used corticosteroids, proton pump inhibitors, statins, or hormone replacement therapy.

The study was funded by the National Institutes of Health's National Institute of Arthritis and Musculoskeletal and Skin Diseases. Bauer and Morin have disclosed no relevant financial relationships.

The American Society of Bone and Mineral Research (ASBMR) 2020 Annual Meeting Virtual Event: Presented September 13, 2020.

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