Fracture Risk During Bisphosphonate Drug Holiday Is a Concern

Nancy A. Melville

May 14, 2018

Approximately 15% of patients with osteoporosis who suspend use of bisphosphonates as part of recommended "drug holidays" suffer fractures during the discontinuation, with fracture risk peaking during years 4 and 5 of the drug holiday, according to a 6-year follow-up study.

"These results add to our knowledge of what happens during bisphosphonate drug holidays, and give clinicians some guidance on how long patients should stay off the drugs," senior author Pauline Camacho, MD, a professor of medicine at Loyola University Medical Center and director of the Loyola University Osteoporosis Metabolic Bone Disease Center, in Maywood, Illinois, told Medscape Medical News.

Camacho, who is the immediate past-president of the American Association of Clinical Endocrinologists, advised that "Patients who have higher fracture risk at baseline, including older age [and] lower bone mineral density, should have shorter holidays as they will have a higher risk of developing fracture."

Drug holidays after several years of bisphosphonate use are recommended to reduce the risk for the rare but potentially serious adverse events of atypical femoral fractures and osteonecrosis of the jaw that have been associated with this class of drugs.

Data are lacking, however, on the safe duration of the drug holiday.

Fractures of the Wrist, Foot, Ribs, and Spine Occurred During Drug Holidays

For the current retrospective study, published recently in Endocrine Practice, Brittany Bindon, MD, from the University of Chicago, Illinois, and colleagues identified 401 patients, including 371 females and 30 males with osteopenia or osteoporosis, who started a bisphosphonate drug holiday between 2004 and 2013 while being treated at the Loyola University Osteoporosis and Metabolic Bone Disease Center.

Of the patients, 62 (15.5%) experienced a fracture during the course of their drug holiday, and although the annual incidence of fractures ranged from 3.7% to 9.9% over the course of 6 years, the peak fracture rates of 9.9% and 9.8% were in years 4 and 5, respectively.

The most significant factors associated with fracture during the drug holiday included a lower baseline measure of femoral neck bone mineral density in those who sustained a fracture (0.75 ± 0.12 g/cm2 vs 0.79 ± 0.10 g/cm2; P = .03), as well as lower T-scores (−2.13 vs −1.78; P = .01).

In fact, for every 1-unit decrease in the femoral neck T-score, the odds of sustaining a fracture increased by approximately 37% (odds ratio, 0.63; P = .02), the authors note.

Whereas those in the fracture group in the current study had a higher mean age (69.2 years) than in the nonfracture group (66.4 years), the differences were not statistically significant (P = .09). The average age at the initiation of the drug holiday was 66.9 years.

Likewise, there were no significant differences between fracture and nonfracture patients in terms of the type of bisphosphonate used before the drug holiday.

Of the patients, 61.6% had been treated with alendronate, 34.3% with risedronate, 13.3% with ibandronate, and 6.9% with zoledronic acid.

The average duration receiving bisphosphonate therapy before the drug holiday was 6.34 years, ranging from 6 months to as much as 30 years.

The leading fractures sustained during the drug holiday were those of the wrist, foot, ribs, and spine; notably, one patient developed osteonecrosis of the jaw, diagnosed after a root canal procedure failed to heal properly approximately 18 months into her bisphosphonate drug holiday.

All patients were resumed on bisphosphonates after a fracture.

Camacho said the incidence of fracture of 15.4% during the drug holiday was unexpected: "(The rate) was somewhat of a surprise to me."

As a comparison, findings from the Fracture Intervention Trial (FIT) showed that 14% of patients receiving alendronate and 18% of patients receiving placebo had any clinical fracture over the course of 3 years, Camacho noted.

"Our fracture percentage was only slightly higher than patients who were treated with alendronate (in the FIT trial), but I personally find 15.4% too high of a risk," she stressed.

Bisphosphonate Drug Holiday Guidelines

Camacho therefore underscored that any benefits of a drug holiday need to be weighed against the risks.

"It is also important to remember the perspective that the reason the drug holidays are initiated is to avoid rare adverse events (osteonecrosis of the jaw and atypical femoral fractures) that have very a low estimated incidence of less than .001%," she added.

The most recent guidelines on bisphosphonate drug holidays from the American Association of Clinical Endocrinologists and American College of Endocrinology suggest that patients with a moderate fracture risk take a drug holiday after 5 years of oral and 3 years of intravenous bisphosphonate treatment.

Those with a higher fracture risk are meanwhile recommended to take the holiday after 10 years of oral and 6 years of intravenous bisphosphonate treatment.

In terms of the duration of the drug holiday, recommendations typically only go so far as to suggest that therapy should be resumed if the patient experiences a fragility fracture or has a significant decline in bone mineral density, or if bone turnover markers increase to pretreatment levels.

A multidisciplinary task force of the American Society for Bone and Mineral Research, as reported by Medscape Medical News, meanwhile, has recommended that patients who are not considered to be at high fracture risk after 3 to 5 years of bisphosphonate treatment can be considered for a 2- to 3-year drug holiday, with continued reevaluation.

In addition to the FIT study, another previous trial, the HORIZON Pivotal Fracture Trial, compared the continuation or discontinuation of zoledronic acid after 3 years of treatment and showed increased new morphometric vertebral fractures in the patients who discontinued therapy, but no difference in other nonvertebral fractures.

The study nevertheless concluded that many patients may discontinue for up to 3 years; however, those with high vertebral fracture risk may benefit from continued therapy.

In other recent developments, as also reported by Medscape Medical News , the European Menopause and Andropause Society has come out with recommendations for drug holidays among low-risk patients, suggesting up to 5 years for alendronate and up to 6 years for zoledronate, while noting that, with risedronate, a shorter holiday of 1 to 2 years is sufficient.

Camacho noted that more research is nevertheless needed to come to a more conclusive recommendation on the duration of bisphosphonate drug holidays.

"A large prospective study is needed to assess how long of a holiday is needed to reduce the risk of these rare adverse events so that we do not unnecessarily expose our patients to increasing fracture risk while off therapy," she concluded.

Camacho serves as a primary investigator for multicenter trials for Amgen.

Endocrine Pract. 2018;24:163-169. Abstract

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