Any pause in taking the osteoporosis drug risedronate (Actonel) should last no longer than 2 years rather than the 2 to 3 years currently recommended for bisphosphonates, new research suggests.

In a cohort of patients aged 66 and older in Ontario, Canada, those who had been taking risedronate had a 34% greater risk of a hip fracture during year 2 to year 3 of a pause in taking the drug — a drug holiday — compared with those who had been taking alendronate (Fosamax). 

The study showed that “risedronate, which has a shorter half-life, confers relatively less hip fracture protection than alendronate during drug holidays longer than 2 years and careful monitoring and follow-up after 2 years is likely warranted,” Kaley (Kaleen) N. Hayes, Pharm D, PhD, summarized in an oral presentation at the American Society of Bone and Mineral Research (ASBMR) 2021 annual meeting. Hayes is an assistant professor in the Department of Health Services, Policy, and Practice at Brown University School of Public Health, Providence, Rhode Island.

“Although alendronate and risedronate have similar effectiveness for preventing fractures on treatment, our findings suggest that older patients on a risedronate drug holiday may benefit from assessment to consider resuming therapy after 2 years to prevent hip fractures,” she elaborated in an email.

Juliet Compston, MD, identified this study as one of the meeting’s Clinical Science Highlights.

“This is the first study to directly to compare fracture incidence during a drug holiday after treatment with the two most commonly prescribed oral bisphosphonates, alendronate and risedronate,” she told Medscape Medical News in an email.

The difference in fracture incidence during the 3-year drug holiday is “consistent with the known difference in pharmacokinetic properties of the two drugs,” noted Compston, professor of bone medicine and honorary consultant physician at the University of Cambridge School of Clinical Medicine, United Kingdom.

Since the increased risk of fracture after stopping risedronate vs alendronate was seen by 2 years, “reevaluation of risk in risedronate-treated patients should therefore be considered earlier than the recommended period of 2 to 3 years after discontinuation,” she said.

“The study does not provide information about the optimal duration of drug holiday for either risedronate or alendronate, but it supports a shorter duration for the former of up to 2 years,” according to Compston.

Study Rationale and Findings

“The question of whether people treated for osteoporosis with oral bisphosphonates should have drug holidays is controversial,” Compston noted, “but many guidelines recommend that in lower-risk individuals who have received bisphosphonates for 5 years, a break from treatment of 2 to 3 years should be considered.”

Five or more years of bisphosphonate treatment for osteoporosis has been associated with rare adverse effects such as atypical femoral fractures, and these drugs appear to have fracture protection effects that linger for a while, so a drug holiday is recommended for most patients, Hayes added.

Guidelines such as the 2016 ASBMR Task Force report on long-term bisphosphonates for osteoporosis, she continued, “acknowledge that evidence for this recommendation comes primarily from the extension trial for alendronate, and patients undergoing a risedronate drug holiday may need to be reassessed earlier because of risedronate’s shorter half-life.”

Compared to alendronate, risedronate accumulates less in the bone and is eliminated more quickly from the body, so its fracture protection during drug holidays may be shorter.

The researchers aimed to estimate the 3-year fracture risk after discontinuing long-term (3 or more years) risedronate vs alendronate therapy among older adults in Ontario.

From healthcare administrative data, they identified 120,368 patients aged 66 years and older who had started taking risedronate or alendronate as initial therapy for osteoporosis during the period 2000-2016. They had taken the therapy for 3 or more years (with at least 80% adherence) before stopping it for 120 days or longer.

The researchers found that 45% of patients were taking risedronate and 55% were taking alendronate, which are the main bisphosphonates used in Ontario, Hayes noted. Etidronate (Didronel) is recommended as second-line therapy and accounts for <2% of patients starting oral bisphosphonate therapy. 

In an earlier study, the researchers identified a shift toward greater use of risedronate than alendronate since 2008, likely related to newer formulations (eg, monthly and weekly delayed-release formulations of risedronate vs only weekly alendronate formulations).

The researchers matched 25,077 patients taking alendronate with 25,077 patients taking risedronate, based on fracture risk-related characteristics, including demographics, diagnoses, medication use, and healthcare use.

The patients had a mean age of 74 when they started taking an oral bisphosphonate; 82% were women and most were White.  

Most patients (78%) had received a prescription from a general practitioner and, on average, they took the bisphosphonate therapy for 5.9 years before the drug holiday.  

The primary outcome of incident hip fracture during a 3-year drug holiday occurred in 915 patients. There were 12.4 events per 1000 patients in the risedronate group vs 10.6 events per 1000 patients in the alendronate group (hazard ratio, 1.18; 95% CI, 1.04 – 1.34).

The risks were not significantly higher during year 1 or year 2 of the drug holiday, but the curves began to diverge after 2 years, co-author Suzanne Cadarette, PhD, of the Leslie Dan Faculty of Pharmacy at the University of Toronto, Canada, explained when replying to a question after the presentation. Cadarette supervised this PhD dissertation research by Hayes.

The researchers acknowledged that the limitations of their study include a lack of information about race or bone mineral density, and the findings may not apply to a younger, more racially diverse population.

The research was supported by the University of Toronto Dalla Lana School of Public Health and the Leslie Dan Faculty of Pharmacy, a Canadian Institutes of Health Research grant, and a doctoral research award. The authors have disclosed no relevant financial relationships.

American Society of Bone and Mineral Research (ASBMR) 2021 annual meeting: Abstract 1028. Presented October 2, 2021.

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