Post-fracture mortality is higher in long-term bisphosphonate users who take a ‘drug holiday’ and discontinue risedronate, but not those who do the same with alendronate, an Australian study has concluded.
Likely reflective of the former’s faster offset and lower bone affinity, the data suggest the type of bisphosphonate being used could be a factor to consider when planning drug holidays after five years of anti-fracture osteoporosis therapy, according to the investigators from Monash University, Melbourne.
The retrospective, population-based, cohort study included patients aged 50 years or older who had been hospitalised for hip fracture in Victoria in the four years to June 2018.
Some 365 patients were identified with good adherence (medication possession ratio ≥80%) to oral alendronate or risedronate for at least five years.
Most patients (69%) continued to use oral bisphosphonates till admission for hip fracture; 17% had discontinued for one year and 14% had discontinued for two years.
But the key finding was that post-fracture mortality was 2.37 times higher in patients who had discontinued risedronate for one year and 3.08 times in those who had discontinued for two years.
By contrast, no change was observed in post-fracture mortality in those who had discontinued alendronate over either time period.
These results remained similar in sensitivity analyses that included patients with at least three years of good adherence, the researchers reported in Journal of Clinical Endocrinology and Metabolism (link here).
“Our results substantiate previous research suggesting that risedronate may have quicker offset than alendronate due to lower bone affinity,” they wrote.
“In addition to the impact on risk of fracture, a systematic review also found a greater decrease in post-fracture all-cause mortality risk among intravenous bisphosphonate users than oral bisphosphonate users when comparing those who persisted treatment for three years to those who ceased.”
“This supports the hypothesis that bisphosphonates with higher affinity to bone might have prolonged effects in fracture sequelae, beyond risk of fracture.”
Nevertheless, the study’s strict inclusion criteria had potentially limited the generalisability of the finding, the authors wrote.
Besides those with less than ideal bisphosphonate adherence, patients on other medications affecting bone structure and mineralisation had been excluded, as had those with recent diagnoses for hip fractures or cancer prior to their index hip fracture, the authors stressed.
On the other hand, by assessing the mortality risk in alendronate and risedronate users separately, alendronate users had functioned as a negative control for risedronate users, they noted.
“The disparate results between alendronate and risedronate users provided additional support that the increased mortality risk observed in risedronate users did not merely reflect medication withdrawal in patients with poorer health status thus higher mortality risk,” they wrote.
The authors concluded: “While our findings suggest drug holiday may be associated with lower post-fracture survival, our findings do not replace the need for an individualized approach to treatment decision making.”
“Other factors associated with fracture risks in patients on an oral bisphosphonate drug holiday include older age, falls risk, use of fall-risk-increasing medications and frailty.
“The risk of osteonecrosis of jaw may be particularly relevant for patients using parenteral bisphosphonates and undergoing invasive dental procedures.”