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30-07-2020 | Osteoporosis | Highlight | News

Delayed denosumab dosing could raise vertebral fracture risk in patients with osteoporosis

Author: Claire Barnard


medwireNews: Delaying denosumab injections by more than 16 weeks is associated with an increased risk for vertebral fracture among patients with osteoporosis, study findings indicate.

However, Daniel Solomon (Brigham and Women’s Hospital, Boston, Massachusetts, USA) and colleagues note in the Annals of Internal Medicine that evidence from their research was “insufficient to conclude that fracture risk is increased at other anatomical sites” with long delays in denosumab dosing.

The team used observational data from The Health Improvement Network UK primary healthcare database to emulate an analysis of a hypothetical randomized trial including 2594 denosumab-treated patients with three dosing intervals: on time (injection given within 4 weeks of the recommended date); short delay (given 4–16 weeks late); and long delay (given more than 16 weeks late).

The cumulative risk for the primary outcome of composite fracture over 6 months was numerically higher among patients in the long-delay group compared with those in the on-time group, at 42.4 versus 27.3 events per 1000 people, but the difference did not reach statistical significance. People in the short-delay group had an intermediate risk for composite fracture, at 32.2 per 1000.

When different fracture types were analyzed separately, the 6-month risk for vertebral fractures was almost fourfold higher in patients with a long denosumab delay compared with those in the on-time arm, with rates of 10.1 versus 2.2 per 1000 and a hazard ratio of 3.91 after adjustment for potentially confounding factors. A short delay was associated with a numerically, but not significantly, increased risk for vertebral fracture relative to on-time treatment, at a rate of 3.6 per 1000.

There were no significant differences in the risk for major osteoporotic, hip, or nonvertebral fractures according to the length of denosumab delay.

Solomon and team note that their study “had limited statistical power for composite fracture and several secondary end points […], except for vertebral fracture,” and that “[f]uture studies with larger sample sizes are needed.” They also point out that fracture rates “may be underestimated” in primary care databases, and that unmeasured confounders may have influenced their results.

Writing in an accompanying editorial, Kristine Ensrud and John Schousboe, both from the University of Minnesota in Minneapolis, USA, say that despite the limitations of the study, the “findings are consistent with known denosumab pharmacokinetics and prior studies of fracture incidence after denosumab treatment discontinuation.”

“Therefore, it is of utmost importance that clinicians considering denosumab treatment carefully counsel patients before its initiation on the importance of not delaying or abruptly discontinuing injections.”

The editorialists believe that the study results are particularly timely considering the potential for treatment delays and disruptions caused by the COVID-19 pandemic.

In light of this, Ensrud and Schousboe say that “some organizations recommend temporary transition to an oral bisphosphonate in patients receiving denosumab treatment for whom continued treatment is not feasible within 7 to 8 months of their most recent injection,” given the longer half-life of bisphosphonates in bone.

medwireNews is an independent medical news service provided by Springer Healthcare. © 2020 Springer Healthcare part of the Springer Nature Group

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Ann Intern Med 2020; doi:10.7326/M20-0882
Ann Intern Med 2020; doi:10.7326/M20-4802