Delayed denosumab injections raise vertebral fracture risks
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Delaying denosumab doses by more than 4 months is associated with increased risks for vertebral fracture compared with on-time injections, according to findings published in Annals of Internal Medicine.
However, researchers reported that evidence was not sufficient to show an association between dose delay and fracture risk at other sites.
“Delaying denosumab infusions can put people at risk for fractures, especially vertebral fractures,” Daniel H. Solomon, MD, MPH, a rheumatologist in the division of rheumatology, inflammation and immunology at Brigham and Women’s Hospital, told Healio. “Brief delays, less than 4 months, are not as worrisome as longer delays, but on-time shots are best.”
In a population-based study, Solomon and colleagues analyzed data from 2,594 adults aged at least 45 years who initiated denosumab (Prolia, Amgen) therapy for osteoporosis, using data from The Health Improvement Network, a database of medical records from primary care practitioners in the United Kingdom (mean age at baseline, 76 years; 94% women; 53% with history of major osteoporotic fracture). Researchers used observational data to emulate an analysis of a hypothetical trial with three dosing intervals: subsequent denosumab injection given within 4 weeks after the recommended date (“on time”), delay by 4 to 16 weeks (“short delay”) and delay by more than 16 weeks (“long delay”). The primary outcome was a composite of all fracture types at 6 months after the recommended date. Secondary outcomes were major osteoporotic fracture, vertebral fracture, hip fracture and nonvertebral fracture.
“The retrospective cohort study takes advantage of naturally occurring variation in the timing of denosumab administration, allowing us to examine the effect of this variation on fracture risk in routine clinical settings,” Solomon and colleagues wrote.
Within the cohort, 1,856 injections were administered within 4 weeks before the index date, leaving 4,288 injections that were delayed.
The risk for composite fracture over 6 months was 27.3 in 1,000 for on-time dosing, 32.2 in 1,000 for short delay and 42.4 in 1,000 for long delay. Compared with on-time injections, the HR for composite fracture was 1.03 for short delay (95% CI, 0.63-1.69) and 1.44 for a long delay (95% CI, 0.96-2.17).
In analyses assessing only risk for vertebral fractures, the HR was 1.48 for a short delay (95% CI, 0.58-3.79) and 3.91 for a long delay (95% CI, 1.62-9.45), compared with on-time injections.
As Healio previously reported, a longer interval between denosumab injections is associated with suboptimal bone mineral density response at the spine and total hip, and strategies to improve the timely administration of denosumab in real-world settings are needed. In that study, the same group of researchers found that adults with good adherence experienced an annualized BMD increase of 3.9% at the lumbar spine compared with those with moderate (3%) or poor adherence (1.4%; P = .002), with results persisting after adjustment for age, sex, BMI, fracture history, bisphosphonate history and duration and number of previous denosumab injections.
“Clinicians need better systems to reduce delays and patients need to take some responsibility for getting in for the denosumab on time,” Solomon said. “We must identify optimal systems for medication adherence in osteoporosis.”
For more information:
Daniel H. Solomon, MD, MPH, can be reached at the division of rheumatology, inflammation and immunity, Brigham and Women’s Hospital, 60 Fernwood Road, Boston, MA 02115; email: dsolomon@bwh.harvard.edu.
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