Longer intervals between denosumab injections are associated with suboptimal bone mineral density (BMD) response at both the spine and total hip, and evidence to support strategies to minimize delayed or missed injections are needed, according to study results published in The Journal of Clinical Endocrinology & Metabolism.

Although it has been shown that denosumab discontinuation leads to rapid reversal of therapeutic improvement, the current study was the first to investigate the effect of delayed or missed denosumab injections on BMD response. The study utilized electronic medical records (EHRs) to determine associations between denosumab injection delays and changes in BMD.

Data were collected from EHRs of 2 academic hospitals; study participants were aged >45 years, had at least 2 dual-energy x-ray absorptiometry (DXA) scans, and received at least 2 injections of 60 mg denosumab between 2010 and 2017. Adherence to denosumab was evaluated by medication coverage ratio (MCR), with good adherence corresponding to a dosing interval of ≤7 months (MCR, ≥93%), moderate adherence to an interval of 7 to 10 months (MCR, 75%-93%), and poor adherence to an interval of ≥10 months (MCR, ≤74%). The primary outcome was annualized percentage change in BMD from baseline at the posteroanterior lumbar spine, total hip, and femoral neck using BMD (g/cm2) from routine DXA scans.

Overall, 151 patients received at least 2 doses of denosumab resulting in a total of 938 denosumab injections. The majority of patients were women (95%), and the mean age at index date was 69 years; 31% of patients were aged <65 years, 42% were aged between 65 and 75 years, and 26% were aged >75 years.

For all study participants, the unadjusted annualized percentage BMD change was 2.7% (95% CI, 2.3%-3.1%) at the lumbar spine, 1.2% (95% CI, 1.0%-1.5%) at the total hip, and 1.1% (95% CI, 0.8%-1.3%) at the femoral neck. When categorized by adherence, the unadjusted annualized percentage BMD change at the lumbar spine was 1.4% for poor adherence, 3.0% for moderate adherence, and 3.9% for good adherence (P =.002). The unadjusted annualized percentage BMD change at the total hip was 0.6%, 1.3% and 2.1%, respectively (P =.001). Changes were not significantly different across the 3 groups at the femoral neck (1.3%, 1.5%, and 1.7%, respectively; P =.49)

After adjusting for age, body mass index, sex, fragility fracture history, rheumatoid arthritis, anabolic treatment history, bisphosphonates history and duration, glucocorticoid history, length of follow-up, and the number of previously received denosumab injections, the annualized BMD change at lumbar spine was highest for patients with good adherence (3.9%) compared with moderate adherence (3.0%) or poor adherence (1.4%; P =.002). A similar trend was seen in BMD change at total hip (2.1% vs 1.3% vs 0.6%; P =.002); however, annualized changes in BMD at femoral neck were not associated with adherence (P =.487).

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“The originality of this study is its evaluation of the [effect] of denosumab dosing delay. Since denosumab administration requires an appointment with the health care system, delays may be unavoidable in routine clinical practice. Currently, little evidence exists regarding how long a delay must be avoided. Our results provide evidence that a delay of over four months (i.e., >10 months between doses) may be unacceptable, but future studies are needed to determine the exact threshold. Determining effective strategies to improve adherence with denosumab, and implementing those strategies, are crucial if we are to optimize the therapeutic benefits of this highly effective therapy while minimizing potential adverse effects,” the researchers concluded.

Disclosure: Several study authors declared affiliations with the pharmaceutical industry. Please see the original reference for a full list of authors’ disclosures.

Reference

Lyu H, Zhao SS, Yoshida K, et al. Delayed denosumab injections and bone mineral density response: An electronic health record-based study [published online January 2, 2020]. J Clin Endocrinol Metab. doi:10.1210/clinem/dgz321