Delayed Denosumab Injections and Bone Mineral Density Response: An Electronic Health Record-based Study

Abstract

Context: Discontinuation of denosumab leads to a rapid reversal of its therapeutic effect. However, there are no data regarding how unintended delays or missed injections of denosumab impact bone mineral density (BMD) response.

Objective: We examined the association of delays in injections of denosumab with BMD change.

Design: We used electronic medical records from two academic hospitals from 2010 to 2017.

Participants: Patients older than 45 years of age and used at least 2 doses of 60 mg denosumab. Denosumab adherence was evaluated by the medication coverage ratio (MCR). Good adherence corresponds to a dosing interval ≤7 months (defined by MCR ≥93%), moderate adherence corresponds to an interval of 7 to 10 months (MCR 75%-93%), and poor adherence corresponds to an interval ≥10 months (MCR ≤75%).

Outcome measures: Annualized percent BMD change from baseline at the lumbar spine, total hip, and femoral neck.

Results: We identified 938 denosumab injections among 151 patients; the mean (SD) age was 69 (10) years, and 95% were female. Patients with good adherence had an annualized BMD increase of 3.9% at the lumbar spine, compared with patients with moderate (3.0%) or poor adherence (1.4%, P for trend .002). Patients with good adherence had an annualized BMD increase of 2.1% at the total hip, compared with patients with moderate (1.3%) or poor adherence (0.6%, P for trend .002).

Conclusions: A longer interval between denosumab injections is associated with suboptimal BMD response at both spine and total hip. Strategies to improve the timely administration of denosumab in real-world settings are needed.

Keywords: Osteoporosis; bone mineral density; denosumab; dosing delay.

Figure 1.

Study population.

Figure 2.

Adherence of denosumab from second to tenth injections Adherence was examined using different adherence window (30 days and 120 days); chronological adherence was high at second injection, but dropped dramatically.

Figure 3.

Results of sensitivity analyses. Comparisons between primary analysis and 6 sensitivity analyses for BMD increase at the lumbar spine, total hip, and femoral neck. Primary result: Annualized BMD changes of the 3 study groups from the primary analyses; use 1-year baseline window: repeat the analyses using a strict baseline DXA window (less than 1 year before the index date); no prior teriparatide: repeat the analysis by excluding patients who received teriparatide before denosumab; females only: restrict the analyses to female patients; DMAb over 24 months: excluded patients who received denosumab for <24 months; alternative measurement MPR: repeat the analyses using MPR; and off-treatment period within 12 months: exclude observations with an off-treatment period > 12 months. The sensitivity analyses were adjusted for age, gender, BMI, rheumatoid arthritis (yes/no), prior fragility fractures (yes/no), prior alendronate (yes/no), prior ibandronate (yes/no), prior risedronate (yes/no), intravenous bisphosphonate (yes/no), prior bisphosphonates treatment length (months), prior anabolic treatment (yes/no), prior glucocorticoid (yes/no), length of follow-up period, and the number of denosumab injections previously received. P value is from a trend test of an ordered relationship across the 3 groups (poor, moderate, and good). BMD, bone mineral density; DMAb, denosumab; DXA, dual-energy X-ray absorptiometry; MPR, medication possession ratio.