Endocrinol Metab.  2024 Dec;39(6):946-955. 10.3803/EnM.2024.2047.

Association of Delayed Denosumab Dosing with Increased Risk of Fractures: A Population-Based Retrospective Study

• Kim KM
• Jang SA
• Hong NK
• Kim CS
• Rhee Y
• Park SW
• Cummings SR
• Seo GH

• KMID: 2562722
• DOI: http://doi.org/10.3803/EnM.2024.2047

Abstract

Background
Inhibitory effects of denosumab on bone remodeling are reversible and disappear once treatment is discontinued. Herein, we examined whether and to what extent delayed denosumab administration is also associated with fracture risk using nation-wide data.
Methods
The study cohort included women aged 45 to 89 years who were started on denosumab for osteoporosis between October 2017 and December 2019 using data from the Korean Health Insurance Review and Assessment service. Participants were stratified according to the time of their subsequent denosumab administration from the last denosumab administration, including those with within 30 days early dosing (ED30), within the planned time of 180–210 days (referent), within 30–90 days of delayed dosing (DD90), within 90–180 days of delayed dosing (DD180), and longer than 181 days of delayed dosing (DD181+). The primary outcome was the incidence of all clinical fractures.
Results
A total of 149,199 participants included and 2,323 all clinical fractures (including 1,223 vertebral fractures) occurred. The incidence of all fractures was significantly higher in the DD90 compared to reference group (hazard ratio [HR], 1.2; 95% confidence interval [CI], 1.1 to 1.4). The risk of all fracture was even higher in the longer delayed DD180 group (HR, 1.9; 95% CI, 1.6 to 2.3) and DD181+ group (HR, 1.8; 95% CI, 1.5 to 2.2). Increased risks of fractures with delayed dosing were consistently observed for vertebral fractures.
Conclusion
Delayed denosumab dosing, even by 1 to 3 months, was significantly associated with increased fracture risk. Maintaining the correct dosing schedule should be emphasized when starting denosumab.

Keyword

Denosumab; Fractures; Osteoporosis; Discontinuation

Figure

• 

  Fig. 1. Study design and participants according to the timing of subsequent denosumab (DMAb) administration from the last DMAb injection. (A) Eligible participants and DMAb doses from October 2017 to December 2019 from the Health Insurance Review and Assessment service database. (B) The study participants were stratified into five subgroups according to when their subsequent DMAb was administered. Patients who received a subsequent DMAb dose during the recommended dosing time of 180–210 days were included in the reference group. Patients who received a subsequent DMAb dose within 30 days, 30–90 days after, 90–180 days after, and ≥181 days after the recommended dosing time were stratified into the ED30 (early dosing), DD90 (delayed dosing), DD180, and DD181+ groups, respectively.

• 

  Fig. 2. Cumulative incidence (%) for all fractures (A) and vertebral fractures (B). Kaplan-Meier survival curves of fractures were plotted according to the study groups for the following 6 months. ED, early dosing; DD, delayed dosing.

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