• Houchen Lyu, Kazuki Yoshida, Sizheng S Zhao, Jie Wei, Chao Zeng, Sara K Tedeschi, Benjamin Z Leder, Guanghua Lei, Peifu Tang, and Daniel H Solomon.
• National Clinical Research Center for Orthopedics, Sports Medicine & Rehabilitation, General Hospital of Chinese PLA, Beijing, China, Xiangya Hospital of Central South University, Changsha, China, and Brigham and Women's Hospital, Boston, Massachusetts (H.L.).
• Ann. Intern. Med. 2020 Oct 6; 173 (7): 516526516-526.

BackgroundDenosumab is effective for osteoporosis, but discontinuation leads to rapid reversal of its therapeutic effect.ObjectiveTo estimate the risk for fracture among users of denosumab who delayed subsequent doses compared with users who received doses on time.DesignPopulation-based cohort study.SettingThe Health Improvement Network U.K. primary care database, 2010 to 2019.PatientsPersons aged 45 years or older who initiated denosumab therapy for osteoporosis.MeasurementsObservational data were used to emulate an analysis of a hypothetical trial with 3 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.ResultsInvestigators identified 2594 patients initiating denosumab therapy. The risk for composite fracture over 6 months was 27.3 in 1000 for on-time dosing, 32.2 in 1000 for short delay, and 42.4 in 1000 for long delay. Compared with on-time injections, short delay had a hazard ratio (HR) for composite fracture of 1.03 (95% CI, 0.63 to 1.69) and long delay an HR of 1.44 (CI, 0.96 to 2.17) (P for trend = 0.093). For vertebral fractures, short delay had an HR of 1.48 (CI, 0.58 to 3.79) and long delay an HR of 3.91 (CI, 1.62 to 9.45).LimitationDosing schedules were not randomly assigned.ConclusionAlthough delayed administration of subsequent denosumab doses by more than 16 weeks is associated with increased risk for vertebral fracture compared with on-time dosing, evidence is insufficient to conclude that fracture risk is increased at other anatomical sites with long delay.Primary Funding SourceNational Clinical Research Center for Orthopedics, Sports Medicine & Rehabilitation.

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