Delayed Denosumab Injections and Fracture Risk Among Patients With Osteoporosis : A Population-Based Cohort Study

Ann Intern Med. 2020 Oct 6;173(7):516-526. doi: 10.7326/M20-0882. Epub 2020 Jul 28.


Background: Denosumab is effective for osteoporosis, but discontinuation leads to rapid reversal of its therapeutic effect.

Objective: To estimate the risk for fracture among users of denosumab who delayed subsequent doses compared with users who received doses on time.

Design: Population-based cohort study.

Setting: The Health Improvement Network U.K. primary care database, 2010 to 2019.

Patients: Persons aged 45 years or older who initiated denosumab therapy for osteoporosis.

Measurements: Observational 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.

Results: Investigators 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).

Limitation: Dosing schedules were not randomly assigned.

Conclusion: Although 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 source: National Clinical Research Center for Orthopedics, Sports Medicine & Rehabilitation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Denosumab / administration & dosage
  • Denosumab / therapeutic use*
  • Drug Administration Schedule
  • Female
  • Fractures, Bone / prevention & control*
  • Humans
  • Male
  • Osteoporosis / drug therapy*
  • Retrospective Studies
  • Risk Factors
  • Time-to-Treatment


  • Denosumab