Efficacy versus effectiveness: The HORIZON Pivotal Fracture Trial and its emulation in Claims Data.

Objectives: To evaluate the concordance of results between the HORIZON-Pivotal Fracture Trial (PFT) and a non-randomized database study designed to emulate the trial.

Methods: HORIZON-PFT evaluated the efficacy of zoledronic acid vs placebo in reducing the risk of hip fractures and found a 41% risk reduction over a 3-year treatment period (HR = 0.59; 95% CI 0.42 to 0.83). Using two U.S. claims databases from 08/2007 to 12/2020 or 06/2021 we applied eligibility criteria from HORIZON-PFT and identified women with osteoporosis who initiated zoledronic acid or raloxifene as a proxy for placebo. The study protocol was registered on ClinicalTrials.gov (NCT04736693) before inferential analyses. We compared HORIZON-PFT and database study results using prespecified metrics.

Results: Due to low adherence in clinical practice, on-treatment follow up was truncated at 18 months in the database study. The hip fracture risk after 18 months was 9.3/1000 in the trial and 8.3/1000 in the database analysis. In the database study, zoledronic acid was associated with a 28% reduction in hip fractures risk compared to raloxifene (HR = 0.72; 95% CI 0.51 to 0.92). The attenuated effect of zoledronic acid in the database study may be explained by its shorter follow-up, as the interpolated estimate of the effect in HORIZON-PFT at 18 months was HR_RCT 0.74, nearly identical to the observational estimate HR_database 0.72.

Conclusion: Real-world emulation of the HORIZON-PFT found that zoledronic acid reduced hip fractures risk over an 18-month follow-up period. Limited adherence in clinical practice diminished the magnitude of its preventive effect and precluded long-term estimation of effectiveness in this setting.