Efficacy Versus Effectiveness: The HORIZON-Pivotal Fracture Trial and Its Emulation in Claims Data

The objective of this study is to evaluate the concordance of results between the Health Outcomes and Reduced Incidence with Zoledronic Acid Once Yearly (HORIZON)-Pivotal Fracture Trial (PFT) and a nonrandomized database study designed to emulate the trial.

HORIZON-PFT evaluated the efficacy of zoledronic acid versus placebo in reducing the risk of hip fractures and found a 41% risk reduction over a three-year treatment period (hazard ratio [HR] = 0.59; 95% confidence interval [95% CI] 0.42-0.83). Using two US claims databases from August 2007 to December 2020 or June 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.

Because of 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 in 1,000 in the trial and 8.3 in 1,000 in the database analysis. In the database study, zoledronic acid was associated with a 28% reduction in hip fractures risk compared with raloxifene (HR = 0.72; 95% CI 0.51-0.92). The attenuated effect of zoledronic acid in the database study may be explained by its shorter follow-up, because the interpolated estimate of the effect in HORIZON-PFT at 18 months was HR_RCT (randomized controlled trial), 0.74, nearly identical to the observational estimate HR_database 0.72.

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.