Osteoporotic fractures remain common despite available therapies, highlighting the need for new, safe, and affordable treatment options. Advances in real-world data and causal inference have enabled target trial emulation, with prior frameworks demonstrating drug repurposing using observational data. However, no large-scale trial emulation framework has been applied to systematic drug repurposing for osteoporotic fracture prevention. To address this gap, we developed REACT (Real-world Emulated Clinical Trials), a scalable framework that operationalizes established target trial principles into an automated, comparator-robust pipeline for high-throughput drug screening. Applied to fracture prevention in older adults with osteoporosis, REACT screened 1,222 drugs and identified 18 with statistically significant associations, including 11 with protective effects and 7 with risk-increasing effects. The convergence of these findings with biological and prior observational evidence underscores REACT’s ability to surface clinically meaningful patterns and its potential as a generalizable platform for accelerating real-world drug discovery and safety surveillance.

The authors have declared no competing interest.

This study was supported by the National Science Foundation (IIS-2145625) and the National Institute on Aging(R01AG080017).

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

Yes

The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

The Institutional Review Board of The Ohio State University determined that this study using de-identified administrative claims data (Merative MarketScan) does not constitute human subjects research - it is an Exempt Research by their definition.

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Yes

I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).

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I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.

Yes

The data used in this study are from Merative MarketScan and were obtained under a data use agreement. These data are not publicly available and cannot be shared by the authors. Researchers may obtain access to the data directly from Merative MarketScan with appropriate permissions.