Addressing Overlooked Variables in Preclinical Fracture Repair Research for Improved Translation.

Abstract

In preclinical research focused on bone fracture repair, a significant gap exists in understanding and incorporating key variables that influence homeostasis and pathophysiological processes. Factors such as immune system responses, sex differences, pain and innervation, and microbiota are often overlooked. Preclinical studies frequently rely on rodent models housed under sterile, specific pathogen-free conditions, resulting in naïve immune responses. Additionally, these studies typically use only one sex, fail to monitor stress behaviors, and do not assess infections or commensal microorganisms. While such controlled approaches enable the study of essential mechanisms, they may hinder the successful translation of findings to immunocompetent and diverse human populations, who do not live in sterile environments and vary widely in biological sex, gender, age, immune history, and living conditions. Here, we summarize the material presented at the Preclinical Models Section and International Section of Fracture Repair Workshop held during the 2026 Orthopaedic Research Society (ORS) Annual Meeting in Charlotte, North Carolina.