Diagnostic biomarkers for non-traumatic osteonecrosis of the femoral head : a systematic review and pathophysiological cascade network.

AIMS: Many studies have focused on identifying specific biomarkers for the early diagnosis of non-traumatic osteonecrosis of the femoral head (NONFH). This systematic review aims to summarize biomarkers associated with the diagnosis and progression prediction of NONFH, thereby providing a molecular level foundation for clinical diagnosis and targeted treatment. METHODS: Following the PRISMA guidelines for systematic reviews, we comprehensively searched original English-language articles published between January 2015 and December 2025 in the Web of Science and PubMed databases. Studies were selected based on the PICOS framework. Extracted data included study design, methodologies, sample sources, identified biomarkers, predictive performance, and the potential pathological pathways involved. RESULTS: Overall, 15 studies were included, reporting a total of 52 biomarkers, all derived from blood samples. Biomarkers from eight studies were used to reflect NONFH progression, while those from seven studies were using for diagnostic prediction purposes. All biomarkers demonstrated favourable predictive performance, with six studies providing external validation. The predictive model comprising ICAM1, NR3C1, IKBKB, and CD4 showed promising performance, with area under the receiver operating characteristic curve (AUC) values each reaching 1.00. Based on their core functions, the biomarkers were categorized into seven functional groups: immune-inflammatory activation and response, signal transduction and regulation, molecular metabolism and energy homeostasis, vascular function and coagulation, oxidative stress, pyroptosis and autophagy, and RNA regulatory. CONCLUSION: Biomarkers for NONFH exhibit considerable potential for early diagnosis and disease progression prediction in the Chinese population. The pathogenesis of NONFH involves a multifaceted pathological process in which various components interact and synergistically exacerbate the condition. This indicates that future therapeutic strategies should adopt a multitarget, multipathway synergistic intervention approach.