Systematic Review of Protein Signatures for Clinical Monitoring of Osteonecrosis of the Jaw: Meta-Analysis and Insights from Bioinformatics-Driven Proteomics

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BACKGROUND: Several studies have investigated the clinical and immunological aspects of medication-related osteonecrosis of the jaw (MRONJ). However, the underlying immunological mechanisms and signaling pathways involved in its pathophysiology remain incompletely understood. This systematic review and meta-analysis, complemented by bioinformatics analyses, aimed to identify proteomic biomarkers associated with MRONJ. METHODS: Six databases (PubMed, Embase, Scopus, Web of Science, Cochrane Library, and VHL) were searched, along with gray literature and manual searches. Observational studies in English comparing proteomic profiles of individuals with and without MRONJ were included. Study selection and data management were conducted using EndNote™ X8 and Rayyan.ai, and risk of bias was assessed using the QUADOMICS tool. Functional enrichment analysis was performed using g:Profiler and Reactome, and interaction networks were constructed using GeneMANIA, STRING, and MetaboAnalyst (Cytoscape program; version 3.10.1). Meta-analysis was performed in RStudio (R-4.5, Rstudio extension 2025.05.1+513) (α = 0.05). RESULTS: Three studies were included in the review, and two in the meta-analysis. The meta-analysis showed higher salivary levels of Apolipoprotein B-100 (APOB), Apolipoprotein A-II (APOA2), and Heparin Cofactor 2 (SERPIND1) in MRONJ patients, while the protein Keratin (KRT16) showed reduced levels without statistical significance. Bioinformatics analyses indicated involvement in lipid metabolism, impaired tissue repair, and inflammatory and immune responses. CONCLUSIONS: These findings suggest altered salivary proteomic signatures in MRONJ for APOB, APOA2, SERPIND1, and KRT16 proteins.

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