Glucose Metabolism-Related Crosstalk Genes Between Osteoporosis and Frozen Shoulder Identified by Integrated Bioinformatics and Machine Learning Reveal Shared Diagnostic Biomarkers and Immune Microenvironment Characteristics

Osteoporosis (OP) and frozen shoulder (FS) are debilitating musculoskeletal diseases frequently complicated by metabolic disorders, while their overlapping molecular mechanisms are largely unclear. This study explored their shared pathogenesis based on glucose metabolism-related genes (GMRGs) and constructed dual-disease diagnostic models. We integrated transcriptomic data from the Gene Expression Omnibus database, screened core crosstalk genes using differential expression analysis, weighted gene co-expression network analysis and three machine learning algorithms[least absolute shrinkage and selection operator, logistic regression, and support vector machine recursive feature elimination]. Four shared key GMRGs[MARCKS, MAP3K1, LTF and ZMIZ1] were identified. The established models showed excellent diagnostic performance for OP in training set GSE56815, lower performance in validation set GSE7429, moderate-to-high efficacy for FS in training set GSE238053, and high accuracy in validation set GSE140731, with LTF showing the greatest contribution in the nomogram analysis. Protein–protein interaction analysis identified NFKBIA, LTF and HP as hub genes. Immune infiltration analysis showed that HP was positively correlated with neutrophils in OP, NFKBIA was negatively correlated with memory B cells in OP, and LTF was positively correlated with M1 macrophages in FS, suggesting a potential glucose metabolism-immune regulatory axis. Consensus clustering classified OP into two subtypes with distinct immune microenvironments. Virtual screening using DrugCLIP identified potential LTF-targeting candidate compounds, including P207-9104 and Z169905102, with molecular docking showing strong predicted binding affinities for LTF-P207-9104 and LTF-Z169905102. This study provide novel insights into the comorbidity mechanism of OP and FS, provides promising diagnostic biomarkers and therapeutic candidates, warranting further experimental validation.