Summary To identify the critical genes and pathways that related to OP development in male AS patients, bioinformatic gene analysis and qRT-PCR validation were performed. SBNO2 and VPS13B were identified as the potential target for OP development, which may be valuable for the prevention of OP in male AS patients. Introduction Osteoporosis (OP) is common in men with ankylosing spondylitis (AS). The specific pathogenesis of OP in AS, however, is still unclear. The present study attempted to identify potential genes associated with the development of OP in males with AS. Methods Gene expression profiles were downloaded from the GSE73754 and GSE35959 datasets from the Gene Expression Omnibus (GEO). Data from OsteoporosAtlas were downloaded as a supplement. Differentially expressed genes (DEGs) were determined with the limma package. The overlapping DEGs between male AS-related genes and OP-related genes were determined. The DEGs were validated by qRT-PCR in the blood samples of males with AS. Weighted gene co-expression network analysis (WGCNA) was utilized to establish a co-expression network to identify the hub genes. Results A total of 17 overlapping DEGs were identified; 6 genes in 17 overlapping DEGs were verified as the essential genes in the pathogenesis of OP in male AS by qRT-PCR analysis. After WGCNA, the modules of MEblue (> 0.6) and MEred (> 0.8) were screened out by the correlation analysis and were determined to function mainly in MAPK signaling pathway and osteoclast differentiation. Analysis of the two modules revealed VPS13B and SBNO2 as key genes due to the high degree of correlation. Both genes play an important role in bone metabolism regulation in male AS. Two hub genes MYD88 in MEblue and NCK1 in MEred with high degree of connectivity were selected. Conclusions Gender-specific SBNO2 and VPS13B may be key genes involved in OP in male AS.