Osteoporosis is the most common systemic and metabolic bone disease. The concentration of serum resistin (RETN) is associated with bone mineral density, but it is still unclear whether there is a causal relationship between RETN and bone density and fractures. This study used Mendelian randomization (MR) to analyze the causal relationship between RETN gene expression and bone mineral density and fractures, and then analyzed the differential expression of RETN gene in single-cell sequencing data of femeral neck fracture (FNF) and osteoarthritis (OA) samples. MR analysis showed that high expression of RETN was found to lead to decreased bone mineral density and increased risk of fractures. RETN expression was upregulated in the FNF group, and RETN was mainly expressed by neutrophils. The inflammatory chemokine CXCL8 related to RETN was significantly upregulated in the FNF group. This study suggested the role of RETN in the pathogenesis of osteoporosis, providing a basis for the diagnosis and treatment of osteoporosis.