Abstract: Objective To analyze the application value of tumor necrosis factor-α (TNF-α) in the diagnosis of osteoporosis (OP) in patients with type 2 diabetes mellitus (T2DM). Methods A total of 123 T2DM patients who were admitted in the Affiliated Suqian Hospital of Xuzhou Medical University from January 2021 to December 2022 were selected for this study. Based on bone mineral density (BMD), these patients were divided into three groups: a normal bone mass group (n=38), a reduced bone mass group (n=52), and an osteoporosis group (n=33). The serum TNF-α levels in each group were measured by enzyme-linked immunosorbent assay (ELISA). Pearson or Spearman correlation analyses were used to examine the relationship between bone density at different sites and various indicators in T2DM patients. Logistic regression analysis was performed to identify risk factors for OP in T2DM patients. A receiver operating characteristic (ROC) curve was plotted to evaluate the diagnostic value of TNF-α for OP in T2DM patients. Results The serum TNF-α levels in the osteoporosis group were significantly higher than those in the normal bone mass group and the reduced bone mass group (P<0.05). Pearson or Spearman correlation analysis showed a significant negative correlation between bone density in T2DM patients and age, female gender, TNF-α, HDL-C, and ALP (r<0, P<0.05), and a significant positive correlation with BMI and UA (r>0, P<0.05). Logistic regression analysis indicated that female gender, TNF-α, and ALP were risk factors for OP in T2DM patients. ROC curve analysis showed that TNF-α had an area under the curve (AUC) of 0.819 for predicting OP in T2DM patients, with a sensitivity of 93.9% and a specificity of 63.3%. Conclusions The serum TNF-α levels in T2DM patients may be associated with the occurrence and development of OP and serve as a potential biomarker for OP in patients with T2DM.