Objective To investigate the correlations of polymorphisms and mutations of osteoprotegerin (OPG) gene rs4355801 and rs6993813 loci with bone metabolism in postmenopausal women with type 2 diabetes mellitus (T2DM). Methods From Oct. 2020 to Oct. 2021, 200 postmenopausal women who visited The First Affiliated Hospital of Shihezi University were enrolled and divided into normal glucose tolerance and bone mass group (group A, n=52), normal glucose tolerance but abnormal bone mass group (group B, n=43), T2DM with normal bone mass group (group C, n=47), and T2DM with abnormal bone mass group (group D, n=58). The baseline data such as age, height, weight, and years since menopause (YSM) were collected, and body mass index (BMI) and waist-hip ratio (WHR) were calculated. Biochemical indicators such as triglyceride (TG), high density lipoprotein-cholesterol (HDL-C), low density lipoprotein-cholesterol (LDL-C), blood calcium, blood phosphorus, alkaline phosphatase (ALP), and fasting blood glucose (FBG) were measured by Roche automatic biochemical analyzer. Glycosylated hemoglobin (HbA1c) was measured by high-performance liquid chromatography. Bone mineral densities (BMDs) of the lumbar spine (L_1-4) and neck of femur (NOF) were measured by dual energy X-rays. Polymorphism and genotyping of OPG gene rs4355801 and rs6993813 loci were determined by time-of-flight mass spectrometry. Multiple linear regression analysis was used to analyze the influencing factors of BMD. Linkage disequilibrium analysis and haplotype analysis of single nucleotide polymorphism loci were performed using SHEsis software. Results There were significant differences in age, BMI, and WHR among the 4 groups (P＜0.05). Compared with groups A and B, the levels of FPG and HbA1c in groups C and D were significantly increased (all P＜0.05). Compared with group B, the level of HDL-C in group C was significantly increased, while the level of ALP was significantly decreased (P＜0.05). Compared with group C, the level of ALP in group D was significantly increased (P＜0.05). The BMD (L_1-4) and BMD (NOF) in groups B and D were significantly decreased compared with groups A and C (all P＜0.05). The OPG gene rs4355801 and rs6993813 loci were in line with Hardy-Weinberg equilibrium. There were no significant differences between groups in rs4355801 genotype or allele frequency distribution (all P＞0.05). Compared with group A, there was a difference in rs6993813 genotype distribution in groups C and D (both P＜0.05), and there was no significant difference in allele frequency distribution among groups (all P＞0.05). The FPG and HbA1c levels of the patients with rs4355801 mutant type were both significantly lower than those with the wild type in group C (both P＜0.05). In group D, the BMD (L_1-4) of rs4355801 mutant type was significantly higher than that with the wild type (P＜0.05). The patients with rs6993813 mutant type in group D had significantly lower blood phosphorus levels and higher BMD (NOF) compared to the wild type (both P＜0.05). Multiple linear regression analysis showed that the increase of YSM and the decreases of BMI, TG, LDL-C, and HDL-C were the risk factors for the decrease of BMD (L_1-4); the increase of YSM and the decreases of HDL-C and blood phosphorus were the risk factors for the decrease of BMD (NOF); and rs4355801 AG genotype was a protective factor for the increases of BMD (L_1-4) and BMD (NOF) in postmenopausal women (both P＜0.05). There was no significant difference in BMD between wild-type and mutant rs4355801 or rs6993813 loci in postmenopausal women (both P＞0.05). There was a significant linkage disequilibrium relationship between the OPG gene rs4355801 and rs6993813 loci (D’＞0.9, r²＞0.3), and the risk of abnormal bone mass in postmenopausal women with GT haplotype was significantly higher (P＜0.05) and the risk of abnormal bone mass in postmenopausal women with AT haplotype was significantly lower (P＜0.05). The interactions of the OPG gene rs4355801 and rs6993813 loci had no effect on BMD in postmenopausal women (both P＞0.05). Conclusion OPG gene rs4355801 mutation may be involved in bone metabolism and glucose metabolism of postmenopausal women, and rs6993813 mutation and polymorphism are involved in bone metabolism of postmenopausal women. The significant linkage relationship of the OPG gene rs4355801 and rs6993813 loci may affect the BMD of postmenopausal women.