Background and aims: Increased inflammation and accumulation of advanced glycation end-products (AGEs) are potential mechanisms underlying low bone turnover and increased fracture risk in type 2 diabetes (T2D) and obesity. Yet, it remains unclear whether circulating inflammation extends to the bone microenvironment and whether it contributes to bone quality. In this study, we aim to investigate the impact of AGEs accumulation and inflammation in bone of postmenopausal women with T2D and obesity. Materials and methods: A cross-sectional study was conducted in postmenopausal women (≥ 65 y.o.) with T2D and obesity undergoing hip replacement surgery. Bone tissues were obtained from 20 T2D (BMI≥25.0 kg/m2), 33 subjects with obesity (BMI≥30 kg/m2), and 43 non-diabetic normal weight (BMI≤25.0 kg/m2) subjects. Total body bone mass was measured by DXA. Trabecular bone was used for compression tests and micro-computed tomography (microCT). AGEs bone content was measured by enzymatic colorimetric assay. Bone gene expression of inflammatory cytokines (IL-6, IL-8, IL-10, and TNF-α) were analyzed by Real-Time PCR. Serum TNF-α was measured by ultrasensitive ELISA. Results: As expected, bone mineral density (BMD) and T-score were not different between groups. However, trabecular microCT analysis showed higher trabecular spacing in T2D compared to subjects with obesity (p=0.0026) and controls (p=0.0038). BV/TV was not different between groups. In line with impaired bone microarchitecture, we also found a trend of reduced bone strength (Young Modulus MPa; p=0.0656) in T2D compared to subjects with obesity and controls. We found a higher AGEs bone content in T2D compared to the other groups (T2D, p=0.0026; Ob, p=0.0743). Gene expression of inflammatory cytokines IL-6, IL-8, IL-15 and TNF-α were not different between groups while circulating TNF-α trended higher in T2D vs controls (p=0.0935). However, gene expression of the anti-inflammatory cytokine IL-10 was lower in T2D compared to controls (p=0.0164) but not different in subjects with obesity and controls. Of note, mRNA level of IL-10 negatively correlated with AGEs bone content (r=-0.7455; p=0.0174). Conclusion: We showed that increased AGEs bone content negatively correlated with IL-10 mRNA levels, and it was associated with reduced bone quality in T2D but not in obesity. We provide novel insights that may help to understand the mechanisms underlying bone fragility in these patients.