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To investigate the association of the midnight cortisol level with bone mineral density (BMD) in patients with type 2 diabetes mellitus (T2DM). Methods: This study included 249 T2DM patients (148 males with an average age of 53.8 years and 101 postmenopausal females with an average age of 63.6 years) admitted to Xiamen Hospital of Zhongshan Hospital Affiliated to Fudan University from January 2018 to April 2020. Baseline data were compared between patients with normal BMD and those with osteoporosis/osteopenia. The patients also were divided into groups according to the tertiles of midnight cortisol levels. Results: Among all T2DM, 178 had osteoporosis/osteopenia, including 98 men and 80 women. The baseline data analysis showed that patients with osteoporosis/osteopenia were more likely to be older, female, and thin, and to have high cortisol. Additionally, elevated estradiol levels had a protective effect on bone; once osteoporosis/osteopenia occurred, the probability of severe osteoporotic fracture was significantly increased. The BMD of the femoral neck, hip joint and lumbar spine decreased with increasing midnight cortisol level in men, postmenopausal women, and all T2DM patients (P< 0.05). Multivariate logistic regression analysis identified body mass index, estradiol level, and midnight cortisol level as independent risk factors for osteoporosis/osteopenia in T2DM patients. Conclusion: Higher midnight cortisol levels are significantly associated with increased risk of osteoporosis/osteopenia in T2DM patients. Thus, the midnight cortisol level represents a valuable marker for assessing osteoporosis/osteopenia risk in these patients. [ABSTRACT FROM AUTHOR]