Objective:To investigate the effect and mechanism of Sufentanil (Suf) on oxidative stress injury in osteoporosis (OP) rats.Methods:Rats were randomly separated into normal group, OP group, low concentration Suf group, high concentration Suf group, alendronate sodium group, and high concentration Suf+AMPK inhibitor (Dorsomorphin) group, with 12 rats in each group. The normal group of rats only removed a small amount of adipose tissue around the ovaries. Except for the normal group, rats in other groups constructed OP models by removing both ovaries. After successful modeling, they were administered once a day for 12 weeks. Micro CT scanners were applied to measure bone density and trabecular structure parameters in rats, including trabecular quantity, trabecular thickness, and trabecular separation. ELISA was applied to detect levels of osteocalcin, alkaline phosphatase (ALP), osteoprotegerin (OPG), and receptor activator of nuclear factor kappa-B ligand (RANKL) in rat serum. HE staining was applied to detect pathological changes in femoral tissue. Reagent kit was applied to detect levels of malondialdehyde (MDA), reactive oxygen species (ROS), and superoxide dismutase (SOD) in femoral tissue. Western blot analysis of phosphorylated adenylate activated protein kinase (p-AMPK), peroxisome proliferator-activated receptor-γ-coactivator 1α (PGC-1α), silence-information regulatory factor2-associated enzyme 1 (SIRT1) proteins in femur tissue.Results:Compared with the normal group, the bone trabecular structure of rats in the OP group was thin and scattered, with fewer bone trabeculae and widened trabecular gaps, mainly in the form of rods, the bone density, number of trabeculae, thickness of trabeculae, levels of ALP, osteocalcin, OPG in serum, the level of SOD, and p-AMPK, PGC-1α, and SIRT1 proteins in femoral tissue decreased ( q=38.00, 67.81, 47.91, 48.32, 28.42, 21.23, 52.22, 30.86, 24.11, 24.55, P all<0.001), the bone trabecular separation, level of RANKL in serum, and the levels of MDA and ROS in femoral tissue increased ( q=42.00, 37.97, 50.56, 72.01, P all<0.001). Compared with the OP group, the number of bone trabeculae in rats in the low concentration Suf group, high concentration Suf group, and alendronate sodium group increased, the gap decreased, and the bone trabecular structure gradually recovered to a plate-like shape, the bone density, number of trabeculae, thickness of trabeculae, levels of ALP, osteocalcin, OPG in serum, the level of SOD, and p-AMPK, PGC-1α, and SIRT1 proteins in femoral tissue increased ( F=214.40, 889.60, 396.10, 480.30, 168.60, 38.09, 367.80, 187.70, 91.17, 101.00, P all<0.001), the bone trabecular separation, level of RANKL in serum, and the levels of MDA and ROS in femoral tissue decreased ( F=174.10, 173.40, 298.90, 607.10, P all<0.001). Dorsomorphin reversed the improvement effect of high concentration of Suf on oxidative stress injury in OP rats. Conclusion:The inhibitory effect of Suf on oxidative stress injury in OP rats may be related to the activation of the AMPK/SIRT1/PGC-1α signaling pathway.