Abstract: Objective: To explore whether osteopeptide（GDT） exerts a protective effect on osteoporotic rats by reducing oxidative damage through the BMP/Smads/RUNX2 pathway. Methods: SD rats were randomly divided into normal control group, model group, alendronate group (1.33 mg/kg), and osteopeptide low, medium and high dose groups (50, 100, 200 mg/kg). After 2 weeks of retinoic acid modeling, the rats were continuously administered by gavage for 4 weeks. Enzyme-linked immunosorbent assay (ELISA) was used to detect serum bone metabolism markers, bone marrow oxidative indicators, and bone mineral elements and trace elements. Micro-CT was used to detect bone density and bone microstructure parameters. RT-qPCR and Western blot methods were used to detect the mRNA and protein expression of BMP/Smads/RUNX2 pathway-related genes. Results: Osteopeptide could alleviate the weight loss, atrophy of heart, lung, kidney, adrenal gland, uterus, testicles, and prostate, as well as hepatosplenomegaly caused by retinoic acid-induced modeling. It significantly reduced the levels of serum bone metabolism markers ALP, PINP, and CTX(P<0.05 or P<0.01), increased the contents of calcium, magnesium, phosphorus, zinc, and iron in bone tissue (P<0.05 or P<0.01), and improved bone metabolism. It increased the number of trabeculae, reduced the trabecular separation, and increased bone mass and bone density in osteoporotic rats, improving bone microstructure. Within the dose range of 50~200 mg/kg, osteopeptide significantly increased the activities of SOD and GSH-PX in bone marrow and reduced the production of MDA (P<0.05 or P<0.01), upregulated the mRNA and protein expression of BMP2, Smad1, Smad5, RUNX2, ColⅠ and OCN (P<0.05 or P<0.01), and activated the BMP/Smads/RUNX2 signaling pathway. Conclusion: Osteopeptide can improve bone metabolism disorders and bone microstructure damage in osteoporotic rats, increase bone mass and bone density. The mechanism is related to the activation of the BMP/Smads/RUNX2 signaling pathway and the inhibition of oxidative damage in bone tissue, providing a new idea for the development of drugs for osteoporosis.