Objective To establish a rat model of glucocorticoid?induced osteoporosis (GIOP) and to explore the interventional effect of the Chinese medicine Fufang Zhenzhu Tiaozhi (FTZ) capsules on regulation of mitogen?activated protein kinase kinase kinase 2 (MEKK2)?Wnt coupling and inhibiting β?catenin ubiquitination, and to investigate the effect of FTZ on the bone mineral density and cell osteogenic ability. Methods SPF male rats were randomly divided into normal control group, methylprednisolone group (model group), methylprednisolone + saline group (blank control group) and methylprednisolone + FTZ group (experimental group). The proximal femoral cancellous bone was examined by micro?CT and histopathology, and assessment of expressions of Wnt3a, MEKK2, and β?catenin proteins. Bone mesenchymal stem cells (BMSCs were isolated and treated with serum containing FTZ, stained by alkaline phosphatase and alizarin red. The expressions of osteogenic differentiation?related genes ALP, Runx2 and OCN, the expressions of MEKK2 and β?catenin proteins, and the transcription level of β?catenin/ TCF were determined. Results 1) The micro?CT imaging showed that compared with the control group, the BV/ TV, Tb. Th and Tb/ N expressions were significntly decreased, and Tb/ sp increased in the experimental group ( P < 0.05). Region of interest (ROI) three?dimensional reconstruction of trabecular bone in the experimental group showed improvement of bone trabeculae and local bone repair. 2) The pathology using hematoxylin and eosin staining showed that in the experimental group, the bone trabecular density was higher than that of the model group, and observed a better trabecula morphology. 3) The Wnt3a, MEKK2 and β?catenin expressions in the experimental group were significantly increased compared with the model model ( P < 0.05). 4) After treated with FTZ and BMP2, the result of alkaline phosphatase and alizarin red staining indicated an enhanced osteogenic response ( P <0.05) in the GIOP rat models. 5) After treatment with seum containing FTZ, The BMSCs isolated from the GIOP rats enhanced the transcriptional activity of β?catenin/ TCF/ LEF ( P <0.05) and promoted the expression of β?catenin and MEKK2 proteins ( P <0.05). Conclusions FTZ can ameliorate GIOP by regulating the MEKK2?Wnt coupling and inhibiting the β?catenin ubiquitination, and improve the bone microstructure.