Background: Long-term glucocorticoid administration represents the main source of 2^ry osteoporosis, jeopardizing bone to fracture and loss. This study presents an innovation regarding the alterations in the osteoporotic Wnt/β-catenin signal encouraged by dexamethasone through studying some markers implicated in the proliferation and differentiation of the major bone remodeling cells using in silico and in vivo studies. Methods and Results: Docked models were used to visualize and evaluate the binding of dexamethasone (DEXA) towards main bone remodeling modulators. Regarding the in vivo study, sixteen Sprague-Dawley adult males were designated into a control group administered saline, and an osteoporosis-induced group was administered 1 mg/kg DEXA intraperitoneally daily for 6 weeks. The molecular docking demonstrated binding and interactions between DEXA and main bone remodeling targets. DEXA treatment caused osteoporotic changes in femoral microscopy, increased femoral oxidative stress, elevated proliferation markers, raised osteoblast differentiation inhibitor, diminished markers for osteoblasts differentiation, and increased markers for differentiation of osteoclasts and adipocytes. Conclusions: Glucocorticoid-induced osteoporosis is manifested through an intensified proliferation of HSCs and MSCs via escalating and changing the Wnt signaling, which acts as a communicator between both cell populations. These alterations brought about the track-change of MSCs differentiation from the osteoblastic to the adipocytic track and accelerated osteoclastic differentiation.