Objective To analyze the effects of simvastatin and risedronate sodium, either alone or in combination, on bone loss induced by dexamethasone in rats. Methods Twelve-week-old female Sprague-Dawley rats were divided into five groups ( n = 8 ) as follows: control group, osteoporosis model group subcutaneously injected with dexamethasone (2. 5 mg, twice / week), simvastatin group (5 mg / ( kg·d)), risedronate group (0. 1 mg / ( kg·d)), and combination group. Eight weeks later, all rats were sacrificed, and the left femurs were harvested for bone mineral density (BMD) and three-point bending testing. In addition, micro-CT was performed on the left tibia. The right femurs were embedded in paraffin for immunohistochemical analysis of OPG and RANKL expression, and the right tibia samples were subjected to RNA extraction to assess OPG and RANKL expression. Results BMD was lowest in the osteoporosis group (0. 207 ± 0. 02) g / cmP>2P>> , and BMD was markedly lower in the simvastatin ( 0. 226 ± 0. 023) g / cmP>2P>> and risedronate (0. 237 ± 0. 021) g / cmP>2P>> groups than in the control (0. 282 ± 0. 013) g / cmP>2P>> and combination groups (0. 257 ± 0. 012) g / cmP>2P>> . The maximum load in the osteoporosis group was significantly lower than that in the control and combination groups. BV/ TV and Tb.N were significantly lower in the osteoporosis group than in the other groups, whereas the opposite trend was noted for Tp.Sp. BV/ TV was significantly lower in the simvastatin (21. 6 ± 2. 8) and risedronate groups (21. 9 ± 2. 6) than in the control (29. 5 ± 2. 7) and combination groups (25. 3 ± 2. 9). Tb.Sp was significantly higher in the simvastatin and risedronate groups than in the control group. On immunohistochemistry, OPG expression was significantly lower in the osteoporosis, risedronate, and combination groups than in the control group, whereas its expression was significantly higher in the simvastatin and combination groups than in the osteoporosis group. RANKL expression was significantly higher in the osteoporosis, simvastatin, risedronate, and combination groups than in the control group and significantly lower in the combination group than in the osteoporosis group. Meanwhile, OPG expression was significantly lower in the osteoporosis group (0. 74 ± 0. 17) than in the control (1. 00 ± 0. 16) and simvastatin groups (1. 27 ± 0. 19). RANKL expression was significantly higher in the osteoporosis group than in the other groups, and its expression was significantly higher in the simvastatin group (1. 31 ± 0. 16) than in the control group (1. 00 ± 0. 18). Conclusions Dexamethasone induced bone loss in rats, and this effect was more obviously prevented by combined treatment with simvastatin and risedronate than by either drug alone.