Background: Osteoporosis is a progressive systematic skeletal illness characterized by low bone mineral density (BMD), deterioration of microarchitecture of bone tissues and susceptibility to fracture caused by bone resorption. The study investigates the possible role of Alfacalcidol; vitamin D (Vit D) to mitigate osteoporosis induced by corticosteroid and γ-rays in rats. Materials and Methods: Eighty Sprague-Dawley rats were divided equally into eight groups: Control group (1 ml olive oil orally), Epirelefan group (7mg/kg sc), Vit D group (20,000 IU/kg orally), Vit D plus Epirelefan group, Vit D plus γ-rays (8 Gy) group, Epirelefan plus γ-rays group, Vit D plus Epirelefan plus γ-rays group and γ-rays groups. Results: In Epirelefan group, mandible bone has small cavities, micro fissures, thinning and decrease in the number of trabecular, which may appear rod-like and concave beside increase marrow cavities. In Epirelefan + γ-rays group, the lesions were more severe with increasing osteoclast and alteration of serum calcium, phosphate and alkaline phosphatase. The administration of Vit D before corticosteroid injection and pre γ-rays-irradiation has significantly reduced mandibular damage. Conclusion: Vit D could be efficient in mitigating osteoporosis occurred by corticosteroid and γ-rays in rat model.