Irisin, the newly identified myokine, is produced by skeletal muscle in response to exercise. The aim of our work is to study the effect of exercise on irisin plasma level and identify the correlation between irisin level in blood and change in bone turnover in glucocorticoids- induced osteoporosis. Forty eight Sprague-Dawley rats were divided equally into four groups: control group, containing sedentary rats; exercise group, these rats were subjected to a swimming exercise protocol (5 days per week for 8 weeks) in a gradual manner; osteoporotic group, rats received methylprednisolone, intramuscular, (0.2 mg/kg three times/ week) for 5 weeks; and exercise – osteoporotic group, exercise training combined with osteoporosis: these rats were subjected to swimming exercise in the same previous protocol and after 3 weeks they received methylprednisolone. Exercise group showed a significant increase in cortical bone thickness and trabecular bone area %. Exercise increased serum irisin level and decreased serum C-terminal telopeptide of type I collagen (CTX) level in exercise group. Also, cortical bone thickness and trabecular bone area % increased relative to total bone area in exercise-osteoporotic group. The results revealed a positive correlation between irisin level and bone mineral content, bone mineral density, microstructure of bone and osteocalcin expression. Also, there is a negative correlation between serum irisin level and CTX level. So, irisin may be the link between the beneficial effects of exercise and the protection against osteoporosis. So, recombinant irisin may be a crucial osteoprotective intervention for those patients whose plasma irisin level is reduced.