Background: Post-menopausal osteoporosis (PMOP) is the most common bone disease in females characterized by decreased bone mineral density (BMD). However, the exact pathogenesis remains unclear. Objective: Investigating the relationship between serum levels of adiponectin and irisin, and their relation to BMD in ovariectomy induced osteoporosis rat model. Material and Methods: Three equal groups of adult female albino rats (n=15) were used; i.e. control, sham operated and ovariectomized (OVX) groups. Nine weeks after ovariectomy, serum analysis of adiponectin, irisin, FSH, estradiol, Ca⁺⁺, phosphorus (P), alkaline phosphatase (ALP), glucose, and insulin were estimated. Final BMI and HOMA-IR were calculated. Bone BMD measurements (dry and ash femur weight, bone Ca⁺⁺ and P together with femur histopathological examination) were done. Results: In OVX osteoporotic rat model, while serum levels of adiponectin significantly elevated and negatively correlated with BMD, serum irisin levels significantly reduced, and showed significant positive correlation with BMD. Changes in OVX adiponectin and irisin levels were significantly associated with the elevated insulin resistance. However, they were not association with FSH or estradiol levels. Conclusion: OVX induced osteoporosis was associated with a significant increase in adiponectin levels, and decrease in irisin levels which are associated with changes in insulin resistance rather than sex hormones. It can be hypothesized that the exact causative of PMOP extends beyond pituitary; ovarian axis to be metabolic, muscle and adiposity cross talks which needs more detailed investigations.