Background: Primary osteoporosis and other metabolic bone disorders have been linked to the proteins osteoprotegerin (OPG) and receptor activator of nuclear factor-kappa B ligand (RANKL). Aim and objectives: Our study's goal was to examine the effects of co-administering estradiol (E2) and ramipril (ACEI) on bone markers in ovariectomized rats and to assess the potential interactions between these medications in order to address the function of the OPG/RANKL system as a potential mechanism of action. Materials and methods: 40 female rats, randomly divided into 5 groups, each group included 8 rats.  Group 1: Control group (sham operated). Group 2: Ovariectomized rats (OVX). Group 3: Ovariectomized rats (OVX)+E2. Group 4: Ovariectomized rats (OVX)+ACEI. Group 5: Ovariectomized rats (OVX)+E2+ACEI. Results: OVX rats showed a significant decrease in serum Ca 2+ and OPG levels with significant increase in serum RANKL, osteocalcin, alkaline phosphatase activity and urinary hydroxyproline levels compared to control group. Treatment with ramipril as well as E2 led to a significant improvement in bone markers levels with a significant increase in serum OPG level with a significant reduction in serum RANKL level compared to OVX group. Conclusion: Ramipril as ACEI had more significant effect on decreasing serum bone markers level than 17-β estradiol in ovariectomized rats. So, we can draw the conclusion that altering OPG/RANKL signalling may be a possible mechanism by which E2 and ACEI prevent osteoporosis.