Osteoporosis and osteopenia is a pathological condition in bones characterized by low bone mineral density (BMD) along with increased risk for fracture. Soy isoflavone has a phytoestrogen activity that binds to the osteoclast receptors and takes effect on osteoclast differentiation. This study aimed to evaluate the effect of soy isoflavone aglycon supplementation on the levels of RANKL and OPG in blood serum, as well as the ratio of RANKL/OPG, in postmenopausal women with osteopenia. A double-blind randomized control trial was performed on postmenopausal women with osteopenia. Subjects were randomized into a treatment group and a control group. The treatment group was given 100 mg soy isoflavone aglycon and 500 mg calcium carbonate, whereas the control group was given 500 mg calcium carbonate. Evaluations of serum RANKL and OPG levels were performed at baseline and at study endpoint after six months of treatment. Eighty post-menopausal women completed the study. In comparison to the control group, the treatment group did not show significant differences in the reduction of serum RANKL and OPG, as well as the RANKL/OPG ratio after six months of treatment. There is a significant reduction of serum RANKL levels and RANKL/OPG ratio at endpoint compared to the baseline in the treatment group. Daily supplementation with 100 mg isoflavone aglycone for six months in postmenopausal women with osteopenia had no significant effect on RANKL, OPG, and the ratio of RANKL/OPG against the control group. However, there was a significant reduction in all if compared to the baseline levels.