Phytoestrogens or S-Equol activated the PI3K-AKT pathway or regulated OPG/RANKL in the DOP rat model, which has been extensively reported to be involved in the improvement of osteoporosis; therefore, we examined whether the protective effect of S-Equol was associated with the AKT and OPG/RANKL pathways. The gene discussed is TNFSF11; the disease is osteoporosis.