Soy isoflavones, due to structural similarity to human estrogen, have been the candidate in numerous studies as a potential natural alternative to estrogen with fewer side effects. However, dietary intake and the use of soy isoflavones as supplement have received both merits and flaws due to inconsistent results reported across different studies on the improvement of many chronic diseases. This study aims to assess the contribution of menopausal status of women on the effects of soy isoflavones on postmenopausal osteoporosis. An animal model mimicking late menopausal stage and treated with the soy isoflavone genistein was used to inspect the timing of intervention on reducing bone loss compared to an early menopausal rat model. Then, a systematic search and review were conducted on prior publications that addressed the action of soy isoflavones on post menopause-related bone loss. Several factors, including dose, formulation, intervention time point, bone sites measured, ethnic background, and menopausal status, that may have influenced the study results, were discussed. Analysis on this regard was also pursued using the Nutrition and Health Survey in Taiwan (NAHSIT) database to examine the association of soy isoflavones with bone mineral density (BMD) in the local Taiwanese adult population. Two sets of isoflavone intakes were calculated based on the consumption of soybean and legume foods from the 24-hour dietary recall and food frequency questionnaire in NAHSIT. The associations between soy isoflavone intakes and BMD or odds of osteoporosis were examined by linear and logistic regression analyses in all subjects and women stratified by menopausal statuses. In animals, both genistein and estrogen in late initiation of treatment following ovariectomy could not rescue bone loss compared to early initiation, which attenuated loss of bone density and volume in the ovariectomized rats. In studies that analyzed sub-groups by time since menopause as the variable, more studies reported positive effects of soy isoflavones in late postmenopausal rather than early postmenopausal women, than studies that reported the opposite finding, yet two studies showed benefits in both women groups. Regression analyses from NAHSIT found significant positive association of soy isoflavone intake with BMD and significant inverse association with osteoporosis risk, but the effects were neutralized after adjustment for covariates. In addition, the timing of isoflavone intervention in terms of menopausal status was critical, in that age was a significant contributing factor for osteoporosis risk in late but not early postmenopausal women, and years since menopause was a significant contributing factor for osteoporosis risk in early but not late postmenopausal women. Combined with previous results, suggests the importance of menopausal status in harvesting the benefit of soy isoflavones on osteoporotic bone loss.