It is known that estrogen plays an important role in coordinating activities of bone-forming osteoblasts and bone-resorbing osteoclasts in bone homeostasis; ovarian hormone deficiency is one of the most important risk factors in postmenopausal osteoporosis, because hormone replacement therapy (HRT) effectively prevents bone loss in postmenopausal women(1,2) and reduces the incidence of fractures.(3–6) However, long-term acceptance or compliance of HRT is generally poor in postmenopausal women,(7,8) partially as a result of fears about the controversial malignance effects on reproductive tissues such as the endometrium. After weighing bone-sparing benefit and risk of cancer in reproductive organs, the findings from the Women's Health Initiative (WHI) Study have undoubtedly triggered research interests in developing alternative therapeutic approaches for interventions for postmenopausal osteoporosis.
Of all the alternatives currently under study, leguminous plant (e.g., soy)–derived phytoestrogen isoflavones seem to be the potential candidates for postmenopausal osteoporosis intervention.(9–12) However, botanical sources of phytoestrogens are not only limited to leguminous plants. A recent review suggested that phytoestrogen is rich in many nonleguminous plants, which may be regarded as prospective candidates for intervention for postmenopausal osteoporosis.(13)
Among nonleguminous plants, Epimedium brevicornum maxim is a centuries-old medicinal herb, which was claimed as having “bone strengthening” function in Traditional Chinese Medicine for treating musculoskeletal disorders.(14) Recently, Epimedium brevicornum maxim–derived phytoestrogen flavonoids (EPFs), which consist of three phytoestrogenic compounds (Icariin, Genistein, and Daidzein; Fig. 1), have been fractioned by a series of standardized extraction-isolation procedures. An in vivo study(15) and in vitro studies reported by others(16,17) generally suggested that EPFs were able to inhibit bone resorption, stimulate bone formation, and prevent ovariectomy-induced osteoporosis, without resulting in uterus hyperplasia. Accordingly, we formulated a hypothesis that EPF might exert beneficial effects on preventing bone loss in postmenopausal women, without resulting in a hyperplasia effect on the endometrium. Until now, no well-controlled clinical trials were performed to test this hypothesis. Therefore, this study was designed to conduct a 24-mo randomized double-blind placebo-controlled clinical trial to evaluate the effect of EPFs on BMD and bone turnover biochemical markers in postmenopausal women. Serum estradiol (E2) and endometrial thickness were also evaluated to address potential safety issues related to reproductive organs.