3. Discussion
bone loss
ADVERSE EVENTS, BONE LOSS
In this randomized placebo-controlled trial, supplementation with an equol/resveratrol combination for 12 months improved the bone anabolism in postmenopausal women. This supplementation promoted an increase in osteoblast markers (osteocalcin and BAP) and a decrease in osteoclast markers (DPD and TRACP-5b) (After menopause, women lose 3% of their BMD each year, resulting in osteopenia or osteoporosis [Equol is a daidzein metabolite produced by anaerobic bacteria with stronger estrogenic activity than any other isoflavone or isoflavone-derived metabolite [Resveratrol has also been reported to act as a phytoestrogen. In a clinical study, resveratrol showed favorable effects on estrogen metabolism and circulating sex steroid hormones [These compounds may act through multiple mechanisms, particularly through the estrogenic pathway. Resveratrol may exert its estrogen-like effect on bone by increasing the gene expression of osteoprotegerin, a protein that inhibits receptor activator of nuclear factor κB ligand (RANKL) to counteract osteoclast differentiation and activity [Soy isoflavones decrease RANKL levels and increase osteoprotegerin levels [In most cases, supplementation included only isoflavones. Recently, Tousen et al. demonstrated that the combination of soy isoflavones and resveratrol prevented bone loss and decreased the RANKL/OPG gene expression ratio in bone marrow cells in unloaded mice [Another factor that might have contributed to these effects could be related to the dosage. The dose of equol applied in this study has been used in several clinical trials and is reported to be effective for general menopausal symptoms without any serious adverse events. Tai et al. demonstrated that 24-month treatment with 300 mg/day isoflavones did not prevent the decline in BMD in postmenopausal women [The present study has several strengths and limitations. The main strength is rep-resented by the 100% retention rate for a 12-month intervention, associated with the investigation of the effects of simultaneous combined supplementation of equol and resveratrol on bone metabolism. The primary limitation of this study was its small sample size. However, several other similar studies did not include larger study populations. The second limitation is the duration of the study. Even though we conducted a 12-month study, a longer intervention duration may be helpful in further assessing the effects of equol and resveratrol on bone turnover and density. Finally, our study did not determine whether the enrolled subjects were equol producers. Therefore, even though the majority of Western women are not equol producers, we did not stratify the treatment and placebo groups based on equol-producing status.In conclusion, our results suggest that combined supplementation of equol and resveratrol has some additional benefits on bone turnover biomarkers, especially in improving bone density formation in postmenopausal women. In the near future, larger studies should be conducted to confirm these results and investigate the molecular mechanisms underlying these effects. This non-pharmacological treatment represents a potential approach for preventing age-related bone loss in postmenopausal women.