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Isoflavones exert estrogenic activity distinct from estrogen, they have the potential to treat diseases and symptoms related to estrogen deficiency with minimal side effects and risks. Isoflavone supplementation, in general, is shown to exert beneficial effects against estrogen-deficient bone loss in women, however, some clinical trials still produce conflicting findings. The purpose of this review is to highlight and summarize the most recent and up-to-date research in the field and to bring attention to factors that play a major role in the outcomes of clinical trials that investigate phytoestrogens. Here, we also discuss the latest and most relevant data regarding the clinical safety of these substances.Isoflavones are naturally occurring secondary metabolites found in the Fabacaea plant family. Clinical data from isoflavone interventions support that aglycones (abundant in fermented products) exert enhanced beneficial effects against estrogen-deficient bone loss in women compared with isoflavone glycosides. Studies that employ methods to determine isoflavone content and form of treatments are more likely detect beneficial effects on bone. EFSA have confirmed the safety of isoflavones for women in the most comprehensive report to date.Isoflavone aglycones exert greater effects against bone loss than glycosides. Isoflavones show promise as a first-line prophylactic/treatment for bone loss in women.