{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,4]],"date-time":"2026-10-04T03:27:55Z","timestamp":1791084475016,"version":"4.1.0"},"reference-count":67,"publisher":"MDPI AG","issue":"24","license":[{"start":{"date-parts":[[2025,12,18]],"date-time":"2025-12-18T00:00:00Z","timestamp":1766016000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000049","name":"National Institutes of Health, National Institute on Aging","doi-asserted-by":"publisher","award":["R01 AG074971"],"award-info":[{"award-number":["R01 AG074971"]}],"id":[{"id":"10.13039\/100000049","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000049","name":"National Institutes of Health, National Institute on Aging","doi-asserted-by":"publisher","award":["P30 AG021332"],"award-info":[{"award-number":["P30 AG021332"]}],"id":[{"id":"10.13039\/100000049","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000049","name":"National Institutes of Health, National Institute on Aging","doi-asserted-by":"publisher","award":["P30 AG024827"],"award-info":[{"award-number":["P30 AG024827"]}],"id":[{"id":"10.13039\/100000049","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Wake Forest University Translational Science Center"},{"name":"NIH funding","award":["S10 OD030295"],"award-info":[{"award-number":["S10 OD030295"]}]},{"name":"NIH funding","award":["UM1TR004929"],"award-info":[{"award-number":["UM1TR004929"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Nutrients"],"abstract":"<jats:p>Background\/Objectives: Osteoporosis is highly prevalent and contributes substantially to morbidity and mortality, yet long-term concerns about pharmacologic therapies leave a major treatment gap. Soy isoflavones have been investigated as safer alternatives, but results across trials are inconsistent. A key unresolved issue is the equol-producer phenotype, the gut microbial ability to convert daidzein to S-equol, the most bioactive isoflavone metabolite, which may explain much of this variability. This narrative review synthesizes mechanistic, translational, and clinical evidence to clarify the potential skeletal relevance of S-equol. Methods: Literature was identified through PubMed and Scopus searches (January 2000\u2013October 2025) for experimental, mechanistic, and clinical studies examining S-equol, estrogen receptor \u03b2 (ER\u03b2), and bone metabolism, with emphasis on equol-producing status, bone strength and bone microarchitecture. Results: S-equol acts as a high-affinity ER\u03b2 agonist with antioxidant and anti-inflammatory properties but lacks the carcinogenic or thrombotic risks linked to ER\u03b1 activation. In estrogen-deficient rodent models, S-equol improves trabecular bone volume by 10\u201320%, increases trabecular number, and enhances biomechanical strength. These findings align with preclinical evidence demonstrating that S-equol preserves trabecular microarchitecture, enhances bone strength, and reduces bone turnover. A limited number of human trials show reductions in bone resorption by 20% at a daily dose of 10 mg S-equol. In contrast, trials of soy isoflavones in humans have produced inconsistent findings, partly because of substantial variability in equol-producer phenotype among participants and the reliance on dual-energy X-ray absorptiometry, which cannot distinguish trabecular from cortical compartments. Advanced bone imaging and microbiome-informed approaches enable the precise evaluation of S-equol\u2019s skeletal effects on trabecular bone and cortical bone, separately. Conclusions: S-equol represents a promising model for \u201cprecision nutrition,\u201d where microbiome, hormonal, and host factors converge with potential to prevent age-related bone fragility. Rigorous trials that integrate microbiome phenotyping and advanced imaging are needed to validate this approach, translate mechanistic promise into clinical benefit, and better define safety.<\/jats:p>","DOI":"10.3390\/nu17243962","type":"journal-article","created":{"date-parts":[[2025,12,18]],"date-time":"2025-12-18T16:42:05Z","timestamp":1766076125000},"page":"3962","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["S-Equol as a Gut-Derived Phytoestrogen Targeting Estrogen Receptor \u03b2: A Promising Bioactive Nutrient for Bone Health in Aging Women and Men: A Narrative Review"],"prefix":"10.3390","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7197-6321","authenticated-orcid":false,"given":"Akira","family":"Sekikawa","sequence":"first","affiliation":[{"name":"Department of Epidemiology, School of Public Health, University of Pittsburgh, Pittsburgh, PA 15213, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4383-0106","authenticated-orcid":false,"given":"Ashley","family":"Weaver","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kelly","family":"Mroz","sequence":"additional","affiliation":[{"name":"Neuromuscular Research Laboratory, School of Health and Rehabilitation Sciences, University of Pittsburgh, Pittsburgh, PA 15219, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3195-7713","authenticated-orcid":false,"given":"Nina Z.","family":"Heilmann","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6465-3153","authenticated-orcid":false,"given":"Diana A.","family":"Madrid Fuentes","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3234-3190","authenticated-orcid":false,"given":"Kristen J.","family":"Koltun","sequence":"additional","affiliation":[{"name":"Neuromuscular Research Laboratory, School of Health and Rehabilitation Sciences, University of Pittsburgh, Pittsburgh, PA 15219, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-9421-2120","authenticated-orcid":false,"given":"Lauren J.","family":"Carlson","sequence":"additional","affiliation":[{"name":"Department of Epidemiology, School of Public Health, University of Pittsburgh, Pittsburgh, PA 15213, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kristin L.","family":"Cattell","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6514-1793","authenticated-orcid":false,"given":"Mengyi","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Epidemiology, School of Public Health, University of Pittsburgh, Pittsburgh, PA 15213, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3778-5633","authenticated-orcid":false,"given":"Jiatong","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Epidemiology, School of Public Health, University of Pittsburgh, Pittsburgh, PA 15213, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Timothy M.","family":"Hughes","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Section on Gerontology and Geriatric Medicine, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elsa","family":"Strotmeyer","sequence":"additional","affiliation":[{"name":"Department of Epidemiology, School of Public Health, University of Pittsburgh, Pittsburgh, PA 15213, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bradley","family":"Nindl","sequence":"additional","affiliation":[{"name":"Neuromuscular Research Laboratory, School of Health and Rehabilitation Sciences, University of Pittsburgh, Pittsburgh, PA 15219, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0752-4408","authenticated-orcid":false,"given":"Jane A.","family":"Cauley","sequence":"additional","affiliation":[{"name":"Department of Epidemiology, School of Public Health, University of Pittsburgh, Pittsburgh, PA 15213, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,12,18]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1837","DOI":"10.1016\/j.clinthera.2015.06.006","article-title":"The Pathophysiology and Treatment of Osteoporosis","volume":"37","author":"Drake","year":"2015","journal-title":"Clin. 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