{"doi":"10.3390/nu17243962","title":"S-Equol as a Gut-Derived Phytoestrogen Targeting Estrogen Receptor β: A Promising Bioactive Nutrient for Bone Health in Aging Women and Men: A Narrative Review","abstract":"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–October 2025) for experimental, mechanistic, and clinical studies examining S-equol, estrogen receptor β (ERβ), and bone metabolism, with emphasis on equol-producing status, bone strength and bone microarchitecture. Results: S-equol acts as a high-affinity ERβ agonist with antioxidant and anti-inflammatory properties but lacks the carcinogenic or thrombotic risks linked to ERα activation. In estrogen-deficient rodent models, S-equol improves trabecular bone volume by 10–20%, 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’s skeletal effects on trabecular bone and cortical bone, separately. Conclusions: S-equol represents a promising model for “precision nutrition,” 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.","journal":"Nutrients","year":2025,"id":535807,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":2,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9529,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":329858,"name":"Ashley A. Weaver","orcid":"0000-0002-4383-0106","position":1,"is_corresponding":false},{"id":1420486,"name":"K. Mörz","orcid":null,"position":2,"is_corresponding":false},{"id":1420005,"name":"Nina Z. Heilmann","orcid":"0000-0003-3195-7713","position":3,"is_corresponding":false},{"id":967776,"name":"Diana Madrid","orcid":"0000-0002-6465-3153","position":4,"is_corresponding":false},{"id":659902,"name":"Kristen J. Koltun","orcid":"0000-0003-3234-3190","position":5,"is_corresponding":false},{"id":443878,"name":"Lauren Carlson","orcid":"0009-0005-9421-2120","position":6,"is_corresponding":false},{"id":1420487,"name":"Kristin L. Cattell","orcid":null,"position":7,"is_corresponding":false},{"id":860234,"name":"Mengyi Li","orcid":"0000-0001-6514-1793","position":8,"is_corresponding":false},{"id":860232,"name":"Jiatong Li","orcid":"0000-0003-3778-5633","position":9,"is_corresponding":false},{"id":325846,"name":"Timothy M. Hughes","orcid":"0000-0002-2919-7199","position":10,"is_corresponding":false},{"id":341578,"name":"Elsa S. Strotmeyer","orcid":"0000-0002-4093-6036","position":11,"is_corresponding":false},{"id":235354,"name":"Bradley C. Nindl","orcid":"0000-0001-7088-5930","position":12,"is_corresponding":false},{"id":109422,"name":"Jane A. Cauley","orcid":"0000-0003-0752-4408","position":13,"is_corresponding":false},{"id":390682,"name":"Akira Sekikawa","orcid":"0000-0002-7197-6321","position":0,"is_corresponding":true}],"reference_count":62,"raw_metadata":null,"created_at":"2026-07-19T02:52:00.885532Z","pmid":"41470907","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}