{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T18:10:24Z","timestamp":1790878224651,"version":"4.1.0"},"reference-count":60,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2025,3,22]],"date-time":"2025-03-22T00:00:00Z","timestamp":1742601600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Osteoporosis is a prevalent metabolic bone disorder characterized by decreased bone mineral density and increased fracture risk, particularly among aging populations. While conventional pharmacological treatments exist, they often have adverse effects, necessitating the search for alternative therapies. Resveratrol, a naturally occurring polyphenol, has gained significant attention for its potential osteoprotective properties through various molecular mechanisms. This systematic review aims to comprehensively analyze the molecular pathways through which resveratrol protects against osteoporosis. Using an advanced search strategy in the Scopus, PubMed, and Web of Science databases, we identified 513 potentially relevant articles. After title and abstract screening, followed by full-text review, 28 studies met the inclusion criteria. The selected studies comprised 14 in vitro studies, 8 mixed in vitro and in vivo studies, 6 in vivo studies, and 1 cross-sectional study in postmenopausal women. Our findings indicate that resveratrol exerts its osteoprotective effects by enhancing osteoblast differentiation through the activation of the Phosphoinositide 3-Kinase\/Protein Kinase B (PI3K\/Akt), Sirtuin 1 (SIRT1), AMP-Activated Protein Kinase (AMPK), and GATA Binding Protein 1 (GATA-1) pathways while simultaneously inhibiting osteoclastogenesis by suppressing Mitogen-Activated Protein Kinase (MAPK) and TNF Receptor-Associated Factor 6\/Transforming Growth Factor-\u03b2-Activated Kinase 1 (TRAF6\/TAK1). Additionally, resveratrol mitigates oxidative stress and inflammation-induced bone loss by activating the Hippo Signaling Pathway\/Yes-Associated Protein (Hippo\/YAP) and Nuclear Factor Erythroid 2-Related Factor 2 (NRF2) pathways and suppressing Reactive Oxygen Species\/Hypoxia-Inducible Factor-1 Alpha (ROS\/HIF-1\u03b1) and NADPH Oxidase 4\/Nuclear Factor Kappa-Light-Chain-Enhancer of Activated B Cells (Nox4\/NF-\u03baB). Despite promising preclinical findings, the low bioavailability of resveratrol remains a significant challenge, highlighting the need for novel delivery strategies to improve its therapeutic potential. This review provides critical insights into the molecular mechanisms of resveratrol in bone health, supporting its potential as a natural alternative for osteoporosis prevention and treatment. Further clinical studies are required to validate its efficacy and establish optimal dosing strategies.<\/jats:p>","DOI":"10.3390\/ijms26072893","type":"journal-article","created":{"date-parts":[[2025,3,24]],"date-time":"2025-03-24T07:46:50Z","timestamp":1742802410000},"page":"2893","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":22,"title":["A Systematic Review on the Molecular Mechanisms of Resveratrol in Protecting Against Osteoporosis"],"prefix":"10.3390","volume":"26","author":[{"given":"Ahmad Nazrun","family":"Shuid","sequence":"first","affiliation":[{"name":"Department of Pharmacology, Faculty of Medicine, Universiti Teknologi MARA, Sungai Buloh Campus, Jalan Hospital, Sungai Buloh 47000, Selangor, Malaysia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4285-7059","authenticated-orcid":false,"given":"Nurul Alimah","family":"Abdul Nasir","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Faculty of Medicine, Universiti Teknologi MARA, Sungai Buloh Campus, Jalan Hospital, Sungai Buloh 47000, Selangor, Malaysia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2375-2163","authenticated-orcid":false,"given":"Norasikin","family":"Ab Azis","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Faculty of Medicine, Universiti Teknologi MARA, Sungai Buloh Campus, Jalan Hospital, Sungai Buloh 47000, Selangor, Malaysia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ahmad Naqib","family":"Shuid","sequence":"additional","affiliation":[{"name":"Advanced Medical and Dental Institute, Universiti Sains Malaysia, Bertam, Kepala Batas 13200, Penang, Malaysia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8439-6713","authenticated-orcid":false,"given":"Norhafiza","family":"Razali","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Faculty of Medicine, Universiti Teknologi MARA, Sungai Buloh Campus, Jalan Hospital, Sungai Buloh 47000, Selangor, Malaysia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9614-6650","authenticated-orcid":false,"given":"Haryati","family":"Ahmad Hairi","sequence":"additional","affiliation":[{"name":"Department of Biochemistry, Faculty of Medicine, Manipal University College Malaysia, Jalan Batu Hampar, Bukit Baru 75150, Melaka, Malaysia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohd Fairudz","family":"Mohd Miswan","sequence":"additional","affiliation":[{"name":"Department of Orthopaedics, Faculty of Medicine, Universiti Teknologi MARA, Sungai Buloh Campus, Jalan Hospital, Sungai Buloh 47000, Selangor Darul Ehsan, Malaysia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Isa","family":"Naina Mohamed","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, Faculty of Medicine, Universiti Kebangsaan Malaysia, Jalan Yaacob Latif, Cheras 56000, Kuala Lumpur, Malaysia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,3,22]]},"reference":[{"key":"ref_1","first-page":"e48582","article-title":"A Comprehensive Review on Postmenopausal Osteoporosis in Women","volume":"15","author":"Charde","year":"2023","journal-title":"Cureus"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"2095","DOI":"10.1056\/NEJMcp1513724","article-title":"Postmenopausal Osteoporosis","volume":"374","author":"Black","year":"2016","journal-title":"N. 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