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While conventional treatments rely heavily on antibiotic\u2010loaded materials, bioactive glass S53P4 offers a dual\u2010action alternative, combining bacteriostatic and bactericidal activity with bone regenerative potential. A systematic review and meta\u2010analysis following PRISMA guidelines was conducted to evaluate the clinical efficacy and safety of S53P4 bioactive glass in osteomyelitis treatment. Twenty\u2010eight studies published between 2000 and 2024, encompassing 1122 patients (mean age: 43.6\u2009years), were included. Outcomes analyzed included infection eradication, recurrence, bone healing, functional recovery, and complications. The risk of bias was assessed using ROBINS\u2010I for observational studies and the JBI checklist for case series. A meta\u2010analysis of 10 studies reporting infection eradication at \u2265\u200912\u2009months was performed using a random\u2010effects model. The pooled infection eradication rate was 88.1% (95% CI: 85.4%\u201390.4%) with no significant heterogeneity (<jats:italic>I<\/jats:italic><jats:sup>2<\/jats:sup>\u2009=\u20090%). Studies reported consistent efficacy across chronic, diabetic foot, mastoid, and jaw osteomyelitis. S53P4 was effective against polymicrobial and multidrug\u2010resistant infections, including <jats:styled-content style=\"fixed-case\"><jats:italic>Staphylococcus aureus<\/jats:italic><\/jats:styled-content> and <jats:styled-content style=\"fixed-case\"><jats:italic>Pseudomonas aeruginosa<\/jats:italic><\/jats:styled-content>. Healing outcomes were favorable, with high rates of bone integration and return to function. Complications were uncommon and primarily related to soft tissue coverage. Most patients received systemic antibiotics; no studies required local antibiotic\u2010loaded materials alongside S53P4. Bioactive glass S53P4 is a safe and effective adjunct in osteomyelitis management, demonstrating high long\u2010term infection control, robust bone regeneration, and a low complication profile. Its nonantibiotic antimicrobial mechanism makes it particularly suitable in settings of antimicrobial resistance. Future studies should assess its long\u2010term durability and applications in high\u2010risk infections.<\/jats:p>","DOI":"10.1002\/jbm.b.35597","type":"journal-article","created":{"date-parts":[[2025,5,27]],"date-time":"2025-05-27T13:38:19Z","timestamp":1748353099000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Safety and Efficacy of <scp>S53P4<\/scp> Bioactive Glass in Osteomyelitis Management: A Systematic Review and Meta\u2010Analysis"],"prefix":"10.1002","volume":"113","author":[{"given":"Antoinette T.","family":"Nguyen","sequence":"first","affiliation":[{"name":"University of Rochester School of Medicine and Dentistry  Rochester New York USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rena A.","family":"Li","sequence":"additional","affiliation":[{"name":"Northwestern University Feinberg School of Medicine  Chicago Illinois USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9552-6483","authenticated-orcid":false,"given":"Robert D.","family":"Galiano","sequence":"additional","affiliation":[{"name":"Northwestern University Feinberg School of Medicine  Chicago Illinois USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,5,27]]},"reference":[{"key":"e_1_2_12_2_1","volume-title":"StatPearls","author":"Momodu I. 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