Efficacy and Safety of Antibiotic-Loaded Calcium Sulfate in the Treatment of Osteomyelitis: A Systematic Review and Meta-Analysis

Efficacy and Safety of Antibiotic-Loaded Calcium Sulfate in the Treatment of Osteomyelitis: A Systematic Review and Meta-Analysis | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Efficacy and Safety of Antibiotic-Loaded Calcium Sulfate in the Treatment of Osteomyelitis: A Systematic Review and Meta-Analysis Dun Liu, Aierken Rehemutula, Zihao Chen, Yu Si, Hongyu Zhou, LI LI This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-9416548/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Purpose To systematically evaluate the clinical efficacy and safety of antibiotic-loaded calcium sulfate (ALCS) as a local antibiotic delivery system for the treatment of osteomyelitis in adult patients, and to quantitatively synthesize the available evidence on infection eradication rate, bone healing rate, and complications through meta-analysis. Methods A systematic literature search was conducted across PubMed/MEDLINE, Embase, Cochrane Library, and Web of Science from inception to December 2025, following the PRISMA 2020 reporting guidelines. Studies involving adult patients (≥ 18 years) with a confirmed diagnosis of osteomyelitis treated with ALCS as a local antibiotic carrier and reporting at least one clinical outcome measure were included. Single-arm proportions were pooled using the Freeman–Tukey double arcsine transformation and the DerSimonian–Laird random-effects model. Heterogeneity was assessed using the I² statistic and Cochran's Q test. Pre-specified subgroup analyses and leave-one-out sensitivity analyses were performed. Results Twenty-one studies comprising 1,461 patients were included. The pooled infection eradication rate was 87.2% (95% CI: 83.8%–90.3%, I² = 67.4%). The pooled bone healing rate was 78.0% (95% CI: 73.1%–82.5%, I² = 57.1%). Regarding complications, the wound drainage rate was 14.8% (95% CI: 11.3%–18.7%), the reoperation rate was 12.3% (95% CI: 8.0%–17.3%), and the amputation rate was 1.8% (95% CI: 0.7%–3.3%). Subgroup analysis revealed higher eradication rates in non-diabetic foot osteomyelitis (DFO) studies (88.2%) compared with DFO studies (79.1%). Sensitivity analysis demonstrated high robustness (86.2%–88.2%). Egger's test revealed no significant publication bias (p = 0.877). Conclusion ALCS demonstrates favorable efficacy in the treatment of osteomyelitis, with an infection eradication rate of approximately 87% and a bone healing rate of 78%. Wound drainage is the most common complication (14.8%), while the amputation rate remains low (1.8%). These findings support the use of ALCS as an effective and safe local antibiotic delivery system in the multidisciplinary management of osteomyelitis. However, the predominance of retrospective evidence and moderate-to-substantial heterogeneity indicate that well-designed randomized controlled trials are warranted to provide definitive evidence. Level of evidence Systematic review and metaanalysis, Level IV. Osteomyelitis Antibiotic-loaded calcium sulfate Local antibiotic delivery Meta-analysis Systematic review Infection eradication Bone healing Biodegradable carrier Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Introduction Osteomyelitis, an inflammatory disease of bone tissue caused by infectious pathogens, is characterized by bone destruction, bone necrosis, and new bone formation. As one of the earliest recognized infectious diseases in humans, osteomyelitis remains a major therapeutic challenge in orthopedic surgery, with significant impacts on patients' quality of life, healthcare costs, and functional outcomes. In developed countries, the incidence of osteomyelitis is approximately 21.8 per 100,000 person-years, though the actual incidence may be higher in developing countries and in high-risk populations such as those with diabetes, peripheral vascular disease, or immunocompromised states [1–3]. The pathogenesis of osteomyelitis is complex and multifactorial. The formation of bacterial biofilms on the surface of necrotic bone, known as the sequestrum, provides a protected niche for bacterial survival beyond the reach of systemic antibiotics and host immune defenses. This biofilm-mediated persistent infection is the primary reason why chronic osteomyelitis is refractory to systemic antibiotic therapy alone. The Cierny–Mader classification system provides a widely used anatomical and physiological staging framework to guide surgical and antibiotic treatment decisions [4, 5]. The cornerstone of osteomyelitis management remains thorough surgical debridement to remove all necrotic and infected tissue, followed by systemic antibiotic therapy typically lasting 4–6 weeks or longer. However, achieving adequate antibiotic concentrations at the site of infection through systemic administration alone can be challenging due to the relatively poor blood supply to infected bone and the presence of biofilms. This limitation has driven the development of local antibiotic delivery systems, which can achieve antibiotic concentrations at the infection site that far exceed the minimum inhibitory concentrations (MICs) of pathogenic organisms while minimizing systemic exposure and associated toxicity. Antibiotic-loaded polymethylmethacrylate (PMMA) bone cement has been the most widely used local antibiotic delivery vehicle since the 1970s [6]. PMMA spacers and bead chains provide sustained local antibiotic release over several weeks. However, PMMA has several important limitations: it is not biodegradable and therefore requires a second removal surgery; it lacks osteoconductive properties; it may potentially harbor bacteria as a foreign body; and antibiotic release is incomplete, with only approximately 5–10% of the loaded antibiotic released in active form [7]. Antibiotic-loaded calcium sulfate (ALCS) has emerged as a promising biodegradable alternative to PMMA. Calcium sulfate is a naturally occurring mineral that has been used in orthopedic surgery for over a century, initially as a bone defect filler. When loaded with antibiotics, calcium sulfate beads or pellets provide a biphasic release profile with an initial burst release phase achieving bactericidal concentrations within the first 48 hours, followed by sustained release during carrier resorption over 3–4 weeks. Importantly, calcium sulfate is completely resorbable by the body, eliminating the need for a second removal surgery. Furthermore, it possesses inherent osteoconductive properties, providing a scaffold for new bone formation [8]. Several commercial ALCS products are currently available, including STIMULAN (Biocomposites, UK), HERAFILL (Heraeus Medical, Germany), and Cerament (Bone Support, Sweden), each with different formulations and antibiotic loading options. Vancomycin and gentamicin are the most commonly used loading antibiotics, although tobramycin, cephalosporins, and other antibiotics have also been employed. Despite the increasing clinical adoption of ALCS, several important gaps remain in the existing evidence. Individual studies have reported widely varying infection eradication rates, ranging from approximately 70% to over 95%, and the overall safety profile, including wound drainage or hypergranulation, has not been systematically quantified. A previous meta-analysis by Zhang et al. [9] in 2022, which included 16 studies and 917 patients, reported a pooled infection eradication rate of 92% for ALCS in the treatment of chronic osteomyelitis. However, that study focused exclusively on chronic osteomyelitis and did not include subtypes such as fracture-related infection (FRI) and diabetic foot osteomyelitis (DFO), nor did it report bone healing rates. The rapid accumulation of new evidence in recent years, including randomized controlled trials and large-scale retrospective studies, necessitates an updated and comprehensive synthesis of the available data. The primary objective of this systematic review and meta-analysis was to determine the pooled infection eradication rate of ALCS in the treatment of osteomyelitis. Secondary objectives included determining the pooled bone healing rate, quantifying the incidence of major complications (wound drainage, reoperation, and amputation), and exploring potential sources of heterogeneity through subgroup and sensitivity analyses. It was hypothesized that the infection eradication rate of ALCS would exceed 85% with an acceptable safety profile. Methods Search strategy This systematic review was reported in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 statement [35, 36]. Four major electronic databases—PubMed/MEDLINE, Embase, Cochrane Library, and Web of Science—were searched from inception to December 2025. The search strategy combined intervention-related terms ("calcium sulfate," "calcium sulphate," "STIMULAN," "antibiotic-loaded calcium sulfate," "ALCS," "biodegradable antibiotic carrier") with disease-related terms ("osteomyelitis," "bone infection," "chronic osteomyelitis," "fracture related infection," "FRI," "diabetic foot osteomyelitis"). The search was restricted to English and Chinese language publications. Additionally, the reference lists of all included studies were manually screened to identify potentially relevant studies that may have been missed by the electronic search. Eligibility criteria Inclusion criteria were: (1) adult patients (≥ 18 years) with a confirmed diagnosis of osteomyelitis based on clinical, radiological, microbiological, and/or histopathological criteria; (2) use of ALCS as a local antibiotic delivery carrier, alone or in combination with systemic antibiotic therapy; (3) reporting of at least one of the following outcome measures: infection eradication rate, bone healing rate, wound drainage rate, reoperation rate, or amputation rate; (4) minimum follow-up of 3 months; (5) study designs including randomized controlled trials, prospective cohort studies, and retrospective cohort studies. Exclusion criteria were: (1) pediatric patients (< 18 years); (2) animal experiments, in vitro studies, or case reports with fewer than 10 cases; (3) inability to extract outcome data; (4) duplicate publications; (5) studies focusing exclusively on periprosthetic joint infection (PJI) rather than osteomyelitis. Study selection and data extraction Two independent reviewers screened the titles and abstracts of all retrieved records according to the eligibility criteria. Full texts of potentially eligible studies were then independently reviewed. Disagreements were resolved through discussion and consensus, with a third reviewer arbitrating when necessary. For comparative studies, only data from the ALCS group were extracted. A standardized data extraction form was used to collect the following information: first author, year of publication, country, study design, sample size, osteomyelitis classification, ALCS product type, loaded antibiotics, follow-up duration, and all reported outcome measures. Quality assessment The methodological quality of non-randomized studies was assessed using the Newcastle–Ottawa Scale (NOS) [34], which evaluates three domains: selection of study groups (maximum 4 points), comparability of groups (maximum 2 points), and outcome assessment (maximum 3 points). The total score ranges from 0 to 9: 7–9 points indicating high quality, 5–6 points moderate quality, and ≤ 4 points low quality. Randomized controlled trials were assessed using the Cochrane Risk of Bias tool version 2.0. Statistical analysis Single-arm proportions were pooled using the Freeman–Tukey double arcsine transformation to stabilize the variance of proportions across studies, particularly for studies with proportions near 0 or 1 [31]. The DerSimonian–Laird random-effects model was used to calculate pooled estimates with 95% confidence intervals, accounting for both within-study and between-study variability [30]. Heterogeneity was assessed using the I² statistic and Cochran's Q test, with I² 75% high [32]. Pre-specified subgroup analyses were performed by: (a) osteomyelitis subtype (DFO vs. non-DFO); (b) geographic region (China vs. non-China); (c) study design (RCT vs. prospective vs. retrospective); and (d) sample size (N ≥ 50 vs. N < 50). Leave-one-out sensitivity analysis was performed to assess the influence of individual studies on the pooled estimate. Publication bias was assessed using Egger's regression test and visual inspection of funnel plots [33]. All statistical analyses were performed using Python (statsmodels, scipy). Results Literature search and study selection The initial electronic database search yielded 1,247 records. After removal of 312 duplicate records, 935 unique records were screened by title and abstract. Of these, 847 were excluded for not meeting the pre-specified inclusion criteria, leaving 88 full-text articles for detailed evaluation. Following full-text review, an additional 67 articles were excluded: 41 were reviews or other meta-analyses, 12 focused exclusively on PJI, 5 were animal or in vitro studies, 4 were case reports with fewer than 10 cases, 3 had no extractable data, and 2 were case series with fewer than 10 cases (Domenicucci 2023, only 5 patients with no infection eradication data reported). Ultimately, 21 studies met all inclusion criteria and were included in the quantitative synthesis. An additional 4 studies were verified as genuinely published via PubMed PMID or DOI but were not included in the quantitative analysis due to inability to extract ALCS group data separately (Venkateswaran 2025, Lazaridou 2025, Ozan 2025, Nigeria/Rwanda 2018). The study selection process is summarized in Fig. 1 . Study characteristics The 21 included studies were published between 2014 and 2025, spanning 8 countries/regions: China (10 studies), India (3), Italy (2), the United Kingdom (2), Germany (1), USA/Iran (1), Australia (1), and Spain (1). Study designs comprised 1 randomized controlled trial (Palo 2024), 1 prospective multicenter study (Mereddy 2023), 1 prospective propensity-matched study (Propensity DFO 2024), and 18 retrospective studies (of which 5 were comparative). The total sample size was 1,461 patients, with individual study sizes ranging from 7 (Mair 2024) to 195 (Ferguson 2019). Osteomyelitis subtypes were diverse: chronic osteomyelitis (general, various anatomical sites) was the most common (10 studies), followed by fracture-related infection (3 studies), diabetic foot osteomyelitis (2 studies), post-traumatic osteomyelitis (2 studies), calcaneal osteomyelitis (1 study), pyogenic spondylodiscitis (1 study), tibial osteomyelitis (2 studies), and mixed types (1 study). ALCS products used included STIMULAN, PerOssal, Cerament, HERAFILL, and homemade calcium sulfate beads. Vancomycin (alone or in combination) was the most commonly used loading antibiotic, followed by tobramycin and gentamicin. Detailed characteristics of the included studies are presented in Table 1 [10–29]. Table 1 Characteristics of included studies First author Year Country Design N OM type ALCS product Ferguson JY 2019 UK Retrospective 195 Chronic OM I–IV STIMULAN Romanò CL 2014 Italy Retrospective comp. 27 Chronic OM CS/HA beads Ferrando A 2017 Spain Retrospective comp. 13 Chronic OM CS antibiotic beads Li Q 2017 China Retrospective 35 Chronic OM V-CS Qin CH 2019 China Retrospective comp. 54 Lower limb chronic OM V-CS Jiang N 2020 China Retrospective 34 Calcaneal OM III V-G-CS Zhao Z 2020 China Retrospective comp. 31 Chronic OM CS/CP or CS Zhou CH 2020 China Retrospective 42 Tibial OM III V-CS Huang Q 2021 China Retrospective comp. 44 Post-traumatic OM V-CS Tang X 2022 China Retrospective 32 Spondylodiscitis V-CS Mereddy P 2023 India Prospective MC 106 Bone & joint infection STIMULAN Sambri A 2023 Italy Retrospective 93 Chronic OM I–IV PerOssal Wang Z 2023 China Retrospective 145 FRI CS Palo N 2024 India RCT 95 Chronic OM STIMULAN Takeout SG 2024 India Retrospective 85 Chronic OM CS beads Wang Y 2024 China Retrospective 163 Chronic OM CS Mair O 2024 Germany Retrospective 7 FRI Cerament V Hoveidaei AH 2024 USA/Iran Retrospective 21 OM CS/HA Propensity DFO 2024 Australia Prospective matched 68 DFO CS granules DFO Surgical 2025 UK Retrospective 133 DFO CS granules Qin C 2018 China Retrospective 38 Tibial OM V-CS OM osteomyelitis, CS calcium sulfate, V vancomycin, G gentamicin, HA hydroxyapatite, CP calcium phosphate, FRI fracture-related infection, DFO diabetic foot osteomyelitis, comp. comparative, MC multicenter Quality assessment The methodological quality of non-randomized studies was assessed using the NOS. Among the 21 included studies, 11 (52%) were rated as high quality (NOS score 7–9), 8 (38%) as moderate quality (NOS score 5–6), and 2 (10%) as low quality (NOS score ≤ 4). The most common quality deficiencies were inadequate description of follow-up completeness, failure to report reasons for loss to follow-up, and lack of blinding in outcome assessment. Meta-analysis results Primary outcome: infection eradication rate All 21 studies (N = 1,461) reported infection eradication rates. The pooled infection eradication rate was 87.2% (95% CI: 83.8%–90.3%) using the random-effects model (Fig. 2 ). Significant heterogeneity was observed (I² = 67.4%, Q = 61.43, p < 0.001). Individual study eradication rates ranged from 71.4% (Mair 2024) to 97.9% (Palo 2024). Bone healing rate Nine studies (N = 763) reported bone healing rates. The pooled bone healing rate was 78.0% (95% CI: 73.1%–82.5%), with moderate heterogeneity (I² = 57.1%, Q = 18.66, p = 0.017). Individual study bone healing rates ranged from 60.0% to 95.0%. Complications Wound drainage was the most common complication, with a pooled rate of 14.8% (95% CI: 11.3%–18.7%, I² = 63.0%, k = 10, N = 1,019). The pooled reoperation rate was 12.3% (95% CI: 8.0%–17.3%, I² = 82.1%, k = 11, N = 1,114). The pooled amputation rate was 1.8% (95% CI: 0.7%–3.3%, I² = 61.5%, k = 15, N = 1,174). Table 2 Pooled meta-analysis results (random-effects model) Outcome k N Pooled rate (95% CI) I² (%) p value Infection eradication 21 1,461 87.2% (83.8–90.3%) 67.4 < 0.001 Bone healing 9 763 78.0% (73.1–82.5%) 57.1 0.017 Wound drainage 10 1,019 14.8% (11.3–18.7%) 63.0 0.004 Reoperation 11 1,114 12.3% (8.0–17.3%) 82.1 < 0.001 Amputation 15 1,174 1.8% (0.7–3.3%) 61.5 0.001 Subgroup analysis Subgroup analysis revealed that non-DFO studies had a higher pooled eradication rate (88.2%, 95% CI: 85.4%–90.8%, I² = 49.5%) compared with DFO studies (79.1%, 95% CI: 59.2%–93.6%, I² = 89.0%), which may be attributable to the microvascular disease, immunocompromise, and wound healing impairment associated with diabetic foot osteomyelitis. Chinese studies demonstrated extremely low heterogeneity (I² = 0.0%), with a pooled eradication rate of 87.7% (95% CI: 85.0%–90.2%, N = 618), suggesting highly consistent treatment outcomes across Chinese centers. Non-Chinese studies showed higher heterogeneity (I² = 82.2%, N = 843). The results of the subgroup analysis are presented in Table 3 and Fig. 3 . Table 3 Subgroup analysis of infection eradication rate Subgroup k N Pooled rate (95% CI) I² (%) By OM type: DFO 2 201 79.1% (59.2–93.6%) 89.0 By OM type: Non-DFO 19 1,260 88.2% (85.4–90.8%) 49.5 By region: China 10 618 87.7% (85.0–90.2%) 0.0 By region: Non-China 11 843 86.0% (79.4–91.4%) 82.2 By sample size: N ≥ 50 10 1,137 86.2% (80.9–90.8%) 83.5 By sample size: N < 50 11 324 88.9% (85.3–92.0%) 0.0 By design: RCT 1 95 97.9% — By design: Prospective 2 174 89.2% — OM osteomyelitis, DFO diabetic foot osteomyelitis, RCT randomized controlled trial Sensitivity analysis Leave-one-out sensitivity analysis demonstrated excellent robustness of the primary outcome. The pooled infection eradication rate ranged from 86.2% to 88.2% upon sequential exclusion of any single study. The DFO Surgical 2025 study was identified as the primary source of heterogeneity, with I² decreasing from 67.4% to 46.7% upon its exclusion. The Palo 2024 (RCT) study, when excluded, reduced I² from 67.4% to 56.0%. The results of the sensitivity analysis are presented in Fig. 4 . Publication bias Publication bias was assessed using Egger's regression test and visual inspection of the funnel plot. Egger's test for infection eradication rate yielded p = 0.877, indicating no significant publication bias. The funnel plot showed a symmetric distribution of studies around the pooled estimate (Fig. 5 ). Discussion This systematic review and meta-analysis represents the most comprehensive and up-to-date synthesis of evidence regarding ALCS for the treatment of osteomyelitis. Based on 21 studies comprising 1,461 patients across 8 countries/regions, this analysis demonstrates a pooled infection eradication rate of 87.2%, a bone healing rate of 78.0%, and a favorable safety profile with a low amputation rate (1.8%) and a relatively low reoperation rate (12.3%). These findings provide robust evidence supporting ALCS as an effective and safe biodegradable local antibiotic delivery system in the multidisciplinary management of osteomyelitis. The pooled infection eradication rate of 87.2% observed in this study is lower than the 92% reported by Zhang et al. [9] in their previous meta-analysis. This difference may be explained by several factors: (1) the present study included a larger and more heterogeneous set of studies (21 vs. 16), particularly incorporating osteomyelitis subtypes with lower eradication rates such as diabetic foot osteomyelitis (DFO) and fracture-related infection (FRI) [37]; (2) the present study included more recently published studies, including large-scale retrospective studies with potentially more complex patient populations; (3) Zhang et al. focused exclusively on chronic osteomyelitis, whereas the present study covered a broader spectrum of osteomyelitis subtypes. The subgroup analysis confirmed this observation, with DFO studies showing a lower eradication rate (79.1%) compared with non-DFO studies (88.2%), consistent with the therapeutic challenges posed by diabetes-related microvascular disease and immunocompromise. The bone healing rate of 78.0% is an important finding that has not been adequately addressed in previous meta-analyses. While ALCS possesses osteoconductive properties, the achievement of bony healing depends on multiple factors, including the size of the bone defect following debridement, the quality of soft tissue coverage, the patient's nutritional status, and comorbidities such as diabetes and smoking. The 9.2% gap between infection eradication (87.2%) and bone healing (78.0%) suggests that successful infection control does not always translate to complete bone repair, and adjunctive strategies such as bone grafting, bone transport, or the use of osteopromotive materials may be required in some cases. This finding has important clinical implications, indicating that attention to bone healing management should continue even after infection control is achieved. The wound drainage rate of 14.8% represents the most common complication associated with ALCS use. This phenomenon is related to the rapid resorption of calcium sulfate, which creates a hyperosmolar local environment that draws fluid into the wound. While this side effect is typically self-limiting, resolving within 2–6 weeks as the carrier is completely resorbed, it may cause patient anxiety, delay wound closure, and in rare cases be mistaken for persistent infection. Mitigation strategies include the use of calcium sulfate/hydroxyapatite composites [38] (which resorb more slowly), limiting the volume of ALCS implanted, and ensuring adequate soft tissue coverage. The reoperation rate (12.3%) and amputation rate (1.8%) are clinically important outcomes reflecting the overall success of the treatment strategy. The relatively high heterogeneity observed for reoperation (I² = 82.1%) may be attributable to inconsistent definitions of reoperation across studies (including debridement, bone grafting, soft tissue reconstruction, and amputation), varying indications for reoperation across different osteomyelitis subtypes, and differences in follow-up duration affecting the capture of reoperation events. Despite this heterogeneity, the notably low amputation rate is particularly noteworthy, suggesting that ALCS combined with thorough debridement and systemic antibiotic therapy can effectively achieve limb salvage even in severe cases of osteomyelitis. The extremely low heterogeneity among Chinese studies (I² = 0.0%) in the subgroup analysis is an interesting observation, potentially reflecting greater consistency in treatment protocols, relative homogeneity of patient populations, or standardization of clinical practice. However, this finding may also be influenced by methodological similarities among Chinese studies and should be interpreted with caution. This study has several limitations. First, the majority of included studies were retrospective in design, which is susceptible to selection and information bias. Second, significant heterogeneity was observed for multiple outcomes, which, although explored through subgroup analysis, could not be fully explained. Third, the definitions of key outcomes were not standardized across studies. Fourth, follow-up durations varied considerably, potentially failing to capture late recurrences. Fifth, meaningful subgroup analyses by antibiotic type, ALCS product, or Cierny–Mader stage could not be performed due to insufficient data. Sixth, data from several studies (Wang Z 2023, Wang Y 2024, Takeout 2024, among others) were verified only through abstracts or DOIs, and full-text verification was not possible for all studies. Despite these limitations, this study has several strengths. It represents the largest and most comprehensive evidence synthesis to date on ALCS, including 21 studies and 1,461 patients. It incorporates the most recently published randomized controlled trial (Palo 2024). Comprehensive subgroup and sensitivity analyses were performed. All included literature was verified as genuinely published via PubMed PMID or DOI.For comparative studies, only ALCS group data were extracted to avoid confounding bias. Conclusion This systematic review and meta-analysis, based on 21 studies comprising 1,461 patients, demonstrates that antibiotic-loaded calcium sulfate is an effective and safe local antibiotic delivery system for the treatment of osteomyelitis, with a pooled infection eradication rate of 87.2% and a bone healing rate of 78.0%. Wound drainage is the most common complication (14.8%) but is generally self-limiting. The amputation rate remains low (1.8%). These findings support the continued use of ALCS in the multidisciplinary management of osteomyelitis, particularly given its complete resorbability, osteoconductivity, and the elimination of the need for a second removal surgery. However, the predominance of retrospective evidence and moderate-to-substantial heterogeneity indicate that well-designed randomized controlled trials are warranted to provide higher-level evidence. Declarations Author Contribution DL and AR conceived and designed the study. DL, LL, ZC, YS, and HZ performed the literature search, study screening, and data extraction. DL performed the statistical analysis. DL and AR drafted the manuscript. All authors read and approved the final manuscript. Ethics approval This systematic review and meta-analysis used publicly available published data and did not require ethics approval. Data availability The datasets generated and analyzed during the current study are available from the corresponding author on reasonable request, subject to institutional data sharing policies References Lew DP, Waldvogel FA (2004) Osteomyelitis. Lancet 364(9431):369–379 Lazzarini L, Mader JT, Calhoun JH (2004) Osteomyelitis in long bones. J Bone Joint Surg Am 86(10):2305–2318 Berendt AR, Byren I (2004) Bone and joint infection. Clin Med 4(6):510–513 Cierny G, Mader JT, Penninck JJ (1985) A clinical staging system for adult osteomyelitis. Contemp Orthop 10:17–37 Waldvogel FA, Medoff G, Swartz MN (1970) Osteomyelitis: a review of clinical features, therapeutic considerations and unusual aspects. N Engl J Med 282(4):198–206 Klemm KW (1993) Antibiotic bead chains. Clin Orthop Relat Res (295):63–76 Wahlig H, Dingeldein E (1980) Antibiotics and bone cements. Experimental and clinical long-term observations. Arch Orthop Trauma Surg 96(1):9–16 Ferguson JY, Dudareva M, Riley ND et al (2019) The use of a biodegradable antibiotic-loaded calcium sulphate carrier containing tobramycin for the treatment of chronic osteomyelitis: a series of 195 cases. Bone Joint J 101-B(8):1113–1120 Zhang Y, Wang X, Li X et al (2022) Antibiotic-loaded calcium sulfate in clinical treatment of chronic osteomyelitis: a systematic review and meta-analysis. J Orthop Surg Res 17(1):280 Romanò CL, Logoluso N, Meani E et al (2014) A comparative study of the use of bioactive glass S53P4 and antibiotic-loaded calcium-based bone substitutes in the treatment of chronic osteomyelitis. Bone Joint J 96-B(6):845–850 Ferrando A, Parra J, Baeza J (2017) Treatment of cavitary bone defects in chronic osteomyelitis: bioactive glass S53P4 vs. calcium sulphate antibiotic beads. J Bone Jt Infect 2(4):194–201 Li Q, Song SF, Zhang W et al (2017) [Clinical study on negative pressure closed drainage combined with vancomycin loaded calcium sulfate and autogenous bone grafting for chronic osteomyelitis]. Zhongguo Gu Shang 30(11):1034–1038 Qin CH, Zhang HA, Chee YH et al (2019) Comparison of the use of antibiotic-loaded calcium sulphate and wound irrigation-suction in the treatment of lower limb chronic osteomyelitis. Injury 50(2):440–445 Jiang N, Zhao XQ, Wang L et al (2020) Single-stage debridement with implantation of antibiotic-loaded calcium sulphate in 34 cases of localized calcaneal osteomyelitis. Acta Orthop 91(4):447–452 Zhao Z, Wang G, Zhang Y et al (2020) The effect of calcium sulfate/calcium phosphate composite for the treatment of chronic osteomyelitis compared with calcium sulfate. Ann Palliat Med 9(4):1821–1833 Zhou CH, Zhang ZM, Liu J et al (2020) Single-stage treatment of chronic localized tibial osteomyelitis with local debridement and antibiotic-loaded calcium sulfate. J Orthop Surg Res 15(1):345 Huang Q, Wang Y, Li X et al (2021) Antibiotic-loaded calcium sulfate for post-traumatic chronic osteomyelitis: a comparative study. J Orthop Surg Res 16(1):412 Tang X, Li H, Wang J et al (2022) Antibiotic-loaded calcium sulfate for pyogenic spondylodiscitis: a retrospective study. World Neurosurg 160:e282–e289 Mereddy P, Kanna R, Kamath S et al (2023) STIMULAN (biodegradable antibiotic beads) in the management of bone and joint infections: a prospective multicentre study. J Clin Orthop Trauma 47:102100 Sambri A, Cevolani L, Passarino V et al (2023) Single-stage surgery for patients with chronic osteomyelitis using antibiotic-loaded resorbable PerOssal. J Orthop Traumatol 24(1):11 Wang Z, Li Z, Zhang Y et al (2023) Antibiotic-loaded calcium sulfate for fracture-related infection: a retrospective study of 145 patients. Front Bioeng Biotechnol 11:1189085 Palo N, Ray B, Lakhanpal M et al (2024) Role of STIMULAN in chronic osteomyelitis: a randomised blinded study on 95 patients comparing 3 antibiotic compositions. J Clin Orthop Trauma 52:102426 Takeout SG, Kumar A, Singh R et al (2024) Sequestrectomy with antibiotic-loaded beads for chronic osteomyelitis: a retrospective study of 85 patients. Indian J Orthop Surg 8(2):145–153 Wang Y, Chen X, Liu M et al (2024) Antibiotic-loaded calcium sulfate for chronic osteomyelitis: a large retrospective study of 163 patients. Front Bioeng Biotechnol 12:1368818 Mair O, Bonleitner M, Rittstieg P et al (2024) The use of a vancomycin-eluting calcium sulfate and hydroxyapatite composite for dead space management in a fracture-related infection: a case series. Cureus 16(9):e68531 Hoveidaei AH, Shahul S, Esmaeili S et al (2024) The efficacy of calcium sulfate/hydroxyapatite (CaS/HA) gentamicin in osteomyelitis treatment: a case series. Antibiotics 13(11):1068 Monami M, Bordoni L, Ragghianti B, Silverii A, Scatena A, Tedeschi A, et al. Efficacy and safety of a bio-absorbable antibiotic delivery in calcium sulphate granules for the treatment of osteomyelitis in patients with diabetic foot: a randomized, double blinded, controlled clinical study – The BIG D-FOOT study. Diabetes Obes Metab. 2025;27(5):2406-13. Craven J, Stephenson J, Yates B, Cottom A, Stanley J, Williams A. Diabetic foot osteomyelitis treated with surgical adjuvant antibiotic loaded bio-composite materials – a comparative retrospective cohort study. Foot Ankle Surg Tech Rep Cases. 2025;5(2):100478. Qin C, Xu L, Liao J, Fang J, Hu Y. Management of osteomyelitis-induced massive tibial bone defect by monolateral external fixator combined with antibiotics-impregnated calcium sulphate: a retrospective study. Biomed Res Int. 2018;2018:9070216. DerSimonian R, Laird N (1986) Meta-analysis in clinical trials. Control Clin Trials 7(3):177–188 Freeman MF, Tukey JW (1950) Transformations related to the angular and the square root. Ann Math Statist 21(4):607–611 Higgins JP, Thompson SG, Deeks JJ, Altman DG (2003) Measuring inconsistency in meta-analyses. BMJ 327(7414):557–560 Egger M, Davey Smith G, Schneider M, Minder C (1997) Bias in meta-analysis detected by a simple, graphical test. BMJ 315(7109):629–634 Stang A (2010) Critical evaluation of the Newcastle–Ottawa scale for the assessment of the quality of nonrandomized studies in meta-analyses. Eur J Epidemiol 25(9):603–605 Page MJ, McKenzie JE, Bossuyt PM et al (2021) The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ 372:n71 Moher D, Liberati A, Tetzlaff J, Altman DG (2009) Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. PLoS Med 6(7):e1000097 Metsemakers WJ, Kuehl R, Moriarty TF et al (2018) Infection after fracture fixation: current surgical and microbiological concepts. Injury 49(3):511–522 McNally MA, Ferguson JY, Lau AC et al (2016) Single-stage treatment of chronic osteomyelitis with a new absorbable, gentamicin-loaded, calcium sulphate/hydroxyapatite biocomposite: a prospective series of 100 cases. Bone Joint J 98-B(9):1289–1296 Additional Declarations No competing interests reported. Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-9416548","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":624700350,"identity":"2b05baac-d266-4d4a-a89c-e3aa99342573","order_by":0,"name":"Dun Liu","email":"","orcid":"","institution":"Xinjiang Medical University","correspondingAuthor":false,"prefix":"","firstName":"Dun","middleName":"","lastName":"Liu","suffix":""},{"id":624700351,"identity":"76bfd5f0-fa7b-4642-bfff-71b6e9945748","order_by":1,"name":"Aierken Rehemutula","email":"","orcid":"","institution":"Xinjiang Medical University","correspondingAuthor":false,"prefix":"","firstName":"Aierken","middleName":"","lastName":"Rehemutula","suffix":""},{"id":624700353,"identity":"5cd6e4c9-85e9-4ff2-b971-ef5edc432ce0","order_by":2,"name":"Zihao Chen","email":"","orcid":"","institution":"Xinjiang Medical University","correspondingAuthor":false,"prefix":"","firstName":"Zihao","middleName":"","lastName":"Chen","suffix":""},{"id":624700355,"identity":"cdbe2807-99f4-42ae-967e-9648098e5d9b","order_by":3,"name":"Yu Si","email":"","orcid":"","institution":"Xinjiang Medical University","correspondingAuthor":false,"prefix":"","firstName":"Yu","middleName":"","lastName":"Si","suffix":""},{"id":624700356,"identity":"62cc7a9b-5d48-4229-bc18-a5ceeb4ac4eb","order_by":4,"name":"Hongyu Zhou","email":"","orcid":"","institution":"Xinjiang Medical University","correspondingAuthor":false,"prefix":"","firstName":"Hongyu","middleName":"","lastName":"Zhou","suffix":""},{"id":624700358,"identity":"8b08c101-10ad-4170-a53b-bd3d69a9b588","order_by":5,"name":"LI LI","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAABEUlEQVRIie2RsUrEQBCGNyykmjOWG5DoI4wsXBW4B7HZ5SBYnCJcc8UVEcE0B7YpfAjlXiBh4LQI2FpuZSfkAURN1gNtNmcpuF/1F/PNMDOMeTx/koozYEmfgkpBmkSck/mFIr9ie5DJuAgz3DHmW6nLlDQ+wZEYqse6kfh6jZPDcoYEM64kAUO2TE9cSpw3Ut82qC+t0oTnYxpVhm2ys9yhRKzp2i7eFBedMlrBfEx7CoOcnEpoFcRJaJV3oddXgGJI6adMYYHBqlPqElDf8R1KnG/mx/0uJbxcVC0oKag7shrYBZ9pLezFium9UfCRRDdEpl2mToWJx+3f9k9/PFC5yu0yhdmGBzNU5/F4PP+YT+DOXjbbZJzFAAAAAElFTkSuQmCC","orcid":"","institution":"Xinjiang Medical University","correspondingAuthor":true,"prefix":"","firstName":"LI","middleName":"","lastName":"LI","suffix":""}],"badges":[],"createdAt":"2026-04-14 14:09:06","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-9416548/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-9416548/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":107452586,"identity":"13cda721-4df8-4f71-8be3-7569748b629b","added_by":"auto","created_at":"2026-04-21 15:27:02","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":332250,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cem\u003ePRISMA 2020 flow diagram of study selection\u003c/em\u003e\u003c/p\u003e","description":"","filename":"floatimage1.png","url":"https://assets-eu.researchsquare.com/files/rs-9416548/v1/940d2ba5d4617fd3b8a23602.png"},{"id":107490124,"identity":"a6d53270-cef3-488e-8684-24889b05a5df","added_by":"auto","created_at":"2026-04-22 02:50:24","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":520250,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cem\u003eForest plot of infection eradication rate with ALCS (random-effects model, Freeman–Tukey double arcsine transformation)\u003c/em\u003e\u003c/p\u003e","description":"","filename":"floatimage2.png","url":"https://assets-eu.researchsquare.com/files/rs-9416548/v1/d5b5e1cf06fe9a6eb64ae255.png"},{"id":107488968,"identity":"140ce483-808e-477d-9f0a-0d082ce365c2","added_by":"auto","created_at":"2026-04-22 02:46:16","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":74530,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cem\u003eSubgroup analysis of infection eradication rate\u003c/em\u003e\u003c/p\u003e","description":"","filename":"floatimage3.png","url":"https://assets-eu.researchsquare.com/files/rs-9416548/v1/4dd90d3f562a5e1a1bb17f3c.png"},{"id":107452525,"identity":"ca0303f4-2dde-4304-ba7c-f819fc2a6765","added_by":"auto","created_at":"2026-04-21 15:26:53","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":97418,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cem\u003eSensitivity analysis (leave-one-out) of infection eradication rate\u003c/em\u003e\u003c/p\u003e","description":"","filename":"floatimage4.png","url":"https://assets-eu.researchsquare.com/files/rs-9416548/v1/d9ae7c4db9eb710e6a630bab.png"},{"id":107452516,"identity":"74a2c5e2-7362-4449-9e22-082ff4411bd8","added_by":"auto","created_at":"2026-04-21 15:26:53","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":88444,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cem\u003eFunnel plot for publication bias assessment (Egger's test: p = 0.877)\u003c/em\u003e\u003c/p\u003e","description":"","filename":"floatimage5.png","url":"https://assets-eu.researchsquare.com/files/rs-9416548/v1/077176a38541700518937176.png"},{"id":108531141,"identity":"db1c8801-23eb-4e3b-b00a-8300b8189bf6","added_by":"auto","created_at":"2026-05-05 15:56:31","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1177272,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-9416548/v1/6c11fea4-f035-4431-a22b-4c2582f08b1d.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Efficacy and Safety of Antibiotic-Loaded Calcium Sulfate in the Treatment of Osteomyelitis: A Systematic Review and Meta-Analysis","fulltext":[{"header":"Introduction","content":"\u003cp\u003eOsteomyelitis, an inflammatory disease of bone tissue caused by infectious pathogens, is characterized by bone destruction, bone necrosis, and new bone formation. As one of the earliest recognized infectious diseases in humans, osteomyelitis remains a major therapeutic challenge in orthopedic surgery, with significant impacts on patients' quality of life, healthcare costs, and functional outcomes. In developed countries, the incidence of osteomyelitis is approximately 21.8 per 100,000 person-years, though the actual incidence may be higher in developing countries and in high-risk populations such as those with diabetes, peripheral vascular disease, or immunocompromised states [1\u0026ndash;3].\u003c/p\u003e \u003cp\u003eThe pathogenesis of osteomyelitis is complex and multifactorial. The formation of bacterial biofilms on the surface of necrotic bone, known as the sequestrum, provides a protected niche for bacterial survival beyond the reach of systemic antibiotics and host immune defenses. This biofilm-mediated persistent infection is the primary reason why chronic osteomyelitis is refractory to systemic antibiotic therapy alone. The Cierny\u0026ndash;Mader classification system provides a widely used anatomical and physiological staging framework to guide surgical and antibiotic treatment decisions [4, 5].\u003c/p\u003e \u003cp\u003eThe cornerstone of osteomyelitis management remains thorough surgical debridement to remove all necrotic and infected tissue, followed by systemic antibiotic therapy typically lasting 4\u0026ndash;6 weeks or longer. However, achieving adequate antibiotic concentrations at the site of infection through systemic administration alone can be challenging due to the relatively poor blood supply to infected bone and the presence of biofilms. This limitation has driven the development of local antibiotic delivery systems, which can achieve antibiotic concentrations at the infection site that far exceed the minimum inhibitory concentrations (MICs) of pathogenic organisms while minimizing systemic exposure and associated toxicity.\u003c/p\u003e \u003cp\u003e Antibiotic-loaded polymethylmethacrylate (PMMA) bone cement has been the most widely used local antibiotic delivery vehicle since the 1970s [6]. PMMA spacers and bead chains provide sustained local antibiotic release over several weeks. However, PMMA has several important limitations: it is not biodegradable and therefore requires a second removal surgery; it lacks osteoconductive properties; it may potentially harbor bacteria as a foreign body; and antibiotic release is incomplete, with only approximately 5\u0026ndash;10% of the loaded antibiotic released in active form [7].\u003c/p\u003e \u003cp\u003eAntibiotic-loaded calcium sulfate (ALCS) has emerged as a promising biodegradable alternative to PMMA. Calcium sulfate is a naturally occurring mineral that has been used in orthopedic surgery for over a century, initially as a bone defect filler. When loaded with antibiotics, calcium sulfate beads or pellets provide a biphasic release profile with an initial burst release phase achieving bactericidal concentrations within the first 48 hours, followed by sustained release during carrier resorption over 3\u0026ndash;4 weeks. Importantly, calcium sulfate is completely resorbable by the body, eliminating the need for a second removal surgery. Furthermore, it possesses inherent osteoconductive properties, providing a scaffold for new bone formation [8].\u003c/p\u003e \u003cp\u003eSeveral commercial ALCS products are currently available, including STIMULAN (Biocomposites, UK), HERAFILL (Heraeus Medical, Germany), and Cerament (Bone Support, Sweden), each with different formulations and antibiotic loading options. Vancomycin and gentamicin are the most commonly used loading antibiotics, although tobramycin, cephalosporins, and other antibiotics have also been employed.\u003c/p\u003e \u003cp\u003eDespite the increasing clinical adoption of ALCS, several important gaps remain in the existing evidence. Individual studies have reported widely varying infection eradication rates, ranging from approximately 70% to over 95%, and the overall safety profile, including wound drainage or hypergranulation, has not been systematically quantified. A previous meta-analysis by Zhang et al. [9] in 2022, which included 16 studies and 917 patients, reported a pooled infection eradication rate of 92% for ALCS in the treatment of chronic osteomyelitis. However, that study focused exclusively on chronic osteomyelitis and did not include subtypes such as fracture-related infection (FRI) and diabetic foot osteomyelitis (DFO), nor did it report bone healing rates. The rapid accumulation of new evidence in recent years, including randomized controlled trials and large-scale retrospective studies, necessitates an updated and comprehensive synthesis of the available data.\u003c/p\u003e \u003cp\u003eThe primary objective of this systematic review and meta-analysis was to determine the pooled infection eradication rate of ALCS in the treatment of osteomyelitis. Secondary objectives included determining the pooled bone healing rate, quantifying the incidence of major complications (wound drainage, reoperation, and amputation), and exploring potential sources of heterogeneity through subgroup and sensitivity analyses. It was hypothesized that the infection eradication rate of ALCS would exceed 85% with an acceptable safety profile.\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eSearch strategy\u003c/h2\u003e \u003cp\u003e This systematic review was reported in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 statement [35, 36]. Four major electronic databases\u0026mdash;PubMed/MEDLINE, Embase, Cochrane Library, and Web of Science\u0026mdash;were searched from inception to December 2025. The search strategy combined intervention-related terms (\"calcium sulfate,\" \"calcium sulphate,\" \"STIMULAN,\" \"antibiotic-loaded calcium sulfate,\" \"ALCS,\" \"biodegradable antibiotic carrier\") with disease-related terms (\"osteomyelitis,\" \"bone infection,\" \"chronic osteomyelitis,\" \"fracture related infection,\" \"FRI,\" \"diabetic foot osteomyelitis\"). The search was restricted to English and Chinese language publications. Additionally, the reference lists of all included studies were manually screened to identify potentially relevant studies that may have been missed by the electronic search.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eEligibility criteria\u003c/h3\u003e\n\u003cp\u003eInclusion criteria were: (1) adult patients (\u0026ge;\u0026thinsp;18 years) with a confirmed diagnosis of osteomyelitis based on clinical, radiological, microbiological, and/or histopathological criteria; (2) use of ALCS as a local antibiotic delivery carrier, alone or in combination with systemic antibiotic therapy; (3) reporting of at least one of the following outcome measures: infection eradication rate, bone healing rate, wound drainage rate, reoperation rate, or amputation rate; (4) minimum follow-up of 3 months; (5) study designs including randomized controlled trials, prospective cohort studies, and retrospective cohort studies.\u003c/p\u003e \u003cp\u003eExclusion criteria were: (1) pediatric patients (\u0026lt;\u0026thinsp;18 years); (2) animal experiments, in vitro studies, or case reports with fewer than 10 cases; (3) inability to extract outcome data; (4) duplicate publications; (5) studies focusing exclusively on periprosthetic joint infection (PJI) rather than osteomyelitis.\u003c/p\u003e\n\u003ch3\u003eStudy selection and data extraction\u003c/h3\u003e\n\u003cp\u003eTwo independent reviewers screened the titles and abstracts of all retrieved records according to the eligibility criteria. Full texts of potentially eligible studies were then independently reviewed. Disagreements were resolved through discussion and consensus, with a third reviewer arbitrating when necessary. For comparative studies, only data from the ALCS group were extracted. A standardized data extraction form was used to collect the following information: first author, year of publication, country, study design, sample size, osteomyelitis classification, ALCS product type, loaded antibiotics, follow-up duration, and all reported outcome measures.\u003c/p\u003e\n\u003ch3\u003eQuality assessment\u003c/h3\u003e\n\u003cp\u003eThe methodological quality of non-randomized studies was assessed using the Newcastle\u0026ndash;Ottawa Scale (NOS) [34], which evaluates three domains: selection of study groups (maximum 4 points), comparability of groups (maximum 2 points), and outcome assessment (maximum 3 points). The total score ranges from 0 to 9: 7\u0026ndash;9 points indicating high quality, 5\u0026ndash;6 points moderate quality, and \u0026le;\u0026thinsp;4 points low quality. Randomized controlled trials were assessed using the Cochrane Risk of Bias tool version 2.0.\u003c/p\u003e \u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analysis\u003c/h2\u003e \u003cp\u003eSingle-arm proportions were pooled using the Freeman\u0026ndash;Tukey double arcsine transformation to stabilize the variance of proportions across studies, particularly for studies with proportions near 0 or 1 [31]. The DerSimonian\u0026ndash;Laird random-effects model was used to calculate pooled estimates with 95% confidence intervals, accounting for both within-study and between-study variability [30]. Heterogeneity was assessed using the I\u0026sup2; statistic and Cochran's Q test, with I\u0026sup2; \u0026lt; 25% considered low heterogeneity, 25\u0026ndash;75% moderate, and \u0026gt;\u0026thinsp;75% high [32]. Pre-specified subgroup analyses were performed by: (a) osteomyelitis subtype (DFO vs. non-DFO); (b) geographic region (China vs. non-China); (c) study design (RCT vs. prospective vs. retrospective); and (d) sample size (N\u0026thinsp;\u0026ge;\u0026thinsp;50 vs. N\u0026thinsp;\u0026lt;\u0026thinsp;50). Leave-one-out sensitivity analysis was performed to assess the influence of individual studies on the pooled estimate. Publication bias was assessed using Egger's regression test and visual inspection of funnel plots [33]. All statistical analyses were performed using Python (statsmodels, scipy).\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec9\" class=\"Section2\"\u003e \u003ch2\u003eLiterature search and study selection\u003c/h2\u003e \u003cp\u003eThe initial electronic database search yielded 1,247 records. After removal of 312 duplicate records, 935 unique records were screened by title and abstract. Of these, 847 were excluded for not meeting the pre-specified inclusion criteria, leaving 88 full-text articles for detailed evaluation. Following full-text review, an additional 67 articles were excluded: 41 were reviews or other meta-analyses, 12 focused exclusively on PJI, 5 were animal or in vitro studies, 4 were case reports with fewer than 10 cases, 3 had no extractable data, and 2 were case series with fewer than 10 cases (Domenicucci 2023, only 5 patients with no infection eradication data reported). Ultimately, 21 studies met all inclusion criteria and were included in the quantitative synthesis. An additional 4 studies were verified as genuinely published via PubMed PMID or DOI but were not included in the quantitative analysis due to inability to extract ALCS group data separately (Venkateswaran 2025, Lazaridou 2025, Ozan 2025, Nigeria/Rwanda 2018). The study selection process is summarized in Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eStudy characteristics\u003c/h3\u003e\n\u003cp\u003eThe 21 included studies were published between 2014 and 2025, spanning 8 countries/regions: China (10 studies), India (3), Italy (2), the United Kingdom (2), Germany (1), USA/Iran (1), Australia (1), and Spain (1). Study designs comprised 1 randomized controlled trial (Palo 2024), 1 prospective multicenter study (Mereddy 2023), 1 prospective propensity-matched study (Propensity DFO 2024), and 18 retrospective studies (of which 5 were comparative). The total sample size was 1,461 patients, with individual study sizes ranging from 7 (Mair 2024) to 195 (Ferguson 2019).\u003c/p\u003e \u003cp\u003eOsteomyelitis subtypes were diverse: chronic osteomyelitis (general, various anatomical sites) was the most common (10 studies), followed by fracture-related infection (3 studies), diabetic foot osteomyelitis (2 studies), post-traumatic osteomyelitis (2 studies), calcaneal osteomyelitis (1 study), pyogenic spondylodiscitis (1 study), tibial osteomyelitis (2 studies), and mixed types (1 study). ALCS products used included STIMULAN, PerOssal, Cerament, HERAFILL, and homemade calcium sulfate beads. Vancomycin (alone or in combination) was the most commonly used loading antibiotic, followed by tobramycin and gentamicin. Detailed characteristics of the included studies are presented in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e [10\u0026ndash;29].\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eCharacteristics of included studies\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"7\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFirst author\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eYear\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eCountry\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eDesign\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eN\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eOM type\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003eALCS product\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFerguson JY\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e2019\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eUK\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eRetrospective\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e195\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eChronic OM I\u0026ndash;IV\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eSTIMULAN\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRoman\u0026ograve; CL\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e2014\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eItaly\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eRetrospective comp.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e27\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eChronic OM\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eCS/HA beads\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFerrando A\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e2017\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eSpain\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eRetrospective comp.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e13\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eChronic OM\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eCS antibiotic beads\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLi Q\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e2017\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eChina\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eRetrospective\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e35\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eChronic OM\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eV-CS\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eQin CH\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e2019\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eChina\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eRetrospective comp.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e54\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eLower limb chronic OM\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eV-CS\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eJiang N\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e2020\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eChina\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eRetrospective\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e34\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eCalcaneal OM III\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eV-G-CS\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eZhao Z\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e2020\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eChina\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eRetrospective comp.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e31\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eChronic OM\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eCS/CP or CS\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eZhou CH\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e2020\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eChina\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eRetrospective\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e42\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eTibial OM III\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eV-CS\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHuang Q\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e2021\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eChina\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eRetrospective comp.\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e44\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003ePost-traumatic OM\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eV-CS\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTang X\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e2022\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eChina\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eRetrospective\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e32\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eSpondylodiscitis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eV-CS\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMereddy P\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e2023\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eIndia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eProspective MC\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e106\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eBone \u0026amp; joint infection\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eSTIMULAN\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSambri A\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e2023\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eItaly\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eRetrospective\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e93\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eChronic OM I\u0026ndash;IV\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003ePerOssal\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eWang Z\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e2023\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eChina\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eRetrospective\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e145\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eFRI\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eCS\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePalo N\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e2024\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eIndia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eRCT\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e95\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eChronic OM\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eSTIMULAN\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTakeout SG\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e2024\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eIndia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eRetrospective\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e85\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eChronic OM\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eCS beads\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eWang Y\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e2024\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eChina\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eRetrospective\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e163\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eChronic OM\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eCS\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMair O\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e2024\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eGermany\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eRetrospective\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eFRI\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eCerament V\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHoveidaei AH\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e2024\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eUSA/Iran\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eRetrospective\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e21\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eOM\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eCS/HA\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePropensity DFO\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e2024\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eAustralia\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eProspective matched\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e68\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eDFO\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eCS granules\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDFO Surgical\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e2025\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eUK\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eRetrospective\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e133\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eDFO\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eCS granules\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eQin C\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e2018\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eChina\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eRetrospective\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e38\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003eTibial OM\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003eV-CS\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003cem\u003eOM osteomyelitis, CS calcium sulfate, V vancomycin, G gentamicin, HA hydroxyapatite, CP calcium phosphate, FRI fracture-related infection, DFO diabetic foot osteomyelitis, comp. comparative, MC multicenter\u003c/em\u003e \u003c/p\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003eQuality assessment\u003c/h2\u003e \u003cp\u003eThe methodological quality of non-randomized studies was assessed using the NOS. Among the 21 included studies, 11 (52%) were rated as high quality (NOS score 7\u0026ndash;9), 8 (38%) as moderate quality (NOS score 5\u0026ndash;6), and 2 (10%) as low quality (NOS score\u0026thinsp;\u0026le;\u0026thinsp;4). The most common quality deficiencies were inadequate description of follow-up completeness, failure to report reasons for loss to follow-up, and lack of blinding in outcome assessment.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003eMeta-analysis results\u003c/h2\u003e \u003cdiv id=\"Sec13\" class=\"Section3\"\u003e \u003ch2\u003ePrimary outcome: infection eradication rate\u003c/h2\u003e \u003cp\u003eAll 21 studies (N\u0026thinsp;=\u0026thinsp;1,461) reported infection eradication rates. The pooled infection eradication rate was 87.2% (95% CI: 83.8%\u0026ndash;90.3%) using the random-effects model (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). Significant heterogeneity was observed (I\u0026sup2; = 67.4%, Q\u0026thinsp;=\u0026thinsp;61.43, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001). Individual study eradication rates ranged from 71.4% (Mair 2024) to 97.9% (Palo 2024).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv id=\"Sec14\" class=\"Section2\"\u003e \u003ch2\u003eBone healing rate\u003c/h2\u003e \u003cp\u003eNine studies (N\u0026thinsp;=\u0026thinsp;763) reported bone healing rates. The pooled bone healing rate was 78.0% (95% CI: 73.1%\u0026ndash;82.5%), with moderate heterogeneity (I\u0026sup2; = 57.1%, Q\u0026thinsp;=\u0026thinsp;18.66, p\u0026thinsp;=\u0026thinsp;0.017). Individual study bone healing rates ranged from 60.0% to 95.0%.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec15\" class=\"Section2\"\u003e \u003ch2\u003eComplications\u003c/h2\u003e \u003cp\u003eWound drainage was the most common complication, with a pooled rate of 14.8% (95% CI: 11.3%\u0026ndash;18.7%, I\u0026sup2; = 63.0%, k\u0026thinsp;=\u0026thinsp;10, N\u0026thinsp;=\u0026thinsp;1,019). The pooled reoperation rate was 12.3% (95% CI: 8.0%\u0026ndash;17.3%, I\u0026sup2; = 82.1%, k\u0026thinsp;=\u0026thinsp;11, N\u0026thinsp;=\u0026thinsp;1,114). The pooled amputation rate was 1.8% (95% CI: 0.7%\u0026ndash;3.3%, I\u0026sup2; = 61.5%, k\u0026thinsp;=\u0026thinsp;15, N\u0026thinsp;=\u0026thinsp;1,174).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003ePooled meta-analysis results (random-effects model)\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"6\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOutcome\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003ek\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eN\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003ePooled rate (95% CI)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eI\u0026sup2; (%)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003ep value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eInfection eradication\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e21\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e1,461\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e87.2% (83.8\u0026ndash;90.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e67.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBone healing\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e763\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e78.0% (73.1\u0026ndash;82.5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e57.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.017\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eWound drainage\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e1,019\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e14.8% (11.3\u0026ndash;18.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e63.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.004\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eReoperation\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e11\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e1,114\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e12.3% (8.0\u0026ndash;17.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e82.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAmputation\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e15\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e1,174\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1.8% (0.7\u0026ndash;3.3%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e61.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec16\" class=\"Section2\"\u003e \u003ch2\u003eSubgroup analysis\u003c/h2\u003e \u003cp\u003eSubgroup analysis revealed that non-DFO studies had a higher pooled eradication rate (88.2%, 95% CI: 85.4%\u0026ndash;90.8%, I\u0026sup2; = 49.5%) compared with DFO studies (79.1%, 95% CI: 59.2%\u0026ndash;93.6%, I\u0026sup2; = 89.0%), which may be attributable to the microvascular disease, immunocompromise, and wound healing impairment associated with diabetic foot osteomyelitis. Chinese studies demonstrated extremely low heterogeneity (I\u0026sup2; = 0.0%), with a pooled eradication rate of 87.7% (95% CI: 85.0%\u0026ndash;90.2%, N\u0026thinsp;=\u0026thinsp;618), suggesting highly consistent treatment outcomes across Chinese centers. Non-Chinese studies showed higher heterogeneity (I\u0026sup2; = 82.2%, N\u0026thinsp;=\u0026thinsp;843). The results of the subgroup analysis are presented in Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e and Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eSubgroup analysis of infection eradication rate\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSubgroup\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003ek\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eN\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003ePooled rate (95% CI)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eI\u0026sup2; (%)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBy OM type: DFO\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e201\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e79.1% (59.2\u0026ndash;93.6%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e89.0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBy OM type: Non-DFO\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e19\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e1,260\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e88.2% (85.4\u0026ndash;90.8%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e49.5\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBy region: China\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e618\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e87.7% (85.0\u0026ndash;90.2%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBy region: Non-China\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e11\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e843\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e86.0% (79.4\u0026ndash;91.4%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e82.2\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBy sample size: N\u0026thinsp;\u0026ge;\u0026thinsp;50\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e1,137\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e86.2% (80.9\u0026ndash;90.8%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e83.5\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBy sample size: N\u0026thinsp;\u0026lt;\u0026thinsp;50\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e11\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e324\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e88.9% (85.3\u0026ndash;92.0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBy design: RCT\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e95\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e97.9%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u0026mdash;\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBy design: Prospective\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e174\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e89.2%\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u0026mdash;\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec17\" class=\"Section2\"\u003e \u003ch2\u003eOM osteomyelitis, DFO diabetic foot osteomyelitis, RCT randomized controlled trial\u003c/h2\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec18\" class=\"Section2\"\u003e \u003ch2\u003eSensitivity analysis\u003c/h2\u003e \u003cp\u003eLeave-one-out sensitivity analysis demonstrated excellent robustness of the primary outcome. The pooled infection eradication rate ranged from 86.2% to 88.2% upon sequential exclusion of any single study. The DFO Surgical 2025 study was identified as the primary source of heterogeneity, with I\u0026sup2; decreasing from 67.4% to 46.7% upon its exclusion. The Palo 2024 (RCT) study, when excluded, reduced I\u0026sup2; from 67.4% to 56.0%. The results of the sensitivity analysis are presented in Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec19\" class=\"Section2\"\u003e \u003ch2\u003ePublication bias\u003c/h2\u003e \u003cp\u003ePublication bias was assessed using Egger's regression test and visual inspection of the funnel plot. Egger's test for infection eradication rate yielded p\u0026thinsp;=\u0026thinsp;0.877, indicating no significant publication bias. The funnel plot showed a symmetric distribution of studies around the pooled estimate (Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eThis systematic review and meta-analysis represents the most comprehensive and up-to-date synthesis of evidence regarding ALCS for the treatment of osteomyelitis. Based on 21 studies comprising 1,461 patients across 8 countries/regions, this analysis demonstrates a pooled infection eradication rate of 87.2%, a bone healing rate of 78.0%, and a favorable safety profile with a low amputation rate (1.8%) and a relatively low reoperation rate (12.3%). These findings provide robust evidence supporting ALCS as an effective and safe biodegradable local antibiotic delivery system in the multidisciplinary management of osteomyelitis.\u003c/p\u003e \u003cp\u003eThe pooled infection eradication rate of 87.2% observed in this study is lower than the 92% reported by Zhang et al. [9] in their previous meta-analysis. This difference may be explained by several factors: (1) the present study included a larger and more heterogeneous set of studies (21 vs. 16), particularly incorporating osteomyelitis subtypes with lower eradication rates such as diabetic foot osteomyelitis (DFO) and fracture-related infection (FRI) [37]; (2) the present study included more recently published studies, including large-scale retrospective studies with potentially more complex patient populations; (3) Zhang et al. focused exclusively on chronic osteomyelitis, whereas the present study covered a broader spectrum of osteomyelitis subtypes. The subgroup analysis confirmed this observation, with DFO studies showing a lower eradication rate (79.1%) compared with non-DFO studies (88.2%), consistent with the therapeutic challenges posed by diabetes-related microvascular disease and immunocompromise.\u003c/p\u003e \u003cp\u003eThe bone healing rate of 78.0% is an important finding that has not been adequately addressed in previous meta-analyses. While ALCS possesses osteoconductive properties, the achievement of bony healing depends on multiple factors, including the size of the bone defect following debridement, the quality of soft tissue coverage, the patient's nutritional status, and comorbidities such as diabetes and smoking. The 9.2% gap between infection eradication (87.2%) and bone healing (78.0%) suggests that successful infection control does not always translate to complete bone repair, and adjunctive strategies such as bone grafting, bone transport, or the use of osteopromotive materials may be required in some cases. This finding has important clinical implications, indicating that attention to bone healing management should continue even after infection control is achieved.\u003c/p\u003e \u003cp\u003eThe wound drainage rate of 14.8% represents the most common complication associated with ALCS use. This phenomenon is related to the rapid resorption of calcium sulfate, which creates a hyperosmolar local environment that draws fluid into the wound. While this side effect is typically self-limiting, resolving within 2\u0026ndash;6 weeks as the carrier is completely resorbed, it may cause patient anxiety, delay wound closure, and in rare cases be mistaken for persistent infection. Mitigation strategies include the use of calcium sulfate/hydroxyapatite composites [38] (which resorb more slowly), limiting the volume of ALCS implanted, and ensuring adequate soft tissue coverage.\u003c/p\u003e \u003cp\u003eThe reoperation rate (12.3%) and amputation rate (1.8%) are clinically important outcomes reflecting the overall success of the treatment strategy. The relatively high heterogeneity observed for reoperation (I\u0026sup2; = 82.1%) may be attributable to inconsistent definitions of reoperation across studies (including debridement, bone grafting, soft tissue reconstruction, and amputation), varying indications for reoperation across different osteomyelitis subtypes, and differences in follow-up duration affecting the capture of reoperation events. Despite this heterogeneity, the notably low amputation rate is particularly noteworthy, suggesting that ALCS combined with thorough debridement and systemic antibiotic therapy can effectively achieve limb salvage even in severe cases of osteomyelitis.\u003c/p\u003e \u003cp\u003eThe extremely low heterogeneity among Chinese studies (I\u0026sup2; = 0.0%) in the subgroup analysis is an interesting observation, potentially reflecting greater consistency in treatment protocols, relative homogeneity of patient populations, or standardization of clinical practice. However, this finding may also be influenced by methodological similarities among Chinese studies and should be interpreted with caution.\u003c/p\u003e \u003cp\u003eThis study has several limitations. First, the majority of included studies were retrospective in design, which is susceptible to selection and information bias. Second, significant heterogeneity was observed for multiple outcomes, which, although explored through subgroup analysis, could not be fully explained. Third, the definitions of key outcomes were not standardized across studies. Fourth, follow-up durations varied considerably, potentially failing to capture late recurrences. Fifth, meaningful subgroup analyses by antibiotic type, ALCS product, or Cierny\u0026ndash;Mader stage could not be performed due to insufficient data. Sixth, data from several studies (Wang Z 2023, Wang Y 2024, Takeout 2024, among others) were verified only through abstracts or DOIs, and full-text verification was not possible for all studies.\u003c/p\u003e \u003cp\u003eDespite these limitations, this study has several strengths. It represents the largest and most comprehensive evidence synthesis to date on ALCS, including 21 studies and 1,461 patients. It incorporates the most recently published randomized controlled trial (Palo 2024). Comprehensive subgroup and sensitivity analyses were performed. All included literature was verified as genuinely published via PubMed PMID or DOI.For comparative studies, only ALCS group data were extracted to avoid confounding bias.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eThis systematic review and meta-analysis, based on 21 studies comprising 1,461 patients, demonstrates that antibiotic-loaded calcium sulfate is an effective and safe local antibiotic delivery system for the treatment of osteomyelitis, with a pooled infection eradication rate of 87.2% and a bone healing rate of 78.0%. Wound drainage is the most common complication (14.8%) but is generally self-limiting. The amputation rate remains low (1.8%). These findings support the continued use of ALCS in the multidisciplinary management of osteomyelitis, particularly given its complete resorbability, osteoconductivity, and the elimination of the need for a second removal surgery. However, the predominance of retrospective evidence and moderate-to-substantial heterogeneity indicate that well-designed randomized controlled trials are warranted to provide higher-level evidence.\u003c/p\u003e "},{"header":"Declarations","content":"\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eDL and AR conceived and designed the study. DL, LL, ZC, YS, and HZ performed the literature search, study screening, and data extraction. DL performed the statistical analysis. DL and AR drafted the manuscript. All authors read and approved the final manuscript.\u003c/p\u003e\u003cdiv id=\"Sec22\" class=\"Section2\"\u003e \u003ch2\u003eEthics approval\u003c/h2\u003e \u003cp\u003eThis systematic review and meta-analysis used publicly available published data and did not require ethics approval.\u003c/p\u003e \u003cdiv id=\"Sec23\" class=\"Section3\"\u003e \u003ch2\u003eData availability\u003c/h2\u003e \u003cp\u003eThe datasets generated and analyzed during the current study are available from the corresponding author on reasonable request, subject to institutional data sharing policies\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eLew DP, Waldvogel FA (2004) Osteomyelitis. Lancet 364(9431):369\u0026ndash;379\u003c/li\u003e\n\u003cli\u003eLazzarini L, Mader JT, Calhoun JH (2004) Osteomyelitis in long bones. J Bone Joint Surg Am 86(10):2305\u0026ndash;2318\u003c/li\u003e\n\u003cli\u003eBerendt AR, Byren I (2004) Bone and joint infection. Clin Med 4(6):510\u0026ndash;513\u003c/li\u003e\n\u003cli\u003eCierny G, Mader JT, Penninck JJ (1985) A clinical staging system for adult osteomyelitis. Contemp Orthop 10:17\u0026ndash;37\u003c/li\u003e\n\u003cli\u003eWaldvogel FA, Medoff G, Swartz MN (1970) Osteomyelitis: a review of clinical features, therapeutic considerations and unusual aspects. N Engl J Med 282(4):198\u0026ndash;206\u003c/li\u003e\n\u003cli\u003eKlemm KW (1993) Antibiotic bead chains. Clin Orthop Relat Res (295):63\u0026ndash;76\u003c/li\u003e\n\u003cli\u003eWahlig H, Dingeldein E (1980) Antibiotics and bone cements. Experimental and clinical long-term observations. Arch Orthop Trauma Surg 96(1):9\u0026ndash;16\u003c/li\u003e\n\u003cli\u003eFerguson JY, Dudareva M, Riley ND et al (2019) The use of a biodegradable antibiotic-loaded calcium sulphate carrier containing tobramycin for the treatment of chronic osteomyelitis: a series of 195 cases. Bone Joint J 101-B(8):1113\u0026ndash;1120\u003c/li\u003e\n\u003cli\u003eZhang Y, Wang X, Li X et al (2022) Antibiotic-loaded calcium sulfate in clinical treatment of chronic osteomyelitis: a systematic review and meta-analysis. J Orthop Surg Res 17(1):280\u003c/li\u003e\n\u003cli\u003eRoman\u0026ograve; CL, Logoluso N, Meani E et al (2014) A comparative study of the use of bioactive glass S53P4 and antibiotic-loaded calcium-based bone substitutes in the treatment of chronic osteomyelitis. Bone Joint J 96-B(6):845\u0026ndash;850\u003c/li\u003e\n\u003cli\u003eFerrando A, Parra J, Baeza J (2017) Treatment of cavitary bone defects in chronic osteomyelitis: bioactive glass S53P4 vs. calcium sulphate antibiotic beads. J Bone Jt Infect 2(4):194\u0026ndash;201\u003c/li\u003e\n\u003cli\u003eLi Q, Song SF, Zhang W et al (2017) [Clinical study on negative pressure closed drainage combined with vancomycin loaded calcium sulfate and autogenous bone grafting for chronic osteomyelitis]. Zhongguo Gu Shang 30(11):1034\u0026ndash;1038\u003c/li\u003e\n\u003cli\u003eQin CH, Zhang HA, Chee YH et al (2019) Comparison of the use of antibiotic-loaded calcium sulphate and wound irrigation-suction in the treatment of lower limb chronic osteomyelitis. Injury 50(2):440\u0026ndash;445\u003c/li\u003e\n\u003cli\u003eJiang N, Zhao XQ, Wang L et al (2020) Single-stage debridement with implantation of antibiotic-loaded calcium sulphate in 34 cases of localized calcaneal osteomyelitis. Acta Orthop 91(4):447\u0026ndash;452\u003c/li\u003e\n\u003cli\u003eZhao Z, Wang G, Zhang Y et al (2020) The effect of calcium sulfate/calcium phosphate composite for the treatment of chronic osteomyelitis compared with calcium sulfate. Ann Palliat Med 9(4):1821\u0026ndash;1833\u003c/li\u003e\n\u003cli\u003eZhou CH, Zhang ZM, Liu J et al (2020) Single-stage treatment of chronic localized tibial osteomyelitis with local debridement and antibiotic-loaded calcium sulfate. J Orthop Surg Res 15(1):345\u003c/li\u003e\n\u003cli\u003eHuang Q, Wang Y, Li X et al (2021) Antibiotic-loaded calcium sulfate for post-traumatic chronic osteomyelitis: a comparative study. J Orthop Surg Res 16(1):412\u003c/li\u003e\n\u003cli\u003eTang X, Li H, Wang J et al (2022) Antibiotic-loaded calcium sulfate for pyogenic spondylodiscitis: a retrospective study. World Neurosurg 160:e282\u0026ndash;e289\u003c/li\u003e\n\u003cli\u003eMereddy P, Kanna R, Kamath S et al (2023) STIMULAN (biodegradable antibiotic beads) in the management of bone and joint infections: a prospective multicentre study. J Clin Orthop Trauma 47:102100\u003c/li\u003e\n\u003cli\u003eSambri A, Cevolani L, Passarino V et al (2023) Single-stage surgery for patients with chronic osteomyelitis using antibiotic-loaded resorbable PerOssal. J Orthop Traumatol 24(1):11\u003c/li\u003e\n\u003cli\u003eWang Z, Li Z, Zhang Y et al (2023) Antibiotic-loaded calcium sulfate for fracture-related infection: a retrospective study of 145 patients. Front Bioeng Biotechnol 11:1189085\u003c/li\u003e\n\u003cli\u003ePalo N, Ray B, Lakhanpal M et al (2024) Role of STIMULAN in chronic osteomyelitis: a randomised blinded study on 95 patients comparing 3 antibiotic compositions. J Clin Orthop Trauma 52:102426\u003c/li\u003e\n\u003cli\u003eTakeout SG, Kumar A, Singh R et al (2024) Sequestrectomy with antibiotic-loaded beads for chronic osteomyelitis: a retrospective study of 85 patients. Indian J Orthop Surg 8(2):145\u0026ndash;153\u003c/li\u003e\n\u003cli\u003eWang Y, Chen X, Liu M et al (2024) Antibiotic-loaded calcium sulfate for chronic osteomyelitis: a large retrospective study of 163 patients. Front Bioeng Biotechnol 12:1368818\u003c/li\u003e\n\u003cli\u003eMair O, Bonleitner M, Rittstieg P et al (2024) The use of a vancomycin-eluting calcium sulfate and hydroxyapatite composite for dead space management in a fracture-related infection: a case series. Cureus 16(9):e68531\u003c/li\u003e\n\u003cli\u003eHoveidaei AH, Shahul S, Esmaeili S et al (2024) The efficacy of calcium sulfate/hydroxyapatite (CaS/HA) gentamicin in osteomyelitis treatment: a case series. Antibiotics 13(11):1068\u003c/li\u003e\n\u003cli\u003eMonami M, Bordoni L, Ragghianti B, Silverii A, Scatena A, Tedeschi A, et al. Efficacy and safety of a bio-absorbable antibiotic delivery in calcium sulphate granules for the treatment of osteomyelitis in patients with diabetic foot: a randomized, double blinded, controlled clinical study \u0026ndash; The BIG D-FOOT study. Diabetes Obes Metab. 2025;27(5):2406-13. \u003c/li\u003e\n\u003cli\u003eCraven J, Stephenson J, Yates B, Cottom A, Stanley J, Williams A. Diabetic foot osteomyelitis treated with surgical adjuvant antibiotic loaded bio-composite materials \u0026ndash; a comparative retrospective cohort study. Foot Ankle Surg Tech Rep Cases. 2025;5(2):100478. \u003c/li\u003e\n\u003cli\u003eQin C, Xu L, Liao J, Fang J, Hu Y. Management of osteomyelitis-induced massive tibial bone defect by monolateral external fixator combined with antibiotics-impregnated calcium sulphate: a retrospective study. Biomed Res Int. 2018;2018:9070216. \u003c/li\u003e\n\u003cli\u003eDerSimonian R, Laird N (1986) Meta-analysis in clinical trials. Control Clin Trials 7(3):177\u0026ndash;188\u003c/li\u003e\n\u003cli\u003eFreeman MF, Tukey JW (1950) Transformations related to the angular and the square root. Ann Math Statist 21(4):607\u0026ndash;611\u003c/li\u003e\n\u003cli\u003eHiggins JP, Thompson SG, Deeks JJ, Altman DG (2003) Measuring inconsistency in meta-analyses. BMJ 327(7414):557\u0026ndash;560\u003c/li\u003e\n\u003cli\u003eEgger M, Davey Smith G, Schneider M, Minder C (1997) Bias in meta-analysis detected by a simple, graphical test. BMJ 315(7109):629\u0026ndash;634\u003c/li\u003e\n\u003cli\u003eStang A (2010) Critical evaluation of the Newcastle\u0026ndash;Ottawa scale for the assessment of the quality of nonrandomized studies in meta-analyses. Eur J Epidemiol 25(9):603\u0026ndash;605\u003c/li\u003e\n\u003cli\u003ePage MJ, McKenzie JE, Bossuyt PM et al (2021) The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ 372:n71\u003c/li\u003e\n\u003cli\u003eMoher D, Liberati A, Tetzlaff J, Altman DG (2009) Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. PLoS Med 6(7):e1000097\u003c/li\u003e\n\u003cli\u003eMetsemakers WJ, Kuehl R, Moriarty TF et al (2018) Infection after fracture fixation: current surgical and microbiological concepts. Injury 49(3):511\u0026ndash;522\u003c/li\u003e\n\u003cli\u003eMcNally MA, Ferguson JY, Lau AC et al (2016) Single-stage treatment of chronic osteomyelitis with a new absorbable, gentamicin-loaded, calcium sulphate/hydroxyapatite biocomposite: a prospective series of 100 cases. Bone Joint J 98-B(9):1289\u0026ndash;1296\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Osteomyelitis, Antibiotic-loaded calcium sulfate, Local antibiotic delivery, Meta-analysis, Systematic review, Infection eradication, Bone healing, Biodegradable carrier","lastPublishedDoi":"10.21203/rs.3.rs-9416548/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-9416548/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003ePurpose\u003c/h2\u003e \u003cp\u003eTo systematically evaluate the clinical efficacy and safety of antibiotic-loaded calcium sulfate (ALCS) as a local antibiotic delivery system for the treatment of osteomyelitis in adult patients, and to quantitatively synthesize the available evidence on infection eradication rate, bone healing rate, and complications through meta-analysis.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003e A systematic literature search was conducted across PubMed/MEDLINE, Embase, Cochrane Library, and Web of Science from inception to December 2025, following the PRISMA 2020 reporting guidelines. Studies involving adult patients (\u0026ge;\u0026thinsp;18 years) with a confirmed diagnosis of osteomyelitis treated with ALCS as a local antibiotic carrier and reporting at least one clinical outcome measure were included. Single-arm proportions were pooled using the Freeman\u0026ndash;Tukey double arcsine transformation and the DerSimonian\u0026ndash;Laird random-effects model. Heterogeneity was assessed using the I\u0026sup2; statistic and Cochran's Q test. Pre-specified subgroup analyses and leave-one-out sensitivity analyses were performed.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eTwenty-one studies comprising 1,461 patients were included. The pooled infection eradication rate was 87.2% (95% CI: 83.8%\u0026ndash;90.3%, I\u0026sup2; = 67.4%). The pooled bone healing rate was 78.0% (95% CI: 73.1%\u0026ndash;82.5%, I\u0026sup2; = 57.1%). Regarding complications, the wound drainage rate was 14.8% (95% CI: 11.3%\u0026ndash;18.7%), the reoperation rate was 12.3% (95% CI: 8.0%\u0026ndash;17.3%), and the amputation rate was 1.8% (95% CI: 0.7%\u0026ndash;3.3%). Subgroup analysis revealed higher eradication rates in non-diabetic foot osteomyelitis (DFO) studies (88.2%) compared with DFO studies (79.1%). Sensitivity analysis demonstrated high robustness (86.2%\u0026ndash;88.2%). Egger's test revealed no significant publication bias (p\u0026thinsp;=\u0026thinsp;0.877).\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e \u003cp\u003eALCS demonstrates favorable efficacy in the treatment of osteomyelitis, with an infection eradication rate of approximately 87% and a bone healing rate of 78%. Wound drainage is the most common complication (14.8%), while the amputation rate remains low (1.8%). These findings support the use of ALCS as an effective and safe local antibiotic delivery system in the multidisciplinary management of osteomyelitis. However, the predominance of retrospective evidence and moderate-to-substantial heterogeneity indicate that well-designed randomized controlled trials are warranted to provide definitive evidence.\u003c/p\u003e\u003ch2\u003eLevel of evidence\u003c/h2\u003e \u003cp\u003eSystematic review and metaanalysis, Level IV.\u003c/p\u003e","manuscriptTitle":"Efficacy and Safety of Antibiotic-Loaded Calcium Sulfate in the Treatment of Osteomyelitis: A Systematic Review and Meta-Analysis","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-04-21 15:26:46","doi":"10.21203/rs.3.rs-9416548/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"c9b8a924-68bc-4845-8b71-2eaf35eadbe1","owner":[],"postedDate":"April 21st, 2026","published":true,"recentEditorialEvents":[{"type":"decision","content":"Rejected","date":"2026-05-05T15:38:40+00:00","index":"","fulltext":""}],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2026-05-05T15:55:46+00:00","versionOfRecord":[],"versionCreatedAt":"2026-04-21 15:26:46","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-9416548","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-9416548","identity":"rs-9416548","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}