- Systematic review
- Open Access
Antibiotic-loaded calcium sulfate in clinical treatment of chronic osteomyelitis: a systematic review and meta-analysis
Journal of Orthopaedic Surgery and Research volume 17, Article number: 104 (2022)
Present work was aimed to gather accessible evidence on the eradication rates and related postoperative complications of antibiotic-loaded calcium sulfate (CS) as an implant in the treatment of chronic osteomyelitis (COM).
Databases including PubMed, EMBASE, Medline, Ovid and Cochrane library were searched from their dates of initiation until November 2021. Two independent authors scrutinized the relevant studies based on the effectiveness of radical debridement combined with antibiotic-loaded CS for COM; data extraction and quality assessment of the Methodological Index for Non-Randomized Studies (MINORS) criteria were also performed by the authors. In addition, clinical efficacy mainly depended on the evaluation of eradication rates and complications, and all the extracted data are pooled and analyzed by STATA 16.0.
A total of 16 studies with 917 patients (920 locations) were recruited, with an overall eradication rate of 92%. Moreover, the overall reoperation rate, overall refracture rate, overall delayed wound healing rate, and the rate of aseptic wound leakage were 9.0%, 2.0%, 20.0%, and 12.0%, respectively. Moreover, the choice of tobramycin-loaded CS or vancomycin combined with gentamicin-loaded CS did not affect the eradication rate, and the incidence of postoperative complications in COM patients (all \(P>0.05\)). The general quality of the included studies was fair.
Our meta-analysis indicated that the overall eradication rate of COM treated with antibiotic-loaded CS was 92%. Delayed healing is the most common postoperative complication. The choice of tobramycin-loaded CS or vancomycin combined with gentamicin-loaded CS did not affect the eradication rate and the incidence of postoperative complications in COM patients.
Chronic osteomyelitis (COM) is defined as a significant and long-standing infection of bone tissue, which lasting more than several months or even years and involved in any bone including periosteum, bone marrow and surrounding tissue. Most infections occur after trauma, surgery or secondary to vascular and neurologic insufficiency (e.g. diabetic foot ulcers), characterized by persistent bacteria, low-grade inflammation, and the prevalence of fistula and dead bone [1, 2]. With the improvement of diagnosis and population aging, COM incidence has apparently increased [3, 4]. In 2004, nearly 600,000 artificial joint replacements and 2 million internal fixation of fracture caused more than 110,000 infections finally in the USA . According to related research estimation, the treatment of implant-related COM will cost $1.62 billion by 2020 in US hospitals, and impose a substantial financial burden on patients and society . Furthermore, infected chronic diabetic foot ulcers may lead to diabetic foot osteomyelitis, which will increase the mortality and risk of amputation [7, 8]. The recurrent and persistent infection is a challenging condition for both the physician and the patient.
The mainstays of COM treatment are radical debridement, then supplemented with targeted antimicrobial therapy (local and/or systemic) for long time. A recent study suggested that the combination of antibiotics and surgery seems to be more effective than any single method ; despite these measures, infection recurred in 20% patients . Due to the vascular injury in infected bone, it is difficult to achieve effective local antibiotic concentration by oral or intravenous antibiotic treatment under local ischemia; and the limited biofilm penetration makes the treatment of COM more difficult [1, 11, 12]. Therefore, the focus of antibiotic therapy is to use the local drug delivery system to avoid the potential toxicity caused by systemic administration, while providing a sustained high concentration at the infection site . It is very important for the long-term treatment of osteomyelitis, especially for the relief of symptoms .
Calcium sulfate (CS) is a kind of biodegradable material with low immunoreactivity, easy reabsorption and good tolerance, which has been proved to be effective and safe as an antibiotic carrier in the past two decades [15,16,17,18]. CS is as effective as polymethyl methacrylate (PMMA) as an antibiotic carrier in bone infections . However, Chang et al.  compared the efficacy of debridement plus CS combined with tobramycin and simple debridement, the results showed that the curative effect was not obvious, and the success rate of bone osteomyelitis was 80% and 60%, respectively. In terms of complications, several experiments indicated that CS products have transient cytotoxicity, leading to inflammation, within the first 60 days after implantation, CS causes inflammation in the surrounding tissue. After 60 days, the inflammation in the affected bone subsided, but the inflammation in the surrounding soft tissue did not subside, and the problem of surgical wound healing followed . Due to the inconsistency on the properties of CS materials and surgical procedures, aseptic wound leakage and re-fracture have gradually got increasing attention, which may become the causes of reoperation or infection recurrence . Jiang et al.  found that the incidence of aseptic wound leakage after antibiotic-loaded CS implantation treated COM was very high. Therefore, in this review, we comprehensively evaluate the efficacy and complications of CS loaded with multiple antibiotics in the treatment of COM (including delayed healing, reoperation, refracture and aseptic wound leakage). Another controversial issue is the efficacy of different antibiotic-loaded CS. The most common antibiotics used with CS are tobramycin and vancomycin, the former effectively reduces the chance of prosthetic infection and prevents biofilm formation and colonization of bacteria such as Methicillin-resistant Staphylococcus aureus ; the latter combined with gentamicin can cover a broad spectrum of both gram-positive and gram-negative bacteria . At present, a variety of products have been sold in the market , and a number of clinical studies have been conducted; but it is still unclear whether there are differences in the efficacy and complications of different antibiotics in the treatment of COM.
The major purpose of this meta-analysis was to investigate the eradication rates and local complications of antibiotic-loaded CS in treating COM patients. Second, we explored difference of curative effect and related postoperative complications between two antibiotic regimens. To provide reference for orthopedic surgeons using antibiotic-loaded CS in the treatment of COM.
Material and methods
This study was presented in accordance with the PRISMA (Preferred Reporting Items for Meta-Analyses and Systematic Reviews) . The PRISMA checklist is in the additional file, and the flow diagram of literature screening process is shown in Fig. 1. Ethical approval was not required.
Online databases were used to identify eligible studies, we searched all articles in PubMed, EMBASE, Medline, Ovid and Cochrane Library up to November 2021. We also performed a supplementary search in the Ovid database to avoid missing articles. In addition, a manual search of references and similar documents of identified articles was also performed to determine potential relevance. Medical subject heading (MeSH) and Embase Tree tool (EMTREE) were used to guide the choice of appropriate search terms in all databases. We performed a search using the strategy (“osteomyelitis” OR “osteitis” OR “bone infection” OR “osteoarticular infection”) AND (“calcium sulfate” OR “calcium sulphate”). The last search was performed on November 15, 2021.
The study selection criteria were established in accordance with the PICOS strategy (Patients, Intervention, Comparison, Outcomes, Study design): population—Patients with COM who underwent radical debridement and antibiotic-loaded CS; intervention—Operation with antibiotic-loaded calcium sulfate(including tobramycin, vancomycin and gentamicin); comparison—none; outcomes—Eradication rate and complications of failure, including reoperation, refracture, and delayed healing; study design—consecutive case–control studies or case series. Several eligibility criteria were applied in the present study. Only case series and consecutive case–control studies regarding the clinical application of antibiotic-loaded CS in the treatment of COM were eligible for inclusion, case reports, review articles, meta-analysis, animal researches, or unpublished studies were excluded. Articles written in a language other than English or German were excluded. Publication, studies involving patients with COM due to any causative mechanism except diabetic ulcer were eligible for inclusion. In order to be included, each eligible report had to contain at least one of the outcomes of interest. The main outcome of interest was eradication rates of infection, but studies that described postoperative local complications (wound-healing problems, aseptic wound leakage, etc.) were also eligible for inclusion. Patient selection was not restricted by age, gender, or other personal characteristics.
All the identified studies were selected according to the title and abstract by two independent authors (XW.S. and YP.W.). Extracted data were performed by 2 other authors independently (NH.N. and MJ.L.) and they screened articles with potential relevance through overall assessment based on the inclusion and exclusion criteria. The extracted data was summarized into a table, divided into three parts: (1) specific information of eligibility studies, including the authors’ names, year of publication, region of research, and study design; (2) basic information of each case, including age, total number of cases and gender, follow-ups, treatment, bacterial culture and application of antibiotics; (3) postoperative condition of each patient including failure, refracture, reoperation, delayed wound healing, local complications and other adverse events. For studies with incomplete or unclear data, we attempted to contact the authors for details. If any disagreement existed, a third reviewer participated and reached consensus.
The Methodological Index for Non-Randomized Studies (MINORS) criteria was used to evaluate the quality of the included studies independently by two authors, which was established to assess the quality of comparative and noncomparative studies . The highest score is 24 for comparative studies and 16 for noncomparative studies. Specific rating criteria are as follows: in noncomparative studies, scores of 0–4 showed to very low quality, 5–7 showed to low quality, 8–12 showed to fair quality, and ≥ 13 showed to high quality; in comparative studies, scores of 0–6 showed to very low quality, 7–10 showed to low quality, 11–15 showed to fair quality, and ≥ 16 showed to high quality.
Stata 16.0 was used to pool the all results of the included studies were for the meta-analysis. A chi-squared-based Q statistical test was used to estimate the statistical heterogeneity. The degree of heterogeneity for each included study was quantified using the I2 statistic. When P > 0.1 and/or I2 < 50%, the heterogeneity was evaluated to be low, and a fixed-effects model was used for the meta-analysis. Otherwise, a random-effects model was used. We calculated the postoperative eradication rates and incidences of complications in COM patients, as well as its 95% confidence interval (CI) for each study. Further, the pooled rates were calculated and publication bias was evaluated with a funnel plot. All results are presented in the form of forest plots and tables, and P < 0.05 was considered statistically significant.
Initially, 816 articles were identified by searching, and two authors selected 162 studies by reading the title and abstract. Finally, through scrutinizing the full text and performing a manual search, a total of 16 articles conforming to requirements were included in our study. The implants used in one study  were self-configured. After careful research and discussion, we decided to include this study because it had a large sample size and a long follow-up period, which provided specific information on the configuration of antibiotics-loaded CS. In addition, there were two studies [29, 30] from the same medical center at different times, but after careful comparison with the inclusive information of patients, we found that duplicate patients were not included, so we considered including these studies. We also contacted the author for more detailed patient information for comparison.
All the included 16 studies were published between 2002 and 2021 [15, 23, 25, 29,30,31,32,33,34,35,36,37,38,39,40,41]. Of the included studies, three consecutive case–control studies were retrospective in nature; the remaining were case series, including 2 prospective studies and 11 retrospective studies. Of the 16 publications, 7 were from China, 2 were from USA, 2 was from UK, and Germany, France, Spain, Italy, and Egypt each account for one case. The implants used in these studies included vancomycin, gentamicin-impregnated CS and tobramycin-impregnated CS. After the antibiotics-loaded CS was implanted, different surgical methods were performed according to the situation, including external fixation, skin or muscle flap transplantation, and skin grafting. Moreover, all the COM patients met the diagnostic criteria: obvious local symptoms, changes in imaging examination, and elevated inflammatory markers. Table 1 lists the COM patients’ characteristics in this meta-analysi s.
The data were extracted and evaluated independently by two authors from the included studies. For 8 noncomparative studies, the results showed that average MINORS score was 8.5 (range from 6 to 13), suggesting fair quality. The remaining two comparative studies had scores of 14 and 15, both suggesting fair quality. Overall, the methodological quality of the included studies was moderate (Table 2).
Rates of infectious eradication and complications
Our analysis showed that the infectious eradication rate among 717 patients (720 locations) receiving antibiotic-loaded calcium sulfate implantation was 92% reported by 16 studies (95% CI 0.89–0.95; P = 0.07), a random-effects model was used due to the low level of heterogeneity (I2 = 36.57%) (Fig. 2). A fixed effects model was used due to no heterogeneity (I2 = 23.96%), and the refracture rate was 2% in 9 studies (95% CI 0.00–0.04; P = 0.23) (Fig. 3). A random-effects model was used due to the low level of heterogeneity (I2 = 46.51%), and the reoperation rate was 9% reported by 15 studies that enrolled 827 cases4 (95% CI 0.05–0.13; P = 0.02) (Fig. 4). A random-effects model was used due to the high level of heterogeneity (I2 = 81.63%), and the delayed healing rate was 20% reported by 14 studies that enrolled 815 cases (95% CI 0.13–0.29; P = 0.001) (Fig. 5). A random-effects model was used due to the high level of heterogeneity (I2 = 92.91%), and the incidence of aseptic mouth leakage was 12% reported by 14 studies that enrolled 794 cases (95% CI 0.03–0.25; P = 0.001) (Fig. 6).
Among the 16 articles we included, we excluded one study that did not specify the location of COM . The tibia was the most commonly affected part of COM and was detected in 46.73% of patients with COM (279/597). The second and third most common locations of COM were femur (139/597, 23.28%) and calcaneum (74/597, 12.40%), respectively. The remaining locations of COM included humerus (21/597, 3.52%), radius (12/597, 2.01%), pelvis (7/597,1.17%), fibula (7/597, 1.17%), ankle (6/597, 1.01%), hip joint (5/597, 0.84%), ulna (5/597, 0.84%), knee (4/597, 0.67%), talus (3/597, 0.50%), clavicle, forefoot, and fourth metatarsal each account for one case (1/597, 0.17%). A several COM patients had two involved locations [33, 37].
Effects and complications of subgroup
In order to further explore the difference between the two kinds of antibiotics in the treatment of COM, the eradication rate and complications were summarized. However, the results showed that the eradication rates of tobramycin-loaded CS group and vancomycin combined with gentamicin-loaded CS group were 92% (95% CI 0.88–0.95; P = 0.9) and 90% (95% CI 0.86–0.94; P = 0.03), respectively, and there was no significant difference (P = 0.96). In terms of the incidence of complications, the reoperation rates of tobramycin-loaded CS and vancomycin combined with gentamicin-loaded CS were 7% (95% CI 0.04–0.10; P = 0.3) and 11% (95% CI 0.86–0.94; P = 0.03), the aseptic wound leakage rates were 24% (95% CI 0.11–0.38; P = 0.06) and 26% (95% CI 0.05–0.46; P = 0.001), the bone fracture rates were 5% (95% CI 0.02–0.08; P = 0.5) and 5% (95% CI 0.01–0.09%; P = 0.9), the incidence of delayed healing rates were 34% (95% CI 0.14–0.28; P = 0.001) and 17% (95% CI 0.13–0.55; P = 0.001), respectively. The results showed no significant difference (all P > 0.05) (Table 3).
A funnel chart would reflect whether there was publication bias in this study, and the symmetry of the funnel chart meant that there was no publication bias (Fig. 7). Furthermore, the symmetry test of the above graph showed that P = 0.882 > 0.05, which meant that the funnel graph was symmetrical. Therefore, it can be judged that there was no publication bias in current study.
We eliminated each included study one by one, and summarized and analyzed the remaining studies to assess whether the individual study had an impact on the results of the meta-analysis. None of the studies had an excessive impact on the results of the meta-analysis, indicating that the results of the remaining studies were stable and reliable (Fig. 8).
CS was discovered in 1970 until it was used clinically in the past two decades, and achieved good results in Europe . However, no research reported the specific efficacy of CS antibiotic delivery system in the treatment of patients with COM. In the current study, 16 studies published from 2000 to 2021 were included, with a total of 717 patients (720 locations) with COM. To the best of our knowledge, this was the first study to investigate the eradication rate in patients with COM, and we concluded that the overall rate of eradication in COM patients was 92%. The eradication rate was also similar to those reported for treatment with antibiotic-loaded PMMA beads in the literature, which showed 60% and 100% in between [42, 43].
The successful eradication of COM remains a challenge for clinicians. Except for a study on chronic jaw osteomyelitis that did not specify the use of antibiotics , the treatment regimen in all 15 studies involving the antibiotics-loaded CS included implantation after radical debridement followed by adjuvant systemic administration of antibiotics. Statistically, the tibia is the most common site for COM to occur , This is similar to our summary study. Of the 597 patients with COM included, nearly half were tibial osteomyelitis, because of its poor blood supply (especially inferior third of tibia), higher risk of injuries, and of course, the inappropriate surgical managements. Unfortunately, even standard treatment protocols have been strictly implemented, the recurrent rate of chronic tibial osteomyelitis remains as high as 20–30% . Although we included 279 patients with tibial osteomyelitis, the recurrence of infection in each study was unable to determine whether it was on tibial or not, therefore made it difficult to calculate the recurrence rate of tibial osteomyelitis.
While infection elimination had shown encouraging results, associated local complications were also of concern. Delayed wound healing was the most frequent complication in our study, with a relatively high incidence of 20%. Bibbo et al.  reported that the delayed healing rate of calcium sulfate loaded with vancomycin in the treatment of calcaneal fractures was 15%, which was similar to our summary results. Kallala et al.  reported that aseptic wound leakage is a common complication of degradation of CS after implantation, which is related to the composition of CS itself, with an incidence of 4.2%, this incidence was variant with each individual, mainly depending on the size of implanted CS and the abundance of soft tissues coverage. Romano et al.  found that the leakage rate of aseptic wound was as high as 27%, while our total leakage rate of aseptic wound was 12%. This may be explained that some of the studies we included used different treatment methods after implantation of CS according to different conditions of patients, such as muscle flap coverage  or external fixation . On the other hand, it may also be attributed to the fact that synthetic CS contains no impurities compared with mined and refined CS. At present, there is no reliable large-sample comparative study to confirm the side effects of calcium sulfate-induced leakage of sterile wounds. In addition to the wound leakage, local CS implantation may also bring other complications, such as heterotopic ossification  and even hypercalcemia . Therefore we also pooled the refracture rate and the reoperation rate, which are 2% and 9%, respectively.
Antibiotic-loaded CS delivery system had been put into clinical application in the past 20 years, loaded with several of the most common antibiotics which made into a variety of products, such as vancomycin, gentamicin and tobramycin. However, the efficacy of calcium sulfate-loaded antibiotics in the treatment of COM is not clear. In an in vitro experiment, vancomycin and tobramycin impregnated materials had similar germicidal properties and elution efficiency . A systematic review shows that there may be no significant difference between CS and other products except for degradation time . The same was true for our subgroup results, we found that there was no significant difference in eradication rate between tobramycin loaded and vancomycin loaded with gentamicin calcium sulfate. However, there was no significant difference in the incidence of complications, including delayed healing rate, aseptic wound leakage rate, bone fracture rate and reoperation rate. That might be explained by different risk factors and patient individual variations.
Our study has some limitations. First, the sample size is not big enough and the summary of patient population characteristics is incomplete, which may hinder the interpretation of research results. Therefore, the results should be interpreted cautiously, and more patients should be enrolled in future studies to draw more precise conclusions. Second, we did not analyze the risk factors of infection relapse and complications because of most included studies’ retrospective design. To better identify potential risk factors, a good comparison of these antibiotics-loaded materials requires large-scale prospective clinical trials, especially multi-center joint studies; crucially, the potential risk of aseptic wound leakage after local CS implantation should be fully considered when patients receive this treatment. Future studies may focus on the risk factors of local complication and infection relapse following local CS implantation, as well as the efficacy of other substitute materials. Third, we all know that the release time and concentration of such antibiotic sustained-release systems are critical to the treatment of COM, but the studies we included lack a detailed description of the pharmacokinetics, which is not conducive to further compare the efficacy of several types of antibiotics. We should pay more attention to the clinical research on the species and drug resistance of COM bacteria in the future . Fourth, the studies included different sites of infection (femur, tibia, humerus, radius, ulna, pelvis, and even calcaneus) and four types of Cierny-Mader staging. Therefore, our research inevitably lacks an in-depth discussion of a single type and location of COM. More detailed data is useful for evaluation of the efficacy of antibiotic CS on different parts of COM in future.
In conclusion, this meta-analysis revealed that the eradication rate of implantation of antibiotic-loaded CS in the treatment of COM was as high as 92%, and the incidence of complications including delayed healing rate, aseptic wound leakage rate, refracture rate and reoperation rate were relatively low. Although there is no significant difference in efficacy and complications between the two antibiotic-loaded CS regimens in the treatment of COM. The clinical efficacy of antibiotic-loaded CS in the treatment of COM needs to be confirmed by further study.
Availability of data and materials
As a meta-analysis, all raw data of this study are extracted from ten included studies. The datasets supporting the conclusions of this article are available in the 16 included studies.
Population, intervention, comparison, outcomes, and study
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This study was funded by National Natural Science Foundation of China: the MIF-based WNT/p38 MAPK/NF-κB Signaling Loop Regulates Differentiation of Osteoblasts, Osteoclasts, and Coupling Under Inflammatory Conditions (81772367); on the Role and Mechanism of Bap/avβ/TLR-4 Signal Regulating Osteogenesis by Osteoblast in Osteomyelitis (82072392); Yunnan Traumatology and Orthopedics Clinical Medical Center (ZX20191001).
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Shi, X., Wu, Y., Ni, H. et al. Antibiotic-loaded calcium sulfate in clinical treatment of chronic osteomyelitis: a systematic review and meta-analysis. J Orthop Surg Res 17, 104 (2022). https://doi.org/10.1186/s13018-022-02980-2
- Chronic osteomyelitis
- Calcium sulfate