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The optimal adjunctive therapies for microfracture treatment of osteochondral lesions of the talus: a systematic review and network meta-analysis of randomized controlled trials

BMC Musculoskeletal Disorders volume 26, Article number: 375 (2025) Cite this article

Abstract

Background

This study systematically compares the efficacy of different adjunctive therapies in enhancing microfracture (MF) treatment for osteochondral lesions of the talus (OLT) through a network meta-analysis, aiming to identify the optimal adjunctive therapy for microfracture.

Methods

A systematic search of PubMed, Embase, Web of Science, Cochrane, and Scopus databases was conducted for relevant literature until October 1, 2024. Two researchers independently screened, extracted data, and assessed quality. The review process was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines.

Results

A total of six randomized controlled trials were included, comprising 295 OLT patients and involving four adjunctive therapies: MF combined with platelet-rich plasma (MF_PRP), hyaluronic acid (MF_HA), collagen scaffold (MF_CS), and pulsed electromagnetic fields (MF_PEMF). The results of the network meta-analysis indicated that while HA is the most commonly used adjunctive therapy, PRP-assisted MF demonstrated the best improvement in AOFAS and VAS scores for OLT. The surface under the cumulative ranking curve (SUCRA) predictions also revealed that PRP has the greatest potential among the four adjunctive therapies, followed by HA. Conversely, MF_PEMF showed the least effectiveness in improving AOFAS and VAS scores. Additionally, only one study reported complications associated with MF_PEMF and MF, with no statistically significant differences between the two.

Conclusion

Among the MF adjunctive therapies validated by RCTs, HA is the most widely used; however, PRP-assisted MF provides the best outcomes for OLT patients, suggesting that its application should be emphasized in clinical practice.

PROSPERO

Registration No: CRD42024546984.

Clinical trial details

Not applicable.

Peer Review reports

Background

Osteochondral lesions of the talus (OLT) have an incidence rate of up to 70% in cases of ankle sprains and fractures [1, 2]. The limited healing capacity of the talus is attributed to its sparse blood supply, the lack of intrinsic vascularization in articular cartilage, and low mitotic activity, which can lead to the progression of more severe osteoarthritis [3]. Currently, conservative treatment can yield satisfactory clinical and radiological outcomes for lesions with mild symptoms [4]. While conservative management may alleviate symptoms and slow the progression of the condition, it is fundamentally incapable of repairing cartilage damage [5]. Consequently, surgical options such as autologous or allogenic osteochondral grafting, autologous chondrocyte implantation, and marrow stimulation techniques have become the primary treatment choices for OLT [6, 7].

Microfracture, as a primary technique for marrow stimulation, involves perforating the subchondral bone to allow marrow cells to refill and repair cartilage defects. Due to its minimally invasive nature, simplicity operation, high safety profile, and cost-effectiveness, it is regarded as a first-line treatment strategy, particularly for OLT with an area of less than 150 square millimeters, where it remains the gold standard for surgical intervention [8, 9]. However, despite the short-term symptom relief provided by microfracture treatment, its long-term outcomes are less satisfactory. This is primarily because the repair tissue induced by microfracture is fibrocartilage rather than the original hyaline cartilage, resulting in inferior performance in terms of compressive strength, elasticity, and wear resistance [10,11,12]. Research by Ferkel et al. further corroborated this finding, revealing that 34% of OLT patients who underwent microfracture experienced cartilage deterioration five years post, with approximately one-third showing progression of degenerative changes in imaging studies, which may ultimately lead to arthritis [13].

Various adjunctive therapies, such as biological scaffolds [14], hyaluronic acid (HA) [15] platelet-rich plasma (PRP) [16], bone marrow aspirate concentrate [17], and mesenchymal stem cells (MSCs) [18], have been proposed to promote tissue proliferation and cartilage differentiation, thereby optimizing the quality of tissue repair following microfracture and significantly enhancing the effectiveness of microfracture treatment for OLT. However, it remains unclear which adjunctive therapy is the most effective, and results for the same therapy can vary widely across different studies. For instance, a randomized controlled trial (RCT) by Guney et al. [16] indicated that PRP could enhance the treatment effects of microfracture for OLT, while a meta-analysis encompassing seven clinical studies concluded that the improvement associated with PRP did not reach the minimal clinically important difference [19].

Although several meta-analyses have compared the effects of adjunctive therapies in enhancing microfracture treatment for OLT, these studies have notable limitations. Many rely on data from observational studies rather than RCTs, leading to limited evidence quality [20]. Additionally, these studies analyze post-follow-up data without considering the impact of baseline characteristics of patients within the same study or across different studies on the treatment effects of various interventions [20, 21]. Furthermore, existing research lacks a comprehensive comparison of multiple adjunctive therapies, thus limiting its practical guidance for clinical practice. Therefore, this study aims to conduct a network meta-analysis of current RCTs on adjunctive therapies to enhance microfracture treatment for OLT, exploring the optimal adjunctive therapy for microfracture and providing references for future clinical practice.

Materials and methods

Study guidelines and search strategy

This study adheres to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines [22] and has registered the research protocol with PROSPERO. We conducted a systematic search of the PubMed, Embase, Cochrane, Web of Science, and Scopus databases using keywords related to osteochondral lesions of the talus and microfracture, covering the time frame from the inception of each database until October 1, 2024. No language restrictions were applied during the search. A combination subject headings and free-text terms was utilized, adjusted according to the characteristics of each database; the specific search strategy is detailed in Supplementary Table 1. To avoid missing studies not explicitly labeled as RCTs in their titles and abstracts, we did not use “RCT” as a search term. Additionally, we manually reviewed the references of published articles to identify other studies that met the inclusion criteria.

Inclusion and exclusion criteria

Inclusion criteria were as follows: (1) subjects diagnosed with OLT due to any cause; (2) patients aged 18 years or older; (3) clinical follow-up duration of at least 6 months; (4) all patients underwent microfracture treatment; (5) at least one of the outcome measures, AOFAS or VAS, was reported and data were available; (6) the study was methodologically defined as an RCT, regardless of whether allocation concealment or blinding was implemented.

Exclusion criteria included: (1) studies that were observational, reviews, conference abstracts, case reports, letters, editorials, or other non-compliant types; (2) studies involving OLT with other severe comorbidities; (3) studies lacking the required outcome measures.

Literature screening, data extraction, and Bias risk assessment

Before literature screening, duplicate records were removed using Endnote X9.1 software. Two researchers independently reviewed the titles and abstracts of the literature to initially exclude those that clearly did not meet the inclusion criteria. For any discrepancies in the screening results, the researchers discussed the findings or sought arbitration from a third-party expert. After obtaining the full text of the studies that passed the initial screening, both researchers independently read and further assessed whether the studies met the inclusion criteria.

We designed a standardized data extraction form that included: (i) basic study information: authors, publication year, country of study; (ii) study population: sample size, patient age, gender, lesion size; (iii) interventions: microfracture and adjunctive therapies; (iv) outcome measures: clinical outcomes (AOFAS and VAS scores), follow-up duration; (v) safety data: incidence of adverse reactions or complications; (vi) key information for bias risk assessment: the Cochrane risk of bias assessment tool (RoB 2.0) recommended by the Cochrane Handbook 6.0 was used to evaluate the risk of bias in randomized controlled trials [23]. (vii) Key elements of evidence quality assessment involve the use of the GRADE system to classify the quality of evidence from included studies. This assessment is primarily based on five dimensions: risk of bias, inconsistency, imprecision, indirectness, and publication bias. Depending on the level of evidence, it is categorized into four quality levels: high quality (no downgrade), moderate quality (downgraded by one level), low quality (downgraded by two levels), and very low quality (downgraded by three levels) [24].

Statistical analysis

Network meta-analysis was performed using Stata 15.0 software [25]. For continuous variables, since the measurement tools and units for AOFAS and VAS are consistent, we used the weighted mean difference (WMD) as the effect size statistic, calculating the combined WMD and 95% confidence interval (CI). To mitigate the impact of differences in baseline characteristics of patients between studies or within studies on the outcomes of regenerative medicine therapies, we extracted pre-treatment and post-treatment data separately and calculated the change in outcomes attributable to treatment. We first conducted tests for consistency and inconsistency, ensuring that there was sufficient homogeneity, similarity, and consistency among the different studies. Subsequent analyses were performed only if the results of and indirect comparisons were consistent within acceptable limits. Otherwise, this study would only involve descriptive analysis without proceeding to a meta-analysis. Forest plots were employed to display the results of comparisons between groups. The surface under the cumulative ranking curve (SUCRA) was used to rank the efficacy of different interventions, with higher SUCRA values (ranging from 0 to 1) indicating a greater probability of that treatment being the best intervention [26]. Additionally, a comparison-adjusted funnel plot was utilized to assess the presence of publication bias and small sample effects [27].

Results

Overview of studies

A total of 849 articles were identified in the initial search, with 556 remaining after removing duplicates. The titles and abstracts of these articles underwent preliminary screening, and irrelevant studies were excluded based on predefined criteria. Subsequently, the selected articles were subjected to full-text review, focusing on evaluating study design, interventions, and outcome measures, ultimately including six RCTs [14,15,16, 28,29,30]. The PRISMA flow diagram is presented in Fig. 1.

Fig. 1
figure 1

PRISMA flow diagram

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The included studies involved a total of 295 patients with OLT, comprising 158 males and 137 females. The sample sizes ranged from 35 to 68 participants, with all patients having lesion diameters of less than 20 mm and an average age ranging from 32 to 42.8 years. All patients had a follow-up duration of over 9 months. The adjunctive therapies validated by RCTs for microfracture included platelet-rich plasma (PRP), hyaluronic acid (HA), collagen scaffold (CS), and pulsed electromagnetic fields (PEMF). Basic information about the included studies is detailed in Table 1.

Table 1 Basic information table
Full size table

Risk of bias assessment results

Among the six included RCTs, five employed computer-generated randomization or sealed envelope methods for patient allocation. Three studies implemented allocation concealment and employed blinding for both patients and researchers, while four studies also blinded the outcome assessors. One study reported a loss to follow-up of four patients post-surgery, but the number of lost patients did not exceed 20%. The remaining five studies did not report any loss to follow-up. Only two studies registered their protocols in clinical trial registries prior to the trials. No conflicts of interest were reported in any of the studies, as detailed in Fig. 2.

Fig. 2
figure 2

Risk of bias assessment results. (A. Assessment results for different items. B. Assessment results for each study.)

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Network meta-analysis results

This study initially performed tests for consistency and inconsistency on the AOFAS and VAS scores. The results indicated that all p-values were greater than 0.05, suggesting a high level of consistency in the current research. Based on this finding, we proceeded with further analyses.

All six studies reported AOFAS scores, and both direct and indirect comparisons demonstrated strong consistency, as detailed in Supplementary Table 2. The evidence network indicated that HA is the most commonly used adjunctive therapy in microfracture treatment (Fig. 3A). The results of the network meta-analysis demonstrated that MF_PRP had the best treatment effect, significantly improving AOFAS scores compared to MF, MF_CS, MF_HA, and MF_PEMF. Additionally, MF_HA also showed a significant improvement in AOFAS scores compared to MF. However, no statistically significant differences were observed among the other therapies (Low to moderate quality) (Fig. 3B). The SUCRA results predicted the effectiveness in improving AOFAS scores in the following order: MF_PRP > MF_HA > MF_CS > MF > MF_PEMF (Fig. 3C). Furthermore, the relatively symmetrical comparison-adjusted funnel plot suggested a low likelihood of publication bias and small sample effects in this study (Fig. 3D).

Fig. 3
figure 3

Analysis results for AOFAS. (A. Network Evidence Diagram. B. Network Meta-Analysis Results. C. SUCRA Results. D. Comparison-Adjusted Funnel Plot.)

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Regarding VAS scores, five studies provided reports and both direct and indirect comparisons demonstrated strong consistency, as detailed in Supplementary Table 2. The evidence network similarly indicated that HA is the most commonly used adjunctive therapy in microfracture treatment (Fig. 4A). The network meta-analysis results revealed that MF_PRP was the most effective in reducing VAS scores, significantly outperforming MF, MF_CS, MF_HA, and MF_PEMF. MF_HA also demonstrated a significant reduction in VAS scores compared to MF_PEMF, MF_CS, and MF, while MF showed a significant improvement over MF_PEMF. No statistically significant differences were found among the remaining therapies (Low to moderate quality) (Fig. 4B). The SUCRA results predicted the effectiveness in reducing VAS scores in the following order: MF_PRP > MF_HA > MF > MF_CS > MF_PEMF (Fig. 4C). Similarly, the relatively symmetrical comparison-adjusted funnel plot indicated a low likelihood of publication bias and small sample effects in this study (Fig. 4D).

Fig. 4
figure 4

Analysis results for VAS. (A. Network Evidence Diagram. B. Network Meta-Analysis Results. C. SUCRA Results. D. Comparison-Adjusted Funnel Plot.)

Full size image

Figure 5 presents the comprehensive predictive results for the improvement of AOFAS and VAS scores across different adjunctive therapies. Among the five therapies, MF_PRP exhibited the best effects in improving both AOFAS and VAS scores, followed by MF_HA, while MF_PEMF showed the least effectiveness in improving both scores. In terms of improving AOFAS scores, MF_CS was more effective than MF; however, for VAS scores, MF outperformed MF_CS.

Fig. 5
figure 5

SUCRA results for AOFAS and VAS scores. (The larger the value, the greater the improvement in the corresponding outcome measure.)

Full size image

Regarding complications, only one study reported adverse events in the MF_PEMF group, including dorsal foot sensory abnormalities and wound leakage, while patients in the MF group experienced nausea, delayed wound healing, and dorsal foot sensory abnormalities. However, the differences in complications between the two groups were not statistically significant [29]. Additionally, two studies reported no complications [14, 30], while three studies did not report outcome measures related to complications [15, 16, 28].

Discussion

This study comprehensively collected clinical studies on microfracture treatment for OLT and found that only four adjunctive therapies—PRP, HA, CS, and PEMF—have been validated through RCTs. Among these, PRP is regarded as an effective adjunctive treatment for microfracture surgery in OLT [16]. A previous meta-analysis based on RCTs indicated that PRP-assisted microfracture treatment is superior to microfracture treatment alone in improving AOFAS and VAS scores in patients with OLT [31]. This study also utilized RCTs and employed a network meta-analysis approach, integrating both direct and indirect comparison results. It was found that the treatment effect of MF_PRP was optimal for improving both AOFAS and VAS scores in OLT patients. However, the meta-analysis conducted by Boffa et al. on the seven included studies suggested that PRP has a beneficial effect on microfracture outcomes for both the knee and ankle joints. Nevertheless, this improvement did not reach the minimum clinically important difference [19]. The discrepancy may be attributed to Boffa et al. including not only randomized controlled trials but also observational studies in their analysis, which significantly undermined the reliability of the results and could be a primary reason for the contradiction with our findings. In fact, PRP can stimulate the migration of subchondral progenitor cells to the osteochondral lesion site, promoting the secretion of type II collagen and proteoglycans, thereby facilitating the differentiation of these progenitor cells into hyaline cartilage [32]. Research by Xie et al. [33] demonstrated that PRP stimulates synovial cells in articular cartilage to secrete metalloproteinases, regulating the synthesis and secretion of endogenous HA. Moreover, due to the autologous nature of PRP, it carries a very low risk of immune rejection and infection, with minimal likelihood of allergic reactions, making it a safe and reliable treatment option for OLT patients [34, 35]. It is noteworthy that studies focused on knee osteoarthritis have indicated that leukocyte-poor PRP therapy results in higher International Knee Documentation Committee (IKDC) scores for patients compared to leukocyte-rich PRP, suggesting it may be a superior treatment option [36, 37]. The preparation methods for PRP are diverse, encompassing both leukocyte-rich and leukocyte-poor variants, which exhibit significant differences in composition and biological activity. Existing research has shown that leukocyte-rich PRP may provoke inflammatory responses in certain cases, while leukocyte-poor PRP may be more conducive to cartilage repair [38]. Therefore, future studies should systematically evaluate the impact of different PRP preparation methods on the outcomes of microfracture treatment to determine which type of PRP is most effective under specific pathological conditions. Additionally, considering individual variability and the complexity of conditions, personalized PRP preparation protocols may emerge as an important direction for future research.

Although PRP demonstrates the best adjunctive treatment effects, HA, another commonly used biological agent, can also significantly enhance the outcomes of microfracture treatment. HA is produced by fibroblasts, synovial cells, and chondrocytes, and is a major component of synovial fluid and cartilage. It can inhibit the expression of matrix metalloproteinases mediated by interleukin-1β under inflammatory conditions [39], reduce the production of reactive oxygen species by the synovium, decrease chondrocyte apoptosis, and suppress inflammatory cytokines in a molecular weight-dependent manner [40, 41]. A meta-analysis by Boffa et al. found very low evidence supporting that HA treatment for OLT is more effective than placebo [42]. This study provides high-quality evidence based on RCTs, indicating that MF_HA treatment significantly outperforms MF alone, thereby strongly supporting the clinical application of HA.

Additionally, collagen scaffolds have been used as adjuncts in microfracture treatment; however, their design primarily focuses on supporting and carrying cells for cartilage regeneration, which limits their actual role in promoting chondrocyte regeneration [43]. Consequently, this study found that the treatment effect of MF_CS did not exceed that of MF. PEMF are considered adenosine A2a agonists that can promote the increase of transforming growth factor-β1, thereby improving cartilage injury [44]. However, a multicenter, randomized, double-blind, placebo-controlled clinical trial found no additional benefits of PEMF in the treatment of OLT with microfracture [29]. This study was also included in our network meta-analysis, which showed no significant statistical difference in treatment effects between MF_PEMF and MF, with SUCRA results predicting that the treatment effect of MF_PEMF is even lower than that of microfracture alone. Therefore, PEMF is not recommended as an adjunctive therapy for microfracture. Although current research indicates that the effects of PEMF in microfracture treatment are suboptimal, there remains significant potential for this therapy. The efficacy of PEMF may be influenced by various factors, including frequency, intensity, and duration of application. Specific frequencies or intensities of PEMF could positively affect the proliferation and differentiation of chondrocytes, thereby promoting cartilage regeneration. For instance, low-frequency PEMF may enhance cellular metabolic activity, while high-frequency PEMF might improve cartilage repair by stimulating cellular signaling pathways [45, 46]. Therefore, future studies should be designed to conduct clinical trials targeting different frequencies and intensities of PEMF to explore its potential benefits in microfracture treatment. In fact, aside from the four adjunctive therapies reported in this study, various other adjunctive therapies for microfracture, such as bone marrow aspirate concentrate, hydrogels, and MSCs, have been clinically attempted with some success, but there is a lack of rigorously designed RCTs to validate their safety and efficacy [47].

Limitations and Future Directions of This Study: (1) Due to insufficient reporting of complication data, this study cannot determine which adjunctive therapy is safer. Furthermore, the current research did not assess the impact on patients’ quality of life or conduct a cost-effectiveness analysis, both of which are crucial for evaluating the effectiveness of interventions and guiding specific clinical practices. These aspects require greater emphasis in future research. (2) The sample sizes of the six included studies were relatively small. Compared to larger samples, small-scale trials are more prone to overestimating treatment effects, and the limited number of studies results in low statistical power. Therefore, more high-quality, large-sample RCTs are needed to further investigate the relative effectiveness of different adjunctive therapies. Additionally, the limited follow-up duration in the current studies makes it difficult to assess long-term effects, which should be further explored in future research. The small number of studies and the limited information on different adjunctive therapies hinder our ability to obtain sufficient data for more in-depth subgroup analyses. (3) Some studies did not implement allocation concealment and blinding during the trial process, increasing the likelihood of selection bias. Most studies were unable to provide access to their study protocols, which may also lead to selective reporting of results, thereby affecting the reliability of the meta-analysis.

Conclusion

Various adjunctive therapies can enhance the efficacy of microfracture treatment for OLT, but currently, only PRP, HA, CS, and PEMF have been validated through RCTs. Although HA is the most commonly used adjunctive therapy, PRP-assisted microfracture shows the best outcomes in improving OLT, warranting greater attention in clinical practice. Future efforts should focus on further improving the composition of PRP to enhance its therapeutic efficacy. Additionally, it is essential to investigate the effectiveness and safety of PRP through larger-scale, high-quality multicenter RCTs.

Data availability

Data is provided within the manuscript or supplementary information files.

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Acknowledgements

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Funding

This research was funded by Xi’an City Innovation Ability Strong Base Plan (No. 22YXYJ0094).

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Authors and Affiliations

  1. Department of Foot and Ankle Surgery, Honghui Hospital Affiliated to Xi’an Jiaotong University, Xi’an, 710054, Shaanxi Province, China

    Taichao Ren, Jian Ma, Dong Hu, Liang Liu, Jun Lu & Bingbing Li

  2. Hospital of Northwestern Polytechnical University, Xi’an, 710054, Shaanxi Province, China

    Xiaoyan Wang

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  1. Taichao Ren
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  2. Xiaoyan Wang
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  3. Jian Ma
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  4. Dong Hu
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  7. Bingbing Li
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Contributions

T. Ren designed the study, collected and analyzed data, and drafted the manuscript. X. Wang conducted the literature search, data extraction, and provided revisions. J. Ma performed statistical analysis and assisted in writing. D. Hu contributed to literature screening and provided clinical insights. L. Liu coordinated the research efforts and contributed to the manuscript. J. Lu analyzed data and reviewed the manuscript. B. Li, as the corresponding author, oversaw the final approval and submission.

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Correspondence to Bingbing Li.

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Ren, T., Wang, X., Ma, J. et al. The optimal adjunctive therapies for microfracture treatment of osteochondral lesions of the talus: a systematic review and network meta-analysis of randomized controlled trials. BMC Musculoskelet Disord 26, 375 (2025). https://doiorg.publicaciones.saludcastillayleon.es/10.1186/s12891-025-08636-6

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  • DOI: https://doiorg.publicaciones.saludcastillayleon.es/10.1186/s12891-025-08636-6

Keywords

BMC Musculoskeletal Disorders

ISSN: 1471-2474

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