Effectiveness of Stem Cell Therapy for Bone Fracture Healing in Patients with Comorbidities: A Systematic Review and Meta-Analysis

Over the past few decades, significant advancements have been made to enhance fracture management. However, complications such as nonunion and delayed union remain prevalent, particularly in patients with comorbidities. Cell therapy, particularly the use of mesenchymal stem cells (MSCs) and osteoblast injections, has emerged as a promising approach for accelerating fracture healing. This study was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. We reviewed the relevant scientific literature published between 2010 and 2023. The pooled risk ratio (RR) with a 95% confidence interval (CI) was assessed using a fixed or random-effects model. A p-value of <0.05 was considered statistically significant for publication bias. Data were synthesized and analyzed using RevMan 5.4 software. After reviewing 240 records, we identified 5 studies that met the inclusion and exclusion criteria. There was no statistically significant reduction in postoperative pain for patients receiving stem cell therapy compared to the control group [95% CI: -0.77 to 0.42] (P = 0.56). Additionally, no significant improvement in fracture healing rates was observed in the stem cell group compared to the control group [95% CI: 0.79 to 1.88] (P = 0.37). There are no significant advantages of stem cell therapy over standard treatments in reducing postoperative pain, improving fracture union rates, or ensuring safety in patients with comorbidities.

Introduction

Over the past few decades, significant advancements have been made in the field of fracture treatment, including the development of various surgical instruments and both external and internal metal fixators designed to enhance fracture management. Despite these improvements, complications such as nonunion and delayed union remain prevalent, particularly in patients with comorbidities [1], [2].

Delayed union is defined as insufficient healing progression over three months, while nonunion refers to a fracture failing to heal within nine months, occurring in approximately 1 out of every 40 fractures. Both are common in long bone fractures, with distal tibial fractures being particularly vulnerable due to poor blood supply and limited soft tissue coverage, affecting up to 15% of cases [3]. These conditions result in significant morbidity and impose an economic burden due to the extensive rehabilitation required [1], [2].

Cell therapy, particularly the use of mesenchymal stem cells (MSCs) and osteoblast injections, has emerged as a promising approach for accelerating fracture healing. MSCs are multipotent stem cells capable of differentiating into various cell types, including osteoblasts, which are critical for bone formation. Typically harvested from bone marrow, adipose tissue, or other mesenchymal tissues, MSCs have shown potential in promoting bone regeneration and healing through their differentiation capabilities and secretion of growth factors [1], [2].

Osteoblast injections involve the direct administration of osteoblasts—cells responsible for bone formation. These osteoblasts are often cultured from the patient’s own bone marrow or other sources, expanded in vitro, and then injected into the fracture site. The primary objective of osteoblast injection is to introduce cells that can directly participate in new bone formation at the site of a fracture or bone defect [4].

Patients with comorbidities such as diabetes, osteoporosis, and peripheral vascular disease frequently experience impaired bone healing. These comorbidities can disrupt the bone healing process through various mechanisms, including reduced blood supply, altered bone metabolism, and impaired cellular responses. MSCs and osteoblast injections offer potential therapeutic benefits for these patients by enhancing the local cellular environment and providing the necessary cellular components for effective bone repair [2], [4].

The purpose of this systematic review and meta-analysis is to evaluate the effectiveness and safety of stem cell therapy, specifically MSCs and osteoblast injections, in promoting bone fracture healing in patients with comorbidities.

Method

This systematic review and meta-analysis adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines (Fig. 1). The methodology followed several key steps:

Fig. 1. Flow chart of data selection.

Literature Search

A comprehensive search of electronic databases, including PubMed, Embase, the Cochrane Library, and Web of Science, was conducted to identify studies published between January 2000 and December 2023. The search terms included combinations of “stem cell therapy,” “bone fracture healing,” “mesenchymal stem cells,” “nonunion,” “comorbidities,” “postoperative VAS score,” “adverse events,” and “union achievement.” Both Medical Subject Headings (MeSH) and free-text keywords were used to maximize the search coverage.

Inclusion and Exclusion Criteria

The inclusion criteria focused on studies involving human participants with bone fractures and comorbidities. Eligible studies assessed the impact of stem cell therapy, such as mesenchymal stem cells, on fracture healing outcomes, specifically postoperative Visual Analog Scale (VAS) scores, adverse events, and union achievement rates. Randomized controlled trials (RCTs), cohort studies, and case-control studies were included.

Exclusion criteria eliminated studies that involved non-human subjects, including animal models and in vitro experiments. Studies without control groups or those lacking relevant outcome data for the meta-analysis were also excluded. Additionally, reviews, case reports, and editorials were not considered.

Study Selection

The study selection process involved two independent reviewers who screened the titles and abstracts of retrieved studies. Full-text articles were then assessed for eligibility based on the predefined inclusion criteria. Discrepancies between reviewers were resolved through discussion or, when necessary, by consulting a third reviewer to ensure consistency and accuracy.

Data Extraction

Data extraction was performed using a standardized form to ensure uniformity and comprehensiveness. Extracted data included study characteristics (author, year of publication, study design, sample size, and follow-up duration), patient demographics (age, gender, fracture type, and associated comorbidities), and details of the intervention (type of stem cell therapy, stem cell source, delivery method, and control interventions). Outcome measures included postoperative pain (VAS scores), incidence of adverse events, and union achievement rates, as defined radiographically or clinically.

Quality Assessment

The quality of included studies was evaluated using the Cochrane Risk of Bias Tool for randomized controlled trials and the Newcastle-Ottawa Scale for observational studies. Scores ranged from 6 to 9, reflecting the generally high quality of the studies. The assessment examined randomization methods, allocation concealment, blinding, completeness of outcome data, and potential selective reporting, ensuring the reliability and validity of the findings.

Data Synthesis and Statistical Analysis

Meta-analysis was conducted using RevMan 5.4 software. Primary outcomes analyzed included postoperative VAS scores (mean differences between stem cell and control groups) and union achievement rates (presented as risk ratios). Secondary outcomes included the incidence of adverse events, also reported as risk ratios. Study heterogeneity was assessed using the I² statistic, and a random-effects model was applied regardless of the heterogeneity level.

Ethical Considerations

Ethical approval was not required as this study synthesized data from previously published research. Ethical standards were maintained throughout the processes of data collection, analysis, and reporting.

Results

After reviewing 240 records, we identified five studies that met the inclusion and exclusion criteria. The meta-analysis evaluated the effectiveness of stem cell therapy for bone fracture healing in patients with comorbidities across three primary outcomes: postoperative pain (VAS scores), adverse events, and fracture union achievement.

Postoperative Visual Analog Scale (VAS) Score

The pooled mean difference for postoperative VAS scores was −0.17 [95% CI: −0.77 to 0.42], indicating no statistically significant reduction in postoperative pain for patients receiving stem cell therapy compared to the control group (p = 0.56; Fig. 2). The heterogeneity was low (I² = 9%), suggesting that the included studies provided relatively consistent results. These findings imply that stem cell therapy does not result in clinically meaningful improvements in postoperative pain management for bone fracture healing.

Fig. 2. Postoperative VAS score.

Union Achievement

The pooled risk ratio for union achievement was 1.22 [95% CI: 0.79 to 1.88], indicating no significant improvement in fracture healing rates in the stem cell therapy group compared to the control group (p = 0.37; Fig. 3). The heterogeneity was minimal (I² = 0%), reinforcing the reliability of these findings. Despite some variability in individual study outcomes, stem cell therapy did not demonstrate a significant benefit in enhancing bone union in patients with comorbidities.

Fig. 3. Union achievement.

Adverse Events

The risk ratio for adverse events was 1.10 [95% CI: 0.93 to 1.32], showing no statistically significant difference in the risk of adverse events between the stem cell therapy group and the control group (p = 0.27; Fig. 4). The heterogeneity was negligible (I² = 0%), indicating that the studies were highly consistent in reporting adverse event risks. These findings suggest that stem cell therapy is relatively safe and does not increase the likelihood of complications in patients with comorbidities.

Fig. 4. Adverse event.

Discussion

This systematic review and meta-analysis evaluated the effectiveness and safety of stem cell therapy, specifically MSCs and osteoblast injections, in promoting bone fracture healing in patients with comorbidities. Despite the theoretical promise of these therapies, the findings revealed limited clinical benefits regarding postoperative pain reduction, adverse event rates, and fracture union achievement compared to conventional treatments.

Postoperative Pain (VAS Scores)

The lack of a statistically significant reduction in postoperative Visual Analog Scale (VAS) scores indicates that stem cell therapy does not effectively alleviate pain associated with fracture healing in patients with comorbidities. Pain management during bone healing is multifactorial, and while MSCs may support the biological processes of bone repair, their impact on subjective pain perception remains unclear. Other studies suggest that MSCs may primarily enhance biological healing rather than directly mitigating pain perception [1], [4]. Factors such as inflammation and nerve sensitization may play a more dominant role in postoperative pain within this population.

The use of bone marrow-derived mesenchymal stem cells (BM-MSCs) combined with hydroxyapatite (HA) granules has been used to treat neglected atrophic nonunion of long bone fractures; however, no statistically or clinically significant difference was also found in VAS scores between the treatment and control groups. Although postoperative pain decreased significantly in all subjects within the first four weeks, the reduction occurred more rapidly in the control group than in the treatment group [1].

The study by Shim et al. also observed limited benefits for MSC-based therapies during early postoperative pain control, with no significant difference. However, the study found a significant reduction in VAS scores in the combined WJ-MSC and teriparatide treatment group over a 12-month follow-up. The improvement may be attributed to the synergistic effects of teriparatide and WJ-MSCs in reducing inflammation and enhanced pain relief [4].

Union Achievement

The pooled risk ratio for union achievement demonstrated no statistically significant improvement in the stem cell therapy group compared to the control group. This result indicates that, despite the potential of stem cell therapy to enhance cellular and molecular mechanisms of healing observed in vitro and animal models, these effects may not consistently translate into clinically relevant outcomes for patients with comorbidities. Furthermore, conditions such as diabetes and osteoporosis may compromise the efficacy of transplanted stem cells by impairing their differentiation into osteoblasts or by reducing the availability of critical growth factors necessary for effective bone healing.

Diabetes mellitus and osteoporosis can negatively impact the efficacy of transplanted stem cells in bone healing through several mechanisms. In diabetic conditions, chronic hyperglycemia causes insulin resistance, induces oxidative stress, and leads to the formation of advanced glycation end products (AGEs) [5], [6]. These biochemical changes impair the ability of mesenchymal stem cells (MSCs) to differentiate into osteoblasts, the cells responsible for bone formation. As a result, the capacity for effective bone regeneration is significantly reduced, compromising the overall success of stem cell-based therapies [5].

In osteoporosis, an imbalance between bone resorption and formation creates a compromised bone microenvironment. This altered environment is less conducive to the functionality and activity of transplanted stem cells, thereby limiting their regenerative potential. The disruption of the structural and cellular framework within osteoporotic bone poses additional challenges for successful bone healing and stem cell integration [7].

Both diabetes and osteoporosis are also associated with a reduction in the availability of critical growth factors essential for bone healing. Growth factors play a pivotal role in supporting the proliferation, migration, and differentiation of transplanted stem cells [8], [9]. A deficiency in these factors further diminishes the therapeutic effectiveness of stem cells, as their regenerative capabilities rely heavily on a supportive and nutrient-rich environment [5], [7].

The study by Thua et al. found that although BM-MCSs could be a superior alternative to traditional autologous cancellous bone grafting, no significant difference in the union rate in managing nonunion. However, the time to union was significantly shorter [10]. A previous study demonstrated a significant reduction in time to union in patients receiving MSC-based intervention. Additionally, no cases of nonunion were observed, while one-fourth of the control group experienced delayed union [3].

The use of BM-MSCs is found to promote quicker callus formation, leading to accelerated radiographic union and faster functional recovery during the first three months postoperatively [1]. On the other hand, the combination of WJ-MSC and teriparatide has been found to significantly improve bone microarchitecture by CT imaging among osteoporotic vertebral fractures, although the bone mineral density (BMD) scores showed no significant differences [4].

A preserved soft tissue envelope creates a favorable biological environment that supports the bone healing process. However, in long-standing nonunion cases, as observed in this study, surgical intervention involving decortication of the fracture site becomes essential. Decortication enhances the local biological environment by exposing viable bone surfaces and stimulating osteogenesis [1], [11].

An optimal biological environment (nonunion bed) is crucial for initiating and sustaining early osteogenesis, ultimately leading to bone continuity and functional restoration. Surgical procedures such as decortication should aim to preserve the integrity of the surrounding soft tissue as much as possible while creating an active biological chamber [12], [13]. This chamber must provide the necessary conditions to support the physiological processes required for effective bone regeneration [1].

Adverse Events

Stem cell therapy was found to be relatively safe. Adverse events associated with stem cell therapies for bone healing are generally minimal; however, careful monitoring is essential to ensure patient safety. Studies have consistently reported that MSC-based treatments are well-tolerated, with no significant increase in adverse events compared to conventional treatments. Liebergall et al. observed no procedure-related adverse events in their intervention group using MSCs, although two minor adverse events occurred in the control group, unrelated to the intervention itself [3]. Similarly, Kim et al. reported typical postoperative complications, such as mild inflammation at the injection site, with no significant difference in the adverse event rates between the experimental and control groups [2].

Despite the overall safety profile, rare complications such as infections and thromboembolic events have been reported. Cases of postoperative wound infections were observed, although were successfully managed with antibiotics and wound care [2], [10]. This underscores the need for sterile techniques and appropriate postoperative care. Additionally, one case of pulmonary embolism occurred in the intervention group, highlighting the importance of monitoring patients for rare but serious complications, particularly in high-risk populations [4]. The lack of long-term safety data, particularly in patients with comorbidities, also highlights the need for further research.

MSC Therapy in Normal and Comorbid Patients

The administration of MSCs to fracture sites in patients with normal physiology generally shows promising outcomes. In healthy individuals, MSCs enhance callus formation by differentiating into osteoblasts and secreting growth factors that promote angiogenesis and osteogenesis [1]. These processes are supported by an optimal microenvironment, including adequate vascularity and an intact immune response.

In contrast, MSC therapy in patients with comorbidities often yields inconsistent results. As discussed, the impaired microenvironment in conditions like DM and osteoporosis diminishes the efficacy of MSCs by limiting their differentiation potential, survival, and integration at the fracture site [5], [7].

Although MSCs inherently possess immunomodulatory and regenerative properties, these capabilities are often insufficient to overcome the pathological barriers imposed by comorbid conditions. The disparity in outcomes between normal and comorbid patients underscores the need for adjunctive strategies, such as preconditioning MSCs or combining them with osteoconductive scaffolds, to enhance therapeutic efficacy.

Challenges and Limitations

Several factors may explain the lack of significant benefits observed in this analysis. One major challenge is the heterogeneity in study designs, including differences in stem cell sources, dosages, delivery methods, and patient populations, which may have diluted the potential effects of MSC therapy. For example, MSCs derived from bone marrow may behave differently from those derived from adipose tissue, affecting their efficacy.

Additionally, the impact of comorbidities such as diabetes and osteoporosis further complicate the healing process. These conditions create a suboptimal microenvironment that limits stem cell survival, differentiation, and functionality, reducing their therapeutic potential. Furthermore, the relatively small number of high-quality studies included in this analysis reduces the statistical power to detect significant differences.

Another limitation is the variation in follow-up durations across studies, which may not have been long enough to observe the full effects of MSC therapy, particularly in patients with delayed union or nonunion. Larger, multicenter randomized controlled trials (RCTs) with standardized protocols and sufficient follow-up periods are needed to address these challenges and provide more definitive conclusions about the efficacy of MSC-based therapies.

Future research should focus on larger, more homogenous patient cohorts and standardized protocols to better evaluate the efficacy of MSC therapy in specific clinical scenarios.

Conclusion

This systematic review and meta-analysis found no significant advantages of stem cell therapy over standard treatments for postoperative pain reduction, fracture union, or safety in patients with comorbidities. While stem cell therapy remains a promising field with potential for future advancements, its current application for fracture healing in this population does not appear to be superior. To fully realize the therapeutic potential of stem cells, further high-quality research is required, focusing on overcoming the challenges posed by comorbidities, optimizing therapeutic protocols, and exploring combination treatments.