Abstract
Nonunions represent one of the major indications for clinical settings with stem cell-based therapies. The objective of this research was to systematically assess the current evidence for the efficacy of bone marrow-derived cell-based approaches associated or not with bone scaffolds for the treatment of nonunions. We searched MEDLINE (PubMed) and CENTRAL up to July 2019 for clinical studies focused on the use of cell-based therapies and bone marrow derivatives to treat bone nonunions. Three investigators independently extracted the data and appraised the risk of bias. We analysed 27 studies including a total number of 347 participants exposed to four interventions: bone marrow concentrate (BMAC), BMAC combined with scaffold (BMAC/Scaffold), bone marrow-derived mesenchymal stromal cells (BMSCs), and BMSC combined with scaffold (BMSC/Scaffold). Two controlled studies showed a positive trend in bone healing in favour of BMAC/Scaffold or BMSC/Scaffold treatment against bone autograft, although the difference was not statistically significant (RR 0.11, 95% CI -0.05; 0.28). Among single cohort studies, the highest mean pooled proportion of healing rate was reported for BMAC (77%; 95% CI 63%-89%; 107 cases, n = 8) and BMAC/Scaffold treatments with (71%; 95% CI 50%-89%; 117 cases, n = 8) at 6 months of follow-up. At 12 months of follow-up, an increasing proportion of bone healing was observed in all the treatment groups, ranging from 81% to 100%. These results indicate that BMAC or BMAC/Scaffold might be considered as the primary choice to treat nonunions with a successful healing rate at a midterm follow-up. Moreover, this meta-analysis highlighted that the presence of a scaffold positively influences the healing rate at a long-term follow-up. More case-control studies are still needed to support the clinical improvement of cell-based therapies against autografts, up to now considered as the gold standard for the treatment of nonunions.
Highlights
Nonunions and delayed unions are a frequent occurrence in fracture healing, with an incidence of 5-10% over the total amount of fractures only in the US [1]
We evaluated the treatment effects based on the healing rate at 6 and 12 months as dichotomized outcomes, using the Risk Difference (RD) expressed as 95% confidence intervals
Two controlled studies investigating cell-based therapies (BMAC/Scaffold or bone marrow-derived mesenchymal stromal cells (BMSCs)/Scaffold interventions) did not show any significant difference in bone healing rate versus the control intervention (2 studies, 100 patients, RD 0.11 95% confidence intervals (95% CIs) -0.05 to 0.28, I2 = 0%; p = 0:18, Figure 2)
Summary
Nonunions and delayed unions are a frequent occurrence in fracture healing, with an incidence of 5-10% over the total amount of fractures only in the US [1]. Hypertrophic nonunions are characterized by a large, broad callus towards the fracture gap, with a radiolucent area instead of bone bridging. In most cases, atrophic nonunions are the expression of an impaired biological support to bone healing, which may depend on a damaged vascular supply, and on the destruction of the periosteum and endosteum. Atrophic nonunions show the absence of callus tissue, the narrowing of bone ends, and a large radiolucent zone in the fracture gap [3]. For all these reasons, atrophic nonunions represent the most challenging occurrence. Atrophic nonunions always require a surgical approach to reduce abnormal mechanical factors and repair the fracture gap by means of bone grafting, which represents the therapeutic gold standard [8]
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