Efficacy and safety of biological agents and physical therapies for delayed union or nonunion of fractures: a network meta-analysis of randomized controlled trials

Background Delayed and nonunion fractures remain a significant clinical challenge in orthopedics. This study compared the effects of biologics and physical therapies for delayed or nonunion fractures. Methods We comprehensively searched and included randomized controlled trials (RCTs) investigating biologics and physical therapies for delayed or nonunion fractures; the outcomes included healing rate, healing time and adverse events. We ranked the interventions’ therapeutic efficacy through data analysis. Results Twenty-seven RCTs (involving 1495 patients and 15 interventions) were included. For fracture healing rate, bone marrow aspirate (BMA) combined with autologous cancellous bone (ACB) exhibited significantly better efficacy than ACB alone (OR = 8.14, 95% CI: 1.69 to 39.32). SUCRA ranking revealed that BMA + ACB (96%), platelet-rich plasma (PRP) + ACB (77.3%) and bone morphogenetic protein (BMP) + ACB (70.5%) ranked among the top three interventions for fracture healing rate. For fracture healing time, LIPUS (SMD = -9.33, 95% CI: -12.94 to -5.73) and PRP + ACB (SMD = -2.43, 95% CI: -4.14 to -0.72) both significantly reduced the fracture healing time relative to ACB. For adverse events, BMA + ACB (OR = 0.12, 95% CI: 0.03 to 0.59) and BMP (OR = 0.15, 95% CI: 0.04 to 0.61) had the lowest risk of adverse events relative to ACB alone. Conclusion Preliminary evidence suggests that among currently available biologics and physical therapies, BMA combined with ACB may be associated with a higher fracture healing rate. LIPUS may help shorten the healing time in patients with mild delayed and nonunion fractures, while BMA combined with ACB potentially exhibits the lowest risk of adverse events. However, the quality of current evidence is low, and these findings require further validation through large-scale RCTs.