Meta-analysis Of Bone Morphogenetic Proteins For Long Bone Fracture And Nonunion

Objective:Fracture is a common disease that has a great impact on patients’lives,with the risk of malunion and persistent nonunion.Conventional mechanical fixation and bone graft often cannot meet the treatment needs.Bone morphogenetic proteins(BMPs)for bone regeneration gained increasing attention in the scientific community.However,controversy still exists over the clinical efficacy and safety of BMPs as previous studies reported.There is no consensus on the specific use of BMPs in the treatment of complex long bone fractures and nonunions.The objectives of this study as follows:1)to investigate the efficacy of BMPs for long bone fresh fractures;2)to investigate the safety of BMPs for long bone fresh fractures;3)to compare the efficacy of long bone nonunion treated with BMPs to autologous bone graft(ABG);4)to compare the efficacy of long bone nonunion treated with BMPs combined bone graft to ABG.By summarizing the results of this study,the final purpose is to provide reference for clinical practice.Methods:A computerised literature search was performed for published trials in CNKI,VIP,WANFANG DATA,Pub Med,Web of Science,Springer Link,Cochrane Library and Google Scholar.The retrieval time limit is from the establishment of the database to February,2020.The clinical trials were selected according to the eligibility criteria and exclusion criteria.The risks of bias of the included trials were evaluated according to the Cochrane Handbook for Systematic Reviews.The data were collected into Microsoft Excel2007 and Stata/SE 12.0.Statistical analysis was performed in the Stata/SE 12.0.Heterogeneity between studies was quantified by calculating the I~2statistic,and RR was calculated for raw counts while SMD for consecutive outcomes.A random-effects model was used for statistical analysis,the subgroup analysis,sensitivity analysis and publication bias test were also performed.All P values were two-sided,and P<0.05 was considered statistically significant.Results:(1)The result of BMPs for long bone fresh fractures:a total of 6 articles were included,of which 5 were randomized controlled trials,with a total of 1217 cases including the trial group(n=773)and the control group(n=444),all of which were tibial fracture cases.After using BMPs,the overall healing rate did not increase significantly[RR=1.11,95%CI(0.99,1.25),P=0.073],but the secondary intervention rate decreased[RR=0.67,95%CI(0.51,0.87),P=0.004].Subgroup analysis showed that the healing rate of open tibial fracture was significantly improved[RR=1.16,95%CI(1.02,1.31),P=0.024].The incidence of heterotopic ossification and soft tissue calcification was increased[RR=2.19,95%CI(1.07,4.50),P=0.032].Postoperative infection(P=0.448),pain(P=0.296),hardware failure(P=0.399),and edema and swelling(P=0.919)were not significantly affected.(2)The result of BMPs for long bone nonunion:a total of 13 articles were included,of which4 were randomized controlled trials,with a total of 983 cases including the trial group(n=439)and the control group(n=544).There was no significant difference in postoperative healing rate between BMPs alone and ABG[RR=0.96,95%CI(0.85,1.09),P=0.542].BMPs combined with bone graft cannot significantly improve the healing rate[RR=1.01,95%CI(0.97,1.05),P=0.693].When using BMPs alone or combined with allograft bone,the operation time was shorter[SMD=-1.27,95%CI(-1.81,-0.73),P<0.001],and the intraoperative blood loss was also less[SMD=-0.7,95%CI(-1.12,-0.29),P=0.001].According to the results of sensitivity analysis,BMPs may have a positive effect on the shortening of bone healing time(P=0.306),hospital stay(P=0.118)and limb function recovery(P=0.19).But it has no significant effect on reducing the secondary intervention rate(P=0.717),infection rate(P=0.954)and pain rate(P=0.524).Conclusions:(1)BMPs has a positive effect on reducing postoperative secondary intervention of tibia fracture,and increases the bone healing rate of open fracture,which is more suitable for complex open tibia fracture.Although it is relatively safe,the high rate of heterotopic ossification and soft tissue calcification still needs to be considered.(2)BMPs can be used as a substitute for ABG in the treatment of long bone nonunion,and it has the advantages of shortening operation time and reducing the intraoperative bleeding.But the current evidences does not support BMPs combined with ABG,because the synergistic effect of the two is not obvious.