| Objective:（1）To explore the effect of NSAIDs on bone healing in patients with bone injury by literature meta-analysis,in order to provide evidence-based medical evidence for the use of NSAIDs in patients with orthopedic diseases.（2）To study the effect of sensory neuropeptide CGRP on the proliferation and osteogenic differentiation of r BMSCs,and to explore its effect on the proliferation and migration of r RVECs.Method:（1）Taking advantage of computer to search the Chinese database:CNKI,Wanfang database,VIP database and English database:Pub Med,Cochrane Library,Embase.The search time is from January 01,2000 to February 15,2023.The studies on the use of NSAIDs in patients with bone injury were screened from the retrieved literature,and then the literature screening and quality evaluation were carried out by two researchers in strict accordance with the inclusion and exclusion criteria of the literature.Furthermore,data such as the name of the first author,publication year,study type,number of cases,age of patients,disease type,treatment method,follow-up time,type of NSAIDs,dosage and duration of use of NSAIDs,type of adverse bone healing,and diagnosis of adverse bone healing were extracted.Finally,using Review Manager 5.4 software for data analysis.（2）On the basis of studying the relationship between NSAIDs and adverse bone healing,and based on the important role of sensory nerve in regulating bone regeneration,using cell experiments to verify the effect of CGRP on osteogenic differentiation of r BMSCs.Firstly,r BMSCs were isolated,and then the extracted cells were identified by flow cytometry.Then,different concentrations of CGRP were used to intervene r BMSCs.CCK-8 method was used to investigate the effects of different concentrations of CGRP on cell proliferation of r BMSCs.Finally,ALP staining were used to identify the ability of CGRP to promote osteogenic differentiation of r BMSCs.On this basis,the effects of CGRP on vascular endothelial cell proliferation and migration were preliminarily discussed.Results:（1）A total of 22 articles were included in the meta-analysis,including 23 studies with26,444 cases,5426 cases in the NSAIDs group with 301 cases of adverse bone union,and21,066 cases in the non-NSAIDs group with 297 cases of adverse bone union.Results of the meta-analysis showed that the use of NSAIDs was associated with an increased risk of adverse bone healing compared with non-NSAIDs treatment（OR=1.65,95%CI:1.13-2.42,P<0.05）.Using of NSAIDs in adults increases the risk of adverse bone healing（OR=2.04,95%CI:1.38-3.02,P<0.05）.In the adult patients,the use of NSAIDs for long bone injuries was associated with an increased risk of adverse bone healing（OR=2.04,95%CI:1.38-3.02,P<0.05）,but patients who underwent spinal surgery were not at increased risk for adverse bone healing（OR=1.53,95%CI:0.44-5.26,P=0.50）.The use of NSAIDs in pediatric patients with bone injury does not increase the risk of adverse bone healing（OR=0.56,95%CI:0.27-1.15,P=0.11）.Short duration and low dose use of NSAIDs did not increase the risk of adverse bone healing（OR=1.06,95%CI:0.60-1.89,P=0.84）.（2）Study on the effect of CGRP on osteogenic differentiation of r BMSCs,flow cytometry was used to identify the r BMSCs.The results indicated that CD29（99.2%）and CD90（99.8%）were highly expressed,and CD45（0.7%）and CD71（4.4%）were low expressed,which indicated that the purity of the cells met the required standards.The results of CCK-8 assay suggested that CGRP could enhance the proliferation ability of r BMSCs,and when its concentration was 10-7mol/L,the effect of promoting the proliferation of r BMSCs was better.ALP staining showed that CGRP could promote osteogenic differentiation of r BMSCs.For the effect of CGRP on r RVECs,the results of CCK-8experiment showed that CGRP could enhance the proliferation ability of r RVECs,and the optimal intervention concentration was 10-7mol/L.Cell scratch experiment also showed that CGRP could significantly improve the cell migration ability of r RVECs.Conclusion:（1）As a painkiller commonly used in clinic and most easily available to patients,NSAIDs has definite analgesic effect,but for patients with bone injury,especially for adult patients with long bone injury,the use of NSAIDs has a negative effect on bone healing,but it has no effect on bone healing in patients with spinal injury,besides,short-term use of low-dose NSAIDs does not increase the risk of adverse bone healing.It does not increase the risk of adverse bone healing in children.（2）CGRP can improve the proliferation ability of r BMSCs,promote the osteogenic differentiation of r BMSCs,and promote the proliferation and migration of r RVECs.Based on the theory of sensory nerve regulating bone regeneration,the mechanism of adverse effects of NSAIDs on bone healing is expected to provide new inspiration for revealing the relationship among NSAIDs,adverse bone healing and sensory nerve. |
