真实世界恒古骨伤愈合剂治疗膝骨关节炎临床疗效和作用机制分析

Clinical Efficacy and Mechanism of Osteoking in Treatment of Knee Osteoarthritis Basedon Real-world Data

目的:探究真实世界恒古骨伤愈合剂治疗膝骨关节炎(KOA)的临床疗效和作用机制,为恒古骨伤愈合剂的临床合理用药提供依据。方法:基于“恒古骨伤愈合剂治疗膝骨关节炎病例注册登记系统”资料,采用SPSS 26.0对638例应用过恒古骨伤愈合剂的KOA病例数据进行分析。临床数据来源于全国20家医院共同收集,时间为2020年5月至2021年12月。对患者的年龄、性别、体质量指数、疗程等指标进行描述性分析。采用Mann-WhitneyU检验比较治疗前后视觉模拟评分(VAS)评分和西安大略和麦克马斯特大学骨关节炎指数(WOMAC)评分的变化。并采用整合药理学研究平台(TCMIP)v2.0对恒古骨伤愈合剂治疗KOA的核心靶标进行关联网络分析。收集2022年10月至12月北京中医药大学第三附属医院就诊的KOA患者作为治疗组,共计20例,接受恒古骨伤愈合剂治疗,另招募健康志愿者20例作为对照组,采用酶联免疫吸附测定法(ELISA)测定两组患者血清相应的指标以验证网络分析结果。结果:使用恒古骨伤愈合剂治疗KOA患者共638例,其中单用组429例(67.24%),多于联用组209例(32.76%)。女性415例(65.05%),多于男性223例(34.95%),平均年龄(63.48±13.51)岁,平均体质量指数(BMI)为(24.09±2.98)kg·m^(-2),平均疗程(15.78±9.66)d;Kellgren-Lawrence(K-L)分级以Ⅱ级(46.24%)、Ⅲ级(34.64%)为主,临床分期分布以缓解期为主(82.45%)为主,临床分期与K-L分级不显著相关。通过聚类分析可以将证型归纳为气滞血瘀证、寒湿痹阻证、肝肾亏虚证。总体临床疗效评价显示,VAS评分治疗前(6.01±0.85)分,治疗后(2.54±1.73)分,VAS评分明显降低(P<0.05);WOMAC评分治疗前(93.25±25.91)分,治疗后(50.73±25.14)分,WOMAC明显降低(P<0.05)。网络分析发现,恒古骨伤愈合剂可能通过调节转化生长因子-β(TGF-β)、肿瘤坏死因子-α(TNF-α)和核转录因子-κB(NF-κB)信号通路发挥作用。实验验证结果显示,治疗后治疗组患者TGF-β1水平显著升高(P<0.01),核转录因子-κB p65(RELA)和肿瘤坏死因子(TNF)受体超家族成员1A(TNFRSF1A)水平均明显降低(P<0.05),这些相互协同的作用共同为KOA治疗提供了一种多维度和全面的疗效,从而有效地减轻患者关节疼痛及活动受限等症状。结论:恒古骨伤愈合剂治疗KOA疗效显著,可能通过多途径参与关节软骨代谢调节和炎症过程,为阐明其治疗KOA的多靶点作用机制提供了实验依据和理论支持。

Objective:To investigate the clinical efficacy and mechanisms of Osteoking in the treatment of knee osteoarthritis(KOA)in real-world practice,so as to provide a basis for the rational clinical use of Osteoking.Method:From the Osteoking for knee osteoarthritis case registration system,638 KOA cases treated with Osteoking were selected and analyzed in SPSS 26.0.The clinical data were collected from 20 hospitals in China from May 2020 to December 2021.Descriptive analyses of patient age,gender,body mass index,course of treatment and other parameters were performed.The Mann-Whitney U test was performed to compare the visual analogue scale(VAS)and Western Ontario and McMaster universities arthritis index(WOMAC)scores before and after treatment.The integrative pharmacology-based research platform of traditional Chinese medicine(TCMIP)v2.0 was used for network analysis of the core targets of Osteoking in treating knee osteoarthritis.Furthermore,20 KOA patients treated with Osteoking in the Third Affiliated Hospital of Beijing University of Chinese Medicine from October to December in 2022 were enrolled in the treatment group,and 20 healthy volunteers in the control group.The enzyme-linked immunosorbent assay was employed to measure the serum levels of related indicators to verify the prediction results.Result:A total of 638 KOA patients were treated with Osteoking,including 429(67.24%)receiving Osteoking alone and 209(32.76%)receiving Osteoking combined with other therapies.The female patients(415,65.05%)were more than the male patients(223,34.95%).The patients showed the mean age of(63.48±13.51)years,mean body mass index of(24.09±2.98)kg·m^(-2),and mean course of treatment of(15.78±9.66)days.Most of the patients were rated as grades I(46.24%)and II(34.64%)in Kellgren-Lawrence(K-L)grading and in the relief stage(82.45%)in clinical staging.There was no significant correlation between clinical staging and K-L grading results.The cluster analysis identified three TCM syndromes:Qi stagnation and blood stasis,cold-dampness obstruction,and liverkidney deficiency.The overall clinical efficacy evaluation showed that VAS score decreased from(6.01±0.85)scores before treatment to(2.54±1.73)scores after treatment(P<0.05),and the WOMAC score decreased from(93.25±25.91)scores before treatment to(50.73±25.14)scores after treatment(P<0.05).The network analysis predicted that Osteoking might regulate the transforming growth factor-beta(TGF-β),tumor necrosis factor-alpha(TNF-α),and nuclear factor-kappa B(NF-kB)signaling pathways to exert the therapeutic effect.The clinical trial showed elevated TGF-β,level(P<0.01)and lowered NF-kB subunit RELA and tumor necrosis factor receptor superfamily,member 1A(TNFRSF1A)levels(P<0.05)after treatment.The synergistic effects of these changes provide a multidimensional and comprehensive therapeutic efficacy for KOA,alleviating the joint pain and limited mobility in patients.Conclusion:Osteoking showed significant therapeutic efficacy in treating KOA.Osteoking may act on multiple pathways involved in cartilage metabolism and inflammation.The findings provide experimental evidence and theoretical support for elucidating the multi-target mechanism of Osteoking in treating KOA.