Chinese Journal of Tissue Engineering Research ›› 2026, Vol. 30 ›› Issue (15): 3993-4009.doi: 10.12307/2026.738
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Guo Yuqi1, Li Jiacheng2, Lu Bowen1, Zhang Jiahao1, Li Gang2
Accepted:2025-07-09
Online:2026-05-28
Published:2025-11-10
Contact:
Li Gang, MD, Professor, Chief physician, Doctoral supervisor, Department of Orthopedics and Traumatology, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan 250014, Shandong Province, China
About author:Guo Yuqi, Master candidate, First Clinical Medical College, Shandong University of Traditional Chinese Medicine, Jinan 250014, Shandong Province, China
Supported by:CLC Number:
Guo Yuqi, Li Jiacheng, Lu Bowen, Zhang Jiahao, Li Gang. Network meta-analysis of core decompression combined with various therapies for early and mid-stage osteonecrosis of the femoral head[J]. Chinese Journal of Tissue Engineering Research, 2026, 30(15): 3993-4009.
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2.2 文献基本特征 共纳入73项随机对照试验[23-95],均为双臂设计,研究对象包括5 148例患者,共计5 777个髋关节,其中试验组2 975髋,对照组2 802髋。所有干预措施均为髓芯减压术联合其他治疗方式,共计15种,包括髓芯减压术+负压吸引术(negative pressure drainage,NPD)3篇[23-25]、髓芯减压术+自体骨髓单核细胞浓缩注射(bone marrow aspirate concentrate of mononuclear cells,BMNC-BMAC)3篇[26-28]、髓芯减压术+自体骨髓间充质干细胞移植(bone marrow mesenchymal stem cell ransplantation,BMSCs)7篇[29-35]、髓芯减压术+自体骨髓细胞联合髂骨植骨(bone marrow cells and iliac bone grafting,BMC-IBG)2篇[36-37]、髓芯减压术+自体源性干细胞局部植入(autologous stem cell implantation,ASCI)2篇[38-39]、髓芯减压术+富血小板血浆局部注射(platelet-rich plasma injection,PRP)2篇[40-41]、髓芯减压术+结构支撑植骨术(structural bone grafting,SBG)3篇[42-44]、髓芯减压术+异体或自体松质骨植骨术(cancellous bone grafting,CBG)5篇[45-49]、髓芯减压术+静脉滴注中药注射液(intravenous Chinese herbal injection,IV-CHI)2篇[50-51]、髓芯减压术+局部动脉穿刺注射治疗(intra-arterial infusion,IAI)4篇[52-55]、髓芯减压术+髓腔定向递药治疗(intramedullary targeted drug delivery,IDD)2篇[56-57]、髓芯减压术+补肾活血类中药(复方汤剂)(kidney-tonifying and blood-activating decoction,KTBA-D)15篇[58-72]、髓芯减压术+活血化瘀类中药(复方汤剂)(blood-activating and stasis-resolving decoction,BASR-D)10篇[73-82]、髓芯减压术+中医药序贯治疗(sequential traditional Chinese medicine therapy,PSTCM)4篇[83-86]、髓芯减压术+中成药联合治疗(补肾活血+活血化瘀)(compound proprietary medicine treatment,CPM)9篇[87-95]。所有研究发表时间为2005-2024年,其中中文文献68篇,英文文献5篇。纳入文献的基本特征见表3。"
2.3 文献质量评价 研究采用Cochrane推荐的RoB 2.0工具对纳入的73项随机对照试验进行偏倚风险评估。在随机过程方面,共有24篇文献采用随机数字表法进行分组[30,33-34,39-40,43,45,52,55,58-60,62,64,69,71,73,75-76,85,90,92,94-95],1篇采用抽签法[47],2篇采用信封法[57,24],5篇依据就诊顺序随机编号分组[51,61,67,86,89],1篇虽未说明随机方法但实施双盲设计[26],评为低风险,其余40篇未报告具体随机方法,评为有一定风险。在盲法方面,1篇提及单盲[91]、2篇提及双盲[26,31],评为低风险;69篇未提及分配隐藏,评为有一定风险;1篇提及不设盲[34],评为高风险。所有文献均具有完整的结局数据,未出现剔除与脱落,评为低风险。所有文献全面报告了明确的结局指标,且报告了结局指标有无统计学意义,评为低风险。所有文献结局数据均采用恰当的测量方法,评为低风险。所有文献均无结果选择性报告偏倚,评为低风险。总体来看,文献质量较好,偏倚主要集中在随机方法和盲法信息的报告不足,见图2。"
2.4 证据网络与模型选择 图3展示了15种髓芯减压术联合干预在5项疗效结局指标(综合临床疗效指数、髋关节功能评分、影像学改善指数、疼痛缓解指数、临床安全性指数)下构建的证据网络。图中节点代表各干预措施,节点大小与样本量相关,连线粗细则反映干预间直接比较研究的数量,体现证据的丰富程度。表4汇总了各结局指标在固定效应与随机效应模型下的一致性模型拟合情况,包括偏差信息准则(DIC)和有效参数数目(effective number of parameters,pD)及异质性评估结果:异质性指数(inconsistency index,I2)和潜在尺度缩减因子(PSRF)。综合模型拟合优度与异质性指标,为每项结局确定最优模型以供后续分析使用。"
2.5 网状Meta分析 44篇随机对照试验报告了综合临床疗效指数[26-29,31,36-37,40-41,43-45,49,53-54,58-60,63-74,76-77,79,81-83,85-89,91-93],涉及11种联合治疗策略。网状Meta分析结果表明,在改善综合临床疗效指数方面,髓芯减压术联合多种治疗策略均显示出优于单纯髓芯减压术治疗的疗效。其中,髓芯减压术+自体骨髓单核细胞浓缩注射[SMD=-1.71,95%CrI(-2.27,-1.16)]、髓芯减压术+自体骨髓间充质干细胞移植[SMD= -1.19,95%CrI(-1.48,-0.90)]、髓芯减压术+自体骨髓细胞联合髂骨植骨[SMD=-1.29,95%CrI (-2.13,-0.44)]、髓芯减压术+富血小板血浆局部注射[SMD=-0.59,95%CrI(-1.08, -0.11)]以及髓芯减压术+结构支撑植骨术[SMD=-1.18,95%CrI(-2.04,-0.32)]在提高综合临床疗效指数方面均具有统计学意义。此外,干预措施之间亦存在差异。髓芯减压术+自体骨髓间充质干细胞移植与髓芯减压术+富血小板血浆局部注射[SMD= 0.59,95%CrI(0.03,1.16)]和髓芯减压术+异体或自体松质骨植骨术[SMD=0.56,95%CrI(0.02,1.13)]的比较中显示出更优的临床疗效,且髓芯减压术+异体或自体松质骨植骨术亦优于髓芯减压术+结构支撑植骨术[SMD=0.65,95%CrI(0.32,1.63)],具有统计学意义。尽管髓芯减压术+局部动脉穿刺与髓芯减压术+自体骨髓单核细胞浓缩注射[SMD=-0.48,95%CrI(-1.03,0.07)]未达到显著性水平,但髓芯减压术+补肾活血类中药(复方汤剂) [SMD=-0.74,95%CrI(-0.96,-0.51)]、髓芯减压术+活血化瘀类中药(复方汤剂)[SMD=-0.69,95%CrI (-1.01,-0.38)]以及髓芯减压术+中医药序贯疗法[SMD=-0.63,95%CrI(-1.13,-0.13)]相较于髓芯减压术单独治疗更具优势且具有统计学意义。值得注意的是,髓芯减压术+中成药联合治疗在与多个干预方案的比较中均表现出更优的疗效,其相较于髓芯减压术[SMD= -0.77,95%CrI(-1.10,-0.44)]和髓芯减压术+富血小板血浆局部注射[SMD=-0.52,95%CrI(-0.39,-1.34)]均具有统计学意义。综上,自体骨髓单核细胞浓缩注射、自体骨髓间充质干细胞移植、自体骨髓细胞联合髂骨植骨、结构支撑植骨术及中成药联合治疗等联合治疗方案在提升综合临床疗效指数方面具有显著优势,见图4。"
50篇随机对照试验报告了髋关节功能评分[24-25,29-35,38-43,45-51,53-54,56-58,60,62,66-68,72-80,84-85,88-90,92-95],涉及13种联合治疗策略。网状Meta分析结果显示,在改善髋关节功能评分方面,髓芯减压术联合多种治疗策略较单纯髓芯减压术表现出更优的疗效,其中髓芯减压术+负压吸引术[SMD=-1.11,95%CrI(-2.13,-0.10)]、 髓芯减压术+自体骨髓间充质干细胞移植[SMD=-1.11,95%CrI (-1.66,-0.56)]、髓芯减压术+富血小板血浆局部注射[SMD= -1.03,95%CrI(-2.04,-0.01)]、髓芯减压术+结构支撑植骨术[SMD=-1.03,95%CrI(-2.09,-0.03)]、髓芯减压术+异体或自体松质骨植骨术[SMD=-1.22,95%CrI(-1.88,-0.56)]、髓芯减压术+静脉滴注中药注射液[SMD=-1.42,95%CrI(-2.49,-0.36)]、 髓芯减压术+活血化瘀类中药(复方汤剂)[SMD=-1.33,95%CrI(-1.84,-0.82)]、 髓芯减压术+中医药序贯疗法[SMD=-2.22,95%CI(-3.27,-1.17)]及髓芯减压术+中成药联合治疗[SMD=-1.50, 95%CI(-2.05,-0.95)]均可显著提高患者的髋关节功能,差异有统计学意义。在不同联合治疗方案的相互比较中,髓芯减压术+中医药序贯疗法相较于髓芯减压术+补肾活血类中药(复方汤剂) [SMD=-1.33,95%CrI(-2.65,-0.27)]、髓芯减压术+活血化瘀类中药(复方汤剂)[SMD=-1.33,95%CrI (-2.68,-0.03)]以及髓芯减压术+中成药联合治疗[SMD=-1.28,95%CrI(-2.24,-0.24)]均显示出显著优势。髓芯减压术+中成药联合治疗亦在部分干预方法对比中表现较好,例如相较于髓芯减压术+富血小板血浆局部注射[SMD=-0.61,95%CrI (-1.84,0.64)]和髓芯减压术+髓腔定向递药[SMD= -0.29,95%CrI(-1.47,0.89)]显示出改善趋势,虽部分差异未达统计学显著性,但潜在的临床价值仍具参考意义,见图4。 26篇随机对照试验报告了疼痛缓解指数[29-30,32-34,38-41,52-55,60-61,74-76,78-79,88-89,92-95], 涉及7种联合治疗策略。网状Meta分析结果显示,在疼痛缓解指数方面,与单独采用髓芯减压术相比,多种联合治疗策略均表现出不同程度的优势。具体而言,髓芯减压术+自体骨髓间充质干细胞移植[SMD=-1.54,95%CrI(-3.69,0.62)]、髓芯减压术+自体源性干细胞局部植入[SMD= -1.06,95%CrI(-4.52,2.40)]、髓芯减压术+富血小板血浆局部注射[SMD=-0.85,95%CrI(-4.25,2.56)]、髓芯减压术+局部动脉穿刺[SMD=-0.70,95%CrI(-3.10,1.71)]、髓芯减压术+补肾活血类中药(复方汤剂)[SMD=-0.81,95%CrI(-4.23,2.61)]、髓芯减压术+活血化瘀类中药(复方汤剂)[SMD=-2.84,95%CrI(-5.05,-0.70)]以及髓芯减压术+中成药联合治疗[SMD=-2.90,95%CrI(-4.91,-0.94)]均显示出疼痛缓解的趋势。其中,髓芯减压术+活血化瘀类中药(复方汤剂)与髓芯减压术+中成药联合治疗的比较差异有统计学意义,提示其在疼痛控制方面具有明确优势。进一步的干预间比较结果显示,髓芯减压术+ 中成药联合治疗相较于髓芯减压术+自体骨髓间充质干细胞移植[SMD=-1.37,95%CrI(-4.33,1.54)]、髓芯减压术+自体源性干细胞局部植入[SMD=-1.85,95%CrI(-5.86,2.15)]以及髓芯减压术+富血小板血浆局部注射[SMD=-2.05,95%CrI(-6.03,1.85)]等在减轻疼痛方面呈现出更为显著的改善趋势。髓芯减压术+活血化瘀类中药(复方汤剂)在与髓芯减压术+富血小板血浆局部注射[SMD=-1.78,95%CrI(-5.91,2.27)]及髓芯减压术+自体骨髓间充质干细胞移植[SMD=-1.31,95%CrI (-4.64,1.73)]的比较中亦展现出一致的疗效优势。尽管部分置信区间较宽,存在一定统计不确定性,但整体疗效趋势明确,见图4。 19篇随机对照试验报告了影像学改善指数[23-24,29-33,35,38-41,76-77,84-85,90,92,95], 涉及7种联合治疗策略。网状Meta分析结果显示,在改善影像学改善指数方面,与单纯髓芯减压术相比,多种联合干预方案在不同程度上呈现出影像结构修复的潜在优势。具体而言,髓芯减压术+负压吸引术[SMD=-1.57,95%CrI(-2.44,0.71)]、髓芯减压术+自体骨髓间充质干细胞移植[SMD=-1.12,95%CrI(-1.53,0.74)]、髓芯减压术+富血小板血浆局部注射[SMD=-0.74,95%CrI(-1.40,0.06)]、髓芯减压术+髓腔定向递药[SMD=-1.26,95%CrI(-1.96,0.51)]、髓芯减压术+中医药序贯疗法[SMD=-1.07,95%CrI(-1.93,0.22)]以及髓芯减压术+中成药联合治疗[SMD=-0.50,95%CrI(-1.16,0.11)]均较常规髓芯减压术表现出更优趋势,尽管差异未达统计学显著性。值得关注的是,髓芯减压术+自体源性干细胞局部植入[SMD=-1.60,95%CrI(-2.54,-0.68)] 为唯一在统计学上具有显著差异的干预组合,提示其在促进骨结构重建方面可能具有确切疗效。进一步的干预间比较结果亦显示,髓芯减压术+中成药联合治疗相较于髓芯减压术+自体源性干细胞局部植入[SMD=1.11,95%CrI(-0.03,2.21)]与髓芯减压术+自体骨髓间充质干细胞移植[SMD=0.63,95%CrI(-0.14,1.46)]表现出一定的结构改善趋势;髓芯减压术+中医药序贯疗法与髓芯减压术+自体源性干细胞局部植入[SMD=0.52,95%CrI(-0.73,1.79)]之间亦呈现出类似正向变化,尽管均未达到统计学显著性,见图4。 14篇随机对照试验报告了临床安全性指数[31,34,43-47,50-51,61,69,73,75,82], 涉及6种联合治疗策略。网状Meta分析结果显示,在降低临床安全性指数方面,髓芯减压术联合不同干预措施在大多数比较中并未展现出统计学显著优势,但部分方案在安全性方面显示出相对良好的趋势。具体来看,髓芯减压术+自体骨髓间充质干细胞移植[SMD=0.27,95%CrI(-0.31,0.86)]、髓芯减压术+结构支撑植骨术[SMD=1.11,95%CrI(0.37,1.85)]、髓芯减压术+异体或自体松质骨植骨术[SMD=0.42,95%CrI(-0.11,0.96)]、髓芯减压术+静脉滴注中药注射液[SMD=0.27,95%CrI (-0.49,1.04)]、髓芯减压术+补肾活血类中药(复方汤剂) [SMD=0.52,95%CrI(-0.20,1.23)]以及髓芯减压术+活血化瘀类中药(复方汤剂)[SMD=0.16,95%CrI(-0.43,0.74)]在减少临床安全性指数方面均未达到统计学显著性,提示联合干预在安全性方面与常规髓芯减压术相近。其中,髓芯减压术+结构支撑植骨术呈现出较高标准化均数差,但置信区间包含0,且上限较宽。进一步的干预间比较结果显示,髓芯减压术+自体骨髓间充质干细胞移植在与髓芯减压术+结构支撑植骨术[SMD=0.84,95%CrI(-0.10,1.78)]、髓芯减压术+异体自体松质骨植骨术[SMD= 0.15,95%CrI(-0.64,0.94)]及其他方案比较中,未见显著差异;而髓芯减压术+结构支撑植骨术相较于髓芯减压术+活血化瘀类中药(复方汤剂)[SMD=-0.95,95%CrI(-1.89,-0.01)]有统计学差异,提示髓芯减压术+活血化瘀类中药(复方汤剂)在降低不良反应方面可能更具安全优势。此外,髓芯减压术+补肾活血类中药(复方汤剂) 与其他组合之间如髓芯减压术+静脉滴注中药注射液[SMD=-0.36,95%CrI(-1.28,0.57)]亦未表现出显著差异,见图4。 2.6 SUCRA排序 为进一步明确不同干预措施在各结局指标上的综合排名,绘制了基于综合临床疗效指数的SUCRA累计排名曲线与干预措施的秩位概率分布图(图5)。 综合临床疗效指数方面:髓芯减压术+自体骨髓单核细胞浓缩注射显示出最优的干预效果。根据SUCRA值排序,髓芯减压术+自体骨髓单核细胞浓缩注射(96.23%)在所有干预措施中占据首位,其后依次为髓芯减压术+自体骨髓间充质干细胞移植(80.23%)、髓芯减压术+自体骨髓细胞联合髂骨植骨(78.95%)、髓芯减压术+结构支撑植骨术(73.53%)、髓芯减压术+中成药联合治疗(49.35%)、髓芯减压术+补肾活血类中药(复方汤剂) (46.23%)、髓芯减压术+活血化瘀类中药(复方汤剂)(41.82%)、髓芯减压术+异体或自体松质骨植骨术(36.83%)、髓芯减压术+中医药序贯疗法(36.67%)、髓芯减压术+富血小板血浆局部注射(33.54%)、髓芯减压术+局部动脉穿刺(25.98%),而单纯髓芯减压术的干预效果最低(0.62%)。 髋关节功能评分方面:髓芯减压术+中医药序贯疗法显示出最优的干预效果。根据SUCRA值排序,髓芯减压术+中医药序贯疗法(93.85%)在所有干预措施中占据首位,其后依次为髓芯减压术+中成药联合治疗(72.46%)、髓芯减压术+静脉滴注中药注射液(64.16%)、髓芯减压术+活血化瘀类中药(复方汤剂)(61.37%)、髓芯减压术+异体或自体松质骨植骨术(53.33%)、髓芯减压术+髓腔定向递药(52.98%)、髓芯减压术+局部动脉穿刺(48.02%)、髓芯减压术+负压吸引术(47.20%)、髓芯减压术+自体骨髓间充质干细胞移植(45.38%)、髓芯减压术+结构支撑植骨术(43.13%)、髓芯减压术+富血小板血浆局部注射(42.77%)、髓芯减压术+自体骨髓单核细胞浓缩注射(37.94%)、髓芯减压术+自体源性干细胞局部植入(36.05%),而单纯髓芯减压术的干预效果最低(1.38%)。 疼痛缓解指数方面:髓芯减压术+中成药联合治疗显示出最优的干预效果。根据SUCRA值排序,髓芯减压术+中成药联合治疗(83.21%)在所有干预措施中占据首位,其后依次为髓芯减压术+活血化瘀类中药(复方汤剂)(81.65%)、髓芯减压术+自体骨髓间充质干细胞移植(55.53%)、髓芯减压术+自体源性干细胞局部植入(44.98%)、髓芯减压术+富血小板血浆局部注射(40.55%)、髓芯减压术+补肾活血类中药(复方汤剂) (40.14%)、髓芯减压术+局部动脉穿刺(36.64%),而单纯髓芯减压术的干预效果最低(17.58%)。 影像学改善指数方面:髓芯减压术+自体源性干细胞局部植入显示出最优的干预效果。根据SUCRA值排序,髓芯减压术+自体源性干细胞局部植入(82.56%)在所有干预措施中占据首位,其后依次为髓芯减压术+负压吸引术(82.02%)、髓芯减压术+髓腔定向递药(66.27%)、髓芯减压术+自体骨髓间充质干细胞移植(57.91%)、髓芯减压术+中医药序贯疗法(54.22%)、髓芯减压术+富血小板血浆局部注射(33.81%)、髓芯减压术+中成药联合治疗(22.09%),而单纯髓芯减压术的干预效果最低(1.12%)。 临床安全性指数方面:髓芯减压术+结构支撑植骨术显示出最优的干预效果。根据SUCRA值排序,髓芯减压术+结构支撑植骨术(94.56%)在所有干预措施中占据首位,其后依次为髓芯减压术+补肾活血类中药(复方汤剂) (63.06%)、髓芯减压术+异体或自体松质骨植骨术(57.38%)、髓芯减压术+自体骨髓间充质干细胞移植(43.73%)、髓芯减压术+静脉滴注中药注射液(43.41%)、髓芯减压术+活血化瘀类中药(复方汤剂)(33.49%),而单纯髓芯减压术的干预效果最低(14.37%)。"
2.7 传递性评估 由于网状证据图中未形成闭合环,各干预措施之间仅存在间接比较关系,因此进一步对传递性假设进行检验。考虑到协变量在不同干预组间分布的潜在差异可能影响间接比较的可靠性,选取年龄作为关键基线变量,采用箱线图对各干预措施下患者年龄的分布情况进行可视化分析,以评估研究人群的可比性。结果显示,大多数干预措施均提供了完整的年龄数据,研究对象的平均年龄主要集中于35-50岁之间,各组间分布相对集中,未见明显结构性差异,支持传递性假设的成立。需要说明的是,部分干预措施(如髓芯减压术+自体骨髓单核细胞浓缩注射)由于未提供完整的年龄信息,未被纳入此次评估。同时,结合性别协变量进一步评估传递性。分析显示,各干预组中男性比例大多分布在50%-70%之间,组间构成相对均衡,未见系统性偏离,提示纳入研究在性别基线特征上具备较好的可比性,见图6。"
2.8 敏感性分析 以髋关节功能评分为例,对纳入文献数不少于3篇的干预措施进行敏感性分析。采用逐一排除法逐项剔除研究,以检验模型对单个研究的依赖程度及结果的稳定性。由于网状证据图呈现出典型的星状结构,髓芯减压术为主要的比较枢纽节点,因此所有干预措施均与髓芯减压术进行直接效应比较。在以髋关节功能评分为结局指标的贝叶斯网状模型中,每剔除一项研究,均重新构建模型,并在保持MCMC迭代次数一致的前提下,评估各干预措施相对于髓芯减压术的标准化均数差变化。分析结果显示,无论剔除哪项研究,标准化均数差及其95%CrI的估计值均保持稳定,未见明显偏倚,提示模型具备良好的鲁棒性,研究结论稳健可靠,见表5与图7。"
2.9 发表偏倚 采用Egger’s回归检验及比较调整漏斗图对各结局指标的发表偏倚进行系统评估。图中圆点代表纳入的文献,横轴为标准误,纵轴为标准化均数差。结果显示,部分结局指标的漏斗图分布不对称,提示可能存在发表偏倚或小样本效应。具体而言,髋关节功能评分(P=0.020 6)与疼痛缓解指数(P=0.001 7)结局的Egger’s检验结果具有统计学意义,图中右上象限显著效应聚集,反映低标准误区域内阳性研究被发表的概率更高,提示存在报告偏倚的可能性。相较之下,综合临床疗效指数(P=0.868 5)、临床安全性指数(P=0.820 2)与影像学改善指数(P=0.056 1)结局的漏斗图分布较为对称,Egger’s检验亦未显示显著性差异,表明当前纳入研究中尚未观察到明显发表偏倚。但需注意,影像学改善指数结果接近统计学阈值,潜在偏倚风险不容忽视。综上,髋关节功能评分与疼痛缓解指数等主观性较强或测量标准异质性较高的结局更易受选择性报告影响,结果见图8。 2.10 证据总结 GRADE评估结果显示,多数干预措施在主要结局指标中具备中等等级证据支持[96],部分结局指标为高等级证据,未发现低或极低等级证据,研究结论的证据基础较为稳固,具备较高可信度。"
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