【作者】 魏秋实；

【导师】 何伟；

【作者基本信息】 广州中医药大学 ， 中医骨伤科学， 2012， 博士

【摘要】 本文临床研究共分两部分,第一部分针对股骨头坏死患者中医证候特点及证型规范化进行研究,在此基础上,第二部分针对临床上单纯应用中医药治疗的股骨头坏死患者进行疗效评价,并建立中医药保髋的适应症。第一部分股骨头坏死患者证候分布特点及中医证型规范化研究目的：运用临床流行病学调查的方法从股骨头坏死患者临床病例资料中筛选常见病证之外的特征性临床辨证要点,结合统计学方法,建立具有科学性、实用性的中医证候及证型体系。方法：2008年7月～2011年10月,选择广州中医药大学第一附属医院三骨科收治的资料完整的股骨头坏死患者532例,其中回顾性分析458例,前瞻性分析74例,平均年龄42.31±12.03岁,根据《股骨头坏死中医证候流行病学临床病例调查表》进行调查,并采取74例前瞻性研究患者的血液进行实验室检查,获得股骨头坏死证候分布特点,提取相关数据,经统计学处理后初步筛选出不同证型之间的差异指标,采用Person相关分析和logistic回归分析,以P值的大小作为衡量证候主次的标准,建立中医证型诊断模型,最后应用诊断性试验评价方法对模型预测能力进行验证。为股骨头坏死“病证同治”提供辨证基础。结果：本次流行病学调查结果显示,根据原始证型诊断标准,本组病例男女比例为2.67。(1)气滞血瘀型105例,常见于50-59岁,半体力劳动者,在创伤性股骨头坏死中分布比例较高,X线表现主要以“股骨头内硬化带不明显,头内密度不均”为特点,MRI所示关节积液程度以2级为主。经Person相关分析和logistic回归分析,关节疼痛、X线示股骨头内硬化带不明显,头内密度不均、舌暗、关节刺痛、舌边有瘀斑、MRI示2级关节积液是气滞血瘀型的主要证候(P<0.01),痛处固定、关节活动受限、腹股沟区压痛、心烦、脉弦、苔白作为气滞血瘀型的次要证候(P<0.05),预测准确率为91.9%,Youden’s指数为0.684。(2)肾虚血瘀型222例,常见于16-29岁、≥70岁,半体力劳动者,多发于华中、华南、华东地区,在激素性股骨头坏死中分布比例较高,以FPS-R C级疼痛为主,X线表现主要以“股骨头内存在连续硬化带”为特点,MRI所示骨髓水肿程度以0、2级为主,关节积液程度以0、1、3级为主。血清200/S、30/S、3/S、Arbe、EPT各指标计数值均高于其它两证型,具有统计学差异。经Person相关分析和logistic回归分析,关节隐痛、X线示股骨头内存在连续硬化带、神疲乏力、MRI示2级骨髓水肿、苔白、潮热盗汗、脉细数是肾虚血瘀型的主要证候(P<0.01),关节沉重、失眠、腰膝酸软、MRI示3级关节积液、血清3/S↑、血清200/S↑是肾虚血瘀型的次要证候(P<0.05),预测准确率为79.7%,Youden’s指数为0.581。(3)痰瘀蕴结型205例,常见于40-69岁,体力劳动与脑力劳动者,多发于华南地区,在酒精性股骨头坏死中分布比例较高,以FPS-R D级疼痛为主,X线表现主要以“股骨头内存在硬化带+囊性改变”为特点,MRI所示骨髓水肿程度以1、3级为主,关节积液程度以1、3级为主。血清CHOL、TG、ApoB、LDL指标计数值增高,ApoA、HDL计数值降低。除LDL外,其余五个指标与气滞血瘀型比较,具有统计学差异；ApoA、HDL与肾虚血瘀型比较,具有统计学差异。经Person相关分析和logistic回归分析,关节酸痛、行走乏力、关节沉重、舌淡胖、苔腻、X线示股骨头内存在硬化带+囊性改变、MRI示3级骨髓水肿是痰瘀蕴结型的主要证候(P<0.01),心烦、脉滑、MRI示1级关节积液、脉濡缓、血清ApoB↑、血清HDL↓是痰瘀蕴结型的次要证候(P<0.05),预测准确率为82.5%,Youden’s指数为0.630。结论：运用临床流行病学调查与统计学研究方法,初步筛查出股骨头坏死临床特征性因素,包括影像学特征性表现与实验室特征性指标,并结合ONFH中医四诊内容,建立了宏观与微观指标相结合的股骨头坏死中医证型诊断模型,提高了辨证论治的精确性,为临床疗效准确评价奠定了基础。第二部分中医药治疗股骨头坏死的疗效评价及适应症的规范化研究目的：评估中医药治疗股骨头坏死的临床疗效,分析预后影响因素对股骨头生存率的影响。方法：2009年6月～2011年5月,回顾性研究91例(133髋)股骨头坏死接受中医药治疗的患者,平均年龄38.81±11.99岁,平均随访14.04±6.77个月。其中气滞血瘀型31例,肾虚血瘀型37例,痰瘀蕴结型23例;ARCOI期11髋,Ⅱ期43髋(CT所示是否存在软骨下骨折,分为稳定Ⅱ期31髋,不稳定Ⅱ期12髋),Ⅲ期58髋,Ⅳ期21髋；通过FPS-R评分评估关节疼痛程度,Harris评分评估髋关节功能,SF-36量表评价生存质量,影像学测量评价塌陷进展情况；以股骨头塌陷>4mm作为研究终点,采用Cox风险比例模型分析疼痛时间、坏死形态、坏死范围、坏死分期及坏死部位对中医药治疗后股骨头生存率的影响,探讨中医药治疗股骨头坏死的适应症。结果：至末次随访时,有7髋转为手术治疗。(1)中医药治疗前(133髋)和治疗后末次随访时(126髋)的各证型患者总体FPS-R评分比较有显著性差异(P<0.01),平均FPS-R评分从2.51±1.95下降到1.03±0.99。(2)治疗前(133髋)和治疗后末次随访时(126髋)各证型患者总体Harris评分比较有显著统计学差异(P<0.01),平均Harris评分从81.04±13.79提高到88.61±8.91。85例126髋(除外转为手术的病例)服用中药治疗前与末次随访时各证型患者SF-36评分各维度比较均有显著统计学差异(P<0.01)。(3)影像学进展评价：49例(59髋)出现了X线进展,其中治疗前无塌陷的54髋,治疗后有4例(4髋)塌陷<4mm,2例(3髋)塌陷≥4mm；治疗前塌陷的79髋,治疗后有19例(24髋)塌陷进展(<4mm),24例(28髋)塌陷进展(>-4mm)。①疼痛时间：<12个月治疗前无塌陷的40髋,治疗后有3髋出现影像学进展,进展率为7.5%,塌陷的31髋有16髋进展,进展率为51.6%；≥12个月的治疗前无塌陷的14髋有4髋进展,进展率为28.6%,塌陷的48髋有36髋进展,进展率为75%。②坏死形态：9髋中心型坏死,治疗前均无塌陷,治疗后无进展；周围型坏死治疗前无塌陷的45髋,治疗后有7髋出现影像学进展,进展率为15.6%,塌陷的79髋有52髋进展,进展率为65.8%。③坏死范围(体积百分比)：≤30%治疗前无塌陷的30髋有1髋进展,进展率为3.3%,塌陷的13髋有6髋进展,进展率为46.2%；30-40%治疗前无塌陷的17髋有1髋进展,进展率为5.9%,塌陷的36髋有23髋进展,进展率为63.9%；≥40%治疗前无塌陷的7髋有5髋进展,进展率为71.4%,塌陷的30髋有23髋进展,进展率为76.7%。④坏死分期(ARCO分期)：Ⅰ期11髋,治疗后无进展；稳定Ⅱ期31髋有3髋进展,进展率为9.7%；不稳定Ⅱ期12髋有4髋进展,进展率为33.3%；Ⅲ期58髋有41髋进展,进展率为70.7%；Ⅳ期21髋有11髋进展,进展率为52.4%。⑤坏死部位(JIC分型)：A型3髋,治疗前均无塌陷,治疗后无进展；B型24髋,治疗前无塌陷,治疗后1髋进展,进展率为4.2%；C1型治疗前无塌陷的19髋有3髋进展,进展率为15.8%,塌陷的48髋有30髋进展,进展率为62.5%；C2型治疗前无塌陷的8髋有3髋进展,进展率为37.5%,塌陷的31髋有22髋进展,进展率为71.0%。(4)坏死股骨头的生存率(以股骨头塌陷>4mm作为观察终点)：本组中医药治疗后共有26例31髋股骨头塌陷>4mm,平均失败时间是13.58±7.01个月(2-28个月)。随访至29个月(14.04±6.77个月)的生存率为76.7%,平均生存时间为22.99±0.86个月。经Cox回归分析结果表明疼痛时间、坏死范围(坏死区体积百分比)和坏死分期(ARCO分期)影响疗效是危险因素。Kaplan-Meier生存曲线分析结果表明：①无痛、疼痛时间≤3个月、3-6个月、6-12个月、≥12个月的患髋生存率分别为100%、83.3%、80.0%、66.7%、66.1%：Log-rank检验X2=22.69,P<0.01,提示疼痛时间≥12个月时,中医药保髋疗效较差。②体积百分比≤30%、30-40%、≥40%的患髋生存率分别为93.0%、77.4%、56.8%；Log-rank检验X2=13.68,P<0.01。③ARCO I期、稳定Ⅱ期、不稳定Ⅱ期、Ⅲ期、Ⅳ期的的患髋生存率分别为100%、96.8%、75.0%、67.2%、61.9%;Log-rank检验x2=20.13,P<0.01。④JIC分型A型、B型、C1型、C2型的的患髋生存率分别为100%、95.8%、76.1%、64.1%；Log-rank检验x2=15.95,P<0.01。⑤中心型坏死、周围型坏死的患髋生存率分别为100%、75.0%,Log-rank检验X2=3.95,P<0.05。结论：合理选择适用范围,中医药治疗ONFH对缓解症状、改善功能、提高生活质量方面具有一定的疗效。中医药保髋适应症：①前提条件：疼痛程度属于B级或以下,同时患髋Harris评分等级为优、良或可。②绝对适应症：中心型、JICA/B型坏死或无痛的ARCO Ⅰ期坏死,可不考虑疼痛时间、坏死范围、分期与形态。③ARCOⅡ期(稳定),发生ONFH后停止服用激素,若无痛,可不考虑坏死范围、疼痛时间、坏死部位与坏死形态,若发生疼痛,则视为头内不稳定,与ARCO Ⅱ期(不稳定)条件一致。④相对适应症：ARCO Ⅱ期(不稳定)、Ⅲ期或Ⅳ期,同时满足坏死体积百分比<40%、疼痛时间<12个月、坏死部位属于C1型。更多还原

【Abstract】 The clinical research in this article is divided into two parts, in the first part, we will aim the standardized research on syndrome type and symptoms characteristics of traditional Chinese medicine(TCM) of femoral head necrosis, the second part will aim the standardized research on indications and effect evaluation of herb therapeutic of femoral head necrosis.Part1The standardized research on syndrome type and symptoms characteristics of traditional Chinese medicine of femoral head necrosisObjectiveTo filter characteristic clinical syndrome points outside of the common syndrome in the use of the clinical epidemiological investigation from the patients suffered from femoral head necrosis, combined with statistical methods, to establish the TCM syndrome and syndrome type system of scientific and practical.MethodsFrom July2008to October2011,532patients whose suffered from femoral head necrosis were collected complete information from department of orthopaedics in First Affiliated Hospital of Guangzhou University of TCM, including458cases retrospective analysis,74cases prospective analysis, the average age of42.31±12.03years, to investigate the cases according to ’clinical cases questionnaire of TCM syndrome epidemiological’, and take the blood from74cases prospective study of patients for laboratory tests, to get the syndrome distribution characteristics of femoral head necrosis, and extract relevant data, after statistically, initial screening of the different indicators between the different syndrome types, adopting Person correlation analysis and logistic regression analysis, according to the size of the P-value as a measure standard of syndromes with primary and secondary, establishing diagnostic model of symptoms of TCM, finally, using assessment method of diagnostic tests to verify the model predictive ability. To provide a dialectical basis for diseases and syndromes contemporary treatment of femoral head necrosis.ResultsAccording to original diagnostic criteria of syndrome type, the epidemiol-ogical survey results show that the male to female ratio was2.67.(1)Qi stagnation and blood stasis type:105cases, common in50to59years, semi-manual workers, a higher distribution proportion in traumatic femoral head necrosis,’No obvious sclerosis and uneven density of femoral head’ is the main performance of the X-ray,’two grade joint effusion’is the main performance of the MRI. By Person correlation analysis and logistic regression analysis, Joint pain, The main performance of the X-ray, Dark tongue, Joint sting, Petechiae at the edge of the tongue, The main performance of the MRI are the main syndrome of the Qi stagnation and blood stasis type(P<0.01). Sore fixed, Limited joint mobility, Inguinal tenderness, Upset, Pulse string, White fur are the secondary syndrome of the Qi stagnation and blood stasis type(P <0.05). Prediction accuracy rate was91.9%, Youden’s index is0.684.(2) Deficiency of the kidney and blood stasis type:222cases, common in16to29years,≥70years, semi-manual workers, a higher distribution proportion in Steroid-induced femoral head necrosis, FPS-R mainly shows C-level pain,’Continuous sclerosis of femoral head’is the main performance of the X-ray,’Zero/two grade Bone marrow edema and Zero/one/three grade joint effusion’ are the main performance of the MRI. Serum200/S,30/S,3/S, Arbe and EPT index count value are higher than the other two syndrome type, there was considered statistically significant. By Person correlation analysis and logistic regression analysis, Joint pain,’Continuous sclerosis of femoral head’of the X-ray, fatigue,’two grade Bone marrow edema’of the MRI, White fur, Hot flushes and night sweats, Pulse breakdown are the main syndrome of the Deficiency of the kidney and blood stasis type (P<0.01). Joint heavy, Insomnia, lumbar acid,’three grade joint effusion’of the MRI, Serum3/S t,200/S t are the secondary syndrome of the Deficiency of the kidney and blood stasis type(P<0.05). Prediction accuracy rate was79.7%, Youden’s index is0.581.(3)Phlegm and Stasis Accumulation type:205cases, common in40to69years, manual and mental workers, a higher distribution proportion in Alcohol-induced femoral head necrosis, FPS-R mainly shows D-level pain,’sclerosis and cystic of femoral head’is the main performance of the X-ray,’One/three grade Bone marrow edema and one/three grade joint effusion’are the main performance of the MRI. Serum CHOL, TG, ApoB and ApoA, HDL, contrast to the Qi stagnation and blood stasis type and ApoA, HDL contrast to the Deficiency of the kidney and blood stasis type, there was considered statistically significant.By Person correlation analysis and logistic regression analysis, Joint pain, Walking fatigue, Joint heavy, Tongue pale, Greasy fur,’sclerosis and cystic of femoral head’of the X-ray,’three grade Bone marrow edema’of the MRI are the main syndrome of Phlegm and Stasis Accumulation type (P<0.01). Upset, Slippery pulse,’one grade joint effusion’of the MRI, slow pulse, Serum ApoB↑, HDL↓are the secondary syndrome of Phlegm and Stasis Accumulation type (P<0.05). Prediction accuracy rate was82.5%, Youden’s index is0.630.ConelusionUse of clinical epidemiology survey and statistical research methods, initial filter characteristic clinical syndrome points of femoral head necrosis. Including the performance of the imaging and characteristics indicators of laboratory tests. Combined with four diagnostic content of TCM of femoral head necrosis. Establishing diagnostic model of symptoms of TCM which combined with macro and micro indicators for improving the accuracy of the diagnosis and treatment and laiding the foundation for an accurate assessment of the clinical efficacy. Part2The standardized research on indications and effect evaluation of herb therapeutic of femoral head necrosisObjectiveThe aim of this study was to evaluate the clinical efficacy of herb therapeutic of femoral head necrosis and analyse the influence of prognostic factors for femoral head survival.MethodsIn this retrospective study the follow-up of91patients with133osteonecrotic femoral heads treated with herb was assessed between Jule2009and May2011. The average age at the time of the treatment was38.81±11.99years.All patients were available for follow-up at a mean of14.04±6.77months. Including31cases Qi stagnation and blood stasis type,37cases Deficiency of the kidney and blood stasis type and23cases Phlegm and Stasis Accumulation type; According to the ARCO classification system,11hip had stage-Ⅰ disease,43hips had stage-Ⅱ disease(Based on the existence of the subchondral fracture from CT,31hips had stable-stage-Ⅱ and12hips had unstable-stage-Ⅱ disease),58hips had stage-Ⅲ disease and21hips had stage-Ⅳ disease;Outcome measures that were used included a FPS-R score,a limb-specific score (Harris hip score), SF-36score, radiographic outcome measures, and survivorship analysis with femoral head collapse)4mm as the end point. Multivariate analysis was performed with use of the Cox proportional hazards model with censoring to identify the independent prognostic factors associated with clinical and radiographic failure for exploring the indications of herb therapeutic of femoral head necrosis.ResultsSeven hips were converted to a surgery at an average of14.04±6.77months (range, two to twenty-nine months) after treatment with herb.(1) Total evalu-ation of three syndrom types:The mean FPS-R within the survivor group after treatment with herb decreased post-treatment during follow-up from2.51±1.95to1.03±0.99(there was considered statistically significant, P<0.01)(2) Total evaluation of three syndrom type:The mean HHS within the survivor group after treatment with herb increased post-treatment during follow-up from81.04±13.79to88.61±8.91(P<0.01). Independent evaluation of three syndrom type:The mean SF-36score within the survivor group after treatment with herb contrast to post-treatment, there was considered statistically significant (P<0.01).(3) Radiographic progression occurred in49cases59hips after treatment with herb.6cases7hips showed progression on the pre-treatment (54hips without collapse) radiographs, including4cases4hips with collapsed <4mm,2cases3hips with collapse≥4mm;43cases52hips showed progression on the pre-treatment(79hips with collapse) radiographs, including19cases 24hips with collapse<4mm,22cases28hips with collapse≥4mm.①Pain time<12months,3hips (7.5%) showed progression on the pre-treatment (40hips without collapse) radiographs,16hips (51.6%) showed progression on the pre-treatment (31hips with collapsed) radiographs;≥12months,4hips (28.6%) showed progression on the pre-treatment(14hips without collapse) radiographs,36hips (75.0%) showed progression on the pre-treatment(48hips with collapse) radiographs.②Necrosis shape of central type,9hips showed no progression on the radiographs; Necrosis shape of Peripheral type,7hips (15.6%) showed progression on the pre-treatment(45hips without collapse) radiographs,52hips (65.8%) showed progression on the pre-treatment (79hips with collapse) radiographs.③Necrosis area(necrotic zone volume ratio)≤30%,1hips (3.3%) showed progression on the pre-treatment(30hips without collapse) radiographs,6hips (46.2%) showed progression on the pre-treatment(13hips with collapse) radiographs;30～40%,1hips (5.9%) showed progression on the pre-treatment(17hips without collapse) radiographs,23hips (63.9%) showed progression on the pre-treatment(36hips with collapse) radiographs;≥40%,5hips (71.4%) showed progression on the pre-treatment (7hips without collapse) radiographs,23hips (76.7%) showed progression on the pre-treatment (30hips with collapse) radiographs.④ARCO classification stage-Ⅰ,11hips showed no progression on the radiographs; stable-stage-Ⅱ,3hips (9.7%) showed progression on the pre-treatment (31hips) radiographs;unstable-stage-Ⅱ,4hips (33.3%) showed progression on the pre-tr eatment(12hips) radiographs; stage-Ⅲ,41hips (70.7%) showed progression on the pre-treatment(58hips) radiographs;stage-Ⅳ,11hips (52.4%) showed progression on the pre-treatment(21hips) radiographs.⑤JIC classification A type,3hips showed no progression on the radiographs;B type,1hips (4.2%) showed progression on the pre-treatment(24hips) radiographs;CI type,3hips (15.8%) showed progression on the pre-treatment(19hips without collapse) radiographs,30hips (62.5%) showed progression on the pre-treatment(48hips with collapse) radiographs;C2type,3hips (37.5%) showed progression on the pre-treatment (8hips without collapse) radiographs,22hips (71.0%) showed progression on the pre-treatment (31hips with collapse) radiographs.(4) Survivorship analysis with femoral head(collapsing>4mm as the end point): there were26cases31hips with collapsing≥4mm, The average failure time at the final follow-up was13.58±7.01months (range, two to twenty-eight months). The estimated survival rates were76.7%at final follow-up for hips, The average survivor time at the final follow-up was22.99±0.86months. The Cox proportional-hazards model revealed that Pain time、necrotic zone volume ratio and ARCO classification were prognostic factor related to Radiographic progression(collapsing≥4mm). The Kaplan-Meier survivorship curve revealed the results, as follows:①The survival rates were100%at painless,83.3%at≤three months,80.0%at three～six months,66.7%at six～twelve months and66.1%at≥twelve months. The log-rank test performed x2=22.69, P<0.01.②necrotic zone volume ratio, the survival rates were91.8%at≤30percents,77.4%at30～40percents, and56.8%at≥40percents. The log-rank test performed x2=13.68, P<0.01.③ARCO classification, the survival rates were100%at Stage-Ⅰ,96.8%at stable-stage-Ⅱ,75.0%at unstable-stage-Ⅱ,67.2%at stage-Ⅲ and61.9%at stage-IV. The log-rank test performed x2=20.13, P<0.01.④JIC classification, the survival rates were100%at A type,95.8%at B type,76.1%at C1type and64.1%at C2type. The log-rank test performed x2=15.95, P<0.01.⑤Necrosis shape, the survival rates were100%at central type and75.0%at Peripheral type. The log-rank test performed x2=3.95, P<0.05.ConclusionWe believe that this method can be suitable for right patients.The herb therapeutic of femoral head necrosis can resolve the pain, improve the functi-on and the quality of life. The indications of herb therapeutic of femoral head necrosis is:①Prerequisite for this method is FPS-F is a Class B or below, at the same time, Harris score is excellent, good or moderate.②Absolute indications:Necrosis shape of central type, JIC A/B type, or ARCO Stage-Ⅰ with painless, there is no significant relationship was found between the clinical efficacy and such factors as Pain time, Necrosis area, ARCO classification and Necrosis shape.③ARCO stable-stage-Ⅱ, the patients stopped to use of corticosteroids after suffered from femoral head necrosis, if painless, there is no significant relationship was found between the clinical efficacy and such factors as necrosis area, pain time, JIC classification and necrosis shape;if pain, it should be seen as unstable-stage-Ⅱ.④Relative indications:unstable-stage-Ⅱ, stage-Ⅲ and stage-Ⅳ, at the same time, necrotic zone volume ratio)<40%, Pain time<12months, JIC Cl type.更多还原