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。
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 necrosis
Objective
To 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.
Methods
From 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.
Results
According 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.
Conelusion
Use 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 necrosis
Objective
The 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.
Methods
In 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.
Results
Seven 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.
Conclusion
We 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.
引文
[1]Drescher W, Pufe T, Smeets R, et al. Avascular Necrosis of the Hip-Diagnosis and Treatme-nt [J].Z Orthop Unfall,2011,149(2):231-242.
[2]Shuai B, Shen L, Yang YP, et al.Low plasma adiponectin as a potential biomarker for osteonecrosis of the femoral head[J].J Rheumatol,2010,37(10):2151-5.
[3]吴海山.成人股骨头缺血性坏死[J].中华关节外科杂志(电子版),2007,1(1)：66-71.
[4]刘铁钢,陈卫衡.非创伤性股骨头坏死的流行病学研究[J].当代医学,2008,14(24)：64-5.
[5]艾自胜.股骨头坏死临床流行病学研究[D].同济大学.上海.2009.3.
[6]赵凤朝,李子荣,张念非,等.不同病因股骨头坏死的临床特征分析[J].中华骨科杂志,2009,29(10)：939-43.
[7]Mont MA, Jones LC,Seyler TM, et al. New treatment approaches for ostecnecrosis of the femoral head:an overview[J]. Instr Course Lect,2007,56:197-212.
[8]Sakaguchi M, Tanaka T, Fukushima W, et al. Impact of oral corticosteroid use for idiopat-hic osteonecrosis of the femoral head:a nationwide multicenter case-control study in Japan[J].J Orthop Sci,2010,15(2):185-91.
[9]Nayagam LS, Rajan SG, Khandelwal N, et al. Bilateral femoral capital avascular necrosis in a renal transplant recipient on tacrolimus-based immunosuppression[J].Nephrol Dial Transplant,2005,20(10):2262-4.
[10]Glueck CJ, Phillips HG, Cameron D, et al. Estrogen replacement in a protein S deficient patient leads to diarrhea, hyperglucagonemia, and osteonecrosis[J]. JOP,2001,2(5):323-9.
[11]Hirota Y, Hirohata T, Fukuda K, et al. Association of alcohol intake, cigarette smoking, and occupational status with the risk of idiopathic osteonecrosis of the femoral head [J]. Am J Epidemiol,1993,137(5):530-8.
[12]Sakata R. A case-control study of association between life-style, alcohol dehydrogen-ase 2 and aldehyde dehydrogenase 2 genotype and idiopathic osteonecrosis of the femoral head[J].Kurume Med J,2003,50(3-4):121-30.
[13]Matsuo K, Hirohata T, Sugioka Y, et al. Influence of alcohol intake, cigarette smoking, and occupational status on idiopathic osteonecrosis of the femoral head[J].Clin Orthop Relat Res,1988, (234):115-23.
[14]Lawal YZ, Ogirima MO, Dahiru IL,et al. Bilateral osteonecrosis of the femoral heads in a patient with systemic lupus erythematosus[J]. Ann Afr Med,2011,10(1):64-5.
[15]Adelowo 00, Oguntona S. Avascular necrosis of femoral head associated with connective tissue disease in Nigerians:case series[J]. West Afr J Med,2009,28(4):262-5.
[16]Hernigou P, Habibi A, Bachir D, et al. The natural history of asymptomatic osteonecrosis of the femoral head in adults with sickle cell disease[J].J Bone Joint Surg Am,2006, 88(12):2565-72.
[17]Akinyoola AL,Adediran IA, Asaleye CM,et al. Risk factors for osteonecrosis of the femoral head in patients with sickle cell disease[J]. Int Orthop,2009,33(4):923-6.
[18]Reinhardt K, Wagner M. Complete destruction of both femoral heads following idiopathic necrosis of the femoral heads in a diabetic patient with hyperuricemia and hyperlipo-proteinemia[J].Arch Orthop Trauma Surg,1980,96(2):135-47.
[19]Cooper A, Minutello R, Vigorita VJ, et al. Case report 763. Osteonecrosis and gout of femoral head[J]. Skeletal Radiol,1992,21(8):555-8.
[20]Montella BJ, Nunley JA, Urbaniak JR. Osteonecrosis of the femoral head associated with pregnancy. A preliminary report [J].J Bone Joint Surg Am,1999,81(6):790-8.
[21]Boechat MI, Winters WD, Hogg RJ, et al.Avascular necrosis of the femoral head in children with chronic renal disease[J]. Radiology,2001,218(2):411-3.
[22]Hauzeur JP, Malaise M, Gangji V. Osteonecrosis in inflammatory bowel diseases:a review of the literature[J]. Acta Gastroenterol Belg,2009,72(3):327-34.
[23]Vogel M, Strach K, Ehren K, et al. Avascular necrosis of the bone after organ transplant-ation [J]. Internist(Berl),2010,51(5):662,664-6.
[24]Lieberman JR, Roth KM, Elsissy P, et al. Symptomatic osteonecrosis of the hip and knee after cardiac transplantation[J]. J Arthroplasty,2008,23(1):90-6.
[25]Karkoulias K, Charokopos N, Kaparianos A, et al. Aseptic femoral head necrosis in a patient receiving long term courses of inhaled and intranasal corticosteroids[J]. Tuberk Toraks,2007,55 (2):182-5.
[26]Renedo RJ, Sousa MM, Perez SF, et al. Avascular necrosis of the femoral head in patients with Hodgkin's disease[J]. Hip Int,2010,20(4):473-81.
[27]李子荣,孙伟,屈辉,等.皮质类固醇与骨坏死关系的临床研究[J].中华外科杂志,2005,43(16)：1048-53.
[28]陈卫衡,林娜,王胜,等.非创伤性股骨头坏死与激素、酒精的相关性研究[J].中国医药导报,2006,3(27)：338-340.
[29]何伟.糖皮质激素与股骨头坏死[J].中国处方药,2004,3(24)：22-6.
[30]Jones JP Jr. Intravascular coagulation and osteoncerosis[J]. Clin Orthop Relat Res, 1992, (277):41-53.
[31]王义生,张春霖,王利民,等.双支撑骨柱移植术治疗成人晚期股骨头缺血坏死[J].中华骨科杂志,1995,15(9)：584.
[32]Liu YF, Chen WM, Lin YF, et al.Type II collagen gene variants and inherited osteone-crosis of the femoral head[J].N Engl J Med,2005,352(22):2294-301.
[33]Su P, Li R, Liu S, et al. Age at onset-dependent presentations of premature hip osteo-arthritis, avascular necrosis of the femoral head, or Legg-Calve-Perthes disease in a single family, consequent upon a p.Gly1170Ser mutation of COL2A1[J]. Arthritis Rheum, 2008,58(6):1701-6.
[34]He W, Li K. Incidence of genetic polymorphisms involved in lipid metabolism among Chinese patients with osteonecrosis of the femoral head[J]. Acta Orthop,2009,80(3):325-9.
[35]刘丙立,李子荣,孙伟,等.酒精性股骨头坏死与亚甲基四氢叶酸还原酶677 C/T单核苷酸多态性的关系[J].中国修复重建外科杂志,2009,23(9)：1079-82.
[36]Molia AC, Strady C, Rouger C, et al. Osteonecrosis in six HIV-infected patients recei- ving highly active antiretroviral therapy[J]. Ann Pharmacother,2004,38(12):2050-4.
[37]Yombi JC, Vandercam B, Wilmes D, et al. Osteonecrosis of the femoral head in patients with typel human immunodeficiency virus infection:clinical analysis and review[J]. Clin Rheumatol,2009,28(7):815-23.
[38]樊粤光,袁浩,何伟等.692例股骨头缺血性坏死病因调查分析[J].广州中医学院学报,1994,11(1)：29-31.
[39]Lequesne M, Bensasson M, Kahn MF, et al. Gout, hyperuricemia and femur head osteonecr-osis[J].Rev Rhum Mal Osteoartic,1975,42(3):177-83.
[40]Hernigou P, Poignard A, Nogier A, et al. Fate of very small asymptomatic stage-Ⅰ osteo-necrotic lesions of the hip[J].J Bone Joint Surg Am,2004,86-A(12):2589-2593.
[41]Hernigou P, Habibi A, Bachir D, et al. The natural history of asymptomatic osteonecrosis of the femoral head in adults with sickle cell disease[J]. J Bone Joint Surg Am,2006, 88(12):2565-2572.
[42]Min BW,Song KS, Cho CH, et al. Untreated Asymptomatic Hips in Patients with osteone-crosis of the Femoral Head[J]. Clin Orthop Relat Res,2008,466:1087-92.
[43]Nam KW, Kim YL, Yoo JJ, et al. Fate of untreated asymptomatic osteonecrosis of the femoral head[J].J Bone Joint Surg Am,2008,90(3):477-484.
[44]董天华.骨坏死病因、诊断与治疗[M].1999：35.
[45]Lee MS, Chang YH, Chao EK, et al. Conditions before Collapse of the Contralateral Hip in Osteonecrosis of the Femoral Head[J]. Chang Gung Med J,2002,25(4):228-237.
[46]Jergesen HE, Khan AS. The natural history of untreated asymptomatic hips in patients who have non-traumatic osteonecrosis[J]. J Bone Joint Surg Am,1997,79(3):359-363.
[47]Nishii T, Sugano N, Ohzono K, et al. Significance of lesion size and location in the prediction of collapse of osteonecrosis of the femoral head:a new three-dimensional quantification using magnetic resonance imaging[J].J Orthop Res,2002,20(1):130-6.
[48]Mont MA,Zywiel MG,Marker DR,et al. The natural history of untreated asymptomatic osteonecrosis of the femoral head:a systematic literature review[J].J Bone Joint Surg Am,2010,92(12):2165-70.
[49]刘艳,陈丽云,卫洪昌.证型标准化研究的文献统计分析方法学探讨[J].江西中医学院学报,2009,22(2)：88-90.
[50]国家中医药管理局.中医病证诊断疗效标准[M].南京：南京大学出版社,1994：193.
[51]卫生部.中药新药临床研究指导原则[M].北京：中国医药科技出版社,2002：354.
[52]王和鸣.中医伤科学[M].北京：中国中医药出版社,2002：323.
[53]何伟.中西医结合骨伤科学[M].广东：广东高等教育出版社,2007：460.
[54]陈卫衡,林娜,王荣田,等.基于聚类主成分分析的股骨头坏死的证候及证型规律探讨.全国股骨头坏死保髋治疗及其相关疾病研究进展研讨会.北京.中国.2009：102.
[55]何伟,袁浩,蔡振基.中西医结合治疗股骨头缺血性坏死[J].新中医,1995,27(8)：26-28.
[56]牛振华,牛立刚,牛艳丽,等.中药治疗股骨头坏死[J].世界中医骨伤科杂志,2001,3(2)：163-165.
[57]熊屹.孙成榆教授治疗股骨头缺血坏死的经验[J].贵阳中医学院学报,2007,29(4)：15-16.
[58]诸福度,崔明,吴材康,等.股骨头缺血性坏死的中医药治疗[J].中国骨伤,1994,7(6)：46.
[59]袁捷,张军,林吉.通络生骨胶囊治疗股骨头坏死的临床研究[J].中药新药与临床药理,2004,15(6)：429-431.
[60]何科,祁开泽.复骨健步片治疗股骨头缺血坏死30例[J].湖南中医杂志,2009,25(1)：34-35.
[61]刘少军,王海彬,袁浩.生脉成骨片对早期股骨头坏死塌陷的影响[J].新中医,2007,39(9)：49-51.
[62]张和平.骨血通丸治疗股骨头缺血性坏死204例临床观察[J].中医正骨,2008,20(8)：63.
[63]曾平,何伟,韦标方.复方生脉成骨胶囊治疗塌陷前期非创伤性股骨头坏死的临床研究[J].中国中医骨伤科杂志,2010,18(02)：14-17.
[64]李勃,杨光,袁浩.生脉成骨胶囊治疗股骨颈骨折后股骨头坏死的疗效观察[J].甘肃中医,2009,22(5)：20-21.
[65]孙文山.股骨头缺血性坏死治疗常用药及组方规律探析[J].中医正骨,2003,15(4)：59-60.
[66]杨春梅.参茸花香胶囊治疗股骨头坏死129例[J].牡丹江医学院学报,2007,28(1)：40-41.
[67]赵万军,肖鲁伟,童培建,等.右归饮、鹿马片对激素诱导的兔股骨头坏死血浆雌二醇、睾酮的影响及疗效观察[J].中医正骨,2000,12(1)：35.
[68]沈映君.中药药理学[M].北京：人民卫生出版社,2000：629-632.
[69]刘少军,袁浩.股骨头坏死的中医临床思路与方法探讨[J].中国医药学报,2002,17(1)：44-47.
[70]乔德荣,刘红,吕海潮.股骨头坏死的病因病机与诊治—袁浩教授临床经验总结[J].内蒙古中医药,2006,(4)：23-24.
[71]何海军,陈卫衡.将生存质量引入中医药治疗股骨头坏死疗效评价体系的思考[J].中国中医骨伤科杂志,2009,17(4)：62-63.
[72]李刚,王均玉.股骨头坏死的中医认识与研究现状[J].山西中医,2010,26(5)：52-54.
[73]Yin L, Li YB, Wang YS, et al. Dexamethasone-induced adipogenesis in primary marrow stromal cell cultures:mechanism of steroid-induced osteonecrosis[J]. Chin Med J,2006, 119(7):581-588.
[74]Suh KT, Kim SW, Roh HL, et al. Decreased osteogenic differenttiation of mesenchymal stem cells in alcohol-induced osteonecrosis[J]. Clin Orthop Relat Res,2005, (431):220-225.
[75]徐传毅.袁浩教授以血瘀论治激素性股骨头坏死经验[J].中医药学刊,2003,21(2)：194-195.
[76]陈卫衡,刘道兵,张洪美,等.股骨头坏死的三期四型辨证思路[J].中国中医基础医学杂志,2003,9(12)：51-2.
[77]何伟,徐传毅,李雄,等.酒精性股骨头坏死血液流变学改变及意义[J].中医正骨,2001,13(10)：8-9.
[78]陈卫衡,刘道兵,孙凯,等.股骨头坏死中医证型与相关理化指标关系的研究[J].中国骨伤,2005,18(9)：513-516.
[79]汪晓燕,陈卫衡,宋剑南,等.非创伤性股骨头坏死及其证候与血脂代谢的关系[J].中国中医基础医学杂志,2007,13(5)：368-369.
[80]刘保延,王永炎.证候、证、症的概念及其关系的研究[J].中医杂志,2007,48(4)：293-298.
[81]张鹤山.股骨头坏死诊断与治疗的专家建议[J].中华骨科杂志,2007,27(2)：146-148.
[82]Gardeniers JW. ARCO international stage of osteonecrosis[J]. ARCO Newsletter,1993, 5:79-82.
[83]Hicks CL, von Baeyer CL, Spafford PA, et al. The Face Pain Scale Revised:toward a common metric in pediatric pain measurement[J]. Pain,2001,93:173-183.
[84]赵培荣,庄奇新,乔瑞华,等.股骨头缺血坏死骨髓水肿的MRI研究[J].实用放射学杂志,2006,22(7)：835-7.
[85]Mitchell DG, Steinberg ME, Dalinka MK, et al. Magnetic resonance imaging of the ischemic hip. Alterations within the osteonecrotic, viable, and reactive zones [J]. Clin Orthop Relat Res,1989, (244):60-77.
[86]Mont MA, Jones LC, Seyler TM, et al. New treatment approaches for ostecnecrosis of the femoral head:an overview[J]. Instr Course Lect,2007,56:197-212.
[87]陈镇秋.酒精性股骨头坏死保髋疗效的相关性研究[D].广州中医药大学.广州.2009.4.
[88]吴淮.补肾活血祛痰法预防兔激素性股骨头坏死的实验研究[D].广州中医药大学.广州.2010.4.
[89]张进,徐志伟,陈群,等.干细胞与中医基础理论中的先天之精学说[J].中国临床康复,2006,10(7)：189-92.
[90]陈薇,曾和平,王春燕,等.中药龟板提取物化学成分及其调控鼠骨髓间充质干细胞(rMSCs)增殖活性的实验研究[J].化学学报,2007,65(3)：265-70.
[91]曾意荣,樊粤光,刘红,等.补肾活血中药对大鼠骨髓间充质干细胞体外增殖的影响[J].中国组织工程研究与临床康复,2008,12(8)：1581-5.
[92]王和鸣,王力,李楠.巴戟天对骨髓基质细胞向成骨细胞分化过程Cbf a 1表达的影响[J].中国中医骨伤科杂志,2004,12(6)：22-6,29.
[93]Lee Ck, Hansen HT, Weiss AB. The'silent hip'of idiopathic ischemic necrosis of the femoral head in adults[J].J Bone Joint Surg Am,1980,62:795-800.
[94]Ito H, Matsuno T, Kaneda K. Prognosis of early stage avascular necrosis of the femoral head[J]. Clin Orthop Relat Res,1999,358:149-57.
[95]石少辉.股骨头坏死硬化带的观察(D).北京.北京协和医学院.2009.4.
[96]Kokubo T,Takatori Y, Ninomiya S, et al. Magnetic resonance imaging and scintigraphy of avascular necrosis of the femoral head. Prediction of subsequent segmental collapse [J].Clin Orthop Relat Res,1992, (277):54-60.
[97]Matsuo K, Irie N. Osteoclast-osteoblast communication[J]. Arch Biochem Biophys,2008, 473(2):201-209.
[98]Glimcher MJ, Kenzora JE. The biology of osteonecrosis of the human femoral head and its clinical implications:II.The pathologic changes in the femoral head as an organ and in the hip joint[J]. Clin Orthop Relat Res,1979, (139):283-312.
[99]Tanamas SK, Wluka AE, Pelletier JP, et al. The association between subchondral bone cys-ts and tibial cartilage volume and risk of joint replacement in people with knee osteo-arthritis:a longitudinal study[J]. Arthritis Res Ther,2010,12(2):R58.
[100]Brown TD, Mutschler TA,Ferquson JR. A non-linear finite element analysis of some early collapse processes in femoral head osteonecrosis[J]. J Biomech,1982,15(9):705-715.
[101]Buckley PD, Gearen PF, Petty RW. Structural bone grafting for early atraumatic avascu- lar necrosis of the femoral head[J].J Bone Joint Surg (Am),1991,73(9):1357.
[102]Etienne G, Mont MA, Ragland PS. The diagnosis and treatment of nontraumatic osteo-necrosis of the femoral head[J].Instr Course Lect,2004,53:67-85.
[103]何伟,曾勤,张庆文,等.非创伤性股骨头坏死骨髓水肿与疼痛分级及坏死分期相关性的研究[J].中国修复重建外科杂志,2008,22(3)：299-302.
[104]Iida S, Harada Y, Shimizu K, et al. Correlation between bone marrow edema and collapse of the femoral head in steroid-induced osteonecrosis[J]. AJR Am J Roentgenol,2000,174 (3):735-743.
[105]Miyanishi K, Kaminomachi S, Hara T, et al. A subchondral fracture in transient osteo-porosis of the hip[J]. Skeletal Radiol,2007,36(7):677-680.
[106]Ito H, Matsuno T, Minami A. Relationship between bone marrow edema and development of symptoms in patients with osteonecrosis of the femoral head[J]. AJR Am J Roentgenol, 2006,186(6):1761-70.
[107]李勇.从骨髓水肿探讨股骨头坏死从瘀论治的辨证基础[D].广州中医药大学.广州.2009.4.
[108]Koo KH, Ahn IO, Kin R, et al. Bone marrow edema and associated pain in early stage osteonecrosis of the femoral head:prospective study with serial MR images [J]. Radiology, 1999,213 (3):715-722.
[109]谢道海,丁乙,付引弟.正常人和股骨头缺血性坏死的髋关节腔液体的MRI[J].临床放射学杂志,2000,19(1)：53-55.
[110]Oreffo R0, Virdi AS, Trif f itt JT. Modulation of osteogenesis and adipogenesis by human serum in human bone marrow cultures[J]. Eur J Cell Biol,1997,74(3):251-261.
[111]王义生,李杰,殷力,等.酒精性骨坏死发病机制的分子生物学实验研究[J].河南医学研究,2004,13(1)：23-27.
[112]章建华,童培健,袁临益,等.丹参注射液防治下肢深静脉血栓形成的实验研究[J].中医正骨,2005,17(9)：3-4.
[113]Jones JP. Intravaseular coagulation and osteonecrosis[J]. Clin Orthop,1992,277:41.
[114]童培建,肖鲁伟,季卫锋,等.脂质代谢及破骨细胞活性在激素性股骨头坏死塌陷发生过程中的作用研究[J].中国骨伤,2009,22(2)：110-113.
[115]吴夏勃,温建民,方逵,等.酒精性股骨头缺血性坏死的血脂变化与气滞血瘀的关系[J].中国中医骨伤科杂志,2004,12(3)：14-16.
[116]李瑞娟,杨文明.中医证候研究方法学探讨[J].中医药临床杂志,2010,22(2)：109：112.
[117]贾运滨,魏江磊.数据挖掘技术在中医证候研究中的应用述评[J].中国中医急症,2010,19(7)：1184-1186.
[118]周态,褚娜,李洁.中医证候研究中的分类算法方法学研究[J].中西医结合学报,2010,8(10)：911-916.
[119]黄粤,高颖,马斌.中医证候研究常用数据挖掘方法述评[J].中医药学报,2010,38(3)：6-10.
[120]Nishii T, Sugano N, Ohzono K, et al. Progression and cessation of collapse in osteo-necrosis of the femoral head[J]. Clin Orthop Relat Res,2002, (400):149-157.
[121]魏秋实,何伟,张庆文,等.股骨头坏死塌陷预测方法的临床意义[J].广东医学,2011,32(19)：2523-2526.
[122]何伟,徐传毅,樊粤光,等.活血化瘀中药对激素性股骨头坏死血浆TXB2与6—keto—PGF1α影响的实验研究[J].中国骨伤,2002,15(9)：531-533.
[124]刘少军,邓彦,王海彬.通络生骨胶囊对骨髓基质干细胞成骨和成脂肪双向分化的影响[J].四川中医,2008,26(3)：22-24.
[125]杨俊兴,方斌,徐传毅.通络生骨胶囊对激素性股骨头坏死大鼠骨钙素、降钙素与骨密度的影响[J].广州中医药大学学报,2007,24(1)：41-43.
[126]袁捷,林吉,徐传毅,等.通络生骨胶囊预防激素性股骨头缺血性坏死的药效学实验[J].中药新药与临床药理,2005,16(3)：185-188.
[127]李雄,袁浩.袁浩教授对股骨头坏死中医药论治的学术思想[J].中国中医骨伤科杂志,1999,7(1)：61-62.
[128]史达.木豆叶联合骨髓间充质干细胞治疗股骨头坏死的实验与相关临床研究[D].广州.广州中医药大学.2007.4.
[129]赵云霞.动静脉溶栓、静滴川芎嗪治疗ALDVT疗效观察[J].中原医刊,2004,33(8)：50-51.
[130]李文若,王海彬.川芎嗪、血液循环泵预防全髋置换术后深静脉血栓形成50例[J].新中医,2006,38(4)：73.
[131]罗月中,李芸,李勇,等.补肾健骨法预防肾病综合症患者激素性股骨头坏死的临床研究[J].中医正骨,2011,23(1)：3-6.
[132]梁晓春.中医药临床疗效评价中的问题和思考[J].中华中医药杂志,2006,21(6)：356-358.
[133]商洪才,张伯礼,李幼平.中医药临床疗效评价实践中的思路与方法[J].中国中西医结合杂志,2008,28(3)：266-268.
[134]Ficat RP. Idiopathic bone necrosis of the femoral head. Early diagnosis and treatment[J].J Bone Joint Surg(Br),1985,67(1):3-9.
[135]褚玉山,曹建民,孔伟东,等.非创伤性股骨头缺血性坏死骨髓水肿的数字减影血管造影研究[J].医学研究生学报,2006,19：712-5.
[136]黄宇琨,黄宇琛,邱氟.中医的医学模式探讨[J].河南中医,2011,31(11)：1236-1238.
[137]Ha YC, Jung WH, Kim JR, et al. Prediction of collapse in femoral head osteonecrosis: a modified Kerboul method with use of magnetic resonance images[J]. J Bone Joint Surg Am,2006,88 Suppl 3:35-40.
[138]赵凤朝,李子荣,张念非,等.坏死面积比例在预测股骨头塌陷中的价值[J].中华骨科杂志,2005,25(09)：12-15.
[139]雷新玮.非创伤性股骨头缺血性坏死塌陷预测的生物力学及影像学研究[D].天津.天津医科大学.2008.5.
[140]Hernigou P, Lambotte JC. Volumetric analysis of osteonecrosis of the femur:Anatomi-cal correlation using MRI[J].J Bone Joint Surg Br,2001,83(5):672-675.
[141]Steinberg DR, Steinberg ME, Garino JP, et al. Determining lesion size in osteonecrosis of the femoral head[J].J Bone Joint Surg Am,2006,88 (Suppl 3):27-34.
[142]韦竑宇.三维CT重建股骨头坏死体积、分布、形状的测定及塌陷预测[D].北京.北京协和医学院.2009.4.
[143]Sugano N, Atsumi T, Ohzono K, et al. The 2001 revised criteria for diagnosis, classify-cation, and staging of idiopathic osteonecrosis of the femoral head[J].J Orthop Sci, 2002,7(5):601-605.
[144]史振才,李子荣,孙伟,等.计算机处理MR图像股骨头坏死体积测定与初步力学测验[J].中华放射学杂志,2006,40(3)：288-292.
[145]Ficat RP, Arlet J. Necrosis of the femoral head//Hungefford DS,ed. Ischemia and necrosis of bone. Baltimore:Williams and Wilkins,1980:53-74.
[146]Steinberg ME, Hayken GD, Steinberg DR. A quantitative system for staging avascular-necrosis[J]. J Bone Joint Surg Br,1995,77:34-41.
[147]Mont MA, Hungerford DS. Non-traumatic avascular necrosis of the femoral head[J].J Bone Joint Sury(Am),1995,77(3):459-74.
[148]庞智晖.股骨头前外侧柱与激素性股骨头坏死预后和保髋疗效的相关性研究[D].广州.广州中医药大学.2008.4.
[149]曾平.非创伤性股骨头坏死塌陷前期的临床研究[D].广州.广州中医药大学.2008.4.