Abstract: Background　Osteoporosis（OP）is a common clinical phenomenon in patients with knee osteoarthritis （KOA），but there lacks an unified homotherapy for heteropathy of OP and KOA. Objective　To explore the multi-dimensional relationship of "traditional Chinese medicine（TCM）syndrome type- clinical feature-molecular typing" in patients with postmenopausal KOA，thus providing references for homotherapy for heteropathy of OP and KOA. Methods　A total of 300 patients with postmenopausal KOA and treated with knee replacement surgery at the Joint Center of the Third Affiliated Hospital of Guangzhou University of Chinese Medicine from 2021 to 2023 were retrospectively included. According to the results of bone density measurement（BMD），patients were divided into three groups：normal bone density group，osteopenia group，and osteoporosis group，with 100 patients in each group. The correlation between the TCM syndrome type and BMD was analyzed in postmenopausal KOA patients by a correspondence analysis. The clinical symptoms［Western Ontario and McMaster Universities Osteoarthritis Index（WOMAC）score］，laboratory indicators［C-reactive protein（CRP），erythrocyte sedimentation rate （ESR），serum calcium，phosphorus，alkaline phosphatase（ALP），and lipids）］，and imaging indicators［Kellgren-Lawrence（K-L）grade，hip knee ankle angle（HKA），joint line convergence angle（JLCA），tibial plateau subchondral area，and low-density area］were investigated and compared among postmenopausal KOA patients with different TCM syndrome types. The knee joint tissues of KOA patients with different TCM syndrome types were analyzed by molecular biology，and the key target molecules were clarified. Subsequently，the key targets obtained by bioinformatics were detected by Western blotting and immunohistochemistry experiments，and their expression differences were compared. An initial molecular classification of TCM syndrome types was established in patients with postmenopausal KOA. Results　The main TCM syndrome types in postmenopausal women with KOA included the liver and kidney deficiency（n=122），Qi stagnation and blood stasis（n=96），cold and damp obstruction（n=72），and phlegm and blood stasis（n=10）. Qi stagnation and blood stasis was the major TCM syndrome type in postmenopausal KOA patients with a normal BMD，while the liver and kidney deficiency dominant in those with decreased bone density and osteoporosis. There was a significant difference in the distribution of TCM syndrome times among the three groups（χ2=55.27，P<0.001）. Logistic regression analysis showed that patients with the TCM syndrome of liver and kidney deficiency had a significantly higher risk of decreased bone density（OR=2.37，95%CI 1.20-4.69，P=0.013） and osteoporosis（OR=3.39，95%CI2.41-4.76，P<0.001）. Patients with the TCM syndrome of liver and kidney deficiency had significantly higher WOMAC body function scores and total WOMAC scores than those with Qi stagnation and blood stasis （P<0.05）. There were no significant differences in ESR，CRP，total calcium，phosphorus，ALP，and four blood lipids between patients with the TCM syndrome types of liver and kidney deficiency，and Qi stagnation and blood stasis（P>0.05）. The HKA was significantly smaller in patients with the TCM syndrome of liver and kidney deficiency than those with Qi stagnation and blood stasis，and the JLCA and tibial plateau subcutaneous low-density area were significantly larger（P<0.05）. There was no significant difference in the area of the tibial plateau between the two TCM types of patients（P > 0.05）. There was a significant difference in K-L grade between the TCM syndrome types of liver and kidney deficiency and Qi stagnation and blood stasis （P<0.05），with the former being significantly greater than the latter（P<0.05）. Western blotting and immunohistochemistry experiments showed that the expression levels of C-X-C chemokine ligand 8（CXCL8），tumor necrosis factor-alpha（TNF-α） and interleukin-1beta（IL-1β）molecules were significantly higher in patients with the TCM syndrome type of Qi stagnation and blood stasis，while the expression levels of peroxisome proliferator-activated receptor gamma（PPAR-γ），stearoyl-CoA desaturase（SCD）and CCAAT/enhancer-binding protein alpha（C/EBPα）molecules were significantly higher in patients with the TCM syndrome type of liver and kidney deficiency（P<0.05）. Conclusion　The multidimensional relationships between "TCM syndrome type-clinical features-molecular typing" in postmenopausal KOA patients are as follows：patients with Qi stagnation and blood stasis have normal bone mass and increased expressions of inflammation-related molecules，and those with liver and kidney deficiency have decreased/osteoporotic bone mass and increased expressions of lipid metabolism-related molecules. Compared with Qi stagnation and blood stasis，patients with liver and kidney deficiency have a higher risk of decreased bone mass，osteoporosis，and lower limb inversion deformity. Their tibial plateau subchondral low-density area is significantly larger，knee function is significantly impaired，and the K-L grade is more severe.

Key words: Osteoarthritis, knee；Osteoporosis, postmenopausal；TCM syndrome type；Clinical features；Molecular typing；Same treatment for different diseases

摘要： 背景　膝骨关节炎（KOA）患者合并骨质疏松症（OP）临床常见，但二者的异病同治目前尚无统一方案。目的　探讨绝经后KOA患者“中医证型-临床特征-分子分型”的多维关系，为KOA和OP的异病同治提供研究基础。方法　回顾性选取2021—2023年于广州中医药大学第三附属医院关节中心住院确诊为绝经后KOA且接受膝关节置换术的患者300例作为研究对象，按照骨密度检查结果将其分为骨量正常组、骨量减少组和骨质疏松组，每组各100例。采用对应分析法探讨绝经后KOA患者的中医证型与骨密度的相关性。调查不同中医证型绝经后KOA患者的临床症状［西安大略和麦克马斯特大学骨关节指数（WOMAC评分）］、实验室检查指标（C反应蛋白、红细胞沉降率、血钙、血磷、碱性磷酸酶、血脂）和影像学指标［K-L分级、髋膝踝角（HKA）、关节线夹角（JLCA）、胫骨平台下面积及低密度影面积］，并进行比较。对不同中医证型KOA患者膝关节标本进行分子生物学分析，明确关键标靶分子，随后通过Western blotting法和免疫组化实验检测生物信息学分析获得的关键靶标，比较不同中医症候绝经后KOA患者的分子表达差异，初步建立不同中医证候的分子分型。结果　300例绝经后KOA患者的主要中医证候可归纳为肝肾亏虚、气滞血瘀、寒湿痹阻和痰瘀互结证，分别为122、96、72、10例，其中骨量正常组中医证候主要表现为气滞血瘀证，而骨量减少、骨质疏松组中医证候则主要表现为肝肾亏虚证。３组不同骨密度类型患者的中医证候比较，差异有统计学意义（χ2=55.27，P<0.001）。Logistic回归分析显示，肝肾亏虚证患者出现骨量减少（OR=2.37，95%CI=1.20~4.69，P=0.013）、骨质疏松（OR=3.39，95%CI=2.41~4.76，P<0.001）的风险更高。肝肾亏虚证患者WOMAC身体功能评分与WOMAC总分高于气滞血瘀证患者（P<0.05），肝肾亏虚证和气滞血瘀证患者红细胞沉降率、C反应蛋白、总钙、磷和碱性磷酸酶及血脂四项比较，差异均无统计学意义（P>0.05）。肝肾亏虚证患者的HKA <气滞血瘀证患者，JLCA、胫骨平台下低密度影面积 >于气滞血瘀证患者（P<0.05），两个证型患者的胫骨平台下面积比较，差异无统计学意义（P>0.05）。肝肾亏虚证和气滞血瘀证患者K-L分级比较，差异有统计学意义（P<0.05），肝肾亏虚证大于气滞血瘀证患者，差异有统计学意义（P<0.05）。Western blotting和免疫组化实验表明，气滞血瘀证患者的CXCL8、TNF-α、IL-1β分子表达量升高，而肝肾亏虚证PPAR-γ、SCD和C/EBPα分子表达量升高（P<0.05）。结论　绝经后KOA患者“中医证型-临床特征-分子分型”的多维关系为：“气滞血瘀-骨量正常-炎症相关分子表达升高”和“肝肾亏虚-骨量减少/骨质疏松-脂代谢相关分子表达升高”。相较气滞血瘀证而言，肝肾亏虚证患者发生骨量减少、骨质疏松的风险更高，更易发生下肢内翻畸形，其胫骨平台下低密度影面积明显更大，膝关节功能显著降低，K-L分级更为严重。

关键词: 骨关节炎, 膝；骨质疏松, 绝经后；中医证型；临床特征；分子分型；异病同治