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Article(id=1211269159422390757, tenantId=1146029695717560320, journalId=1189873630562394117, issueId=1211269157790806494, articleNumber=null, orderNo=null, doi=10.11855/j.issn.0577-7402.2021.04.07, pmid=null, cstr=null, oa=null, hot=null, price=null, onlineType=0, articleFormat=0, articleType=null, articleTypeStr=research-article, receivedDate=1610294400000, receivedDateStr=2021-01-11, revisedDate=1614614400000, revisedDateStr=2021-03-02, acceptedDate=null, acceptedDateStr=null, onlineDate=1766718671899, onlineDateStr=2025-12-26, pubDate=1619539200000, pubDateStr=2021-04-28, doiRegisterDate=null, doiRegisterDateStr=null, onlineIssueDate=1766718671899, onlineIssueDateStr=2025-12-26, onlineJustAcceptDate=null, onlineJustAcceptDateStr=null, onlineFirstDate=null, onlineFirstDateStr=null, sourceXml=null, magXml=null, createTime=1766718671899, creator=13701087609, updateTime=1766718671899, updator=13701087609, issue=Issue{id=1211269157790806494, tenantId=1146029695717560320, journalId=1189873630562394117, year='2021', volume='46', issue='4', pageStart='319', pageEnd='424', issueExtLink='null', onlineDate='null', pubDate='null', beforeIssueId=null, nextIssueId=null, price=null, status=1, issueComplete=1, articleOrder=1, issueType=-1, specialIssue=0, createTime=1766718671510, creator=13701087609, updateTime=1766718756000, updator=13701087609, preIssue=null, nextIssue=null, ext={EN=IssueExt(id=1211269512217882745, tenantId=1146029695717560320, journalId=1189873630562394117, issueId=1211269157790806494, language=EN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=), CN=IssueExt(id=1211269512217882746, tenantId=1146029695717560320, journalId=1189873630562394117, issueId=1211269157790806494, language=CN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=)}, issueFiles=null}, startPage=361, endPage=366, ext={EN=ArticleExt(id=1211269159669854700, articleId=1211269159422390757, tenantId=1146029695717560320, journalId=1189873630562394117, language=EN, title=Clinical diagnostic value of dickkopf-1 test for menopausal women with rheumatoid arthritis secondary to osteoporosis, columnId=1190310109000602400, journalTitle=Medical Journal of Chinese People’s Liberation Army, columnName=Clinical Research, runingTitle=null, highlight=null, articleAbstract=

Objective To explore the clinical diagnostic value of serum dickkopf-1 (DKK1) level in menopausal women with rheumatoid arthritis (RA) secondary to osteoporosis (OP). Methods A total of 236 menopausal female patients diagnosed in the Second Affiliated Hospital of Nanchang University from May 2019 to September 2020 were collected, including 44 patients with OP secondary to RA set as RA+OP group, 150 patients with RA without OP set as RA group, and 42 patients with OP set as OP group, respectively. At the same time, 43 healthy menopausal women in our hospital at the same period were selected as control group. Serum DKK1 was detected by ELISA. The erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) were detected by capillary method and rate-scattering turbidimetry, respectively; The bone metabolism indexes such as parathyroid hormone(PTH), type Ⅰ procollagen C-terminal propeptide (CTX), 25-hydroxy vitamin D3 [25-(OH)D3], type Ⅰ procollagen N-terminal propeptide (PINP) and osteocalcin were detected by electro-chemiluminescence method. While, bone alkaline phosphatase (BALP)was determined by chromatography; The bone mineral density (BMD), Z-score and T-score of total hip joint and lumbar spine L1-4 in all patients were detected by Lunar Prodigy dual energy X-ray absorptiometry. The area under the ROC curve was used to analyze the diagnostic efficacy of DKK1 in patients with RA combined with OP and those with RA or OP alone. Results DKK1, ESR, CRP, BMI, PTH, CTX, 25-(OH)D3, total hip BMD, total hip T-score, total hip Z-score, lumber spine L1-4 BMD, lumber spine L1-4 T score and lumber spine L1-4 Z score, CTX and BALP were significantly different among the 4 groups (P<0.01 or P<0.05); The difference of fracture story was statistically significant between RA+OP group and OP group (P<0.01). Bivariate correlation analysis conducted between DKK1 and each index showed that serum DKK1 was positively correlated with ESR, CRP, fracture story and BALP (P<0.05), and negatively correlated with BMI, total hip BMD, total hip T-score, total hip Z-score, lumber spine L1-4 BMD, lumber spine L1-4 T-score and lumber spine L1-4 Z-score, PINP, 25-(OH)D3 and PTH (P<0.01 or P<0.05). Multiple linear regression analysis showed that DKK1 was positively correlated with CRP and BMI (R2=0.048, β=0.034, P=0.003; and R2=0.008, β=0.178, P=0.042, respectively), and negatively correlated with PINP and total hip T-score (R2=0.003, β=–0.022, P=0.009; and R2=0.235, β=–2.375, P=0.000). ROC curve analysis showed that and the optimal cut-off value of DKK1 in the diagnosis of RA secondary to OP was 9.21 μg/L, the sensitivity was 93.2%, the specificity was 91.1%, and the Kappa consistency index was 0.630. The diagnostic efficiency of DKK1 for OP was higher than that of DKK1 for RA, and the Kappa consistency index was relatively stable. Conclusion The serum level of DKK1 is increased in menopausal women with RA secondary to OP, the detection of DKK1 has good diagnostic efficiency in the diagnosis of menopausal women with RA secondary to OP.

, correspAuthors=Li-Ming Tan, authorNote=null, correspAuthorsNote=
*E-mail:
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目的 探讨血清Dickkopf-1(DKK1)对女性绝经期类风湿关节炎(RA)继发骨质疏松(OP)的临床诊断价值。方法 选择2019年5月—2020年9月在南昌大学第二附属医院确诊的236例绝经期患者，其中，44例RA继发OP患者为RA+OP组，150例无OP的RA患者为RA组，42例无RA的OP患者为OP组。以该院同期43名绝经期健康女性作为对照组。采用ELISA法检测血清DKK1水平；分别采用毛细管法及速率散射比浊法检测红细胞沉降率(ESR)及C反应蛋白(CRP)水平；采用电化学发光法检测骨代谢指标甲状旁腺素(PTH)、Ⅰ型胶原C-末端肽(CTX)、25-羟维生素D3[25-(OH)D3]、Ⅰ型前胶原N-末端肽(PINP)及骨钙素(OC)水平，采用色谱法检测骨碱性磷酸酶(BALP)水平；采用Lunar Prodigy双能X线骨密度仪检测所有患者包括全髋及腰椎L1-4等部位的骨密度(BMD)、Z分数、T分数；采用ROC曲线下面积分析DKK1对RA、OP及RA继发OP的诊断效能。结果 四组间DKK1、ESR、CRP、BMI、PTH、CTX、25-(OH)D3、全髋BMD、全髋T分数、BALP、全髋Z分数、腰椎L1-4 BMD、腰椎L1-4 T分数、腰椎L1-4 Z分数等指标差异均有统计学意义(P<0.01或P<0.05)；RA+OP组骨折史与OP组比较差异有统计学意义(P<0.01)。双变量相关性分析及多元线性回归分析结果显示，血清DKK1与ESR、CRP、骨折史及BALP呈正相关(P<0.05)，与BMI、全髋BMD、全髋T分数、全髋Z分数、腰椎L1-4 BMD、腰椎L1-4 T分数、腰椎L1-4 Z分数、PINP、25-(OH)D3、PTH等指标呈负相关(P<0.01或P<0.05)。多元线性回归分析结果显示，DKK1与CRP及BMI呈独立正相关(R2=0.048，β=0.034，P=0.003；R2=0.008，β=0.178，P=0.042)，与PINP及全髋T分数呈独立负相关(R2=0.003，β=–0.022，P=0.009；R2=0.235，β=–2.375，P=0.000)。ROC曲线分析结果显示，DKK1诊断RA继发OP的最佳截断值为9.21 μg/L，灵敏度为93.2%，特异度为91.1%，Kappa一致性指数为0.630，且DKK1对OP的诊断效能高于对RA的效能，Kappa一致性指数较稳定。结论 女性绝经期RA继发OP患者血清DKK1水平增高，且对绝经期患者RA继发OP具有较好的诊断价值。

, correspAuthors=谭立明, authorNote=null, correspAuthorsNote=
谭立明，E-mail：
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裴子欢，硕士研究生，主要从事自身免疫性疾病等方面的研究

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裴子欢，硕士研究生，主要从事自身免疫性疾病等方面的研究

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裴子欢，硕士研究生，主要从事自身免疫性疾病等方面的研究

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DKK1. Dickkopf-1；RA. 类风湿关节炎；OP. 骨质疏松；ROC. 受试者工作特征曲线

, figureFileSmall=ZHNt8uN4pGvNMJpBcXSM0Q==, figureFileBig=zhW0lXmxJi+7+dIKvQhPuQ==, tableContent=null), ArticleFig(id=1211322035259699648, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1211269159422390757, language=EN, label=Tab.1, caption=

Comparison of the general data among each group

, figureFileSmall=null, figureFileBig=null, tableContent=
指标对照组(n=43)RA组(n=150)OP组(n=42)RA+OP组(n=44)P
ESR[mm/h，M(Q1，Q3)]36.0(3.6，97.0)62.4(2.0，120.1)(2)37.5(3.0，97.0)(4)58.5(7.0，129.4)(2)(6)0.000
CRP[mg/L，M(Q1，Q3)]3.5(1.0，72.0)15.9(1.5，142.4)(2)4.7(1.6，98.5)(1)(4)21.3(1.9，124.0)(2)(6)0.000
身高[cm，M(Q1，Q3)]160.1(140.0，170.0)158.4(143.0，176.0)158.0(140.0，172.0)(2)158.5(141.0，170.0)(1)0.002
体重[kg，M(Q1，Q3)]60(45，76)53(35，76)(2)55.5(38，88)(2)50(34，76)(2)(5)0.000
BMI[kg/m2，M(Q1，Q3)]23.2(18.0，30.0)21.1(14.0，27.0)(2)22.9(16.0，32.0)(2)(3)20.2(15.0，29.0)(2)(6)0.000
骨折史[例(%)]0(0.0)4(2.7)21(50.0)(2)(4)4(9.1)(6)0.000
DKK1[μg/L，$\bar{x}±s$]5.63±1.637.09±3.07(2)12.05±6.11(2)(4)17.17±7.96(2)(4)(6)0.000
PTH[pg/ml，M(Q1，Q3)]50.2(22.3，108)50.2(16.0，79.7)46.4(16.3，83.5)39.2(11.8，86.4)(2)(4)0.005
CTX[pg/ml，M(Q1，Q3)]443.8(56.4，1025)464.2(89.9，2584289.3(67.3，1523)(1)(4)435.9(56.4，1796)(5)0.015
25-(OH)D3[ng/ml，M(Q1，Q3)]30.1(21.1，67.9)29.9(5.9，56.4)(2)29.1(8.9，59.2)(2)34.3(9.1，65.0)(5)0.009
PINP[ng/ml，M(Q1，Q3)]43.5(12.0，176.0)42.8(11.1，217)39.9(5.0，113.0)(1)46.2(7.0，176.0)0.189
BALP[U/L，M(Q1，Q3)]75.0(40.0，100.0)75.0(50.0，115.0)(2)75.0(50.0，115.0)77.5(45.0，105.0)0.025
骨钙素[ng/ml，M(Q1，Q3)]15.2(5.3，34.5)17.1(5.2，88.2)13.9(4.5，75.1)17.5(1.9，75.1)0.206
全髋BMD[g/cm2，M(Q1，Q3)]0.9(0.6，1.7)0.8(0.5，1.1)(2)0.7(0.5，0.9)(2)(4)0.6(0.4，0.8)(2)(4)(6)0.000
全髋T分数[g/cm2，M(Q1，Q3)]–0.6(–2.8，1.6)–1.7(–3.4，1.8)(2)–2.2(–3.8，–0.3)(2)(4)–2.8(–4.0，–1.4)(2)(4)(6)0.000
全髋Z分数[g/cm2，M(Q1，Q3)]0.1(–2.2，1.5)–0.3(–1.4，2.0)(1)–0.5(–2.8，1.5)(2)(4)–1.15(–2.9，0.1)(2)(4)(6)0.000
腰椎L1-4 BMD[g/cm2，M(Q1，Q3)]1.1(0.7~2.0)0.9(0.7~1.3)(2)0.8(0.5~1.5)(2)(4)0.8(0.7~1.8)(2)(4)(5)0.000
腰椎L1-4 T分数[g/cm2，M(Q1，Q3)]–0.6(–2.6，1.6)–1.4(–2.8，1.8)(2)–2.8(–5.1，–0.3)(2)(4)–2.5(–3.7，1.2)(2)(3)(6)0.000
腰椎L1-4 Z分数[g/cm2，M(Q1，Q3)]0.7(–2.1，2.0)0.5(–1.7，1.6)–1.3(–4.3，1.6)(2)(4)–0.2(–2.6，2.3)(1)(4)(6)0.000
), ArticleFig(id=1211322035347780034, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1211269159422390757, language=CN, label=表1, caption=

各组患者一般资料比较

, figureFileSmall=null, figureFileBig=null, tableContent=
指标对照组(n=43)RA组(n=150)OP组(n=42)RA+OP组(n=44)P
ESR[mm/h，M(Q1，Q3)]36.0(3.6，97.0)62.4(2.0，120.1)(2)37.5(3.0，97.0)(4)58.5(7.0，129.4)(2)(6)0.000
CRP[mg/L，M(Q1，Q3)]3.5(1.0，72.0)15.9(1.5，142.4)(2)4.7(1.6，98.5)(1)(4)21.3(1.9，124.0)(2)(6)0.000
身高[cm，M(Q1，Q3)]160.1(140.0，170.0)158.4(143.0，176.0)158.0(140.0，172.0)(2)158.5(141.0，170.0)(1)0.002
体重[kg，M(Q1，Q3)]60(45，76)53(35，76)(2)55.5(38，88)(2)50(34，76)(2)(5)0.000
BMI[kg/m2，M(Q1，Q3)]23.2(18.0，30.0)21.1(14.0，27.0)(2)22.9(16.0，32.0)(2)(3)20.2(15.0，29.0)(2)(6)0.000
骨折史[例(%)]0(0.0)4(2.7)21(50.0)(2)(4)4(9.1)(6)0.000
DKK1[μg/L，$\bar{x}±s$]5.63±1.637.09±3.07(2)12.05±6.11(2)(4)17.17±7.96(2)(4)(6)0.000
PTH[pg/ml，M(Q1，Q3)]50.2(22.3，108)50.2(16.0，79.7)46.4(16.3，83.5)39.2(11.8，86.4)(2)(4)0.005
CTX[pg/ml，M(Q1，Q3)]443.8(56.4，1025)464.2(89.9，2584289.3(67.3，1523)(1)(4)435.9(56.4，1796)(5)0.015
25-(OH)D3[ng/ml，M(Q1，Q3)]30.1(21.1，67.9)29.9(5.9，56.4)(2)29.1(8.9，59.2)(2)34.3(9.1，65.0)(5)0.009
PINP[ng/ml，M(Q1，Q3)]43.5(12.0，176.0)42.8(11.1，217)39.9(5.0，113.0)(1)46.2(7.0，176.0)0.189
BALP[U/L，M(Q1，Q3)]75.0(40.0，100.0)75.0(50.0，115.0)(2)75.0(50.0，115.0)77.5(45.0，105.0)0.025
骨钙素[ng/ml，M(Q1，Q3)]15.2(5.3，34.5)17.1(5.2，88.2)13.9(4.5，75.1)17.5(1.9，75.1)0.206
全髋BMD[g/cm2，M(Q1，Q3)]0.9(0.6，1.7)0.8(0.5，1.1)(2)0.7(0.5，0.9)(2)(4)0.6(0.4，0.8)(2)(4)(6)0.000
全髋T分数[g/cm2，M(Q1，Q3)]–0.6(–2.8，1.6)–1.7(–3.4，1.8)(2)–2.2(–3.8，–0.3)(2)(4)–2.8(–4.0，–1.4)(2)(4)(6)0.000
全髋Z分数[g/cm2，M(Q1，Q3)]0.1(–2.2，1.5)–0.3(–1.4，2.0)(1)–0.5(–2.8，1.5)(2)(4)–1.15(–2.9，0.1)(2)(4)(6)0.000
腰椎L1-4 BMD[g/cm2，M(Q1，Q3)]1.1(0.7~2.0)0.9(0.7~1.3)(2)0.8(0.5~1.5)(2)(4)0.8(0.7~1.8)(2)(4)(5)0.000
腰椎L1-4 T分数[g/cm2，M(Q1，Q3)]–0.6(–2.6，1.6)–1.4(–2.8，1.8)(2)–2.8(–5.1，–0.3)(2)(4)–2.5(–3.7，1.2)(2)(3)(6)0.000
腰椎L1-4 Z分数[g/cm2，M(Q1，Q3)]0.7(–2.1，2.0)0.5(–1.7，1.6)–1.3(–4.3，1.6)(2)(4)–0.2(–2.6，2.3)(1)(4)(6)0.000
), ArticleFig(id=1211322035435860420, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1211269159422390757, language=EN, label=Tab.2, caption=

Correlation between DKK1 level and each parameter

, figureFileSmall=null, figureFileBig=null, tableContent=
变量rP
ESR0.1300.007
CRP0.2400.000
BMI0.2000.000
骨折史0.3910.000
PTH–0.1330.006
CTX0.0280.566
25-(OH)D3–0.1060.028
PINP–0.1150.016
BALP0.1140.017
骨钙素0.0060.896
全髋BMD–0.4710.000
全髋T分数–0.5500.000
全髋Z分数–0.2370.000
腰椎L1-4BMD–0.4190.000
腰椎L1-4T分数–0.5200.000
腰椎L1-4Z分数–0.2980.000
), ArticleFig(id=1211322035507163590, tenantId=1146029695717560320, journalId=1189873630562394117, articleId=1211269159422390757, language=CN, label=表2, caption=

血清DKK1水平与各指标的相关性

, figureFileSmall=null, figureFileBig=null, tableContent=
变量rP
ESR0.1300.007
CRP0.2400.000
BMI0.2000.000
骨折史0.3910.000
PTH–0.1330.006
CTX0.0280.566
25-(OH)D3–0.1060.028
PINP–0.1150.016
BALP0.1140.017
骨钙素0.0060.896
全髋BMD–0.4710.000
全髋T分数–0.5500.000
全髋Z分数–0.2370.000
腰椎L1-4BMD–0.4190.000
腰椎L1-4T分数–0.5200.000
腰椎L1-4Z分数–0.2980.000
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Dickkopf-1检测对女性绝经期类风湿关节炎继发骨质疏松的临床诊断价值
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裴子欢 1 , 黄家翌 1 , 刘宇晗 1 , 胡廷婷 1 , 李小航 1 , 李旭 1 , 曾婷婷 2 , 田永建 3 , 余建林 1 , 吴洋 1 , 谭立明 1, *
解放军医学杂志 | 临床研究 2021,46(4): 361-366
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解放军医学杂志 | 临床研究 2021, 46(4): 361-366
Dickkopf-1检测对女性绝经期类风湿关节炎继发骨质疏松的临床诊断价值
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裴子欢1, 黄家翌1, 刘宇晗1, 胡廷婷1, 李小航1, 李旭1, 曾婷婷2, 田永建3, 余建林1, 吴洋1, 谭立明1, *
作者信息
  • 1南昌大学第二附属医院检验科/江西省检验医学重点实验室，南昌 330006
  • 2南昌大学第一附属医院检验科，南昌 330006
  • 3安徽省阜阳市人民医院检验科，安徽 阜阳 236000

    • 裴子欢，硕士研究生，主要从事自身免疫性疾病等方面的研究

通讯作者:

谭立明，E-mail：
Clinical diagnostic value of dickkopf-1 test for menopausal women with rheumatoid arthritis secondary to osteoporosis
Zi-Huan Pei1, Jia-Yi Huang1, Yu-Han Liu1, Ting-Ting Hu1, Xiao-Hang Li1, Xu Li1, Ting-Ting Zeng2, Yong-Jian Tian3, Jian-Lin Yu1, Yang Wu1, Li-Ming Tan1, *
Affiliations
  • 1Department of Clinical Laboratory, the Second Affiliated Hospital of Nanchang University, Jiangxi Key Laboratory of Laboratory Medicine, Nanchang 330006, China
  • 2Department of Clinical Laboratory, the First Affiliated Hospital of Nanchang University, Nanchang 330006, China
  • 3Department of Clinical Laboratory, People's Hospital of Fuyang City, Fuyang, Anhui 236000, China
出版时间: 2021-04-28 doi: 10.11855/j.issn.0577-7402.2021.04.07
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摘要
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目的 探讨血清Dickkopf-1(DKK1)对女性绝经期类风湿关节炎(RA)继发骨质疏松(OP)的临床诊断价值。方法 选择2019年5月—2020年9月在南昌大学第二附属医院确诊的236例绝经期患者，其中，44例RA继发OP患者为RA+OP组，150例无OP的RA患者为RA组，42例无RA的OP患者为OP组。以该院同期43名绝经期健康女性作为对照组。采用ELISA法检测血清DKK1水平；分别采用毛细管法及速率散射比浊法检测红细胞沉降率(ESR)及C反应蛋白(CRP)水平；采用电化学发光法检测骨代谢指标甲状旁腺素(PTH)、Ⅰ型胶原C-末端肽(CTX)、25-羟维生素D3[25-(OH)D3]、Ⅰ型前胶原N-末端肽(PINP)及骨钙素(OC)水平，采用色谱法检测骨碱性磷酸酶(BALP)水平；采用Lunar Prodigy双能X线骨密度仪检测所有患者包括全髋及腰椎L1-4等部位的骨密度(BMD)、Z分数、T分数；采用ROC曲线下面积分析DKK1对RA、OP及RA继发OP的诊断效能。结果 四组间DKK1、ESR、CRP、BMI、PTH、CTX、25-(OH)D3、全髋BMD、全髋T分数、BALP、全髋Z分数、腰椎L1-4 BMD、腰椎L1-4 T分数、腰椎L1-4 Z分数等指标差异均有统计学意义(P<0.01或P<0.05)；RA+OP组骨折史与OP组比较差异有统计学意义(P<0.01)。双变量相关性分析及多元线性回归分析结果显示，血清DKK1与ESR、CRP、骨折史及BALP呈正相关(P<0.05)，与BMI、全髋BMD、全髋T分数、全髋Z分数、腰椎L1-4 BMD、腰椎L1-4 T分数、腰椎L1-4 Z分数、PINP、25-(OH)D3、PTH等指标呈负相关(P<0.01或P<0.05)。多元线性回归分析结果显示，DKK1与CRP及BMI呈独立正相关(R2=0.048，β=0.034，P=0.003；R2=0.008，β=0.178，P=0.042)，与PINP及全髋T分数呈独立负相关(R2=0.003，β=–0.022，P=0.009；R2=0.235，β=–2.375，P=0.000)。ROC曲线分析结果显示，DKK1诊断RA继发OP的最佳截断值为9.21 μg/L，灵敏度为93.2%，特异度为91.1%，Kappa一致性指数为0.630，且DKK1对OP的诊断效能高于对RA的效能，Kappa一致性指数较稳定。结论 女性绝经期RA继发OP患者血清DKK1水平增高，且对绝经期患者RA继发OP具有较好的诊断价值。

绝经期  /  类风湿关节炎  /  骨质疏松  /  Dickkopf-1  /  骨代谢

Objective To explore the clinical diagnostic value of serum dickkopf-1 (DKK1) level in menopausal women with rheumatoid arthritis (RA) secondary to osteoporosis (OP). Methods A total of 236 menopausal female patients diagnosed in the Second Affiliated Hospital of Nanchang University from May 2019 to September 2020 were collected, including 44 patients with OP secondary to RA set as RA+OP group, 150 patients with RA without OP set as RA group, and 42 patients with OP set as OP group, respectively. At the same time, 43 healthy menopausal women in our hospital at the same period were selected as control group. Serum DKK1 was detected by ELISA. The erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) were detected by capillary method and rate-scattering turbidimetry, respectively; The bone metabolism indexes such as parathyroid hormone(PTH), type Ⅰ procollagen C-terminal propeptide (CTX), 25-hydroxy vitamin D3 [25-(OH)D3], type Ⅰ procollagen N-terminal propeptide (PINP) and osteocalcin were detected by electro-chemiluminescence method. While, bone alkaline phosphatase (BALP)was determined by chromatography; The bone mineral density (BMD), Z-score and T-score of total hip joint and lumbar spine L1-4 in all patients were detected by Lunar Prodigy dual energy X-ray absorptiometry. The area under the ROC curve was used to analyze the diagnostic efficacy of DKK1 in patients with RA combined with OP and those with RA or OP alone. Results DKK1, ESR, CRP, BMI, PTH, CTX, 25-(OH)D3, total hip BMD, total hip T-score, total hip Z-score, lumber spine L1-4 BMD, lumber spine L1-4 T score and lumber spine L1-4 Z score, CTX and BALP were significantly different among the 4 groups (P<0.01 or P<0.05); The difference of fracture story was statistically significant between RA+OP group and OP group (P<0.01). Bivariate correlation analysis conducted between DKK1 and each index showed that serum DKK1 was positively correlated with ESR, CRP, fracture story and BALP (P<0.05), and negatively correlated with BMI, total hip BMD, total hip T-score, total hip Z-score, lumber spine L1-4 BMD, lumber spine L1-4 T-score and lumber spine L1-4 Z-score, PINP, 25-(OH)D3 and PTH (P<0.01 or P<0.05). Multiple linear regression analysis showed that DKK1 was positively correlated with CRP and BMI (R2=0.048, β=0.034, P=0.003; and R2=0.008, β=0.178, P=0.042, respectively), and negatively correlated with PINP and total hip T-score (R2=0.003, β=–0.022, P=0.009; and R2=0.235, β=–2.375, P=0.000). ROC curve analysis showed that and the optimal cut-off value of DKK1 in the diagnosis of RA secondary to OP was 9.21 μg/L, the sensitivity was 93.2%, the specificity was 91.1%, and the Kappa consistency index was 0.630. The diagnostic efficiency of DKK1 for OP was higher than that of DKK1 for RA, and the Kappa consistency index was relatively stable. Conclusion The serum level of DKK1 is increased in menopausal women with RA secondary to OP, the detection of DKK1 has good diagnostic efficiency in the diagnosis of menopausal women with RA secondary to OP.

menopause  /  rheumatoid arthritis  /  osteoporosis  /  Dickkopf-1  /  bone metabolism
裴子欢, 黄家翌, 刘宇晗, 胡廷婷, 李小航, 李旭, 曾婷婷, 田永建, 余建林, 吴洋, 谭立明. Dickkopf-1检测对女性绝经期类风湿关节炎继发骨质疏松的临床诊断价值. 解放军医学杂志, 2021 , 46 (4) : 361 -366 . DOI: 10.11855/j.issn.0577-7402.2021.04.07
Zi-Huan Pei, Jia-Yi Huang, Yu-Han Liu, Ting-Ting Hu, Xiao-Hang Li, Xu Li, Ting-Ting Zeng, Yong-Jian Tian, Jian-Lin Yu, Yang Wu, Li-Ming Tan. Clinical diagnostic value of dickkopf-1 test for menopausal women with rheumatoid arthritis secondary to osteoporosis[J]. Medical Journal of Chinese People’s Liberation Army, 2021 , 46 (4) : 361 -366 . DOI: 10.11855/j.issn.0577-7402.2021.04.07
正文
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女性绝经期发生类风湿关节炎(rheumatoid arthritis，RA)继发骨质疏松(osteoporosis，OP)的病因目前尚不明确，且其发病机制复杂，诊断困难。女性RA患者随着年龄增长，雌激素水平不断降低，机体代谢紊乱，骨吸收及骨形成不平衡等导致骨量加速丢失，最终形成OP[1]。RA患者较健康人群更易发生OP及骨折，目前RA及OP在诊断及治疗中均存在一定的困难且一直未得到改善[2]。近年来研究发现，Dickkopf-1(DKK1)参与了RA的骨侵蚀过程，DKK1水平升高可抑制成骨细胞的生成，影响破骨细胞的活性[3]，尤其在RA继发OP患者中可加速骨破坏[4]。本研究通过检测南昌大学第二附属医院确诊的女性绝经期患者血清DKK1水平，并对其与体重指数(body mass index，BMI)，骨密度(bone mineral density，BMD)相关指标如全髋BMD、全髋T分数、全髋Z分数、腰椎L1-4 BMD、腰椎L1-4 T分数、腰椎L1-4 Z分数，以及骨代谢指标的关系进行分析，探讨了DKK1对女性绝经期RA继发OP的临床诊断价值。
1 资料与方法
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1.1 研究对象
纳入2019年5月—2020年9月在南昌大学第二附属医院确诊的236例绝经期患者，年龄49~85(62.5±8.8)岁。其中44例RA继发OP患者为RA+OP组，年龄49~85(63.2±8.9)岁；150例无OP的RA患者为RA组，年龄49~85(60.2±8.8)岁；42例无RA的OP患者为OP组，年龄50~82(66.1±8.7)岁；上述患者均符合RA和(或)OP的国际诊断标准[5-6]。以该院体检科同期未患相关疾病43名绝经期健康女性作为对照组，年龄49~82(61.1±8.9)岁。本研究经南昌大学第二附属医院伦理委员会批准，所有参与者均签署书面知情同意书。
1.2 纳入和排除标准
纳入标准：(1)绝经期女性；(2)RA的诊断符合2010年美国风湿病协会/欧洲抗风湿病联盟(ACR/EULAR)分类标准[5]；(3)OP的诊断符合中国2017年版原发性骨质疏松症诊疗指南[7]；(4)临床资料完整且接受随访。排除标准：(1)除RA外，还患有其他关节炎或关节疾病；(2)合并严重肝肾功能损害、代谢性疾病(如甲状腺及甲状旁腺疾病)影响骨代谢；(3)合并严重心脑血管疾病或慢性肾脏疾病；(4)合并血液系统疾病、肿瘤骨转移者；(5)服用抗癌药等影响骨代谢药物者。
1.3 检测指标及方法
通过本院His系统收集患者的性别、年龄、身高、体重、BMI及骨折史等一般资料。采集符合纳入标准的患者清晨空腹静脉血3 ml，1026×g离心15 min后分离血清，分别采用毛细管法及Beckman公司的IMMAGE分析仪以速率散射比浊法及其配套试剂检测红细胞沉降率(erythrocyte sedimentation rate，ESR)和C反应蛋白(C-reactive protein，CRP)水平；血清DKK1水平采用美国R&D公司的ELISA试剂进行检测；骨代谢指标中甲状旁腺素(parathyroid hormone，PTH)、骨钙素、Ⅰ型前胶原N-末端肽(procollagenⅠ of aminoterminal propeptide，PINP)、25-羟维生素D3[25-hydroxy vitamin D3，25-(OH)D3]、Ⅰ型胶原C-末端肽(C-terminal telopeptide of typeⅠ collagen，CTX)均采用Cobase601全自动电化学发光仪检测，骨碱性磷酸酶(bone alkaline phosphatase，BALP)采用北京中生金域诊断技术股份有限公司的色谱法试剂测定；采用美国GE公司Lunar Prodigy双能X线骨密度仪检测全髋和腰椎L1-4的骨密度(bone mineral density，BMD)、T分数、Z分数，并使用WHO的结果判断标准[6]，即T值≤–2.5为骨质疏松，–2.5<T值<–1为骨量减少，T值≥–1为骨量正常。T值=(实测值—同种族同性别正常青年人峰值骨密度)/同种族同性别正常青年人峰值骨密度的标准差。所有操作严格遵照试剂、仪器说明书及南昌大学第二附属医院标准化操作程序(standard operation procedure，SOP)进行。
1.4 构建多元线性回归模型分析DKK1与各指标的相关性
采用Spearman分析DKK1与各指标的相关性后，进一步以DKK1为因变量，以ESR、CRP、BMI、骨折史、PTH、CTX、25-(OH)D3、PINP、BALP、骨钙素、全髋BMD、全髋T分数、全髋Z分数、腰椎L1-4 BMD、腰椎L1-4 T分数及腰椎L1-4 Z分数等指标为自变量，构建多元线性回归模型分析DKK1与各自变量之间是否存在独立相关性及相关程度。
1.5 统计学处理
采用SPSS 22.0软件进行统计分析。采用Kolmogorov-Smirnov检验对所有数据进行正态性分析，符合正态分布的计量资料以$\bar{x}±s$表示，非正态分布则以M(Q1, Q3)表示；正态数据多组间比较采用ANOVA检验，进一步两两比较采用LSD-t检验事后多重比较；非正态数据多组间比较采用Kruskal-Wallis H检验，进一步两两比较采用Mann-Whitney U检验；分类变量以例(%)表示，骨折史多组间比较采用R×C列联表χ2检验，进一步两两比较采用Fisher确切概率法进行分析；采用受试者工作特征曲线(receiver operating characteristic curve，ROC)确定DKK1水平的最佳临界值并计算曲线下面积(area under the curve，AUC)。P<0.05为差异有统计学意义。
2 结果
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2.1 一般资料比较
四组DKK1、ESR、CRP、BMI、PTH、CTX、25-(OH)D3、BALP、全髋BMD、全髋T分数、全髋Z分数、腰椎L1-4 BMD、腰椎L1-4 T分数、腰椎L1-4 Z分数等指标差异均有统计学意义(P<0.01或P<0.05)；RA+OP组骨折史与OP组比较差异有统计学意义(P<0.01，表1)。
2.2 血清DKK1水平与各检测指标的相关性
Spearman相关分析结果显示，血清DKK1与ESR、CRP、骨折史及BALP呈正相关(P<0.05)，与BMI、全髋BMD、全髋T分数、全髋Z分数、腰椎L1-4 BMD、腰椎L1-4 T分数及腰椎L1-4 Z分数、PINP、25-(OH)D3、PTH等指标呈负相关(P<0.01或P<0.05，表2)。多元线性回归分析结果显示，DKK1与CRP及BMI呈独立正相关(R2=0.048，β=0.034，P=0.003；R2=0.008，β=0.178，P=0.042)，与PINP及全髋T分数呈独立负相关(R2=0.003，β=–0.022，P=0.009；R2=0.235，β=–2.375，P=0.000)。
2.3 DKK1对女性绝经期RA继发OP的诊断效能
ROC曲线分析结果显示，DKK1诊断RA继发OP的最佳截断值为9.21 μg/L，曲线下面积(AUC)为0.987，明显高于诊断OP及RA的AUC(分别为0.957、0.739)；DDK1对OP、RA及RA继发OP的诊断灵敏度分别为93.2%、59.1%、88.6%，特异度分别为91.1%、85.7%、100%(图1)。DKK1对OP的诊断效能(阳性预测值为60.3%、阴性预测值为97.6%，阳性似然比为10.47、阴性似然比为0.075、Kappa值为0.630)优于DKK1对RA的诊断效能(阳性预测值为59.4%，阴性预测值为82.4%，阳性似然比为4.133，阴性似然比为0.477，Kappa值为0.269)。
3 讨论
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RA是一种慢性炎症性疾病，主要特征是慢性滑膜炎、关节破坏及骨量过度丢失[8-9]，其患病率为0.5%~2.0%，常见于女性[10]。绝经期女性OP为最常见的骨病[11]，而RA患者更易并发OP[12]。本研究发现，女性绝经期RA继发OP的患病率为22.7%，与Lee等[12]的研究略有不同，本研究发病年龄略大且均为绝经期女性。近年来研究发现，DKK1是Dickkopf家族富半胱氨酸蛋白的成员之一，也是Wnt信号通路中的一种可溶性抑制剂，可通过Wnt信号通路刺激破骨细胞的分化，影响成骨细胞形成，调节骨稳态，此外，DKK1也参与了RA患者骨细胞的分化成熟，可负调控RA患者的Wnt通路，阻断成骨细胞分化，影响成骨细胞的生成和破骨细胞活性，诱导骨硬化蛋白(sclerostin，SCL)表达，导致骨细胞死亡[13]，此通路依赖于低密度脂蛋白受体相关蛋白5(low density lipoprotein receptor-related protein 5，LRP5)或LRP6，LRP5可通过调控成骨细胞增殖、生成和活化且激活此突变功能区导致骨量增加，而LRP5突变区缺失可导致OP[14]。此外，长期慢性炎症刺激关节可导致关节周围骨质破坏，使全身骨量流失，最终发展为骨质疏松，而DKK1水平在RA及OP患者血清中均升高，高水平的DKK1可影响RA继发OP患者的骨重塑[11,15]。本研究结果也显示，绝经期RA继发OP女性患者的DKK1水平明显高于RA组、OP组及对照组，考虑是由于本研究均为绝经期患者及存在区域差异使得患病组的DKK1水平较高。
本研究发现，ESR、CRP对RA继发OP的影响明显高于OP、RA及健康对照，且多元线性回归分析显示DKK1与CRP呈独立正相关(β=0.034，P=0.003)，与Wang等[16]研究基本一致，且BMI与DKK1也呈正相关(β=0.178，P=0.042)。分析原因，考虑本研究纳入研究对象均为绝经期女性，随着年龄的增长，机体及骨代谢减慢，尤其是绝经期RA继发OP女性患者体内脂肪堆积，更易造成体型肥胖。此外，高龄女性绝经期骨骼脆性增加，RA继发OP也增加了患者发生骨折的风险[2,17]。本研究结果显示，DKK1与女性绝经期患者骨折史呈正相关(r=0.391，P=0.000)，与Ramli等[18]研究基本一致。
PTH及25-(OH)D3是预测维生素D和钙摄入不足的两个良好指标[19]，T淋巴细胞通过增加骨髓基质细胞对甲状旁腺激素的反应来促进甲状旁腺激素诱导破骨细胞形成，RA可影响维生素D转化为25-(OH)D3，从而影响维生素D和钙的吸收，RA患者缺乏维生素D或钙摄入不足是其继发OP的重要危险因素[20-21]。骨转化标志物(bone turnover markers，BTMs)来源于成骨细胞(骨形成标志物如BALP、骨钙素及PIPN)和破骨细胞(骨吸收标志物如CTX)[22]，对于监测骨相关疾病的进展及抗骨质疏松治疗的疗效具有较好的参考价值。PINP是Ⅰ型胶原蛋白的氨基端降解产物，是骨形成的标志物，可反映成骨细胞的分化情况[23]。DKK1可影响破骨细胞活性及成骨细胞分化成熟[24]，易受Wnt通路的调控[25]。本研究发现，DKK1与PTH和25-(OH)D3呈负相关，与Rossini等[26]的研究不同，考虑高水平的DKK1影响RA患者维生素D转化为25-(OH)D3，继而影响血清PTH的水平。多元线性回归分析结果显示，DKK1独立负向影响PINP(β=–0.022，P=0.009)，表明DKK1水平升高在一定程度上可能影响PINP的生成，与国内外研究[11,15]略不同，考虑与本研究人群为绝经期女性且为骨质疏松患者，以及地域差异有关。此外，BMD是反映骨量的另一重要指标，本研究发现在绝经期女性RA继发OP患者血清中DKK1高表达，BMD降低更明显，DKK1与绝经期全髋部BMD、全髋T分数及腰椎BMD等指标均呈负相关性(P<0.01)，多元线性回归分析显示DKK1与全髋T分数呈明显负相关(β=–2.375，P=0.000)，与Diarra等[15]的研究基本一致。
DKK1可影响破骨细胞活性及成骨细胞的分化成熟[24]，然而其在绝经期RA继发OP女性患者中的诊断价值未见报道。Idriss等[27]对63例RA患者与健康对照的血清DKK1进行ROC曲线分析，结果显示其诊断RA的最佳截断值为4876 pg/ml，灵敏度和特异度分别为68.3%和95.2%，AUC为0.87，与本研究结果不同。本研究发现，DKK1对RA继发OP的最佳截断值为9.21 μg/L，AUC为0.987，灵敏度为88.6%，特异度为100%。此外本研究还发现，DKK1对OP的诊断效能优于DKK1对RA的诊断效能，Kappa一致性指数较稳定，不易受发病率的影响。本研究结果提示，血清DKK1对女性绝经期RA继发OP的诊断效能较高，具有一定的临床应用价值。
综上所述，女性绝经期RA继发OP患者血清DKK1水平增高且具有较好的诊断效能和临床应用价值。绝经期女性RA患者是继发OP的高危人群，应定期进行DKK1、BTMs及BMD等检查，重视各种相关危险因素，及早发现OP并进行早期治疗，以降低OP的发生率。在绝经期女性RA尚未发生OP的患者中DKK1的变化可能与其骨侵蚀未发生明显偶联有关，此时，应采取积极的治疗措施来控制DKK1水平(如DKK1单克隆抗体等)，有利于阻止DKK1水平升高导致的骨侵蚀的发生和发展。
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2021年第46卷第4期
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doi: 10.11855/j.issn.0577-7402.2021.04.07
  • 接收时间：2021-01-11
  • 首发时间：2025-12-26
  • 出版时间：2021-04-28
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  • 收稿日期：2021-01-11
  • 修回日期：2021-03-02
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Key Research and Development Program of Jiangxi Province(2019BBG70033)
江西省重点研发计划(2019BBG70033)
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    1南昌大学第二附属医院检验科/江西省检验医学重点实验室，南昌 330006
    2南昌大学第一附属医院检验科，南昌 330006
    3安徽省阜阳市人民医院检验科，安徽 阜阳 236000

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