摘要
目的了解特异骨代谢标志物骨钙素N端中分子(OCN-MID)、β-胶原特殊序列(β-CTx)在多发性骨髓瘤(MM)患者血清中的含量变化,探讨OCN-MID和β-CTx检测的临床应用价值。
方法选取2006年8月~2007年2月收治于甘肃省人民医院、兰州大学第二医院、兰州军区总医院的新诊断的MM患者34例,以34例性别和年龄相匹配的体检健康者作为对照组。检测其血清骨钙素N端中分子(OCN-MID)、β-胶原特殊序列(β-CTx)、甲状旁腺激素(PTH)、碱性磷酸酶(ALP)、钙(Ca)和磷(P)值。以ROC曲线分析OCN-MID和β-CTx的临床应用价值。
结果(1)与对照组比较,MM组血清OCN-MID明显低于对照组(P<0.05),β-CTx含量高于对照组(P<0.05),而血清Ca、P、PTH以及ALP差异无显著性(P>0.05);(2)不同分期MM患者分析结果表明,分期越晚,OCN-MID水平越低,而β-CTx水平却升高。(3)ROC曲线显示OCN-MID和β-CTx灵敏度高、特异性好,ROC曲线下面积均大于0.9。
结论OCN-MID和β-CTx反映骨形成和骨吸收情况,该方法简便、快速、有效且特异性较高,可以帮助临床了解MM骨损害的程度和评价病情,具有十分良好的临床应用价值。
Objective To investigate the value variation of N-MID osteocalcin and 6-CrossLaps (β-CTx) in serum of patients with multiple myeloma (MM), and to explore their clinical significance.
Methods To collect 34 newly diagnosed multiple myeloma patients from Gansu province people's hospital, the second hospital of Lanzhou university and the general hospital of Lanzhou military area at the time from August 2006 to February 2007. Serum N-MID osteocalcin,β-CTx, alkaline phosphatase (ALP), calcium (Ca) and phosphonium (P) were measured in 34 MM patients and in 34 sex-age-matched controls.
Results Compared to control group , the content of N-MID osteocalcin was obviously lower in serum of MM group, while the content ofβ-CTx was much higher (P<0.05). The serum ALP,Ca,P concentrations were similar between MM patients and controls(P>0.05).By analysising the results of the MM patients in different stages, the later the stage was classified, the lower the level of N-MID osteocalcin was, but the level of serumβ-CTx was much higher. ROC curve demonstrated the detections of N-MID osteocalcin andβ-CTx had high sensitivity and specificity, and the area under the curve exceeded 0.9.
Conclusions N-MID andβ-CTx are brief, fast, valid bone metabolic markers to reflect bone formation and bone resorption. They can aid the clinical utility to comprehend the damage extent of patients with MM and to estimate pathogenetic condition. So they have important clinical value.
引文
[1]王晖.多发性骨髓瘤的发病机制及药物治疗进展[J].国际病理科学与临床杂志.2006;26(5):403-406.
[2]Guido T.Multiple myeloma and other plasma cell disorders[M].//Hoffman R.Hematology-basic principles and practice.4thed.Elsevier,2005:1501-1505.
[3]傅卫军,冯丽.浆细胞疾病的流行病学[M].多发性骨髓瘤及其相关疾病.上海:上海科学技术出版社,2002:1-9.
[4]麦玉洁,邱录贵,李睿,等.432例多发性骨髓瘤临床分析[J].白血病·淋巴瘤.2004;13(4):198-201.
[5]庄俊玲,武永吉,钟玉萍,等.多发性骨髓瘤218例临床分析[J].中国实用内科杂志.2004,24(2):108-110.
[6]邱录贵,麦玉洁.多发性骨髓瘤[M].白细胞疾病基础理论与临床.上海:上海科学技术出版社,2006:789-812.
[7]邱录贵.多发性骨髓瘤的发病与国人特点[J].中国实用内科杂志.2006;26(12):886-888.
[8]于世风.破骨细胞及其骨吸收调控研究进展[J].中国骨质疏松杂志.2001;6(1):78-83.
[9]Kawano M,Yamamoto I,Iwato K,et al.Interleukin-1 beta rather than Lymphotoxin as the major bone resorbing activity in human multiple myeloma[J].Blood.1989;73(6):1646-1649.
[10]Kelly T,Borset M,Abe E,et al.Matrix Metalloproteinases in multiple myeloma[J].Leuk Lymphoma.2000;37(3-4):273-281.
[11]Anqtuaco EJ,Fassas AB,Walker R,et al.Multiple myeloma:clinical review and diagnostic imaging[J].Radiology.2004;231(1):11-23.
[12]黄仲夏.RANKL/OPG与人多发性骨髓瘤骨病的关系[J].国外医学·生理、病理科学与临床分册.2005;25(2):151-152.
[13]Mahnken AH,Wildberger JE,Gehbauer G,et al.Multidetector CT of the spine in multiple myeloma:comparison with MR imaging and radiography[J].AJR Am J Roentgenol.2002;178(6):1429-1436.
[14]Moehler TM,Hawighorst H,Neben K,et al.Bone marrow microcirculation analysis in multiple myeloma by contrast-enhanced dynamic magnetic resonance imaging[J].Int J Cancer.2001;93(6):862-868.
[15]Carlson K,Larsson A,Simonsson B,et al.Evaluation of bone disease in multiple myeloma:a comparison between the resorption markers urinary deoxypyridinoline/creatinine(DPD)and serum ICTP,and an evaluation of the DPD/osteocalcin and ICTP/osteocalcin ratios[J].Eur J Haematol.1999;62(5):300-306.
[16]胡四龙,刘永昌,林祥通等.多发性骨髓瘤骨显像的临床价值[J].上海医学影像杂志.2001;10(1):8-11.
[17]Diamond T,Levy S,Day P,et al.Biochemical,histomorphometric and densitometric changes in patients with multiple myeloma:effects of glucocorticoid therapy and disease activity[J].Br J Haematol.1997;97(3):641-648.
[18]Tomiska M,Adam Z,Prokes B,et al.Bone mineral density in multiple myeloma patients after intravenous clodronate therapy[J].Acta Med Austriaca.2001;28(2):38-42.
[19]Bataille R,Manolagas SC,Berenson JR.Pathogenesis and management of bone lesions in multiple myeloma[J].Hematol Oncol Clin North Am.1997;11(2):349-361.
[20]Klaus J.Comparison of 10 serum bone turnover makers in prostate carcinoma patients with bone metastatic spread:diagnostic and prognostic implication [J].Int J Cancer.2004;11(1):783-791.
[21]Delmas PD.Biochemical markers of bone turnover:methodology and clinical use in osteoporosis[J].Am J Med.1991;91(5):59S-563S.
[22]Garnero P,Grimaux M,Seguin P,et al.Characterization of immunoreactive forms of human osteocalcin generated in vivo and in vitro[J].J Bone Miner Res.1994;9(2):255-264.
[23]Christenson RH.Biochemical markers of bone metabolism:an overview[J].Clin Binchem.1997;30(8):573-593.
[24]Okabe R,Nakatsukal K,Inabala M,et al.Clinical evaluation of the Elecsys β-crossLaps serum assay,a new assay for degradation products of type I collagen C-telopeptides[J].Clin Chem.2001;47(8):1410-1414.
[25]Fledelius C,Johnsen AH,Cloos PA,et al.Characterization of urinary degradation products derived from type I collagen.Identification of a beta-isomerized Asp-Gly sequence within the C-terminal telopeptide(alphal)region[J].J Biol Chem.1997;272(15):9755-9763.
[26]Ekins RP.The estimation of thyroxine in human plasma by an electrophoretic technique[J].Clin Chim Acta.1960;5:453-459.
[27]Yalow RS,Berson SA.Immunoassay of endogenous plasma insulin in man.1960[J].Obes Res.1996;4(6):583-600.
[28]Kohler G,Milstein C.Continuous cultures of fused cells secreting antibody of predefined specificity.1975[J].J Immunol.2005;174(5):2453-2455.
[29]Weber SG.Comprehensive Analytical Chemistry[M].New York:Elservier Science Publishing Company Iic.1992:91.
[30]吴健民.临床化学自动化免疫分析[M].北京:科学出版社.2000:52.
[31]李振甲.时间分辨荧光分析技术与应用[M].北京:科学出版社.1995:21.
[32]Engvall E,Jonsson K,Perlman P.Enzyme-linked immunosorbent assay.ⅡQuantitative assay of protein antigen immunoglobulin G,by means of enzyme-labelled antigen and antibody-coated tubes[J].Biochim Biophys Acta.1971;25:427-434.
[33]王自正.现代医学标记免疫学[M].北京:人民军医出版社.2000:17.
[34]Blackburn GF,Shah HP,Kenten JH,et al.Electrochemiluminescence detection for development of immunoassays and DNA probe assays for clinical diagnostics[J].Clin Chem.1991;37(9):1534-1539.
[35]Leland JK,Powel MJ.Electrogenerated chemiluminescence:an oxidative-reduction type ECL reaction sequence using tripropyl amine[J].J Electrochem.Soc.1990;137(10):3127-3131.
[36]Nicbolas RH,Hoyle NR,Eckert B.Electrochimiluminescence:leading-edge technology for automated immunoassays analyse detection[J].Clin Chem.1996;42(9):1576-1578.
[37]Tokel NE,Bard AJ.Electrogenerated chemiluminescence Ⅸ.Electrochemistry and emission from systems containing tris(2,2'-bipyridine)ruthenium(Ⅱ)dichloride[J].J Am Chem Soc.1972;94:2862-2863.
[38]Bard AJ.New Challenges in Electrochemistry and Electroanalysis[J].Pure Appl Chem.1992;64:185-192.
[39]Zhang X,Bard AJ.Electrogenerated ehemikmainescence emission from 8n organized(LB)monolayer of a Ru[(bpy)_3]~(2+)based surfactant on semiconductor and metaldectrodes[J].Phys Chem.1988;92:5566-5569.
[40]Bard AJ,Abruna HD,Chidsey CE,et al.The electrode/electrolyte interface-A status report[J].J Phys Chem,1996;97:7147-7173.
[41]张津辉,蒋中华,陈惠鹏.制备电泳中蛋白质区带定位与染色方法的比较[J].军事医学科学院院刊.1997;21(2):159-162.
[42]张津辉,蒋中华.生物医学研究的有力工具——磁性微载体[J].解放军医学情报.1996;10(2):94-97.
[43]蒋中华,张津辉.生物分子固定化技术及应用[M].北京:化学工业出版社.1998:7.
[44]尹伯元,王仁芝,李振甲等.标记免疫学(第一版)[M].北京:原子能出版社.1998:255.
[45]张之楠主编.血液学诊断及疗效标准.第三版[M].北京:科学出版社.2007:232-235.
[46]Barille-Nion S,Bataille R.New insights in myeloma-induced osteolysis[J].Leuk Lymphoma.2003;44(9):1463-1467.
[47]Bataille R,Harousseau JL.Multiple myeloma[J].N Engl J Med.1997;336(23):1657-1664.
[48]Bataille R,Chappard D,Marcelli C,et al.Mechanisms of bone destruction in multiple myeloma:the importance of an unbalanced process in determining the severity of lytic bone disease[J].Clin Oncol.1989;7(12):1909-1914.
[49]Heider U,Fleissner C,Zavrsk I,et al.Bone markers in multiple myeloma[J].Eur J Cancer.2006;42(11):1544-1553.
[50] Croucher PI, Apperley JF. Bone disease in multiple myeloma[J].Br J Haematol.1998; 103:902-910.
[51] Callander NS, Roodman GD. Myeloma bone disease [J].Semin Hematol.2001; 38(3):276-285.
[52] Giuliani N, Colla S, Rizzoli V. New insight in the mechanism of osteoclast activation and formation in multiple myeloma: Focus on the receptor activator of NF-KB ligand (RANKL)[J].Exp Hematol.2004; 32(8):685-691.
[53] Terpos E, Dimopoulos MA. Myeloma bone disease: pathophysiology and management [J].Ann Oncal.2005; 16(8):1223-1231.
[54] Ehrlich LA, Chung HY, Ghobrial I, et al. IL-3 is a potential inhibitor of osteoblast differentiation in multiple myeloma [J].Blood. 2005;106(4):1407-1414.
[55] Oshima T, Abe M, Asano J, et al. Myeloma cells suppress bone formation by secreting a soluble Wnt inhibitor, sFRP-2[J].Blood.2005; 106(9):3160-3165.
[56] Tian E, Zhan F, Walker R, et al. The role of the Wnt-signaling antagonist DKK1 in the development of osteolytic lesions in multiple myeloma [J].N Engl J Med.2003; 349(26):2483-2494.
[57] Robins SP, Woitge H, Hesley R, et al. Direct, enzyme-linked immunoassay for urinary deoxypyridinoline as a specific marker for measuring bone resorption [J]. J Bone Miner Res. 1994;9(10):1643-1649.
[58] Coen G, Mantella D, Calabria S, et al. Urinary deoxypyridinoline excretion for the evaluation of bone turnover in chronic renal failure [J]. Am J Nephrol. 2000; 20(4):283-290.
[59] Garnero P, Ferreras M, Karsdal MA, et al. The type I collagen fragments ICTP and CTX reveal distinct enzymatic pathways of bone collagen degradation [J]. J Bone Miner Res. 2003; 18(5):859-867.
[60] Schonau E, Rauch F. Markers of bone and collagen metabolism problems and perspectives in paediatrics [J].Horm Res. 1997; 48(S15):50-59.
[61] Fonseca R, Trendle MC, Leong T,et al. Prognostic value of serum markers of metabolism in untreated multiple myeloma patients [J] .Br J Haematol.2000;109(1):24-29.
[62] Hernandez JM, Suquia B, Queizan JA, et al. Bone remodelation markers are useful in the management of monoclonal gammopathies[J]. Hematology J. 2004; 5(6):480-488.
[63] Abildgaard N, Brixen K, Eriksen EF, et al. Sequential analysis of biochemical markers of bone resorption and bone densitometry in multiple myeloma[J].Haematologic.2004;89(5):567-577.
[64] Bataille R, Chappard D, Marcelli C, et al. Mechanisms of bone destruction in multiple myeloma: the importance of an unbalanced process in determining the severity of lytic bone disease [J] J Clin Oncol. 1989; 7(12):1909-1914.
[65] Swets JA.Measuring the accuracy of diagnostic system [J] .Science. 1988; 240(4857): 1285-1293.
[1]邱录贵.多发性骨髓瘤的发病与国人特点[J].中国实用内科杂志.2006;26(12):886-888.
[2]袁敏敏,宋美芳,高怡.骨代谢生化指标测定在妇科临床中的应用价值[J].中华检验医学杂志.2001;24:16-18.
[3]Ross PD,Kress BC,Parson RE,et al.Serum bone alkaline phosphatase and calcaneus bone density predict fractures:a prospective study[J].Osteoporosis Int.2000;11(1):76-82.
[4]Plebani M,Beruardi D,Zaninotto M,et al.New and traditional serum markers of bone metabolism in the detection of skeletal metastases[J].Clin Biochem.1996;29(1):67-72.
[5]Delmas P D,Eastell R,Garnero P,et al.The use of biochemical markers of bone turnover in osteoporosis.Committee of Scientific Advisors of the International Osteoporosis Foundation[J].Osteoporos Int.2000;11(S6):S2-S17.
[6]Charles P,Mosekilde L,Risteli L,et al.Assessment of bone remodeling using biochemical indicators of type I collagen synthesis and degradation:relation to calcium kinetics[J].Bone Miner.1994;24(2):81-94.
[7]Garnero P,Delmas PD.Biochemical markers of bone turnover.Applications for osterporosis[J].Endocrinol Metab Clin North Am.1998;27(2):303-323.
[8]Deacon AC,Hulme P,Hesp R,et al.Esitimation of whole body bone resorption rate:a comparison of urinary total hydroxyproline excretion with two radioisotopic tracer methods in osteoporosis[J].Clin Chin Acta.1987;166(2-3):297-306.
[9]Vesper HW,Audain C,Woolfitt A,et al.High-performance liquid chromatography method to analyze free and total urinary pyridinoline and deoxypyridinoline[J].Anal Biochem.2003;318(2):204-211.
[10]Delmas PD,Eastell R,Garnero P,et al.The use of biochemical markers of bone turnover in osteoporosis.Committee.of scientific advisors of the international osteoporosis foundation[J].Osteoporosis Int.2000;11(S6):S2-S17.
[11]Demers LM.Biochemical markers in the management of patients with metastatic bone diseases[J].Clin Chem.1999;45:1131-1132.
[12]张劲丰.尿脱氧吡啶酚作为新一代骨质疏松症检测指标的价值[J].齐鲁医学检验.2004;15(5):26-27.
[13]Gamero P,Ferreras M,Karsdal MA,et al.The type I collagen fragments ICTP and CTX reveal distinct enzymatic pathways of bone collagen degradation[J]Bone Miner Res.2003;18(5):859-867.
[14]Gamero P,Ferreras M,Karsda MA,et al.The type I collagen fragments ICTP and CTX reveal distinct enzymatic pathways of bone collagen degradation[J].J Bone Miner Res.2003;18(5):859-867.
[15]Seibel MJ.Binchenmical markers of bone remodeling[J].Endocrinol Metab Clin North Am.2003;32(1):83-113.
[16]Okabe R,Nakatsukal K;Inabala M,et al.Clinical evaluation of the Elecsys β-crossLaps serum assay,a new assay for degradation products of type I collagen C-telopeptides[J].Clin Chem.2001;47(8):1410-1414.
[17]Fledelius C,Johnsen AH,Cloos PA,et al.Characterization of urinary degradation products derived from type I collagen.Identification of a beta-isomerized Asp-Gly sequence within the C-terminal telopeptide(alphal)region[J].J Biol Chem.1997;272(15):9755-9763.
[18]Nakasato YR,Janckila AJ,Halleen JM,et al.Clinical significance of immunoassays for type-5 tartrate-resistant acid phosphatase[J].Clin Chem.1999;45(12):2150-2157.
[19]Nowak Z,Konieczna M,Wankowicz Z.Tartrate-resistant acid phosphatase-TRAP 5b-as a novel marker of bone resorption in patients with irreversible renal failure treated with dialysis[J].Pol Merkuriusz Lek.2004;17(98):138-141.
[20]甘洁民,朱汉民.抗酒石酸盐酸性磷酸梅的测定及临床应用[J].上海医学检验 杂志.1997; 12(1):31-32.
[21] Karmatschek M, Maier I, Seibel MJ, et al. Improved purification of human bone sialoprotein and development of a homologous radioimmunoassay [J].Clin Chem. 1997; 43(11):2076-2082.
[22] Fonseca R, Trendle MC, Leong T, et al. Prognostic value of serum markers of bone metabolism in untreated multiple myeloma patients [J] .Br J Haematol. 2000; 109(1):24-29.
[23] Aris RM, Ontjes DA, Buell HE, et al. Abnormal bone turnover in cystic fibrosis adults [J].Osteoporos Int. 2002; 13(2):151-157.
[24] Pecherstorfer M, Seibel MJ, Woitge HW, et al. Bone resorption in multiple myeloma and in monoclonal gammopathy of undetermined significance: quantification by urinary pyridinium cross-links of collagen [J].Blood. 1997; 90(9):3743-3750.
[25] Moehler TM, Hawighorst H, Neben K, et al. Bone marrow microcirculation analysis in multiple myeloma by contrast-enhanced dynamic magnetic resonance imaging[J]. Int J Cancer. 2001; 93(6):862-868.
[26] Carlson K, Larsson A, Simonsson B, et al. Evaluation of bone disease in multiple myeloma: a comparison between the resorption markers urinary deoxypyridinoline/creatinine (DPD) and serum ICTP, and an evaluation of the DPD/osteocalcin and ICTP/osteocalcin ratios[J].Eur J Haematol. 1999;62(5):300-306.
[27] Jakob C, Zavrski I, Heider U, et al. Bone resorption parameters [carboxy-terminal collagen type-1 collagen(ICTP),amino-terminal collagen type- I telopeptide(NTx),and deoxypyridinoline(Dpd)]in MGUS and multiple myeloma [J].Eur J Haematol. 2002; 69(1):37-42.
[28] Abildgaard N, Brixen K, Kristensen JE, et al. Comparison of five biochemical markers of bone resorption in multiple myeloma: elevated pre-treatment levels of S-ICTP and U-NTx are predictive for early progression of the bone disease during standard chemotherapy [J].Br J Haematol. 2003; 120(2):235-242.
[29] Abildgaard N, Brixen K, Eriksen EF, et al. Sequential analysis of biochemical markers of bone resorption and bone densitometry in multiple myeloma [J].Haematologica. 2004; 89(5):567-577.
[30] Xue Y, Jia W, Zhang H, et al. Urinary cross-linked N-telopeptides of type I collagen and bone metabolic diseases [J].Chin Med J (Engl). 1999; 112(2): 149-152.
[31] Terpos E, de la Fuente J, Szydlo R, et al. Tartrate-resistant acid phosphatase isoform 5b: a novel serum marker for monitoring bone disease in multiple myeloma [J].Int J Cancer. 2003; 106(3):455-457.
[32] Woitge HW, Pecherstorfer M, Horn E, et al. Serum bone sialoprotein as a marker of tumour burden and neoplastic bone involvement and as a prognostic factor in multiple myeloma [J].Br J Cancer. 2001; 84 (3):344-351.
[33] Vejlgaard T, Abildgaard N, Jans H, et al. Abnormal bone turnover in monoclonal gammopathy of undetermined significance: analyses of type I collagen telopeptide, osteocalcin, bone2specific alkaline phosphatase and propeptides of type I and type III procollagens [J].Eur J Haematol. 1997; 58 (2):104-108.
[34] Pecherstorfer M, Seilbel MJ, Woiltge HW, et al. Bone Resorption in Multiple Myeloma and in Monoclonal Gammopathy of Undetermined Significance: Quantification by Urinary Pyridinium Cross-Links of Collagen[J].Blood.l997;90(9):3743-3750.