滋补肝肾方对去卵巢骨质疏松模型大鼠治疗作用及机制研究
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摘要
目的：
本研究课题拟通过滋补肝肾方和乙烯雌酚对治疗去卵巢骨质疏松模型大鼠的对比研究，观察去卵巢骨质疏松模型大鼠血清性激素水平FSH、LH、E_2，血清骨钙素(BGP)，胰岛素样生长因子-1(IGF-1)水平的变化、脏器指数测定、骨组织病理改变、RT-PCR方法观测IGF-1、OPG-mRNA的表达来探讨滋补肝肾方对去卵巢骨质疏模型大鼠的治疗作用及作用机制。
方法：
1血液性激素指标测定：摘眼球取血，分离血清，放射免疫法测定血清性激素指标雌二醇(E_2)、卵泡刺激素(FSH)、黄体生成激素(LH)
2血液骨代谢生化指标测定：摘眼球取血，分离血清，放射免疫法测定血清骨钙素(BGP)、胰岛素样生长因子-1(IGF-1)。
3子宫湿重、脏器指数、骨组织病理改变：将动物断头处死，游离子宫组织，计算脏器指数；取出右侧股骨，以甲醛固定，取股骨头／股骨干处做病理切片，做成石蜡包块，HE染色，光学显微镜下进行病理观察。
4骨标本的RT-PCR：断头处死大鼠后完整取出左侧股骨，放入液氮中冷冻，并分装在无菌EP管中密封，以备检测IGF-1、OPG-mRNA水平。
结果：
1．去势后形成的实验性骨质疏松症大鼠模型，其血清E_2水平明显降低，FSH、LH水平明显升高；血清BGP、IGF-1水平显著降低；子宫湿重和脏器指数明显降低；骨小梁变细，骨皮质变薄，骨密度和面积减少；IGF-1、OPG-mRNA表达水平显著低于正常，出现了典型的骨质疏松症。
2．滋补肝肾方可以改善去卵巢骨质疏松模型大鼠的生殖内分泌水平，能显著升高E_2水平，降低FSH、LH水平。
3．滋补肝肾方能显著升高去势大鼠体内血清BGP、IGF-1的水平。
4．滋补肝肾方对去势大鼠的子宫湿重和脏器指数有升高趋势；减轻去势大鼠的骨质疏松程度。
5．滋补肝肾方能上调去势大鼠骨组织IGF-1、OPGmRNA的基因表达。
结论：
综上所述，滋补肝肾方具有调节去势大鼠的生殖内分泌，改善去势大鼠的血液骨代谢，减轻去势大鼠的骨质疏松程度，上调骨组织IGF-1、OPGmRNA的表达。从多途径、多靶点使去势大鼠引起的生殖内分泌、骨代谢指标及骨组织的变化等接近正常水平，避免了雌激素替代治疗带来的副作用。
Objectives: This research subject is plans to treats the ovariectomized rats with the traditional Chinese medicine compound prescription and the ethylene female phenol ,and be observed ovary osteoporosis model big mouse blood serum sex hormone level FSH, LH, E_2, insulin type growth factor - 1 (IGF-1) the level change, the internal organs index determination, the bone tissue pathology change, the RT-PCR method observe IGF-1, the OPG-mRNA expression in bone tissues to discuss the traditional Chinese medicine compound prescription to go to the ovary ossein sparse model big mouse's therapeutic action and to affect the mechanism.
Methods:
1. Blood sex hormone target determination: Picks the eyeball to draw blood, the separation blood serum, emits the immunization to determine the blood serum sex hormone : estradiol (E_2), the graafian follicle stimulin (FSH), the yellow body production hormone (LH)
2. Blood bone metabolism biochemistry target determination: Picks the eyeball to draw blood, the separation blood serum, emits the immunization to determine the blood serum bone calcium element (BGP), insulin type growth factor - 1 (IGF-1).
3. Womb wet weight, internal organs index, bone tissue pathology change: Beheads the execution the animal, drifts away the womb organization, calculates the internal organs index; Right flank takes out the thighbone, is fixed by the formaldehyde, takes the femoral head/stock backbone place to make the pathological section, makes a paraffin wax package of block, HE dyes, under the optical microscope carries on the pathology observation.
4. Bone specimen RT-PCR: Left side beheading executes the big mouse, takes out the thighbone completely, puts in the liquid nitrogen to freeze, and loads separately in the aseptic EP tube seals, prepares examines IGF-1, the OPG-mRNA level.
Results
1. After been ovariectomized, the big mouse be formed the experimental osteoporosis; the blood serum E_2 level reduces obviously, FSH, the LH level elevates obviously; Blood serum BGP, the IGF-1 level obviously reduces; The womb wet weight and the internal organs index reduce obviously; The bone cerebral cortex thins, the bone density and the area reduce; IGF-1, the OPG-mRNA expression level obviously is lower than normally, presented the model osteoporosis mouse.
2. The nutritious hepatorenal traditional Chinese medicine may adjust the reproduction endocrine system to a certain extent, reduces FSH, the LH level, and elevates the E_2 level.
3. The traditional Chinese medicine compound prescription can obviously elevate the blood serum BGP, the IGF-1 level in model mouse.
4. The traditional Chinese medicine compound prescription can elevates the big mouse's womb wet weight and the internal organs index; and can reduces the big mouse's osteoporosis degree.
5. The traditional Chinese medicine compound prescription can elevates the IGF-1-mRNA, the OPG-mRNA expression state in bone tissue.
Conclusion;
The possible mechanism of Bushen Huatan Treatment ofosteoporosis is; Huatan Treatment to inhibit adipogenic differentiation of BMSCs, and Bushen Huatan Treat- ment to promote osteoblastic differentiation of BMSCs.
本研究课题拟通过滋补肝肾方和乙烯雌酚对治疗去卵巢骨质疏松模型大鼠的对比研究，观察去卵巢骨质疏松模型大鼠血清性激素水平FSH、LH、E_2，血清骨钙素(BGP)，胰岛素样生长因子-1(IGF-1)水平的变化、脏器指数测定、骨组织病理改变、RT-PCR方法观测IGF-1、OPG-mRNA的表达来探讨滋补肝肾方对去卵巢骨质疏模型大鼠的治疗作用及作用机制。
方法：
1血液性激素指标测定：摘眼球取血，分离血清，放射免疫法测定血清性激素指标雌二醇(E_2)、卵泡刺激素(FSH)、黄体生成激素(LH)
2血液骨代谢生化指标测定：摘眼球取血，分离血清，放射免疫法测定血清骨钙素(BGP)、胰岛素样生长因子-1(IGF-1)。
3子宫湿重、脏器指数、骨组织病理改变：将动物断头处死，游离子宫组织，计算脏器指数；取出右侧股骨，以甲醛固定，取股骨头／股骨干处做病理切片，做成石蜡包块，HE染色，光学显微镜下进行病理观察。
4骨标本的RT-PCR：断头处死大鼠后完整取出左侧股骨，放入液氮中冷冻，并分装在无菌EP管中密封，以备检测IGF-1、OPG-mRNA水平。
结果：
1．去势后形成的实验性骨质疏松症大鼠模型，其血清E_2水平明显降低，FSH、LH水平明显升高；血清BGP、IGF-1水平显著降低；子宫湿重和脏器指数明显降低；骨小梁变细，骨皮质变薄，骨密度和面积减少；IGF-1、OPG-mRNA表达水平显著低于正常，出现了典型的骨质疏松症。
2．滋补肝肾方可以改善去卵巢骨质疏松模型大鼠的生殖内分泌水平，能显著升高E_2水平，降低FSH、LH水平。
3．滋补肝肾方能显著升高去势大鼠体内血清BGP、IGF-1的水平。
4．滋补肝肾方对去势大鼠的子宫湿重和脏器指数有升高趋势；减轻去势大鼠的骨质疏松程度。
5．滋补肝肾方能上调去势大鼠骨组织IGF-1、OPGmRNA的基因表达。
结论：
综上所述，滋补肝肾方具有调节去势大鼠的生殖内分泌，改善去势大鼠的血液骨代谢，减轻去势大鼠的骨质疏松程度，上调骨组织IGF-1、OPGmRNA的表达。从多途径、多靶点使去势大鼠引起的生殖内分泌、骨代谢指标及骨组织的变化等接近正常水平，避免了雌激素替代治疗带来的副作用。
Objectives: This research subject is plans to treats the ovariectomized rats with the traditional Chinese medicine compound prescription and the ethylene female phenol ,and be observed ovary osteoporosis model big mouse blood serum sex hormone level FSH, LH, E_2, insulin type growth factor - 1 (IGF-1) the level change, the internal organs index determination, the bone tissue pathology change, the RT-PCR method observe IGF-1, the OPG-mRNA expression in bone tissues to discuss the traditional Chinese medicine compound prescription to go to the ovary ossein sparse model big mouse's therapeutic action and to affect the mechanism.
Methods:
1. Blood sex hormone target determination: Picks the eyeball to draw blood, the separation blood serum, emits the immunization to determine the blood serum sex hormone : estradiol (E_2), the graafian follicle stimulin (FSH), the yellow body production hormone (LH)
2. Blood bone metabolism biochemistry target determination: Picks the eyeball to draw blood, the separation blood serum, emits the immunization to determine the blood serum bone calcium element (BGP), insulin type growth factor - 1 (IGF-1).
3. Womb wet weight, internal organs index, bone tissue pathology change: Beheads the execution the animal, drifts away the womb organization, calculates the internal organs index; Right flank takes out the thighbone, is fixed by the formaldehyde, takes the femoral head/stock backbone place to make the pathological section, makes a paraffin wax package of block, HE dyes, under the optical microscope carries on the pathology observation.
4. Bone specimen RT-PCR: Left side beheading executes the big mouse, takes out the thighbone completely, puts in the liquid nitrogen to freeze, and loads separately in the aseptic EP tube seals, prepares examines IGF-1, the OPG-mRNA level.
Results
1. After been ovariectomized, the big mouse be formed the experimental osteoporosis; the blood serum E_2 level reduces obviously, FSH, the LH level elevates obviously; Blood serum BGP, the IGF-1 level obviously reduces; The womb wet weight and the internal organs index reduce obviously; The bone cerebral cortex thins, the bone density and the area reduce; IGF-1, the OPG-mRNA expression level obviously is lower than normally, presented the model osteoporosis mouse.
2. The nutritious hepatorenal traditional Chinese medicine may adjust the reproduction endocrine system to a certain extent, reduces FSH, the LH level, and elevates the E_2 level.
3. The traditional Chinese medicine compound prescription can obviously elevate the blood serum BGP, the IGF-1 level in model mouse.
4. The traditional Chinese medicine compound prescription can elevates the big mouse's womb wet weight and the internal organs index; and can reduces the big mouse's osteoporosis degree.
5. The traditional Chinese medicine compound prescription can elevates the IGF-1-mRNA, the OPG-mRNA expression state in bone tissue.
Conclusion;
The possible mechanism of Bushen Huatan Treatment ofosteoporosis is; Huatan Treatment to inhibit adipogenic differentiation of BMSCs, and Bushen Huatan Treat- ment to promote osteoblastic differentiation of BMSCs.
引文
[1]刘忠厚．骨质疏松症[M]．北京；化学工业出版社，1992
[2]姚远，胡丽娜．绝经后骨质疏松症概述．实用妇产科杂志，2006，22(7)：385～387
[3]王翔．补肾中药防治骨质疏松症基础研究进展．中医正骨，2003
[1]丁桂芝，李榕。从骨矿含量变化规律看肾主骨理论的科学性。湖北中医杂志1991； 13(2)； 27
[2]赵玉堂，刘凯军，李金花，等。骨矿含量与肾虚、肾主骨关系的研究。中国骨质疏松杂志1996； 2(3)； 19
[3]李边达。中药治疗无菌性股骨头坏死及骨质疏松症的主要药效学研究技术要求。中药新药与临床1992； 3 (2) ； 7
[4]张洪，魏之玉，王景存。补肾疏肝健脾方治疗老年原发性骨质疏松症38例。山东中医药大学学报1997； 21(5)；375
[5]李祥炜，周德祥。中医治疗原发性骨质疏松症最新进展。中医药信息1998； 6； 9
[6]魏之玉，张洪，朱振铎，等。196例原发性骨质疏松症辨证分析。山东中医学院学报1996； 20 (1) ； 30
[7]罗为民。健脾补肾法防治绝经后骨质疏松症的计量学研究。中国中医骨伤科1995； 3 (2) ； 1
[8]张荣华，丘和明。中医防治退行性骨质疏松症用药分析。 中医药学报1997； 4； 30
[9]齐振熙．辨证治疗绝经后骨质疏松症[J]．中国中医骨伤科杂志，1998， 6 (3)： 28～29．
[10]谢金华，张晓晖，徐敏．绝经后骨质疏松症的中医辨证研究．中国中医基础医学杂志，2003， 9 (7) ： 55- 57
[11]薛延．骨质疏松症诊断与治疗指南[M]．北京：科学出版社，2000．
[12]陈维静，刘新梅，廉红真．中医辨证治疗原发性骨质疏松症(附109例报告)[J]．中医药研究，1999， 15 (3) ； 29 - 31．
[13]王军，杜乐年．补肾为主治疗骨质疏松症[J]．云南中医学院学报，1999， 22(2)； 17～20．
[14]胡军．辨证治疗绝经期骨质疏松780例[J]．中国民间疗法，2000，8(2)；40～41．
[15[于向东，崔军，周文泉，等．骨质疏松症的中西医结合研究热点与思考[J]．中国中医基础医学杂志，2002， 8 (3) ： 9～12．
[16]刘庆思，李奋儒，魏合伟，等．中医治疗骨质疏松症的原则及骨康方的应用[J]．新中医，2002， 34： 3- 4
[17]季晖，刘康，李绍平，等．淫羊藿总黄酮对维A酸诱导大鼠骨质疏松症的防治作用[J]．中国药科大学学报，2000，31(3)；222～225．
[18]李斌斌，于世凤．葛根素调控骨代谢的体外实验研究[J]．北京大学学报，2003， 35 (1) ； 74～77．
[19]马中书，王蕊，邱明才，等．四种补肾中药对去卵巢大鼠骨质疏松骨形态的作用[J]．中华妇产科杂志，1999， 34(2)；82～85．
[20]赵文海．鹿茸生长素对维甲酸所致大鼠骨质疏松影响的实验研究[J]．中国骨伤，2003， 16(8)； 468．
[21]王良鑫，赵新红·中西医结合治疗原发性骨质疏松症骨痛60例[J]·湖南中医杂志，2004， 20(2)： 24
[22]韩麦鲜，杜良杰·综合疗法治疗原发性骨质疏松症的临床观察[J]·中医正骨，2004， 16(8)： 12
[23]杨莉·温针灸为主治疗骨质疏松症腰背痛43例[J]·实用中医药杂志，2005， 21(1)： 28
[24]潘霞，王东岩·黄芪注射液穴位注射治疗原发性骨质疏松症34例[J]·陕西中医，2004， 25(12)： 1133
[25]唐义泉，周红胜·运动锻炼对老年骨质疏松症防治观察[J]·福建中医药，2003， 34(3)： 25
[26]肖建德，阎德文，刘景芳，等．中药龟丝补骨片对绝经后早期妇女性激素和钙调节激素的影响．中国骨质疏松杂志，2002，8(3)：258～262
[27]支会英，李恩．补肾方药对去卵巢大鼠骨质疏松的骨组织ER 表达的影响．中国中医基础医学杂志，2001， 7 (4) ： 41 ～ 44
[28]安胜军，李恩，赵京山．补肾方药对地塞米松所致实验性骨质疏松大鼠卵巢功能的影响，中国中西医结合杂志，2000，20(1)：46～49
[29]姚建峰，许鹏，郭雄，等．谷康泰灵对骨质疏松模型大鼠骨形成和骨吸收功能的影响．中国骨质疏松杂志，2002； 8 (3)：255～257
[30]马涛，崔燎，吴铁，等．老年大鼠含淫羊霍血清对成骨细胞的增殖与分化的影响．中国骨质疏松杂志 2002 ，8(1)：55～57
[31]詹红生，赵咏芳，石印玉，等．用含药血清方法观察补肾益精方对破骨细胞功能的影响．中国骨伤，2001 14 (3) ：145～147
[32]刘和娣，李恩，终晓旭，等．补肾中药对骨质疏松大鼠CaBP-D9K基因及表达的影响．中国骨质疏松杂志，1996，2(3)：62～64
[33]刘秀明，王淑云，李锐，等．微量元素对大鼠颅盖骨成骨细胞样细胞体外培养增殖分化的影响．中华骨科杂志，1995，15(3)：177～179
[34]Holloway WR，Collier FM，Herbst RE，et al．Osteoblast mediated effects of zinc on isolated rat osteoblasts：inhib ition of bone resorption and enhanceme of osteoclast nu-mber．Bone， 1996，19(2)：137～142
[35]陈训华，危剑安，陈燕平，等．肾虚骨痛胶囊对去势大鼠股骨无机元素含量和骨灰重量的影响．中国中西医结合杂志，1998， 2， 18 (2)：101～103
[36]沈霖，杜靖远，曾晖，等．补肾方对成骨细胞生长因子表达的影响〔J〕中医正骨，2001， 13 (5)：35
[37]鞠大宏，张春英，王安民，等．温补肾阳方对去卵巢所致骨质疏松大鼠IL1和IL6活性的影响[J]．中国中医基础医学杂志，2000， 6(10)：59
[38]程志安，萧劲夫，曾志勇，等．健骨二仙丸对去势大鼠骨结构和血清IGF-1的影响[J]．中国中医骨伤科杂志，2001，9(6)：912
[39]沈霖，杜靖远，赵海波，等．补肾法对实验性骨质疏松MMP-9及Ⅰ型胶原表达的影响[J]．中国中医骨伤科杂志，1998，6(4)：1～4
[40]支会英，李恩．补肾方药对去卵巢大鼠骨质疏松的骨组织ER表达的影响[J]．中国中医基础医学杂志，2001 ，7(4)：41～45
[1]Kalu DN，Hardin RH，Coekrhma R，et al．Aging and dieting modulation of rats Skeleton and Parathyroid homrone[J]．Endocrinology 1984，115：1239
[2]KaluDN，LiuCC，HadrinRR，et al．The aged rat model of ovarian homrone deficiency bonel055[J]．Endocrinology 19 89，124：7
[3]Foodanddrugedinstruction：Guidelinesof Preclinicand clinical evaluation of aged tissues in the prevention or treatment of Postmenopausal of Osteoporosis．Division of metabolism and endocrine durg Products〔J]．Dratfs，APril，1994
[4]汪青，孙兰，恭海洋，等．骨质疏松动物模型的建立与评价[J]．中国药理学通报．1999，15(5)：391
[5]Thomson DD，et al．FDA Guidelines and animal models of Osteoporosis [J]．Bone．1995，17(45)：1258
[6]Jee．WS．S．The aged rat model bonebiology sutdies．Cells and Materials．[J]．Seamring Microscopy Internation．Chiegao： 1991：25
[7]刘垒．中药强骨煎剂对去卵巢大鼠骨质疏松症防治效果及机制探讨．山东中医药大学硕士学位论文，2005
[8]安胜军，杨学辉，李恩．雌激素与骨质疏松症．中国骨质疏松杂志，1999；5 (3) ：77～78．
[9]Komm BS ．Estrogen binding receptor mRNA and biologic response in osteoblast-like osteosarcom cells．Science，1988； 241：81～84．
[10]Mano H，Yuasa T，Kameda T．Mammalian mature osteoclast as estrogen target cells ．Biochem Biophys Res Commun，1996；223：637～642．
[11]蔡丽慧，张秀兰，刘云莲．中西医结合治疗多囊卵巢综合征的临床研究．中医函授通讯，1997， 16(3)：38
[12]罗元恺．实用中医妇科学．上海：上海科学技术出版社，1996．290
[13]朱文新，等．妇产科情报资料．1989～1990，(3) ：33
[1]Komm BS．Estrogen binding receptor mRNA and biologic response in osteoblast-like osteosarcoma cells ．Science，1988； 241：81～84．
[2]赵亚力，徐晓虹，郭萍．C0PD患者营养状态及骨质代谢的研究[J]，黑龙江医学，2002；26(9)：665．
[3]苏赞妍，冯雪萍．更年期骨质疏松症妇女血清骨钙素水平的检测及其意义[J]．中华临床新医学，2002；2(5)：410．
[4]章明放，黄风歧，谭郁彬，等．去势大鼠血清骨钙素水平及意义．中国骨质疏松杂志，1999；5 (3) ：22～24．
[5]Celiker R，Ars l a n S．Comparison of serum insulin-like growth factor-land growthhormonelevelsinosteoporoticand non-osteoporotic postmenopausal women．Rheumatol Int，2000，19：205～208．
[6]舒强，王桂兰，董建军．绝经后骨质疏松与胰岛素样生长因子-1、表皮生长因子的关系〔]J．中华内分泌代谢杂志，2000，8：257
[7]王睿，郑洪新．骨质疏松症与胰岛素样生长因子-1的研究探讨[J]．2001，18：24～26
[8]Jehle P，Schulten K，Schulz W，et al．Serum levels of insulin-like growth factor (IGF)-1 and IGF binding protein (IGFBP)-1 to-6 and their relationship to bone metabolism in osteoporosis patients．Eur J Intern Med，2003，14：32～38．
[1]陈奇．中药药理实验方法「M]．北京：人民卫生出版社．1994．12
[2]党耕叮．骨组织形态测量学[M]．中华外科杂志，1989 ，27(1)：57
[3]RayN，F Chan JK，Thamer M，etal．Medical expenditures f-or the treatment of osteoporotic fracturein the United States in1995：Repeat fome the National osteoporosisFou-ndation[J]．Bone MnierRes，1997，12：24
[4]sotekJ．L，eoderreJ．A，MalleetL．E．Eeffets of a short course of estrogen on Mineral metbaolism in postmenopuasal women [J]． Clin Endoenrial Metba．1985：61：595
[5]王晓达，张风华，符诗聪，等．健骨冲剂对去卵巢大鼠股骨及腰椎的生物力学作用[J]．中国骨伤，2001， 14(10)：601
[1]Camacho-Hubner C，SavageM．Insulin-like growth factor-1 deficiency．Horm Res，2001，55(Suppl 1)：17．
[2]杜松．密骨颗粒对肾虚骨质疏松大鼠及成骨细胞IGF-1mRNA基因表达影响的实验研究．辽宁中医学位硕士学位论论文， 2003
[3]Suliman IA，El-Bakri NK，Adem A，et al．The effect of ovariectomy and ovarian steroid treatment on growth hormone and insulin-like growth factor-1 levels in the rat femur．J Orthop Res，2001，19：1008～1012．
[4]NasuM，Sugimoto T，Kaji H，et al．Estrogen modulates osteoblast proliferation and function regulated by parathyroid hormone in osteoblastic SaOS-2 cells： role of insulin-like growthfactor(IGF)-1 andIGF-bind-ingprotein-5．J Endocrinol，2000，167：305～313．
[5]Jehle，PeterM：Sehulten，Klaus：Sehul，Z Walter：et al．Serum levels of insulin-like growth factor(IGF)-1 and IGF binding Portein(IGFBP)-Ito-6andtheirrelationshiptobone metbaolisminosteoPorosis Patients．EuroPenaJounral of internal Medieine 2003；14(1)：32～38
[6]Kveibogr，M．Flyvbjegr，A Rattna，5．I．5；et al．Chnages in the insulin-like growth factor system may contribute to in vitro age-related imparied osteoblast functions．Epxerimental Georniology 2000：35(8)：1061～1074
[7]Ving，A；McCarthy．TL．The Neuropeptide Caleitonin Gene-Related peptide stimulates Insulin-like Growth Factor 1 Production by Primary Fetal Rat osteoblasts．Bone1996：18(4)：331～335
[8]廉凯，杜靖远．降钙素基因相关肤对鼠成骨细胞IGF-1及IGF-1 mRNA表达的影响．中国矫形外科杂志2001；8(11)：1084～1087
[1]Tsuda E，Goto M，Mochizuki S，et al．Isolation of a novel cytokine from human fibroblast that specifically inhibits osteoclasteogenesis．Biochem Biophys Res Commun，1997，234：137
[2]Simonet WS，Lacey DL，Dunstan CR，et al．Osteoprotegerin：a novel secreted protein involved in the regulation of bone density．Cell，1997，89：309
[3]Hofbauer LC，Khosla S，Dunstan CR，et al．The roles of osteoprotegerin and osteoprotegerin ligand in the paracrine regulation of bone resorption [J]．J Bone and Miner Res，2000，15(1)：2～12．
[4]Simonet WS，Lacey DL，Dunstan CR，et al．Osteoprotegerin：a novel secreted protein involved in the regulation of bone density[J]．Cell， 1997， 89(2)：309～319．
[5]Aubin JE，Bonnelye E．Osteoprotegerin and its ligand：a new paradigm for regulation of osteoclastogenesis and bone resorption[J]．Osteoporosis International，2000，11(11)：905～913．
[6]BoyleWJ,Simonet WS,Lacey DL.Osteoclast different-iation and activation[J].Nature,2003,423:337 ～ 342
[7]Shimizu-Ishiura M,Kawana F,et al.Osteoprotegerin admi-nistration reduces femural bone loss in ovariectomized mic-e via impairment of osteoclast structure and function[J].J Electron Microsc,2002,(51):315 ～ 325.
[1]李平生．老年人骨质疏松[J]．人民军医，2004， 47 (7) ； 419～421．
[2]Bonjour JP，Chevalley T，Amimann P，et al．Gain in bonemineral mass in prepubertal girls 3．5 years after discontinuation of calcium supplementation； a follow-up study．Lancet， 2001，358；1208～1212．
[3]Feskanich D，Willett WC，Colditz GA．Calcium，vitaminD，milk consumption，and hip fractures；A prospective study among postmenopausal women．Am J Clin Nutr，2003，77 (2)；504～511．
[4]刘忠厚主编．骨质疏松学．北京；科学出版社，1998， 167- 195．
[5]Hannan MT，Tucker KL，Dawson-Hughes B，et al．Effect of dietary protein on bone loss in elderly men and women；the framingham osteoporosis study．J Bone Miner Res，2000，15(12)；2 504～2 512．
[6]Horiuchi T，Onouchi T，Takahashi M，et al ．Effect of soy protein on bone metabolism in postmenopausal Japanesewomen．Osteoporos Int，2000，11(8)；721～724．
[7]IshidaM，YaoN，YaehikuS，etal ．Managementofealeium，phosphorus And bone metabolism in dialysis Patients using sevel maerhydrochloride and vitamine D therapy ．The Apher Dial．2005 Aug； 9 Suppll； 516～21．
[8]ZhaoX，ZhaoX，CuiW，etal．Preventive effete of vitamin K_1 and Calcium on osteoporosis in ovarieetomized rat．Wei Sheng Yan Jiu ．1999 Nov；28(6)；367～369
[9]曲玉蓉，高月华．运动与女性原发性骨质疏松症．中国骨质疏松杂志，1999， 5 (2) ； 24～25．
[10]Ferrari S，Manen D，Bonjour JP，et al．Bone mineral mass and calcium and phosphate metabolism in young men；relationships with vitamin D receptor allelic polymorphism．J Clin Endocrinol Metba，1999，84(6)；2043～2048．
[11]Keen RW， Woodford-Richens KL， Grant SF， et al．Association of polymorphism at the type I collagen locus with reduced bone mineral density increased fracture risk，and increased collagen turnover．Arthritis Rheum，1999，42(2)；285～290．
[12]汪德华，龚敏．影响老年性骨质疏松症发生的多因素探讨．中国临床康复，2003， 7(30)；4150．
[13]焦翔，张志宏，李瑾．老年性骨质疏松所致骨折的血清钙磷和1GF-1的调查分析．标记免疫分析与临床，2004， 11 (2) ；128～129．
[14]]GordonCM，BinelloE，LeboffMS，et al．Relationship between insulin-like growth factor 1，dehydroepiandrosterone sulafate and Proresorptive cytokines and bone density in evstiefibrosis．osteoporosis Int．2006(16)；
[15]武文红，王光哲，王惠芳，等．老年原发性骨质疏松患者血清IGF-1，IGF-BP3水平与骨密度及骨折的关系．西安交通大学学报(医学版)，200526(2)；195～198．
[16]沈辉，潘时中．骨保护素与骨质疏松．国外医学内分泌学分册，2004， 24 (4)：230～233
[17]孔璐，陈永军．骨质疏松症的病因与防治．临床荟萃，1999，14(6)；284～285
[18]Nawata H，Soen S，Takayanagi R，et al．Guidelines on the management and treatment of glucocorticoid-induced osteoporosis of the Japanese society for bone and mineral research (2004)[J]．J Bone Miner Metab，2005，23(2)；105～109．
[19]Kuller LH，Matthews KA，Meilahn EN．Estrogens and women's health；interrelation of coronary heart disease，breast cancer and osteoporosis[J]．J Steroid BiochemMol Biol，2000，74(5)；297～309．
[20]PlotkinLI，ManolagasSC，BellidoT．Dissociation of the proapoptotic effects of bisphosphonates on osteoclasts from their anti-apoptotic effects on osteoblasts／osteocytes with novel analogs[J]．Bone，2006，39(3)；443～452．
[21]Yen ML,Yen BL,JangMH,et al.Effects of alendronate on osteopenic postmenopausal Chinese women[J].Bone,2000,27(5);681 ～ 685.
[22]McClung MR.Bisphosphonates in osteoporosis;recent clinical experience[J].Expert Opin Pharmacother,2000,1(2);225～238.
[23]Cohen D,Adachi JD.The treatment of glucocorticoid-ind-uced osteoporosis[J].J Steroid BiochemMol Biol,2004,88(4-5);337～ 349.
[24]McClung MR,Geusens P,Miller PD,et al.Effect of ri-sedronate on the risk of hip fracture in elderlywomen.Hi-p intervention program study group[J].NEngl JMed,2001,344(5);333 ～ 340.
[25]Cauley JA,Norton L,Lippman ME,et al.Continued breast cancer risk reduction in ostmenopausal women treated with raloxifene;4-year results from the MORE trial.Mul-tiple outcomes of raloxifene evaluation[J].Breast Cancer ResTreat,2001,65(2);125 ～ 134.
[26]Hodsman AB,Bauer DC,Dempster DW,et al.Parathyro-id hormone and teriparatide for the treatment of osteoporo-sis;a review of the evidence and suggested guidelines for its use[J].Endocr Rev,2005,26(5);688～703.
[27]WhitfieldJ,Morley P,Willick G.The parathyroid hormon-e,its fragments and analogues—potent bone-builders for tr-eating osteoporosis[J].Expert Opin Investigate Drugs,2000,9(6);1293 ～ 1315.
[1]Celiker R，Arslan S．Comparison of serum insulin-like growth factor-1 and growth hormone levels in osteoporotic and non-osteoporotic post-menopausal women．Rheumatol Ⅰ nt，2000．19：205～208．
[2]Kanatani M，SugimotoT，Kano J，et al．IGF-1 mediatesthe stimulatory effect of high phosphate concentration on osteoblastic cell proliferation．J Cell Physiol，2002．190：306～312．
[3]Sakata T，Halloran BP，Elalieh HZ，et al．Skeletal unloading induces resistance to insulin-like growth factor 1 on bone formation．Bone，2003，32：669～680．
[4]Farley JR，Stilt-Coffing B．Apoptosis may determine the release of skeletal alkaline phosphatase activity from human osteoblast-line cells．Calcif Tissue Int， 2001，68：43～52．
[5]涂意辉，杨安礼：脉冲电磁场对去势大鼠骨组织胰岛素样生长因子1表达的影响[J]中国临床康复2 0 0 3．7 (15 )： 2137
[6]李万根，张彤等 绝经后妇女骨密度与胰岛素、胰岛素样生长因子1及瘦素的关系 中国临床康复第8卷第24期2004-08-25
[7]Suliman IA，E1-Bakri NK，Adem A。et al．The effect of ovariectomy and ovarian steroid treatment on growth hormone and insulin-like growth factor-1 levels in the rat femur．J Orthop Res，2001，19：1008～1012．
[8]NasuM，SugimotoT，Kaji H，et al．Estrogen modulates osteoblast proliferation and function regulated by parathyroi -d hormone in osteoblastic SaOS-2 cells： role of insulin-like growth factor (IGF)-1 and IGF-binding protein-5．J Endocrinol， 2000，167：305～313．
[9]陈露文等。老年男性骨质疏松与IGF-1及性激素水平的相关研究广西医科大学学报2003； 20 (5)
[10]Jehle P，Schulten K，Schulz W，et al。Serum levels of insulin-like growth factor (IGF)-1 and IGF binding protein (IGFBP)-1 to-6 and their relationship to bone metabolism in osteoporosis patients．Eur J Intern Med，2003，14：32～38．
[11]Grinspoon S，ThomasL，Miller K，et al．Effects of recombinant human IGF-1 and oral contraceptive administration on bone density in anorexia nervosa．J Clin Endocrinol Metab， 2002，87：2883～2891．
[12]JonesJl，Lemmers DR．IGFs and their binding proteins[J]Endoerinol Rev，1995，16(3)：3～35
[13]张胜利等，骨质疏松骨折愈合过程中IGF-1mRNA的基因表达[J]第三军医大学学报，2001， 23(6)：686～ 688
[14]Boonen S，Rosen C，Bouillon R，et al Musculoskeletal effects of the recombinant human IGF-1 ／IGFbinding protein-3 complex in osteoporotic patients with proximal femoral fracture： a double-blind，placebo-controlled pilot study．J Clin Endocrinol Metab，2002，87：1593～1599．
[1]Simonet SW， Lacey D L，Dunstan C R，et al．Osteoprotege-rin：a novel secreted protein involved in the regulation of density[J]．Cell 1997， 89： 309～319．
[2]Yasuda H，Shima N，Nakagawa N et al，Osteoclast；differentiat-ionfactorisaligandfor osteoprotegerin／osteoclastogenesis inhibitory factor and is identical to TRANCE／RANKL．Proc Natl Acad Sci USA 1998；95 (7)：3957～602
[3]Yamaguchi K，Kinosaki M，Goto M et al，Characterization of structured domains of human osteoclastogenesis inhibitory factor．J Biol Chem 1998；273：5117～23
[4]Tomoyasu A，Goto M，Fujise N，Characterization of mono-meric and homodimeric forms of osteoclastogenesis inhibit-ory factor．J Biochem Biophys Res Commun 1998；245(2)：382～387
[5]LACEY D L， TIMMS E， TANH L et al Osteoprotegerin 11-gand is a cytokine that regulaties osteoclast differentiation and activation [J]．Cel，1 1998，93：165～176．
[6]Lacey DL， Timms E，Tan HL et al．Osteoprotegerin ligand is a cytokine that regulatesosteoclast differentiation and activation．Cell 1998；93：165～76
[7]张克勤，陈家伟9王美莲9等(甲状旁腺激素对大鼠成骨细胞转化生长因子-1基因转录的影响[J]．中国临床康复，200337(2)： 230～1
[8]Hsu H， Lacey D L， Dunstan C R， et a]．Tumor necrosis fa-ctor receptorfamilymemberPANKmediates osteoclast di-fferentiation and activation induced by osteoprotegerin lig-and [J]．Proc Natl Acad Sci USA， 1999， 96： 3540～3545．
[9]Hofbaus LC，Khosla S，Dunstan CR，ei al The roles of osteoprotegerin and osteoprotegerin ligand in the paracrine regulation of bone restorption．J Bone Mine Res 2000；15：2～ 12
[10]Nagai M，Sato N．Reciprocal gene expression of osteoclast -ogenesis inhibitory factor and osteoclast differentiation fa-ctor regulates osteoclast formation.J Biochem Biophys Re-s Commun 1999;257:719 ～ 23
[11]Hin H,Morony S,Sarosi I,et al osteoprotegerin reverses ost-eoporsis by inhibiting endosteal osteoclasts and prevents vascular calcification by blocking a process resembling ost-eoclastogenesis.J Exp Med 2000;192:463 ～ 74
[12]Vano K,Tsuda E,Washida N,et al.Immunological characterization of circulating osteoprotegerin/osteoclastogenesis,inhibitory factor:increased serum concentrations in postmenop-ausal women with osteoporosis.J Bone Mine Res 1999;14(4):4367～ 70
[13]Makhluf HA,Mueller SM,Mizuno Set al.Age-related declin-e in osteoprotegerin expression by human bone marrow ce-lls cultured in three-dimensional collagen sponges.Bioche-m Biochem Biophys Res Commun 2000;2668(3):669 ～ 72
[14]Gravallese EM,Manning C,Tsay A,et al.Synovial tissue in rheumatoid arthritis is a soource os osteoclast differentiat-ion factor.Arthritis Rheum 2000;43(2)250 ～ 8
[15]Kong YY,Feige U,Sarosi I,et al.Activated T cells regulate bone loss and joint destruction in adjuvant arthritis throu-gh osteoprotegerin ligand[J].Nature.1999;402:304 ～ 08.
[16]Karin Vanderkerken,Evy De Leenheer,Claire Shipman,et al.Recombinant Osteoprotegrin Decreases Tumor Burden and Increases Survival in a Murine Model of Multiple Myelo-ma[J].Cancer Research,2003,63:287 ～ 89.
[17]Nancy M.Luger,Prisca Honore,Mary Ann C,Sabino,et al.osteoprotegerin Diminishes Advanced Bone Cancer Pain[J].CANCER RESEARCH,2001;61:4038 ～ 47.
[2]姚远，胡丽娜．绝经后骨质疏松症概述．实用妇产科杂志，2006，22(7)：385～387
[3]王翔．补肾中药防治骨质疏松症基础研究进展．中医正骨，2003
[1]丁桂芝，李榕。从骨矿含量变化规律看肾主骨理论的科学性。湖北中医杂志1991； 13(2)； 27
[2]赵玉堂，刘凯军，李金花，等。骨矿含量与肾虚、肾主骨关系的研究。中国骨质疏松杂志1996； 2(3)； 19
[3]李边达。中药治疗无菌性股骨头坏死及骨质疏松症的主要药效学研究技术要求。中药新药与临床1992； 3 (2) ； 7
[4]张洪，魏之玉，王景存。补肾疏肝健脾方治疗老年原发性骨质疏松症38例。山东中医药大学学报1997； 21(5)；375
[5]李祥炜，周德祥。中医治疗原发性骨质疏松症最新进展。中医药信息1998； 6； 9
[6]魏之玉，张洪，朱振铎，等。196例原发性骨质疏松症辨证分析。山东中医学院学报1996； 20 (1) ； 30
[7]罗为民。健脾补肾法防治绝经后骨质疏松症的计量学研究。中国中医骨伤科1995； 3 (2) ； 1
[8]张荣华，丘和明。中医防治退行性骨质疏松症用药分析。 中医药学报1997； 4； 30
[9]齐振熙．辨证治疗绝经后骨质疏松症[J]．中国中医骨伤科杂志，1998， 6 (3)： 28～29．
[10]谢金华，张晓晖，徐敏．绝经后骨质疏松症的中医辨证研究．中国中医基础医学杂志，2003， 9 (7) ： 55- 57
[11]薛延．骨质疏松症诊断与治疗指南[M]．北京：科学出版社，2000．
[12]陈维静，刘新梅，廉红真．中医辨证治疗原发性骨质疏松症(附109例报告)[J]．中医药研究，1999， 15 (3) ； 29 - 31．
[13]王军，杜乐年．补肾为主治疗骨质疏松症[J]．云南中医学院学报，1999， 22(2)； 17～20．
[14]胡军．辨证治疗绝经期骨质疏松780例[J]．中国民间疗法，2000，8(2)；40～41．
[15[于向东，崔军，周文泉，等．骨质疏松症的中西医结合研究热点与思考[J]．中国中医基础医学杂志，2002， 8 (3) ： 9～12．
[16]刘庆思，李奋儒，魏合伟，等．中医治疗骨质疏松症的原则及骨康方的应用[J]．新中医，2002， 34： 3- 4
[17]季晖，刘康，李绍平，等．淫羊藿总黄酮对维A酸诱导大鼠骨质疏松症的防治作用[J]．中国药科大学学报，2000，31(3)；222～225．
[18]李斌斌，于世凤．葛根素调控骨代谢的体外实验研究[J]．北京大学学报，2003， 35 (1) ； 74～77．
[19]马中书，王蕊，邱明才，等．四种补肾中药对去卵巢大鼠骨质疏松骨形态的作用[J]．中华妇产科杂志，1999， 34(2)；82～85．
[20]赵文海．鹿茸生长素对维甲酸所致大鼠骨质疏松影响的实验研究[J]．中国骨伤，2003， 16(8)； 468．
[21]王良鑫，赵新红·中西医结合治疗原发性骨质疏松症骨痛60例[J]·湖南中医杂志，2004， 20(2)： 24
[22]韩麦鲜，杜良杰·综合疗法治疗原发性骨质疏松症的临床观察[J]·中医正骨，2004， 16(8)： 12
[23]杨莉·温针灸为主治疗骨质疏松症腰背痛43例[J]·实用中医药杂志，2005， 21(1)： 28
[24]潘霞，王东岩·黄芪注射液穴位注射治疗原发性骨质疏松症34例[J]·陕西中医，2004， 25(12)： 1133
[25]唐义泉，周红胜·运动锻炼对老年骨质疏松症防治观察[J]·福建中医药，2003， 34(3)： 25
[26]肖建德，阎德文，刘景芳，等．中药龟丝补骨片对绝经后早期妇女性激素和钙调节激素的影响．中国骨质疏松杂志，2002，8(3)：258～262
[27]支会英，李恩．补肾方药对去卵巢大鼠骨质疏松的骨组织ER 表达的影响．中国中医基础医学杂志，2001， 7 (4) ： 41 ～ 44
[28]安胜军，李恩，赵京山．补肾方药对地塞米松所致实验性骨质疏松大鼠卵巢功能的影响，中国中西医结合杂志，2000，20(1)：46～49
[29]姚建峰，许鹏，郭雄，等．谷康泰灵对骨质疏松模型大鼠骨形成和骨吸收功能的影响．中国骨质疏松杂志，2002； 8 (3)：255～257
[30]马涛，崔燎，吴铁，等．老年大鼠含淫羊霍血清对成骨细胞的增殖与分化的影响．中国骨质疏松杂志 2002 ，8(1)：55～57
[31]詹红生，赵咏芳，石印玉，等．用含药血清方法观察补肾益精方对破骨细胞功能的影响．中国骨伤，2001 14 (3) ：145～147
[32]刘和娣，李恩，终晓旭，等．补肾中药对骨质疏松大鼠CaBP-D9K基因及表达的影响．中国骨质疏松杂志，1996，2(3)：62～64
[33]刘秀明，王淑云，李锐，等．微量元素对大鼠颅盖骨成骨细胞样细胞体外培养增殖分化的影响．中华骨科杂志，1995，15(3)：177～179
[34]Holloway WR，Collier FM，Herbst RE，et al．Osteoblast mediated effects of zinc on isolated rat osteoblasts：inhib ition of bone resorption and enhanceme of osteoclast nu-mber．Bone， 1996，19(2)：137～142
[35]陈训华，危剑安，陈燕平，等．肾虚骨痛胶囊对去势大鼠股骨无机元素含量和骨灰重量的影响．中国中西医结合杂志，1998， 2， 18 (2)：101～103
[36]沈霖，杜靖远，曾晖，等．补肾方对成骨细胞生长因子表达的影响〔J〕中医正骨，2001， 13 (5)：35
[37]鞠大宏，张春英，王安民，等．温补肾阳方对去卵巢所致骨质疏松大鼠IL1和IL6活性的影响[J]．中国中医基础医学杂志，2000， 6(10)：59
[38]程志安，萧劲夫，曾志勇，等．健骨二仙丸对去势大鼠骨结构和血清IGF-1的影响[J]．中国中医骨伤科杂志，2001，9(6)：912
[39]沈霖，杜靖远，赵海波，等．补肾法对实验性骨质疏松MMP-9及Ⅰ型胶原表达的影响[J]．中国中医骨伤科杂志，1998，6(4)：1～4
[40]支会英，李恩．补肾方药对去卵巢大鼠骨质疏松的骨组织ER表达的影响[J]．中国中医基础医学杂志，2001 ，7(4)：41～45
[1]Kalu DN，Hardin RH，Coekrhma R，et al．Aging and dieting modulation of rats Skeleton and Parathyroid homrone[J]．Endocrinology 1984，115：1239
[2]KaluDN，LiuCC，HadrinRR，et al．The aged rat model of ovarian homrone deficiency bonel055[J]．Endocrinology 19 89，124：7
[3]Foodanddrugedinstruction：Guidelinesof Preclinicand clinical evaluation of aged tissues in the prevention or treatment of Postmenopausal of Osteoporosis．Division of metabolism and endocrine durg Products〔J]．Dratfs，APril，1994
[4]汪青，孙兰，恭海洋，等．骨质疏松动物模型的建立与评价[J]．中国药理学通报．1999，15(5)：391
[5]Thomson DD，et al．FDA Guidelines and animal models of Osteoporosis [J]．Bone．1995，17(45)：1258
[6]Jee．WS．S．The aged rat model bonebiology sutdies．Cells and Materials．[J]．Seamring Microscopy Internation．Chiegao： 1991：25
[7]刘垒．中药强骨煎剂对去卵巢大鼠骨质疏松症防治效果及机制探讨．山东中医药大学硕士学位论文，2005
[8]安胜军，杨学辉，李恩．雌激素与骨质疏松症．中国骨质疏松杂志，1999；5 (3) ：77～78．
[9]Komm BS ．Estrogen binding receptor mRNA and biologic response in osteoblast-like osteosarcom cells．Science，1988； 241：81～84．
[10]Mano H，Yuasa T，Kameda T．Mammalian mature osteoclast as estrogen target cells ．Biochem Biophys Res Commun，1996；223：637～642．
[11]蔡丽慧，张秀兰，刘云莲．中西医结合治疗多囊卵巢综合征的临床研究．中医函授通讯，1997， 16(3)：38
[12]罗元恺．实用中医妇科学．上海：上海科学技术出版社，1996．290
[13]朱文新，等．妇产科情报资料．1989～1990，(3) ：33
[1]Komm BS．Estrogen binding receptor mRNA and biologic response in osteoblast-like osteosarcoma cells ．Science，1988； 241：81～84．
[2]赵亚力，徐晓虹，郭萍．C0PD患者营养状态及骨质代谢的研究[J]，黑龙江医学，2002；26(9)：665．
[3]苏赞妍，冯雪萍．更年期骨质疏松症妇女血清骨钙素水平的检测及其意义[J]．中华临床新医学，2002；2(5)：410．
[4]章明放，黄风歧，谭郁彬，等．去势大鼠血清骨钙素水平及意义．中国骨质疏松杂志，1999；5 (3) ：22～24．
[5]Celiker R，Ars l a n S．Comparison of serum insulin-like growth factor-land growthhormonelevelsinosteoporoticand non-osteoporotic postmenopausal women．Rheumatol Int，2000，19：205～208．
[6]舒强，王桂兰，董建军．绝经后骨质疏松与胰岛素样生长因子-1、表皮生长因子的关系〔]J．中华内分泌代谢杂志，2000，8：257
[7]王睿，郑洪新．骨质疏松症与胰岛素样生长因子-1的研究探讨[J]．2001，18：24～26
[8]Jehle P，Schulten K，Schulz W，et al．Serum levels of insulin-like growth factor (IGF)-1 and IGF binding protein (IGFBP)-1 to-6 and their relationship to bone metabolism in osteoporosis patients．Eur J Intern Med，2003，14：32～38．
[1]陈奇．中药药理实验方法「M]．北京：人民卫生出版社．1994．12
[2]党耕叮．骨组织形态测量学[M]．中华外科杂志，1989 ，27(1)：57
[3]RayN，F Chan JK，Thamer M，etal．Medical expenditures f-or the treatment of osteoporotic fracturein the United States in1995：Repeat fome the National osteoporosisFou-ndation[J]．Bone MnierRes，1997，12：24
[4]sotekJ．L，eoderreJ．A，MalleetL．E．Eeffets of a short course of estrogen on Mineral metbaolism in postmenopuasal women [J]． Clin Endoenrial Metba．1985：61：595
[5]王晓达，张风华，符诗聪，等．健骨冲剂对去卵巢大鼠股骨及腰椎的生物力学作用[J]．中国骨伤，2001， 14(10)：601
[1]Camacho-Hubner C，SavageM．Insulin-like growth factor-1 deficiency．Horm Res，2001，55(Suppl 1)：17．
[2]杜松．密骨颗粒对肾虚骨质疏松大鼠及成骨细胞IGF-1mRNA基因表达影响的实验研究．辽宁中医学位硕士学位论论文， 2003
[3]Suliman IA，El-Bakri NK，Adem A，et al．The effect of ovariectomy and ovarian steroid treatment on growth hormone and insulin-like growth factor-1 levels in the rat femur．J Orthop Res，2001，19：1008～1012．
[4]NasuM，Sugimoto T，Kaji H，et al．Estrogen modulates osteoblast proliferation and function regulated by parathyroid hormone in osteoblastic SaOS-2 cells： role of insulin-like growthfactor(IGF)-1 andIGF-bind-ingprotein-5．J Endocrinol，2000，167：305～313．
[5]Jehle，PeterM：Sehulten，Klaus：Sehul，Z Walter：et al．Serum levels of insulin-like growth factor(IGF)-1 and IGF binding Portein(IGFBP)-Ito-6andtheirrelationshiptobone metbaolisminosteoPorosis Patients．EuroPenaJounral of internal Medieine 2003；14(1)：32～38
[6]Kveibogr，M．Flyvbjegr，A Rattna，5．I．5；et al．Chnages in the insulin-like growth factor system may contribute to in vitro age-related imparied osteoblast functions．Epxerimental Georniology 2000：35(8)：1061～1074
[7]Ving，A；McCarthy．TL．The Neuropeptide Caleitonin Gene-Related peptide stimulates Insulin-like Growth Factor 1 Production by Primary Fetal Rat osteoblasts．Bone1996：18(4)：331～335
[8]廉凯，杜靖远．降钙素基因相关肤对鼠成骨细胞IGF-1及IGF-1 mRNA表达的影响．中国矫形外科杂志2001；8(11)：1084～1087
[1]Tsuda E，Goto M，Mochizuki S，et al．Isolation of a novel cytokine from human fibroblast that specifically inhibits osteoclasteogenesis．Biochem Biophys Res Commun，1997，234：137
[2]Simonet WS，Lacey DL，Dunstan CR，et al．Osteoprotegerin：a novel secreted protein involved in the regulation of bone density．Cell，1997，89：309
[3]Hofbauer LC，Khosla S，Dunstan CR，et al．The roles of osteoprotegerin and osteoprotegerin ligand in the paracrine regulation of bone resorption [J]．J Bone and Miner Res，2000，15(1)：2～12．
[4]Simonet WS，Lacey DL，Dunstan CR，et al．Osteoprotegerin：a novel secreted protein involved in the regulation of bone density[J]．Cell， 1997， 89(2)：309～319．
[5]Aubin JE，Bonnelye E．Osteoprotegerin and its ligand：a new paradigm for regulation of osteoclastogenesis and bone resorption[J]．Osteoporosis International，2000，11(11)：905～913．
[6]BoyleWJ,Simonet WS,Lacey DL.Osteoclast different-iation and activation[J].Nature,2003,423:337 ～ 342
[7]Shimizu-Ishiura M,Kawana F,et al.Osteoprotegerin admi-nistration reduces femural bone loss in ovariectomized mic-e via impairment of osteoclast structure and function[J].J Electron Microsc,2002,(51):315 ～ 325.
[1]李平生．老年人骨质疏松[J]．人民军医，2004， 47 (7) ； 419～421．
[2]Bonjour JP，Chevalley T，Amimann P，et al．Gain in bonemineral mass in prepubertal girls 3．5 years after discontinuation of calcium supplementation； a follow-up study．Lancet， 2001，358；1208～1212．
[3]Feskanich D，Willett WC，Colditz GA．Calcium，vitaminD，milk consumption，and hip fractures；A prospective study among postmenopausal women．Am J Clin Nutr，2003，77 (2)；504～511．
[4]刘忠厚主编．骨质疏松学．北京；科学出版社，1998， 167- 195．
[5]Hannan MT，Tucker KL，Dawson-Hughes B，et al．Effect of dietary protein on bone loss in elderly men and women；the framingham osteoporosis study．J Bone Miner Res，2000，15(12)；2 504～2 512．
[6]Horiuchi T，Onouchi T，Takahashi M，et al ．Effect of soy protein on bone metabolism in postmenopausal Japanesewomen．Osteoporos Int，2000，11(8)；721～724．
[7]IshidaM，YaoN，YaehikuS，etal ．Managementofealeium，phosphorus And bone metabolism in dialysis Patients using sevel maerhydrochloride and vitamine D therapy ．The Apher Dial．2005 Aug； 9 Suppll； 516～21．
[8]ZhaoX，ZhaoX，CuiW，etal．Preventive effete of vitamin K_1 and Calcium on osteoporosis in ovarieetomized rat．Wei Sheng Yan Jiu ．1999 Nov；28(6)；367～369
[9]曲玉蓉，高月华．运动与女性原发性骨质疏松症．中国骨质疏松杂志，1999， 5 (2) ； 24～25．
[10]Ferrari S，Manen D，Bonjour JP，et al．Bone mineral mass and calcium and phosphate metabolism in young men；relationships with vitamin D receptor allelic polymorphism．J Clin Endocrinol Metba，1999，84(6)；2043～2048．
[11]Keen RW， Woodford-Richens KL， Grant SF， et al．Association of polymorphism at the type I collagen locus with reduced bone mineral density increased fracture risk，and increased collagen turnover．Arthritis Rheum，1999，42(2)；285～290．
[12]汪德华，龚敏．影响老年性骨质疏松症发生的多因素探讨．中国临床康复，2003， 7(30)；4150．
[13]焦翔，张志宏，李瑾．老年性骨质疏松所致骨折的血清钙磷和1GF-1的调查分析．标记免疫分析与临床，2004， 11 (2) ；128～129．
[14]]GordonCM，BinelloE，LeboffMS，et al．Relationship between insulin-like growth factor 1，dehydroepiandrosterone sulafate and Proresorptive cytokines and bone density in evstiefibrosis．osteoporosis Int．2006(16)；
[15]武文红，王光哲，王惠芳，等．老年原发性骨质疏松患者血清IGF-1，IGF-BP3水平与骨密度及骨折的关系．西安交通大学学报(医学版)，200526(2)；195～198．
[16]沈辉，潘时中．骨保护素与骨质疏松．国外医学内分泌学分册，2004， 24 (4)：230～233
[17]孔璐，陈永军．骨质疏松症的病因与防治．临床荟萃，1999，14(6)；284～285
[18]Nawata H，Soen S，Takayanagi R，et al．Guidelines on the management and treatment of glucocorticoid-induced osteoporosis of the Japanese society for bone and mineral research (2004)[J]．J Bone Miner Metab，2005，23(2)；105～109．
[19]Kuller LH，Matthews KA，Meilahn EN．Estrogens and women's health；interrelation of coronary heart disease，breast cancer and osteoporosis[J]．J Steroid BiochemMol Biol，2000，74(5)；297～309．
[20]PlotkinLI，ManolagasSC，BellidoT．Dissociation of the proapoptotic effects of bisphosphonates on osteoclasts from their anti-apoptotic effects on osteoblasts／osteocytes with novel analogs[J]．Bone，2006，39(3)；443～452．
[21]Yen ML,Yen BL,JangMH,et al.Effects of alendronate on osteopenic postmenopausal Chinese women[J].Bone,2000,27(5);681 ～ 685.
[22]McClung MR.Bisphosphonates in osteoporosis;recent clinical experience[J].Expert Opin Pharmacother,2000,1(2);225～238.
[23]Cohen D,Adachi JD.The treatment of glucocorticoid-ind-uced osteoporosis[J].J Steroid BiochemMol Biol,2004,88(4-5);337～ 349.
[24]McClung MR,Geusens P,Miller PD,et al.Effect of ri-sedronate on the risk of hip fracture in elderlywomen.Hi-p intervention program study group[J].NEngl JMed,2001,344(5);333 ～ 340.
[25]Cauley JA,Norton L,Lippman ME,et al.Continued breast cancer risk reduction in ostmenopausal women treated with raloxifene;4-year results from the MORE trial.Mul-tiple outcomes of raloxifene evaluation[J].Breast Cancer ResTreat,2001,65(2);125 ～ 134.
[26]Hodsman AB,Bauer DC,Dempster DW,et al.Parathyro-id hormone and teriparatide for the treatment of osteoporo-sis;a review of the evidence and suggested guidelines for its use[J].Endocr Rev,2005,26(5);688～703.
[27]WhitfieldJ,Morley P,Willick G.The parathyroid hormon-e,its fragments and analogues—potent bone-builders for tr-eating osteoporosis[J].Expert Opin Investigate Drugs,2000,9(6);1293 ～ 1315.
[1]Celiker R，Arslan S．Comparison of serum insulin-like growth factor-1 and growth hormone levels in osteoporotic and non-osteoporotic post-menopausal women．Rheumatol Ⅰ nt，2000．19：205～208．
[2]Kanatani M，SugimotoT，Kano J，et al．IGF-1 mediatesthe stimulatory effect of high phosphate concentration on osteoblastic cell proliferation．J Cell Physiol，2002．190：306～312．
[3]Sakata T，Halloran BP，Elalieh HZ，et al．Skeletal unloading induces resistance to insulin-like growth factor 1 on bone formation．Bone，2003，32：669～680．
[4]Farley JR，Stilt-Coffing B．Apoptosis may determine the release of skeletal alkaline phosphatase activity from human osteoblast-line cells．Calcif Tissue Int， 2001，68：43～52．
[5]涂意辉，杨安礼：脉冲电磁场对去势大鼠骨组织胰岛素样生长因子1表达的影响[J]中国临床康复2 0 0 3．7 (15 )： 2137
[6]李万根，张彤等 绝经后妇女骨密度与胰岛素、胰岛素样生长因子1及瘦素的关系 中国临床康复第8卷第24期2004-08-25
[7]Suliman IA，E1-Bakri NK，Adem A。et al．The effect of ovariectomy and ovarian steroid treatment on growth hormone and insulin-like growth factor-1 levels in the rat femur．J Orthop Res，2001，19：1008～1012．
[8]NasuM，SugimotoT，Kaji H，et al．Estrogen modulates osteoblast proliferation and function regulated by parathyroi -d hormone in osteoblastic SaOS-2 cells： role of insulin-like growth factor (IGF)-1 and IGF-binding protein-5．J Endocrinol， 2000，167：305～313．
[9]陈露文等。老年男性骨质疏松与IGF-1及性激素水平的相关研究广西医科大学学报2003； 20 (5)
[10]Jehle P，Schulten K，Schulz W，et al。Serum levels of insulin-like growth factor (IGF)-1 and IGF binding protein (IGFBP)-1 to-6 and their relationship to bone metabolism in osteoporosis patients．Eur J Intern Med，2003，14：32～38．
[11]Grinspoon S，ThomasL，Miller K，et al．Effects of recombinant human IGF-1 and oral contraceptive administration on bone density in anorexia nervosa．J Clin Endocrinol Metab， 2002，87：2883～2891．
[12]JonesJl，Lemmers DR．IGFs and their binding proteins[J]Endoerinol Rev，1995，16(3)：3～35
[13]张胜利等，骨质疏松骨折愈合过程中IGF-1mRNA的基因表达[J]第三军医大学学报，2001， 23(6)：686～ 688
[14]Boonen S，Rosen C，Bouillon R，et al Musculoskeletal effects of the recombinant human IGF-1 ／IGFbinding protein-3 complex in osteoporotic patients with proximal femoral fracture： a double-blind，placebo-controlled pilot study．J Clin Endocrinol Metab，2002，87：1593～1599．
[1]Simonet SW， Lacey D L，Dunstan C R，et al．Osteoprotege-rin：a novel secreted protein involved in the regulation of density[J]．Cell 1997， 89： 309～319．
[2]Yasuda H，Shima N，Nakagawa N et al，Osteoclast；differentiat-ionfactorisaligandfor osteoprotegerin／osteoclastogenesis inhibitory factor and is identical to TRANCE／RANKL．Proc Natl Acad Sci USA 1998；95 (7)：3957～602
[3]Yamaguchi K，Kinosaki M，Goto M et al，Characterization of structured domains of human osteoclastogenesis inhibitory factor．J Biol Chem 1998；273：5117～23
[4]Tomoyasu A，Goto M，Fujise N，Characterization of mono-meric and homodimeric forms of osteoclastogenesis inhibit-ory factor．J Biochem Biophys Res Commun 1998；245(2)：382～387
[5]LACEY D L， TIMMS E， TANH L et al Osteoprotegerin 11-gand is a cytokine that regulaties osteoclast differentiation and activation [J]．Cel，1 1998，93：165～176．
[6]Lacey DL， Timms E，Tan HL et al．Osteoprotegerin ligand is a cytokine that regulatesosteoclast differentiation and activation．Cell 1998；93：165～76
[7]张克勤，陈家伟9王美莲9等(甲状旁腺激素对大鼠成骨细胞转化生长因子-1基因转录的影响[J]．中国临床康复，200337(2)： 230～1
[8]Hsu H， Lacey D L， Dunstan C R， et a]．Tumor necrosis fa-ctor receptorfamilymemberPANKmediates osteoclast di-fferentiation and activation induced by osteoprotegerin lig-and [J]．Proc Natl Acad Sci USA， 1999， 96： 3540～3545．
[9]Hofbaus LC，Khosla S，Dunstan CR，ei al The roles of osteoprotegerin and osteoprotegerin ligand in the paracrine regulation of bone restorption．J Bone Mine Res 2000；15：2～ 12
[10]Nagai M，Sato N．Reciprocal gene expression of osteoclast -ogenesis inhibitory factor and osteoclast differentiation fa-ctor regulates osteoclast formation.J Biochem Biophys Re-s Commun 1999;257:719 ～ 23
[11]Hin H,Morony S,Sarosi I,et al osteoprotegerin reverses ost-eoporsis by inhibiting endosteal osteoclasts and prevents vascular calcification by blocking a process resembling ost-eoclastogenesis.J Exp Med 2000;192:463 ～ 74
[12]Vano K,Tsuda E,Washida N,et al.Immunological characterization of circulating osteoprotegerin/osteoclastogenesis,inhibitory factor:increased serum concentrations in postmenop-ausal women with osteoporosis.J Bone Mine Res 1999;14(4):4367～ 70
[13]Makhluf HA,Mueller SM,Mizuno Set al.Age-related declin-e in osteoprotegerin expression by human bone marrow ce-lls cultured in three-dimensional collagen sponges.Bioche-m Biochem Biophys Res Commun 2000;2668(3):669 ～ 72
[14]Gravallese EM,Manning C,Tsay A,et al.Synovial tissue in rheumatoid arthritis is a soource os osteoclast differentiat-ion factor.Arthritis Rheum 2000;43(2)250 ～ 8
[15]Kong YY,Feige U,Sarosi I,et al.Activated T cells regulate bone loss and joint destruction in adjuvant arthritis throu-gh osteoprotegerin ligand[J].Nature.1999;402:304 ～ 08.
[16]Karin Vanderkerken,Evy De Leenheer,Claire Shipman,et al.Recombinant Osteoprotegrin Decreases Tumor Burden and Increases Survival in a Murine Model of Multiple Myelo-ma[J].Cancer Research,2003,63:287 ～ 89.
[17]Nancy M.Luger,Prisca Honore,Mary Ann C,Sabino,et al.osteoprotegerin Diminishes Advanced Bone Cancer Pain[J].CANCER RESEARCH,2001;61:4038 ～ 47.