绝经影响骨量和激素疗法抑制骨丢失的前瞻性研究

【作者】 陈瑛；

【导师】 林守清；

【作者基本信息】 中国协和医科大学 ， 妇产科学， 2007， 博士

【摘要】 [背景]女性从胎儿形成到衰老是一个渐进的生理过程,也是下丘脑—垂体—卵巢轴功能发育、成熟和衰退的过程。相应地,随这个变化过程产生的问题也具有连续的,渐进性的变化特点。性激素是机体内环境的一个稳定因素,它除了保持女性第二性征和生育能力等生殖功能外,还参与调节全身各器官系统的生理功能,即非生殖功能。对于骨骼关节肌肉系统,已明确性激素影响骨骼的生长发育。各种病理情况缺乏性激素,都是骨质疏松症发生的危险因素。绝经后骨质疏松症属于Ⅰ型原发性骨质疏松症,可以通过DEXA测定BMD来进行评价,这种方法是利用骨矿盐在骨基质（松质骨及皮质骨）中含量和分布的密度来反映骨量值,使骨量具有可测性,是一种较客观、有较好重复性的骨量测定手段。因而,绝经后骨质疏松症的研究也是近年来绝经后相关疾病中研究最多的领域之一。妇女进入绝经过渡期,骨吸收相对明显增强,骨丢失加快。绝经后骨质疏松症多为高转换型,表现为骨量迅速丢失,以松质骨丢失为主。绝经后骨质疏松症的预防是主要措施之一为激素疗法（HT）。在国内,关于绝经对骨量的影响,大部分数据来自于横断面研究,缺乏来自于前瞻性随诊证据的支持。关于激素疗法预防绝经后骨质疏松的研究,也缺乏从绝经过渡期或绝经早期开始低剂量激素疗法预防妇女绝经后骨质疏松症的随机双盲安慰剂对照研究的证据。[研究目的]本研究运用流行病学方法,对社区来源的人群进行调查并跟踪随访,以期了解妇女绝经过程中骨量的变化以及相关影响因素的作用。并通过随机双盲安慰剂对照研究,在进一步评价绝经过渡期或经早期妇女骨量变化的同时,评估妇女从绝经过渡期或绝经早期开始低剂量HT（戊酸雌二醇1mg/天,序贯联合MPA6mg*12天/月）长期应用（5年）对椎骨和髋骨骨密度以及骨代谢指标的影响。通过对血脂代谢、血糖、胰岛素以及绝经相关症状的改变等对绝经过渡期或绝经早期开始低剂量HT的效果进行总体评价,为激素疗法预防妇女绝经后骨质疏松症增添一级证据。本论文分为三部分:第一部分社区妇女卵巢衰退过程中的骨量变化第二部分医院来源的绝经过渡期和绝经早期妇女骨量变化的前瞻性研究第三部分激素疗法对抑制骨丢失的随机双盲安慰剂对照研究第一部分社区妇女卵巢衰退过程中的骨量变化[研究目的]通过对社区35-64岁妇女进行调查并随访1年,观察卵巢衰退过程中腰椎及股骨骨密度以及骨转换指标的变化。[内容与方法]1.本研究为分析性研究,包括基线调查和随访两部分。首先通过整群抽样方法,在知情同意的情况下,对社区743名35-64岁常住户籍妇女进行面对面调查。调查内容包括:主要的社会人口学特征、疾病史、性激素治疗史、月经状况。1年后,对参加基线调查者进行随诊,随诊内容包括近1年的上述调查内容的变化情况,同时再次进行骨密度检查和激素测定。2.检查项目:1).骨密度检查:采用美国Lunar公司的DPXL型双能X线骨密度仪（DEXA）测定腰椎2-4(L_2-4)与Neck、Wards、Troch骨密度以及股骨上部和股骨全部骨密度,CV为0.5%-1.1%。2).血清E₂:采用电化学发光法:采用电化学发光法:应用电化学发光法（Elecsys2010型全自动电化学发光仪,为美国Roche公司生产）测定E₂水平,E₂批间差异6.4%,批内差异6%。3).血清Ca、P和ALP检测:常规生化方法测定血清Ca、P和ALP值,批间变异系数分别为1.94%、3.13%和5.01%。3.统计学分析:全部资料输入Epidata3.02数据库,经两遍计算机录入、修改、整理后进行统计学处理。用SPSS 12.0统计软件包进行分析。计数资料描述分析采用频数、百分比,计量资料采用均数±标准差分析;各组之间人口统计学特征资料中计量资料之间采用t检验或方差分析;计数资料之间采用X²检验。将妇女根据STRAW月经状态分期方法将妇女分为绝经前（根据FSH水平分为FSH≤8IU/L和FSH＞8IU/L两组）,绝经过渡期早期、绝经过渡期晚期、绝经早期（绝经5年及5年以内）,绝经晚期（绝经5年以上）。采用重复测量的方差分析的方法比较腰椎和股骨骨密度在月经状态组之间的差别。P＜0.05认为具有统计学显著性差异。[结果]1.社区35-64岁的常住妇女共有773名,其中有743名参加了本研究,应答率为96.1%;其中522人完成随诊,因各种原因失访221人,随访率70.3%。2.腰椎和股骨各个部位的骨密度值在各组之间均存在显著性差别（p=0.0001）。L_2-4、股骨Neck、Wards和Troch区、股骨上部和股骨全部以及全身的骨密度均随着生殖衰老的过程逐渐下降,在绝经前、绝经过渡期早期和晚期之间差别不显著,但此几组各部位的骨密度值均显著高于绝经早期和绝经晚期,同时绝经早期显著高于绝经晚期。经过1年的随诊,各个部位及全身骨密度值均有所下降,且均在进入绝经过渡期后显著下降,其中以绝经过渡期晚期和绝经早期下降幅度最大,与其他几组相比差别显著（p=0.0001）。将年龄进行分层后,45-54岁参加者的骨密度变化相同。3.以皮质骨为主的Neck在绝经3年内下降最快,为2.6%,绝经4-10年仍继续下降,为1.1%-1.7%。之后稳定在0.6%左右;以松质骨为主的L_2-4在绝经3年内下降最快为3.3%,绝经4-5年为2.2%左右,之后稳定在0.6-0.7%左右。4.比较不同月经状态血清Ca、P和ALP值的变化特点。结果发现,Ca、P和ALP在各组之间均存在显著性差别。ALP值随着生殖衰老的过程逐渐升高。经过1年的随诊,Ca、P值均显著下降,ALP显著上升,且均以绝经过渡期晚期变化幅度最大。[结论]妇女进入绝经过渡期后,腰椎和股骨骨密度开始明显下降;绝经3-5年以内妇女骨量丢失加速,表现为高转换型骨丢失。第二部分医院来源的绝经过渡期和绝经早期妇女骨量变化的前瞻性研究[研究目的]评估绝经早期（年龄45-60岁,闭经半年以上,5年以内）或绝经过渡期（年龄40-55岁,已经发生月经紊乱）妇女随访5年间腰椎和股骨骨密度以及尿Ca/cr、Ntx/cr和血清ALP的变化特点[内容与方法]1.从医院招募61名绝经过渡期和47名绝经早期妇女,给予钙剂900mg/日,VitD 200iu/日;锻练（每天快走两次,每次10分钟）。每年随诊一次,共观察5年。2.观察项目:1).骨密度检查:采用美国Lunar公司的DPXL型双能X线骨密度仪（DEXA）于0、1、2、3、4、5年测定腰椎2-4(L_2-4)与股骨颈、Wards、Troch骨密度,CV分别为1.1%、1.7%、3.7%和2.1%。2).骨代谢指标:于0、1、2、3、4、5年采用酶联免疫吸附实验法（ELISA）测定尿Ⅰ型胶原N端肽交联物（NTX）,试剂盒购自美国西雅图OSTEX公司,批内、批间CV分别＜5%和＜10%。3).血清E₂:应用电化学发光法（Elecsys 2010型全自动电化学发光仪,为美国Roche公司生产）测定雌二醇水平,批内变异6%,批间变异6.4%。3.统计学分析:全部资料输入Epidata3.02数据库,经两遍计算机录入、修改、整理后进行统计学处理。用SPSS 12.0软件包进行分析。腰椎2-4、股骨各部位骨密度:尿钙/肌酐（Ca/Cr）、NTX/肌酐（NTX/Cr）和雌激素（E₂）采用均数±标准差表示。[结果]1.绝经过渡期组L_2-4、Neck在随诊的第3年开始明显下降,在-1.9%—-3.9%之间。Wards区在随诊的第4年开始明显下降,达-.3.2%—-5.2%。绝经早期组各部位骨密度从随诊的第1—2年起开始显著下降,为-1.2%—-8.5%,以Wards区下降最为显著。2.随诊5年NTX/Cr的变化绝经过渡期组和绝经早期组均从第3年开始显著高于0月值（p＜0.01）。[结论]绝经后的最初几年腰椎和股骨骨丢失加速。以Wards区丢失最为显著。第三部分激素疗法对抑制骨丢失的随机双盲安慰剂对照研究[研究目的]1.评估妇女从绝经早期（年龄45-60岁,闭经半年以上,5年以内）或绝经过渡期（年龄40-55岁,已经发生月经紊乱）开始低剂量激素疗法（Hormonetherapy,HT）对腰椎和股骨骨密度的影响。2.评估妇女从绝经早期或绝经过渡期开始低剂量HT对妇女尿Ca/cr、Ntx/cr和血清ALP的影响。3.综合评价绝经早期或绝经过渡期开始低剂量HT对妇女总体健康的影响。[内容与方法]1.本研究为随机双盲安慰剂平行对照试验。将124名40-55岁绝经过渡期妇女和96名45-60岁绝经早期妇女随机分配至治疗组和安慰剂组。治疗组给予E₂V1.0mg/d+周期应用MPA6.0mg/d 12天+钙剂900mg/日,VitD 200iu/日;锻练（每天快走两次,每次10分钟）。安慰剂组仅给予钙剂900mg/日,Vit D 200iu/日;锻练（每天快走两次,每次10分钟）。研究时间为5年。2.检查项目:1).骨密度检查:采用美国Lunar公司的DPXL型双能X线骨密度仪（DEXA）于0、1、2、3、4、5年测定腰椎2-4(L_2-4)与股骨颈、Wards、Troch骨密度,CV分别为1.1%、1.7%、3.7%和2.1%。2).骨代谢指标:于0、1、2、3、4、5年常规生化方法测定空腹第2次晨尿钙/肌酐（Ca/Cr）。采用酶联免疫吸附实验法（ELISA）测定尿Ⅰ型胶原N端肽交联物（NTX）,试剂盒购自美国西雅图OSTEX公司,批内、批间CV分别＜5%和＜10%。采用常规生化方法测定血清Ca,P和ALP,变异系数为1.94%、3.13%和5.01%。3).血清E₂:应用电化学发光法（Elecsys 2010型全自动电化学发光仪,为美国Roche公司生产）测定雌二醇水平,批内变异6%,批间变异6.4%。4).椎体骨质疏松性骨折:于入组第0、2、5年进行胸腰椎侧位x线片,运用Genant半定量法评估椎体骨质疏松性骨折。5).入组第0、1、2、3、4、5年进行血脂（TC、TG、HDL、LDL）的检查以及空腹血糖和空腹胰岛素水平的检测。3.统计学分析:全部资料输入Epidata3.02数据库,经两遍计算机录入、修改、整理后进行统计学处理。用SPSS 12.0软件包进行分析。计数资料描述分析采用频数、百分比,计量资料采用均数±标准差分析;各组之间人口统计学特征资料中计量资料之间采用t检验或方差分析;计数资料之间采用X²检验。采用重复测量的方差分析方法检测腰椎2-4、股骨各部位骨密度;尿钙/肌酐（Ca/Cr）、NTX/肌酐（NTX/Cr）和雌激素（E2）。P＜0.05认为具有统计学显著性差异。分别采用意向性分析（ITT）和符合方案分析（PP）两种方法进行分析。[结果]1.筛选人数332人,220人入选参加研究。绝经早期组96人,5年内退组29人。绝经过渡期组124人,5年内退组38人。所有入选的、随机化的受试者纳入全分析集。年龄、体重,教育程度、绝经早期的绝经年龄、糖尿病、高血压、冠心病家族史在HT组和对照组间均无显著性差别。2.E₂:绝经早期组,HT组E₂水平在治疗后显著高于治疗前（p＜0.01）,并维持在27.25-57.86pg/ml;安慰剂组无明显变化;两组的变化趋势有显著性差别（p=0.0001）。绝经过渡期组,HT组在各时间点E₂水平均较稳定,与治疗前比较无显著差别,安慰剂组E₂呈波动性下降;两组的变化趋势无显著性差别;组间比较在随诊的第1、3、4年有显著性差异（p＜0.05）。除0年外,组间比较在随诊各年限间差别显著（p＜0.01）。3.骨密度及椎体骨质疏松性骨折:绝经早期组,用药后第1年,腰椎和股骨Neck和Troch的骨密度显著升高,之后维持在较稳定水平;股骨Wards区骨密度与治疗前相比无明显变化;安慰剂组中,上述各部位的骨密度值在随诊的5年中均呈下降趋势;除0年外,在随诊的第1年至第5年,各个部位的骨密度在HT组和安慰剂组之间均存在显著性差别。绝经过渡期组,HT组各部位的骨密度在用药的第1年均明显升高,之后又渐回落至0年水平;安慰剂组妇女腰椎和股骨Neck和Wards区骨密度则在用药的第3-4年开始显著下降,Troch部位骨密度无明显变化。腰椎和股骨各部位的骨密度在HT组和安慰剂组之间均无显著性差别。将妇女按照入组时腰椎骨密度≤1.062 g/cm²（T值在正常年轻女性平均BMD减去1个标准差以下）和＞1.062 g/cm²（T值在正常年轻女性平均BMD减去1个标准差以上）分为两组,比较骨量减少者和骨量正常者应用HT 5年后骨密度的变化。结果发现,除了L_2-4在HT的第1年的变化率有显著性差别（p＜0.01）外,各部位的骨密度变化率在各年限均无显著性差别。在随访的5年期间,发生椎体骨质疏松性骨折5例,其中安慰剂组4例（0.5级2例,1级2例,均发生在入组后的第5年）,HT组1例（1级,分别发生在入组后的第2年和第5年）。4.骨转换指标:尿Ca/Cr在HT组和安慰剂组之间无显著性差别。Ntx/Cr值,在HT的第1年下降,之后维持在稳定水平,安慰剂组则逐渐升高;用药的3-5年,HT组和安慰剂组比较有显著性差异（p＜0.05）。ALP水平,除0年外,HT组在随诊各时间点均显著低于安慰剂组（p＜0.05）。5.HT组和安慰剂组的各项血脂水平均无显著性差别,但TC、TG、LDL分别在安慰剂组中呈显著升高趋势;而HDL在HT组呈显著升高趋势,在安慰剂组呈显著下降趋势。空腹血糖和胰岛素水平在HT组和安慰剂组之间无显著性差别。在随诊第6个月时,各组乳腺胀痛发生率最高（最高为绝经过渡期HT组,61.90%）,之后逐渐下降。除在1、2年（绝经过渡期组）和1年（绝经早期组）外,HT组和安慰剂组在其余时间点间无显著性差别。在基线和随诊的5年中,HT组和安慰剂组中子宫内膜厚度≥5mm的人数均无明显差别。[结论]1.E₂V 1.0mg+周期应用安宫黄体酮（MPA）6.0mg/d 12天+钙剂900mg/日5年,能显著增加并维持绝经早期妇女骨量,延缓绝经过渡期妇女骨量的下降趋势。2.E₂V 1.0mg+周期应用安宫黄体酮（MPA）6.0mg/d 12天+钙剂900mg/日5年,对增加或维持骨量正常和骨量减少妇女骨密度的效果相似。3.绝经过渡期或绝经早期妇女应用E₂V 1.0mg+安宫黄体酮（MPA）6.0mg/d12天+钙剂900mg/日5年,对血脂和血糖、胰岛素以及乳腺、子宫内膜无不利影响,副作用小。更多还原

【Abstract】 Part 1 Changes of body mass during the process of ovary agingObjectiveWomen aged 35-64 year old from community were investigated and followed up once one year later,with the objective of the changes of body mass density during the process of ovary aging.Materials and methodsThe study belonged to analysis one including baseline inestigatrion and 1 year follow up.743 women aged 35-64 years who lived Beijing community attended our survey by the stratum clustering sample method.We conducted the survey by face-to-face interview with the questionnaire.The items of the questionnaire are detailed as follow:the basic conditions（such as age,career, education,income,etc）,illness medical history,sex hormone treatment history, menstruation condition.Examination items:1.BMD examination:using DEXA BMD instrument made of American Lunar company.Examine the lunar 2-4(L_2-4) and femur Neck,Wards,and Troch,the total and upper site of BMD.The CV are 0.5%-1.1%。2.Serum E₂:Using the electrochemiluminescence（Elecsys 2010 automatic electrochemiluminescence instrument made of American Roche company）. The cv are 6.4%of interest and 6%of intraset respectively.3.Serum Ca,P and ALP:Exaimine the serumCa,P and ALP using conventional biochemistry method,the CV are1.94%,3.13%and 5.01%of interest espectively.A year later these women were investigated again for the changes of the above situations and re-measured the above indexes.Statistics:All data were entered into database Epidata 3.02 and were analyzed by SPSS 12.0（statistics software package for social science）.Qualitative data were analyzed by frequency,proportion;quantitative data were analyzed by mean and standard deviation.Chi-square test was applied to the comparison of the category data between menopausal status.Women were divided according to the menstruation condition standard by STRAW:premenopause（women’s menstrual cycles are regular）,early menopausal transition（women’s menstrual cycles changes more than 7 days at least one cycle）,late menopausal transition（amenorrhoea 2-11 months） early menopause（women without menstruation for no more than 5 years） and late postmenopause（women without menstruation over 5 years）.Repeated measures modeling was used to evaluate the relationship between the lumbar and femur BMD and menopausal status.The level of statistical significance was set at p＜0.05.Results1.743 women aged 35-64 years（96.1%of the total participants） participated in he present study and were accepted for it;among which 522 women finished the follow-up,with the follow-up rate at 70.3%。2.The lumbar and femur BMD were significant different between the menopausal status（p=0.0001）.The BMD of L_2-4,Neck,wards,total and upper site and as well as Troch descended as reproductive aging,the value of BMD were not different among the premenopause,early menopausal transition and late menopausal transition but statistically higher than the other groups.After one year,the BMD of all lumbar and femur declined,the BMD and total BMD declined statistically when women entered menopausal transition,the extent of late menopausal transition and early menopause was bigger than that of the other groups（p=0.0001）.The most obvious site of bone loss was lumbar BMD in the menopausal transition and early menopause.The BMD changes of women at 45-54 ages were similar.3.The decline extent of Neck site was the biggest within the first 3 years from menopause as 2.6%,and as 1.6%-1.8%at the 4-10 years since menopause, followed by 0.6%;the decline extent of L_2-4 was the biggest within the first 3 years as 3.3%,and as 2.2%at the 4-5 years since menopause,followed by 0.6%-0.7%after 5 years since menopause.4.Ca,P and ALP are statistically different between the menopausal status.ALP value upgraded with reproductive aging.After one year,Ca and P declined, ALP increased,the extent is the biggest in the late menopausal transition group.ConclusionsWomen’s lumbar and femur BMD begin decline when entering menopausal transition,the bone loss speed within 3-5 year of menopause,representing as high transfer bone loss. Part 2 Cohort study about the changes of bone mass based on menopausal transition early menopausal women from clinicObjectiveTo evaluate the changes of women’s bone mineral density and biochemical markers of bone metabolism at menopausal transition period（age 40-55 years old, has irregular menstruation）,or early menopause（age 45-60 years old, amenorrhea over six months,within five years）.Materials and methods61 menopausal transition women and 47 early menopausal women were recruited from clinicl and were given the calcium medicine 900mg/day,Vit D 200 in/day,taking exercise（10 minutes once,twice a day）.The research time is 5 years.2.Investigating items:1) BMD examination:using DEXA BMD instrument made of American Lunar company.Examine the lunar 2-4(L_2-4) and femur Neck,Wards,Troch.The CV are1.1%,1.7%,3.7%and 2.1%.Repeat these indexes measures once a year.2) Bone metabolism index:Examine the NTX using ELISA method from American OSTEX company.The CV are＜5%of intraset and＜10%of interest respectively.3) Serum E2:Using the electrochemiluminescence（Elecsys 2010 automatic electrochemiluminescence instrument made of American Roche company）. The cv are 6.4%of interest and 6%of intraset respectively.3.Statistics:All data were entered into database Epidata3.02 and were analyzed by SPSS 12.0（statistic software package for social science）,quantitative data were analyzed by mean and standard deviation;Results3.menopausal transition women’s BMD at L_2-4 and Neck sites began to decline at the 3-year follow up between-1.9%and-3.9%;Wards site’s BMD began to decline at the 4-year follow up between-3.2%and-5.2%. Early menopausal women’s BMD at L_2-4 and Neck sites began to decline at the 1-2-year follow up between-1.2%and-8.5%,being Wards as the maximum site. 4.Menopausal transition and early menopausal women’s NTX/Cr changes significantly at the 3-year follow up（p＜0.01）。ConclusionsBone loss speed at the first year after menopause,being Wards as the maximum site. Part 3 A random,double-blinded placebo study of hormone therapy on restraining from bone lossObjective1.To evaluate the effects of long-term HT starting from menopausal transition period（（age of 40-55 years,having irregular menstruation） and early menopausal women（age of 45-60 years,amenorrhea between half a year and 5 years） on lumbar and femur BMD.2.To evaluate the effects of long-term HT starting from menopausal transition period（having irregular menstruation） and early menopausal women （amenorrhea between half a year and 5 years） on urinary Ca/Cr、Ntx/Cr and serum ALP.3.To evaluate the effects of long-term HT starting from menopausal transition period and early menopausal women on the whole health.Materials and methods1.124 menopausal transition women aged 40-55 years and 96 early menopausal women aged 45-60 year were randomly distributed into treatment group and placebo group.The treatment group was given E2V 1.0mg/d plus sequent MPA 6.0mg ^*12 days/month and calcium medicine 900mg/day,Vit D 200 iu/day.The placebo group was only given the calcium medicine 900mg/ day,Vit D 200 in/day,taking exercise（10 minutes once,twice a day）.The research time is 5 years.2.Investigating items:1） BMD examination:using DEXA BMD instrument made of American Lunar company.Examine the lunar 2-4(L_2-4) and femur Neck,Wards,Troch.The CV are1.1%,1.7%,3.7%and 2.1%.Repeat these indexes measures once a year.2) Bone metabolism index:examine the second fasting urinary Ca/Cr using the conventional biochemistry method.Examine the NTX using ELISA method from American OSTEX company.The CV are＜5%of intraset and＜10% o finterest respectively.Examine the serum ALP,the CV are both 5.01%of intraset and interest.Serum Ca,P,Mg and ALP:Exaimine the serum Ca,P and ALP using conventional biochemistry method,the CV are1.94%、3.13%, and 5.01%of interest respectively. 3) Serum E2:Using the electrochemiluminescence（Elecsys 2010 automatic electrochemiluminescence instrument made of American Roche company）. The cv are 6.4%of interest and 6%of intraset respectively.4) The osteoporosis centrum fracture:Using the image of thoracic and lumbar vertebra by Genant semi-quantify method at the 0,2 and 5 year of study.5) Examine the serum TC,TG,HDL and LDL level;fasting glucose and insulin level at the 0,1,2,3,4 and 5 year of follow up.3.Statistics:All data were entered into database Epidata3.02 and were analyzed by SPSS 12.0（statistic software package for social science）.Qualitative data were analyzed by frequency,proportion;quantitative data were analyzed by mean and standard deviation;measurement data were compared by T test or ANOVA for continuous variables.Chi-square test was applied to the comparison of the category data between menopausal status using.Repeated measures modeling was used to evaluated effect of HT on the BMD as well as Ca/Cr,NTX/Cr and E2.The level of statistical significance was set at p＜0.05.ITT（intention-to-treat） analysis and PP（Per Protocol） analysis were both used.Results1.332 women were filtered,220 women were participated.Among the 96 early menopause women,29 women dropped and 38 dropped among the 124 menopausal transition.All participants were recruited ITT analysis.There were not statistically different between age,weight,educational level,the length of menopause and all sites of chronic diseases.2.E2:In the menopausal transition group,the E2 level was stable through the 5-year study and was not different from the baseline level in the HT group;the E2 level in the placebo group fluctuated with declined trend;The E2level were different in the first,third and fourth year between the two groups（p＜0.05）.In the early menopause group,the E2 level after therapy was significantly higher than that of baseline（p＜0.01） and sustained the stable level;the E2 level in the placebo group did not marked change.There was significantly different between the groups in all the follow-up years expect 0 year.3.BMD:In the early menopause group,after the first year of therapy,the lumbar,femur Neck and Troch BMD increased significantly,then sustained the stable level;femur Wards BMD did not marked change;the BMD of all above sites declined in the placebo group;the BMD of all above sites were statistically different between the HT and placebo groups except the baseline. In the menopausal transition group,the BMD of all above sites after the first year of therapy increased significantly,then declined to the level of baseline; the lumbar,femur Neck and Wards BMD declined significantly in the 3-4 year of therapy,Troch BMD did not marked change.The BMD of all above sites were not statistically different between the HT and placebo group.Staging the women in to normal bone mass group and bone loss group（using the lumbar bone mass of above or under 1.062 g/ cm2 as limit）,we found the BMD changes between the two groups was not significantly different except the lumbar site at the first year of follow-up.4.Bone transfer index:The urinary Ca/Cr was not different between HT and placebo group;Ntx/Cr value declined after the first year in the HT group and then sustained stably,which in the placebo group upgraded.There was significant different at the 3-5 year follow-up（p＜0.05） The serum ALP level in the HT group was significantly lower than placebo group but baseline.5.The serum lipids levels between the HT and placebo group were not significantly different,but the level of TC,TG and LDL increased significantly in the placebo group;while the level of HDL increased significantly in the HT group and decreased in the placebo group.The fasting glucose and insulin level were not significantly different between the HT and placebo group.At the sixth month,the morbidity of mammary tenderness was highest（as 61.90%in the menopausal transition HT group）,then declined gradually.There were not significantly different but the first,second year（menopausal transition） and the first year（early menopause） between the HT and placebo group.The women of endometrium of≥5mm were not significantly different between the HT and placebo group in the five year study.Conclusions1.The 5 year therapy of E2V 1.0mg plus sequent MPA 6.0mg ^*12 days/month and calcium medicine 900mg/day and Vit D 200 iu/day,can increase or sustain the BMD early menopause women,staying the BMD of menopausal transition.2.The 5 year therapy of E2V 1.0mg plus sequent MPA 6.0mg ^*12 days/month and calcium medicine 900mg/day and Vit D 200 in/day have the similar effect of increasing or sustaining the BMD on the normal bone mass group and bone loss group.3.The 5 year therapy of E2V 1.0mg plus sequent MPA 6.0mg ^*12 days/month and calcium medicine 900mg/day and Vit D 200 in/day have no negative impact on serum glucose,lipid and insulin with few side-effects.更多还原