雌激素_運(yùn)動(dòng)與絕經(jīng)后骨質(zhì)疏松研究現(xiàn)狀

1、隨著社會(huì)的老齡化,骨質(zhì)疏松的患病率也在逐年增加,主要發(fā)生在中老年人,尤其是絕經(jīng)后婦女。普遍認(rèn)為,絕經(jīng)導(dǎo)致的雌激素水平下降,骨形成和骨吸收失衡,是絕經(jīng)后骨質(zhì)疏松發(fā)生的主要原因1。因此,雌激素替代療法對(duì)絕經(jīng)后骨質(zhì)疏松具有明顯的預(yù)防和治療作用,而運(yùn)動(dòng)作為一種新型的骨質(zhì)疏松康復(fù)手段,越來(lái)越受到人們的關(guān)注。本文就雌激素、運(yùn)動(dòng)與絕經(jīng)后骨質(zhì)疏松進(jìn)行綜述。1雌激素對(duì)骨代謝的調(diào)節(jié)骨代謝是一個(gè)由成骨細(xì)胞介導(dǎo)的骨形成和破骨細(xì)胞介導(dǎo)的骨吸收構(gòu)成的動(dòng)態(tài)平衡過(guò)程。雌激素通過(guò)直接和間接兩種作用方式對(duì)骨代謝進(jìn)行調(diào)節(jié),其直接作用是通過(guò)受體途徑實(shí)現(xiàn)的。隨著成骨細(xì)胞和破骨細(xì)胞上雌激素受體(estrogen receptor,ER的

2、相繼發(fā)現(xiàn)3,4,雌激素通過(guò)與成骨細(xì)胞和破骨細(xì)胞上的ER結(jié)合直接調(diào)節(jié)骨代謝的方式亦得到證實(shí)。Sims等5對(duì)ER基因敲除大鼠行去卵巢手術(shù)并補(bǔ)充雌二醇的研究發(fā)現(xiàn),雌二醇并沒(méi)有阻止骨量的丟失,進(jìn)一步明確ER是雌激素調(diào)節(jié)骨代謝的必由途徑。雌激素與成骨細(xì)胞上的ER結(jié)合后,可促進(jìn)成骨細(xì)胞的增殖、分化及礦化6,7,還可促進(jìn)骨保護(hù)素(Osteopro-tegerin,OPG的表達(dá)8。OPG又稱破骨細(xì)胞生成抑制因子,其可以頡頏破骨細(xì)胞前體細(xì)胞上RANK(receptor ac-tivator of nuclear factor-kB與其配體的結(jié)合,阻斷破骨細(xì)胞前體細(xì)胞分化、成熟,從而抑制骨吸收9。目前,OPG 已

3、被用于骨質(zhì)疏松的臨床治療中10。雌激素對(duì)破骨細(xì)胞的調(diào)節(jié)也是通過(guò)破骨細(xì)胞上的ER實(shí)現(xiàn)的,雌激素可抑制破骨細(xì)胞前體細(xì)胞的募集和分化,抑制破骨細(xì)胞的形成及活性11,12,并可誘導(dǎo)破骨細(xì)胞及破骨細(xì)胞前體細(xì)胞的凋亡,降低破骨細(xì)胞的數(shù)量13,14。Katavic等15對(duì)去卵巢大鼠骨髓細(xì)胞培養(yǎng)發(fā)現(xiàn),破骨細(xì)胞樣細(xì)胞明顯增加,因此,雌激素缺失可使破骨細(xì)胞數(shù)目及活性均增加,骨吸收增強(qiáng)。雌激素對(duì)骨代謝間接調(diào)節(jié)作用是指雌激素通過(guò)調(diào)節(jié)鈣調(diào)激素(降鈣素、甲狀旁腺素、活性維生素D3等和骨代謝相關(guān)細(xì)胞因子(IL-1、IL-6、TNF-、TGF-等,來(lái)調(diào)節(jié)骨形成和骨吸收的動(dòng)態(tài)平衡。近年來(lái)的研究顯示,通過(guò)細(xì)胞因子作用亦是雌激素調(diào)

4、節(jié)骨代謝的重要途徑。雌激素與成骨細(xì)胞的ER結(jié)合,刺激成骨細(xì)胞分泌骨保護(hù)素(OPG9、胰島素樣生長(zhǎng)因子(IGF和轉(zhuǎn)移生長(zhǎng)因子(TGF-16,這些細(xì)胞因子不僅抑制破骨細(xì)胞的增殖、分化和活化,還促進(jìn)破骨細(xì)胞的凋亡。此外,雌激素還可抑制IL-1、IL-6、TNF-、GM-CSF、M-CSF的分泌,這些細(xì)胞因子經(jīng)過(guò)不同的信號(hào)轉(zhuǎn)導(dǎo)通路,直接或間接影響OPG/ RANKL/RANK軸,從而影響骨代謝17,18。2運(yùn)動(dòng)對(duì)骨代謝的調(diào)節(jié)國(guó)內(nèi)外眾多研究已證實(shí),運(yùn)動(dòng)和骨代謝關(guān)系密切,但不同的運(yùn)動(dòng)方式、運(yùn)動(dòng)負(fù)荷、運(yùn)動(dòng)時(shí)間對(duì)骨代謝的影響有所不同,總的來(lái)說(shuō),運(yùn)動(dòng)對(duì)骨代謝的影響具有雙重效應(yīng),即適宜的運(yùn)動(dòng)有助于增加骨量,過(guò)量運(yùn)

5、動(dòng)對(duì)骨量產(chǎn)生負(fù)面影響。適宜的運(yùn)動(dòng)可以增加對(duì)骨骼的機(jī)械性刺激,提高骨代謝水平,使骨質(zhì)總量適度增加。所謂適宜的運(yùn)動(dòng)是指適宜的運(yùn)動(dòng)方式、強(qiáng)度和持續(xù)時(shí)間。不同的運(yùn)動(dòng)方式所造成的骨質(zhì)變化的部位也有所不同。Hind19等研究發(fā)現(xiàn),6個(gè)月抗重力訓(xùn)練(包括游戲、跳舞、跳躍訓(xùn)練均可提高青春前期和青春期受試者的骨量。Lehtonen等20的研究認(rèn)為,為期1年的體操訓(xùn)練顯著增加股骨頸和大轉(zhuǎn)子的骨密度,單純跑步對(duì)骨密度影響較小。Kohrt等21通過(guò)對(duì)39名絕經(jīng)后婦女11個(gè)月不同方案的訓(xùn)練發(fā)現(xiàn),抗重力訓(xùn)練(步行、慢跑、爬樓梯等以及抗阻力訓(xùn)練(劃船、提拿重物等均可增加全身、腰椎及Wards的骨密度,但只有抗重力訓(xùn)練有助于

6、增加股骨頸骨密度。Kelley等22的研究也認(rèn)為絕經(jīng)后婦女抗阻力訓(xùn)練對(duì)其腰椎、股骨和橈骨的骨密度有正性刺激作用。由此可見(jiàn),提高骨密度的適宜運(yùn)動(dòng)方式為抗重力、抗阻力和高沖擊性的運(yùn)動(dòng)方式。運(yùn)動(dòng)強(qiáng)度對(duì)骨量的影響報(bào)道結(jié)果有很大差異。據(jù)報(bào)道,運(yùn)動(dòng)強(qiáng)度刺激存在一個(gè)閾值,在該閾值下運(yùn)動(dòng),強(qiáng)度增大,骨密度提高;超過(guò)該閾值,運(yùn)動(dòng)強(qiáng)度增大,骨密度不再隨之增長(zhǎng)。一般認(rèn)為,小于80%VO2max的跑臺(tái)運(yùn)動(dòng)使骨量增加,而如果運(yùn)動(dòng)強(qiáng)度超過(guò)80%VO2max,反而使骨量降低23,24。Hatori等25對(duì)絕經(jīng)期婦女采取高于無(wú)氧閾強(qiáng)度的跑臺(tái)運(yùn)動(dòng)(30分鐘/天,3次/周,訓(xùn)練7個(gè)月后,骨密度顯著增加,而采用低于無(wú)氧閾的同樣方案

7、的運(yùn)動(dòng)對(duì)骨密度無(wú)影響。也有研究認(rèn)為,以不超過(guò)本人最大心率的80%運(yùn)動(dòng)強(qiáng)度運(yùn)動(dòng)12個(gè)月后,腰椎和髖部骨密度明顯增加26?？偨Y(jié)以上研究結(jié)果發(fā)現(xiàn),中等強(qiáng)度的抗重力性運(yùn)動(dòng)、抗阻力性及高沖擊性運(yùn)動(dòng)訓(xùn)練有利于骨量的增加。由于骨的重建周期要經(jīng)歷靜止、激活、轉(zhuǎn)換和最后成型4個(gè)過(guò)程,1個(gè)重建周期歷時(shí)46個(gè)月,因此,運(yùn)動(dòng)干預(yù)若要引起骨量的顯著增加,運(yùn)動(dòng)持續(xù)時(shí)間至少在1年以上27。雖然適宜的運(yùn)動(dòng)負(fù)荷可以增加對(duì)骨骼的機(jī)械性刺激,提高骨代謝水平,使成骨細(xì)胞活動(dòng)加強(qiáng),促進(jìn)骨形成,有助于骨量增加,但運(yùn)動(dòng)負(fù)荷過(guò)大則易導(dǎo)致骨吸收增加,骨量降低23,28。早在1984年,Drinkwater29就發(fā)現(xiàn)運(yùn)動(dòng)性閉經(jīng)的長(zhǎng)跑運(yùn)動(dòng)員骨量下

8、降明顯,自此運(yùn)動(dòng)性骨量降低逐漸引起學(xué)者的關(guān)注。隨后眾多人體和動(dòng)物實(shí)驗(yàn)也證實(shí)了此觀點(diǎn),大負(fù)荷運(yùn)動(dòng)訓(xùn)練易導(dǎo)致女運(yùn)動(dòng)員月經(jīng)周期紊亂,乃至閉經(jīng),體內(nèi)雌激素水平明顯下降29,30,如月雌激素、運(yùn)動(dòng)與絕經(jīng)后骨質(zhì)疏松研究現(xiàn)狀楊明杭州師范大學(xué)(杭州310000經(jīng)紊亂的狀態(tài)長(zhǎng)期未得到改善,將會(huì)出現(xiàn)骨密度降低、骨質(zhì)疏松,甚至骨折31-33。Khan等34的研究發(fā)現(xiàn),10%閉經(jīng)長(zhǎng)跑女運(yùn)動(dòng)員(平均年齡21.8歲患有骨質(zhì)疏松,50%有骨量減少。動(dòng)物實(shí)驗(yàn)亦有一致的結(jié)果,雌性大鼠在遞增負(fù)荷運(yùn)動(dòng)訓(xùn)練中,逐漸出現(xiàn)動(dòng)情周期紊亂、全身骨密度降低等特征性表現(xiàn)35。在由此可見(jiàn),大負(fù)荷運(yùn)動(dòng)訓(xùn)練與骨量降低之間關(guān)系密切,其原因可能與持續(xù)大強(qiáng)

9、度運(yùn)動(dòng)抑制機(jī)體下丘腦垂體性腺軸功能,出現(xiàn)月經(jīng)失調(diào)、雌激素水平下降等表現(xiàn),而雌激素又通過(guò)多種方式影響骨代謝,機(jī)體出現(xiàn)類似于絕經(jīng)后導(dǎo)致的骨量降低。3雌激素、運(yùn)動(dòng)與絕經(jīng)后骨質(zhì)疏松絕經(jīng)后骨質(zhì)疏松(Postmenopausal Osteoporosis,PMOP又被稱為型骨質(zhì)疏松癥,是指絕經(jīng)后婦女發(fā)生的以骨量降低及骨組織微結(jié)構(gòu)退行性病變?yōu)樘卣鞯囊环N全身性骨骼疾病。女性絕經(jīng)后,卵巢功能逐漸減退,雌激素分泌減少,骨組織在逐漸失去雌激素保護(hù)后,骨吸收和骨形成變得活躍,但骨吸收大于骨形成,最終出現(xiàn)骨量下降2,骨強(qiáng)度降低,骨折風(fēng)險(xiǎn)性增加。此過(guò)程持續(xù)約510年,尤以絕經(jīng)后的前3年骨丟失速度最快。當(dāng)絕經(jīng)后婦女骨密度(

10、bone mineral density,BMD值低于骨峰值2.5個(gè)標(biāo)準(zhǔn)差(SD以上即可診斷為絕經(jīng)后骨質(zhì)疏松。研究人員試圖通過(guò)補(bǔ)充外源性的雌激素預(yù)防并治療絕經(jīng)后骨質(zhì)疏松。對(duì)大鼠去卵巢所致骨質(zhì)疏松動(dòng)物模型的研究發(fā)現(xiàn),17-雌二醇可使去卵巢大鼠成骨細(xì)胞數(shù)量及血堿性磷酸酶活性增加,逆轉(zhuǎn)由去卵巢導(dǎo)致的腰椎和脛骨骨密度的降低36。人體實(shí)驗(yàn)的結(jié)果亦表明,絕經(jīng)后婦女使用雌激素后,腰椎和髖骨的骨密度明顯增加,并降低腰椎和髖部的骨質(zhì)疏松發(fā)生率37-39。雌激素雖對(duì)骨質(zhì)疏松有確定的療效,但由于其存在心血管疾病和乳腺癌發(fā)生風(fēng)險(xiǎn)的弊端,其相關(guān)研究進(jìn)入困境38。相反,運(yùn)動(dòng)作為一種經(jīng)濟(jì)、方便、無(wú)毒副作用的健骨方式,逐漸成

11、為近年來(lái)研究的新熱點(diǎn)。運(yùn)動(dòng)之所以對(duì)預(yù)防絕經(jīng)后骨質(zhì)疏松有積極效果,主要是因?yàn)檫\(yùn)動(dòng)對(duì)骨的機(jī)械應(yīng)力刺激,以及由此產(chǎn)生的激素和細(xì)胞因子對(duì)骨代謝的調(diào)節(jié)效應(yīng)18,40。Vainionpaa等的41研究發(fā)現(xiàn),高沖擊性運(yùn)動(dòng)可降低血漿基礎(chǔ)PTH水平,對(duì)骨形成有正性刺激作用42。West等43也發(fā)現(xiàn),運(yùn)動(dòng)可升高血漿中OPG的水平,可抑制由于雌激素缺失導(dǎo)致的OPG降低,在一定程度上抑制絕經(jīng)后的骨丟失。不僅如此,適宜的運(yùn)動(dòng)還能增強(qiáng)四肢及軀干肌肉力量,提高身體平衡能力,減少跌倒的危險(xiǎn)性,降低骨折的發(fā)生率。Englund等44對(duì)絕經(jīng)后婦女的研究發(fā)現(xiàn),持續(xù)12個(gè)月的力量、有氧及平衡和協(xié)調(diào)性訓(xùn)練,使受試者Wards三角的骨密

12、度顯著升高,與此同時(shí),肌力及最大步行速度也有明顯提高。張林等45的研究也發(fā)現(xiàn),為期6個(gè)月的有氧健身操、彈力操和健身器械練習(xí),使絕經(jīng)期婦女骨吸收指標(biāo)生化標(biāo)志物(血抗酒石酸酸性磷酸酶、尿鈣/肌酐和尿羥脯氨酸/肌酐明顯減少,骨吸收受到抑制。也有學(xué)者認(rèn)為,高沖擊性的跳躍訓(xùn)練、抗阻訓(xùn)練能有效提高肌力及腰椎和髖部的骨密度46?？偟膩?lái)說(shuō),持續(xù)時(shí)間大于1年的有規(guī)律的的抗重力、抗阻力和高沖擊性訓(xùn)練可以顯著抑制絕經(jīng)后婦女的骨丟失。動(dòng)物實(shí)驗(yàn)的結(jié)果也認(rèn)為,中等強(qiáng)度的跑臺(tái)運(yùn)動(dòng)可以顯著增加大鼠成骨細(xì)胞的數(shù)量47,增加成骨細(xì)胞活性,增加骨形成,減少骨丟失48。鑒于雌激素和運(yùn)動(dòng)對(duì)骨質(zhì)疏松防治的良好效果,專家推測(cè),雌激素和運(yùn)動(dòng)

13、聯(lián)合應(yīng)用對(duì)骨質(zhì)疏松可能會(huì)有更明顯的療效。為此,Yeh等49對(duì)去卵巢大鼠采用跑臺(tái)運(yùn)動(dòng)和/或雌二醇,研究不同實(shí)驗(yàn)方案對(duì)大鼠骨量的影響,發(fā)現(xiàn)運(yùn)動(dòng)和雌二醇聯(lián)合治療組大鼠的長(zhǎng)骨和椎骨骨量顯著高于單純運(yùn)動(dòng)組。章曉霜等48的研究也得出相似的結(jié)果,即兩者的聯(lián)合應(yīng)用使骨吸收和骨形成均顯著降低,對(duì)骨代謝高轉(zhuǎn)換狀態(tài)起到抑制作用,骨密度也較雌激素對(duì)照組和單純運(yùn)動(dòng)組均顯著性增加。由此可見(jiàn),運(yùn)動(dòng)和雌激素聯(lián)合治療骨質(zhì)疏松比單純給予雌激素或單純運(yùn)動(dòng)有更好的療效。但基于雌激素對(duì)心血管系統(tǒng)及乳腺、子宮的毒副作用,此聯(lián)合治療在臨床研究中具有一定的局限性,但近年來(lái)植物性雌激素的發(fā)展,以及其對(duì)子宮乳腺相對(duì)較小的副作用50,51,為絕經(jīng)

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