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    雙膦酸鹽治療腎性骨病的研究進展
    關鍵字:進展,研究,治療,GH,IJ,EF,CD,yz,AB,KL, 發布時間:2011-08-20

    浙江實用醫學2010年8月第15卷第4期ZhejiangPracticalMedicineAugust,2010,V01.15,No.4 ?327? 雙膦酸鹽治療腎性骨病的研究進展 李佳 (杭州市第一人民醫院,浙江杭州310006) 絕經后的骨質疏松會引起骨礦密度的減少和 骨折風險的增加。在絕經后骨質疏松的患者中,雌 激素的缺乏增加了骨轉化,進而引起骨量的減少, 因此骨礦密度的測量在診斷和治療中顯得十分重 要。此外,骨吸收抑制劑雙膦酸鹽可以十分有效地 阻止骨量的丟失,減少骨折的發生。雖然在慢性腎 臟病中骨折的發病率增加,但是致病因素卻有別于 絕經后的骨質疏松。本文將綜述腎性骨病的發病 機制和雙膦酸鹽的有效性、安全性。 1腎性骨病 腎性骨病在慢性腎臟病的早期就開始,其發病 率越來越高,從而使患者的生活質量進一步下 降…1。當腎小球濾過率(GFR)<50%時,已有一半 患者出現腎性骨病。當進人慢性腎臟病(Cl①)終末 期時,幾乎所有的患者出現腎性骨病。椎骨和髖骨 骨折的發生率是非慢性腎臟病患者的3.4倍[2-3]。 尤其是合并低血清甲狀旁腺素(啪)的終末期腎病 患者髖部骨折的發生率增加了17倍【4l。 腎性骨病又稱腎性骨營養不良,是一類影響慢 性腎臟病(CI(D)患者骨骼系統的病理生理狀態的總 稱uJ。通過活檢,進行骨組織形態學的檢查可以明 確骨營養不良。根據骨轉化率和骨的礦化程度可 以將骨營養不良分成纖維囊性骨炎,骨軟化,混合 型骨病,輕微型骨病,無動力性骨病等五類[5]5。在 無動力性骨病中,骨轉化率很低,骨礦化程度也不 同。雖然骨活檢被認為是診斷骨營養不良的金標 準,但它是有創性的檢查,而且價格昂貴。因此,血 清PrH的濃度被用來作為檢測骨轉化率和指導治 療的替代指標舊J。 在絕經后的骨質疏松患者中,用雙能X線檢測 骨礦密度可以準確地預測未來骨折的風險,指導治 療方案的選擇∽J。然而骨礦密度的變化與慢性腎 病患者骨折風險的相關性尚不確定,因此單憑骨礦 密度不能指導這些患者治療方案的選擇18J。 ?綜述? 2雙膦酸鹽 此類藥物可以抑制骨吸收。雙膦酸鹽與骨結 合后,其作用主要由副鏈決定,含氮類雙膦酸鹽通 過抑制焦磷酸鹽合成酶,阻止丙氨酸氨基轉移酶 (ALT酶)信號蛋白的合成從而抑制破骨細胞的功 能,還可以改變破骨細胞的功能,包括細胞形態、間 斷信號、破壞緩沖邊界等;除了抑制破骨細胞活性, 含氮雙膦酸鹽還通過抑制破骨細胞聚集、黏附,促 進凋亡,縮短細胞壽命,從而減少破骨細胞的數量。 另外,此類藥物還通過抑制成骨細胞和骨細胞的凋 亡從而增加成骨細胞的數量。不含氮類雙膦酸鹽 則是通過合成有毒的、不溶于水的三磷酸腺苷,從 而抑制破骨細胞能量供給,導致細胞凋亡。這類藥 物可以減少絕經后骨質疏松和其他原因骨質疏松 患者的骨折風險i9J。雙膦酸鹽主要是經腎臟排泄 的。因此,慢性腎病患者的藥物停留時間可能長一 些【10J。在先前有關雙膦酸鹽的研究中,慢性腎病患 者的排除標準是血肌酐濃度,而現在的標準更多的 則是肌酐清除率。在絕經后骨質疏松患者中長期 使用阿侖膦酸鈉可以引起無動力性骨病和骨折L11|。 因為慢性腎臟病中無動力性骨病的發病率很高,而 雙膦酸鹽可以降低骨轉化率,故在這些使用雙膦酸 鹽的患者中會增加骨折的風險。 3雙膦酸鹽在慢性腎臟病中的臨床試驗 骨折干預試驗(Frr試驗)是阿侖膦酸鈉的隨機 對照臨床試驗,觀察絕經后骨質疏松患者用藥前后 的骨礦密度和骨折發生率H2|。其中一個排除標準 是血肌酐大于1.27mg/cU。可是,一般來說,骨質疏 松患者的年齡偏大,肌肉量偏少,因此同樣的血肌 酐水平可能他們的腎小球濾過率更低。Jamal等H2J 進行了數據分析,并對腎小球濾過率進行了評估, 發現入選的患者中,9.9%的患者腎小球濾過率小 于45mL/min,37.5%的患者腎小球濾過率在45— 59mL/min之間。結果顯示用阿侖膦酸鈉治療的慢 性腎臟病患者骨礦密度更高.骨折發生率更低,這 萬方數據 換頁 ?328?浙江實用醫學2010年871第15卷第4期ZhejiangPracticalMedicineAu刪,2010,V01.15,No.4 一結果和肌酐清除率較高的患者是相似的。另一 項對利噻膦酸鹽三期l臨床試驗回顧性分析了這類 藥物在腎功能減退患者中的安全性和有效性【l3l。 其中一個排除標準是血肌酐水平大于正常峰值的 1.1倍,同樣也對腎小球濾過率進行了評估。其中 44%的患者腎小球濾過率在50—80raL/rain,41%的 患者‘£IIJ,球濾過率在30—50raL/rain,而6%的患者 腎小球濾過率小于30mL/min。在安慰劑組,肌酐清 除率小于30raL/rain組的新發骨折率最高。而在利 噻膦酸鹽治療組(5mg/a),肌酐清除率小于30 mL/ min組,50—80mL/min組,30—50mL/min組的新發 骨折率是相似的,這一結果與其他利噻膦酸鹽的臨 床研究類似。 最近有一項試驗,研究唑侖膦酸降低骨折的風 險,肌酐清除率小于30mL/min的患者予以剔除【14J。 唑侖膦酸治療后骨折發生率明顯降低。通過對阿 侖瞵酸鹽,利噻膦酸鹽,唑侖膦酸鹽的研究,顯示雙 膦酸鹽在慢性腎臟病2.3期中是安全和有效的。 此外,利噻膦酸鹽在4期慢性腎臟病中也是安全和 有效的。現在國內有少量研究和觀察是針對5期 慢性。腎臟病的,但需進一步的臨床試驗。 4雙膦酸鹽對腎功能的影響 研究表明,唑侖膦酸和帕瞇膦酸鹽均有腎毒 性。唑侖膦酸可以引起急性腎小管壞死,特別是對 于短時間大劑量給藥的患者¨5I。帕咪膦酸鹽按推 薦劑量90mg,每月靜脈注射1次使用時很少引起腎 毒性,但超過這一劑量時可以引起腎小球病變[16J。 在最近一項試驗中,1.3%靜脈注射唑侖膦酸的患 者血肌酐水平升高了0.5mg/dL,而在安慰劑組中只 有0.4%的患者血肌酐升高了0.5mg/dL。然而,這 些變化是暫時的,肌酐水平大多在30天內恢復原 先水平¨4I。最新的一項研究評估了唑侖膦酸對絕 經后骨質疏松患者腎功能的影響,唑侖膦酸的給藥 時間是1年1次,持續3年,每次5mg靜脈注射超過 15分鐘【17J。雖然短時間內可引起肌酐水平的升 高,但經過3年的長期觀察,肌酐清除率沒有明顯 的變化。在利噻瞵酸鹽的研究中,給藥組和安慰劑 組血肌酐水平都發生了相同程度的下降。 5結論 雙膦酸鹽對絕經后骨質疏松的治療是安全和 有效的。然而該藥在慢性腎臟病中的使用還是存 在顧慮的,原因是該藥可引起腎臟毒性,還可能使 終末期腎病中的無動力性骨病進一步惡化。通過 以上各項研究表明,雙膦酸鹽治療2—3期慢性腎 臟病的骨質疏松是安全和有效的。在其中一項研 究中,利噻膦酸鹽對4期慢性腎臟病患者也是安全 的。然而,這些結論都是基于回顧性的分析。美國 食品藥品管理局已經批準將雙膦酸鹽用于肌酐清 除率在30—35mL/min之間的患者。然而,該藥在 慢性腎臟病5期患者中已有少量的研究和觀察,但 需進一步的臨床試驗。 參考文獻 [1]l ̄lIoeS.嘁eT,c∞nin出ⅫJ,eta1.Definition,evaluation,and clarificationof札mlostesdystrophy:apositionstatementf而Kidney Disease:l,.provi地GlobalOutcomes(KI)IGO).KidneyInt,2006, 69:1945 [2]AtsumiK,KmhidaK。YamazakiK,eta1.mskFactorsforvertebral fracturesinrenalosteodystroohy.AmJKidneyDis.1999,33:287 [3]DooleyAC,WeissNS,KestenbattmB.Irmeasedrisk ofhipfrature amongmenwithCKD.AmJKidneyDis。2008,51:38 【4]CocoM,fhlsllH.Increasedincidenceofhipfraturesindialysispa- tientswithlowⅨmⅧparathyroidhomlone.AmJKid.eyDis,2000, 36:lll5 [5]lttmkaKA,TeitelbaumSL.Mechmi∞∞0fdi/lea∞.*Renal06一 teoaystrmhy.NEngJlVled,1995,333?166 [6]MartinKJ,olgaaIdK,CobumJW,ela1.Diagnosis,舶眈跏目t, andtre,almentoi"boneII.unoverabnormalitiesinrenalosteoaysh-ophy. AmJKia,℃-yDis,2004,43:558 [7]ReportofaWHOStudy娜.A∞am蜘toffractureriskandits complicntionto∞m∞iIlgforpos岫H10刪osteoporosis.W140 l"f!chnicalReportSeries,1994..843 [8]ClminOⅢJ,Sp,-agueSM,C∞mta—AndillJ,ela1.OsteolⅪroeis inchronickidneydisease.AmJKidneyDis.2004,43:566 [9]llmsellRGBi8p}losphm岫:modect"actionandpharmacology.Pedi- msics。2007,119(Suppl2):S150 [10]FIeischH.Bi印hospI嘲塒锫:mechanislmofaction.EndoerRev. 1998.19.∞ [1l】OdvinacV,ZerwekhJE,ltaoDS,ela1.Severelysuppressedbone Iunlovel-*.apotentialcomplicationofalendronatetherapy.JClinEn— doerinolbletab,2005,90:1294 [12]JamalSA,BauerDC,En.srudKE。eta1.Alendronatetrealmentin womenwithncmnaltoseverelyimpairedrenalflUlctioil:allanalysisof thef.瑚tLlminterventi∞trial.JBoneMinerltes。2007,22:503 [13]MillerPD,RouxC,BoonenS,eta1.Safetyandefficacyofrise- dl’onaleinpati∞tswithage—l吐ttedreducedremlfunction∞esti— matedbyltheCockcrotlandGIDdtmethod:apooledanalysis0fnine eliniealtrials.JBoneMinerRes,2005,20.2105 [14]BlackDM,DelmasPD,EastdlR,et81.olw.e—yearlyzoledronie acidfortreatmentdp0曲∞r10p齜salo咀即p0糯.惜.NEngjMed。 2007,356:1809 [15]嘶JT,GreenL,BeitzJ.Renalfailurewithfileu∞ct"zol豳onie acid.NEngJl~led,2003,349:1676 [16]MarkowitzGS,AppleGB,FinePL,eta1.conapsi.gfocalflemen- talgIqIknd∞claU6isfollowinglreatmentwithIIi曲一dose p蚵d『日?mle,J AmS0cN印hoJ,200】,12:1164 [17]ltoonen’S,SellmeyerDE,LippunerK,ela1.Renalsafetyofaralual n,ledrunieacidinfusionin∞t。叩鯽正cpc融m∞qp∞salwomen.Kidr呵 Int,2008,74(5):64l 萬方數據 換頁

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