新型双膦酸药物-唑来膦酸-课件.ppt

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1、新型双膦酸药物-唑来膦酸,从化学结构看双膦酸药物的发展,3,R1=OH,R2=CH2 利塞膦酸,膦酸基团是药物与骨组织羟基膦灰石结合的关键部位，决定药物的生化特性,R1=OH,R2=(CH2)2NH2 帕米膦酸R1=OH,R2=(CH2)3NH2 阿伦膦酸,N,R1=OH,R2=CH2 唑来膦酸,N,N,R2,R1,C,O,OH,OH,OH,OH,O,P,P,双膦酸类药物的功能基团,R.GRAHAM G.RUSSELL,Bisphosphonates,From Bench to Beside Ann.N.Y.Acad.Sci.1068:367401(2006).R.GRAHAM G.RUSSE

2、LL,Bisphosphonates，An Update on Mechanisms of Action and How These Relate to Clinical EfficacyR.GRAHAM G.RUSSELL,Mechanisms of action of bisphosphonates:similarities and differences and their potential influence on clinical efficacy.Osteoporos Int(2008)19:733759,4,双膦酸药物分类,不含氮双膦酸,含氨基侧链双膦酸,含氮环链双膦酸,R.G

3、RAHAM G.RUSSELL,Bisphosphonates,From Bench to Beside Ann.N.Y.Acad.Sci.1068:367401(2006).R.GRAHAM G.RUSSELL,Bisphosphonates，An Update on Mechanisms of Action and How These Relate to Clinical EfficacyR.GRAHAM G.RUSSELL,Mechanisms of action of bisphosphonates:similarities and differences and their pote

4、ntial influence on clinical efficacy.Osteoporos Int(2008)19:733759,5,双膦酸药物的研发进展,R.GRAHAM G.RUSSELL,Bisphosphonates,From Bench to Beside Ann.N.Y.Acad.Sci.1068:367401(2006).R.GRAHAM G.RUSSELL,Bisphosphonates，An Update on Mechanisms of Action and How These Relate to Clinical EfficacyR.GRAHAM G.RUSSELL,

5、Mechanisms of action of bisphosphonates:similarities and differences and their potential influence on clinical efficacy.Osteoporos Int(2008)19:733759,6,1.Green JR,et al.J Bone Miner Res.1994;9:745-751.2.Data on file,Novartis.,体外颅骨测量：抑制重吸收 vs 矿化作用,抑制矿化/抑制骨吸收比值,抑制矿化,抑制骨吸收,化合物,400,20,0.05,阿伦膦酸,IC50(M)2

6、,IC50(M)1,0.4,氯屈膦酸,50,125,0.02,伊班膦酸,400,8,双膦酸药物抑制骨吸收与矿化作用治疗比,双膦酸药物的作用机制,8,双膦酸药物进入体内的药代分布,Data from Chen T,et al.J Clin Pharmacol.2002;42:12281236.,药物在骨组织的结合率受到骨丢失活跃状态以及肾功能等因素的影响。骨丢失活跃的患者结合率更高。双膦酸药物进入体内后24小时内有1/32/3的药物以原型形式排出，绝大部分在给药最初几小时内即排出。,9,ALN,alendronate;CLO,clodronate;ETD,etidronate;IBA,iband

7、ronate;RIS,risedronate;ZOL,zoledronic acid.Nancollas GH,et al.Bone.2006;38:617-627.,双膦酸药物与骨表面羟基膦灰石结合力,0,1,2,4,羟磷灰石,CLO,ETD,RIS,IBA,ALN,ZOL,3,KL(L/mol x 106),吸附力指数,KL,10,与骨表面结合,BP=bisphosphonatesCourtesy of Professor M.Rogers.,从细胞学角度看双膦酸药物的作用机制,11,FPP 合成酶,甲羟戊酸,香叶基焦磷酸（IPP）,法尼基焦磷酸（FPP）,双香叶基基焦磷酸（GGPP）,H

8、MG-CoA3羟3甲戊二酰辅酶A,含氮双膦酸类药物对于FPP合成酶的作用,Masarachia et al Bone 1996;19:281Coxon et al Bone 2008;42:848,x,单核细胞摄入含氮双膦酸药物后IPP累积,IPP,IPP,IPP,IPP与-T细胞表面受体结合,含氮双膦酸药物：阿仑膦酸伊班膦酸帕米膦酸利塞膦酸唑来膦酸,合成破骨细胞功能与存活必需的结构蛋白,-T细胞释放TNF患者出现急性反应,12,*,ALN,alendronate;CLO,clodronate;ETD,etidronate;FPP,farnesyl pyrophosphate;IBA,iban

9、dronate;PAM,pamidronate;RIS,risedronate;ZOL,zoledronic acid.1.Dunford JE,et al.J Pharmacol Exp Ther.2001;296:235-242.,FPP 合成酶活性(%control),*,0,25,50,75,100,ETD,PAM,*,IBA,RIS,*,ZOL,*P.001,双膦酸类药物(0.1 M),ALN,*,FPP 合成酶1,FPP合成酶抑制与骨吸收抑制的相关性（体外研究）,13,双膦酸药物在骨组织的循环,R.GRAHAM G.RUSSELL,Bisphosphonates,From Benc

10、h to Beside Ann.N.Y.Acad.Sci.1068:367401(2006).R.GRAHAM G.RUSSELL,Bisphosphonates，An Update on Mechanisms of Action and How These Relate to Clinical EfficacyR.GRAHAM G.RUSSELL,Mechanisms of action of bisphosphonates:similarities and differences and their potential influence on clinical efficacy.Oste

11、oporos Int(2008)19:733759,高吸附力双膦酸药物(如阿仑膦酸、唑来膦酸)快速骨吸收低脱落率强大再吸收骨内扩散少,低吸附力双膦酸药物(如利塞膦酸)少量骨吸收高脱落率少量再吸收骨内扩散多,从循证医学证据看唑来膦酸的疗效,15,唑来膦酸治疗骨质疏松症的临床疗效,改善骨转换指标提升骨密度全面提升骨密度髋部骨折后患者骨密度提升改善骨结构降低骨折风险起效时间降低多发椎体骨折风险全面降低各部位骨折风险降低老年患者骨折风险降低死亡率中国人群疗效数据,16,唑来膦酸5mg迅速降低平均血浆-CTX*水平并持续,月,0.2,0.0,0.6,0.7,0.8,1.0,平均血浆-CTX(ng/mL)

12、,0,6,12,18,24,30,36,0.9,0.5,0.1,0.3,0.4,唑来膦酸5mg,摘自Black DM,et al.N Engl J Med.2007;356:1809-1822.,*-CTX:I型胶原C端肽+所有时间点降低程度与安慰剂组比较均有显著差异,HORIZON-PFT,唑来膦酸5mg,唑来膦酸5mg,+P.0001,17,唑来膦酸5mg迅速降低平均血浆BALP*水平并持续,平均血浆骨特异性ALP(ng/mL),0,6,12,18,24,30,36,月,摘自Black DM,et al.N Engl J Med.2007;356:1809-1822.,*BALP：骨特异性

13、碱性磷酸酶+所有时间点降低程度与安慰剂组比较均有显著差异,HORIZON-PFT,唑来膦酸5mg,唑来膦酸5mg,唑来膦酸5mg,P.0001,18,唑来膦酸5mg显著降低平均血浆 P1NP*并持续,摘自Black DM,et al.N Engl J Med.2007;356:1809-1822.,*P1NP：I型前胶原氨基端前肽+与安慰剂组比较均有显著差异,HORIZON-PFT,唑来膦酸5mg,唑来膦酸5mg,唑来膦酸5mg,P.0001,19,唑来膦酸治疗骨质疏松症的临床疗效,改善骨转换指标提升骨密度全面提升骨密度髋部骨折后患者骨密度提升改善骨结构降低骨折风险起效时间降低多发椎体骨折风险

14、全面降低各部位骨折风险降低老年患者骨折风险降低死亡率中国人群疗效数据,20,唑来膦酸5mg显著增加各部位骨密度,6个月时，各部位BMD显著提升3年结束时唑来膦酸提升椎体BMD 6.71%唑来膦酸提升全髋BMD 6.02%唑来膦酸提升股骨颈BMD 5.06%,月,月,椎体BMD,股骨颈BMD,Black DM,et al.N Engl J Med.2007;356:1809-1822.,HORIZON-PFT,与基线比较变化率%,全髋BMD,*与安慰剂组比较P.0001,唑来膦酸 5 mg,安慰剂,21,唑来膦酸显著提升髋部骨折后患者骨密度,HORIZON-RFT研究中纳入2127名髋部新发骨折

15、患者随机分配接受唑来膦酸5毫克静脉输注或安慰剂治疗,Colon-Emeric C,et al.Abstract SA0281:Bone Mineral Density after Hip Fracture:Variations in Response to Once-Yearly i.v.Zoledronic acid 5 mg.2009 ASBMR,Denver,CO.,Treatmentt-by-subgroup interaction was considered significant if p0.10,HORIZON-RFT,22,Statistical significance i

16、s noted within each age subgroup.Treatment-by-subgroup interaction was statically significant for only those 85 yrs of age.Colon-Emeric C,et al.Abstract SA0281:Bone Mineral Density after Hip Fracture:Variations in Response to Once-Yearly i.v.Zoledronic acid 5 mg.2009 ASBMR,Denver,CO.,85岁以上亚组患者在12个月时

17、骨密度提升水平最为显著,p0.0001,p0.0001,p0.0001,p=0.0001,n=131,n=139,n=218,n=194,n=277,n=281,n=55,n=69,唑来膦酸显著提升髋部骨折后患者骨密度,HORIZON-RFT,23,部骨密度T值-2.5 亚组患者12个月时骨密度提升最为显著,Statistical significance is noted within each T-score subgroup.Treatment-by-subgroup interaction was statically significant for only those with a

18、 baseline hip T-score-2.5.Colon-Emeric C,et al.Abstract SA0281:Bone Mineral Density after Hip Fracture:Variations in Response to Once-Yearly i.v.Zoledronic acid 5 mg.2009 ASBMR,Denver,CO.,p0.0001,p0.0001,p0.0001,唑来膦酸显著提升髋部骨折后患者骨密度,HORIZON-RFT,24,既往存在骨折史患者亚组，12个月、24个月全髋骨密度显著提升,Statistical significanc

19、e is noted within each previous baseline fracture group.Treatment-by-subgroup interaction was statically significant for only those with a previous baseline vertebral and non-vertebral fractureColon-Emeric C,et al.Abstract SA0281:Bone Mineral Density after Hip Fracture:Variations in Response to Once

20、-Yearly i.v.Zoledronic acid 5 mg.2009 ASBMR,Denver,CO.,全髋骨密度变化率（%）,24个月,12个月,p0.0001,p0.0001,p=0.17,p=0.005,n=248,n=268,n=124,n=112,n=14,n=14,n=19,n=6,p0.0001,p0.0001,p=0.0006,p=0.0005,n=401,n=451,n=226,n=192,n=22,n=21,n=32,n=19,唑来膦酸显著提升髋部骨折后患者骨密度,HORIZON-RFT,25,唑来膦酸治疗骨质疏松症的临床疗效,改善骨转换指标提升骨密度全面提升骨密度髋

21、部骨折后患者骨密度提升改善骨结构降低骨折风险起效时间降低多发椎体骨折风险全面降低各部位骨折风险降低老年患者骨折风险降低死亡率中国人群疗效数据,26,一年一次唑来膦酸显著增加绝经后骨质疏松患者股骨强度,QCT检查可以避免骨组织周围结构对于骨密度的影响，直接了解到小梁骨骨密度情况，从而对骨强度以及骨折风险有更好的评估。HORIZON-PFT研究3年内177名女性患者接受髋部以及椎体QCT检查结果显示：唑来膦酸治疗后通过DXA和QCT均看到椎体以及髋部BMD显著提升的结果QCT结果看到唑来膦酸提升骨密度作用主要在骨小梁QCT结果看到唑来膦酸治疗后骨强度得到全面提升，从而进一步降低患者再骨折风险,R.

22、Eastell,et al.Osteoporos Int.2009;10.,HORIZON-PFT,27,唑来膦酸显著改善骨结构DXA和QCT测量的椎体与髋部骨密度变化,与基线比变化率（%）,R.Eastell,et al.Osteoporos Int.2009;10.,QCT与DXA检查结果一致显示，骨密度显著提升,HORIZON-PFT,28,与基线比变化率（%）,唑来膦酸显著改善骨结构QCT测量全髋骨小梁和皮质骨密度变化,R.Eastell,et al.Osteoporos Int.2009;10.,QCT结果一致显示，髋部骨小梁骨密度显著提升，皮质骨骨密度变化不显著,HORIZON-P

23、FT,29,与基线比变化率（%）,唑来膦酸显著改善骨结构QCT测量骨强度参数变化,R.Eastell,et al.Osteoporos Int.2009;10.,BSI:弯曲强度指数，CSI:压力强度指数全髋皮质骨体积以及CSI指数的提升，均提示唑来膦酸可以进一步降低骨折风险,HORIZON-PFT,30,唑来膦酸治疗骨质疏松症的临床疗效,改善骨转换指标提升骨密度全面提升骨密度中国人群骨密度改善结果髋部骨折后患者骨密度提升改善骨结构降低骨折风险起效时间降低多发椎体骨折风险全面降低各部位骨折风险降低老年患者骨折风险降低死亡率中国人群疗效数据,31,Values above bars are 3-

24、year cumulative event rates based on Kaplan-Meier estimates.*P=.0024;P.0001;P=.0002;相对风险：与安慰剂组比较包括髋部骨折.Black DM,et al.N Engl J Med.2007;356:1809-1822.,41%*,70%,25%,椎体骨折,髋部骨折,非椎体骨折,1.4%(52/3875),0.5%(19/3875),2.5%(88/3861),2.6%(84/3861),8.0%(292/3875),10.7%(388/3861),3年新发骨折累积危险性（%）,0,10,5,15,唑来膦酸5mg降

25、低各部位骨折风险,HORIZON-PFT,32,0,2,4,6,8,10,12,14,16,18,20,临床骨折,非椎体骨折,临床椎体骨折,10.7%(107/1062),8.6%(92/1065),13.9%(139/1062),7.6%(79/1065),3.8%(39/1062),1.7%(21/1065),35%*(16%,50%),27%(2%,45%),46%(8%,28%),*P=.0012;P=.0338;P=.0210,relative risk reduction vs placebo;NS=not significant.Values above bars are cum

26、ulative event rates based on Kaplan-Meier estimates at Month 24.,发生率(%),唑来膦酸5毫克降低再发骨折风险,Lyles KW,et al.N Engl J Med.2007.e-publication 10.1056/NEJMoa074941 at www.nejm.org,HORIZON-RFT,33,对两项临床研究中共9375名女性患者进行回顾性分析，观察唑来膦酸降低骨折风险的起效时间唑来膦酸治疗组，临床椎体骨折风险在6个月看到降低6个月时，骨折风险降低53%(p=0.0553)12个月时，骨折风险显著降低57%(p=0.

27、0035),并在36个月的观察期内持续维持36个月时，临床椎体骨折风险显著降低70%(p0.0001),临床椎体骨折风险(%),9,n=,19,53%ns(-4%,87%),57%*(25%,76%),69%*(47%,81%),76%*(61%,85%),70%*(56%,79%),16,37,19,60,21,85,36,117,绝经后骨质疏松症以及近期髋部脆性骨折患者再发临床椎体骨折风险,*p=0.0035;*p=0.0001;ns=0.0553.Bucci-Rechtweg C,et al.Abstract FR0365:Time to Onset of Anti-Fracture E

28、fficacy and Persistence of Effect of Zoledronic Acid 5 mg in Women with Osteoporosis or Recent Hip Fracture.2009 ASBMR,Denver,CO.,唑来膦酸降低临床椎体骨折风险起效时间,34,对两项临床研究中共9375名女性患者进行回顾性分析，观察唑来膦酸降低骨折风险的起效时间唑来膦酸治疗组，非椎体骨折风险在6个月看到降低6个月时，骨折风险降低15%(p=0.3227)18个月时，骨折风险显著降低23%(p=0.0049),并在36个月的观察期内持续维持36个月时，非椎体骨折风险显著

29、降低26%(p0.0001),非椎体骨折风险(%),*p=0.0049;p=0.0002;*p=0.0001;ns=0.0553.Bucci-Rechtweg C,et al.Abstract FR0365:Time to Onset of Anti-Fracture Efficacy and Persistence of Effect of Zoledronic Acid 5 mg in Women with Osteoporosis or Recent Hip Fracture.2009 ASBMR,Denver,CO.,72,n=,84,15%ns(-34%,35%),16%ns(-5%

30、,36%),23%*(8%,36%),26%*(14%,37%),26%*(16%,36%),151,180,208,268,261,349,357,480,绝经后骨质疏松症以及近期髋部脆性骨折患者再发非椎体骨折风险,唑来膦酸降低非椎体骨折风险起效时间,35,唑来膦酸治疗3年显著降低绝经后女性患者多发椎体形态骨折风险（2处以上骨折）,唑来膦酸治疗3年显著降低绝经后女性患者临床多发骨折（2处以上骨折）风险,RR=risk reduction(95%CI);=Seeman E,et al.Abstract SA0366:Zoledronic Acid Substantially Reduces t

31、he Risk of Morphometric Vertebral and Clinical Fractures.2009 ASBMR,Denver,CO.,结论唑来膦酸一年一次可以缓解绝经后女性患者脆性骨折后骨脆性的进一步增加。,RR 89%(77%,95%),RR 38%(28%,46%),唑来膦酸显著降低多发椎体形态骨折与临床骨折风险,HORIZON-PFT研究中对于3年中患者再发椎体骨折以及再发临床骨折风险进行了评估,HORIZON-PFT,36,唑来膦酸 5 mg治疗3年可以降低6个部位骨折风险，显著降低髋部、肱骨和骨盆的骨折风险。骨盆骨折风险降低高达50%，而髋部骨折风险降低最为显

32、著。(p0.0024),唑来膦酸降低6处非椎体骨折风险的临床疗效,HORIZON-PFT 回顾性亚组分析结果显示，唑来膦酸可以显著降低患者6处常见非椎体骨折风险。(腕部,髋部,骨盆,肱骨,锁骨和下肢骨),Based on Kaplan-Meier estimates at Month 36;HR,Hazard ratio;Values in brackets are 95%confidence interval*Includes tailbone,coccyx and sacrum;p=0.0024;*p=0.0036;p=0.0175Black D,et al.Abstract SU0360

33、:Effect of Once-Yearly Zoledronic Acid 5 mg on a Sub-set of Six Nonvertebral Fractures.2009 ASBMR,Denver,CO.,HR=0.81(0.62-1.06)NS,HR=0.59(0.42-0.83),HR=0.53(0.35-0.82)*,HR=0.62(0.35-1.09)NS,HR=0.50(0.28-0.90),HR=0.63(0.21-1.92)NS,HORIZON-PFT,37,双膦酸药物降低椎体骨折风险的比较：唑来膦酸具有最强效果,1.Black DM,et al.N Engl J M

34、ed.2007;356:1809-1822.2.Harris ST,et al.JAMA.1999;282:1344.3.Actonel Prescribing Information.4.Black D,et al.J Clin Endocrinol Metab.2000;85:4118-4124.,Years,0-1,0-3,0-2,Years,0-1,0-3,0-2,Years,0-1,0-3,0-2,唑来膦酸 5 mg1,阿伦膦酸(FIT)4,利塞膦酸(VERT-NA)2,3,椎体骨折风险(%),非头对头研究结果,71%,0,10,20,30,40,50,60,70,60%,70%,6

35、5%,55%,41%,62%,48%,65%,老年患者数据,39,唑来膦酸用于老年患者的数据唑来膦酸5 mg 降低3年中的椎体骨折风险(按年龄),6569 岁,80%*(66%,88%),75岁,60%*(45%,71%),2.0%(17/832),10.0%(85/852),4.8%(52/1083),12.0%(129/1078),7074 岁,76%*(62%,84%),2.5%(23/907),10.4%(96/923),0,10,5,15,%新发椎体骨折患者百分率,*P.0001,与安慰剂比较相对风险降低Cauley J,et al.Osteoporos Int.2007;18(su

36、ppl 1):S26.Abstract OC53.,HORIZON-PFT,40,唑来膦酸用于老年患者的数据唑来膦酸降低3年中的髋部骨折风险(按年龄),70 岁,70%*(30%,87%),75岁,20%(-28%,50%),0.7%(7/1140),2.1%(24/1174),2.4%(32/1497),3.0%(39/1452),7074 岁,47%(-3%,73%),1.1%(13/1238),2.3%(25/1235),0,2,1,3,*P.0029,与安慰剂比较相对风险降低(95%置信区间)柱子上方的数值为基于Kaplan-Meier估计的3年累计事件率。Cauley J,et al

37、.Osteoporos Int.2007;18(suppl 1):S26.Abstract OC53.,%新发髋部骨折患者百分率,HORIZON-PFT,41,唑来膦酸用于老年患者的数据唑来膦酸降低3年中的临床骨折风险(按年龄),*P=.0012;P=.0077;P.001,与安慰剂比较相对风险降低(95%置信区间)柱子上方的数值为基于Kaplan-Meier估计的3年累计事件率。Cauley J,et al.Osteoporos Int.2007;18(suppl 1):S26.Abstract OC53.,70 岁,27%*(17%,53%),75岁,44%(18%,47%),7.1%(7

38、8/1140),11.2%(126/1174),14.5%(189/1452),7074 岁,29%(9%,45%),8.3%(100/1238),12.6%(141/1235),%新发临床骨折患者百分率,0,10,5,15,9.6%(130/1497),HORIZON-PFT,42,唑来膦酸显著降低75岁以上老年患者骨折风险,对两项临床研究中共9375名女性患者进行回顾性分析，分析75岁以及75岁患者临床疗效以及安全性数据,Steven Boonen，Journal of the American Geriatrics Society 2010,Volume 58,Issue 2,Pages

39、:292-299,43,唑来膦酸显著提升75岁以上老年患者髋部骨密度,*为唑来膦酸和安慰剂相对于基线变化率的差值,Steven Boonen，Journal of the American Geriatrics Society 2010,Volume 58,Issue 2,Pages:292-299,唑来膦酸可以显著改善患者髋部骨密度，但髋部骨折风险降低不显著，可能老年患者髋部骨折主要由于非骨骼原因存在，如跌倒风险等,44,唑来膦酸显著降低75岁以上老年患者骨吸收指标 CTX,Steven Boonen，Journal of the American Geriatrics Society 20

40、10,Volume 58,Issue 2,Pages:292-299,与各年龄亚组比较，唑来膦酸均显著降低骨转换指标（P0.001）,75岁以及75岁患者CTX基线水平无显著差异,45,唑来膦酸显著降低75岁以上老年患者骨形成指标 骨特异性碱性磷酸酶,Steven Boonen，Journal of the American Geriatrics Society 2010,Volume 58,Issue 2,Pages:292-299,与各年龄亚组比较，唑来膦酸均显著降低骨转换指标（P0.001）,75岁以及75岁患者BALP基线水平无显著差异,46,唑来膦酸显著降低75岁以上老年患者骨形成指

41、标 P1NP,Steven Boonen，Journal of the American Geriatrics Society 2010,Volume 58,Issue 2,Pages:292-299,与各年龄亚组比较，唑来膦酸均显著降低骨转换指标（P0.001）,75岁以及75岁患者P1NP基线水平无显著差异,47,唑来膦酸两项核心研究结果表明,唑来膦酸用于75岁以上的老年患者与其他口服双膦酸药物一样，可以降低椎体以及非椎体骨折风险显著改善患者髋部骨密度显著降低主要骨转换指标（75岁以及75岁患者骨转换指标基线水平无显著差异）与75岁以下年龄患者安全性一致,48,唑来膦酸治疗骨质疏松症的临床

42、疗效,改善骨转换指标提升骨密度全面提升骨密度中国人群骨密度改善结果髋部骨折后患者骨密度提升改善骨结构降低骨折风险起效时间降低多发椎体骨折风险全面降低各部位骨折风险降低老年患者骨折风险降低死亡率中国人群疗效数据,49,唑来膦酸5毫克治疗总死亡率降低达28%,月,风险率,0.72(95%CI,0.560.93)P=.0117,累积危险性(%),危险人数,ZOL 5 mg 10541029987943806674507348237144安慰剂10571028993945804681511364236149,28%,绝对风险降低,3.7%,Lyles KW,et al.N Engl J Med.200

43、7.e-publication 10.1056/NEJMoa074941 at www.nejm.org,HORIZON-RFT,50,唑来膦酸治疗骨质疏松症的临床疗效,改善骨转换指标提升骨密度全面提升骨密度中国人群骨密度改善结果髋部骨折后患者骨密度提升改善骨结构降低骨折风险起效时间降低多发椎体骨折风险全面降低各部位骨折风险降低老年患者骨折风险降低死亡率中国人群疗效数据,51,中国人群骨密度提升情况,全髋,HORIZON-PFT研究中国两个研究中心共133名绝经后骨质疏松患者入组随机结果唑来膦酸一年一次或安慰剂治疗两组患者同时补充元素钙1000mg/d，维生素D400IU/d观察患者髋部骨密度

44、以及椎体和髋部骨折风险发生率,52,中国人群骨折风险数据,椎体,全髋,从研究数据看唑来膦酸的安全性,54,从研究数据看唑来膦酸的安全性,对骨折愈合的影响骨组织安全性急性一过性症状发生率与原因,55,髋部骨折手术后首次给药时间,HORIZON-RFT,56,骨折不愈合发生率与给药时间的关系,HORIZON-RFT,57,HORIZON-PFT,HORIZON-PFT股骨干骨折发生率,HORIZON-PFT研究中发生的所有股骨干骨折被独立专家组通过x线以及外科检查报告进行评估以明确其发生率结果研究中5名患者（6处骨折）符合股骨干骨折的定义，3名为唑来膦酸组患者，2名为安慰剂组(HR=1.5,95%

45、CI:0.25,9.0),1Black DM,Delmas PD,Eastell R et al.Once-yearly zoledronic acid for treatment of postmenopausal osteoporosis.N Engl J Med 2007;356:18091822.Black D,et al.Abstract MO0344:Does Zoledronic Acid Increase Risk of Atypical Subtrochanteric Femoral Shaft Fractures?Results from the HORIZON-PFT.2

46、009 ASBMR,Denver,CO.,股骨干骨折发生率,患者数,58,Adachi J,et al.Oral Session 1098:Subtrochanteric Fractures:Results from the HORIZON-Recurrent Fracture Trial.2009 ASBMR,Denver,CO.HR=Hazard ratio,NS=not significant(p=0.18)Values above bars are cumulative event rates based on Kaplan-Meier estimates at Month 24.Ly

47、les KW,et al.N Engl J Med.2007;357:17991809.,非典型股骨干骨折发生于皮质骨异常增厚不良事件报告中共有2名患者出现股骨干骨折，安慰剂组与唑来膦酸组各一例患者，没有患者被定义为非典型股骨干骨折结论回顾性分析发现，股骨干骨折并非罕见骨折，并且在没有使用双膦酸盐的患者中同样可以发生。实际应用以及研究中唑来膦酸治疗后股骨干骨折非常罕见，无法得到有临床意义的结果。,HORIZON-RFT股骨干骨折发生率,HORIZON-RFT,59,59,Note:AEs with an incidence of at least 2.0%in the first 3 days

48、 are compared to their incidence after the first 3 days.,唑来膦酸5mg给药后一过性症状多在发生后3天内缓解,HORIZON-PFT,60,0,2,4,6,8,10,12,14,16,给药次数,发热,肌痛,流感样症状,头痛,关节痛,1,2,3,1,2,3,1,2,3,1,2,3,1,2,3,发生率(%),15%,2%,1%,1%,2%,1%,2%,1%,2%,1%,8%,7%,6%,5%,1%,Data from Black DM,et al.N Engl J Med.2007;356:1809-1822.,再次给予唑来膦酸5mg时一过性

49、症状发生率显著降低,HORIZON-PFT,61,0.0,0.1,0.2,0.3,0.4,0.5,0.6,0.7,0.8,0.9,1.0,0,5,10,15,24,29,34,39,48,53,58,63,给药后时间(小时),口表测量平均体温变化(SEM)(C),唑来膦酸&扑热息痛唑来膦酸&布洛芬,唑来膦酸&安慰剂安慰剂&安慰剂,Design:2 x 500 mg paracetamol vs 2 x 200 mg ibuprofen vs placebo every 6 hours for 3 days.Oral study medication started 4 hours after infusion,OTC解热镇痛药可以有效缓解用药后一过性症状,62,唑来膦酸治疗骨质疏松症疗效总结,快速改善骨转换指标，并持续维持在正常低限水平全面快速提升骨密度，显著改善骨结构快速降低各种类型以及各部位骨折风险降低患者长期死亡率整体安全性良好,谢谢,