密固達(dá)臨床試驗介紹

1、MA-1,目 錄,密固達(dá)作用機制分子結(jié)構(gòu)—決定獨特的效果體外研究—最強的抗骨吸收作用藥理結(jié)構(gòu)特點—強大吸附力與抗骨吸收作用密固達(dá)與Paget骨病密固達(dá)與絕經(jīng)后骨質(zhì)疏松,MA-2,密固達(dá)簡介,通用名稱：唑來膦酸注射液商品名稱：密固達(dá)（Aclasta）規(guī)格:100ml：5mg（以唑來膦酸無水物計）性狀:本品為無色的澄明液體,MA-3,雙膦酸藥物—不同的 R2 側(cè)鏈結(jié)構(gòu),,利塞膦酸,唑來膦酸,伊班膦酸,阿倫膦酸,M

2、A-4,唑來膦酸是作用最強的雙膦酸鹽,Green JR, et al. J Bone Miner Res. 1994;9:745-751.,動物研究證實：唑來膦酸的骨吸收抑制強度是帕米膦酸鹽的100-850倍,MA-5,高吸附力的雙膦酸藥物在骨組織中很少彌散，停留在骨表面附近,G Russell 2005,注射后幾個月內(nèi)組織液中仍可檢測到雙膦酸類藥物,唑來膦酸與骨礦鹽的強大結(jié)合力:,唑來膦酸在骨組織循環(huán)的可能機制,,MA-6,近端脛骨干

3、骺端pQCT,Gasser JA, Green J. Bone. 2002;30(3):41S.,松質(zhì)骨 BMD (%),周,–60,–40,–20,0,0,4,8,12,16,20,24,28,32,,,,,,,,,,唑來膦酸單次靜脈給藥對于去卵巢大鼠的長期抗骨吸收作用,,MA-7,,去卵巢大鼠治療32周后近端脛骨干骺端Micro-CT圖像,,Gasser JA, Green JR. Bone. 2002;30(3):41S.,

4、成人唑來膦酸5mg的等效劑量,OVX,4 µg/kg,20 µg/kg,100 µg/kg,SHAM,單次靜脈注射人類的等效劑量對于骨組織微結(jié)構(gòu)具有保護作用,,MA-8,唑來膦酸防止去卵巢大鼠骨組織結(jié)構(gòu)惡化以及生物力學(xué)的降低,防止去卵巢導(dǎo)致的以下參數(shù)降低: 骨體積分?jǐn)?shù) 1 骨小梁厚度1 骨小梁數(shù)量 1 連接的密度 1 承受最大應(yīng)力 (椎體)1 承受最大壓力 (股骨: 3點彎曲試驗 )2能

5、量吸收2防止去卵巢導(dǎo)致的以下參數(shù)增加: 骨小梁間隙 1 結(jié)構(gòu)模型參數(shù) 1,1. Glatt M, et al. Osteoporos Int. 2004;15:707-715.2. Hornby SB, et al. Calcif Tissue Int. 2003;72:519-527.,,MA-9,1. Green JR, et al. J Bone Miner Res. 1994;9:745-751. 2. Data

6、on file, Novartis.,體外顱骨測量：抑制重吸收 vs 礦化作用,治療比,抑制礦化,抑制骨吸收,化合物,400,20,0.05,阿倫膦酸,IC50 (μM) 2,IC50 (μM)1,,,0.4,氯屈膦酸,50,125,0.02,伊班膦酸,400,8,唑來膦酸抑制骨吸收與礦化作用具有更高的治療比,,,唑來膦酸在Paget’s骨病的應(yīng)用,MA-11,* HORIZON (Health Outcomes and Reduce

7、d Incidence with Zoledronic Acid Once Yearly).Reid IR, et al. N Engl J Med. 2005;353:898-908.,HORIZON*-Paget’s骨病臨床研究: 療效終點,,患者總數(shù): N = 357主要終點: 治療反應(yīng) 過高的SAP水平降低≥ 75%或治療6個月SAP水平達(dá)到正常的百分比 次要終點：治療28天SAP水平達(dá)到正常的百分比產(chǎn)生治療

8、反應(yīng)的時間骨吸收指標(biāo)的變化血漿 CTX尿 CTX,MA-12,… 2 個月1,Zoledronic Acid(n = 176),% 產(chǎn)生治療反應(yīng)的患者百分比*,,,… 6 個月2,,,,90,63,,,,96,89,,%, P < .001,%, P < .001,反應(yīng)患者,,堿性磷酸酶正?；颊?,% 產(chǎn)生治療反應(yīng)的患者百分比*,*產(chǎn)生治療反應(yīng): 過高的SAP水平降低?75%.Dosage: RIS: 60 day

9、s: 1 x 30 mg/day; Zoledronic Acid: single infusion of 5 mg. 1. Lyles K, et al. Poster presented at ECCEO5; March 16-19, 2005; Rome, Italy. 2. Reid IR, et al. N Engl J Med. 2005;353:898-908.,治療2個月和6個月時唑來膦酸具有比利塞膦酸更好的臨床療效,

10、,Risedronate (n = 171),,,47,26,,,74,58,Zoledronic Acid(n = 176),Risedronate (n = 171),MA-13,天數(shù),,,,,,,,,,,,,,10,28,63,91,182,*7%,堿性磷酸酶水平正常患者百分比 (%),,,*P < .001.,唑來膦酸與利塞膦酸治療：堿性磷酸酶正?；熜П容^,Zoledronic Acid (n = 176),R

11、isedronate (n = 171),Reid IR, et al. N Engl J Med. 2005;353:898-908.,1%,*63%,*76%,*89%,26%,49%,58%,,,,,,MA-14,,,*P < .001,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,0,10,28,63,91,182,天數(shù),0,100,200,300,400,50

12、0,全血堿性磷酸酶水平 (U/L),*,*,*,*,*,,,,,,,,隨訪時平均血漿堿性磷酸酶水平(? SE),,唑來膦酸 (n = 176),利塞膦酸 (n = 171),,,,,,正常范圍,Reid IR, et al. N Engl J Med. 2005;353:898-908.,*P <.001,*P < .001,*P <.001,*P < .001,唑來膦酸使平均血漿堿性磷酸酶水平恢

13、復(fù)正常,,,HORIZON-PFT (Pivotal Fracture Trial關(guān)鍵部位骨折試驗) 2301 研究核心內(nèi)容,密固達(dá)與絕經(jīng)后骨質(zhì)疏松 ---全面降低各部位骨折風(fēng)險,提高骨密度,MA-16,Health Outcomes and Reduced Incidence With Zoledronic Acid Once Yearly Pivotal Fracture Trial,Black DM, et al. N E

14、ngl J Med. 2007;356:1809-1822.,,MA-17,HORIZON Pivotal Fracture TrialHORIZON關(guān)鍵骨折臨床研究(PFT) 概述,研究目的：觀察唑來膦酸5毫克治療降低絕經(jīng)后骨質(zhì)疏松患者骨折風(fēng)險的療效為期3年，隨機、雙盲、安慰劑對照、多中心臨床研究27個國家，239各研究中心的7736名女性入組 治療方法：每年一次靜脈輸注唑來膦酸5毫克或安慰劑基礎(chǔ)補充鈣劑 1000–150

15、0 mg/d; 維生素 D 400–1200 IU/d主要療效終點第I層面：降低3年椎體骨折風(fēng)險第I和II層面：延長3年發(fā)生髖部骨折的時間,ZOL = zoledronic acidBlack DM, et al. N Engl J Med. 2007;356:1809-1822.,,MA-18,新發(fā)椎體骨折發(fā)生率%,60%*(43%, 72%),71%*(62%, 78%),,,,,,,,,0,10,0–1,0–2,0–3

16、,年,5,15,,,,1.5%(42/2822),3.7%(106/2853),2.2%(63/2822),7.7%(220/2853),3.3%(92/2822),10.9%(310/2853),70%*(62%, 76%),,,,,,,,*P < .0001, relative risk reduction vs placebo (95% confidence interval) Adapted from Bl

17、ack DM, et al. N Engl J Med. 2007;356:1809-1822.,,唑來膦酸治療3年椎體形態(tài)骨折發(fā)生率降低達(dá)70%,,MA-19,唑來膦酸治療3年多發(fā)(≥2)椎體形態(tài)骨折發(fā)生率降低達(dá)89%,,,89%*(77%, 95%),,,3年多發(fā)(≥2)椎體骨折,0.2%(7/2822),2.3%(66/2853),多發(fā)(≥2) 椎體骨折發(fā)生率%,0,2,1,3,,,,,*P = .0001, relati

18、ve risk reduction vs placebo (95% confidence interval)Data from Black DM, et al. N Engl J Med. 2007;356:1809-1822.,MA-20,*Relative risk reduction vs placebo (95% confidence interval)Adapted from Black DM, et al. N Engl

19、 J Med. 2007;356:1809-1822.,,P = .0024,,1,2,3,0,,,,,,,,,,,,,,,,,首次髖部骨折發(fā)生的時間 (月),0,3,6,9,12,15,18,21,24,27,30,33,36,41%*(17%, 58%),,唑來膦酸治療3年髖部骨折累積危險性降低達(dá)41%,累積危險性 (%),MA-21,P < .0001,,,,,,,,,,,,,,,,,,累積危險性(%),發(fā)生第一次臨床椎體

20、骨折的時間（月）,0,3,6,9,12,15,18,21,24,27,30,33,36,77%*(63%, 86%),1,2,3,0,,*Relative risk reduction vs placebo (95% confidence interval)Adapted from Black DM, et al. N Engl J Med. 2007;356:1809-1822.,,唑來膦酸治療3年臨床椎體骨折累積危險性降低達(dá)7

21、7%,MA-22,P = .0002,,,,,,,發(fā)生第一次非椎體骨折的時間（月）,2,4,6,8,10,12,,,,,,,,,,,,,,,,0,3,6,9,12,15,18,21,24,27,30,33,36,,25%*(13%, 36%),,0,,,*Relative risk reduction vs placebo (95% confidence interval)Adapted from Black DM, et al.

22、N Engl J Med. 2007;356:1809-1822.,,唑來膦酸治療3年非椎體骨折累積危險性降低達(dá)25%,累積危險性(%),MA-23,Values above bars are 3-year cumulative event rates based on Kaplan-Meier estimates. *P = .0024; ?P < .0001; ?P = .0002; relative risk reduc

23、tion vs placebo §Hip fracture was not excluded from analysis of non-vertebral fracture.Black DM, et al. N Engl J Med. 2007;356:1809-1822.,,,,,41%*(17%, 58%),77%?(63%, 86%),25%?(13%, 36%),臨床椎體骨折,,,,,,,,髖部骨折,非椎體骨

24、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年新發(fā)臨床骨折累積危險性（%）,0,10,5,15,,,,,,,,,唑來膦酸治療3年降低臨床骨折累積危險性（髖部、椎體、非椎體）,MA-24,,0,6,12,18,24,30,36,月,,,,,,,,,,,,,,,,,,,,,,,,

25、,[5.90*],[3.66*],[2.39*],與基線比較變化率 %,ZOL 5 mg,Placebo,,,ZOL n =PBO n =,Bracketed values are least square mean difference, ZOL vs placebo*P < .0001, P-value computed from 3-way ANOVA with treatment, stratum and center

26、 as explanatory variables.Adapted from Black DM, et al. N Engl J Med. 2007;356:1809-1822.,,6.71%*,,,,,,,,,,,,,,,,,,,與安慰劑比較唑來膦酸治療3年顯著增加椎體BMD,MA-25,與安慰劑比較唑來膦酸治療3年顯著增加全髖BMD,ZOL n =PBO n =,Bracketed values are least squa

27、re mean difference, ZOL vs placebo*P < .0001, P-value computed from 3-way ANOVA with treatment, stratum and region as explanatory variables.Adapted from Black DM, et al. N Engl J Med. 2007;356:1809-1822.,,MA-26,,,,,

28、,,,,,與安慰劑比較唑來膦酸治療3年顯著增加股骨頸BMD,0,6,12,18,24,30,36,月,,,,,,,,,,,,,,,,,,,,[2.17*],[1.58*],[3.89*],ZOL 5 mg,Placebo,,,ZOL n =PBO n =,Bracketed values are least square mean difference, ZOL vs placebo*P < .0001, P-value c

29、omputed from 3-way ANOVA with treatment, stratum and region as explanatory variables.Adapted from Black DM, et al. N Engl J Med. 2007;356:1809-1822.,,5.06%*,,,與基線比較變化率 %,,,,,,,,,,,,,,,,,MA-27,,Placebo,?CT檢測骨結(jié)構(gòu)結(jié)果顯示唑來膦酸治

30、療后骨小梁結(jié)構(gòu)得到保留,Recker R, et al. Presented at: 34th European Symposium on Calcified Tissues; May 5-9, 2007;Copenhagen, Denmark. Abstract PO21-M.,,ZOL 5 mg,唑來膦酸與安慰劑組間比較骨小梁體積(BV/TV，16.59% vs,13.52%, P<0.015 )骨小梁數(shù)量(1.3

31、1/mm vs.1.22/mm, P<0.006),骨小梁空間(0.76 mm vs.0.82 mm, P<0.008),連接的密度(4.32/mm3 vs.3.57/mm3, P<0.052).,MA-28,唑來膦酸靜脈給藥后3天內(nèi)出現(xiàn)的常見癥狀 （≥5%）,,,,,,,,,,,,,,,,,,,,,,,,,,,,0,2,4,6,8,10,12,14,16,給藥次數(shù),,,,,,發(fā)熱,,肌痛,,流感樣癥狀,

32、,頭痛,,關(guān)節(jié)痛,1,2,3,1,2,3,1,2,3,1,2,3,1,2,3,發(fā)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.,,MA-29,,,,,OTC解熱鎮(zhèn)痛藥可以有效降低給用后癥狀,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,

33、,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,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,給藥后時間 (小時),,,,,,,,,,,,,口表測量平均體溫變化(± SEM) (°C),ZOL & 撲熱息痛ZOL & 布洛芬,,,,,ZOL & P

34、LACPLAC & PLAC,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,,,,,MA-30,唑來膦酸治療絕經(jīng)后骨質(zhì)疏松患者具有廣泛療效,絕經(jīng)后骨質(zhì)疏松女性，一年一次靜脈給予唑來膦酸

35、5mg，治療3年可以顯著降低1：椎體骨折 (變形性骨折70%, 臨床骨折77%)1髖部骨折 (41%)1非椎體骨折 (25%)1骨折或疼痛導(dǎo)致的臥床/活動受限時間身高縮短1與安慰劑比較具有顯著增加BMD作用136個月內(nèi)骨形成與骨吸收指標(biāo)降低至絕經(jīng)前水平，并維持1 患者對藥物的耐受性良好1預(yù)防骨折的療效以及良好的依從性提示唑來膦酸5mg治療骨質(zhì)疏松具有顯著優(yōu)勢1,1.Black DM, et al. N Engl J