密固達(dá)第二版課件

1、新型雙膦酸藥物-唑來(lái)膦酸從化學(xué)結(jié)構(gòu)看雙膦酸藥物的發(fā)展3R1 = OH, R2 = CH2 利塞膦酸膦酸基團(tuán)是藥物與骨組織羥基膦灰石結(jié)合的關(guān)鍵部位，決定藥物的生化特性R1 = OH, R2 = (CH2)2NH2 帕米膦酸R1 = OH, R2 = (CH2)3NH2 阿倫膦酸NR1 = OH, R2 = CH2 唑來(lái)膦酸NNR2R1COOHOHOHOHOPPR2 基團(tuán)決定的是藥物抗骨吸收能力，以及與羥基磷灰石的結(jié)合力當(dāng)R1 基團(tuán)是羥基時(shí)，可以增加藥物與骨的結(jié)合力雙膦酸類藥物的功能基團(tuán)R. GRAHAM G. RUSSELL, Bisphosphonates, From Bench to Bes

2、ide Ann. N.Y. Acad. Sci. 1068: 367401 (2019). 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 efficac

3、y. Osteoporos Int (2019) 19:7337594雙膦酸藥物分類不含氮雙膦酸含氨基側(cè)鏈雙膦酸含氮環(huán)鏈雙膦酸R. GRAHAM G. RUSSELL, Bisphosphonates, From Bench to Beside Ann. N.Y. Acad. Sci. 1068: 367401 (2019). R. GRAHAM G. RUSSELL, Bisphosphonates，An Update on Mechanisms of Action and How These Relate to Clinical EfficacyR. GRAHAM G. RUSSELL,

4、Mechanisms of action of bisphosphonates: similarities and differences and their potential influence on clinical efficacy. Osteoporos Int (2019) 19:7337595雙膦酸藥物的研發(fā)進(jìn)展1970 1980 1990 2000含氮環(huán)形側(cè)鏈具有更強(qiáng)的抗骨吸收效果，效果強(qiáng)于依替膦酸約10,000倍R. GRAHAM G. RUSSELL, Bisphosphonates, From Bench to Beside Ann. N.Y. Acad. Sci. 10

5、68: 367401 (2019). 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. Osteoporos Int (2019) 19

6、:73375961. Green JR, et al. J Bone Miner Res. 1994;9:745-751. 2. Data on file, Novartis.體外顱骨測(cè)量：抑制重吸收 vs 礦化作用抑制礦化/抑制骨吸收比值抑制礦化抑制骨吸收化合物400200.05阿倫膦酸IC50 (M) 2IC50 (M)1500帕米膦酸1000.215,0000.00230唑來(lái)膦酸 0.4氯屈膦酸 50125利塞膦酸0.0160060.02伊班膦酸40084.0依替膦酸102.5雙膦酸藥物抑制骨吸收與礦化作用治療比雙膦酸藥物的作用機(jī)制8雙膦酸藥物進(jìn)入體內(nèi)的藥代分布Data from Che

7、n T, et al. J Clin Pharmacol. 2019;42:12281236.24 小時(shí)藥物在骨組織的結(jié)合率受到骨丟失活躍狀態(tài)以及腎功能等因素的影響。骨丟失活躍的患者結(jié)合率更高。雙膦酸藥物進(jìn)入體內(nèi)后24小時(shí)內(nèi)有1/32/3的藥物以原型形式排出，絕大部分在給藥最初幾小時(shí)內(nèi)即排出。24小時(shí)腎臟排出率唑來(lái)膦酸39%阿侖膦酸44%利塞膦酸65%氯曲膦酸73%9ALN, alendronate; CLO, clodronate; ETD, etidronate; IBA, ibandronate; RIS, risedronate; ZOL, zoledronic acid.Nancol

8、las GH, et al. Bone. 2019;38:617-627.雙膦酸藥物與骨表面羥基膦灰石結(jié)合力0124羥磷灰石CLOETDRISIBAALNZOL3KL (L/mol x 106)吸附力指數(shù), KL10與骨表面結(jié)合釋放以及細(xì)胞的吸收BPBPBPBPBoneBPBPBPBPBPBPBP在骨吸收活躍的部位濃集BoneBone喪失骨吸收能力BPBPBPBPBP = bisphosphonatesCourtesy of Professor M. Rogers.從細(xì)胞學(xué)角度看雙膦酸藥物的作用機(jī)制11FPP 合成酶甲羥戊酸香葉基焦磷酸（IPP）法尼基焦磷酸（FPP）雙香葉基基焦磷酸（GGPP

9、）HMG-CoA3羥3甲戊二酰輔酶A 含氮雙膦酸類藥物對(duì)于FPP合成酶的作用Masarachia et al Bone 2019; 19:281Coxon et al Bone 2019; 42:848x單核細(xì)胞攝入含氮雙膦酸藥物后IPP累積IPPIPPIPPIPP與-T細(xì)胞表面受體結(jié)合 含氮雙膦酸藥物：阿侖膦酸伊班膦酸帕米膦酸利塞膦酸唑來(lái)膦酸合成破骨細(xì)胞功能與存活必需的結(jié)構(gòu)蛋白-T細(xì)胞釋放TNF患者出現(xiàn)急性反應(yīng)12*ALN, alendronate; CLO, clodronate; ETD, etidronate; FPP, farnesyl pyrophosphate; IBA, iba

10、ndronate; PAM, pamidronate; RIS, risedronate; ZOL, zoledronic acid.1. Dunford JE, et al. J Pharmacol Exp Ther. 2019;296:235-242. FPP 合成酶活性 (% control)*0255075100ETDPAM*IBARIS*ZOL*P .001雙膦酸類藥物 (0.1 M)ALN*FPP 合成酶1FPP合成酶抑制與骨吸收抑制的相關(guān)性（體外研究）13雙膦酸藥物在骨組織的循環(huán)R. GRAHAM G. RUSSELL, Bisphosphonates, From Bench t

11、o Beside Ann. N.Y. Acad. Sci. 1068: 367401 (2019). 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 ef

12、ficacy. Osteoporos Int (2019) 19:733759高吸附力雙膦酸藥物(如阿侖膦酸、唑來(lái)膦酸) 快速骨吸收低脫落率強(qiáng)大再吸收骨內(nèi)擴(kuò)散少低吸附力雙膦酸藥物(如利塞膦酸) 少量骨吸收高脫落率少量再吸收骨內(nèi)擴(kuò)散多從循證醫(yī)學(xué)證據(jù)看唑來(lái)膦酸的療效15唑來(lái)膦酸治療骨質(zhì)疏松癥的臨床療效改善骨轉(zhuǎn)換指標(biāo)提升骨密度全面提升骨密度髖部骨折后患者骨密度提升改善骨結(jié)構(gòu)降低骨折風(fēng)險(xiǎn)起效時(shí)間降低多發(fā)椎體骨折風(fēng)險(xiǎn)全面降低各部位骨折風(fēng)險(xiǎn)降低老年患者骨折風(fēng)險(xiǎn)降低死亡率中國(guó)人群療效數(shù)據(jù)16唑來(lái)膦酸5mg迅速降低平均血漿-CTX*水平并持續(xù)唑來(lái)膦酸 5 mg安慰劑絕經(jīng)前水平范圍月0.20.00.60.70.

13、81.0平均血漿-CTX (ng/mL)061218243030.30.4唑來(lái)膦酸5mg摘自Black DM, et al. N Engl J Med. 2019;356:1809-1822.*-CTX: I型膠原C端肽+所有時(shí)間點(diǎn)降低程度與安慰劑組比較均有顯著差異HORIZON-PFT唑來(lái)膦酸5mg唑來(lái)膦酸5mg+P .000117唑來(lái)膦酸5mg迅速降低平均血漿BALP*水平并持續(xù)平均血漿骨特異性ALP (ng/mL)061218243036月40161820122810614唑來(lái)膦酸 5 mg安慰劑絕經(jīng)前水平范圍摘自Black DM, et al. N Engl J M

14、ed. 2019;356:1809-1822.*BALP：骨特異性堿性磷酸酶+所有時(shí)間點(diǎn)降低程度與安慰劑組比較均有顯著差異HORIZON-PFT唑來(lái)膦酸5mg唑來(lái)膦酸5mg唑來(lái)膦酸5mgP .000118唑來(lái)膦酸5mg顯著降低平均血漿 P1NP*并持續(xù)平均血漿 P1NP (ng/mL)0122436月20060708050103040唑來(lái)膦酸 5 mg安慰劑絕經(jīng)前水平范圍摘自Black DM, et al. N Engl J Med. 2019;356:1809-1822.*P1NP： I型前膠原氨基端前肽+與安慰劑組比較均有顯著差異HORIZON-PFT唑來(lái)膦酸5mg唑來(lái)膦酸5mg唑來(lái)膦酸5

15、mgP .000119唑來(lái)膦酸治療骨質(zhì)疏松癥的臨床療效改善骨轉(zhuǎn)換指標(biāo)提升骨密度全面提升骨密度髖部骨折后患者骨密度提升改善骨結(jié)構(gòu)降低骨折風(fēng)險(xiǎn)起效時(shí)間降低多發(fā)椎體骨折風(fēng)險(xiǎn)全面降低各部位骨折風(fēng)險(xiǎn)降低老年患者骨折風(fēng)險(xiǎn)降低死亡率中國(guó)人群療效數(shù)據(jù)20唑來(lái)膦酸5mg顯著增加各部位骨密度6個(gè)月時(shí)，各部位BMD顯著提升3年結(jié)束時(shí)唑來(lái)膦酸提升椎體BMD 6.71%唑來(lái)膦酸提升全髖BMD 6.02%唑來(lái)膦酸提升股骨頸BMD 5.06%0612182430362.00.02.04.06.08.05.90*3.66*2.39*6.71%*0612182430362.01.00.01.02.03.04.03.05.02.

16、17*1.58*3.89*5.06%*月月椎體BMD股骨頸BMDBlack DM, et al. N Engl J Med. 2019;356:1809-1822.HORIZON-PFT與基線比較變化率 % 061218243036月2.83*1.93*4.70*6.02%*2.01.00.01.02.03.04.03.05.0全髖BMD*與安慰劑組比較P .0001, 唑來(lái)膦酸 5 mg安慰劑21唑來(lái)膦酸顯著提升髖部骨折后患者骨密度HORIZON-RFT研究中納入2127名髖部新發(fā)骨折患者隨機(jī)分配接受唑來(lái)膦酸5毫克靜脈輸注或安慰劑治療 不同亞組患者全髖或股骨頸骨密度相對(duì)提升變量與安慰機(jī)組比較

17、變化率% (p-value)12個(gè)月 (n=1364)24個(gè)月 (n=805)85 歲全髖6.5 (p=0.0045)骨密度T值 -2.5全髖4.5 (p0.0001)骨折史(椎體或非椎體)全髖8.7 (p=0.0031) 13.4 (p=0.0692)股骨頸7.9 (p=0.0190)12.8 (p=0.0682)Colon-Emeric C, et al. Abstract SA0281: Bone Mineral Density after Hip Fracture: Variations in Response to Once-Yearly i.v. Zoledronic acid 5

18、 mg. 2009 ASBMR, Denver, CO.Treatmentt-by-subgroup interaction was considered significant if p0.10HORIZON-RFT22Statistical significance is 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:

19、 Bone Mineral Density after Hip Fracture: Variations in Response to Once-Yearly i.v. Zoledronic acid 5 mg. 2009 ASBMR, Denver, CO.85歲以上亞組患者在12個(gè)月時(shí)骨密度提升水平最為顯著p0.0001p0.0001p0.0001p=0.0001n=131n=139n=218n=194n=277n=281n=55n=69唑來(lái)膦酸顯著提升髖部骨折后患者骨密度HORIZON-RFT23部骨密度T值-2.5 亞組患者12個(gè)月時(shí)骨密度提升最為顯著Statistical signi

20、ficance is noted within each T-score subgroup. Treatment-by-subgroup interaction was statically significant for only those with a 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

21、. 2009 ASBMR, Denver, CO.p0.0001p0.0001p0.0001n=303n=295n=284n=287n=92n=95n=2唑來(lái)膦酸顯著提升髖部骨折后患者骨密度HORIZON-RFT24既往存在骨折史患者亞組，12個(gè)月 、24個(gè)月全髖骨密度顯著提升Statistical significance is noted within each previous baseline fracture group. Treatment-by-subgroup interaction was statically significant for only those with

22、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-Yearly i.v. Zoledronic acid 5 mg. 2009 ASBMR, Denver, CO.全髖骨密度變化率（%）24個(gè)月12個(gè)月p0.0001p0.0001p=0.17p=0.005n=248n=268n=124n=112n=14n=14n

23、=19n=6p0.0001p0.0001p=0.0006p=0.0005n=401n=451n=226n=192n=22n=21n=32n=19唑來(lái)膦酸顯著提升髖部骨折后患者骨密度HORIZON-RFT25唑來(lái)膦酸治療骨質(zhì)疏松癥的臨床療效改善骨轉(zhuǎn)換指標(biāo)提升骨密度全面提升骨密度髖部骨折后患者骨密度提升改善骨結(jié)構(gòu)降低骨折風(fēng)險(xiǎn)起效時(shí)間降低多發(fā)椎體骨折風(fēng)險(xiǎn)全面降低各部位骨折風(fēng)險(xiǎn)降低老年患者骨折風(fēng)險(xiǎn)降低死亡率中國(guó)人群療效數(shù)據(jù)26一年一次唑來(lái)膦酸顯著增加絕經(jīng)后骨質(zhì)疏松患者股骨強(qiáng)度QCT檢查可以避免骨組織周圍結(jié)構(gòu)對(duì)于骨密度的影響，直接了解到小梁骨骨密度情況，從而對(duì)骨強(qiáng)度以及骨折風(fēng)險(xiǎn)有更好的評(píng)估。HORIZO

24、N-PFT研究3年內(nèi)177名女性患者接受髖部以及椎體QCT檢查結(jié)果顯示：唑來(lái)膦酸治療后通過(guò)DXA和QCT均看到椎體以及髖部BMD顯著提升的結(jié)果QCT結(jié)果看到唑來(lái)膦酸提升骨密度作用主要在骨小梁QCT結(jié)果看到唑來(lái)膦酸治療后骨強(qiáng)度得到全面提升，從而進(jìn)一步降低患者再骨折風(fēng)險(xiǎn)R. Eastell, et al. Osteoporos Int. 2009;10.HORIZON-PFT27唑來(lái)膦酸顯著改善骨結(jié)構(gòu)DXA和QCT測(cè)量的椎體與髖部骨密度變化與基線比變化率（%）R. Eastell, et al. Osteoporos Int. 2009;10.QCT與DXA檢查結(jié)果一致顯示，骨密度顯著提升HORI

25、ZON-PFT28與基線比變化率（%）唑來(lái)膦酸顯著改善骨結(jié)構(gòu)QCT測(cè)量全髖骨小梁和皮質(zhì)骨密度變化R. Eastell, et al. Osteoporos Int. 2009;10.QCT結(jié)果一致顯示，髖部骨小梁骨密度顯著提升，皮質(zhì)骨骨密度變化不顯著HORIZON-PFT29與基線比變化率（%）唑來(lái)膦酸顯著改善骨結(jié)構(gòu)QCT測(cè)量骨強(qiáng)度參數(shù)變化R. Eastell, et al. Osteoporos Int. 2009;10.BSI:彎曲強(qiáng)度指數(shù)，CSI:壓力強(qiáng)度指數(shù)全髖皮質(zhì)骨體積以及CSI指數(shù)的提升，均提示唑來(lái)膦酸可以進(jìn)一步降低骨折風(fēng)險(xiǎn)HORIZON-PFT30唑來(lái)膦酸治療骨質(zhì)疏松癥的臨床療效

26、改善骨轉(zhuǎn)換指標(biāo)提升骨密度全面提升骨密度中國(guó)人群骨密度改善結(jié)果髖部骨折后患者骨密度提升改善骨結(jié)構(gòu)降低骨折風(fēng)險(xiǎn)起效時(shí)間降低多發(fā)椎體骨折風(fēng)險(xiǎn)全面降低各部位骨折風(fēng)險(xiǎn)降低老年患者骨折風(fēng)險(xiǎn)降低死亡率中國(guó)人群療效數(shù)據(jù)31Values above bars are 3-year cumulative event rates based on Kaplan-Meier estimates. *P = .0024; P .0001; P = .0002;相對(duì)風(fēng)險(xiǎn)：與安慰劑組比較包括髖部骨折.Black DM, et al. N Engl J Med. 2019;356:1809-1822.41%*70%25%椎體

27、骨折髖部骨折非椎體骨折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年新發(fā)骨折累積危險(xiǎn)性（%）010515唑來(lái)膦酸5mg降低各部位骨折風(fēng)險(xiǎn)唑來(lái)膦酸 5 mg 安慰劑HORIZON-PFT32 0 2 4 6 8 10 12 14 16 18 20臨床骨折非椎體骨折臨床椎體骨折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%,

28、 45%)46%(8%, 28%)*P = .0012; P = .0338; P = .0210, relative risk reduction vs placebo; NS = not significant. Values above bars are cumulative event rates based on Kaplan-Meier estimates at Month 24. 發(fā)生率 (%)ZOL 5 mg 安慰劑唑來(lái)膦酸5毫克降低再發(fā)骨折風(fēng)險(xiǎn)Lyles KW, et al. N Engl J Med. 2019. e-publication 10.1056/NEJMoa07

29、4941 at HORIZON-RFT33對(duì)兩項(xiàng)臨床研究中共9375名女性患者進(jìn)行回顧性分析，觀察唑來(lái)膦酸降低骨折風(fēng)險(xiǎn)的起效時(shí)間唑來(lái)膦酸治療組，臨床椎體骨折風(fēng)險(xiǎn)在6個(gè)月看到降低6個(gè)月時(shí)，骨折風(fēng)險(xiǎn)降低53% (p=0.0553)12個(gè)月時(shí)，骨折風(fēng)險(xiǎn)顯著降低57% (p=0.0035), 并在36個(gè)月的觀察期內(nèi)持續(xù)維持36個(gè)月時(shí)，臨床椎體骨折風(fēng)險(xiǎn)顯著降低70% (p0.0001) 唑來(lái)膦酸 (n=4,692)安慰劑 (n=4,663)臨床椎體骨折風(fēng)險(xiǎn) (%)9n=1953% ns(-4%, 87%)57%*(25%, 76%)69%*(47%, 81%)76%*(61%, 85%

30、)70%*(56%, 79%)16371960218536117 絕經(jīng)后骨質(zhì)疏松癥以及近期髖部脆性骨折患者再發(fā)臨床椎體骨折風(fēng)險(xiǎn)*p=0.0035; *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

31、.唑來(lái)膦酸降低臨床椎體骨折風(fēng)險(xiǎn)起效時(shí)間34對(duì)兩項(xiàng)臨床研究中共9375名女性患者進(jìn)行回顧性分析，觀察唑來(lái)膦酸降低骨折風(fēng)險(xiǎn)的起效時(shí)間唑來(lái)膦酸治療組，非椎體骨折風(fēng)險(xiǎn)在6個(gè)月看到降低6個(gè)月時(shí)，骨折風(fēng)險(xiǎn)降低15% (p=0.3227)18個(gè)月時(shí)，骨折風(fēng)險(xiǎn)顯著降低23% (p=0.0049), 并在36個(gè)月的觀察期內(nèi)持續(xù)維持36個(gè)月時(shí)，非椎體骨折風(fēng)險(xiǎn)顯著降低26% (p0.0001) 非椎體骨折風(fēng)險(xiǎn) (%)*p=0.0049; p=0.0002; *p=0.0001; ns=0.0553.Bucci-Rechtweg C, et al. Abstract FR0365: Time to Onset of

32、Anti-Fracture Efficacy and Persistence of Effect of Zoledronic Acid 5 mg in Women with Osteoporosis or Recent Hip Fracture. 2009 ASBMR, Denver, CO.72n=8415% ns(-34%, 35%)16% ns(-5%, 36%)23%*(8%, 36%)26%*(14%, 37%)26%*(16%, 36%)151180208268261349357480絕經(jīng)后骨質(zhì)疏松癥以及近期髖部脆性骨折患者再發(fā)非椎體骨折風(fēng)險(xiǎn)唑來(lái)膦酸 (n=4,692)安慰劑 (n

33、=4,663)唑來(lái)膦酸降低非椎體骨折風(fēng)險(xiǎn)起效時(shí)間35唑來(lái)膦酸治療3年顯著降低絕經(jīng)后女性患者多發(fā)椎體形態(tài)骨折風(fēng)險(xiǎn)（2處以上骨折）唑來(lái)膦酸治療3年顯著降低絕經(jīng)后女性患者臨床多發(fā)骨折（2處以上骨折）風(fēng)險(xiǎn)RR = risk reduction (95% CI); =Seeman E, et al. Abstract SA0366: Zoledronic Acid Substantially Reduces the Risk of Morphometric Vertebral and Clinical Fractures. 2009 ASBMR, Denver, CO.結(jié)論唑來(lái)膦酸一年一次可以緩解絕經(jīng)后

34、女性患者脆性骨折后骨脆性的進(jìn)一步增加。RR 89%(77%, 95%)RR 38%(28%, 46%)唑來(lái)膦酸顯著降低多發(fā)椎體形態(tài)骨折與臨床骨折風(fēng)險(xiǎn)HORIZON-PFT研究中對(duì)于3年中患者再發(fā)椎體骨折以及再發(fā)臨床骨折風(fēng)險(xiǎn)進(jìn)行了評(píng)估HORIZON-PFT36唑來(lái)膦酸 5 mg治療3年可以降低6個(gè)部位骨折風(fēng)險(xiǎn)，顯著降低髖部、肱骨和骨盆的骨折風(fēng)險(xiǎn)。骨盆骨折風(fēng)險(xiǎn)降低高達(dá)50%，而髖部骨折風(fēng)險(xiǎn)降低最為顯著。 (p0.0024)唑來(lái)膦酸降低6處非椎體骨折風(fēng)險(xiǎn)的臨床療效HORIZON-PFT 回顧性亞組分析結(jié)果顯示，唑來(lái)膦酸可以顯著降低患者6處常見非椎體骨折風(fēng)險(xiǎn)。 (腕部, 髖部, 骨盆, 肱骨, 鎖骨和

35、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: Effect of Once-Yearly Zoledronic Acid 5 mg on a Sub-set of Six Nonvertebral Fractures.

36、 2009 ASBMR, Denver, CO.HR=0.81 (0.62-1.06)NSHR=0.59 (0.42-0.83)HR=0.53 (0.35-0.82)*HR=0.62 (0.35-1.09)NSHR=0.50 (0.28-0.90)HR=0.63 (0.21-1.92)NSHORIZON-PFT37雙膦酸藥物降低椎體骨折風(fēng)險(xiǎn)的比較：唑來(lái)膦酸具有最強(qiáng)效果1. Black DM, et al. N Engl J Med. 2019;356:1809-1822. 2. Harris ST, et al. JAMA. 2019;282:1344. 3. Actonel Prescrib

37、ing Information. 4. Black D, et al. J Clin Endocrinol Metab. 2000;85:4118-4124. Years0-10-30-2Years0-10-30-2Years0-10-30-2唑來(lái)膦酸 5 mg1阿倫膦酸(FIT)4利塞膦酸(VERT-NA)2,3椎體骨折風(fēng)險(xiǎn) (%)非頭對(duì)頭研究結(jié)果71%01020304050607060%70%65%55%41%62%48%65%老年患者數(shù)據(jù)39唑來(lái)膦酸用于老年患者的數(shù)據(jù)唑來(lái)膦酸5 mg 降低3年中的椎體骨折風(fēng)險(xiǎn)(按年齡) 6569 歲80%*(66%, 88%) 75歲60%*(45%,

38、71%) 2.0%(17/832)10.0%(85/852)4.8%(52/1083)12.0%(129/1078)7074 歲76%*(62%, 84%) 2.5%(23/907)10.4%(96/923)010515ZOL 5 mg 安慰劑% 新發(fā)椎體骨折患者百分率*P .0001, 與安慰劑比較相對(duì)風(fēng)險(xiǎn)降低Cauley J, et al. Osteoporos Int. 2019;18(suppl 1):S26. Abstract OC53.HORIZON-PFT40唑來(lái)膦酸用于老年患者的數(shù)據(jù)唑來(lái)膦酸降低3年中的髖部骨折風(fēng)險(xiǎn)(按年齡) 70 歲70%*(30%, 87%) 75歲20%(

39、-28%, 50%) 0.7%(7/1140)2.1%(24/1174)2.4%(32/1497)3.0%(39/1452)7074 歲47%(-3%, 73%) 1.1%(13/1238)2.3%(25/1235)0213ZOL 5 mg 安慰劑*P .0029,與安慰劑比較相對(duì)風(fēng)險(xiǎn)降低(95%置信區(qū)間) 柱子上方的數(shù)值為基于Kaplan-Meier估計(jì)的3年累計(jì)事件率。Cauley J, et al. Osteoporos Int. 2019;18(suppl 1):S26. Abstract OC53.% 新發(fā)髖部骨折患者百分率HORIZON-PFT41唑來(lái)膦酸用于老年患者的數(shù)據(jù)唑來(lái)膦酸

40、降低3年中的臨床骨折風(fēng)險(xiǎn)(按年齡) *P = .0012; P = .0077; P .001,與安慰劑比較相對(duì)風(fēng)險(xiǎn)降低(95%置信區(qū)間) 柱子上方的數(shù)值為基于Kaplan-Meier估計(jì)的3年累計(jì)事件率。 Cauley J, et al. Osteoporos Int. 2019;18(suppl 1):S26. Abstract OC53.70 歲27%*(17%, 53%) 75歲44%(18%, 47%) 7.1%(78/1140)11.2%(126/1174)14.5%(189/1452)7074 歲29%(9%, 45%) 8.3%(100/1238)12.6%(141/1235)

41、% 新發(fā)臨床骨折患者百分率0105159.6%(130/1497)ZOL 5 mg 安慰劑HORIZON-PFT42唑來(lái)膦酸顯著降低75歲以上老年患者骨折風(fēng)險(xiǎn)對(duì)兩項(xiàng)臨床研究中共9375名女性患者進(jìn)行回顧性分析，分析75歲以及75歲患者臨床療效以及安全性數(shù)據(jù)75歲以上人群新發(fā)骨折風(fēng)險(xiǎn)（%）臨床骨折椎體骨折非椎體骨折髖部骨折28%*35%*61%*66%*15%27%*26%18%*P0.05Steven Boonen，Journal of the American Geriatrics Society 2019, Volume 58, Issue 2, Pages: 292-29943唑來(lái)膦酸顯

42、著提升75歲以上老年患者髖部骨密度骨密度測(cè)定部位與安慰劑組比較差異*P值股骨頸1年2.30.0013年5.00.001全髖1年3.00.0013年6.30.001*為唑來(lái)膦酸和安慰劑相對(duì)于基線變化率的差值Steven Boonen，Journal of the American Geriatrics Society 2019, Volume 58, Issue 2, Pages: 292-299唑來(lái)膦酸可以顯著改善患者髖部骨密度，但髖部骨折風(fēng)險(xiǎn)降低不顯著，可能老年患者髖部骨折主要由于非骨骼原因存在，如跌倒風(fēng)險(xiǎn)等44唑來(lái)膦酸顯著降低75歲以上老年患者骨吸收指標(biāo) CTXSteven Boonen，

43、Journal of the American Geriatrics Society 2019, Volume 58, Issue 2, Pages: 292-299與各年齡亞組比較，唑來(lái)膦酸均顯著降低骨轉(zhuǎn)換指標(biāo)（P0.001）75歲以及75歲患者CTX基線水平無(wú)顯著差異45唑來(lái)膦酸顯著降低75歲以上老年患者骨形成指標(biāo) 骨特異性堿性磷酸酶Steven Boonen，Journal of the American Geriatrics Society 2019, Volume 58, Issue 2, Pages: 292-299與各年齡亞組比較，唑來(lái)膦酸均顯著降低骨轉(zhuǎn)換指標(biāo)（P0.001）75

44、歲以及75歲患者BALP基線水平無(wú)顯著差異46唑來(lái)膦酸顯著降低75歲以上老年患者骨形成指標(biāo) P1NPSteven Boonen，Journal of the American Geriatrics Society 2019, Volume 58, Issue 2, Pages: 292-299與各年齡亞組比較，唑來(lái)膦酸均顯著降低骨轉(zhuǎn)換指標(biāo)（P0.001）75歲以及75歲患者P1NP基線水平無(wú)顯著差異47唑來(lái)膦酸兩項(xiàng)核心研究結(jié)果表明唑來(lái)膦酸用于75歲以上的老年患者與其他口服雙膦酸藥物一樣，可以降低椎體以及非椎體骨折風(fēng)險(xiǎn)顯著改善患者髖部骨密度顯著降低主要骨轉(zhuǎn)換指標(biāo)（ 2-4196 (18.4)17

45、7 (16.7) 4-6233 (21.9)272 (25.6) 6-8161 (15.1)170 (16.0) 8-10144 (13.5)124 (11.7) 10-12148 (13.9)130 (12.2) 12126 (11.8)142 (13.4)HORIZON-RFT56骨折不愈合發(fā)生率與給藥時(shí)間的關(guān)系Zoledronic acid (N=1054)Placebo (N=1057)術(shù)后給藥時(shí)間不愈合患者數(shù)/總患者數(shù)n/N (%)不愈合患者數(shù)/總患者數(shù)n/N (%) 2 weeks1/56 (1.8)4/46 (8.7)2-4 weeks6/191 (3.1)7/176 (4.0)

46、4-6 weeks12/231 (5.2)8/271 (3.0) 6 weeks18/575 (3.1)12/564 (2.1)HORIZON-RFT57HORIZON-PFTHORIZON-PFT股骨干骨折發(fā)生率HORIZON-PFT研究中發(fā)生的所有股骨干骨折被獨(dú)立專家組通過(guò)x線以及外科檢查報(bào)告進(jìn)行評(píng)估以明確其發(fā)生率結(jié)果研究中5名患者（6處骨折）符合股骨干骨折的定義，3名為唑來(lái)膦酸組患者，2名為安慰劑組 (HR=1.5, 95%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 2019;356:18091822.Black D, et al. Abstract MO0344: Does Zoledronic Acid Increase Risk of Atypical Subtrochanteric Femoral Shaft Fractures? Results from the HORIZON-PFT. 2009 ASBMR, Denver, CO.唑來(lái)膦酸安慰劑股骨干骨折發(fā)