骨質(zhì)疏松癥與藥物

1、會計(jì)學(xué)1骨質(zhì)疏松癥與藥物骨質(zhì)疏松癥與藥物第1頁/共85頁正常骨組織正常骨組織 骨質(zhì)疏松性骨組織骨質(zhì)疏松性骨組織骨質(zhì)疏松癥定義骨質(zhì)疏松癥定義(WHO)第2頁/共85頁u轉(zhuǎn)換率轉(zhuǎn)換率u微構(gòu)筑微構(gòu)筑u礦化礦化u膠原膠原u微損傷及修復(fù)微損傷及修復(fù)骨質(zhì)疏松癥定義骨質(zhì)疏松癥定義(NIH)第3頁/共85頁骨質(zhì)疏松的分類骨質(zhì)疏松的分類第4頁/共85頁第5頁/共85頁骨質(zhì)疏松診斷方法骨質(zhì)疏松診斷方法1）骨的合成代謝指標(biāo)）骨的合成代謝指標(biāo)：PICP（I型原膠原羥基端延型原膠原羥基端延長肽），長肽），PINP（I型原膠原氨基端延長肽），型原膠原氨基端延長肽），bALP（骨堿性磷酸酶），（骨堿性磷酸酶），BGP（血清

2、骨鈣素）等（血清骨鈣素）等2）骨的分解代謝指標(biāo)）骨的分解代謝指標(biāo)：CTX(骨膠原羧基端肽骨膠原羧基端肽), NTX(骨膠原氨基端肽骨膠原氨基端肽), HOP（尿羥脯氨酸），（尿羥脯氨酸），PYD，DPYD（I型膠原吡啶交聯(lián)物），型膠原吡啶交聯(lián)物），TRAP（抗（抗酒石酸酸性磷酸梅），以及空腹尿鈣酒石酸酸性磷酸梅），以及空腹尿鈣/肌肝比值等肌肝比值等生化診斷方法生化診斷方法第6頁/共85頁7第7頁/共85頁/health_professionals/consensus_guidelines/cd_orf.html4.0 -3.5 -3.0 -2.5

3、 -2.0 -1.5 -1.0 -0.5 0 +0.5 +1.0T值值骨質(zhì)疏松癥：1.無骨折者2. 伴有一處或多處骨折者 嚴(yán)重的骨質(zhì)疏松癥低骨量正常骨量WHOWHO的的BMDBMD診斷分類：診斷分類：n 正常正常：BMDBMD骨峰值骨峰值 （青年成人平均值）（青年成人平均值）-1SD-1SDn 骨量減少骨量減少：BMD=BMD=骨峰值（青年成人平均值）骨峰值（青年成人平均值）- -（1SD-2.5SD)1SD-2.5SD)n 骨質(zhì)疏松骨質(zhì)疏松：BMDBMD骨峰值骨峰值-2.5SD-2.5SDn 嚴(yán)重骨質(zhì)疏松嚴(yán)重骨質(zhì)疏松：BMDBMD骨峰值骨峰值-2.5SD-2.5SD同時(shí)同時(shí), ,伴有一處或多

4、處脆性骨折伴有一處或多處脆性骨折第8頁/共85頁危險(xiǎn)因素彼此相關(guān)，相互影響，如二種危險(xiǎn)因素同時(shí)存在則危害更大。第9頁/共85頁第10頁/共85頁評估藥物療效的最終指標(biāo)評估藥物療效的最終指標(biāo)中華醫(yī)學(xué)會骨質(zhì)疏松與骨礦鹽疾病分會，原發(fā)性骨質(zhì)疏松癥診治指南第11頁/共85頁第12頁/共85頁NIH Consensus. Development panel on osteoporosis: prevention, diagnosis and therapy. JAMA. 2001, 285: 785-795第13頁/共85頁抑制骨吸收抑制骨吸收促進(jìn)骨形成促進(jìn)骨形成第14頁/共85頁藥物藥物核心試驗(yàn)核心試

5、驗(yàn)發(fā)表雜志與時(shí)間發(fā)表雜志與時(shí)間阿倫膦酸阿倫膦酸 FIT study: Fracture Risk Reduction with Alendronate in Womenwith Osteoporosis: The Fracture Intervention TrialFLEXstudy: Effects of Continuing or Stopping Alendronate After 5 Years of Treatment: The Fracture Intervention Trial Long-term Extension : A Randomized TrialLancet 19

6、96JAMA 2006伊班膦酸伊班膦酸BONE study:Daily an intermittent oral ibandronate normalize bone turnover and provide significant reduction in vertebral fracture risk: results from the BONE study.Ostero Int 2004利塞膦酸利塞膦酸VERT study: Effects of risedronate treatment on vertebral and non-vertebral fractures in women

7、 with postmenopausal osteoporosis: A randomized controlled trialJAMA 1999唑來膦酸唑來膦酸HORIZON-PFT: Once-Yearly Zoledronic Acid for Treatment of Postmenopausal OsteoporosisHORIZON-RFT:Zoledronic Acid and Clinical Fracturesand Mortality after Hip FractureNEJM 2007NEJM2007 鮭魚降鈣素鮭魚降鈣素PROOF:A Randomized Trial

8、 of Nasal Spray Salmon Calcitonin in Postmenopausal Women with Established Osteoporosis: the Prevent Recurrence of Osteoporotic Fractures StudyQUEST: Effects of Salmon Calcitonin on Trabecular Microarchitecture as Determined by Magnetic Resonance Imaging: Results from the QUEST StudyAm J Med 2000JBM

9、R 2005雷洛昔芬雷洛昔芬Effect of raloxifene on vertebral fracture risk reduction in postmenopausal women with osteoporosis: four year results from a randomized clinical trial.J Clin Endo Metab 2002特立帕肽特立帕肽Effect of parathyroid hormone(1-34) on fractures and bone mineral density in postmenopausal women with o

10、steoporosis.NEJM 2001雷奈酸鍶雷奈酸鍶SOTI: The Effects of Strontium Ranelate on theRisk of Vertebral Fracture in Women with Postmenopausal OsteoporosisTROPOS: Strontium Ranelate Reduces the Risk of NonvertebralFractures in Postmenopausal Women with Osteoporosis:Treatment of Peripheral Osteoporosis StudyNEJM

11、 2004J Clin Endo Metab 2005第15頁/共85頁Data are from EU and US labels, or EU or US labels (as indicated in brackets), or from pivotal trials; *Trochanter BMD instead of total hip; Small study; data are limited1. Fosamax (alendronate) SmPC. London, UK: EMA; 2010; 2. Fosamax (alendronate) PI. Whitehouse

12、Station, NJ: Merck & Co Inc. 2011; 3. Black DM, et al. J Clin Endo Metab. 2000;85:41184124; 4. Bonviva (ibandronate) SmPC. London, UK: EMA; 2011; 5. Boniva (ibandronate) PI. South San Francisco, US: Genentech Inc.; 2011; 6. Actonel (risedronate) PI. Manati, Puerto Rico; Warner Chilcott Puerto Ri

13、co LLC; 2011; 7. Harris ST, et al. JAMA. 1999;282:13441352; 8. Reginster JY, et al. Osteoporos Int. 2000;11:8391; 9. Aclasta (zoledronic acid) SmPC. London, UK: EMA; 2011; 10. Reclast (zoledronic acid) PI. East Hanover, NJ: Novartis Pharmaceuticals; 2011; 11. Prolia (denosumab) SmPC. London, UK: EMA

14、; 2011; 12. Prolia (denosumab) PI. Thousand Oaks, CA: Amgen; 2011; 13. Protelos (strontium ranelate) SmPC. London, UK: EMA; 2011; 14. Reginster JY, et al. J Clin Endo Metab. 2005;90:28162822; 15. Meunier PJ, et al. N Engl J Med. 2004; 350:459468; 16. Miacalcic (SCT nasal spray) SmPC. London, UK: EMA

15、; 2011; 17. Miacalcin (SCT nasal spray) PI. East Hanover, NJ: Novartis Pharmaceuticals Corp.; 2011; 18. Forteo (teriparatide) SmPC. London, UK: EMA; 2011; 19. Forsteo (teriparatide) PI. Indianapolis, IN; Eli Lilly & Co.; 2011; 20. Evista (raloxifene) SmPC. London, UK: EMA; 2011; 21. Evista (ralo

16、xifene) PI. Indianapolis, IN: Eli Lilly & Co.; 2011相對骨折風(fēng)險(xiǎn)降低相對骨折風(fēng)險(xiǎn)降低, %椎體形態(tài)骨折椎體形態(tài)骨折非椎體骨折非椎體骨折髖部骨折髖部骨折阿倫膦酸阿倫膦酸 13482754 (EU)53伊班膦酸伊班膦酸 4,562 (EU)52 (US)沒有降低沒有降低(US)利塞膦酸利塞膦酸6841493339 NR唑來膦酸唑來膦酸9,10702541鮭魚降鈣素鮭魚降鈣素16,1733 (EU)NR沒有降低(EU)雷洛昔芬雷洛昔芬10,1147 (EU) 55 (US)沒有降低(EU)NRNR特立帕肽特立帕肽18,196553雷奈酸鍶雷奈

17、酸鍶13153941 (EU)1936 (EU)第16頁/共85頁Data are from EU and US labels, or EU or US labels (as indicated in brackets), or from pivotal trials; *Trochanter BMD instead of total hip; Small study; data are limited; Adjusted for strontium; Unadjusted for strontium1. Fosamax (alendronate) SmPC. London, UK: EMA;

18、 2010; 2. Fosamax (alendronate) PI. Whitehouse Station, NJ: Merck & Co Inc. 2011; 3. Black DM, et al. J Clin Endo Metab. 2000;85:41184124; 4. Bonviva (ibandronate) SmPC. London, UK: EMA; 2011; 5. Boniva (ibandronate) PI. South San Francisco, US: Genentech Inc.; 2011; 6. Actonel (risedronate) PI.

19、 Manati, Puerto Rico; Warner Chilcott Puerto Rico LLC; 2011; 7. Harris ST, et al. JAMA. 1999;282:13441352; 8. Reginster JY, et al. Osteoporos Int. 2000;11:8391; 9. Aclasta (zoledronic acid) SmPC. London, UK: EMA; 2011; 10. Reclast (zoledronic acid) PI. East Hanover, NJ: Novartis Pharmaceuticals; 201

20、1; 11. Prolia (denosumab) SmPC. London, UK: EMA; 2011; 12. Prolia (denosumab) PI. Thousand Oaks, CA: Amgen; 2011; 13. Protelos (strontium ranelate) SmPC. London, UK: EMA; 2011; 14. Reginster JY, et al. J Clin Endo Metab. 2005;90:28162822; 15. Meunier PJ, et al. N Engl J Med. 2004; 350:459468; 16. Mi

21、acalcic (SCT nasal spray) SmPC. London, UK: EMA; 2011; 17. Miacalcin (SCT nasal spray) PI. East Hanover, NJ: Novartis Pharmaceuticals Corp.; 2011; 18. Forteo (teriparatide) SmPC. London, UK: EMA; 2011; 19. Forsteo (teriparatide) PI. Indianapolis, IN; Eli Lilly & Co.; 2011; 20. Evista (raloxifene

22、) SmPC. London, UK: EMA; 2011; 21. Evista (raloxifene) PI. Indianapolis, IN: Eli Lilly & Co.; 2011與安慰劑比較骨密度變化與安慰劑比較骨密度變化, %椎體椎體股骨頸股骨頸全髖全髖阿倫膦酸阿倫膦酸 138.8 (EU)711 (US)5.9 (EU)57 (US)7.8* (EU)79* (US)伊班膦酸伊班膦酸 4,5NRNRNR利塞膦酸利塞膦酸6*唑來膦酸唑來膦酸9,鮭魚降鈣素鮭魚降鈣素16,1712NSBMD 維持 (EU)雷洛昔芬雷洛昔芬10,

23、112 (EU)2.6 (US)NR (EU)2.1 (US)2 (EU)NR (US)特立帕肽特立帕肽18,199.0 (EU)NR4.0 (EU)雷奈酸鍶雷奈酸鍶139.8不同骨質(zhì)疏松治療藥物的臨床療不同骨質(zhì)疏松治療藥物的臨床療第17頁/共85頁雷洛昔芬雷洛昔芬60(MORE)*阿倫膦酸阿倫膦酸 5/10(FIT1)*利塞膦酸利塞膦酸(VERT-北美北美)*雷奈酸鍶雷奈酸鍶(SOTI)*PTH 1-84伊班膦酸伊班膦酸(每日給藥每日給藥)特立帕肽特立帕肽20g狄諾塞麥狄諾塞麥(FREEDOM)RR 95% CI*有椎體骨折史有椎體骨折史*無椎體骨折史無椎體骨折史*伴髖

24、部骨折伴髖部骨折Updated and adapted from Delmas PD (2000). lancet 359:2018.雷洛昔芬雷洛昔芬60(MORE)*阿倫膦酸阿倫膦酸 5/10(FIT1)*利塞膦酸利塞膦酸(VERT-多國多國)*伊班膦酸伊班膦酸(間歇給藥間歇給藥)唑來膦酸唑來膦酸(HORIZON)唑來膦酸唑來膦酸(HORIZON)*CT 200(PROOF)*雷奈酸鍶雷奈酸鍶(SOTI+TROPOS)*第18頁/共85頁第19頁/共85頁R1 = OH, R2 = CH2 利塞膦酸利塞膦酸R1 = OH, R2 = (CH2)2NH2 帕米膦酸帕米膦酸R1 = OH, R2

25、 = (CH2)3NH2 阿倫膦酸阿倫膦酸NR1 = OH, R2 = CH2 唑來膦酸唑來膦酸NN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R2R1R2 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 Mechani

26、sms 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第20頁/共85頁Kanis, 1998 藥物藥物相對強(qiáng)度相對強(qiáng)度唑來膦酸唑來膦酸10,000利塞膦酸利塞膦酸2,000阿侖膦酸阿侖膦酸50

27、0帕米膦酸帕米膦酸100替魯膦酸替魯膦酸10氯曲膦酸氯曲膦酸10 依替膦酸依替膦酸1第21頁/共85頁39%24小時(shí)內(nèi)排出小時(shí)內(nèi)排出61%骨組織結(jié)合骨組織結(jié)合100%生物利用度生物利用度不經(jīng)過體內(nèi)代謝不經(jīng)過體內(nèi)代謝以原型經(jīng)腎臟排出以原型經(jīng)腎臟排出1) Aclasta SmPC; 2) Fosamax weekly tablets SmPC; 3) Fosavance tablets SmPC; 4) Actonel weekly tablets SmPC; 5) Bonviva tablets SmPC 第22頁/共85頁ALN, alendronate; CLO, clodronate; E

28、TD, etidronate; IBA, ibandronate; RIS, risedronate; ZOL, zoledronic acid.Nancollas GH, et al. Bone. 2006;38:617-627.0124CLO ETD RISIBA ALN ZOL3KL (L/mol x 106)羥磷灰石羥磷灰石吸附力指數(shù)吸附力指數(shù), , KL第23頁/共85頁與骨表面結(jié)合與骨表面結(jié)合釋放以及細(xì)胞的吸收釋放以及細(xì)胞的吸收BPBPBPBPBPBPBPBPBoneBoneBPBPBPBPBPBPBPBPBPBPBPBPBPBP在骨吸收活躍的部位濃集在骨吸收活躍的部位濃集Bone

29、BoneBoneBone喪失骨吸收能力喪失骨吸收能力BPBPBPBPBPBPBPBPBP = bisphosphonatesCourtesy of Professor M. Rogers.從細(xì)胞學(xué)角度看雙膦酸藥物的作用機(jī)制從細(xì)胞學(xué)角度看雙膦酸藥物的作用機(jī)制第24頁/共85頁雙香葉基基焦磷酸（GGPP） 細(xì)胞存細(xì)胞存活信號活信號傳導(dǎo)傳導(dǎo)含氮雙膦酸類藥物對于含氮雙膦酸類藥物對于FPP合成酶的作用合成酶的作用Masarachia et al Bone 1996; 19:281Coxon et al Bone 2008; 42:848x急性反應(yīng)急性反應(yīng)單核細(xì)胞攝入含氮雙膦酸藥物后IPP累積IPPIPP

30、IPPIPP與-T細(xì)胞表面受體結(jié)合 含氮雙膦酸藥物：含氮雙膦酸藥物：阿侖膦酸阿侖膦酸伊班膦酸伊班膦酸帕米膦酸帕米膦酸利塞膦酸利塞膦酸唑來膦酸唑來膦酸第25頁/共85頁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.

31、 GRAHAM G. RUSSELL, Mechanisms of action of bisphosphonates: similarities and differences and their potential influence on clinical efficacy. Osteoporos Int (2008) 19:733759親和力高的雙膦酸藥物（如：阿倫膦酸，唑來膦酸）l吸收率高l解析率低l再吸附率高l骨內(nèi)擴(kuò)散較少親和力低的雙膦酸藥物（如：利塞膦酸）l吸收率少l解析率高l再吸附率低l骨內(nèi)擴(kuò)散較多第26頁/共85頁阿侖膦酸鈉阿侖膦酸鈉依替膦酸鈉依替膦酸鈉伊班膦酸鈉伊班膦酸鈉利

32、噻膦酸鈉利噻膦酸鈉唑來膦酸注唑來膦酸注射液射液適應(yīng)癥絕經(jīng)后骨質(zhì)疏松癥男性骨質(zhì)疏松癥糖皮質(zhì)激素誘發(fā)的骨質(zhì)疏松癥原發(fā)性骨質(zhì)疏松癥絕經(jīng)后骨質(zhì)疏松癥藥物引起的骨質(zhì)疏松癥絕經(jīng)后骨質(zhì)疏松癥絕經(jīng)后骨質(zhì)疏松癥糖皮質(zhì)激素誘發(fā)的骨質(zhì)疏松癥絕經(jīng)后骨質(zhì)疏松癥療效腰椎和髖部骨密度椎體和非椎體骨折風(fēng)險(xiǎn)腰椎和髖部骨密度椎體骨折風(fēng)險(xiǎn)腰椎和髖部骨密度椎體和非椎體骨折風(fēng)險(xiǎn)腰椎和髖部骨密度椎體和非椎體骨折風(fēng)險(xiǎn)腰椎和髖部骨密度椎體和非椎體骨折風(fēng)險(xiǎn)用法口服70mg/周或10mg/日空腹，保持直立口服0.2g/次，每日二次兩餐間服用靜脈注射2mg/三月口服5mg/日或35mg/周空腹，保持直立靜脈注射5mg/年注意胃及十二指腸潰瘍、反流

33、性食管炎慎用腎功能損害者、孕婦及哺乳期婦女慎用肌酐清除率35ml/分不用胃及十二指腸潰瘍、反流性食管炎慎用肌酐清除率35ml/分不用第27頁/共85頁唑來膦酸 5 mg安慰劑絕經(jīng)前水平范圍月月0.20.01.0平均血漿平均血漿-CTX (ng/mL)061218243030.30.4唑來膦酸5mg摘自Black DM, et al. N Engl J Med. 2007;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唑來膦酸5mg唑來膦酸5mg+P 0.0001第28頁/共85頁0612 18 24

34、30 362.00.02.04.06.08.05.90*3.66*2.39*0612 18 24 30 362.01.00.01.02.03.04.03.05.02.17*1.58*3.89*月月月月椎體椎體BMD股骨頸股骨頸BMDBlack DM, et al. N Engl J Med. 2007;356:1809-1822.與基線比較變化率與基線比較變化率 % 061218243036 月月2.83*1.93*4.70*2.01.00.01.02.03.04.03.05.0全髖全髖BMD*與安慰劑組比較與安慰劑組比較P 0.0001 唑來膦酸 5 mg安慰劑治療組治療組6 6個(gè)月骨密度提

35、升個(gè)月骨密度提升治療組治療組3636個(gè)月骨密度提升個(gè)月骨密度提升椎體椎體2.39%2.39%6.71%6.71%全髖全髖1.93%1.93%6.02%6.02%股骨頸股骨頸1.58%1.58%5.06%5.06%摘自Black DM, et al. N Engl J Med. 2007;356:1809-1822.第29頁/共85頁Adapted from Black DM, et al. N Engl J Med 2007;356:18091822唑來膦酸 5 mg 安慰劑新發(fā)椎體骨折風(fēng)險(xiǎn)發(fā)生率新發(fā)椎體骨折風(fēng)險(xiǎn)發(fā)生率(%)60%*(43%, 72%)71%*(62%, 78%)0100102

36、03年年5151.5%(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%)*P0.0001， VS 安慰劑第30頁/共85頁Black DM, et al. N Engl J Med 2007;356:1809182241%*(17%, 58%) 77%(63%, 86%)25%(13%, 36%)臨床椎體骨折臨床椎體骨折髖部骨折髖部骨折非椎體骨折非椎體骨折1.4%(52/3875)0.5%(19/3875)2.5%(88/3861)2.6%(84/3861)8.

37、0%(292/3875)10.7%(388/3861)3年累積新發(fā)臨床骨折風(fēng)險(xiǎn)發(fā)生率年累積新發(fā)臨床骨折風(fēng)險(xiǎn)發(fā)生率(%)010515唑來膦酸 5 mg 安慰劑柱子上方的數(shù)值為基于Kaplan-Meier估計(jì)的3年累計(jì)事件率 *P = .0024; P .0001; P = .0002; 與安慰劑比較，相對風(fēng)險(xiǎn)降低髖部骨折未從非椎體骨折分析中排除.第31頁/共85頁uHORIZON-PFT 回顧性亞組分析結(jié)果顯示，唑來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, 鎖骨和下肢骨)唑來膦酸 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)。

38、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。 (p2-4 weeks6/191 (3.1)7/176 (4.0)4-6 weeks12/231 (5.2)8/271 (3.0) 6 weeks18/575 (3.1)12/564 (2.1)第37頁/共85頁MA-381 1. .8 83 3. .1 15 5. .2 23 3. .1 18 8. .7 74 43 32 2. .1 10 01 12 23 34 45 56 67 78 89 91 10 0骨折延遲愈合的發(fā)生率（%）1/584/467/1768/27112/5646/19112/23118/575唑來膦酸5mg安慰劑

39、髖部骨折術(shù)和第一次滴注密固達(dá)之間隨時(shí)間延長而延遲的骨折愈合2周2-4周4-6周6周P值OR（95%CI）0.19 (0.01, 1.35)0.78 (0.25, 2.40)1.80 (0.73, 4.67)1.48 (0.72, 3.20)0.100.670.200.29Coln-Emeric C,et al.Osteoporos Int.2010.Epub ahead of print第38頁/共85頁u雙膦酸鹽類藥物總體安全性較好，但以下幾點(diǎn)應(yīng)特別關(guān)注：胃腸道胃腸道反應(yīng)反應(yīng)流感樣流感樣不良反應(yīng)不良反應(yīng)腎功能腎功能下頜骨壞下頜骨壞死死心房心房纖顫纖顫非典型性非典型性骨折骨折口服口服雙膦雙膦酸

40、鹽酸鹽輕度上腹疼痛輕度上腹疼痛反酸等食管炎反酸等食管炎胃潰瘍癥狀胃潰瘍癥狀無無肌酐清除肌酐清除率率35ml/分不用分不用罕見罕見對患有嚴(yán)對患有嚴(yán)重口腔疾重口腔疾病或需要病或需要接受牙科接受牙科手術(shù)的患手術(shù)的患者不建議者不建議不確不確定定長期應(yīng)用，長期應(yīng)用，非典型性非典型性骨折的少骨折的少數(shù)報(bào)道，數(shù)報(bào)道，確切原因確切原因尚不清楚尚不清楚靜脈靜脈雙膦雙膦酸鹽酸鹽無無一過性發(fā)一過性發(fā)熱、骨痛、熱、骨痛、肌痛，肌痛，3天后緩解天后緩解第39頁/共85頁第40頁/共85頁7575歲以上人群新發(fā)骨折風(fēng)險(xiǎn)（歲以上人群新發(fā)骨折風(fēng)險(xiǎn)（% %）臨床骨折臨床骨折椎體骨折椎體骨折非椎體骨折非椎體骨折髖部骨折髖部骨折2

41、8%28%* *35%35%* *61%61%* *66%66%* *15%15%27%27%* *26%26%18%18%* *P0.05P0.05Steven BoonenSteven Boonen，Journal of the American Geriatrics Society 2010,Journal of the American Geriatrics Society 2010, Volume 58, Issue 2, Pages: Volume 58, Issue 2, Pages: 292-299292-299第41頁/共85頁骨密度測定部位與安慰劑組比較差異*P值股骨頸1年

42、2.30.0013年5.00.001全髖1年3.00.0013年6.30.001* *為唑來膦酸和安慰劑相對于基線變化率的差值為唑來膦酸和安慰劑相對于基線變化率的差值Steven BoonenSteven Boonen，Journal of the American Geriatrics Society 2010,Journal of the American Geriatrics Society 2010, Volume 58, Issue 2, Pages: Volume 58, Issue 2, Pages: 292-299292-299唑來膦酸可以顯著改善患者髖部骨密度，但髖部骨折風(fēng)險(xiǎn)

43、降低不顯著，可能唑來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)等第42頁/共85頁Least square mean (g-LSM) of ratio = exponential of the LSM on the log(e) (ratio = visit/baseline) scale1.Boonen S, et al. J Am Geriatr Soc 2010;58:292299g-LSM -CTx Ration=103n=71n=99n=53n=841.41.21

44、0.2061218243036月月n=149n=130n=103n=149n=124n=109n=73n=61n=116n=97n=120n=70n=96n=97n=83n=66n=95n=93n=91Placebo; 75 yearsPlacebo; 75 yearsZol;75 yearsZol;75 years密固達(dá)顯著降低各年齡組患者主要骨轉(zhuǎn)換指標(biāo)密固達(dá)顯著降低各年齡組患者主要骨轉(zhuǎn)換指標(biāo)顯著降低兩組患者血漿CTX水平(P0.001)1顯著降低兩組患者血漿BALP水平(P0.001)1n=63n=124n=111n=91n=96n=62n=159n=167n=11000

45、.11.261218243036月月n=148n=104n=141n=167n=128n=159n=109n=131n=97n=80n=106n=113n=97n=90n=86Placebo; 75 yearsZol; 77天累積天累積患者比患者比唑來膦酸組顯著低于安慰劑組唑來膦酸組顯著低于安慰劑組(尤其是既往存在椎體骨折患者尤其是既往存在椎體骨折患者)唑來膦酸唑來膦酸累計(jì)發(fā)生率（累計(jì)發(fā)生率（% %）累計(jì)發(fā)生率（累計(jì)發(fā)生率（% %）安慰劑安慰劑臥床臥床7 7天天( (月份月份) )安慰劑安慰劑唑來膦酸唑來膦酸活動受限活動受限7 7天天( (月份月份) )J Bone Min

46、er Res. 2010 Nov 18第45頁/共85頁唑唑來來膦膦酸酸安慰安慰劑劑患者發(fā)生骨折百分比（患者發(fā)生骨折百分比（% %）椎體形椎體形態(tài)測態(tài)測量量（分（分層層1 1） ）髖髖部部任一任一臨臨床骨折床骨折臨臨床椎體床椎體非椎體非椎體3 3年研究期間骨折發(fā)生率。唑來膦酸組（灰色）與安慰劑組（年研究期間骨折發(fā)生率。唑來膦酸組（灰色）與安慰劑組（白色）的比較。白色）的比較。* *P P 0.050.05唑來膦酸唑來膦酸（N=163N=163），），n n（% %）安慰劑安慰劑（N=160N=160），），n n（% %）P P值值5 5種最常見的種最常見的滴注后癥狀滴注后癥狀（滴注后（滴注后

47、3 3天天內(nèi)）內(nèi)）關(guān)節(jié)痛關(guān)節(jié)痛3535（21.521.5）2 2（1.31.3）0.00010.0001肌痛肌痛2424（14.714.7）0 0（0.00.0）0.00010.0001全身乏力全身乏力1616（9.89.8）6 6（3.83.8）0.04500.0450頭痛頭痛1111（6.86.8）3 3（1.91.9）0.05240.0524發(fā)熱發(fā)熱J Bone Miner Metab. 2010 Oct 5. 第46頁/共85頁密固達(dá)顯著增加中國密固達(dá)顯著增加中國PMO患者骨密度患者骨密度轉(zhuǎn)子骨BMD安慰劑唑來膦酸5mg月BMD至基線變化百分比（%）全髖BMD00-1-2-312346

4888%P 0.0016012345-1-2-3-4061218243036月7.04%P 0.001Jawl-Shan Hwang, et al. J Bone Miner Metab. 2011;29:328-333.數(shù)據(jù)來自HORIZON-PFT研究香港及臺灣患者資料第47頁/共85頁密固達(dá)降低中國密固達(dá)降低中國PMO患者骨折風(fēng)險(xiǎn)患者骨折風(fēng)險(xiǎn)Jawl-Shan Hwang, et al. J Bone Miner Metab. 2011;29:328-333.治療期間患者骨折率（%）形態(tài)學(xué)椎體骨折髖部椎體骨折任何臨床骨折臨床椎體骨折非椎體骨折唑來膦酸5mg安慰劑*P

49、 0.05下降51%下降39%數(shù)據(jù)來自HORIZON-PFT研究香港及臺灣患者資料第48頁/共85頁J Clin Endocrinol Metab. 2010 Sep;95(9):4380-7第49頁/共85頁急性期癥狀發(fā)生機(jī)制說明急性期癥狀發(fā)生機(jī)制說明Masarachia et al Bone 1996; 19:281Coxon et al Bone 2008; 42:848激活的激活的 T 細(xì)胞細(xì)胞IPPIFN-TNF-IFN-TNF-IFN-TNF-IL-6 急性期反應(yīng)第50頁/共85頁Data are odds ratios (95% confidence intervals) der

50、ived from a stepwise logistic regression analysis. Variables entered were: history of previous Data are odds ratios (95% confidence intervals) derived from a stepwise logistic regression analysis. Variables entered were: history of previous bisphosphonatebisphosphonate use, age, race, body mass inde

51、x, use, age, race, body mass index, country/geographic region of residence, baseline co-morbidities and concomitant medications at the time of country/geographic region of residence, baseline co-morbidities and concomitant medications at the time of zoledroniczoledronic acid dosing, with particular

52、reference to non-steroidal anti- acid dosing, with particular reference to non-steroidal anti-inflammatory drugs, COX2 inhibitors and inflammatory drugs, COX2 inhibitors and statinsstatins; ; NSAID = non-steroidal anti-inflammatory drug; BP = NSAID = non-steroidal anti-inflammatory drug; BP = bispho

53、sphonatebisphosphonateReid I, et al. Presented at American Society for Bone and Mineral Research 31st Annual Meeting; September 1115, 2009 Colorado Convention Centre, Denver, Colorado, USA. Poster 0352.Reid I, et al. Presented at American Society for Bone and Mineral Research 31st Annual Meeting; Se

54、ptember 1115, 2009 Colorado Convention Centre, Denver, Colorado, USA. Poster 0352.急性期癥狀在以下人群發(fā)生較少急性期癥狀在以下人群發(fā)生較少: :吸煙吸煙 (p=0.003)(p=0.003)有糖尿病患者有糖尿病患者(p=0.008)(p=0.008)既往雙膦酸藥物應(yīng)用患者既往雙膦酸藥物應(yīng)用患者(p=0.002)(p=0.002)降鈣素正在應(yīng)用患者降鈣素正在應(yīng)用患者(p=0.001)(p=0.001)急性期癥狀在以下人群發(fā)生較多急性期癥狀在以下人群發(fā)生較多: : 年輕患者年輕患者 (p0.0001)(p0.0001

55、)使用使用NSAIDsNSAIDs藥物患者藥物患者(p0.0001)(p -1中-1 -4高 11 2.52.5 2-4 weeks6/191 (3.1)7/176 (4.0)4-6 weeks12/231 (5.2)8/271 (3.0) 6 weeks18/575 (3.1)12/564 (2.1)第82頁/共85頁837575歲歲7575歲歲安慰劑安慰劑唑來膦酸唑來膦酸P值值安慰劑安慰劑唑來膦酸唑來膦酸P值值給藥后癥狀給藥后癥狀 （3 3天內(nèi)發(fā)熱天內(nèi)發(fā)熱、肌痛、骨、肌痛、骨痛、流感樣癥狀、寒顫）痛、流感樣癥狀、寒顫）24.9%51.8%0.00125.7%41.5%0.001死亡率死亡率2.1%2.3%0.717.5%7.0%0.58嚴(yán)重不良事件嚴(yán)重不良事件27.4%25.6%0.1237.9%37.5%0.82增加血肌酐增加血肌酐 0.5mg/dl0.5mg/dl1.8%2.2%0.333.5%4.7%0.08肌酐清除率肌酐清除率 30ml/min30ml/min1.5%1.7%0.669.6%10.4%0.431.Boonen S, et al. J Am Geriatr Soc 2010;58:29229975歲與75歲年齡組患者，唑來膦酸治療組3天內(nèi)的發(fā)熱、肌痛、流感樣癥狀、骨痛、寒顫