密固达第二版课件

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3R1 = 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NR1 = OH, R2 = CH2 唑来膦酸NNR2R1COOHOHOHOHOPPR2 基团决定的是药物抗骨吸收能力，以及与羟基磷灰石的结合力当R1 基团是羟基时，可以增加药物与骨的结合力双膦酸类药物的功能基团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. 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双膦酸药物的研发进展1970 1980 1990 2000含氮环形侧链具有更强的抗骨吸收效果，效果强于依替膦酸约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.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400200.05阿伦膦酸IC50 (M) 2IC50 (M)1500帕米膦酸1000.215,0000.00230唑来膦酸 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 Che

7、n T, et al. J Clin Pharmacol. 2019;42:12281236.24 小时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。24小时肾脏排出率唑来膦酸39%阿仑膦酸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.双膦酸药物与骨表面羟基膦灰石结合力0124羟磷灰石CLOETDRISIBAALNZOL3KL (L/mol x 106)吸附力指数, KL10与骨表面结合释放以及细胞的吸收BPBPBPBPBoneBPBPBPBPBPBPBP在骨吸收活跃的部位浓集BoneBone丧失骨吸收能力BPBPBPBPBP = bisphosphonatesCourtesy of Professor M. Rogers.从细胞学角度看双膦酸药物的作用机制11FPP 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

9、）HMG-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 2019; 19:281Coxon et al Bone 2019; 42:848x单核细胞摄入含氮双膦酸药物后IPP累积IPPIPPIPPIPP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, 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双膦酸类药物 (0.1 M)ALN*FPP 合成酶1FPP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 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*水平并持续唑来膦酸 5 mg安慰剂绝经前水平范围月0.20.00.60.70.

13、81.0平均血浆-CTX (ng/mL)061218243030.30.4唑来膦酸5mg摘自Black DM, et al. N Engl J Med. 2019;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 .000117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)061218243036月40161820122810614唑来膦酸 5 mg安慰剂绝经前水平范围摘自Black DM, et al. N Engl J M

14、ed. 2019;356:1809-1822.*BALP：骨特异性碱性磷酸酶+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5mgP .000118唑来膦酸5mg显著降低平均血浆 P1NP*并持续平均血浆 P1NP (ng/mL)0122436月20060708050103040唑来膦酸 5 mg安慰剂绝经前水平范围摘自Black DM, et al. N Engl J Med. 2019;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5

15、mgP .000119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%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%*月月椎体BMD股骨颈BMDBlack DM, et al. N Engl J Med. 2019;356:1809-1822.HORIZON-PFT与基线比较变化率 % 061218243036月2.83*1.93*4.70*6.02%*2.01.00.01.02.03.04.03.05.0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 不同亚组患者全髋或股骨颈骨密度相对提升变量与安慰机组比较

17、变化率% (p-value)12个月 (n=1364)24个月 (n=805)85 岁全髋6.5 (p=0.0045)骨密度T值 -2.5全髋4.5 (p0.0001)骨折史(椎体或非椎体)全髋8.7 (p=0.0031) 13.4 (p=0.0692)股骨颈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岁以上亚组患者在12个月时骨密度提升水平最为显著p0.0001p0.0001p0.0001p=0.0001n=131n=139n=218n=194n=277n=281n=55n=69唑来膦酸显著提升髋部骨折后患者骨密度HORIZON-RFT23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 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唑来膦酸显著提升髋部骨折后患者骨密度HORIZON-RFT24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 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.全髋骨密度变化率（%）24个月12个月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唑来膦酸显著提升髋部骨折后患者骨密度HORIZON-RFT25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。HORIZO

24、N-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. Eastell, et al. Osteoporos Int. 2009;10.HORIZON-PFT27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HORI

25、ZON-PFT28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-PFT29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-PFT30唑来膦酸治疗骨质疏松症的临床疗效

26、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31Values above bars are 3-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. 2019;356:1809-1822.41%*70%25%椎体

27、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（%）010515唑来膦酸5mg降低各部位骨折风险唑来膦酸 5 mg 安慰剂HORIZON-PFT32 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%,

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. 发生率 (%)ZOL 5 mg 安慰剂唑来膦酸5毫克降低再发骨折风险Lyles KW, et al. N Engl J Med. 2019. e-publication 10.1056/NEJMoa07

29、4941 at HORIZON-RFT33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=0.0035), 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) 唑来膦酸 (n=4,692)安慰剂 (n=4,663)临床椎体骨折风险 (%)9n=1953% ns(-4%, 87%)57%*(25%, 76%)69%*(47%, 81%)76%*(61%, 85%

30、)70%*(56%, 79%)16371960218536117 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 Efficacy and Persistence of Effect of Zoledronic Acid 5 mg in Women with Osteoporosis or Recent Hip Fracture. 2009 ASBMR, Denver, CO

31、.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

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 (n=4,692)安慰剂 (n

33、=4,663)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 the 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

34、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-PFT36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

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 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%01020304050607060%70%65%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%,

38、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)010515ZOL 5 mg 安慰剂% 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. 2019;18(suppl 1):S26. Abstract OC53.HORIZON-PFT40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%(

39、-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)0213ZOL 5 mg 安慰剂*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. Osteoporos Int. 2019;18(suppl 1):S26. Abstract OC53.% 新发髋部骨折患者百分率HORIZON-PFT41唑来膦酸用于老年患者的数据唑来膦酸

40、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. 2019;18(suppl 1):S26. Abstract OC53.70 岁27%*(17%, 53%) 75岁44%(18%, 47%) 7.1%(78/1140)11.2%(126/1174)14.5%(189/1452)7074 岁29%(9%, 45%) 8.3%(100/1238)12.6%(141/1235)

41、% 新发临床骨折患者百分率0105159.6%(130/1497)ZOL 5 mg 安慰剂HORIZON-PFT42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75岁以上人群新发骨折风险（%）临床骨折椎体骨折非椎体骨折髋部骨折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唑来膦酸显

42、著提升75岁以上老年患者髋部骨密度骨密度测定部位与安慰剂组比较差异*P值股骨颈1年2.30.0013年5.00.001全髋1年3.00.0013年6.30.001*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 2019, 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 CTXSteven Boonen，

43、Journal of the American Geriatrics Society 2019, 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 2019, 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

44、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标 P1NPSteven Boonen，Journal of the American Geriatrics Society 2019, 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（ 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骨折不愈合发生率与给药时间的关系Zoledronic acid (N=1054)Placebo (N=1057)术后给药时间不愈合患者数/总患者数n/N (%)不愈合患者数/总患者数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%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.唑来膦酸安慰剂股骨干骨折发