藥物治療教學(xué)課件：D-Osteoporosis

1.SideeffectDrug失眠&激動(dòng)鎮(zhèn)靜直立性低血壓抗膽堿惡心性功能障礙體重↑SSRIs++0/+0/+0/++++++文拉法辛(Venlafaxine)++0/+0/+0/+++++0/+杜洛西汀(Duloxetine)0/++0/++++0/+0/+米氮平(Mirtazapine)0/+++++0/+0/+0/++++安菲他酮(Bupropion)++0/+0/+++0/+0/+OsteoporosisAnnInternMed.2014;161:711-723.doi:10.7326/M14-0317BonePhysiologyandRemodelingBoneChemistryOrganicComponentsCollagenMatrix(膠原基質(zhì)):themajorcomponentofbone,formsafoundationuponwhichmineralizationwithhydroxyapatite(羥磷灰石)occursOrganicComponentsOsteonectin(骨粘連蛋白)acarbohydratethatbindscollagenandhydroxyapatite(羥磷灰石)regulatesrateofmineralizationOrganicComponentsOsteocalcin(骨鈣蛋白):Vitamin-Kdependentprotein,comprises1-2%oftotalboneproteinsynthesizedbyosteoblasts(造骨細(xì)胞)BindsCa&hydroxyapatite(羥磷灰石)tothecollagenmatrix(膠原基質(zhì))secretionisstimulatedbyVitaminDInorganicComponentsHydroxyapatite=Ca10(PO4)6(OH)2(羥磷灰石)acrystallinestructurecomposedprimarilyofCa&P.providethetensilestrengthtoadsorbimpact.Cortical(Compact)Bone:密質(zhì)骨*forms80%oftheskeleton*predominatesinthelongbonesTrabecular(Spongy)Bone:松質(zhì)骨ahighersurfacearea>corticalbonedegreeofboneremodelingrateoffractureControlofBoneFormationandResorptionboneremodelingisadynamicprocessinvolvingthedestructionandregenerationofnewbone.3typesofbonecellsformabonemulticellularunit(BMU)Osteoclasts(破骨細(xì)胞):@thebonesurfaceinareasofactiveboneresorption(骨吸收)shareacommonprecursorwithGranulocytes(粒性白細(xì)胞),macrophages(巨噬細(xì)胞),monocytes(單核細(xì)胞)activatedbyCytokines(細(xì)胞因子),PTH(甲狀旁腺激素)Calcitriol(骨化三醇)Osteoclasts(破骨細(xì)胞):causesthereleaseofH+&lysosomes(溶酶體)?boneresorptionH+ions:demineralizebonematrixlysosomes:degradetheproteinmatrixOsteoblast(造骨細(xì)胞):responsibleformatrixformation&mineralization@thebonesurfaceinareasofboneremodelingOsteocyte(骨細(xì)胞)havebeenencasedbynewosteoidmaterialprovidenutritiontotheboneissueBoneResorption(骨吸收)BoneFormation(骨形成)accomplishedthroughactivationofosteoclasts(破骨細(xì)胞)accomplishedthroughactivationoftheosteoblasts(造骨細(xì)胞)Therateofboneturnover(骨轉(zhuǎn)化)isdeterminedbytheosteoclasticactivity.begins10daysafterresorptionisfinishedtakesupto3weeksmaytakeupto3monthstobecompleted.NormalBoneResorption=FormationOsteoporosisResorption>Formation甲狀旁腺激素(PTH)骨化三醇(Calcitriol)降鈣素(Calcitonin)NeteffectonSerumConcentration↑Ca↓PO4↑Ca↑PO4↓CaMechanism↑urinePO4excretionstimulatesosteoclastsstimulatesVitDformation↑intestinalabsorptionstimulatesosteoclastsinhibitsosteoclastssHormonalRegulationofCa&PEvaluationofBoneMineralDensity雙能X射線吸收(DualEnergyX-rayabdorptimoetry,DEXA)veryprecise,involveslittleradiationexposurereportedasaTscorepreferredsitetomeasureisthehip(髖關(guān)節(jié))如果在多個(gè)部位測(cè)量,最低Tscore用于診斷ifperipheralDEXAusedasascreeningtool,miss?10%ofPtsformenandwoman@anygivenBMD:theriskofhipfractureriskappearsequalIndicationsforMeasurementofBMD>65歲女性,or>60伴隨風(fēng)險(xiǎn)因素NOTrecommendedroutinelyforwomenatmenopausew/suspectedosteoporosisviaX-rayorclinicalevidence原發(fā)性甲狀腺功能亢進(jìn)慢性腎病,長(zhǎng)期癲癇治療皮質(zhì)激素治療(>可的松prednisone7.5mg/d)>3monthsfollow-uptomonitorPatientsresponsetotherapynomoreoftenthanevery2yearsOsteoporosisDefinitionaDzcharacterizedbya↓intotalbonemasswitha↓inbothbonematrix(collagen膠原基質(zhì))bonemineralization(hydroxyapatitie羥磷灰石)leadingto↑bonefragilityand↑riskoffracture.和年輕女性的理論Tscore值比較，WHO分類骨質(zhì)流失骨質(zhì)正常：BMD>-1骨質(zhì)減少：BMD(-2.5,-1)骨質(zhì)疏松：BMD<-2.5嚴(yán)重骨質(zhì)疏松：BMD<-2.5+骨折Epidemiologyaffects1/3postmenopausalwomen15-17%ofadultswillhaveahipfracturebyage9012-20%ofallPtswithahipfracturediewithin1year70%ofallfractures>age45arerelatedtoosteoporosisbonemasspeaksinthe40thdecadeage-relatedbonelossis0.5-1%peryearCauses:PrimaryCharacteristicTypeI(絕經(jīng)后)TypeII(老年性)PrimaryCause雌激素缺乏老齡化Age(years)>50>70TypeofBoneLoss松質(zhì)骨為主松質(zhì)骨和密質(zhì)骨FracturesitesVertebraeandradiusVertebraeandhipsCauses:Secondary內(nèi)分泌失常:糖皮質(zhì)激素過(guò)量甲狀腺機(jī)能亢進(jìn)性腺機(jī)能減退高泌乳素血癥糖尿病甲狀旁腺功能亢進(jìn)營(yíng)養(yǎng):鈣缺乏、蛋白缺乏藥物引發(fā):Heparin,anticonvulsantsImmobilizationHepaticDiseaseRheumatoidArthritisClinicalPresentation1stsign:背部疼痛+椎體骨折Pain:oftenisgradualonset¬recognizedfracturesoccurlongafterthestartofthe↓inBMD主要骨折部位:松質(zhì)骨>密質(zhì)骨椎骨43%,髖關(guān)節(jié)17%前臂13%.椎體骨折導(dǎo)致脊柱畸形TypeI(絕經(jīng)后):RiskFactors高齡女性白種或亞洲血統(tǒng)身材消瘦過(guò)早絕經(jīng)攝入含Ca低的飲食久坐生活方式家庭病史使用皮質(zhì)類固醇激素性腺衰竭吸煙長(zhǎng)期使用warfarinProtectiveFactorsofTypeI

(絕經(jīng)后)噻嗪類藥物使用雌激素使用鍛煉高身體質(zhì)量指數(shù)(BMI,normalrange18.5~25)Prevention&

Treatment預(yù)防對(duì)所有人群試用應(yīng)注意:生活方式，Ca,VitaminD

如下情況需治療：

骨密度T-score≤-2<-1.5，絕經(jīng)同時(shí)伴隨風(fēng)險(xiǎn)因素骨質(zhì)疏松性骨折Lifestyle&NonpharmacologicweightbearingactivityWalking/dancinglowimpactexerciseshouldbeavoided:smokingheavycaffeinealcoholVitaminDsupplementationVitaminD不足老年常見(jiàn)跌倒和骨質(zhì)疏松的風(fēng)險(xiǎn)因素飲食來(lái)源:全脂奶粉,奶酪,黃油,魚(yú),肝...日補(bǔ)充量400-800IUVitaminD3

alternative:exposuretosun10~15minqd,2-3timesqwthebenefit:dependonthebaselineVitaminDstatusDrugsFDAapprovedDrug預(yù)防治療GIOPMenEstrogen(雌激素)XCalcitonin(降鈣素)XRaloxifene(雷洛昔芬)XXRisedronate(利塞膦酸)XXXAlendronate(阿侖膦酸)XXXXIbandronate(依班磷酸)XXTeriparatide(特立帕肽)XXGIOP=glucocorticoidinducedosteoporosisCalciumSupplement幾乎對(duì)全部人群適用efficacy:howlowbaselinedietaryisadequateCa:essentialtogivealong碳酸鈣(CaCO3):containsgreatestamountofCalcium富含鈣的食物:乳制品,無(wú)花果,豆腐,菠菜serumCaconcentrationisNOTavalidindicator!RecommendedDailyCaIntake4-8yrs800mg9-18yrs1300mgMen&Women19-50yrs1000mgMen&Women>50yrs1200mgCommonlyAvailableFormsofCa鈣鹽鈣元素含量產(chǎn)品名稱Calciumcarbonate(碳酸鈣)40.0%Calciumcitrate(檸檬酸鈣)21.1%Calciumglubionate6.4%Calciumgluconate(葡萄糖酸鈣)9.0%Calciumphosphatetribasic(磷酸鈣)37.5%CaSupplementUse“天然”

鈣:noadvantageoverplainCaCO3碳酸鈣(CalciumCarbonate):用餐時(shí)服用ifdoseqd>500mg,分多次服用磷酸鈣(Calciumphosphatetribasic):對(duì)P吸收低者有益足量水：↓便秘和胃氣脹PharmacologicManagement

激素替代療法(HormoneReplacementTherapy,HRT)

選擇性雌激素受體調(diào)節(jié)劑(SERMs)

降鈣素(Calcitonin)

雙磷酸鹽(Bisphosphonates)

合成代謝類(AnabolicDrugs)

其他治療(OtherTherapies)

組合治療(Combinations)HormoneReplacementTherapy激素替代療法雌激素(estrogens)雌二醇(estradiol)Efficacy直接調(diào)節(jié)骨代謝:破骨&造骨細(xì)胞上有其受體↓破骨細(xì)胞活動(dòng),↑Ca吸收

↑降鈣素(Calcitonin)合成,↑造骨細(xì)胞中VitaminD受體Efficacy↓骨質(zhì)流失和骨質(zhì)疏松性骨折風(fēng)險(xiǎn)絕經(jīng)后3年并繼續(xù)服用:手腕,脊椎,髖關(guān)節(jié)骨折↓30-60%口服&透皮可和其他藥物連用需長(zhǎng)期服用：停藥后骨質(zhì)損失重新開(kāi)始UsualDose結(jié)合雌激素(conjugatedestrogens):0.625mgqd常和甲羥孕酮(medroxyprogesterone)2.5mg合用雌二醇(estradiol):0.5mgqd,3wkon,1wkoff透皮雌二醇:0.025mg/day;3wkon,1wkoffSafety最常見(jiàn)副作用：陰道出血其他：體重↑,乳房脹痛,惡心,頭痛單獨(dú)使用雌激素:↑子宮內(nèi)膜癌乳腺癌風(fēng)險(xiǎn):↑25-35%HRT不應(yīng)用于預(yù)防心血管疾病:nooverallbenefit!coronaryarterydiseaseincidence↑duringthe1styear*TheHeartandEstrogen/ProgestinReplacement,HERSstudy

*TheEstrogenReplacementandAtherosclerosisstudy

*Women’sHealthInitiativeStudy

PlaceinTherapyWASonceconsidered1stlineagentforpreventionNOWinappropriatesolelyforosteoporosis心血管疾病和乳腺癌風(fēng)險(xiǎn)缺乏持久效果絕經(jīng)癥狀且心血管和乳腺癌風(fēng)險(xiǎn)較小的患者短期、低劑量用于絕經(jīng)癥狀仍然適用SelectiveEstrogenReceptorModulators選擇性雌激素受體調(diào)節(jié)劑(SERMs)雷洛昔芬(Raloxifene)Raloxifene(雷洛昔芬)@破骨&造骨細(xì)胞:雌激素受體興奮劑@乳房受體:雌激素受體拮抗劑↑BMDby2-3%@腰脊柱和髖骨,↓50%椎體骨折adirect6-monthcomparisontoHRT:lesseffective@↑BMDhasbeenshowninplacebo-controlledtrialstoreduceonlyvertebralfractures;reductionintheriskforhipornonvertebralfractureswasnotstatisticallysignificant.Raloxifene(雷洛昔芬)60mgqd副作用：潮熱、腿抽筋、↑血栓栓塞風(fēng)險(xiǎn)，肺栓塞中風(fēng)適用于無(wú)絕經(jīng)癥狀，特別是有乳腺癌風(fēng)險(xiǎn)的患者Calcitonin降鈣素MOA32個(gè)氨基酸組成的單鏈多肽直接抑制破骨細(xì)胞的骨吸收↑Ca&P的腎排泄(hypercalcemia)Efficacyprobablytheleastpotentalternativea5yearstudyofintranasalCalcitoninnotblinded,veryhighdropoutrate200IUqd↓椎骨骨折,100or400IUnoteffective有鎮(zhèn)痛作用，可用于椎骨折的嚴(yán)重疼痛用于不能使用雌激素/Ca聯(lián)合治療的骨質(zhì)疏松Dose鮭魚(yú)降鈣素(Calcitoninsalmon)dose100IUscqd×5dayseachweek200IUintranasallyqd×5dayseachweekCalcitoninhuman:0.5mgsc.qdAdverseEffects胃腸道(惡心、嘔吐、腹痛)皮膚潮紅罕見(jiàn)過(guò)敏(鮭魚(yú)),需要皮膚測(cè)試Bisphosphonates雙磷酸鹽阿侖膦酸(Alendronate)利塞膦酸(Risedronate)依班磷酸(Ibandronate)羥乙磷酸(Etidronate)唑來(lái)膦酸(Zoledronicacid)MOA焦磷酸鹽類似物(骨代謝的天然抑制劑)吸附羥磷灰石，阻斷其溶解和吸收↓破骨細(xì)胞數(shù)量Efficacy抗骨吸收最強(qiáng)↑BMD4-8%over3years,asmuchas10%over10years↓fracturesby30-50%阿侖膦酸:beststudied,documentedfor?10years停藥時(shí)BMD↓遠(yuǎn)遠(yuǎn)<雌激素停藥Onecomparativestudy:BMD↑:阿侖膦酸75mgqwk>利塞膦酸35mgqwksideeffectorfracturerates:nodifferenceDosingDrug預(yù)防治療Risedronate(利塞膦酸)35mgweekly35mgweeklyAlendronate(阿侖膦酸)35mgweekly70mgweeklyIbandronate(依班磷酸)150mgmonthly150mgmonthly吸收差，須空腹服用(不要與Ca劑或其他藥物共同服用)服用后需背部直立半小時(shí),否則刺激食道,可造成胃酸返流AdverseEffects胃灼熱、腹痛、痢疾對(duì)食道非常刺激，大量水送服空腹半小時(shí)內(nèi)避免躺臥罕見(jiàn)嚴(yán)重肌肉或關(guān)節(jié)疼痛Zoledronicacid唑來(lái)膦酸statisticallysignificantreductionsinnearlyalltypesoffracturesassessed,withrelativeriskreductionsrangingfrom0.23to0.73attimepointsfrom24to36monthsafterinitiationoftreatment.Zoledronicacid唑來(lái)膦酸DosingOsteoporosistreatment,postmenopausal,

male,

steroid-induced5mgIVq12monthOsteoporosisprevention,postmenopausal5mgIVq24month低血鈣riskforhypocalcemiaOR7.22[1.81-42.70]OR=(a/b)/(c/d)；e.g.OR7.22[1.81-42.70]RR=[a/(a+b)]/[c/(c+d)]DataSynthesisEvidencebasedMedicineDesignofaRCTDesignofacohortstudyDesignofacase-controlstudyZoledronicacid唑來(lái)膦酸Adverseevents:肌痛關(guān)節(jié)痛發(fā)熱寒顫流感癥狀acompositeofthesesysptomOR6.39(5.76-7.09)Anabolicdrugs合成代謝類藥物甲狀旁腺激素衍生物(ParathyroidHormonederivative)鍶(Strontium)氟化物(Fluoride)Teriparatide(特立帕肽)a34aminoacidportionofParathyroidHormonemolecule

(甲狀旁腺激素衍生物)MOA:↑boneformationforPtsw/previousfractures,20mcg/dSC@thigh/abdomenadisposablepen,refrigerated,discarded28daysafterusetakepenoutoffridgeonlylongenoughtouseit,Teriparatide(特立帕肽)adverseeffects:

riskformilduppergastrointestinalsideeffectsOR3.26[2.82-3.78]headache,legcramps,associatedwith

riskforhypercalcemia:OR12.90[10.49-16.00]maycombow/HRT(激素替代療法)orraloxifene(雷洛昔芬)Denosumab(迪諾單抗)MOA:inhibitingosteoclastformationDose:60mgSCq6monthOsteoprosis,postmenopausal/maleBoneloss,cancertreatment-inducedDenosumab(迪諾單抗)significantly

ineachfracturetype(hip,nonvertebral,vertebral,andnewclinicalvertebral),withhazardratiosof0.31to0.80.Adverseevents:

riskformilduppergastrointestinalsideeffectsOddsRatio1.74[1.29-2.38]Apooledanalysisof4trialsfound

riskforinfection:riskratio1.28[1.02-1.60]Pregnancysafety:XFluoride(氟化物)MOA:formsfluorapatite,↑osteoblastEfficacy:clinicalresponsedependonthedose&formulationadverseeffects:nausea,vomiting,diarrhea,abdominalpainbone&jointpainPreventionEfficacygood-qualityevidencethatalendronate,etidronate,ibandronate,risedronate,zoledronicacid,estrogen,parathyroidhormone,andraloxifenepreventedosteoporoticfractures,althoughnotalloftheseagentspreventedhipfractures.E.g.ibandronateriskreductionunclearOtherTherapies其他治療OtherTherapiesThiazidediuretics(噻嗪類利尿劑)↓urinaryCaexcretion,mayretardbonelosswhether↓fractureshasnotbeentestedinarandomizedtrialβblocker(β受體阻滯劑)↓fracturesin1case-controlstudyStatin(他汀類)somecase-controlstudiesfound↓fracturesrecentlargeprospectivestudiesfoundnobenefitCombinations組合治療Combotherapynotwellstudied,orcommonlyused1study:estrogen+abiophosphonate↑BMD>eitheraloneraloxifene+alendronateonlyslightly>alendronatealoneTeriparatide+denosumabRandomizedcontrolledtrial:Teriparatide:31Denosumab:33Teriparatide+Denosumab:30At12months,BMDincreasedmoreinthecombinationgroup(9·1%,[SD3·9])thanintheteriparatide(6·2%[4·6],p=0·0139)ordenosumab(5·5%[3·3],p=0·0005)groups.Combinationtreatmentmight,therefore,beusefultotreatpatientsathighriskoffracture.TsaiJN,UihleinAV,LeeH,KumbhaniR,Siwila-SackmanE,McKayEA,etal.Teriparatideanddenosumab,aloneorcombined,inwomenwithpostmenopausalosteoporosis:theDATAstudyrandomisedtrial.Lancet.2013;382:50-6.[PMID:23683600]doi:10.1016/S0140-6736(13)60856-9Teriparatide+RisedronateRandomizedcontrolledtrial,doubleblinded:Teriparatide:n=9risedronate:n=10Teriparatide+risedronate:n=10Totalhip(TH)BMDincreasedtoagreaterextentinthecombinationgroup(3.86±1.1%SE)versusteriparatide(0.29±0.95%)orrisedronate(0.82±0.95%;p\0.05forboth).Combinationtreatmentmight,therefore,beusefultotreatpatientsathighriskoffracture.CombinationRisedronate–ParathyroidHormoneTrialinMaleOsteoporosis(RPM).Bethesda,M