藥物治療教學(xué)課件：D-Osteoporosis

1.SideeffectDrug失眠&激動鎮(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))如果在多個部位測量,最低Tscore用于診斷ifperipheralDEXAusedasascreeningtool,miss?10%ofPtsformenandwoman@anygivenBMD:theriskofhipfractureriskappearsequalIndicationsforMeasurementofBMD>65歲女性,or>60伴隨風(fēng)險因素NOTrecommendedroutinelyforwomenatmenopausew/suspectedosteoporosisviaX-rayorclinicalevidence原發(fā)性甲狀腺功能亢進慢性腎病,長期癲癇治療皮質(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)激素過量甲狀腺機能亢進性腺機能減退高泌乳素血癥糖尿病甲狀旁腺功能亢進營養(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)同時伴隨風(fēng)險因素骨質(zhì)疏松性骨折Lifestyle&NonpharmacologicweightbearingactivityWalking/dancinglowimpactexerciseshouldbeavoided:smokingheavycaffeinealcoholVitaminDsupplementationVitaminD不足老年常見跌倒和骨質(zhì)疏松的風(fēng)險因素飲食來源:全脂奶粉,奶酪,黃油,魚,肝...日補充量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幾乎對全部人群適用efficacy:howlowbaselinedietaryisadequateCa:essentialtogivealong碳酸鈣(CaCO3):containsgreatestamountofCalcium富含鈣的食物:乳制品,無花果,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):用餐時服用ifdoseqd>500mg,分多次服用磷酸鈣(Calciumphosphatetribasic):對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,↑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期服用：停藥后骨質(zhì)損失重新開始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最常見副作用：陰道出血其他：體重↑,乳房脹痛,惡心,頭痛單獨使用雌激素:↑子宮內(nèi)膜癌乳腺癌風(fēng)險:↑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)險缺乏持久效果絕經(jīng)癥狀且心血管和乳腺癌風(fēng)險較小的患者短期、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，肺栓塞中風(fēng)適用于無絕經(jīng)癥狀，特別是有乳腺癌風(fēng)險的患者Calcitonin降鈣素MOA32個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)皮膚潮紅罕見過敏(鮭魚),需要皮膚測試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↑BMD4-8%over3years,asmuchas10%over10years↓fracturesby30-50%阿侖膦酸:beststudied,documentedfor?10years停藥時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,否則刺激食道,可造成胃酸返流AdverseEffects胃灼熱、腹痛、痢疾對食道非常刺激，大量水送服空腹半小時內(nèi)避免躺臥罕見嚴(yán)重肌肉或關(guān)節(jié)疼痛Zoledronicacid唑來膦酸statisticallysignificantreductionsinnearlyalltypesoffracturesassessed,withrelativeriskreductionsrangingfrom0.23to0.73attimepointsfrom24to36monthsafterinitiationoftreatment.Zoledronicacid唑來膦酸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