药物治疗教学课件：D-Osteoporosis

1.SideeffectDrug失眠&激动镇静直立性低血压抗胆碱恶心性功能障碍体重↑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(胶原基质):themajorcomponentofbone,formsafoundationuponwhichmineralizationwithhydroxyapatite(羟磷灰石)occursOrganicComponentsOsteonectin(骨粘连蛋白)acarbohydratethatbindscollagenandhydroxyapatite(羟磷灰石)regulatesrateofmineralizationOrganicComponentsOsteocalcin(骨钙蛋白):Vitamin-Kdependentprotein,comprises1-2%oftotalboneproteinsynthesizedbyosteoblasts(造骨细胞)BindsCa&hydroxyapatite(羟磷灰石)tothecollagenmatrix(胶原基质)secretionisstimulatedbyVitaminDInorganicComponentsHydroxyapatite=Ca10(PO4)6(OH)2(羟磷灰石)acrystallinestructurecomposedprimarilyofCa&P.providethetensilestrengthtoadsorbimpact.Cortical(Compact)Bone:密质骨*forms80%oftheskeleton*predominatesinthelongbonesTrabecular(Spongy)Bone:松质骨ahighersurfacearea>corticalbonedegreeofboneremodelingrateoffractureControlofBoneFormationandResorptionboneremodelingisadynamicprocessinvolvingthedestructionandregenerationofnewbone.3typesofbonecellsformabonemulticellularunit(BMU)Osteoclasts(破骨细胞):@thebonesurfaceinareasofactiveboneresorption(骨吸收)shareacommonprecursorwithGranulocytes(粒性白细胞),macrophages(巨噬细胞),monocytes(单核细胞)activatedbyCytokines(细胞因子),PTH(甲状旁腺激素)Calcitriol(骨化三醇)Osteoclasts(破骨细胞):causesthereleaseofH+&lysosomes(溶酶体)⇒boneresorptionH+ions:demineralizebonematrixlysosomes:degradetheproteinmatrixOsteoblast(造骨细胞):responsibleformatrixformation&mineralization@thebonesurfaceinareasofboneremodelingOsteocyte(骨细胞)havebeenencasedbynewosteoidmaterialprovidenutritiontotheboneissueBoneResorption(骨吸收)BoneFormation(骨形成)accomplishedthroughactivationofosteoclasts(破骨细胞)accomplishedthroughactivationoftheosteoblasts(造骨细胞)Therateofboneturnover(骨转化)isdeterminedbytheosteoclasticactivity.begins10daysafterresorptionisfinishedtakesupto3weeksmaytakeupto3monthstobecompleted.NormalBoneResorption=FormationOsteoporosisResorption>Formation甲状旁腺激素(PTH)骨化三醇(Calcitriol)降钙素(Calcitonin)NeteffectonSerumConcentration↑Ca↓PO4↑Ca↑PO4↓CaMechanism↑urinePO4excretionstimulatesosteoclastsstimulatesVitDformation↑intestinalabsorptionstimulatesosteoclastsinhibitsosteoclastssHormonalRegulationofCa&PEvaluationofBoneMineralDensity双能X射线吸收(DualEnergyX-rayabdorptimoetry,DEXA)veryprecise,involveslittleradiationexposurereportedasaTscorepreferredsitetomeasureisthehip(髋关节)如果在多个部位测量,最低Tscore用于诊断ifperipheralDEXAusedasascreeningtool,miss≃10%ofPtsformenandwoman@anygivenBMD:theriskofhipfractureriskappearsequalIndicationsforMeasurementofBMD>65岁女性,or>60伴随风险因素NOTrecommendedroutinelyforwomenatmenopausew/suspectedosteoporosisviaX-rayorclinicalevidence原发性甲状腺功能亢进慢性肾病,长期癫痫治疗皮质激素治疗(>可的松prednisone7.5mg/d)>3monthsfollow-uptomonitorPatientsresponsetotherapynomoreoftenthanevery2yearsOsteoporosisDefinitionaDzcharacterizedbya↓intotalbonemasswitha↓inbothbonematrix(collagen胶原基质)bonemineralization(hydroxyapatitie羟磷灰石)leadingto↑bonefragilityand↑riskoffracture.和年轻女性的理论Tscore值比较，WHO分类骨质流失骨质正常：BMD>-1骨质减少：BMD(-2.5,-1)骨质疏松：BMD<-2.5严重骨质疏松：BMD<-2.5+骨折Epidemiologyaffects1/3postmenopausalwomen15-17%ofadultswillhaveahipfracturebyage9012-20%ofallPtswithahipfracturediewithin1year70%ofallfractures>age45arerelatedtoosteoporosisbonemasspeaksinthe40thdecadeage-relatedbonelossis0.5-1%peryearCauses:PrimaryCharacteristicTypeI(绝经后)TypeII(老年性)PrimaryCause雌激素缺乏老龄化Age(years)>50>70TypeofBoneLoss松质骨为主松质骨和密质骨FracturesitesVertebraeandradiusVertebraeandhipsCauses:Secondary内分泌失常:糖皮质激素过量甲状腺机能亢进性腺机能减退高泌乳素血症糖尿病甲状旁腺功能亢进营养:钙缺乏、蛋白缺乏药物引发:Heparin,anticonvulsantsImmobilizationHepaticDiseaseRheumatoidArthritisClinicalPresentation1stsign:背部疼痛+椎体骨折Pain:oftenisgradualonset¬recognizedfracturesoccurlongafterthestartofthe↓inBMD主要骨折部位:松质骨>密质骨椎骨43%,髋关节17%前臂13%.椎体骨折导致脊柱畸形TypeI(绝经后):RiskFactors高龄女性白种或亚洲血统身材消瘦过早绝经摄入含Ca低的饮食久坐生活方式家庭病史使用皮质类固醇激素性腺衰竭吸烟长期使用warfarinProtectiveFactorsofTypeI

(绝经后)噻嗪类药物使用雌激素使用锻炼高身体质量指数(BMI,normalrange18.5~25)Prevention&

Treatment预防对所有人群试用应注意:生活方式，Ca,VitaminD

如下情况需治疗：

骨密度T-score≤-2<-1.5，绝经同时伴随风险因素骨质疏松性骨折Lifestyle&NonpharmacologicweightbearingactivityWalking/dancinglowimpactexerciseshouldbeavoided:smokingheavycaffeinealcoholVitaminDsupplementationVitaminD不足老年常见跌倒和骨质疏松的风险因素饮食来源:全脂奶粉,奶酪,黄油,鱼,肝...日补充量400-800IUVitaminD3

alternative:exposuretosun10~15minqd,2-3timesqwthebenefit:dependonthebaselineVitaminDstatusDrugsFDAapprovedDrug预防治疗GIOPMenEstrogen(雌激素)XCalcitonin(降钙素)XRaloxifene(雷洛昔芬)XXRisedronate(利塞膦酸)XXXAlendronate(阿仑膦酸)XXXXIbandronate(依班磷酸)XXTeriparatide(特立帕肽)XXGIOP=glucocorticoidinducedosteoporosisCalciumSupplement几乎对全部人群适用efficacy:howlowbaselinedietaryisadequateCa:essentialtogivealong碳酸钙(CaCO3):containsgreatestamountofCalcium富含钙的食物:乳制品,无花果,豆腐,菠菜serumCaconcentrationisNOTavalidindicator!RecommendedDailyCaIntake4-8yrs800mg9-18yrs1300mgMen&Women19-50yrs1000mgMen&Women>50yrs1200mgCommonlyAvailableFormsofCa钙盐钙元素含量产品名称Calciumcarbonate(碳酸钙)40.0%Calciumcitrate(柠檬酸钙)21.1%Calciumglubionate6.4%Calciumgluconate(葡萄糖酸钙)9.0%Calciumphosphatetribasic(磷酸钙)37.5%CaSupplementUse“天然”

钙:noadvantageoverplainCaCO3碳酸钙(CalciumCarbonate):用餐时服用ifdoseqd>500mg,分多次服用磷酸钙(Calciumphosphatetribasic):对P吸收低者有益足量水：↓便秘和胃气胀PharmacologicManagement

激素替代疗法(HormoneReplacementTherapy,HRT)

选择性雌激素受体调节剂(SERMs)

降钙素(Calcitonin)

双磷酸盐(Bisphosphonates)

合成代谢类(AnabolicDrugs)

其他治疗(OtherTherapies)

组合治疗(Combinations)HormoneReplacementTherapy激素替代疗法雌激素(estrogens)雌二醇(estradiol)Efficacy直接调节骨代谢:破骨&造骨细胞上有其受体↓破骨细胞活动,↑Ca吸收

↑降钙素(Calcitonin)合成,↑造骨细胞中VitaminD受体Efficacy↓骨质流失和骨质疏松性骨折风险绝经后3年并继续服用:手腕,脊椎,髋关节骨折↓30-60%口服&透皮可和其他药物连用需长期服用：停药后骨质损失重新开始UsualDose结合雌激素(conjugatedestrogens):0.625mgqd常和甲羟孕酮(medroxyprogesterone)2.5mg合用雌二醇(estradiol):0.5mgqd,3wkon,1wkoff透皮雌二醇:0.025mg/day;3wkon,1wkoffSafety最常见副作用：阴道出血其他：体重↑,乳房胀痛,恶心,头痛单独使用雌激素:↑子宫内膜癌乳腺癌风险:↑25-35%HRT不应用于预防心血管疾病:nooverallbenefit!coronaryarterydiseaseincidence↑duringthe1styear*TheHeartandEstrogen/ProgestinReplacement,HERSstudy

*TheEstrogenReplacementandAtherosclerosisstudy

*Women’sHealthInitiativeStudy

PlaceinTherapyWASonceconsidered1stlineagentforpreventionNOWinappropriatesolelyforosteoporosis心血管疾病和乳腺癌风险缺乏持久效果绝经症状且心血管和乳腺癌风险较小的患者短期、低剂量用于绝经症状仍然适用SelectiveEstrogenReceptorModulators选择性雌激素受体调节剂(SERMs)雷洛昔芬(Raloxifene)Raloxifene(雷洛昔芬)@破骨&造骨细胞:雌激素受体兴奋剂@乳房受体:雌激素受体拮抗剂↑BMDby2-3%@腰脊柱和髋骨,↓50%椎体骨折adirect6-monthcomparisontoHRT:lesseffective@↑BMDhasbeenshowninplacebo-controlledtrialstoreduceonlyvertebralfractures;reductionintheriskforhipornonvertebralfractureswasnotstatisticallysignificant.Raloxifene(雷洛昔芬)60mgqd副作用：潮热、腿抽筋、↑血栓栓塞风险，肺栓塞中风适用于无绝经症状，特别是有乳腺癌风险的患者Calcitonin降钙素MOA32个氨基酸组成的单链多肽直接抑制破骨细胞的骨吸收↑Ca&P的肾排泄(hypercalcemia)Efficacyprobablytheleastpotentalternativea5yearstudyofintranasalCalcitoninnotblinded,veryhighdropoutrate200IUqd↓椎骨骨折,100or400IUnoteffective有镇痛作用，可用于椎骨折的严重疼痛用于不能使用雌激素/Ca联合治疗的骨质疏松Dose鲑鱼降钙素(Calcitoninsalmon)dose100IUscqd×5dayseachweek200IUintranasallyqd×5dayseachweekCalcitoninhuman:0.5mgsc.qdAdverseEffects胃肠道(恶心、呕吐、腹痛)皮肤潮红罕见过敏(鲑鱼),需要皮肤测试Bisphosphonates双磷酸盐阿仑膦酸(Alendronate)利塞膦酸(Risedronate)依班磷酸(Ibandronate)羟乙磷酸(Etidronate)唑来膦酸(Zoledronicacid)MOA焦磷酸盐类似物(骨代谢的天然抑制剂)吸附羟磷灰石，阻断其溶解和吸收↓破骨细胞数量Efficacy抗骨吸收最强↑BMD4-8%over3years,asmuchas10%over10years↓fracturesby30-50%阿仑膦酸:beststudied,documentedfor≃10years停药时BMD↓远远<雌激素停药Onecomparativestudy:BMD↑:阿仑膦酸75mgqwk>利塞膦酸35mgqwksideeffectorfracturerates:nodifferenceDosingDrug预防治疗Risedronate(利塞膦酸)35mgweekly35mgweeklyAlendronate(阿仑膦酸)35mgweekly70mgweeklyIbandronate(依班磷酸)150mgmonthly150mgmonthly吸收差，须空腹服用(不要与Ca剂或其他药物共同服用)服用后需背部直立半小时,否则刺激食道,可造成胃酸返流AdverseEffects胃灼热、腹痛、痢疾对食道非常刺激，大量水送服空腹半小时内避免躺卧罕见严重肌肉或关节疼痛Zoledronicacid唑来膦酸statisticallysignificantreductionsinnearlyalltypesoffracturesassessed,withrelativeriskreductionsrangingfrom0.23to0.73attimepointsfrom24to36monthsafterinitiationoftreatment.Zoledronicacid唑来膦酸DosingOsteoporosistreatment,postmenopausal,

male,

steroid-induced5mgIVq12monthOsteoporosisprevention,postmenopausal5mgIVq24month低血钙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唑来膦酸Adverseevents:肌痛关节痛发热寒颤流感症状acompositeofthesesysptomOR6.39(5.76-7.09)Anabolicdrugs合成代谢类药物甲状旁腺激素衍生物(ParathyroidHormonederivative)锶(Strontium)氟化物(Fluoride)Teriparatide(特立帕肽)a34aminoacidportionofParathyroidHormonemolecule

(甲状旁腺激素衍生物)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(激素替代疗法)orraloxifene(雷洛昔芬)Denosumab(迪诺单抗)MOA:inhibitingosteoclastformationDose:60mgSCq6monthOsteoprosis,postmenopausal/maleBoneloss,cancertreatment-inducedDenosumab(迪诺单抗)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其他治疗OtherTherapiesThiazidediuretics(噻嗪类利尿剂)↓urinaryCaexcretion,mayretardbonelosswhether↓fractureshasnotbeentestedinarandomizedtrialβblocker(β受体阻滞剂)↓fracturesin1case-controlstudyStatin(他汀类)somecase-controlstudiesfound↓fracturesrecentlargeprospectivestudiesfoundnobenefitCombinations组合治疗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