內(nèi)科學教學課件：骨質疏松

骨質疏松

osteoporosisosteoporosisSystemicdisorderofbonemetabolismCharacterizedbylowbonemassdensityandimpairmentofthemicrostructureofbonetissueIncreasedbonefragility,susceptibletofracture

Osteoporosis:WorldwidePrevalenceAffects200millionwomenworldwide1-1/3ofwomenaged60to70-2/3ofwomenaged80orolderApproximately30%ofwomenovertheageof50haveoneormorevertebralfractures21.

InternationalOsteoporosisFoundationOsteoporosInt1996,6:2332.Dennison,2000

Osteoporoticfracturesinwomen:comparisonwithotherdiseases1500000*0500100015002000OsteoporoticFractures *annualincidenceallages?annualestimatewomen29+ ?annualestimatewomen30+

§1996newcases,allages513000?228000?184300§750000vertebral250000

othersites250000

forearm250000

hipHeartAttackStrokeBreastCancerAnnualincidencex1000RiggsBL,MeltonLJ.Bone1995HeartandStrokeFacts,1996,AmericanHeartAssociationCancerFacts&Figures,1996,AmericanCancerSocietyPrevalenceofvertebralfractures

inBeijing:menvs.women%Zhang,Nevitt,Xu.FelsonandCummings,2000PrevalenceofOsteoporosisinPostmenopausalChineseWomen101020304050607040-49 50-59 60-69 70-79 80-89 40-49 50-59 60-69 70-79 80-89%ofWomen1.325.453.360.253.80011.128.942.3SpineFemoralNeckAgeRangeAgeRange1BaseduponHologiccut-offvalues.Spine=0.717g/cm2,femoralneck=0.493g/cm2Wooetal.OsteoporInt(2001);12:289-293ImpactofOsteoporosis

inPostmenopausalChineseWomen34%ofChinesewomeninHongKong(age

50years)haveosteoporosisatthelumbarspine1PrevalenceofvertebralfracturesinwomenfromBeijingincreasesfrom4.9%(age50-59years)to36.6%(age80+years)2ElderlyChinesewomen(age70-79years)withavertebraldeformityhavea2.3-foldincreasedriskofbackpainandalowermoralescore3Hoetal.Maturitas1999:32;171-8Lingetal.JBoneMineralRes2000:15;2019-25Lauetal.CalcifTissInt1998:63;1-4RatesofhipfracturesinBeijing45505560657075808590+01020304050WomenMenAgeRateper10,000HipfracturesareassociatedwithmorbidityandmortalityCooper,19971yearafterahipfracture:30%40%80%UnabletowalkindependentlyPermanentdisability20%DeathUnabletocarryoutatleast1independentactivityofdailylivingPatients(%)OSTEOPOROSIS:

AMAJORHEALTHPROBLEMFORBOTH

MENANDWOMEN11OSTEOPOROSIS

“ Askeletaldisorder characterizedbycompromisedbone

strength

predisposingtoanincreasedriskoffracture.”

HealthyboneOsteoporoticboneNIHConsensusDevelopmentConferenceonOsteoporosis,2000.+BonestrengthDeterminantsofBoneStrength=BonedensityBoneQuality+BonestrengthDeterminantsofBoneStrength=BonedensityOtherbonequalitiesAdiagnosticgoldstandardCentralDXA(dualX-rayabsorptiometry)isthegoldstandardfordiagnosisMeasuresthemostimportantfracturesites(hipandspine)CanbeusedtomonitorresponsetotherapyHologicGELunarNorlandCentralDXABoneDensityMeasurementsRelationshipBetweenBMDand

FractureRiskinUntreatedPatientsRelativeRiskofFractureBonedensity(SDunits)-1SD2xReducedbonemassisakeyriskfactorforthefragilityfractureReducedbonedensityreflectsreducedbonestrengthRateofremodeling(turnover)MicroarchitectureBonesizeandshapeMineralization+BonestrengthDeterminantsofBoneStrength=BonedensityOtherbonequalitiesResorptionReversalFormationRestingphaseActivationFROM:PrimerontheMetabolicBoneDiseasesandDisordersofMineralMetabolism;2ndEd.BoneturnoverisanintrinsicallynegativeexperienceintheadultskeletonActivationFrequency(#PerYear),Median(Age49)n=75(Age55)n=75(Age60)n=34(Age67)n=90(Nonosteoporotic)(Osteoporotic)Reckeretal.JBoneMinerRes.2004;19:1628–1633.RateofBoneTurnover(ActivationFrequency)IncreasesAfterMenopauseTherateofboneturnoverincreasesaftermenopauseandremainsincreasedinuntreatedwomenwithosteoporosisGarneroP,etal.JBoneMinerRes1996;11:1531-8.FoldfractureriskBoneturnoverisanindependentriskfactorforfractureWomenover75yearsold;n=75982.71.94.10.01.02.03.04.05.0LowBMDHighboneturnoverLowBMD+highboneturnoverclassificationprimaryTypeI（postmenopausal）TypeII（elderly）Secondary:endocrinedisease,hematologicdisease,GI,immobilizationEtiologyandPathogenesisboneremodeling：

boneresorption,boneneogenesis comparativelystableboneturnoverBoneresorptionandrelatedfactorsPregnancyandbreastfeeding：lowintakeandmalabsorptionofminiralsubstance;mobilizebonesalttomaintainthecalciumlevelestrogen：lowerpeakbonemass;increasedosteoclasticactivity,increasedbonelossActivatedvitaminD：increasegenesisofcalciumbindingprotein,increasethecalciumabsorptioninGIcalcitonin：inhibitthedifferentiation,maturationandactivityofosteroclastsBoneresorptionandrelatedfactorsPTH：targetsonosteoblasts;inhancetheactivityofosteoclasts.cytokines：IL-6:stimulatethedifferentiationandactivationofearlyosteoclasts,stimulatetheboneresorption.。IL-1inducetheosteoprogenitorcellstodifferentiatetoosteoclastsTGF-α、TNFmaysimulatetheboneresorptionandaccelaeratetheboneloss.BoneformationandrelatedfactorsGeneticfactor：70－80％ofthePeakBoneMass(PBM)Calciumuptake：calciumisthemaincomponentsofboneminiralsLifestyleandenvironment：physicalexercisestimulatesosteoblasticactivity.smoking,heavydrinking,highsaltintake,lesssunshineandimmobilizationareriskfactors.SecondaryosteoporosisEndocrinediseasehyper-parathyroidismCushingSyndromeSexualhormonehypofunctionhyperthyroidismprolactinomadiabetesacromagalySecondaryosteoporosisLiverdiseaseandnutritiousdiseaseLowerGIabsorptionLoweractivityof25-hydroxylaseLowercapacityofinactivateboneresorptionfactorbyliverMalabsorptionofvitDHematologicdiseaselymphomaLymphacyticproliferativemalignancedrugsheparinAnti-convulsivedrugsphenytoinsBarbituratecarmacepinecyclosporinCRHagonist、GnRHantagonist、LHRHagonistApoptosisofbonetissue

andrelatedfactorsBonemetabolismandmaintainenceofbonemassdependsonthecellnumbersofbonetissue.Thenumberofbonetissuecellsdependsonthecelldifferentiationandmaturecellsapoptosis.Biphosphateandcalcitoninmaystoptheapoptosisofbonecells.ConsequencesofIncreased

BoneRemodeling.ConsequencesofIncreasedBoneRemodelingConsequencesofIncreasedBoneRemodelingConsequencesofIncreasedBoneRemodelingConsequencesofIncreasedBoneRemodelingConsequencesofIncreasedBoneRemodelingdiagnosisAccordingtobonemassdensity(BMD)osteopenia:lowerthan1SDbuthigherthan2.5SDofPBMofcounterpartswithsamegenderosteoporosis：lowerthan-2.5SDofPBMSevereosteoporosis：withoneormorespontaneousfracture.-4.0-3.5-3.0-2.5-2.0-1.5-1.0-0.50+0.5+1.0InterpretingT-scores(WHO)T-scoreOsteoporosisNormalBoneMassLowBoneMass(Osteopenia)Correlateswithlifetimefractureriskforpost-menopausalCaucasianWomendiagnosisPrimaryorsecondary?：ExclusivemethodPrimaryosteoporosiscanbediagnosedonlyafterallthesecondarycausesbeexcluded.ClinicalmanifestationBackpainSystemicbonepainLesscapacityofweightburdenNosymptomsinmildcaseInseverecase,“shortstature”,fractureandhumpbackmayoccur.Higgs,2003LabtestandspecifictestBiochemicalparametersofbonemetabolism：Boneresorption：Fastingurinecalcium,24hoursurinecalcium,urineCa/Crurinehydroxylprolineandhydroxyllysine(尿羥脯氨酸和羥賴氨酸)血漿抗酒石酸酸性磷酸酶(TRAP,titrate-resistantacidphosphatase)尿膠原吡啶啉和脫氧膠原吡啶啉(pyridinolineanddeoxypyridinoline)血清1型膠原交聯(lián)C-末端肽（S-CTX）Boneformation：血清堿性磷酸酶(ALP)骨鈣素(osteocalcin)I型前膠原羧基端前肽（PICP,propeptideoftypeIprocollagen）1型原膠原N-端前肽（PINP)

90%的骨基質是由I型膠原蛋白組成的，I型前膠原有N-(氨基)和C-(羧基)延長端

I型膠原合成過程釋放P1NP，每合成一個膠原分子，就會有一個分子的PINP產(chǎn)生PINP是I型膠原沉積的特異性標志物，因此是一個具有真正意義的骨形成標志物

成骨細胞活性增強，前膠原蛋白合成增多，血PINP濃度增高直接反應成骨細胞合成骨膠原的速率，可監(jiān)測成骨細胞活力和骨形成情況P1NP(1型前膠原氨基端延長肽)β-CrossLaps(血I型膠原蛋白的羧基端降解產(chǎn)物)

血I型膠原交聯(lián)羧基端肽（S-CTX）血β-CrossLaps是骨吸收過程中，1型膠原被被破骨細胞溶解釋放入血的片段

β-CrossLaps從腎臟排泄血β-CrossLaps檢測很穩(wěn)定，尿β-CrossLaps檢測穩(wěn)定性有待確定MRI

(Oscalcis,wrist,hip)BoneBiopsy(Histomorphometry,Micro-CT)BoneMarker(NTX,DPD,BsAP)BONEQUALITYSTUDYDXA(Spine,Hip,Forearm,OsCalcis)treatmentAnti-symptomatic：NSAID、calcitoninforpainOrthopedicmanagementtreatmentgeneral：exercisecalciumagentsVitDLifestylemodificationAnti-etiologictreatmentRecommendationsforCalciumandVitaminDCalciumandvitaminDsufficiencyareimportantCalciumintakeshouldbe1200-1500mg/day維生素D對骨骼和礦物質的作用1.需要完整的皮膚、肝臟、腎臟和腸道來進行合成和吸收2.1,25(OH)2D作用于小腸，增加上皮細胞中鈣通道和鈣結合蛋白的表達3.1,25(OH)2D通過調節(jié)成骨細胞RANKL的表達來誘導破骨細胞成熟4.這些作用增加了血清鈣和磷的水平，促進了骨礦化紫外線加熱7-脫氫膽固醇皮膚飲食維生素D3腎臟肝臟靶器官(包括腎臟)排泄的

代謝產(chǎn)物腸道骨骼血清鈣

和磷維生素D的非傳統(tǒng)作用抑制細胞生長調節(jié)細胞凋亡調節(jié)免疫反應負向調節(jié)腎素-血管緊張素系統(tǒng)控制胰島素的分泌控制肌肉的生長和分化Holick,NEJM2007細胞因子調節(jié)活化的T淋巴細胞免疫球蛋白

合成免疫調節(jié)活化的B淋巴細胞脂多糖或

結核結節(jié)巨噬細胞/

單核細胞結核

結節(jié)天然免疫甲狀

旁腺血液腎臟胰腺乳腺、結腸、前列腺等胰島素增加控制血糖調節(jié)血壓調節(jié)甲狀旁腺激素增強p21和p27抑制血管生成

誘導凋亡甲狀旁腺激素減少腎素減少抗菌肽

增加維生素D3-23羧酸25OHD的連續(xù)水平BoonenS,etal.OsteoporosInt.2004;15:511–9.LipsP.EndocrRev.2001;22:477–501.HeaneyRP.OsteoporosInt.2000;11:553–5.HeaneyRP.AmJClinNutr.2004;80(suppl):1706S-9S.ThomasMK.NEJM.1998;338:777–83.(ng/ml)

0255075100125150(nmol/L)“正?！?/p>

0102030405060“不足”“缺乏”“典型的缺乏”？ng/mlnmol/LTherapeuticsofcalciumandvitaminDInosteoporosis,adequatecalciumandvitaminDarenecessarybutnotsufficientforthetreatmentofosteoporosisDataforefficacyofcalciumandvitaminDaloneinosteoporosisareavailableonlyfordeficientpopulationsItisunlikelythatosteoporosiscanbeoptimallytreatedorpreventedwithcalciumandvitaminalonePharmacologicalapproachesaregenerallyneededtotreatosteoporosisHormonetherapyEvistaBisphosphonatesCalcitoninTeriparatide(1-34rhPTH)StrontiumRanelate

Therapiesforosteoporosis

tobediscussed

BonedensityisimprovedSpecifictreatmentHormonereplacementtherapy：MosteffectivetherapyforpostmenopausalosteoporosisThosearoundmenopausalperiodwithorwithoutbonemasslossEarlyovaryfailureorafterovarysectionelderlycontraindication：BreastcancerandendometriumcancerVaginalbleedingwithunkownreasonActiveliverdiseaseSLEThromboembolicdiseasemonitoring：breast,endometriumandgynecologicexamSpecifictreatmentprogestin：MayenhanceeffectofestrogenAntagonizethehyperplasiaofendometriumandbreasttissueandrogen：IncreasethebonetissuedifferentiationandactivityofALPIncreasetheIGF－2andTGF－βsynthesisLivertoxicityandfluidretentionSpecifictreatmentcalcitonin：inhibitorofboneresorptionHighturnoverOPWithorwithoutfracture,bettereffectinpain-killingOstitiswithdistortionAcutehypercalcemiaorhypercalcemiacrisisMultiplepeptide,contraindicatedinsensitivepatientsBisphosphate:inhibittheactivityofosteoclast抑制焦膦酸法尼醇合酶的活性Specifictreatmentbisphosphate：changethepropertyofbonematrix,inhibittheosteo