系统性红斑狼疮的骨质疏松与皮质激素的相关性

GCinducedosteoporosis 北京协和医院风湿免疫科张烜 Introduction GCsareeffectiveinmanyrheumaticdiseasesButGCinducedOPisacommonsideeffectTrabecularrichsitesegspine ribsareespeciallyatriskEffectiveRxcanpreventorreverseGCboneloss OPinRAonGCRx 多因素RAOsteoclast活化 TNFa RANK PhysicalinactivityGCRxMenopause不同部位骨丢失不同Hand Femur Spine腰椎骨丢失与GC强相关 Pathophysiology MostofthebiologicalactivitiesmediatedviaPassageacrosscellmembraneattachmenttocytosolicGCreceptorbindingtoGCresponseelement regulatinggenetranscriptionMayactviaothertranscriptionfactors activatedprotein AP 1NF B GCreceptor binding EffectsofGConbonemetabolism BoneformationMostimportant BoneresorbtionProbablyonlyduring1st6 12monthsofRx OCproduction postponedapoptosisLongterm boneturnover Intestinalabsorbtionofcalcium Urinaryphosphate calciumlossDirecteffectonkidneySecondaryHyperparathyroidism BonelossEarlybuttemporary Boneformation MostimportantDirecteffectsonosteoblasts cellreplication osteocyteapoptosis type1collagengeneexpressionIndirecteffects synthesis release receptorbindingorbindingproteinsofgrowthfactorsegIGFI IIrelatedtosexsteroidproduction EffectsofGConbonemetabolism Epidemiology CommonFirstrecognisedbyCushingRiskofOPwithGCRxunclearReportedinupto50 onlongtermRxFractureriskProspectivedatalackingRetrospectivecohortstudy244236ptsonGCRxvs244235controlpts UKGPregistry RRofvertebral 2 6 hip 1 6 nonvertebral 1 3Estimatedvertebralfractureincidence13 22 infirstyrofRxfromcalciumtreatedcontrolarmsofrecentrandomisedcontroltrialsCumulativeprevalenceofvertebralfractures Upto28 crosssectionalstudies FactorsassociatedwithfractureriskwithGCRx AgeBMDInitial subsequenttoGCRxPostmenopausalwomen highestriskGlucorticoiddoseCumulative meandailydoseDurationofexposureUnderlyingdisease RelativeRiskofFracture Riskfactorsforboneloss fracture Riskvariesaccordingtoage dose underlyingdiseaseThecaseforprimarypreventionisstrongestforpostmenopausalwomen oldermenwithlowBMD BoneDensity FractureRisk Inpostmenopausalwomena in1SDinBMDisassociatedwith 2x riskInptsonGCRxriskmaybegreateratlowerBMD Dose duration formulationofRx BoneLoss doseGCRx 10mg yr vertebralboneloss5 10 yr dose lowerrateofbonelossBonelossmostrapidin1st6 12monthsofRxGCbonelossappearsreversibleRxofCushing sInhaledsteroidslesslikelytohavesystemiceffectsexceptathighdoses Investigations DEXAscanBiochemicalmarkersBoneformationegosteocalcinFallwithinafewhoursofRxBoneresorptionRiseafteracuteadministration TreatmentofGCOP PrimarypreventionMostrapidbonelosswithin1st6 12monthsofRxSecondaryprevention PreventionofGC inducedboneloss UselowestdoseGCpossibleMinimiselifestyleriskfactorssmokingIndividualisedexerciseprogrammesDrugRxCalciumVitaminD metabolitesHRTBisphosphonatesPTHCalcitonin DrugRx Beneficialeffectsinspine hipdemonstratedinspine hipbyseveralinterventionsPosthoc safetyanalysisoftrialsofetidronate alendronate residronate vertebralfractures Calcium GC intestinalcalciumabsorbtion urinarycalciumexcretionConflictingdataonefficacyinprimarypreventionACR Calciumintake diet suppl 1000 1500mg d VitaminDactive metabolites Calcitriol 1 25dihydroxyvitaminD Alfacalcidiol 1 vitaminD 1oprevention BMDvsplacebo2oprevention activevitDmetabolitesbetterthansimplevitD BMD fracture painRisk hypercalcaemia hypercalcuria HRT 1controlledtrialinmen BMDwithtestosteronevscalcium1randomisedcontroltrialinpostmenopausalwomen BMDwithoestrogenvscalciumNotrialsinpremenopausalwomenNofracturedataReservedforptswithhormonedeficiency Bisphosphonates boneresorbtionMay GCinducedapoptosisofosteoblasts Alendronate Combinedanalysisoftrials 477pts vertebral femoralneck trochanter wholebodyBMDPosthocanalysisofvertebralfracturesfavouredAlendronateinpostmenopausalwomen Risedronate Primarypreventiontrial 224pts Placebo calciumvsRisedronateAfter1yr BMDonRisedronateunchangedbut withplaceboIncidenceofvertebralfractures17 withcalciumvs5 7 withRisedronate5mg p 0 072 Vertebralfracturesseenonlyinpostmenopausalwomen5 RisedronateSuggested70 fracturerisk PTH lifespanonosteoclasts osteoblasts osteoblastno BMDinpostmenopausalwomenwithGCinducedOPStudynotpoweredtodetermineeffectonfracturerate Calcitonin VariabledataoneffectonBMD Bonepaininducedbyfractures Thiazidediuretics saltrestriction urinarycalciumexcretionEffectonBMD fractureriskuncertainIngeneralpopulation chronicthiazideRxisassociatedwith BMDInelderlyptsRxfor 2yrs hipfractures GIOP干预措施实施时机 分为三个时机 第一时机无论BMD多少 一开始用糖皮质激素就实施干预第二时机激素治疗前发现BMD低时或治疗后出现BMD降低时第三时机糖皮质激素治疗过程中发生骨折后才实施干预 long termGC equivalentof5mg day 纠正对OP不良的生活习惯停止或少吸烟减少过度饮酒负重体育锻炼指导开始补钙开始补充VitD plainoractivatedform 如缺乏或有临床指征 HRT测定腰椎和 或髋关节BMD IfBMDabnormal i e T scorebelow 1 BPT 绝经期前妇女使用小心 BPT有禁忌或不能耐受 calcitoninIfBMDisnormal 随诊 每年或每两年复查BMD GIOP ACRGuideline 2 Guideline 英国 BoneandToothSocietyofGreatBritain theNationalOsteoporosisSocietyandtheRoyalCollegeofPhysicians 口服GC可引起髋关节和脊柱骨折危险增加 LevelIa 尽管大剂量风险最大 但每天小于7 5mg也会引起风险增加 LevelIII 治疗开始骨折风险迅速增加 停药后骨折风险迅速下降 LevelIII 口服GC头几个月BMD丢失最大 LevelIIa TheeffectsofinhaledGCsonBMDarelesscertain althoughsomestudiesreportincreasedbonelosswithhighdoses LevelIIa andlong termuseoflowerdosesmayresultinsignificantdeficitsofBMD LevelIII Guideline 英国 BoneandToothSocietyofGreatBritain theNationalOsteoporosisSocietyandtheRoyalCollegeofPhysicians GC对骨折风险增加的影响较低BMD更显著 LevelIa 对特定BMD GIOP较绝经后OP更易引起骨折 有高风险患者 如 65岁 或有骨折史 在开始用GC时即应该用保护骨治疗 GradeA 此时不一定要测骨密度对其它患者 在开始用GC时应该用DEXA测定BMD评价骨折风险 GradeC 对有骨折史患者应该排除其它继发OP原因 GradeC Guideline 英国 BoneandToothSocietyofGreatBritain theNationalOsteoporosisSocietyandtheRoyalCollegeofPhysicians 一般原则包括尽量少用GC 使用不同剂型或方法 尽量用其它IC替代 GradeC 营养 充足钙吸收 必要体育锻炼 减少吸烟和酗酒 GradeC 不同治疗在预防和治疗GIOP及对脊柱和髋关节BMD的影响见表1 LevelIa 尽管骨折并不是这些研究的原发终点 etidronate alendronateandrisedronate可减少骨折 LevelIb DrugRx Guideline 英国 BoneandToothSocietyofGreatBritain theNationalOsteoporosisSocietyandtheRoyalCollegeofPhysicians 口服GC3月以上 应进行BMD测定 GradeC Tscore 1 5应行治疗 LevelIV 在治疗时应考虑年龄对骨折影响 GradeC 尽管GIOP治疗疗效如何监测意见不一 但有些患者在治疗1 2年后通过脊柱BMD测定提示有显著反应 LevelIV GIOP BelgiumGuideline 所有患者补CaandVitD 规律锻炼 No烟酒像绝经妇女和雄激素水平低男性一样 对年轻绝经妇女也考虑HRT 长期GC加用BPT GIOP BelgiumGuidelineCaandVitD 一线治疗 GC减少肠钙吸收不需联合其它 7 5mg Dand or 3m其它情况与其它有效药物联合 GIOP BelgiumGuidelineCaandVitD 在服用GC过程中可作为维持治疗停用激素可终止补充 停用激素BMD可恢复 系统性红斑狼疮的骨质疏松与皮质激素的相关性 北京协和医院风湿免疫科资料 研究对象 1998年3月到1999年1月北京协和医院风湿免疫科 SLE58例 男性3例 女性55例平均年龄 33 8 9 5 岁 病程 76 6 85 8 个月 激素治疗时间 39 2 53 7 个月 激素累积量 按泼尼松折算 21 1 25 0 g 研究阶段还符合 1 年龄 45岁 2 能自由活动 3 肾功能正常 4 无其他代谢性骨病或股骨头坏死 骨质疏松的诊断按世界卫生组织1994年提出的标准 1 骨密度值低于正常年轻人峰值2 5个标准差 s 为骨质疏松 2 骨密度值在正常年轻人峰值以下1 0 2 5s之间为骨量减少 方法 1 患者均有详细的病历 包括性别 年龄 骨密度或骨超声速率检查的时间 病程 激素疗程及累积量 各种激素均折合为泼尼松量 2 骨密度测量采用双能X线骨密度仪 DXA 正位测量L2 L4 股骨颈 Ward三角和大转子骨密度 3 骨超声速率使用Soundscan2000型骨超声仪 测量部位为右胫骨内髁下缘至髌骨下缘连线的中点 49例作了DXA骨密度测定 26例作了骨超声速率测定 2