系统性红斑狼疮的骨质疏松与皮质激素的相关性研究GCinducedosteoporosis

1、系统性红斑狼疮的骨质疏松与皮质激素的相关性研究GC induced osteoporosisIntroductionGCs are effective in many rheumatic diseases But GC induced OP is a common side effectTrabecular rich sites eg spine & ribs are especially at riskEffective Rx can prevent or reverse GC bone loss OP in RA on GC Rx多因素RAOsteoclast 活化 ( TNFa，RANK

2、)Physical inactivityGC RxMenopause 不同部位骨丢失不同Hand Femur Spine腰椎骨丢失与GC强相关PathophysiologyMost of the biological activities mediated viaPassage across cell membrane attachment to cytosolic GC receptor binding to GC response element & regulating gene transcriptionMay act via other transcription factors:a

3、ctivated protein (AP)-1NFBGC receptor & bindingEffects of GC on bone metabolism Bone formationMost important Bone resorbtion Probably only during 1st 6 12 months of Rx OC production & postponed apoptosisLongterm, bone turnover Intestinal absorbtion of calcium Urinary phosphate & calcium loss Direct

4、effect on kidneySecondary Hyperparathyroidism Bone loss Early but temporary Bone formationMost important Direct effects on osteoblasts cell replication osteocyte apoptosis type 1 collagen gene expressionIndirect effects synthesis, release, receptor binding or binding proteins of growth factors eg IG

5、F I & II related to sex steroid productionEffects of GC on bone metabolismEpidemiologyCommonFirst recognised by CushingRisk of OP with GC Rx unclearReported in up to 50% on longterm RxFracture riskProspective data lackingRetrospective cohort study 244 236 pts on GC Rx vs 244 235 control pts ( UK GP

6、registry)Estimated vertebral fracture incidence13 22% in first yr of Rxfrom calcium treated control arms of recent randomised control trialsCumulative prevalence of vertebral fractures : Up to 28% (cross sectional studies) Factors associated with fracture risk with GC RxAgeBMDInitial & subsequent to

7、 GC RxPostmenopausal women highest riskGlucorticoid doseCumulative & mean daily doseDuration of exposureUnderlying diseaseRelative Risk of FractureRisk factors for bone loss & fractureRisk varies according to age, dose & underlying diseaseThe case for primary prevention is strongest for postmenopaus

8、al women & older men with low BMDBone Density & Fracture RiskIn postmenopausal women a in 1 SD in BMD is associated with 2 x # riskIn pts on GC Rxrisk may be greater at lower BMDDose, duration & formulation of Rx & Bone Loss dose GC Rx ( 10mg/yr) vertebral bone loss 5- 10 % / yr dose lower rate of b

9、one lossBone loss most rapid in 1st 6 12 months of RxGC bone loss appears reversibleRx of CushingsInhaled steroids less likely to have systemic effects except at high dosesInvestigationsDEXA scanBiochemical markersBone formation eg osteocalcinFall within a few hours of RxBone resorptionRise after ac

10、ute administrationTreatment of GC OPPrimary preventionMost rapid bone loss within 1st 6 12 months of RxSecondary preventionPrevention of GC-induced bone lossUse lowest dose GC possibleMinimise lifestyle risk factors smokingIndividualised exercise programmesDrug RxCalciumVitamin D & metabolitesHRTBis

11、phosphonatesPTHCalcitoninDrug RxBeneficial effects in spine & hip demonstrated in spine & hip by several interventionsPost hoc/ safety analysis of trials of etidronate, alendronate & residronate vertebral fracturesCalciumGC intestinal calcium absorbtion & urinary calcium excretionConflicting data on

12、 efficacy in primary preventionACR :Calcium intake (diet/ suppl) 1000 1500 mg/dVitamin D active - metabolitesCalcitriol (1,25 dihydroxy vitamin D)Alfacalcidiol (1 vitamin D)1o prevention : BMD vs placebo2o prevention : active vit D metabolites better than simple vit D BMD/ fracture/ painRisk : hyper

13、calcaemia & hypercalcuriaHRT1 controlled trial in men BMD with testosterone vs calcium1 randomised control trial in postmenopausal women BMD with oestrogen vs calciumNo trials in premenopausal womenNo fracture dataReserved for pts with hormone deficiencyBisphosphonates bone resorbtionMay GC induced

14、apoptosis of osteoblasts AlendronateCombined analysis of trials (477 pts) vertebral/ femoral neck/ trochanter & whole body BMD Post hoc analysis of vertebral fractures favoured Alendronate in postmenopausal womenRisedronatePrimary prevention trial (224 pts)Placebo + calcium vs RisedronateAfter 1 yr,

15、 BMD on Risedronate unchanged but with placeboIncidence of vertebral fractures 17% with calcium vs 5.7% with Risedronate 5mg (p=0.072)Vertebral fractures seen only in postmenopausal women & men, not premenopausal womenStudy of 290 pts L spine & femoral neck BMD vs Ca + Vit DNot powered to show fract

16、ure efficacyVertebral fractures: 15% controls; 5% RisedronateSuggested 70% fracture riskPTH lifespan on osteoclasts & osteoblasts osteoblast no. BMD in postmenopausal women with GC induced OPStudy not powered to determine effect on fracture rateCalcitoninVariable data on effect on BMD Bone pain indu

17、ced by fracturesThiazide diuretics & salt restriction urinary calcium excretionEffect on BMD & fracture risk uncertainIn general population, chronic thiazide Rx is associated with BMD In elderly pts Rx for 2 yrs hip fracturesGIOP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

18、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 GIOP-ACR Guideline(1)Patient begining therapy with GC ( 5 mg/day) of 3 m: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 (plain or activated form).Bisphosphonate处方 (绝经期前妇女使用小心). long-term GC (equivalent of 5 mg/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 (plain or

19、 activated form).如缺乏或有临床指征-HRT测定腰椎和/或髋关节BMD. If BMD abnormal (i.e., T-score below -1)BPT (绝经期前妇女使用小心). BPT有禁忌或不能耐受calcitonin If BMD is normal随诊，每年或每两年复查BMD.GIOP-ACR Guideline (2)Guideline英国（Bone and Tooth Society of Great Britain, the National Osteoporosis Society and the Royal College of Physicians

20、）口服 GC可引起髋关节和脊柱骨折危险增加(Level Ia). 尽管大剂量风险最大，但每天小于7.5 mg也会引起风险增加 (Level III).治疗开始骨折风险迅速增加，停药后骨折风险迅速下降(Level III). 口服GC头几个月BMD丢失最大(Level IIa). The effects of inhaled GCs on BMDare less certain, although some studies report increased bone loss with high doses (Level IIa) and long-term use of lower doses

21、 may result in significant deficits of BMD(Level III).Guideline英国（Bone and Tooth Society of Great Britain, the National Osteoporosis Society and the Royal College of Physicians）GC对骨折风险增加的影响较低BMD更显著(Level Ia).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(Grade A). 此时不一定要测骨密度对其它患者，在开始用GC

22、时应该用DEXA测定BMD评价骨折风险(Grade C). 对有骨折史患者应该排除其它继发OP原因 (Grade C).Guideline英国（Bone and Tooth Society of Great Britain, the National Osteoporosis Society and the Royal College of Physicians） 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 (Grade C). 营养，充足钙吸收，必要体育锻炼，减少吸烟和酗酒 (Grade C).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(Level

23、 Ia).尽管骨折并不是这些研究的原发终点，etidronate, alendronate and risedronate可减少骨折 (Level Ib).Drug RxGuideline英国（Bone and Tooth Society of Great Britain, the National Osteoporosis Society and the Royal College of Physicians） 口服GC3月以上，应进行BMD测定应行治疗 (Level IV), 在治疗时应考虑年龄对骨折影响 (Grade C).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

24、通过脊柱BMD测定提示有显著反应 (Level IV).GIOP-Belgium Guideline所有患者补 Ca and Vit D. 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-Belgium Guideline Ca and VitD一线治疗: GC减少肠钙吸收 不需联合其它7.5 mg/D and/or3m其它情况与其它有效药物联合.GIOP-Belgium Guideline Ca and VitD 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(33.89.5)岁，病程(76.685.8)个月，激素治疗时间(39.253.7)个月，激素累积量（按泼尼松折算）(21.125.0)g。研究阶段还