系統(tǒng)性紅斑狼瘡的骨質(zhì)疏松與皮質(zhì)激素的相關性研究GCinducedosteoporosis

1、系統(tǒng)性紅斑狼瘡的骨質(zhì)疏松與皮質(zhì)激素的相關性研究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 不同部位骨丟失不同Hand Femur Spine腰椎骨丟失與GC強相關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干預措施實施時機分為三個時機：第一時機 無論BMD多少，一開始用糖皮 質(zhì)激素就實施干預第二時機 激素治療前發(fā)現(xiàn)BMD低時或治 療后出現(xiàn)BMD降

18、低時第三時機 糖皮質(zhì)激素治療過程中發(fā)生骨折 后才實施干預 GIOP-ACR Guideline(1)Patient begining therapy with GC ( 5 mg/day) of 3 m:糾正對OP不良的生活習慣 停止或少吸煙 減少過度飲酒負重體育鍛煉指導開始補鈣開始補充VitD (plain or activated form).Bisphosphonate處方 (絕經(jīng)期前婦女使用小心). long-term GC (equivalent of 5 mg/day):糾正對OP不良的生活習慣 停止或少吸煙 減少過度飲酒負重體育鍛煉指導開始補鈣開始補充VitD (plain or

19、 activated form).如缺乏或有臨床指征-HRT測定腰椎和/或髖關節(jié)BMD. If BMD abnormal (i.e., T-score below -1)BPT (絕經(jīng)期前婦女使用小心). BPT有禁忌或不能耐受calcitonin If BMD is normal隨診，每年或每兩年復查BMD.GIOP-ACR Guideline (2)Guideline英國（Bone and Tooth Society of Great Britain, the National Osteoporosis Society and the Royal College of Physicians

20、）口服 GC可引起髖關節(jié)和脊柱骨折危險增加(Level Ia). 盡管大劑量風險最大，但每天小于7.5 mg也會引起風險增加 (Level III).治療開始骨折風險迅速增加，停藥后骨折風險迅速下降(Level III). 口服GC頭幾個月BMD丟失最大(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英國（Bone and Tooth Society of Great Britain, the National Osteoporosis Society and the Royal College of Physicians）GC對骨折風險增加的影響較低BMD更顯著(Level Ia).對特定BMD,GIOP較絕經(jīng)后OP更易引起骨折。有高風險患者，如65歲，或有骨折史，在開始用GC時即應該用保護骨治療(Grade A). 此時不一定要測骨密度對其它患者，在開始用GC

22、時應該用DEXA測定BMD評價骨折風險(Grade C). 對有骨折史患者應該排除其它繼發(fā)OP原因 (Grade C).Guideline英國（Bone and Tooth Society of Great Britain, the National Osteoporosis Society and the Royal College of Physicians） 一般原則包括盡量少用GC,使用不同劑型或方法，盡量用其它IC替代 (Grade C). 營養(yǎng)，充足鈣吸收，必要體育鍛煉，減少吸煙和酗酒 (Grade C).不同治療在預防和治療GIOP及對脊柱和髖關節(jié)BMD的影響見表 1(Level

23、 Ia).盡管骨折并不是這些研究的原發(fā)終點，etidronate, alendronate and risedronate可減少骨折 (Level Ib).Drug RxGuideline英國（Bone and Tooth Society of Great Britain, the National Osteoporosis Society and the Royal College of Physicians） 口服GC3月以上，應進行BMD測定應行治療 (Level IV), 在治療時應考慮年齡對骨折影響 (Grade C).盡管GIOP治療療效如何監(jiān)測意見不一，但有些患者在治療1-2年后

24、通過脊柱BMD測定提示有顯著反應 (Level IV).GIOP-Belgium Guideline所有患者補 Ca and Vit D. 規(guī)律鍛煉， No煙酒 像絕經(jīng)婦女和雄激素水平低男性一樣，對年輕絕經(jīng)婦女也考慮HRT. 長期GC加用BPT GIOP-Belgium Guideline Ca and VitD一線治療: GC減少腸鈣吸收 不需聯(lián)合其它7.5 mg/D and/or3m其它情況與其它有效藥物聯(lián)合.GIOP-Belgium Guideline Ca and VitD 在服用GC過程中可作為維持治療 停用激素可終止補充: 停用激素BMD可恢復 系統(tǒng)性紅斑狼瘡的骨質(zhì)疏松與皮質(zhì)激素的相關性-北京協(xié)和醫(yī)院風濕免疫科資料 研究對象1998年3月到1999年1月北京協(xié)和醫(yī)院風濕免疫科SLE58例，男性3例，女性55例平均年齡(33.89.5)歲，病程(76.685.8)個月，激素治療時間(39.253.7)個月，激素累積量（按潑尼松折算）(21.125.0)g。研究階段還