系统性红斑狼疮的骨质疏松与皮质激素的相关性.ppt

GC induced osteoporosis 北京协和医院风湿免疫科 张 烜 Introduction GCs are effective in many rheumatic diseases But GC induced OP is a common side effect Trabecular rich sites eg spine&ribs are especially at risk Effective Rx can prevent or reverse GC bone loss OP in RA on GC Rx 多因素 RA Osteoclast 活化(TNFa，RANK)Physical inactivity GC Rx Menopause 不同部位骨丢失不同 Hand Femur Spine 腰椎骨丢失与GC强相关 Pathophysiology Most of the biological activities mediated via Passage across cell membrane attachment to cytosolic GC receptor binding to GC response element&regulating gene transcription May act via other transcription factors:activated protein(AP)-1 NFB GC receptor&binding Effects of GC on bone metabolism Bone formation Most important Bone resorbtion Probably only during 1st 6 12 months of Rx OC production&postponed apoptosis Longterm,bone turnover Intestinal absorbtion of calcium Urinary phosphate&calcium loss Direct effect on kidney Secondary Hyperparathyroidism Bone loss Early but temporary Bone formation Most important Direct effects on osteoblasts cell replication osteocyte apoptosis type 1 collagen gene expression Indirect effects synthesis,release,receptor binding or binding proteins of growth factors eg IGF I&II related to sex steroid production Effects of GC on bone metabolism Epidemiology Common First recognised by Cushing Risk of OP with GC Rx unclear Reported in up to 50%on longterm Rx Fracture risk Prospective data lacking Retrospective cohort study 244 236 pts on GC Rx vs 244 235 control pts(UK GP registry)RR of vertebral#2.6,hip#1.6,nonvertebral#1.3 Estimated vertebral fracture incidence 13 22%in first yr of Rx from calcium treated control arms of recent randomised control trials Cumulative prevalence of vertebral fractures:Up to 28%(cross sectional studies)Factors associated with fracture risk with GC Rx Age BMD Initial&subsequent to GC Rx Postmenopausal women highest risk Glucorticoid dose Cumulative&mean daily dose Duration of exposure Underlying disease Relative Risk of Fracture Risk factors for bone loss&fracture Risk varies according to age,dose&underlying disease The case for primary prevention is strongest for postmenopausal women&older men with low BMD Bone Density&Fracture Risk In postmenopausal women a in 1 SD in BMD is associated with 2 x#risk In pts on GC Rx risk may be greater at lower BMD Dose,duration&formulation of Rx&Bone Loss dose GC Rx(10mg/yr)vertebral bone loss 5-10%/yr dose lower rate of bone loss Bone loss most rapid in 1st 6 12 months of Rx GC bone loss appears reversible Rx of Cushings Inhaled steroids less likely to have systemic effects except at high doses Investigations DEXA scan Biochemical markers Bone formation eg osteocalcin Fall within a few hours of Rx Bone resorption Rise after acute administration Treatment of GC OP Primary prevention Most rapid bone loss within 1st 6 12 months of Rx Secondary prevention Prevention of GC-induced bone loss Use lowest dose GC possible Minimise lifestyle risk factors smoking Individualised exercise programmes Drug Rx Calcium Vitamin D&metabolites HRT Bisphosphonates PTH Calcitonin Drug Rx Beneficial effects in spine&hip demonstrated in spine&hip by several interventions Post hoc/safety analysis of trials of etidronate,alendronate&residronate vertebral fractures Calcium GC intestinal calcium absorbtion&urinary calcium excretion Conflicting data on efficacy in primary prevention ACR:Calcium intake(diet/suppl)1000 1500 mg/d Vitamin D active-metabolites Calcitriol(1,25 dihydroxy vitamin D)Alfacalcidiol(1 vitamin D)1o prevention:BMD vs placebo 2o prevention:active vit D metabolites better than simple vit D BMD/fracture/pain Risk:hypercalcaemia&hypercalcuria HRT 1 controlled trial in men BMD with testosterone vs calcium 1 randomised control trial in postmenopausal women BMD with oestrogen vs calcium No trials in premenopausal women No fracture data Reserved for pts with hormone deficiency Bisphosphonates bone resorbtion May GC induced apoptosis of osteoblasts Alendronate Combined analysis of trials(477 pts)vertebral/femoral neck/trochanter&whole body BMD Post hoc analysis of vertebral fractures favoured Alendronate in postmenopausal women Risedronate Primary prevention trial(224 pts)Placebo+calcium vs Risedronate After 1 yr,BMD on Risedronate unchanged but with placebo Incidence 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 women Study of 290 pts L spine&femoral neck BMD vs Ca+Vit D Not powered to show fracture efficacy Vertebral fractures:15%controls;5%Risedronate Suggested 70%fracture risk PTH lifespan on osteoclasts&osteoblasts osteoblast no.BMD in postmenopausal women with GC induced OP Study not powered to determine effect on fracture rate Calcitonin Variable data on effect on BMD Bone pain induced by fractures Thiazide diuretics&salt restriction urinary calcium excretion Effect on BMD&fracture risk uncertain In general population,chronic thiazide Rx is a