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GC induced osteoporosis

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 .

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GC induced osteoporosis

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  1. GC induced osteoporosis 北京协和医院风湿免疫科 张 烜

  2. 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

  3. 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

  4. 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 • NFB

  5. GC receptor & binding

  6. 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

  7.  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

  8. Effects of GC on bone metabolism

  9. 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)

  10. 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

  11. Relative Risk of Fracture

  12. 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

  13. 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

  14. 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 Cushing’s • Inhaled steroids less likely to have systemic effects except at high doses

  15. Investigations • DEXA scan • Biochemical markers • Bone formation eg osteocalcin • Fall within a few hours of Rx • Bone resorption • Rise after acute administration

  16. Treatment of GC OP • Primary prevention • Most rapid bone loss within 1st 6 – 12 months of Rx • Secondary prevention

  17. 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

  18. 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

  19. Calcium • GC   intestinal calcium absorbtion &  urinary calcium excretion • Conflicting data on efficacy in primary prevention • ACR : • Calcium intake (diet/ suppl) 1000 – 1500 mg/d

  20. 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

  21. 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

  22. Bisphosphonates •  bone resorbtion • May  GC induced apoptosis of osteoblasts

  23. 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

  24. 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

  25. PTH •  lifespan on osteoclasts & osteoblasts •   osteoblast no. •  BMD in postmenopausal women with GC induced OP • Study not powered to determine effect on fracture rate

  26. Calcitonin • Variable data on effect on BMD •  Bone pain induced by fractures

  27. Thiazide diuretics & salt restriction •  urinary calcium excretion • Effect on BMD & fracture risk uncertain • In general population, chronic thiazide Rx is associated with  BMD • In elderly pts Rx for > 2 yrs   hip fractures

  28. 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

  29. GIOP--ACR Guideline (2) 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 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.

  30. Guideline－－英国（Bone and Tooth Society of Great Britain, the National Osteoporosis Society and the Royal College of Physicians） • 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 may result in significant deficits of BMD(Level III).

  31. 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 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).

  32. 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 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).

  33. Drug Rx

  34. Guideline－－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 (Grade C). T score《−1.5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年后通过脊柱BMD测定提示有显著反应 (Level IV).

  35. 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

  36. GIOP--Belgium GuidelineCa and VitD • 一线治疗: GC减少肠钙吸收 • 不需联合其它<7.5 mg/D and/or<3m • 其它情况与其它有效药物联合.

  37. GIOP--Belgium GuidelineCa 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

  38. 系统性红斑狼疮的骨质疏松与皮质激素的相关性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

  39. 研究对象 • 1998年3月到1999年1月北京协和医院风湿免疫科—SLE • 58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。

  40. 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1.0～2.5 s 之间为骨量减少。

  41. 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Soundscan 2000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种方法同时进行的17例。

  42. DXA检查的49例，24例（48.9%）L2～L4、股骨颈、Ward三角及股骨大转子4处中至少有1处骨密度值减少达到骨量减少或骨质疏松标准，14例（28.5%）骨量减少，10例（20.4%）骨质疏松。DXA检查的49例，24例（48.9%）L2～L4、股骨颈、Ward三角及股骨大转子4处中至少有1处骨密度值减少达到骨量减少或骨质疏松标准，14例（28.5%）骨量减少，10例（20.4%）骨质疏松。 • 3例男性患者各部位均正常。 • 26例骨超声速率检查在正常峰值以下1.0～2.5 s的有7例（26.9%），低于正常峰值2.5 s的有4例（15.4%）。2例男性患者结果正常。

  43. 49例的L2～L4、股骨颈、Ward三角及大转子骨密度值与激素疗程及累积量呈负相关。49例的L2～L4、股骨颈、Ward三角及大转子骨密度值与激素疗程及累积量呈负相关。 将其分为2组，接受激素治疗<1年的25例，≥1年的24例。2组患者年龄差异无显著性，激素疗程≥1年的患者以上4个区的骨密度值均显著低于激素疗程<1年的患者，

  44. 表1　激素疗程对骨密度的影响( ±s) 项目 疗程＜1年(25例) 疗程≥1年（24例） P值 年龄（岁） 32.1±10.4 35.5±8.4 =0.18 L2～4(g/cm2)1.18±0.09 1.01±0.17 <0.001 股骨(g/cm2) 0.98±0.11 0.82±0.15 <0.001 Ward三角(g/cm2)0.92±0.15 0.73±0.16 <0.001 大转子(g/cm2)0.82±0.09 0.68±0.14 <0.001

  45. 纳入本研究的SLE患者有一定选择性，即年龄≤45岁、肾功能正常、非卧床不起而有一定体力活动者。 这样排除了某些可能造成骨质疏松的可预见的危险因素后，经DXA及骨超声检查有48.9%及42.3%服用激素的SLE患者出现骨量减少和骨质疏松。

  46. 激素造成的骨量丢失主要发生在松质骨，因此Ward三角的骨质疏松最为多见。激素造成的骨量丢失主要发生在松质骨，因此Ward三角的骨质疏松最为多见。 • 本研究证实SLE患者骨质疏松的发生与应用激素的疗程和累积量相关。当激素累积量>30g时最常见的骨质疏松部位为L2～L4及Ward三角。

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