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

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
– NFB
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 Cushing’s

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 associated with  BMD
 In elderly pts Rx for > 2 yrs   hip
fractures

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
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).
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.
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).
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).
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).
Drug Rx
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).
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/or<3m
 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—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。
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。
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。

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。
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，
表1
项目
激素疗程对骨密度的影响( ±s)
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
<0.001
0.68±0.14
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。

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。