Corticosteroid - Induced Osteoporosis

Chatlert Pongchaiyakul. MD. Endocrinology Unit, Medicine Department

Faculty of Medicine, Khon Kaen Uni versity.

Osteoporosis

• Systemic skeletal disease– Low bone mass– Microarchitectural deterioration of bone tissue– Increase in bone fragility and fracture

susceptibility

Clinical Burden of CIO

• Most common form of drug-related osteoporosis in men and women

• Occurs at any age, in both genders, across

races

• Up to 50% of patients on chronic steroid

therapy sustain osteoporotic fractures and/or

develop osteonecrosis

Corticosteroid-Induced Osteoporosis

• Common, iatrogenic form of secondary osteoporosis

• Associated with corticosteroid use in chronic, noninfectious medical conditions– Asthma - Nephrotic syndrome– Chronic lung disease - Transplantation– Rheumatologic disorders - etc– Inflammatory bowel disease

Clinical significant

- Increase bone loss and fracture : 6 Mo.

- Trabecular > cortical bone

- 7.5 mg of prednisolone ( equivalent )

- Incidence of osteoporosis ~ 30-50%

- Vertebral fracture 30-35 % , hip fracture 50%

- Rate of bone loss 2-4 % per year

- Alternate day regimen , inhale steroids

Fracture Risk and Dose of Corticosteroids

Relative risk of fracture by dosages of corticosteroids of prednisolone. van Staa TP, et al, 1998.

0

1

2

3

4

5

6

2.5 mg/d 2.5-7.5 mg/d >7.5 mg/d

Rel

ativ

e ri

sk o

f fr

actu

re

com

par

ed w

ith

co

ntr

ol

Hip fractureVertebral fracture

CIO in Patients With Asthma

Relationship of percentage predicted bone density to duration of corticosteroid use in 44 corticosteroid-treated asthmatic patients. Schatz M, Dudl J, Zeiger RS, et al. Allergy Proc. 1993;14:341-345. Reprinted with permission.

Per

cen

t p

r ed

ict e

d b

on

e d

en

sit y

r=-0.39 (P=0.009)

Duration of corticosteroid use (years)

120

100

80

60

402 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36

CIO in Patients With Rheumatoid Arthritis

CS=corticosteroid; therapy = 7 mg prednisone equivalent per day. Density change measured as change in absolute or Z score (difference in standard deviation compared with healthy age-matched controls of the same race and sex) compared to baseline. Verhoeven AC, et al, 1997.

-3

-2.5

-2

-1.5

-1

-0.5

0

Patients not on CStherapy (n=371)

Patients on low-doseCS therapy (n=66)

Cha

nge

in B

MD

fr

om b

asel

ine

(%)

Lumbar spineFemoral neck

*P<0.001; **P=0.002. Percentage of SLE patients (N=97) with low BMD, as measured by DXA. Kipen Y, et al, 1997.

CIO and Systemic Lupus Erythematosus

*

*

**

**

0

10

20

30

40

50

T scores < -1.0 T scores < -2.5

Pat

ients w

ith B

MD

bel

ow

refe

rence

val

ues

(%)

Lumbar spineFemoral neck

Potential Factors Causing Bone Loss in Inflammatory Bowel Disease

• Corticosteroids

• Vitamin D / Calcium deficiency

• Poor nutritional status

• Inflammation

• Physical inactivity

• Concurrent medications (immunosuppressive agents)

CIO and Chronic Obstructive Pulmonary Disease

*P<0.05 vs. ISU or NSU; **P<0.005 vs ISU. McEvoy CE, et al, 1998.

**

*

0

10

20

30

40

50

60

70

Systemicsteroid users

(n= 125)

Never steroid users

(n= 117)

Inhaledsteroid users

(n= 70)

Pat

ient

s w

ith

mul

tip

le i

nju

ries

(%

)

At least one vertebralfracture

Multiple vertebralfractures (> 2)

Severe vertebralfractures

Pathophysiology of CIO: Overview

• Bone remodeling occurs throughout adulthood• Osteoporosis results from an imbalance between osteoclast

and osteoblast activity• Two metabolic abnormalities contribute to increased bone

resorption– Secondary hyperparathyroidism due to decreased GI

absorption and urinary excretion of calcium– Altered gonadal function and decreased adrenal

production of androgens

Pathophysiology of CIO

• Calcium homeostasis

• Gonadal hormone

• Inhibit bone formation

Increase bone resorption

• other

Calcium homeostasis

• Decrease calcium and phosphate from GI tracts

unknown mechanism

• Increase urinary calcium excretion

decrease calcium reabsorption at distal tubules

• Stimulatiom PTH secretion

Gonadal hormone effects

Decrease sex hormone : direct & indirect

Decrease LH from pituitary gland :

estrogen and testosterone

Decrease synthesis from adrenal glands

Decrease sex hormone binding globulin

Bone formation and bone resorption

Osteoblast

- inh. Osteoblast proliferation

- decrease matrix synthesis

- increase apoptosis

- decrease protein synthesis ( type 1 collagen and noncollagenous

protein

- decrease osteocalcin , IGF1, IGFBP3,5 , insulin-like growth factor

s, transforming growth factor B , prostaglandin E

Osteoclast

increase osteoclast activity

increase apoptosis of mature osteoclast

Bone formation and bone resorption

Osteoblast

proliferation

Apoptosis OB number

Protein synthesis Bone formation

Differentiation

Bone mass Fracture Risk

Androgen

Osteoclast apoptosis Bone resorption

Osteoclast formation

PTH

Calcium and phosphate absorption ( gut and kidney )

Glucocorticoid

Diagnosis of CIO: Initial Clinical Work-Up

• Medical history

• Risk factors for bone loss

• Physical exam

• Clinical signs and symptoms

Patient Evaluation

History

Documentation of height , weight , muscle strength , balance , vision

Documentation of medical history

Documentation of menstrual history, infertility in men

Fracture history and Family history of fractures

Other risk factors for osteoporosis :

- Lifestyles influences : calcium and vitamin D intake, smoking, alcohol intake, medications, prevention of falling

- Patient education : prevention of falling , exercise

General health and prognosis

Patient Evaluation

Physical examination

Evidence of osteoporosis : evidence of fracture ,

kyphosis , loss of height , muscle strength and size

General physical findings : assessment of

underlying disorder , other medical conditions

Patient Evaluation

• Complete blood count and erythrocyte

sedimentation rate ( ESR )• Serum calcium, phosphate, creatinine, electrolyte, alkaline phosphatase, 25-hydroxyvitamin D, estradiol, testosterone ( male ) • 24 hr-Urinary calcium and creatinine• BMD of spine and hip• X-rays of appropriate areas

laboratory

Diagnostic Criteria* Classification

T= 0 to -1 SD Normal

T= -1 to -2.5 SD Osteopenia

T -2.5 SD Osteoporosis

T -2.5 SD + fragility fractures Severe osteoporosis

* Measured in “T scores,” ie, the number of standard deviations below or above the peak bone mass in a young adult reference population of the same sex; SD=standard deviation.

WHO Criteria for Assessing Disease Severity

Guidelines for BMD Measurement

• Baseline BMD prior to/within 6 months of initiating therapy

• Antero-posterior measurement of lumbar spine and femoral neck

• Follow-up at 6 and 12 months, annually thereafter until bone mass stabilizes

• Measuring hip alone may miss more rapid loss in spine

Management of CIO: Goals of Treatment

• Reduce fracture risk

• Maintain current BMD, prevent additional bone loss

• Alleviate pain associated with existing fracture(s)

• Maintain/increase muscle strength

• Initiate lifestyle changes as needed

BMD, Vitamin D, and Calcium

Adachi JD, et al, 1996.

-12

-10

-8

-6

-4

-2

0

6 months

12months

18months

24months

30months

36months

Ch

ang

e in

lu

mb

ar s

pin

e B

MD

fro

m b

asel

ine

(%)

Vitamin D & calcium Placebo

Treatment

Hormonal replacement therapy

Calcitonin

Bisphosphonates

Action

• Inhibit bone resorption

• Prevent apoptosis of osteoblasts

• Partially reverse bone loss

• Prevent early resorptive phase

of bone loss

• Inhibit bone resorption

• Maintain or increase bone mass

Pharmacologic Treatment of CIO: Overview

Pharmacologic treatment of CIO

Thiazide diuretics increase calcium absorption from GI tract

decrease urinary calcium excretion

Fluorides stimulate osteoblast activity

Anabolic steroids increase bone formation

Patient group

Postmenopausal women

Premenopausal women w/intact ovarian functions (ages 13-50)

Men

Recommendation• Estrogen + progestin for women with

intact uteri• Bisphosphonate or calcitonin if HRT

contraindicated

• Estrogen-containing OCs (50 g estradiol) or equivalent

• Bisphosphonate or calcitonin ifestrogen contraindicated

• Testosterone (if serum testosterone levels low)

• Bisphosphonate or calcitonin if testosterone contraindicated

Hormone Replacement Therapy in the Treatment of CIO: ACR Guidelines

American College of RheumatologyTask Force on Osteoporosis Guidelines, 1996.

-0.06

-0.04

-0.02

0

0.02

0.04

0.06

Group 1 Prednisone

only

Group 2 Prednisone

+ ERTGroup 3 Control

Group 4 ERT only

Ch

ang

es i

n l

um

bar

sp

ine

BM

D (

g/c

m2)

at 1

yea

r

Estrogen Replacement Therapy in the Treatment of CIO

*P=0.008 vs. baseline; P=0.027 between groups 1 and 2. Lukert BP, et al, 1992.

*

Testosterone Replacement Therapy in the Treatment of CIO

*P=0.005 vs control; P=0.05 between-group difference. Reid IR, et al, 1996.

*

-5.0

-2.5

0.0

2.5

5.0

Testosterone therapyperiod

Control period

Ch

ang

es i

n l

um

bar

sp

ine

BM

D (

%)

at 1

yea

r

Cyclical Etidronate and Prevention of Corticosteroid-Induced Bone Loss

*P<0.05 between-group difference. Adachi JD, et al, 1997. Roux C, et al,1998.

**

-4-3-2-1012

Lumbarspine

Femoralneck

Trochanter Lumbarspine

Femoralneck

Trochanter

Ch

ang

es

in B

MD

fro

m b

asel

ine

(%

) a

t 1

year

Etidronate Control

0

2

4

6

Lumbar spine* Femoral neck Trochanter

Ch

ang

e in

BM

D f

rom

bas

elin

e (%

)

Men Pre-menopausal women Post-menopausal women

Etidronate: Pooled Results from Three Randomized Trials

*P<0.05 between-group difference. Roux C, et al,1998.

Efficacy of Pamidronate in the Prevention of Bone Loss

Boutsen Y, et al, 1997.

-6

-4

-2

0

2

4

6

6 months 12 months 6 months 12 monthsCh

ang

es in

BM

D f

rom

bas

elin

e (%

)

Pamidronate + calcium Calcium only

Efficacy of Alendronate in Increasing BMD

*P <0.001 vs. control; **P <0.01 vs. control; †P <0.001 vs. baseline, ‡P <0.01 vs. baseline; Saag KG, et al, 1998.

-1.5

-0.5

0.5

1.5

2.5

3.5

Lumbar spine Femoral neck Trochanter Total bodyCh

ang

e in

BM

D f

rom

bas

elin

e (%

)at

48

wee

ksControl Alendronate 5 mg Alendronate 10 mg

*†

*†

*‡ *‡

‡

**‡

*†

**

Efficacy of Alendronate: Two Years Follow-Up

*P<0.001 vs. control; **P<0.01 vs. control; †P<0.05 vs. control. Saag KG, et al, 1998.

**

** **

†

†

-4

-3

-2

-1

0

1

2

3

4

Lumbar spine Femoral neck Trochanter

Ch

ang

e in

BM

D f

rom

bas

elin

e (%

) Control Alendronate 10 mg

Alendronate 5 mg Alendronate 2.5 mg year 1, 10 mg year 2

Effect of Risedronate on BMD inPatients Initiating Corticosteroid Therapy

*P<0.05 vs control. Cohen S, et al, 1998.

** *

**

*

-4.0

-2.0

0.0

2.0

4.0

Lumbar spine Femoral neck Trochanter

Ch

ang

e in

BM

D f

rom

bas

elin

e (%

) at

12

mo

nth

sControl

Risedronate 2.5 mg

Risedronate 5 mg

Effect of Risedronate on BMD in Patients on Long-Term Corticosteroid Therapy

*P<0.05 vs. control. Devogelaer JP, et al, 1998.

*

*

*

*

-3.0

-2.0

-1.0

0.0

1.0

2.0

3.0

Lumbar spine Femoral neck Trochanter

Ch

ang

e in

BM

D f

rom

bas

elin

e (%

)at

12

mo

nth

s

Control Risedronate 2.5 mg Risedronate 5 mg

0

5

10

15

20

Pooled control patients Pooled risedronatepatients

Pat

ien

ts w

ith

ve

rte

bra

l fr

actu

res

(%)

Effect of Risedronate on Vertebral Fracture Rates

Pooled vertebral fracture rates from 518 patients on steroid therapy. *P=0.016 vs. control. Reid D, et al, 1998.

*

Treatment Number of Change in lumbar

pooled trials spine BMD (%)*

Vitamin D 18 +1.96

Calcitonin 11 +2.11

Bisphosphonates 18 +5.31†

Bisphosphonates in the Management of CIO: A Meta-Analysis

*Compared with no treatment or with calcium alone†P=0.0001 compared with calcitonin or vitamin D

Glucocorticoid therapy evaluation

Plan- at start of glucocorticoid therapy1. Minimize glucocorticoid dose

2. Use alternate day therapy , topical steroid or bone sparing steroid if possible

3. Prescribe exercise ( weight baring ) , physical therapy , prevent falling

4. Avoid smoking and excess alcohol

5. Assure adequate calcium intake

6. Add supplement calcium up to 1000-15000 mg calcium /day

7. Add multivitamin containing 400-800 IU vitamin D

8. BMD measurement of the spine and hip : if T-score lower

than –1 SD start HRT and if more than –1 SD start HRT only in

postmenopausal woman

Glucocorticoid therapy evaluation

Reassessment at 2-3 mo1. Review glucocorticoid therapy : attempt to decrease or discontinue

2. Assess exercise and calcium intake

3. Measure serum calcium , 24 hr urinary calcium if more than 4 mg/kg/d

use hydrochlorothiazide 25-50 mg twice daily

Reassessment at 6 mo 1. Review glucocorticoid therapy and minimize

2. Assess exercise and calcium intake

3. Repeat serum calcium and 24 hr urinary calcium measurement

4. Alter calcium / vitamin D / thiazide therapy if necessary

5. If pateint is to continue glucocorticoid ,consider to repeat BMD

6. Consider HRT / bisphosphonate/ calcitonin

Glucocorticoid therapy evaluation

Reassessment at 1 yr 1. Review glucocorticoid therapy and minimize

2. Assess exercise and calcium intake

3. Repeat serum calcium and 24 hr urinary calcium measurement

4. BMD measurement ( spine and hip )

5. Alter calcium / vitamin D / thiazide therapy if necessary

6. Alter further thereapy if bone loss if continues

Reassessment thereafter if glucocorticoids continue1. Repeat annual assessment as above

2. Change therapy as needed

3. Consider newer drugs as they become available

ACR Task Force on Osteoporosis: Initiating Long-Term Corticosteroid Therapy

Initial history & physical, lab/DXA measurementsCalcium/vitamin D supplementation

Patient educationT score < -1

Initiate HRT; bisphosphonates or calcitonin if HRT

contraindicated

T score > -1Monitor regularly

One month follow-up:Obtain 24h urine to measure calcium

If > 300 mg/d: add thiazide diureticAdjust dosage of calcium and vitamin D supplementation

6-12 months follow-up:Repeat BMD

Decrease >5%: change/add medicationIncrease, no change, or decrease <5%: no change in therapy

American College of Rheumatology Task Force on Osteoporosis Guidelines, 1996.

Anticipated therapy with glucocorticoid

Atraumatic fractures

Yes No

Calcium 1500 mg/day yes Measurement of bone mineral densityVitamin D 400-800 IU/day Lower than 2SD below the mean for Exercise >5 % young adults or Lower than 1 SD below the Screen for hypogonadism bone loss mean for aged-match controls

No

If hypogonadism present : Calcium 1000 mg/dayAdd hormone replacement with Vitamin D 400-800 IU/day Estrogen in woman and testosterone in men ExerciseCheck BMD in one year : add anti-resorptive Repeat bone mineral density in 1 yr.Therapy if > 2 percent bone loss

If hypogonadism absent: < 5 % bone lossAdd bisphosphanate if no fracture pain

Add calcitonin if fracture pain Continue conservative therapy as

long as bone density criteria above not

met

Corticosteroid-Induced Osteoporosis: Conclusions

• Most common form of drug-related osteoporosis– Imbalance in bone formation and resorption– Resultant bone loss and fracture

• Bone densitometry is recommended for all patients on chronic steroid therapy– T scores -2.5 indicate osteoporosis– T scores -1 indicate osteopenia– Each standard deviation change in bone density is

associated with at least a two-fold change in fracture risk

Corticosteroid-Induced Osteoporosis: Conclusions

• Primary treatment goals– Reduce fracture risk– Maintain or increase bone mass

• Vitamin D and calcium may slow early resorptive changes• HRT is recommended for patients with T scores <1 to prevent

bone resorption (use bisphosphonates or calcitonin if HRT is contraindicated)

• Bisphosphonates are an efficacious treatment– Inhibit bone resorption– Maintain or increase bone mass

• Advanced generation bisphosphonates– Increase BMD of hip, spine, and total body– May lower risk for vertebral, hip, and forearm fractures