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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