Corticosteroid Induced Osteoporosis

1
Corticosteroid - Induced Osteoporosis

• Chatlert Pongchaiyakul. MD.
• Endocrinology Unit Medicine Department
• Faculty of Medicine Khon Kaen University.

2
Osteoporosis

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

3
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

4
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

5
Clinical significant

• - Increase bone loss and fracture 6 Mo.
• - Trabecular gt 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

6
Fracture Risk and Dose of Corticosteroids
6
5
4
Relative risk of fracture
compared with control
Hip fracture
3
Vertebral fracture
2
1
0
2.5 mg/d
2.5-7.5 mg/d
gt7.5 mg/d
Relative risk of fracture by dosages of
corticosteroids of prednisolone. van Staa TP et
al 1998.
7
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.
199314341-345. Reprinted with permission.
8
CIO in Patients With Rheumatoid Arthritis
CScorticosteroid 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.
9
CIO and Systemic Lupus Erythematosus




Plt0.001 P0.002. Percentage of SLE patients
(N97) with low BMD as measured by DXA. Kipen
Y et al 1997.
10
Potential Factors Causing Bone Loss in
Inflammatory Bowel Disease

• Corticosteroids
• Vitamin D / Calcium deficiency
• Poor nutritional status
• Inflammation
• Physical inactivity
• Concurrent medications (immunosuppressive agents)

11
CIO and Chronic Obstructive Pulmonary Disease


Plt0.05 vs. ISU or NSU Plt0.005 vs ISU. McEvoy
CE et al 1998.
12
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

13
Pathophysiology of CIO

• Calcium homeostasis
• Gonadal hormone
• Inhibit bone formation
• Increase bone resorption
• other

14
Calcium homeostasis

• Decrease calcium and phosphate from GI tracts
• unknown mechanism
• Increase urinary calcium excretion
• decrease calcium reabsorption at distal tubules
• Stimulatiom PTH secretion

15
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

16
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 IGFBP35
  insulin-like growth factors transforming growth
  factor B prostaglandin E

17
Bone formation and bone resorption

• Osteoclast
• increase osteoclast activity
• increase apoptosis of mature osteoclast

18
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
19
Diagnosis of CIO Initial Clinical Work-Up

• Medical history
• Risk factors for bone loss
• Physical exam
• Clinical signs and symptoms

20
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

21
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

22
Patient Evaluation
laboratory

• 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

23
WHO Criteria for Assessing Disease Severity
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
SDstandard deviation.
24
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

25
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

26
BMD Vitamin D and Calcium
6
12
18
24
30
36
months
months
months
months
months
months
0
-2
-4
from baseline ()
Change in lumbar spine BMD
-6
-8
-10
-12
Vitamin D calcium
Placebo
Adachi JD et al 1996.
27
Pharmacologic Treatment of CIO Overview
28
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

29
Hormone Replacement Therapy in the Treatment of
CIO ACR Guidelines
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

American College of RheumatologyTask Force on
Osteoporosis Guidelines 1996.
30
Estrogen Replacement Therapy in the Treatment of
CIO
Group 1
Group 2
)
2
Prednisone
Prednisone
Group 3
Group 4
only
ERT
Control
ERT only
0.06

0.04
Changes in lumbar spine BMD (g/cm
0.02
at 1 year
0
-0.02
-0.04
-0.06
P0.008 vs. baseline P0.027 between groups 1
and 2. Lukert BP et al 1992.
31
Testosterone Replacement Therapy in the
Treatment of CIO

5.0
2.5
Changes in lumbar spine BMD ()
at 1 year
0.0
Testosterone therapy
Control period
period
-2.5
-5.0
P0.005 vs control P0.05 between-group
difference. Reid IR et al 1996.
32
Cyclical Etidronate and Prevention of
Corticosteroid-Induced Bone Loss
Etidronate
Control

2

1
0
-1
-2
-3
Changes in BMD from baseline () at 1 year
-4
Lumbar
Femoral
Trochanter
Lumbar
Femoral
Trochanter
spine
neck
spine
neck
Plt0.05 between-group difference. Adachi JD et
al 1997. Roux C et al1998.
33
Etidronate Pooled Results from Three Randomized
Trials
6
4
Change in BMD from baseline ()
2
0
Lumbar spine
Femoral neck
Trochanter
Men
Pre-menopausal women
Post-menopausal women
Plt0.05 between-group difference. Roux C et
al1998.
34
Efficacy of Pamidronate in the Prevention of
Bone Loss
6
4
2
Changes in BMD from baseline ()
0
-2
-4
-6
6 months
12 months
6 months
12 months
Pamidronate calcium
Calcium only
Boutsen Y et al 1997.
35
Efficacy of Alendronate in Increasing BMD








P lt0.001 vs. control P lt0.01 vs. control P
lt0.001 vs. baseline P lt0.01 vs. baseline Saag
KG et al 1998.
36
Efficacy of Alendronate Two Years Follow-Up
Control
Alendronate 10 mg
Alendronate 5 mg
Alendronate 2.5 mg year 1 10 mg year 2


4


3
2
1
Change in BMD from baseline ()


0
-1
-2
-3
-4
Lumbar spine
Femoral neck
Trochanter
Plt0.001 vs. control Plt0.01 vs. control
Plt0.05 vs. control. Saag KG et al 1998.
37
Effect of Risedronate on BMD inPatients
Initiating Corticosteroid Therapy
Control
Risedronate 2.5 mg
4.0
Risedronate 5 mg
2.0






at 12 months
0.0
Change in BMD from baseline ()
-2.0
-4.0
Lumbar spine
Femoral neck
Trochanter
Plt0.05 vs control. Cohen S et al 1998.
38
Effect of Risedronate on BMD in Patients on
Long-Term Corticosteroid Therapy

3.0


2.0
1.0

at 12 months
Change in BMD from baseline ()
0.0
Lumbar spine
Femoral neck
Trochanter
-1.0
-2.0
Control
Risedronate 2.5 mg
Risedronate 5 mg
-3.0
Plt0.05 vs. control. Devogelaer JP et al 1998.
39
Effect of Risedronate on Vertebral Fracture Rates
20
15
10
Patients with vertebral fractures ()

5
0
Pooled control patients
Pooled risedronate
patients
Pooled vertebral fracture rates from 518
patients on steroid therapy. P0.016 vs.
control. Reid D et al 1998.
40
Bisphosphonates in the Management of CIO A
Meta-Analysis
Treatment Number of Change in lumbar
pooled trials spine BMD () Vitamin
D 18 1.96 Calcitonin 11 2.11
Bisphosphonates 18 5.31
Compared with no treatment or with calcium
alone P0.0001 compared with calcitonin or
vitamin D
41
Glucocorticoid therapy evaluation

• Plan- at start of glucocorticoid therapy
• 1. 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

42
Glucocorticoid therapy evaluation

• Reassessment at 2-3 mo
• 1. 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

43
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
  continue
• 1. Repeat annual assessment as above
• 2. Change therapy as needed
• 3. Consider newer drugs as they become available

44
ACR Task Force on Osteoporosis Initiating
Long-Term Corticosteroid Therapy
Initial history physical lab/DXA
measurements Calcium/vitamin D supplementation Pat
ient education
T score lt -1 Initiate HRT bisphosphonates or
calcitonin if HRT contraindicated
T score gt -1 Monitor regularly
One month follow-up Obtain 24h urine to measure
calcium If gt 300 mg/d add thiazide
diuretic Adjust dosage of calcium and vitamin D
supplementation
6-12 months follow-up Repeat BMD Decrease gt5
change/add medication Increase no change or
decrease lt5 no change in therapy
American College of Rheumatology Task Force on
Osteoporosis Guidelines 1996.
45
Anticipated therapy with
glucocorticoid Atraumatic
fractures Yes
No Calcium 1500 mg/day
yes Measurement of bone mineral
density Vitamin D 400-800 IU/day
Lower than 2SD below the mean for
Exercise
gt5 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/day Add
hormone replacement with
Vitamin D 400-800 IU/day Estrogen in woman and
testosterone in men Exercise Check BMD
in one year add anti-resorptive Repeat bone
mineral density in 1 yr. Therapy if gt 2 percent
bone loss If hypogonadism absent
lt 5 bone loss Add bisphosphanate if no
fracture pain Add calcitonin if fracture pain
Continue
conservative therapy as long as
bone density criteria above not met
46
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

47
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 lt1
  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

48
I will always...
Love you with all my fractured bones.