“silent disease” until complicated by fractures most common bone disease in humans ...
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Glucocorticoid-Induced Bone Disease
Osteoporosis “Silent disease” until complicated by
fractures Most common bone disease in
humans Characterized by:
Low bone mass Microarchitectural deterioration Compromised bone strength Increased risk for fracture
Risk FactorsMajor History of fracture as an
adult Fragility fracture in first
degree relative Caucasian/Asian
postmenopausal woman Low body weight (< 127
lb) Current smoking Use of oral
corticosteroids > 3 mo.
Additional Impaired vision Estrogen deficiency at
early age (< 45 YO) Dementia Poor health/frailty Recent falls Low calcium intake
(lifelong) Low physical activity > 2 alcoholic drinks per
day
Medical Conditions Associated with Increased Risk of Osteoporosis
COPD Cushing’s syndrome Eating disorders Hyperparathyroidism Hypophosphatasia IBS RA, other
autoimmune connective tissue disorders
Insulin dependent diabetes
Multiple sclerosis Multiple myeloma Stroke (CVA) Thyrotoxicosis Vitamin D deficiency Liver diseases
Drugs Associated with Reduced Bone Mass
Aluminum Anticonvulsants Cytotoxic drugs Glucocorticosteroids
(oral/high dose inhaled)
Immunosuppresants Gonadotropin-
releasing hormone
Lithium Heparin (chronic use) Supraphysiologic
thyroxine doses Aromatase inhibitors Depo-Provera
Glucocorticoid-Induced Osteoporosis
Common, iatrogenic form of secondary osteoporosis
Associated with corticosteroid use in chronic, noninfectious medical conditions Asthma Chronic lung disease Rheumatologic disorders Inflammatory bowel disease Skin diseases
Pathophysiology of GIO: 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
Glucocorticoid-induced osteoporosis predominantly affects regions of the
skeleton that have abundant cancellous bone, such as the lumbar spine and proximal femur
the loss of bone mineral density is biphasic; it occurs rapidly (6 to 12% loss) within the first year and more slowly (approximately 3% loss yearly) thereafter
increase in the risk of fractures has been
reported with the use of inhaled glucocorticoids,
as well as with alternate-day and intermittent oral regimens
Risk Factors for Glucocorticoid-Induced Osteoporosis
Advanced age Low body-mass index (<24) Underlying disease Prevalent fractures, smoking, excessive alcohol
consumption, frequent falls, family history of hip fracture Glucocorticoid receptor genotype Increased 11β-HSD1 expression High glucocorticoid dose (high current or cumulative
dose; long duration of therapy) alternate-day or inhaled therapies also confer risks of
glucocorticoidinduced osteoporosis Low bone mineral density
PATHOGENESIS
Glucocorticoid excess
Glucocorticoid excess
osteoblast
Glucocorticoid excess
osteoblastDecreased
osteoblastogenesis
Glucocorticoid excess
osteoblastDecreased
osteoblastogenesisIncreased apoptosis
Glucocorticoid excess
osteoblastDecreased
osteoblastogenesisIncreased apoptosis
Early and continual decrease in
Glucocorticoid excess
osteoblastDecreased
osteoblastogenesisIncreased apoptosisEarly and continual decrease in *Cancellous
osteoblast*Synthetic ability*Bone formation
Glucocorticoid excess
osteocytes
Glucocorticoid excess
osteocytes
Increased apoptosis
Glucocorticoid excess
osteocytes
Increased apoptosis
Decreased canalicular circulation
Glucocorticoid excess
osteocytes
Increased apoptosis
Decreased canalicular circulation
Decreased bone quality
Glucocorticoid excess
osteoclasts
Glucocorticoid excess
osteoclastsDecreased osteoclastogenesis
Glucocorticoid excess
osteoclastsDecreased osteoclastogenesisEarly transient increase in
Glucocorticoid excess
osteoclastsDecreased osteoclastogenesisEarly transient increase in
*Osteoclast survival*cancellous osteoclasts*bone resorption
Glucocorticoid excess
osteoclastsDecreased osteoclastogenesisEarly transient increase in
*Osteoclast survival*cancellous osteoclasts*bone resorption
Osteonecrosis Fracture
OsteocytesIncreased apoptosis
Deceased bone quality
Decreased canalicular circulation
OsteoblastsDecreased osteoblastogenesisIncreased apoptosisEarly and continual decrease in *cancellous osteoblasts *synthetic ability *bone formation
Strategies and Evidence
Evaluation (side effects ) Patients receiving long-term glucocorticoid
therapy should wear medication identification jewelry
Measurement of the patient’s height Laboratory testing should be performed Measurement of bone mineral density
and plain films
Strategies and Evidence
Evaluation (side effects ) Patients receiving long-term glucocorticoid
therapy should wear medication identification jewelry
Measurement of the patient’s height Laboratory testing should be performed Measurement of bone mineral density
and plain films
Strategies and Evidence
Evaluation (side effects ) Patients receiving long-term glucocorticoid
therapy should wear medication identification jewelry
Measurement of the patient’s height Laboratory testing should be performed Measurement of bone mineral density
and plain films
Strategies and Evidence
Evaluation (side effects ) Patients receiving long-term glucocorticoid
therapy should wear medication identification jewelry
Measurement of the patient’s height Laboratory testing should be performed Measurement of bone mineral density
and plain films
Strategies and Evidence
Evaluation (side effects ) Patients receiving long-term glucocorticoid
therapy should wear medication identification jewelry
Measurement of the patient’s height Laboratory testing should be performed Measurement of bone mineral density
and plain films
Strategies and Evidence
Evaluation (side effects ) Patients receiving long-term glucocorticoid
therapy should wear medication identification jewelry
Measurement of the patient’s height Laboratory testing should be performed Measurement of bone mineral density
and plain films
Osteonecrosis
Persistant hip,knee, shoulder pain especially with movement
MRI needed for diagnosis Incidence :5-40% Mechanisms: fat embolism, vascular
thrombosis, osteocyte apoptosis
Treatment
adequate calcium supplementation (1200mg)
adequate vitamin D supplementation (800 to 2000 IU )
Bisphosphonates are considered to be the first-line options for the treatment (alendronate,risedronate,and zoledronic acid)
Alendronate
Alendronate, 10 mg/ day or 70 mg/wk Advantage: Osteoclast inhibition, reduces bone loss
and reduces vertebral fractures in patients with glucocorticoid-induced osteoporosis
alendronate also prevents glucocorticoid-
induced osteocyte apoptosis; if glucocorticoid therapy is discontinued,
these drugs can be stopped
Alendronate
Disadvantage *Do not directly address the decreased bone
formation that is characteristic of glucocorticoid-induced bone disease and have not been shown to reduce hip fractures;
*Gastrointestinal side effects*Musculoskeletal discomfort* Osteonecrosis of the jaw, uveitis* Atypical femoral fractures* Bisphosphonates should be avoided in patients
with creatinine clearance of ≤30 ml/min
Osteonecrosis of jow
Subtrochanteric fracture
Zoledronic acid(Aclasta)
Dose:5 mg/yr, IVAdvantage: Osteoclast inhibition reduces bone loss; more rapid onset of skeletal effectsDisadvantage : Acute-phase reaction (flue-like syndrome),can be effectively managed withacetaminophen or ibuprofen
Teriparatide
Dose :20 μg/day,SC for 2 yrs , followed by bisphosphonate treatment for as long as glucocorticoids are required
directly addresses the increase in osteoblast and osteocyte apoptosis and the decrease in osteoblast number, bone formation,
and bone strength that are characteristic of glucocorticoid-induced osteoporosis
and reduces vertebral fractures
Teriparatide(forteo)
Disadvantage Costs are greater than with oral or intravenous bisphosphonates
daily injections are required
Response is reduced when teriparatide is given with high-dose glucocorticoids;
it has not been studied in patients with elevated PTH levels
Adverse effects include mild hypercalcemia, headache, nausea, legcramps,
dizziness;
Caution must be taken in patients nephrolithiasis serum calcium should be checked at least once 16 hours or more
after injection and oral calcium intake adjusted as needed
Teriparatide(forteo)
Denosumab(prolia)
Dose : 60 mg every 6 mo, SC
A potent inhibitor of osteoclasts,with ease of administration
It can be stopped if glucocorticoids ar discontinued
It can be used in patients with creatinineclearance of ≤30 ml/minDenosumab does not address the reduced bone formationcaused by glucocorticoid excessHypocalcemia and vitamin D deficiency must be treated before theuse of denosumab
Areas of Uncertaint y
More data are needed to predict the risk of fractures among patients taking glucocorticoids and to establish clinical thresholds for intervention
Additional studies are needed to determine the minimum dose of glucocorticoids and duration of therapy thatwarrant interventions to prevent fractures
Guidelines
Conclusion and recomendationA 55-year-old woman with severe, persistent asthma requiring
glucocorticoid therapy for the past 3 months presents for care. Her medications include albuterol, inhaled fluticasone with salmeterol, montelukast, and prednisone (at a dose of 10 mg/day). In the past, she received several intermittent courses of prednisone at a dose of 15 mg or more .
Her weight is 45.5 kg (100 lb), and her height 157.5 cm the body-mass index is 18. Scattered wheezing is heard during expiration. Findings on vertebral percussion and rib-cage compression are
unremarkable.
How should her case be evaluated and managed to minimize the risk of fractures
Risk factors in this case:
Slender Age taking prednisone at a dose of 10 mg
daily for 3 months, and previously received
higher doses of glucocorticoids Underlying asthma disease Other asthma therapies should be used as efficiently as possible in an effort to
taper the prednisone
Assessment
BMD Plain film or Vertebral morphometric
assessment Adequate intake of Ca and vit.D Bisphosphonate Teriparatide
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