glucocorticoid -induced bone disease

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 apoptosisEarly and continual decrease in

Glucocorticoid excess

osteoblastDecreased

osteoblastogenesisIncreased apoptosisEarly and continual decrease in *Cancellous

osteoblast*Synthetic ability*Bone formation

Glucocorticoid excess

osteocytes

Glucocorticoid excess

osteocytesIncreased apoptosis

Glucocorticoid excess

osteocytesIncreased apoptosis

Decreased canalicular circulation

Glucocorticoid excess

osteocytesIncreased 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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