Glucocorticoid -Induced Bone Disease

1. Glucocorticoid-Induced Bone Disease

2. 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

3. Risk Factors Major • 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

4. 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

5. 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

6. 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

7. Pathophysiology of GIO: Overview • Bone remodeling occurs throughout adulthood • Osteoporosis results from an imbalance between osteoclast and osteoblastactivity • 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

9. Glucocorticoid-induced osteoporosis predominantly affects regions of the skeleton that have abundant cancellous bone, such as the lumbar spine and proximal femur

10. 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

11. 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

12. PATHOGENESIS

13. Glucocorticoid excess

14. Glucocorticoid excess osteoblast

15. Glucocorticoid excess osteoblast Decreased osteoblastogenesis

16. Glucocorticoid excess osteoblast Decreased osteoblastogenesis Increased apoptosis

17. Glucocorticoid excess osteoblast Decreased osteoblastogenesis Increased apoptosis Early and continual decrease in

18. Glucocorticoid excess osteoblast Decreased osteoblastogenesis Increased apoptosis Early and continual decrease in *Cancellousosteoblast *Synthetic ability *Bone formation

19. Glucocorticoid excess osteocytes

20. Glucocorticoid excess osteocytes Increased apoptosis

21. Glucocorticoid excess osteocytes Increased apoptosis Decreased canalicular circulation

22. Glucocorticoid excess osteocytes Increased apoptosis Decreased canalicular circulation Decreased bone quality

23. Glucocorticoid excess osteoclasts

24. Glucocorticoid excess osteoclasts Decreased osteoclastogenesis

25. Glucocorticoid excess osteoclasts Decreased osteoclastogenesis Early transient increase in

26. Glucocorticoid excess osteoclasts Decreased osteoclastogenesis Early transient increase in *Osteoclast survival *cancellousosteoclasts *bone resorption

27. Glucocorticoid excess osteoclasts Osteoblasts Decreased osteoblastogenesis Increased apoptosis Early and continual decrease in *cancellousosteoblasts *synthetic ability *bone formation Decreased osteoclastogenesis Early transient increase in Osteocytes Increased apoptosis *Osteoclast survival *cancellousosteoclasts *bone resorption Decreased canalicular circulation Deceased bone quality Osteonecrosis Fracture

29. 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

30. 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

31. 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

32. 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

33. 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

36. 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

38. Osteonecrosis • Persistanthip,knee, shoulder pain especially with movement • MRI needed for diagnosis • Incidence :5-40% • Mechanisms: fat embolism, vascular thrombosis, osteocyte apoptosis

41. Treatment • adequate calcium supplementation (1200mg) • adequate vitamin D supplementation (800 to 2000 IU ) • Bisphosphonatesare considered to be the first-line options for the treatment (alendronate,risedronate,andzoledronic acid)

42. 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

43. 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

44. Osteonecrosis of jow

45. Subtrochanteric fracture

46. Zoledronic acid(Aclasta) • Dose:5 mg/yr, IV Advantage: Osteoclast inhibition reduces bone loss; more rapid onset of skeletal effects Disadvantage : • Acute-phase reaction (flue-like syndrome),can be effectively managed with acetaminophen or ibuprofen

47. Teriparatide Teriparatide (forteo) • 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

48. 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

49. Denosumab(prolia) Dose : 60 mg every 6 mo, SC A potent inhibitor of osteoclasts, with ease of administration It can be stopped if glucocorticoidsar discontinued It can be used in patients with creatinineclearance of ≤30 ml/min Denosumab does not address the reduced bone formation caused by glucocorticoid excess Hypocalcemia and vitamin D deficiency must be treated before the use of denosumab

50. 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