1. Osteoporosis 2008 Compromised bone strength predisposing to increased risk of FRAGILITY FRACTURES Michael T. McDermott MD Director, Endocrinology and Diabetes Practice University of Colorado Hospital

2. Disclosure Speakers Bureau: n Eli Lilly n Novartis n Sanofi Aventis n Procter and Gamble

3. Objectives n Explain the new guidelines for the evaluation of osteoporosis. n Review the treatment options for osteoporosis. n Discuss efficacy and safety issues related to osteoporosis therapy.

4.   Spine ~ 700,000/year in US   Hip ~ 300,000/year in US   Wrist ~ 250,000/year in US Total Fragility Fractures: 1.5 million Osteoporosis Fragility Fractures (Low Trauma)

5.   Normal T-score > -1.0   Osteopenia T-score = -1.0 to -2.5   Osteoporosis T-score < -2.5 Osteoporosis Pre-fracture Diagnosis Bone Densitometry Diagnosis made at lowest site

6. Who to Treat in 2008? Anyone with a Fragility Fracture Vertebral Fracture Hip Fracture Less than 20% of patients with fractures are treated

7. WHO Absolute Fracture Risk Weighted Probability Calculation Treat when probability of: Hip Fracture > 3% Major Osteoporosis Fracture > 20% Previous Fractures Glucocorticoid Use Parental Hip Fracture Current Smoking www.shef.ac.uk/FRAX Femoral Neck BMD Alcohol > 3 unit/day Rheumatoid Arthritis Secondary Osteoporosis AgeHeightWeightSex

8. www.shef.ac.uk/FRAX WHO Absolute Fracture Risk Treat when probability of: Hip Fracture > 3% Major Osteoporosis Fracture > 20%

9. Who to Treat in 2008? High Risk: Treat All Moderate Risk: Treat a) Prior fracture b) 2 o cause of bone loss c) FRAX > 3% hip fracture > 20% major fracture Low Risk: Recheck in 1-2 years < -2.5 -1.0 to -2.5 > -1.0 National Osteoporosis Foundation 2008. * Based on DXA Spine, Hip or FN T-Score*Therapy Decision

10. Low Bone Mass is not always Osteoporosis

11. Differential Diagnosis of Low Bone Mass  Osteoporosis  Osteomalacia  Osteogenesis Imperfecta  Hyperparathyroidism  Hyperthyroidism  Hyperprolactinemia  Hypogonadism  Cushing’s Syndrome  Celiac Disease  Inflammatory Bowel Dz  Primary Biliary Cirrhosis  Eating/exercise disorders  Multiple Myeloma  Rheumatoid Arthritis  Renal Failure  Idiopathic Hypercalciuria  Renal Tubular Acidosis  Mastocytosis

12. Evaluation of Low Bone Mass  History and Physical Examination  Routine laboratory  Calcium, Phosphorus, Alkaline Phosphatase  25 OH vitamin D  eGFR (creatinine clearance)  Testosterone (men)  Urine (24 hour): calcium, creatinine  Consider  Tissue transglutaminase antibodies  TSH

13. Non-Pharmacological Therapy

14. Osteoporosis Prevention and Treatment  Calcium: 1000-1500 mg/day  Vitamin D: 800-1200 units/day  Exercise: aerobic and resistance  Fall prevention

15. Calcium Supplements Which are best? Heaney R, Calc Tissue Int 1990; 46:300-304 40% 30% 20% 10% 0% Absorption Without Food Calcium carbonate Calcium citrate With Food 24% 30% Solubility 0.14 mmol/L 7.3 mmol/L Conclusions: 1.Calcium carbonate + Calcium citrate are both well absorbed 2.Calcium is absorbed better with meals 30% Proton Pump Inhibitors: Reduce calcium carbonate absorption by 60% Increased Hip Fracture Risk O’Connell M, Am J Med 2005; 118:778 Yang Y, JAMA 2006: 296:2947

16. Calcium Nutrition  Dairy products (CaPO4) best calcium source  Calcium: 300 mg/serving  Calcium carbonate and calcium citrate both well absorbed with meals  Gastric acid needed for calcium absorption  PPI:  calcium carbonate absorption 60%  PPI: may  risk of hip fractures  Ca citrate or higher dose of Ca carbonate if PPI is used; keep urine calcium 150-300 mg/24 h Heaney R, Calc Tissue Int 1990; 46:300 O’Connell M, Am J Med 2005; 118:778 Yang Y, JAMA 2006: 296:2947

17. SkinDiet Vitamin D 25 OH Vitamin D 1,25 (OH)2 Vitamin D Vitamin D Metabolism D2 Ergocalciferol D3 Cholecalciferol Major storage form of Vitamin D ng/ml quantities Active form of Vitamin D pg/ml quantities PTH

18. Vitamin D Nutrition Maintenance  Optimal intake: 800-1200 U/day  Safe intake: up to 2000 U/day  Goal 25 Vitamin D level: 30-100 ng/ml Thomas M, N Engl J Med 1998; 338:777 Armas L, J Clin Endocrinol Metab 2004; 89:5387 Dawson Hughes B, Osteoporosis Int 2005, epub Dawson Hughes B, Am J Clin Nutr 2004; 80:1763-6S Vitamin D Deficiency  25 OH Vitamin D < 10 ng/ml: 50,000* U D BIW x 3 mos.  25 OH Vitamin D 10-20 ng/ml: 50,000* U D QW x 3 mos.  25 OH Vitamin D 20-30 ng/ml: 1000-2000 U D3 QD x 3 mos. *50,000 U caps now available as D2 or D3

19. Pharmacological Therapy

20. OC Old Bone Bone Remodeling

21. OC OB Old Bone Bone Remodeling Osteoid

22. Old Bone Bone Remodeling Calcifying Osteoid Ca P04 New Bone

23. OC OB Old Bone New Bone Ca P04 Bone Remodeling RANK-L Signaling RANK RANK-L OPG RANK: Receptor Activator of Nuclear Factor  RANK-L: Rank Ligand OPG: Osteoprogeterin (decoy receptor for RANK-L) RANK-L  Bone resorption OPG  Bone resorption

24. OC OB Old Bone New Bone Osteoporosis Treatment Anti-Resorptive Agents Bisphosphonates Raloxifene Calcitonin Estrogens Rank-L Inhibitors Anabolic Agents Teriparatide Strontium Growth hormone Fluoride

25. Anti-Resorptive Therapy

26. OC OB Old Bone New Bone Osteoporosis Treatment Anti-Resorptive Agents Bisphosphonates Raloxifene Calcitonin Estrogens Rank-L Inhibitors

27. n n Risedronate [Actonel] u u 5 mg q day u u 35 mg q week u u 150 mg q month n n Alendronate [Fosamax] u u 10 mg q day u u 70 mg q week (+ Vit D3 2800 U) u u 70 mg q week (+ Vit D3 5600 U) n n Ibandronate [Boniva] u u 150 mg q month Oral Bisphosphonates Oral Bisphosphonates all approved for treatment of Osteoporosis

28. n n Zoledronic Acid [Reclast]* u u 5 mg in 100 ml NS, IV over 15-30 min. u u Once a year n n Ibandronate [Boniva]* u u 3 mg in NS, IV over 15-30 sec. u u Every 3 months n n Pamidronate [Aredia] u u 30 mg in 250-500 ml NS, IV over 2-4 hrs. u u Every 3 months Intravenous Bisphosphonates *FDA approved for treatment of Osteoporosis

29. Anabolic Therapy

30. OC OB Old Bone New Bone Osteoporosis Treatment Anabolic Agents Teriparatide Strontium Growth hormone Fluoride

31. Teriparatide Effects on Bone Matrix Micro CT Studies: Baseline and After 20 Months Before Teriparatide Treatment Jiang et al, J Bone Miner Res. 2002;17(Suppl 1):S135 After Teriparatide Treatment

32. Fracture Reduction Demonstrated Women with Postmenopausal Osteoporosis Agent Vertebral Fx Hip Fx Nonvertebral Fx Alendronate Risedronate Zoledronate Ibandronate Raloxifene Calcitonin Teriparatide Chesnut C, AM J Med 2000, 109:267 Harris S, JAMA 1999, 282:1344 Ettinger B, JAMA 1999, 282:637 Black D, Lancet 1996, 348:1535 Writing Group, JAMA 2002, 288:321 Delmas P, Osteo Int 2004, 15:792 Black DM, NEJM 2007, 365:1809Black D, NEJM 2007, 365:1809 Yes No Yes No Yes

33. Osteoporosis Treatment Decisions -3.0 NormalOsteopeniaOsteoporosis T-score-2.5 Calcium Vitamin D Exercise Fracture Patients Bisphosphonates Teriparatide Bisphosphonates Raloxifene Bisphosphonates Raloxifene Bisphosphonates Teriparatide Non-Fracture Patient 2 0 cause of bone loss, or FRAX > 3% hip fx, or > 20% major fx

34. Osteonecrosis of the Jaw

35. Non-healing exposed bone in oral cavity for > 8 weeks

36. Osteonecrosis of the Jaw Primary Diagnosis Cases Multiple myeloma47% Metastatic breast cancer39% Metastatic prostate cancer 6% Metastatic disease (other) 4% Osteoporosis 4% Paget’s disease 1% Woo S, Ann Intern Med 2006; 144:753 Literature Review: 368 cases of ONJ

37. Osteonecrosis of the Jaw Medication Cases Zoledronic acid35% Pamidronate31% Zoledronic acid and pamidronate28% Alendronate (oral) 4% Risedronate (oral).3% Ibandronate (oral).3% Woo S, Ann Intern Med 2006; 144:753 Literature Review: 368 cases of ONJ

38. Osteonecrosis of the Jaw n n Highest Risk: High dose IV BP; Cancer; Chemotherapy; Radiation; Steroids; Trauma; Poor oral hygiene; Periodontal disease n n Bisphosphonate causality not validated n n Discuss; follow appropriate dental guidelines n n DC bisphosphonate x 3 mos reasonable; no data

39. Atypical Fractures of the Femoral Diaphysis

40. Copyright ©2008 The Endocrine Society Visekruna, J Clin Endocrinol Metab 2008;93:2948-2952 FIG. 3. Case 3 Atypical Fractures of Femoral Diaphysis

41. n n Thigh pain, discomfort, weakness n n Transverse fractures of the femoral shaft n n Bilateral in 2/3 of patients n n Delayed healing or non-healing n n Prolonged use (> 5 years) of alendronate +/- other anti-resorptive medications n n Severely suppressed bone turnover Atypical Fractures of Femoral Diaphysis

42. Atrial Fibrillation and Bisphosphonates

43. Atrial Fibrillation and Bisphosphonates FDA Press Release Oct 1, 2007 n n Conducting ongoing safety review of atrial fibrillation with all bisphosphonates. n n No population currently identified at being at increased risk of atrial fibrillation. n n Do not suggest healthcare providers alter bisphosphonate prescribing practices. http://www.fda.gov/medwatch/safety/2007/safety07.htm#bisphosphonates

44. Osteoporosis Medications and Renal Disease

45. Renal Failure and Bisphosphonates n n FDA: Bisphosphonates not recommended if eGFR < 30 ml/min (Stage 4 and 5 CKD) n n Limited published experience with eGFR 15-30 ml/min - appears safe and effective n n No experience with eGFR < 15 ml/min: may be toxic to kidneys +/or bone (adynamic bone)

46. Monitoring Therapy

47. n n Minimum serial change that is a true change n n LSC must be established for each instrument n n Serial changes only valid on same instrument n n Calculate for absolute BMD (g/cm2), not T-score Monitoring Treatment Response Least Significant Change Cummings S, JAMA 2000; 283:1318 Bonnick S, J Clin Densitom 2001; 4:1 Lenchik L, J Clin Densitom 2002; 5:S1 LSC in Clinical Trials Spine 2.7% Hip 5.7%

48. Monitoring Treatment Response Therapy Started Response Failure BMD > LSC On Same Machine > 50% fracture reduction ~ 20-25% fracture reduction Cummings S, JAMA 2000; 283:1318 Chapurlat R, Osteo Int 2005; 16:842 Wasnich R, J Clin Endocrinol Metab 2000; 85:231

49. Therapy Started Response BMD No Therapy Change Evaluation Therapy Change Response Failure Monitoring Treatment Response ISCD Recommendations

50. Failure to Respond to Therapy Common Causes   Poor compliance   Calcium / Vitamin D deficiency   Co-morbid conditions   Medications   Wrong dose or dose interval   Lack of efficacy Lewiecki M, J Clin Densitom 2003; 6:307-14

51. Failure to Respond to Therapy Management   Poor compliance  Education   Calcium / Vitamin D deficiency  Correct   Co-morbid conditions  Correct   Medications  Adjust   Wrong dose or dose interval  Correct   Lack of efficacy  Change therapy Lewiecki M, J Clin Densitom 2003; 6:307-14

52. Thank You