1. Osteoporosis Rajesh Kataria, D.O.

2. Osteoporosis “…is a systemic skeletal disease characterized by low bone mass and microarchitectural deterioration of bone tissue, with a consequent increase in bone fragility and susceptibility to fracture.” Consensus Development Conference: Diagnosis, Prophylaxis, and Treatment of Osteoporosis, Am J Med 1993;94:646-650. WHO Study Group 1994.

3. Definition of Osteoporosis

4. What Is Bone Strength? The Bone Quality Framework

5. Osteoporosis Osteoporosis is common - 44 million Americans have osteoporosis or low bone mineral density (BMD) Osteoporosis is serious - Osteoporotic fractures cause increased morbidity and mortality Osteoporosis is easy to diagnose - Bone density testing can detect osteoporosis before the first fracture occurs Good treatments are available- Fracture risk can be reduced by about 50%

6. Osteoporosis Prevalence 10 million with osteoporosis 8 million females 34 million with osteopenia

7. Osteoporosis Fractures 1 in 2 females and 1 in 4 males over age 50 will fracture Approximately 1.5 million fractures annually in U.S. – –700,000 vertebral fractures – –300,000 hip fractures – –250,000 radial fractures

8. Osteoporosis Fractures Increased mortality seen after hip and vertebral fractures 20% mortality in first year after hip fracture 25% require long-term nursing home care after hip fracture 80,000 male hip fractures annually (2x mortality with age matched females)

9. Prior Fracture as a Predictor of Fracture Risk

10. Osteoporosis Cost Each hip fracture costs $40,000 (2001) Fractures cost $18 billion per year (2002) Expected costs to exceed $60 billion by 2030

11. Major Risk Factors for Fracture

12. Osteoporosis Risk Factors Estrogen deficiency (menopause, amenorrhea, anorexia nervosa) Vitamin D deficiency Medications (chemotherapy, anticonvulsants) Testosterone deficiency Inactive lifestyle Caucasian or Asian race

13. DXA “Gold-standard” for BMD measurement Measures “central” or “axial” skeletal sites: spine and hip May measure other sites: total body and forearm Extensive epidemiologic data Validated in many clinical trials Widely available (about 10,000 DXA machines in USA)

14. WHO Study Group. 1994. 14 Diagnostic Classification ClassificationT-score Normal-1 or greater OsteopeniaBetween -1 and -2.5 Osteoporosis-2.5 or less Severe Osteoporosis -2.5 or less and fragility fracture

15. Diagnosis Caveats T-score -2.5 or less does not always mean osteoporosis –Example: osteomalacia Clinical diagnosis of osteoporosis may be made with T-score greater than -2.5 –Example: atraumatic vertebral fracture with T-score equals -1.9 Low T-score does not identify the cause –Medical evaluation should be considered –Example: celiac disease with malabsorption

16. Fracture Risk Doubles With Every SD Decrease in BMD Bone Density (T-score) Relative Risk for Fracture

17. Indications For Bone Mineral Density (BMD) Testing Women aged 65 and older Postmenopausal women under age 65 with risk factors Men aged 70 and older Adults with a fragility fracture Adults with a disease or condition associated with low bone mass or bone loss Adults taking medications associated with low bone mass or bone loss Anyone being considered for pharmacologic therapy Anyone being treated, to monitor treatment effect Anyone not receiving therapy in whom evidence of bone loss would lead to treatment Women discontinuing estrogen should be considered for bone density testing according to the indications listed above

18. Only about 25% of vertebral fractures are clinically apparent Vertebral fractures are often unrecognized

19. Vertebral Fractures Are Often Not Recognized But Are Important To Diagnose Because They: Predict future fractures Are associated with increased mortality and morbidity Can be prevented with appropriate therapy

20. Densitometric Vertebral Fracture Assessment (VFA)

21. VFA: DXA Imaging of the Spine For Detection of Vertebral Fractures Hologic: IVA or RVA Normal Fracture GE: DVA or LVA Normal Fracture

22. Indications for Vertebral Fracture Analysis (VFA) When BMD measurement is indicated, performance of VFA should be considered in clinical situations that may be associated with vertebral fractures. Examples include:  Documented height loss of greater than 2 cm (0.75 in) or historical height loss greater than 4 cm (1.5 in) since young adult  History of fracture after age 50  Commitment to long-term oral or parenteral glucocorticoid therapy  History and/or findings suggestive of vertebral fracture not documented by prior radiologic study

23. Comparison of X-ray and VFA *Medicare reimbursement X-rayVFA Radiation dose800μSv2-8 μSv AccessSeparate visitPoint of service CostHigher ($92*)Lower ($40*) ResolutionHigherLower VisualizationSuperior above T7May be superior in LS ObliquityCommon in LSLess parallax effect Automated morphometry NoYes

24. Who Should Be Treated?

25. Osteoporosis Treatment: Goals and Strategies

26. Average Daily Intake of Calcium in Women in the General Population Who Had Low Bone Mass

27. Calcium Purchase Habits in Households With Patients on Bisphosphonates

28. Pharmacotherapy for Osteoporosis

29. Pharmacotherapy for Osteoporosis (Continued)

30. Osteoporosis Calcitonin Binds to osteoclast Daily nasal spray Reduction in vertebral fractures Short-term analgesic effect Tachyphylaxis

31. Osteoporosis Raloxifene Selective estrogen receptor modulator (SERM) Anti-resorptive effects on bone Reduction in vertebral fractures Cholesterol reduction Increased VTE, hot flushes, leg cramps

32. Osteoporosis Teriparatide Recombinant human PTH (1-34) Anabolic agent (stimulates osteoblasts) Daily SQ injection Reduction in vertebral and non-vertebral fractures Osteosarcoma in rats

33. Teriparatide: Effect on a Composite Endpoint of Nonvertebral Fractures at 21 Months†‡

34. Osteoporosis Bisphosphonate formulations Alendronate 5 mg,10mg,35 mg,70 mg tablets (daily or weekly) 70 mg/75 ml oral solution (weekly) Ibandronate 2.5 mg, 150 mg tablets (daily or monthly) 3 mg/3 ml intravenous injection (quarterly) Risedronate 5mg, 35 mg tablets (daily or weekly)

35. Osteoporosis Anti-fracture Efficacy of Bisphosphonates: A Review of the Evidence

36. Osteoporosis Anti-fracture Results with Alendronate FIT I: Fracture Intervention Trial – Patients with Vertebral Fracture at Baseline FIT II:Fracture Intervention Trial – Patients with Low Bone Mass But Without a Baseline Radiographic Vertebral Fracture

40. Osteoporosis Anti-fracture Results with Risedronate VERT-NA:Vertebral Efficacy with Risedronate Therapy - North America VERT-MN: Vertebral Efficacy with Risedronate Therapy - Multinational

44. Osteoporosis Anti-fracture Results with Ibandronate BONE: Oral IBandronate Osteoporosis Vertebral Fracture Trial in North America and Europe

48. Proven Reduction on Vertebral Fracture AlendronateCalcitoninIbandronateRaloxifeneRisedronateTeriparatide

49. Proven Reduction on Nonvertebral Fracture AlendronateRisedronateTeriparatide

50. Utility of BMD Measures

52. Osteoporosis Osteoporosis is defined as a skeletal disorder characterized by compromised Bone Strength predisposing to an increased risk of fracture. Bone Density Bone Quality Bone Strength and 1.Architecture 2.Turnover 3.Damage Accumulation 4.Mineralization BMD NIH Consensus Conference: Osteoporosis Prevention, Diagnosis, and Therapy JAMA 2001;285:785-795

53. Osteoporosis Rajesh Kataria, D.O.

55. Osteonecrosis of the Jaws (ONJ) Bisphosphonate-associated osteonecrosis (BON) 368 reported cases (5/06) 94% with intravenous bisphosphonate use (multiple myeloma or bone mets) 15 cases in patients taking bisphosphonates for osteoporosis 20 million users for osteoporosis

56. Osteonecrosis of the Jaws (ONJ) Bisphosphonate-associated osteonecrosis (BON) Mandible affected more than 2x maxilla Sores often painful though 1/3 are painless Usually follows an invasive dental procedure (tooth extraction) Also seen with periosteal denture trauma Can be seen as soon as 4 months after therapy (mean 9 to 14 months)

57. Woo, S.-B. et. al. Ann Intern Med 2006;144:753-761 Osteonecrosis of the right mandible after tooth extraction in a patient taking zoledronic acid for metastatic breast cancer

58. Woo, S.-B. et. al. Ann Intern Med 2006;144:753-761 Osteonecrosis of the palatal torus in a patient with osteoporosis taking alendronate

59. Woo, S.-B. et. al. Ann Intern Med 2006;144:753-761 Primary Diagnoses and Types of Bisphosphonates in Reported Cases of Osteonecrosis of the Jaws

60. Woo, S.-B. et. al. Ann Intern Med 2006;144:753-761 Management Recommendations