1. ADVANCES IN DIAGNOSIS & TREATMENT OF OSTEOPOROSIS Jerry Tenenbaum MD FRCPC Professor of Medicine:University of Toronto Mount Sinai Hospital

2. DISCLOSURES SPEAKER ON OCCASION FOR 1. P&G 2. Pfizer 3. Merck 4. Novartis

3. GOAL Review advances in the diagnosis and treatment of osteoporosis

4. OBJECTIVES 1. Show the impact of osteoporosis on the health of the elderly 2. Advise on screening and diagnosis of osteoporosis 3. Outline evidence-based treatment

5. Osteoporosis Osteoporosis is defined as a skeletal disorder characterized by compromised bone strength predisposing to an increased risk of fracture. Osteoporosis is defined as a skeletal disorder characterized by compromised bone strength predisposing to an increased risk of fracture. NIH Consensus Development Conference, March 2000 Normal BoneOsteoporotic Bone

6. Vertebral Fracture Cascade

7. THE HUMAN COST Downward Spiral

8. Definition of a Fragility Fracture A fragility fracture is one that results from mechanical forces that would not ordinarily cause fracture in a healthy young adult. This is quantified as forces equivalent to a fall from a standing height or less. This is quantified as forces equivalent to a fall from a standing height or less.

9. Osteoporosis 8 million Osteoporotic Women and 2.5 million Osteoporotic Men in USA Expected to increase by about 40% by 2020 1 Estimated Direct costs in 2001 = $ 11.6 - 17.1 billion annually 1 Based on relative older Canadian population 2 & Australian estimates of 7:1 ratio for Indirect to direct costs 3  $6 - $40 million every single day in Canada Mortality increased 2-3 fold in women and women after all types of Osteoporotic fractures 4 1 Surgeon-Generals Report 2 Canadian and US census data 3 Access Economics, 4 Center 1999

10. Prevalence of VCF’s Lifetime prevalence in Caucasians: 15% in women 5-9% in men Higher than risk of breast cancer

11. Osteoporotic fractures, Cardiovascular events & Breast cancer in osteoporotic postmenopausal women Any fracture Spine # Clinical Spine # Hip fracture CVS event Breast Cancer No prior spine fracture (938) Prior spine fracture (1627) 0 20 40 60 80 100 120 from Silverman et al, 2004 J Am Geriatr Soc 52:1543-8 Events per 1000 women-yr MORE study placebo arm over 3 years

12. SITE INCREASE IN MORTALITY RISK Vertebrae8.6 Hip6.7 Any Clinical Fracture 2.2 Fracture and Mortality Risk

13. Each year, one in three Ontarians over the age of 65 will take a serious tumble that may land them in hospital with a broken hip. One in three of those who do break their hip will die within a year. Two thirds will experience dementia-like symptoms. Most will never see home again.

14. Osteoporosis-associated Mortality Age-standardised mortality risk increased 2-3 fold after all types of osteoporotic fracture Women Men Women Men Proximal femur 2.2 3.2 Vertebral1.7 2.4 Vertebral1.7 2.4 Other major1.9 2.2 Other major1.9 2.2 Center et al, Lancet 1999

15. “THE CARE GAP” IN OSTEOPOROSIS Despite the introduction of methods to identify those with osteoporosis and despite effective treatment, a large ‘care gap’ continues to exist for these patients.

16. THE TIP OF THE ICEBERG ASSESSMENT MANAGEMENT

17. Recommendations for Bone Mineral Density Reporting in Canada. Siminoski K, Leslie WD, Brown JP, Frame H, Hodsman A, Josse RG, Khan A, Lentle BC, Levesque J, Lyons DJ, Tarulli G Can Assoc Radiol J 2005; 56: 178-188

18. 2002 Definitions: BMD Results 1. Kanis JA, et al. J Bone Miner Res 1994;9:1137-1141. 2. WHO, Geneva 1994. Status 1, 2 T-score Normal +2.5 to −1.0, inclusive Osteopenia Between −1.0 and −2.5 Osteoporosis ≤−2.5 Severe osteoporosis ≤−2.5 + fragility fracture

19. ABOUT T-SCORES? Advantages Unitless Basis for the majority of osteoporosis guidelines Simplicity Disadvantages Depends on site measured Depends on technology Depends on reference database—population mean and standard deviation Only includes BMD information and not additional risk factors Adapted from Faulkner K. Osteoporos Int 2005;16(4):347-52.

20. Fracture Risk vs. BMD At Different Ages Fracture Risk vs. BMD At Different Ages BMD PREDICTS FRACTURES Hui et al. J Clin Invest 1988; 81:1804-9

21. AGET-Score = -1.0 T-Score = -2.5 50 6 % 6 % 11 % 60 8 % 8 % 16 % 70 12 % 23 % 80 13 % 26 % Risk of Fractures Over 10 Years in Women

22. Proposed Change Previous OSC guidelines advised intervention based on WHO category as a marker of relative fracture risk. Now propose that an individual’s 10-year absolute fracture risk, rather than BMD alone, be used for fracture risk categorization

23. 5-STEPS IN 5-STEPS IN TREATING OSTEOPOROSIS TREATING OSTEOPOROSIS STEPS 1 and 2 STEPS 1 and 2 Begin with the table appropriate for the patient’s sex Identify the row that is closest to the patient's age

24. CATEGORIZATION BASED ON 10-YEAR FRACTURE RISK Absolute fracture risk in 10 years: low: <10% moderate: 10-20% high: >20%

25. USING LOWEST T-SCORE TO FIND 10-YEAR FRACTURE RISK - WOMEN Moderate Risk High Risk Low Risk

26. 5-STEPS IN 5-STEPS IN TREATING OSTEOPOROSIS TREATING OSTEOPOROSIS STEP 3 STEP 3 Determine the preliminary fracture risk category by using the lowest T-score from the recommended skeletal sites

27. 5-STEPS IN 5-STEPS IN TREATING OSTEOPOROSIS TREATING OSTEOPOROSIS STEP 4 STEP 4 Evaluate clinical factors that may move the patient into an even higher fracture risk category

28. USING LOWEST T-SCORE TO FIND 10-YEAR FRACTURE RISK - MEN Low Risk High Risk Moderate Risk

29. Additional Clinical Factors Certain clinical factors increase fracture risk independent of BMD. The most important are: –Fragility fractures after age 40 (especially vertebral compression fractures) –Systemic glucocorticoid therapy >3 months duration.

30. Additional Risk Factors Each factor effectively increases risk categorization to the next level: –from low risk to moderate risk, or –from moderate risk to high risk When both factors are present the patient should be considered at high risk regardless of the BMD result.

31. 5-STEPS IN 5-STEPS IN TREATING OSTEOPOROSIS TREATING OSTEOPOROSIS STEP 5 STEP 5 Determine the individual’s final absolute fracture risk category.

32. Woman – age 52 - t is -2.6 - t is -2.6 Fracture Risk Category? CASE EXAMPLE

33. High Risk Moderate Risk Low Risk CASE EXAMPLE Low Risk Moderate Risk High Risk

34. CASE EXAMPLE -2.2- -3.9

35. Fracture Risk Category Moderate Risk CASE EXAMPLE

36. Fracture Risk Category High Risk Moderate Risk If Fragility Fracture History CASE EXAMPLE

37. 70 year-old man CASE EXAMPLE Lowest T-score –2.7 in total hip BMD done because of strong family history of osteoporosis (mother fractured hip, sister has OP)

38. USING LOWEST T-SCORE TO FIND 10-YEAR FRACTURE RISK - MEN Low Risk High Risk Moderate Risk X

39. Fracture Risk Category Moderate Risk CASE EXAMPLE

40. OTHER ISSUES FOR THIS 70 YEAR OLD MALE Chest x-ray – mild loss of vertebral height at T4, T5 What if he had had polymyalgia rheumatica at age 69 and was on prednisone 10 mg./day?

41. Fracture Risk Category Moderate Risk Moderate Risk If Fragility Fracture History, Corticosteroid use High Risk CASE EXAMPLE

42. Endorsements Canadian Association of Nuclear Medicine Canadian Association of Radiologists Canadian Rheumatology Association International Society of Clinical Densitometry Society of Obstetricians and Gynecologists of Canada Canadian Society of Endocrinology and Metabolism Canadian Orthopedic Association College of Family Physicians of Canada

43. Osteoporosis Prevention and Treatment Age Hormonal Replacement Bisphosphonates Strontium SERM 20406080 Vitamin D PTH Life Style Treatment choice

44. * with prev vert fracture(s) ** without prev vert fractures *** with or without prev verfractures Antifracture efficacy of antiosteoporotic agents 0.61.00.2 Incident nonvertebral fractures Relative risk RLX 60, 120 (MORE)*** CT 200 (PROOF)* Teriparatide 20µg* ALN 5/10 (FIT1)* ALN 5/10 (FIT2)** RIS 5 (VERT-NA)* RIS 5 (VERT-MN)* RIS 2.5/5 (Hip Study)*** Incident vertebral fractures Relative risk 0.61.00.2 RLX 60 (MORE)* RLX 60 (MORE)** CT 200 (PROOF)* Teriparatide 20µg* ALN 5/10 (FIT1)* ALN 5/10 (FIT2)** RIS 5 (VERT-NA)* RIS 5 (VERT-MN)* Strontium ranelate (SOTI)* Strontium ranelate (SOTI +TROPOS )** Strontium ranelate (TROPOS) *** Strontium ranelate (SOTI)* Updated from Delmas, Lancet 2002 RR ± 95% CI

45. Medications Available for Post-Menopausal Osteoporosis Actonel ® (risedronate sodium tablets) (1/day;1/wk; 1/mo) Didrocal® (etidronate sodium tablets) Fosamax ® (alendronate sodium tablets) 1day/1/wk; Fosovance) Aclasta ® (zolendronate IV) Estrogen (some use) Evista ® (raloxifene HCl) Miacalcin ® (calcitonin salmon) Nasal Spray Forteo (Teriparatide) (sc) Consult with your physician to determine what medication may be best for you

46. Bisphosphonates — Cyclical Etidronate p=NS 0 10 20 30 40 50 18 Etidronate (n = 20) 43 Placebo (n = 20) Lumbar spine fracture rate (fractures/100 patient-years) Storm T. N Engl J Med 1990;322:1265. 3-year RCT, 66 subjects 3-year RCT, 66 subjects High risk subgroup: reduction in fracture rate with etidronate, p = 0.023 High risk subgroup: reduction in fracture rate with etidronate, p = 0.023 No statistically significant effect at nonvertebral sites No statistically significant effect at nonvertebral sites

47. Cumulative Hip Fracture Incidence BaselineMonth 6Month 12 % of cohort with a hip fracture 0.00 0.10 0.20 0.30 0.40 0.50 0.58 alendronate risedronate Silverman SL. Osteoporos Int 2007 Jan;18(1):25-34. Epub 2006 Nov 15. ↓ 43%* Adjusted Relative Rate Reduction at Month 12 p = 0.01 95% CI: 13% - 63% ↓ 46%* Adjusted Relative Rate Reduction at Month 6 p = 0.02 95% CI: 9% - 68% 80 fractures n= 21,615 29 fractures n = 12,215

48. Osteoporosis in Men Has Its Time Come?

49. HEADLINES 7.8.07

50. HIP FRACTURES MORBIDITY AND MORTALITY “One-third of all hip fractures occur in men and are associated with as much illness and increased risk of death as those that occur in women.” “The average 50-year-old Caucasian man has a 13 per cent chance of having a fracture related to osteoporosis sometime in his remaining lifetime. A 60-year-old Caucasian man has a 29 per cent chance.” Dr. John Schousboe, Minneapolis 2007

51. Male Osteoporosis: Morbidity and Mortality As compared to women, while lifetime fracture risk may be less, –Men have higher rates of morbidity and mortality due to fractures –Men are twice as likely to die in hospital after a hip fracture –Men have a higher mortality rate than women one year after a hip fracture Cooper C, et al. Osteoporos Int 1992;2:285-9; Singer BR, et al. J Bone Joint Surg Br 1998;80:243-8; Center JR, et al. The Lancet 1999;353:878-82; Forsen L, et al. Osteoporos Int 1999;10:73-8; Johnell O., et al. Calcif Tissue Int 2001;69:182-4; Amin S. Curr Osteoporos Rep 2003;1:71-7; Campion JM, et al. Am Fam Phys 2003;67:1521-6.

52. GLUCOCORTICOIDS and BONE Have a reflex! SGC > 3 mo > 7.5 mg./day -Ca, vitamin D, bisphosphonate -Ca, vitamin D, bisphosphonate Bone density evaluation?

54. Back injuries. If you think that golf is for wimps, consider this: A golf swing puts a higher compressive load on the low back (8 times body weight) than running (3 times) or even rowing (7 times). That’s why a single swing can produce a herniated disc or even a compression fracture of one of the vertebral bodies. Although these injuries are extremely painful and can be quite serious, they are rare. Muscle strains, however, are quite common because of the twisting that is required for a good swing. The “modern” swing, with its inverted-C follow-through, may make for longer drives than the “classic” swing but it also produces more torque — and more injuries (see Golf injuries above). Harvard Men’s Health Watch Aug 2004

55. SUMMARY REDUCING THE ‘CARE GAP’ Assess bone health in woman >50 and in men > 60. Evaluate risk factors; evaluate BMD Consider preventative approach to reduction of fracture risk (the way you think of hypertension and MI and stroke) Treat and monitor