1. Postmenopausal Osteoporosis Overview Bruce Ettinger, MD Senior Investigator Division of Research Kaiser Permanente Medical Care Program Oakland, California

2. Summary of Presentation l Importance of Osteoporotic Fracture l Making the diagnosis l Drug Treatments u what works u who should be treated u changing treatments

3. * Morphometric 3SD deformities Wasnich RD: Primer Metabolic Bone Diseases and Disorders of Mineral Metabolism. 1999 Wasnich RD: Primer Metabolic Bone Diseases and Disorders of Mineral Metabolism. 1999 Incidence Rates for Vertebral, Wrist and Hip Fractures in Women After Age 50 4.03.02.01.0 Vertebrae* Hip Wrist Annual incidence/100 50 60 Age (yrs) 70 80

4. Effect of Preexisting Vertebral Fracture on Risk of Subsequent Vertebral Fracture R Lindsay, et al. JAMA 2001;285:320-23 2725 postmenopausal women randomized to placebo. 0 5 10 15 % new vertebral fracture Number baseline vertebral fractures RR = 7.3 RR = 2.6 01 2222

5. Cumulative Hip Fracture Probability 20.7 21.4 10.6 10.3 0 5 10 15 20 25 HawaiiMinnesotaHawaii All Japan CaucasianJapanese

6. Relative Risk of Death Following Fractures Fracture Intervention Trial (FIT)* JA Cauley, et al. Osteoporos Int. 2000;11:556-61. *6459 postmenopausal women, 55-81 yr, followed for an average of 3.8 years. Any Clinical Age-Adjusted Relative Risk (95% CI) 01.02.05.0 Non-spine Other Forearm Spine Hip 10.0 6.7 8.6

7. Mortality Rates by Number of Prevalent Vertebral Fractures Age-adjustedmortality (per 1000 person-years) (per 1000 person-years) DM Kado, et al. Arch Intern Med 1999;159:1215-20 Number baseline vertebral fractures Number baseline vertebral fractures p for trend <.001 0 5 10 15 20 25 30 35 40 0123 4 5+ 45

8. Kyphosis Kyphosis Height loss Height loss Ribs compress abdomen Ribs compress abdomen Acute and chronic pain Limited activity Limited activity Breathing difficulties Breathing difficulties Indigestion Indigestion Gastric reflux Gastric reflux Depression Depression Impaired quality of life Impaired quality of life Consequences of Vertebral Fractures

9. Vertebral Fractures Are Overlooked l Radiologist fail to diagnose vertebral deformities in routine x-rays l Physicians fail to diagnose vertebral fractures clinically u Back pain is common u Painful vertebral fractures are not common u Height and stature are not assessed

10. Symptoms: Acute and severe Acute and severe Mid-back Mid-back Localized Localized May radiate anteriorly May radiate anteriorlySigns: Point tenderness over specific vertebra Point tenderness over specific vertebra Tender paravertebral muscles Tender paravertebral muscles Pain increases with motion Pain increases with motion Distinguishing Vertebral Fracture From Other Back Problems

11. Prevalence and Site of Vertebral Fracture Japanese in Hawaii Japanese in Hiroshima Caucasian in Minnesota WEDGE ENDPLATE CRUSH

12. Case Finding for Primary Care Physicians l Thinness l Smoking l Family history l History of fractures History History l Height loss l Kyphosis l Lateral spine film l Bone density Examination Examination

13. Review of Clinical Trials of Drugs for Treatment of Osteoporosis l Double-blind, placebo-controlled l Adequate power to detect effect l Fracture endpoint u spine fractures u non-spine fractures

14. Osteoporosis Drugs l Calcium with Vitamin D l Hormone Therapy l Raloxifene l Bisphosphonates u alendronate u risedronate l Parathyroid hormone-teriparatide

15. Effects of Calcium (500mg) Plus Vitamin D (700 IU) on Fractures in Elderly* Men and Women 06121824 Months 3036 15 10 5 0 Calcium + vitamin D Placebo Cumulativefracture incidence (%) B Dawson Hughes, et al. NEJM 1997; 337:670 * All >65 yrs mean 71 yrs

16. Effects of Vitamin D (800 IU) and Calcium (1200 mg) in Elderly* Women TreatmentPlacebo% Reduction Fracturesn=872n=893in risk Hip10915529 Non-vertebral21828424 36 Months Follow-up MC Chapuy, et al. NEJM 1992;327:1637 MC Chapuy, et al. BMJ 1994;308:1081 *All in care centers Mean age 84 yrs

17. Use Combination of Calcium and Vitamin D in the Elderly l After age 65, calcium intake is low and absorption is inefficient. l Vitamin D alone does not reduce fracture risk. * l Calcium with Vitamin D form the cornerstone of treatment but may not be enough. * HE Meyer, et al. JBMR 2002;17:709 * P Lips, et al. Ann Intern Med 1996;124:400

18. MORE Study Multiple Outcomes of Raloxifene Evaluation l Multicenter, double-blind, placebo- controlled- 4 year study l Raloxifene 60 mg, 120 mg, or placebo (with calcium and vitamin D) l 7705 women, mean age 67-68 years  Endpoints  Primary: vertebral fracture BMD  Secondary: non-vertebral fracture, CVD, breast cancer, uterine safety, cognitive function

19. Effect of Raloxifene in Women With or Without Prevalent Fractures Four Years No Prevalent Fractures Prevalent Fractures % Incident Fracture RR 0.51 RR 0.66 RR 0.62 RR 0.54 0 5 10 15 20 25 Placebo RLX 60 RLX120 K Harper, ASBMR, 2000

20. Efficacy of Raloxifene Through 4 Years PD Delmas, et al. JCEM 87: 3609-17, 2002 Months of Exposure 0243648 0 5 10 15 Incidence of New Vertebral Fractures (%) Placebo RLX 60 mg/d 12 First Scheduled Radiograph P<0.001

21. Design of the Fracture Intervention Trial FIT-1FIT-2 Follow-up: 4.25 years Follow-up: 3 years Vertebral fracture arm n=2027 Baseline visits l BMD l Eligibility l Spinal radiograph Clinical Fracture arm n=4432 DM Black, et al. Lancet 348:1535, 1996

22. Effect of Alendronate* on Risk of Vertebral Fractures FIT-1 & FIT-2 DM Black,et al. Lancet 348:1535, 1996 SR Cummings, et al. JAMA 280:2077, 1998 No Prevalent Fractures Prevalent Fractures % Incident Fracture RR 0.56 RR 0.54 0 5 10 15 20 Placebo Alendronate * 5mg/day for 2 yr, then 10mg/day

23. VERT Study  5 years post-menopausal  5 years post-menopausal  85 years of age  85 years of age l Multi-National (n = 1226)*   2 vertebral fractures (T4-L4) l North American (n = 2458)**   2 vertebral fractures (T4-L4), or  1 vertebral fracture and lumbar spine T-score  -2 Inclusion Criteria * J-Y Reginster, et al. Osteopor Int 11:83, 2000 * J-Y Reginster, et al. Osteopor Int 11:83, 2000 ** ST Harris, et al. JAMA 282:1344, 1999

24. Effect of Risedronate on Incident Vertebral Fractures VERT - North American VERT - Multi-National % wtih fracture MonthsMonths J-Y Reginster et al, Osteopor Int 11:83, 2000 ST Harris et al, JAMA 282: 1344, 1999 * 5.0 mg vs. placebo p < 0.01 0 5 10 15 20 25 30 0122436 * * * 0 5 10 15 20 25 30 0122436 * * * Placebo Risedronate 5 mg 65%  41%  61%  49% 

25. Secondary Endpoint: Incident Non-Vertebral Fracture l Ascertained by direct questioning at each clinic visit l Excluded u fractures due to severe trauma u finger, toe, face, and skull fractures u pathologic fractures

26. Effect of Raloxifene on Risk of Non-Vertebral Fractures Four Years RR=0.99 RR=0.87 0 2 4 6 8 10 12 14 PlaceboRaloxifene 60 mg Raloxifene 120 mg % Incident Fracture PD Delmas, et al. JCEM 87: 3609-17, 2002

27. Risk of Nonvertebral* Fracture in Women With Baseline SQ Grade 3 MORE Trial - 3 Years 0 5 10 15 20 % with  1 non-vertebral fracture RH = 0.53 ( 0.29-0.99) Placebo Raloxifene 60 mg/d * Clavicle, humerus, wrist, pelvis, hip, leg P Delmas, et al. Osteoporosis Int, 2002, Suppl.1 (presented at IOF)

28. Effect of Alendronate on Risk of Non-vertebral Fractures FIT-1 plus selected FIT-2 061218243036 16 10 6 0 Months Alendronate % Incident Fracture Placebo D Black, et al. JCEM 85:4118, 2000 4 8 12 14 2 27%

29. Alendronate Fracture Risk Reduction Depends on Degree of Osteoporosis Relative risk vs. placebo Relative risk vs. placebo Femoral Neck t-score Vert. Fx Clinical Fx Femoral Neck t-score Vert. Fx Clinical Fx -1.6 to - 2.0 0.81.1 -1.6 to - 2.0 0.81.1 -2.5 to - 2.00.51.0 -2.5 to - 2.00.51.0 below - 2.50.50.6 below - 2.50.50.6 FIT-2 SR Cummings, et al. JAMA 280:2077, 1998

30. Effect of Risedronate on Risk of Non-Vertebral Fractures MonthsMonths 0 5 10 15 20 0122436 0 5 10 15 20 0122436 North American Multi-National % with Fracture Harris et. al. JAMA. 1999;282(14):1344-52. Reginster et al. Osteoporos Int. 2000;11:83-91. Placebo Risedronate 5 mg

31. Hip Intervention Program Group 1 Low Bone Density n=5445 70-79 years old Fem. Neck T-Score < - 3 plus  1 Risk Factor Group 2 Clinical Risk Factor n=3886  80 years old  1 Risk Factor no BMD requirement Inclusion Criteria MR McClung, et al. NEJM 344:333, 2001

32. Effect of Risedronate on Incidence of Hip Fracture 39% % with fracture Placebo Risedronate 0 1 2 3 4 56061218243036 Months Low Bone Density Group (Group 1) MR McClung, et al. NEJM 344:333, 2001

33. Risedronate May Not Reduce Hip Fracture Risk in Non-Osteoporotic Women Risk Reduction Risk Reduction Cohort Hip Fracture Cohort Hip Fracture 70-79 years with 70-79 years with t-score <3.0 39% t-score <3.0 39% 80+ years 80+ years all 18% t-score <2.5 26% t-score <2.5 26% M McClung, et al. NEJM 344:333, 2001

34. Fracture Risk Reductions Observed in Trials of Anti-resorptive Therapies Spine 3 yr 1 yr 3 yr 1 yr 45% 60% 45% 60% 43% 68%* 43% 68%* 45% 63% 45% 63%AlendronateRaloxifeneRisedronate Non-Spine Non-Spine 3 yr 3 yr 12, 22, 27% 12, 22, 27% 12, 48% 12, 48% 12, 33, 18, 39% 12, 33, 18, 39% * M Maricic, et al. Arch Intern Med 162:1140-1143, 2002

35. Evista Versus Alendronate EVA l Outcome- any osteoporotic fracture l 3000 osteoporotic women (hip t-score -2.5 to - 4.0) l Start 2002, Finish 2007

36. CASE 1 l 50 year-old woman l Natural menopause 2 years ago l Vasomotor symptoms l Bone density: t-score -1.6 l Tried HRT but stopped due to breast tenderness and bloating Not a candidate for raloxifene or alendronate

37. CASE 2 l 65 year-old women l Concerned about memory l No menopausal symptoms l Wrist fracture 3 years ago l Bone density: t-score -3.0 High risk of fracture- requires treatment

38. Rationale for Raloxifene Use for Postmenopausal Women with Osteoporosis l To reduce risk of osteoporotic fracture l To reduce the risk of breast cancer l To reduce risk of CHD l To prevent cognitive decline l Long-term safety and acceptance

39. CASE 3 l 75 year-old woman l prior wrist fracture l presents with a painful L-1 crush fracture l X-ray shows wedging T-7 and T-8 l Bone density t-score -3.5 Needs strong, rapidly acting osteoporosis drug

40. Antiresorptive Drugs Increase BMD but Not Bone Volume Early BMD increase is due to filling in of remodelling (resorption) space Early BMD increase is due to filling in of remodelling (resorption) space Later BMD increase is due to increased mineralization of BMU Later BMD increase is due to increased mineralization of BMU Most of BMD effect can be explained by mineralization Most of BMD effect can be explained by mineralization GY Boivin, et al. Bone 27:687-694, 2000 CJ Hernandez, et al. Bone 29:511-516, 2001

41. Excessive Suppression of Bone Turnover ProlongedMineralization Insufficient Repair of Microdamage Damage Accumulation Decrease in Bone Toughness Long-term Safety? Relationship Between Excessive Suppression Of Bone Turnover and Damage Accumulation

42. Hypothetical Effects of Increasing Bone Mineralization Displacement CH Turner Osteoporos Int 13:97-104, 2002 Force Optimum Hypo-mineralized Hyper-mineralized x x x

43. Hypothetical Effects of Increasing Bone Mineralization Percentage Mineralization Resistance to fracture to fracture forces forces Improved resistance to bending = stiffness Increasing brittleness

44. Safety Concerns Regarding Long-term Alendronate l Rate of clinical spine fractures during years 5-7 was 3 times higher than during years 1-3 l Height loss (1.2mm/yr) during years 5-7 tended to be higher than during years 1-3 (1.0mm/yr) RP Tonino, et al. JCEM 85:3109, 2000

45. Efficacy Time 0 Drug A Drug B Concept of Sustained vs. Unsustained Efficacy

46. For Severe Osteoporosis: Prescribe Sequentially l Short-term “quick-fix” with a strong bone-specific agent l Long-term bone maintenance with a milder (and safer) effect: u multipurpose drug - raloxifene

47. Key Messages for Primary Care Physicians l Osteoporosis is frequently overlooked l Osteoporosis is treatable l Drug treatment should be encouraged for those at highest risk