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Postmenopausal Osteoporosis Overview

Postmenopausal Osteoporosis Overview. Bruce Ettinger, MD Senior Investigator Division of Research Kaiser Permanente Medical Care Program Oakland, California. Summary of Presentation. Importance of Osteoporotic Fracture Making the diagnosis Drug Treatments what works

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Postmenopausal Osteoporosis Overview

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

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

  3. Incidence Rates for Vertebral, Wrist and Hip Fractures in Women After Age 50 Annual incidence/100 4.0 3.0 2.0 1.0 Vertebrae* Hip Wrist 50 60 Age (yrs) 70 80 * Morphometric 3SD deformities Wasnich RD: Primer Metabolic Bone Diseases and Disorders of Mineral Metabolism. 1999

  4. Effect of Preexisting Vertebral Fracture on Risk of Subsequent Vertebral Fracture RR = 7.3 15 % new vertebralfracture 10 RR = 2.6 5 0 0 1 2 Number baseline vertebral fractures 2725 postmenopausal women randomized to placebo. R Lindsay, et al. JAMA 2001;285:320-23

  5. Cumulative Hip Fracture Probability 25 20 21.4 20.7 15 10 10.6 10.3 5 0 Hawaii Minnesota Hawaii All Japan Caucasian Japanese

  6. Relative Risk of Death Following Fractures Fracture Intervention Trial (FIT)* Any Clinical Non-spine 6.7 Hip 8.6 Spine Forearm Other 0 1.0 2.0 5.0 10.0 Age-Adjusted Relative Risk (95% CI) JA Cauley, et al. Osteoporos Int. 2000;11:556-61. *6459 postmenopausal women, 55-81 yr, followed for an average of 3.8 years.

  7. Mortality Rates by Number of Prevalent Vertebral Fractures 45 40 35 Age-adjusted mortality (per 1000 person-years) 30 25 20 15 10 5 0 5+ 0 1 2 3 4 Number baseline vertebral fractures p for trend <.001 DM Kado, et al. Arch Intern Med 1999;159:1215-20

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

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

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

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

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

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

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

  15. Effects of Calcium (500mg) Plus Vitamin D (700 IU) on Fractures in Elderly* Men and Women 15 Placebo 10 Cumulative fracture incidence (%) 5 Calcium + vitamin D 0 * All >65 yrs mean 71 yrs 0 6 12 18 24 30 36 Months B Dawson Hughes, et al. NEJM 1997; 337:670

  16. 36 Months Follow-up Treatment Placebo % Reduction Fractures n=872 n=893 in risk Hip 109 155 29 Non-vertebral 218 284 24 Effects of Vitamin D (800 IU) and Calcium (1200 mg) in Elderly* Women *All in care centers Mean age 84 yrs MC Chapuy, et al. NEJM 1992;327:1637 MC Chapuy, et al. BMJ 1994;308:1081

  17. Use Combination of Calcium and Vitamin D in the Elderly • After age 65, calcium intake is low and absorption is inefficient. • Vitamin D alone does not reduce fracture risk. * • 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 StudyMultiple Outcomes of Raloxifene Evaluation • Multicenter, double-blind, placebo-controlled- 4 year study • Raloxifene 60 mg, 120 mg, or placebo (with calcium and vitamin D) • 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 WomenWith or Without Prevalent Fractures Four Years RR 0.54 RR 0.66 25 20 15 Placebo % Incident Fracture RR 0.62 RLX 60 10 RLX120 RR 0.51 5 0 No Prevalent Fractures Prevalent Fractures K Harper, ASBMR, 2000

  20. Efficacy of Raloxifene Through 4 Years Incidence of New Vertebral Fractures (%) Placebo RLX 60 mg/d 15 First Scheduled Radiograph P<0.001 10 5 0 12 0 24 36 48 Months of Exposure PD Delmas, et al. JCEM 87: 3609-17, 2002

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

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

  23. VERT Study Inclusion Criteria •  5 years post-menopausal •  85 years of age • Multi-National (n = 1226)* •  2 vertebral fractures (T4-L4) • North American (n = 2458)** •  2 vertebral fractures (T4-L4), or • 1 vertebral fracture and lumbar spine T-score  -2 * 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 30 30 25 49%  25 41%  20 20 * 61%  % wtih fracture 15 15 * * 65%  10 10 * * 5 5 * 0 0 0 12 24 36 0 12 24 36 Months Months * 5.0 mg vs. placebo p < 0.01 Risedronate 5 mg Placebo ST Harris et al, JAMA 282: 1344, 1999 J-Y Reginster et al, Osteopor Int 11:83, 2000

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

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

  27. Risk of Nonvertebral* Fracture in Women With Baseline SQ Grade 3MORE Trial - 3 Years % with 1 non-vertebral fracture RH = 0.53 ( 0.29-0.99) 20 15 10 5 0 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 Riskof Non-vertebral Fractures FIT-1 plus selected FIT-2 16 14 Placebo 27% 12 10 % Incident Fracture 8 Alendronate 6 4 2 0 0 6 12 18 24 30 36 Months D Black, et al. JCEM 85:4118, 2000

  29. Alendronate Fracture Risk ReductionDepends on Degree of Osteoporosis FIT-2 Relative risk vs. placebo Femoral Neck t-score Vert. Fx Clinical Fx -1.6 to - 2.0 0.8 1.1 -2.5 to - 2.0 0.5 1.0 below - 2.5 0.5 0.6 SR Cummings, et al. JAMA 280:2077, 1998

  30. Effect of Risedronate on Risk of Non-Vertebral Fractures 20 North American Multi-National 20 15 15 % with Fracture 10 10 5 5 0 0 0 12 24 36 0 12 24 36 Months Months Placebo Risedronate 5 mg Harris et. al. JAMA. 1999;282(14):1344-52. Reginster et al. Osteoporos Int. 2000;11:83-91.

  31. 6 5 4 % with fracture Placebo 3 39% 2 Risedronate 1 0 6 12 18 24 30 36 0 Months Effect of Risedronate on Incidence of Hip Fracture Low Bone Density Group (Group 1) MR McClung, et al. NEJM 344:333, 2001

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

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

  34. Evista Versus AlendronateEVA • Outcome- any osteoporotic fracture • 3000 osteoporotic women (hip t-score -2.5 to - 4.0) • Start 2002, Finish 2007

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

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

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

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

  39. Antiresorptive Drugs Increase BMD but Not Bone Volume • Early BMD increase is due to filling in of remodelling (resorption) space • Later BMD increase is due to increased mineralization of BMU • 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

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

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

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

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

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

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

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

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