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Osteoporosis Management: What Does the Data Support?

Osteoporosis Management: What Does the Data Support?. Osteoporosis Definition 2001 : Compromised bone strength predisposing to increased risk of fragility fractures. Osteoporosis - Diagnosis Fragility Fractures. Spine ~ 700,000/year in US Hip ~ 300,000/year in US Wrist ~ 250,000/year in US.

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Osteoporosis Management: What Does the Data Support?

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  1. Osteoporosis Management: What Does the Data Support? Osteoporosis Definition 2001: Compromised bone strength predisposing to increased risk of fragility fractures

  2. Osteoporosis - DiagnosisFragility Fractures • Spine ~ 700,000/year in US • Hip ~ 300,000/year in US • Wrist ~ 250,000/year in US

  3. Osteoporosis - DiagnosisBone Densitometry Criteria • Normal T-score > -1.0 • Osteopenia T-score = -1.0 to -2.5 • Osteoporosis T-score < -2.5 Established in Postmenopausal Women

  4. Bone Densitometry Report T-score Age (years) 20 30 40 50 60 70 80 90 100 SD (T-score) T-score = -3.0 x T-score predicts fracture risk

  5. Who to Treat? All Patients With Existing Osteoporotic Fractures (Hip, Spine, Wrist) or . . . National Osteoporosis Foundation. Washington, DC. 1998.

  6. Who to Treat? T-Score* Below -2.0 -1.5 to -2.0 Above -1.5 • Therapy Decision • High Risk • Treat • Moderate Risk • Treat if other risk factors • Low Risk • Check again in 1-2 years * Based on measurements from central DXA. National Osteoporosis Foundation. Washington, DC. 1998.

  7. Case Presentation A 56 year old woman inquires about her osteoporosis risk. No prior fractures. PMH: negative Family Hx: mother - osteoporosis Dietary calcium: 600 mg/day Meds: calcium 600 mg/day, vitamins PE: Ht 5’7’’ 128 lb. no kyphosis BMD: T-scoreZ-score Spine (L2-L4) -1.91 -1.31 Femoral Neck -1.68 -1.08

  8. What does the data support? T-Score* Below -2.0 -1.5 to -2.0 Above -1.5 • Therapy Decision • High Risk • Treat • Moderate Risk • Treat if other risk factors • Low Risk • Check again in 1-2 years * Based on measurements from central DXA. National Osteoporosis Foundation. Washington, DC. 1998.

  9. Treatment of Patients with OsteopeniaClinical Fracture Prevention - Alendronate 37% Reduction P=0.044 60% Reduction P=0.005 Osteoporosis Osteopenia Black et al, ASBMR M352 2002

  10. Case Presentation A 75 year old woman with 2 past vertebral fractures. No back pain at present. PMH: HTN, DJD Fam Hx: no osteoporosis Dietary calcium: 300 mg/day Meds: lisinopril, calcium 500 mg/day, vitamins PE: Ht 5’4’’ 116 lb. dorsal kyphosis BMD: T-scoreZ-score Spine (L2-L4) -3.69 -1.42 Femoral Neck -2.98 -1.01

  11. What does the data support? T-Score* Below -2.0 -1.5 to -2.0 Above -1.5 • Therapy Decision • High Risk • Treat • Moderate Risk • Treat if other risk factors • Low Risk • Check again in 1-2 years * Based on measurements from central DXA. National Osteoporosis Foundation. Washington, DC. 1998.

  12. OsteoporosisNon-Pharmacological Measures • Calcium: 1500 mg/day • Vitamin D: 400-800 units/day • Exercise • Aerobic • Resistance • Hip Protectors • Fall Prevention • Habit Alteration (cigarettes, alcohol)

  13. OsteoporosisNon-Pharmacological Measures • Calcium: 1500 mg/day • Vitamin D: 400-800 units/day • Exercise • Aerobic • Resistance • Hip Protectors • Fall Prevention • Habit Alteration (cigarettes, alcohol)

  14. Dietary Calcium IntakeEstimate • 300 mg calcium in general diet • 300 mg calcium in every dairy serving • 1 cup of milk • 1 oz. of cheese • 1 cup of yogurt • 1 cup of calcium fortified citrus drink

  15. Calcium SupplementsSolubility and Absorption 352 calcium absorption studies in normal subjects Double isotope (45Ca, 47Ca) or single isotope (45Ca) Fractional Fractional Solubility Absorption Absorption Preparation(mM/liter)w Mealw/o Meal Calcium carbonate 0.14 30% 24% Tricalcium phosphate 0.97 25% Calcium citrate 7.3 24% Calcium citrate malate 80 36% Heaney R, Calc Tissue Int 1990; 46:300-304

  16. Osteoporosis TreatmentCalcium Supplementation RCT: 197 healthy women (mean age: 73.5 yr.)(< 1 gm Ca/day) Previous fracture (n=94); No previous fracture (n=103) Calcium carbonate (1,200 mg/d) vs. Placebo x 4 years 42% reduction % Who Fractured P=.023 No reduction P=.435 Recker R, J Bone Min Res 1996; 11:1961-6

  17. OsteoporosisNon-Pharmacological Measures • Calcium: 1500 mg/day • Vitamin D: 400-800 units/day • Exercise • Aerobic • Resistance • Hip Protectors • Fall Prevention • Habit Alteration (cigarettes, alcohol)

  18. Osteoporosis TreatmentVitamin D Supplementation RCT: 389 ambulatory subjects (mean age: 71 yr; 213 F, 176 M) Vitamin D (700 U/d) + Calcium (500 mg/d) vs. Placebo % Who Fractured 55% reduction P=.02 Dawson-Hughes, NEJM 1997; 337:670-6

  19. Osteoporosis TreatmentCalcium and Vitamin D RCT: 3270 healthy elderly women (mean age: 84 yr.) Calcium (1,200 mg/d) + Vitamin D (800 U/d) vs. Control 32% reduction Number of Fractures P=.015 43% reduction P=.043 Chapuy M, NEJM 1992; 327:1637-42

  20. OsteoporosisNon-Pharmacological Measures • Calcium: 1500 mg/day • Vitamin D: 400-800 units/day • Exercise • Aerobic • Resistance • Hip Protectors • Fall Prevention • Habit Alteration (cigarettes, alcohol)

  21. Osteoporosis TreatmentExercise RCT: 39 women, sedentary, no estrogen (Age: 50-70 yr.) Strength training (n=20) vs. Controls (n=19) for 1 year P=.04 P=.03 P=.02 BMD Change (%) Muscle Mass Change (Kg) Control Exercise Control Exercise Nelson M, JAMA 1994; 272:1909-14

  22. OsteoporosisNon-Pharmacological Measures • Calcium: 1500 mg/day • Vitamin D: 400-800 units/day • Exercise • Aerobic • Resistance • Hip Protectors • Fall Prevention • Habit Alteration (cigarettes, alcohol)

  23. Osteoporosis TreatmentHip Protectors RCT: 1801 elderly adults (mean age: 82 yr.) (1409 F, 392 M) Hip protector group (n=653) vs. Control group (n=1148) Hip Fractures per 1000 patient years 60% reduction P = .008 Kannus P, NEJM 2000; 343:1506-13

  24. OsteoporosisNon-Pharmacological Measures • Calcium: 1500 mg/day • Vitamin D: 400-800 units/day • Exercise • Aerobic • Resistance • Hip Protectors • Fall Prevention • Habit Alteration (cigarettes, alcohol)

  25. Osteoporosis TreatmentFall Prevention RCT: 402 Nursing home residents (age > 65 yr.; median 83 yr.) Multiple Risk Factor Intervention (n=194) vs. Control (n=208) % Who Fell % Who Fractured Hip 22% reduction 77% reduction Jensen J, Ann Intern Med 2002; 136:733-41

  26. Ca P04 OB OC OB OldBone NewBone OB Bone Remodeling

  27. Ca P04 OB OC OB OldBone NewBone OB Osteoporosis Treatment Anti-ResorptiveAgents Bisphosphonates Raloxifene Calcitonin Estrogens Anabolic Agents Parathyroid hormone Growth hormone Testosterone Fluoride

  28. Ca P04 OB OC OB OldBone NewBone OB Osteoporosis Treatment Anti-ResorptiveAgents Bisphosphonates Raloxifene Calcitonin Estrogens Anabolic Agents Parathyroid hormone Growth hormone Testosterone Fluoride

  29. Women’s Health Initiative - HRTVertebral Fracture Prevention RCT: 16,608 postmenopausal women treated with Premarin + Provera for 5.2 years – baseline bone status unknown Placebo 1.0 HRT % Women With New Vertebral Fracture Nominal 95% CI: 0.44-0.98 Adjusted 95% CI: 0.32-1.34 0.75 34%* 0.50 0.25 N=41 N=60 0 Writing Group. JAMA. 2002;288(3):321–333.

  30. Women’s Health Initiative - HRTHip Fracture Prevention RCT: 16,608 postmenopausal women treated with Premarin + Provera for 5.2 years – baseline bone status unknown Placebo 1.0 HRT % Women With New Hip Fracture Nominal 95% CI: 0.45-0.98 Adjusted 95% CI: 0.33-1.33 34%* 0.75 0.50 0.25 N=44 N=62 0 Writing Group. JAMA. 2002;288(3):321–333.

  31. Ca P04 OB OC OB OldBone NewBone OB Osteoporosis Treatment Anti-ResorptiveAgents Bisphosphonates Raloxifene Calcitonin Estrogens Anabolic Agents Parathyroid hormone Growth hormone Testosterone Fluoride

  32. Calcitonin: PROOF StudyVertebral Fracture Prevention RCT: 1255 women with PMO and vertebral fracture treated for 5 years Placebo 40 100 IU/day 200 IU/day % Women With 1 New VertebralFracture 30 400 IU/day 33%* 20 10 N=70 N=59 N=51 N=61 0 * Relative risk reduction, P=0.03 vs placebo. N = number of women with new fracture. Chesnut CH, Am J Med. 2000;109:267-276

  33. Ca P04 OB OC OB OldBone NewBone OB Osteoporosis Treatment Anti-ResorptiveAgents Bisphosphonates Raloxifene Calcitonin Estrogens Anabolic Agents Parathyroid hormone Growth hormone Testosterone Fluoride

  34. Raloxifene: MORE StudyVertebral Fracture Prevention RCT: 7705 women with PMO, with and without vertebral fracture, treated for 3 years % Women With New VertebralFracture 30%* 50%* N=163 N=113 N=68 N=35 Preexisting Fractures No Preexisting Fractures * P<0.05. N = number of women with new fracture. Ettinger B, JAMA. 1999;282:637-645

  35. Ca P04 OB OC OB OldBone NewBone OB Osteoporosis Treatment Anti-ResorptiveAgents Bisphosphonates Raloxifene Calcitonin Estrogens Anabolic Agents Parathyroid hormone Growth hormone Testosterone Fluoride

  36. Risedronate: VERT NA Trial Vertebral Fracture Reduction RCT: 2458 women with PMO and vertebral fracture treated for 3 years 41%* % Women With New Vertebral Fracture N=93 N=61 * Relative risk reduction, P=0.003 vs placebo. N = number of women with new fracture. Harris ST, JAMA. 1999;282:1344-1352

  37. 36% 27% Risedronate Treatment Meta-analysisFracture Prevention Vertebral Fx Non-Vertebral Fx 0.64  Harris 0.64  Harris  1.52 Clemensen 0.70  0.76  Clemensen McClung  0.62 Fogelman  0.69 Fogelman 0.71  Reginster 0.60  0.71  Reginster McClung   0.64 (0.54 - 0.77) (n=2604) Pooled Estimate 0.73 (0.61 - 0.87) (n=12958) Cranney A, Endocrine Reviews 2002; 23:495-578

  38. Risedronate: Hip StudyHip Fracture Reduction RCT: 9331 women with PMO and/or non-skeletal risk factors treated for 3 years Low BMD Group 70-79 years old Osteoporosis Femoral Neck T-Score < -4 or Femoral Neck T-Score < -3 plus 1 Risk Factor Clinical Risk Factor(s) Group 80 years old No BMD Requirement 1 Risk Factor or Femoral Neck T-Score < -4 Femoral Neck T-Score < -3and Hip Axis 11.1 cm McClung MR, N Engl J Med. 2001;344:333-340.

  39. Risedronate: Hip StudyHip Fracture Reduction RCT: 9331 women with PMO and/or non-skeletal risk factors treated for 3 years % Women With Hip Fracture 30%* 40%** N=95 N=137 N=46 N=55 N=49 N=82 Overall Low BMD Clinical Risk Factor(s) Relative risk reduction: * P=0.02 vs placebo; ** P=0.009 vs placebo.N = number of women with new fracture. McClung MR, N Engl J Med. 2001;344:333-340.

  40. Alendronate: FIT TrialVertebral Fracture Prevention RCT: 2027 women with PMO and vertebral fracture treated for 3 years % Women With New Vertebral Fracture 47%* N=145 N=78 * Relative risk reduction, P<0.001. N = number of women with new fracture. Black DM, Lancet. 1996;348:1535-1541

  41. 47% 51% Alendronate Treatment Meta-analysisFracture Prevention Vertebral Fx Non-Vertebral Fx 0.36  Adami 0.68  Bone 0.43  Chesnut 0.25  Chesnut 0.55  Liberman (USA) 0.52  Liberman (USA) 0.65 0.52  Liberman (INT)  Liberman (INT) 0.47 0.53  Black  Pols 0.35 0.51  Cummings  Rosen 0.51  (25.47) Adami  0.53 (0.43 - 0.65) (n=8005)  Pooled Estimate 0.49 (0.36-0.67) (n=3456) Cranney A, Endocrine Reviews 2002; 23:495-578

  42. Alendronate: FIT TrialHip Fracture Prevention RCT: 2027 women with PMO and vertebral fracture treated for 3 years % Women With HipFracture 51%* N=11 N=22 * Relative risk reduction, P=0.047 vs placebo. N = number of women with new fracture. Black DM, Lancet. 1996;348:1535-1541

  43. Risedronate: Weekly vs DailySpine and Hip BMD No Fracture Data 1456 women with PMO and an existing vertebral fracture treated for 1 year % Increasein BMD N=480 N=485 N=480 N=485 N = number of women with BMD measurement. Lindsay R, November 2001. Abstract.

  44. Alendronate: Weekly vs DailySpine and Hip BMD No Fracture Data 1258 women with PMO and vertebral fracture treated for 1 year % ChangeFrom Baselinein BMD N=370 N=519 N=370 N=519 N = number of women with BMD measurement. Schnitzer T, Aging Clin Exp Res. 2000;12:1-12

  45. Intravenous BisphosphonatesVertebral BMD Change Pamidronate 30 mg (250-500 cc NS) IV over 2 hours every 3 months 8% 6% 4% 2% 0% Na Fluoride Pamidronate Thiebaud D, Osteoporosis Int 4:76-83, 1994

  46. Intravenous BisphosphonatesBMD Change Zoledronate Intravenously Spine 8% Hip 6% 4% 2% 0% 1 mg q 3mos 2 mg q 6mos 4 mg q year Placebo Reid IR, NEJM 346:653-61, 2002

  47. Osteoporosis TreatmentAlendronate added to ongoing HRT BMD Change 4% HRT + Placebo HRT + Alend 2% 0% Spine Hip Lindsay R, JCEM 84:3076-81, 1999

  48. Ca P04 OB OC OB OldBone NewBone OB Osteoporosis Treatment Anti-ResorptiveAgents Bisphosphonates Raloxifene Calcitonin Estrogens Anabolic Agents Parathyroid hormone Growth hormone Testosterone Fluoride

  49. PTH: Mode of Delivery Determines Bone Activity Continuous exposure results in increased osteoclastic bone resorption Intermittent exposure results in increased osteoblast number and bone formation. Dobnig & Turner. Endocrinology 1997;138:4607-4612

  50. PTH 1-34 Therapy18 Month BMD Data RCT: 1637 postmenopausal women with previous vertebral fractures PTH (n=1093) vs placebo (n=544) PTH 20 ug/d PTH 40 ug/d +14% 15% 0% +10% BMD Change +5% +3% Spine Spine Hip Hip Neer R, NEJM 344:1434, 2001

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