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

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Presentation on theme: "Osteoporosis Management: What Does the Data Support? Osteoporosis Definition 2001: Compromised bone strength predisposing to increased risk of fragility."— Presentation transcript:

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

2 Osteoporosis - Diagnosis Fragility Fractures Spine ~ 700,000/year in US Spine ~ 700,000/year in US Hip ~ 300,000/year in US Hip ~ 300,000/year in US Wrist ~ 250,000/year in US Wrist ~ 250,000/year in US

3 Normal T-score > -1.0 Normal T-score > -1.0 Osteopenia T-score = -1.0 to -2.5 Osteopenia T-score = -1.0 to -2.5 Osteoporosis T-score < -2.5 Osteoporosis T-score < -2.5 Established in Postmenopausal Women Osteoporosis - Diagnosis Bone Densitometry Criteria

4 Bone Densitometry Report 2030405060708090100 Age (years) SD (T-score) x T-score T-score = -3.0 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? Therapy Decision High Risk Treat Moderate Risk Treat if other risk factors Low Risk Check again in 1-2 years T-Score* Below -2.0 -1.5 to -2.0 Above -1.5 National Osteoporosis Foundation. Washington, DC. 1998. * Based on measurements from central DXA.

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-score Z-score Spine (L2-L4) -1.91 -1.31 Femoral Neck -1.68 -1.08

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

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

10 Case Presentation A 75 year old woman with 2 past vertebral fractures. No back pain at present. PMH: HTN, DJDFam 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-score Z-score Spine (L2-L4) -3.69 -1.42 Femoral Neck -2.98 -1.01

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

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

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

14 Dietary Calcium Intake Estimate 300 mg calcium in general diet 300 mg calcium in general diet 300 mg calcium in every dairy serving 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 Supplements Solubility and Absorption Heaney R, Calc Tissue Int 1990; 46:300-304 Fractional Fractional Solubility Absorption Absorption Preparation (mM/liter) w Meal w/o Meal Calcium carbonate 0.14 30% 24% Tricalcium phosphate 0.97 25% Calcium citrate 7.3 24% Calcium citrate malate 80 36% 352 calcium absorption studies in normal subjects Double isotope ( 45 Ca, 47 Ca) or single isotope ( 45 Ca)

16 Osteoporosis Treatment Calcium 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 Recker R, J Bone Min Res 1996; 11:1961-6 % Who Fractured P=.023 P=.435 42% reduction No reduction

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

18 Osteoporosis Treatment Vitamin 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 Dawson-Hughes, NEJM 1997; 337:670-6 % Who Fractured P=.02 55% reduction

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

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

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

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

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

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

25 Osteoporosis Treatment Fall Prevention Jensen J, Ann Intern Med 2002; 136:733-41 % Who Fell% Who Fractured Hip 22% reduction77% reduction RCT: 402 Nursing home residents (age > 65 yr.; median 83 yr.) Multiple Risk Factor Intervention (n=194) vs. Control (n=208)

26 OC OB Old Bone New Bone Ca P04 Bone Remodeling

27 OC OB Old Bone New Bone Ca P04 Osteoporosis Treatment Anti-Resorptive Agents Bisphosphonates Raloxifene Calcitonin Estrogens Anabolic Agents Parathyroid hormone Growth hormone Testosterone Fluoride

28 OC OB Old Bone New Bone Ca P04 Osteoporosis Treatment Anti-Resorptive Agents Bisphosphonates Raloxifene Calcitonin Estrogens Anabolic Agents Parathyroid hormone Growth hormone Testosterone Fluoride

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

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

31 OC OB Old Bone New Bone Ca P04 Osteoporosis Treatment Anti-Resorptive Agents Bisphosphonates Raloxifene Calcitonin Estrogens Anabolic Agents Parathyroid hormone Growth hormone Testosterone Fluoride

32 0 10 20 30 40 Placebo 100 IU/day 200 IU/day 400 IU/day RCT: 1255 women with PMO and vertebral fracture treated for 5 years Calcitonin: PROOF Study Vertebral Fracture Prevention * 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% * % Women With  1 New Vertebral Fracture N=70N=51N=59N=61

33 OC OB Old Bone New Bone Ca P04 Osteoporosis Treatment Anti-Resorptive Agents Bisphosphonates Raloxifene Calcitonin Estrogens Anabolic Agents Parathyroid hormone Growth hormone Testosterone Fluoride

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

35 OC OB Old Bone New Bone Ca P04 Osteoporosis Treatment Anti-Resorptive Agents Bisphosphonates Raloxifene Calcitonin Estrogens Anabolic Agents Parathyroid hormone Growth hormone Testosterone Fluoride

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

37 Vertebral Fx 0.69 Non-Vertebral Fx Harris 0.64  Pooled Estimate0.64 (0.54 - 0.77) (n=2604)   0.60  0.70  0.64 Harris Clemensen Fogelman Reginster  0.73 (0.61 - 0.87) (n=12958)   1.52 0.76   0.62  0.71  Clemensen McClung Fogelman Reginster McClung Risedronate Treatment Meta-analysis Fracture Prevention Risedronate Treatment Meta-analysis Fracture Prevention Cranney A, Endocrine Reviews 2002; 23:495-578 36%27%

38 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 < -3 and Hip Axis  11.1 cm RCT: 9331 women with PMO and/or non-skeletal risk factors treated for 3 years McClung MR, N Engl J Med. 2001;344:333-340. Risedronate: Hip Study Hip Fracture Reduction

39 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. OverallLow BMDClinical Risk Factor(s) 30%* 40%** % Women With Hip Fracture N=95N=137N=46N=55N=49N=82 RCT: 9331 women with PMO and/or non-skeletal risk factors treated for 3 years Risedronate: Hip Study Hip Fracture Reduction

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

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

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

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

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

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

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

47 Osteoporosis Treatment Alendronate added to ongoing HRT 4% 2% 0% BMD Change Lindsay R, JCEM 84:3076-81, 1999 HRT + Placebo HRT + Alend SpineHip

48 OC OB Old Bone New Bone Ca P04 Osteoporosis Treatment Anti-Resorptive Agents 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 RCT: 1637 postmenopausal women with previous vertebral fractures PTH (n=1093) vs placebo (n=544) BMD Change PTH 1-34 Therapy 18 Month BMD Data Neer R, NEJM 344:1434, 2001 15% 0% +14% Hip Spine +10% +5% +3% Hip Spine PTH 20 ug/dPTH 40 ug/d

51 RCT: 1637 postmenopausal women with previous vertebral fractures PTH (n=1093) vs placebo (n=544) Fracture Reduction PTH 1-34 Therapy 18 Month Fracture Data Neer R, NEJM 344:1434, 2001 0% -75% -69% Non-spine Spine -65% -40% -35% PTH 20 ug/dPTH 40 ug/d Non-spine Spine

52 BMD Monitoring on Treatment Response Patterns Anti-resorptive AgentAnabolic Agent Least Significant Change* 2.7% in Spine 5.7% in Hip *must be established for each instrument

53 RiskBenefit Stroke Coronary Artery Disease Breast Cancer Plan to Study Until 2005 Additional Benefits: Osteoporosis Colon Cancer Overall Mortality Additional Risks: VTE Writing Group. JAMA. 2002;288:321-333. Women’s Health Initiative Hormone Replacement Hypotheses

54 Women’s Health Initiative Hormone Replacement Design Hysterectomy Premarin 0.625 mg/d Placebo Premarin/Provera 0.625/2.5 mg/d YES N=10,739 NO N=16,608 Placebo (Age: 50-79; mean 63 yr.) Study Duration 8.5 years with interim analysis at 5.2 years Writing Group, JAMA 2002; 288:321-333

55 26% Increase Breast Cancer WHI HRT Study 5.2 Year Findings in Premarin/Provera Group 211% increase VTE 37% Colon Cancer reduction 34% Fracture reduction Early STOP=Clear Harm 29% Increase Coronary Artery Disease 41% Increase Stroke RiskBenefit Writing Group. JAMA. 2002;288:321-333.

56 Women’s Health Initiative Interim Analysis at 5.2 Years Hysterectomy Premarin 0.625 mg/d Placebo Premarin/Provera 0.625/2.5 mg/d YES N=10,739 NO N=16,608 Placebo ERT Arm Continued Writing Group, JAMA 2002; 288:321-333 HRT Arm Stopped

57 Coronary Heart Disease7 more cases Coronary Heart Disease7 more cases Breast Cancer8 more cases Breast Cancer8 more cases VTE8 more cases VTE8 more cases Stroke8 more cases Stroke8 more cases Colon Cancer6 fewer cases Colon Cancer6 fewer cases Hip Fracture5 fewer cases Hip Fracture5 fewer cases Women’s Health Initiative Attributable Risk of HRT – 5.2 Year Analysis 10,000 patient years (2000 patients treated for 5 years) Writing Group. JAMA. 2002;288(3):321–333.

58 These results do not address: These results do not address:  Premarin alone (data analysis in 2005)  Oral estradiol +/- progesterone/norethindrone  Patch estradiol +/- progesterone/norethindrone  Women under age 50  Quality of Life Women’s Health Initiative Caveats – 5.2 Year Analysis

59 Vertebral Fracture Reduction RCTs in Women with PMO and Vertebral Fractures 0% -10% -20% -30% -40% -50% Calcitonin Raloxifene Estrogen RisedronateAlendronate PROOFMOREWHIVERT-NAFIT Chesnut C, AM J Med 2000, 109:267 Harris S, JAMA 1999, 282:1344 Ettinger B, JAMA 1999, 282:637 Black D, Lancet 1996, 348:1535 Writing Group, JAMA 2002, 288:321 33% 30% 34% 41% 47%

60 Hip Fracture Reduction RCTs in Women with PMO 0% -10% -20% -30% -40% -50% Calcitonin Raloxifene Estrogen RisedronateAlendronate WHIHIPFIT Writing Group, JAMA 2002, 288:321 McClung M, NEJM 2001, 344:333 Black D, Lancet 1996, 348:1535 34% 40% 51%


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