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Critical Challenges in Osteoporosis— From Patient Presentation To Therapeutic Decision Points: An Overview of Issues, C

Critical Challenges in Osteoporosis— From Patient Presentation To Therapeutic Decision Points: An Overview of Issues, Concepts, and Clinical Strategies SCREEN AND INTERVENE Evidence-Basis for Patient Screening

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Critical Challenges in Osteoporosis— From Patient Presentation To Therapeutic Decision Points: An Overview of Issues, C

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  1. Critical Challenges in Osteoporosis—From Patient Presentation ToTherapeutic Decision Points: An Overview of Issues, Concepts,and Clinical Strategies SCREEN AND INTERVENEEvidence-Basis for Patient Screening and Risk Stratification: Principles for Approaching aBroad Population of Patients at Risk for Osteoporosis

  2. Program Contents • Definitions • Epidemiology • Pathophysiology • Clinical Features • Diagnosis • Therapy

  3. Definition Osteoporosis is defined as a skeletal disorder characterized by compromised bone strength predisposing a person to increased risk of fracture1 1. NIH Consensus Development Panel on Osteoporosis Prevention, Diagnosis, and Therapy. JAMA. 2001;285:785-795.

  4. Key Features of Osteoporosis • Bone involution in both sexes with aging and a superimposed acceleration of bone loss in women after the menopause • Low bone mass coupled with micro-architectural deterioration leading to enhanced bone fragility and ultimately fracture

  5. Risk Factors You Can’t Change

  6. Contents • Epidemiology • Prevalence • Incidence • Sites • Cost • Status of care

  7. Prevalence • 44 million Americans have or are at risk of osteoporosis • 55% of all people ages 50 years • 10 million have osteoporosis • 34 million more have low bone mass • 50% of women aged 50 years will experience a fracture in their lifetime • Prevalence is expected to increase with the growth of the elderly population

  8. Prevalence of Osteoporosis Will Increase With an Increasing Aging Population 20 1900 1950 15 % 1985 Projected 2020 Population 10 >65 Years 5 0 Paiement GD, Perrier L. In: Comprehensive Management of Menopause. 1994:32-38. US Census Bureau. 2000.

  9. Osteoporotic Fracture Incidence Is High 1,600,000 1,400,000 1,200,000 1,000,000 Cases/Year 800,000 600,000 400,000 200,000 0 Breast Heart Osteoporotic Cancer Disease Fractures Women’s Health Facts and Figures. Washington, DC: ACOG; 2000.

  10. Vertebral 46% (700,000) Hip Wrist 19% 16% (300,000) (250,000) Other 19% (300,000) Distribution of Fractures NIH/ORBD National Resource Center. October 2000.

  11. High Economic Burden Estimated $13.8 billion/year Hospitalization ($8.6) Outpatient ($1.3) Nursing Home ($3.9) Ray NF et al. J Bone Miner Res. 1997;12:24-35.

  12. Current Status of Care • 3% to 5% of hip fracture patients are diagnosed for osteoporosis and treated • 3% of wrist fracture patients receive BMD testing • Only 12% of vertebral fractures are diagnosed and 2% are treated Freedman KB et al. J Bone Joint Surg Am. 2000;82:1063-1070. Gehlbach SH et al. Osteoporosis Int. 2000;11:577-582. Wiktorowicz ME. J Bone Miner Res. 1997;12:S252.

  13. Content • Pathophysiology • Bone Remodeling • Types of Osteoporosis

  14. Osteoblast Osteoclast Mineralization Osteoid Deposition The Bone Remodeling Cycle Osteoblast Recruitment Resorption Courtesy: Dr. Mone Zaidi

  15. Disordered Bone Remodelingas the Cause of Osteoporosis • High Remodeling • Hypogonadal (including post-menopausal) • Hyperparathyroidism • Hyperthyroidism • Others • Low Remodeling • Involutional (Aging) • Glucocorticoids (high dose) • HIV

  16. Pathogenesis of OsteoporosesResorption Must Exceed Formation Normal Remodeling Osteoclast Overactivity Hypogonadal States Parathyroid and Thyroid Osteoblast Dysfunction Involutional (Aging) Glucocorticoids HIV Courtesy: Mone Zaidi, MD Mount Sinai School of Medicine

  17. Content • Clinical Features • Vertebral Fractures • Non-Vertebral Fractures • Risk Stratification

  18. Vertebral Fractures • Most common fractures (46%) • Insidious • Progressive • Often unrecognized • Associated with • Deformity, height loss, back pain • Morbidity and mortality • Predict future vertebral and non-vertebral fractures

  19. NonVertebral Fractures • Entire skeleton can be involved • Wrist • Ankle • Pelvis • Humerus • Rib • Others • Associated with significant disability

  20. Hip Fracture • Most serious clinical event • Morbidity is high • 50% do not regain independence • 50% do not regain previous mobility • Mortality is high • 1 in 5 patients die within 1 year • Patients not treated for osteoporosis NIHConsensus Development Panel. JAMA. 2001;285:785-795.

  21. Risk of Fracture All postmenopausal women with the following: • Low BMD • Fracture after 50 years • Age 65 years • Maternal history of fracture after 50 years • Low body weight (125 lb) • Smoking • Corticosteroid use • Other secondary causes Black DM et al. Osteoporosis Int. 2001;12:519-528.

  22. A Fracture Begets a Future Fracture Future Fractures (Fold Increase) Existing Fracture Wrist 3.3 1.4 - Vertebral 1.7 4.4 2.5 Hip 1.9 2.3 2.3 Wrist Vertebral Hip Klotzbuecher CM et al. J Bone Miner Res. 2000;15:721-739.

  23. Fracture Stratification Key Points • Main risk factors • Low BMD • Presence of a fracture after 50 years • Risk for fracture increases • With number of risk factors • With each subsequent fracture

  24. Content • Diagnosis • Clinical Assessment • Diagnostic Criteria • Bone Densitometry

  25. Clinical Evaluation • History • Risk factor assessment • Medical history • Family history • Social history (smoking, alcohol) • Evaluation of fall risk • Physical • Height loss >1.5 inches • Kyphosis • Tests • BMD • X-ray of thoracic/lumbar spine • Bone turnover markers • Laboratory tests as necessary AACE Guidelines. Endocr Pract. 2001;7:293-312.

  26. The Kyphotic Woman Kyphotic vs. Non-Kyphotic The Non-Kyphotic Woman • Likely has osteoporosis and vertebral fractures • Confirmatory spinal x-ray for diagnosis • Baseline BMD • Spinal x-ray or DXA if height loss >1.5 inches • Atraumatic vertebral fractures = osteoporosis a

  27. Diagnosis BMD Criteria: Low T-Score Non-BMD Criteria: Fragility Fracture

  28. WHO Diagnostic Criteria The WHO Study Group. Geneva, 1994 T-Score* Classification > -1.0 Normal -1.0 to -2.5 Osteopenia < -2.5 or lower Osteoporosis < -2.5 + fracture Severe osteoporosis *T-score = number of standard deviations (SDs) below or above the peak bone massin young adults.

  29. Risk Assessment/ Research Peripheral DXA (pDXA) Ultrasound Quantitative computed tomography (QCT) Diagnosis Central dual energy x-ray absorptiometry (DXA) Gold standard WHO criteria applied Techniques National Osteoporosis Foundation. Washington, DC; 1999.

  30. Central vs Peripheral DXA Peripheral DXA • Different from WHOT-score criteria • Fracture risk assessment in elderly with low T-scores Central DXA • Establish or confirm diagnosis • Assess fracture risk • Follow up • Enhance patient compliance

  31. Content • Therapeutic Considerations • Mode of Action • Anti-resorptive Agents • Anabolic Agents • Bisphosphonate Failure • Efficacy Testing

  32. Goals for Therapy • Fracture prevention • Stabilize or increase bone mass • Provide tolerability and long-term safety • Ensure compliance and adherence

  33. Nonpharmacologic Approaches • Calcium intake • Diet and/or supplementation: 1200 mg/day • Vitamin D supplementation • Diagnose and treat deficiency/insufficiency • Supplement: 400-800 IU/day • Regular load-bearing and muscle-strengthening exercise (no weight lifting if BMD in spine is low) • Fall prevention advice • Home safety evaluation

  34. Calcitonin (Miacalcin®) No Yes Ibandronate Injection (Boniva®) Ibandronate (Boniva®) Raloxifene (Evista®) Yes Yes Yes Yes Yes Yes Alendronate (Fosamax®) Yes Yes Parathyroid hormone (Forteo®) * Yes Medications Prevention Treatment FDA-Approved Hormone replacement Yes No Risedronate (Actonel®) Yes Yes *Not considered.

  35. Osteoporosis Therapeutics Decrease Resorption Enhance Formation • Parathyroid Hormone • Bisphosphonates • Estrogen • Raloxifene • Calcitonin

  36. Anti-Resorptive Versus Anabolic Anti-Resorptive High Turnover Bone Loss Low Turnover Bone Loss PTH - Anabolic Courtesy: Mone Zaidi, MD Mount Sinai School of Medicine

  37. Intermittent versus Continuous = Osteoblasticversus Osteoclastic = Formationversus Resorption = Bone Gain versus Bone Loss PTH Mode of Delivery = Bone Activity Courtesy: Mone Zaidi, MD Mount Sinai School of Medicine

  38. PTH – Anabolic Action Receptor Binding and Signal Transduction Increased Osteoblast Survival Enhanced Osteoblast Differentiation Net Increase in Number and Activity of Bone-Forming Osteoblasts

  39. Calcitonin Courtesy: Mone Zaidi, MD Mount Sinai School of Medicine

  40. Nasal Calcitonin: Efficacyat the Spine and Hip PROOF: Three Year Analysis

  41. Estrogen and Raloxifene • Reduce the birth (genesis) of new osteoclasts from bone marrow • Does not inhibit the activity of mature resorbing osteoclasts • Osteoclast birth increases exponentially to a peak within the first few years of the menopausal transition • Maximum bio-efficacy in early menopause and declines with age and disease severity/fractures Zaidi, M., et. al. (2001) Journal of Bone and Mineral Research.

  42. Structure of Bisphosphonates R1 OH OH OH OH O = P – C – P = O O = P – O – P = O R2 OH OH OH OH Bisphosphonate Polyphosphate

  43. Bisphosphonate Mechanism of Action Courtesy: Mone Zaidi, MD Mount Sinai School of Medicine

  44. Possible Causes of Poor Adherence? Complex dosing guidelines? Poor patient education? Disruption to daily routine? (less frequent dosing) Lack of positive reinforcement? Osteoporosis eclipsed by other chronic conditions? POORADHERENCE Concern about side effects?

  45. Adherence With Osteoporosis Medications Is Poor 30 25 20 15 10 5 0 26% 19% 19% Patients AbandoningTreatment (%) Hormone Replacement Therapy (n=334) Bisphosphonate (n=366) Selective Estrogen Receptor Modulator (n=256) Tosteson ANA, et al. Am J Med. 2003;115:209-216.

  46. Long-term Compliance Reduces Fracture Risk % Patients With Fracture 12.6% 14 * 12 9.4% 10 8 6 4 2 0 † Compliant Noncompliant (n=3425) (n=3400) Siris E, et al. Presented at: Sixth International Symposium on Osteoporosis. April 6-10, 2005; Washington, DC.

  47. 100 90 80 70 60 Patients on Therapy (%) 54.6% 50 40 36.9% 30 P<0.001 vs daily therapy Weekly Bisphosphonates (n=177,552) 20 Daily Bisphosphonates (n=33,767) 10 Daily vs. Weekly Bisphosphonates Has Led To Increased Compliance Oct2002 Nov Dec Jan Feb Mar Apr May Jun Jul Aug Sep Oct2003 DailyWeekly Ettinger M, et al. Arthritis Rheum. 2004;50(suppl):S513-S514. Abstract 1325. Data on file (Reference # 161-040), Hoffmann-La Roche Inc., Nutley, NJ 07110.

  48. 30-minute postdose fast 60-minute postdose fast BMD Changes: 30-Minute vs 60-Minute Postdose Fast With Ibandronate-Sodium 7 6 5 4 Mean % Change in BMD (95% Cl) 3 2 1 0 Spine (L1-L4) Trochanter Total Hip Femoral Neck Although significant vs baseline, the BMD gains seen in the 30-minute postdose fast group were inferior to those seen in the 60-minute postdose group. Tankó LB, et al. Bone. 2003; 32:421-426.

  49. Efficacy Testing OfAnti-osteoporosis Drugs The FDA-mandated primary outcome measures (end point) for all pivotal trials is the demonstration of efficacy in reducing vertebral fractureNon-vertebral fractures, BMD and bone remodeling markers are secondary end pointsSecondary end points are never statistically powered in terms of patient numbers to detect differences between placebo and drug

  50. Non-Vertebral Fractures • Multiple non-vertebral sites, the definition of which varies across clinical trials • Heterogenous group of bones, with different proportions of cortical and cancellous bone • Differences in non-vertebral fracture incidence and disease severity in placebo groups

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