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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 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


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Program Contents

  • Definitions

  • Epidemiology

  • Pathophysiology

  • Clinical Features

  • Diagnosis

  • Therapy


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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.


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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



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Contents

  • Epidemiology

    • Prevalence

    • Incidence

    • Sites

    • Cost

    • Status of care


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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


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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.


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Osteoporotic Fracture Incidence Is High Aging Population

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.


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Vertebral Aging Population

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.


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High Economic Burden Aging Population

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.


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Current Status of Care Aging Population

  • 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.


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Content Aging Population

  • Pathophysiology

    • Bone Remodeling

    • Types of Osteoporosis


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Osteoblast Aging Population

Osteoclast

Mineralization

Osteoid

Deposition

The Bone Remodeling Cycle

Osteoblast

Recruitment

Resorption

Courtesy: Dr. Mone Zaidi


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Disordered Bone Remodeling Aging Populationas the Cause of Osteoporosis

  • High Remodeling

    • Hypogonadal (including post-menopausal)

    • Hyperparathyroidism

    • Hyperthyroidism

    • Others

  • Low Remodeling

    • Involutional (Aging)

    • Glucocorticoids (high dose)

    • HIV


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    Pathogenesis of Osteoporoses Aging PopulationResorption 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


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    Content Aging Population

    • Clinical Features

      • Vertebral Fractures

      • Non-Vertebral Fractures

      • Risk Stratification


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    Vertebral Fractures Aging Population

    • 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


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    NonVertebral Fractures Aging Population

    • Entire skeleton can be involved

      • Wrist

      • Ankle

      • Pelvis

      • Humerus

      • Rib

      • Others

    • Associated with significant disability


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    Hip Fracture Aging Population

    • 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.


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    Risk of Fracture Aging Population

    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.


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    A Fracture Begets a Future Fracture Aging Population

    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.


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    Fracture Stratification Key Points Aging Population

    • 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


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    Content Aging Population

    • Diagnosis

      • Clinical Assessment

      • Diagnostic Criteria

      • Bone Densitometry


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    Clinical Evaluation Aging Population

    • 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.


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    The Kyphotic Woman Aging Population

    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


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    Diagnosis Aging Population

    BMD Criteria: Low T-Score

    Non-BMD Criteria: Fragility Fracture


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    WHO Diagnostic Criteria Aging Population

    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.


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    Risk Assessment/ Research Aging Population

    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.


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    Central vs Peripheral DXA Aging Population

    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


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    Content Aging Population

    • Therapeutic Considerations

      • Mode of Action

      • Anti-resorptive Agents

      • Anabolic Agents

      • Bisphosphonate Failure

      • Efficacy Testing


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    Goals for Therapy Aging Population

    • Fracture prevention

    • Stabilize or increase bone mass

    • Provide tolerability and long-term safety

    • Ensure compliance and adherence


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    Nonpharmacologic Approaches Aging Population

    • 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


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    Calcitonin (Miacalcin Aging Population®)

    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.


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    Osteoporosis Therapeutics Aging Population

    Decrease Resorption

    Enhance Formation

    • Parathyroid Hormone

    • Bisphosphonates

    • Estrogen

    • Raloxifene

    • Calcitonin


    Anti resorptive versus anabolic l.jpg
    Anti-Resorptive Aging PopulationVersus Anabolic

    Anti-Resorptive

    High Turnover Bone Loss

    Low Turnover Bone Loss

    PTH - Anabolic

    Courtesy: Mone Zaidi, MD Mount Sinai School of Medicine


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    Intermittent Aging Population 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


    Pth anabolic action l.jpg
    PTH – Anabolic Action Aging Population

    Receptor Binding and

    Signal Transduction

    Increased Osteoblast

    Survival

    Enhanced Osteoblast

    Differentiation

    Net Increase in Number and

    Activity of Bone-Forming

    Osteoblasts


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    Calcitonin Aging Population

    Courtesy: Mone Zaidi, MD Mount Sinai School of Medicine


    Slide40 l.jpg

    Nasal Calcitonin: Efficacy Aging Populationat the Spine and Hip

    PROOF: Three Year Analysis


    Estrogen and raloxifene l.jpg
    Estrogen and Raloxifene Aging Population

    • 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.


    Structure of bisphosphonates l.jpg

    Structure of Bisphosphonates Aging Population

    R1

    OH

    OH

    OH

    OH

    O = P – C – P = O

    O = P – O – P = O

    R2

    OH

    OH

    OH

    OH

    Bisphosphonate

    Polyphosphate


    Bisphosphonate mechanism of action l.jpg
    Bisphosphonate Mechanism of Action Aging Population

    Courtesy: Mone Zaidi, MD Mount Sinai School of Medicine


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    Possible Causes of Poor Adherence? Aging Population

    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?


    Adherence with osteoporosis medications is poor l.jpg
    Adherence With Osteoporosis Aging PopulationMedications 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.


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    Long-term Compliance Reduces Aging PopulationFracture 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.


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    100 Aging Population

    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.


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    30-minute postdose fast Aging Population

    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.


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    Efficacy Testing Of Aging PopulationAnti-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


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    Non-Vertebral Fractures Aging Population

    • 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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    Conclusions Aging Population

    • Characterized by a loss of bone mass and architecture

    • Inevitable consequence of aging in both sexes

    • Accelerated following menopause, disease and drugs

    • Early detection and intervention is mandatory

    • Fracture stratification allows identification beyond BMD

    • Bisphosphonates are the mainstay of therapy

    • Ensuring compliance through less complex dosing should lead to greater therapeutic benefit


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    Fracture Risk Reporting Aging Population

    • Since the goal of osteoporosis therapy is fracture prevention, patient selection is best based on fracture risk

    • T-score alone does not provide a complete assessment of fracture risk

    • Combination of clinical risk factors with BMD may provide a better way of identifying patients for treatment


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    Selection of Clinical Risk Factors Aging Population

    • Independent of BMD (if BMD is known)

    • Validated in multiple populations (sex, ethnicity, country)

    • Easily obtainable

    • Amenable to intended treatment

    • Intuitive

    Adapted from Kanis JA et al. Osteoporos Int. 2005;16:581-589.


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    Clinical Risk Factors Aging Population

    Femoral neck T-score +

    • Age

    • Previous low trauma fracture

    • Current cigarette smoking

    • Rheumatoid arthritis

    • High alcohol intake (> 2 units/day)

    • Parental history of hip fracture

    • Prior or current glucocorticoid use

    Adapted from Kanis JA et al. Osteoporos Int. 2005;16:581-589.


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    Intervention Threshold Aging Population

    • A fracture probability above which it is cost-effective to treat with pharmacological agents

    • Based on statistical modeling using many medical, social, and economic assumptions


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