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Critical Challenges in Osteoporosis— From Patient Presentation To Therapeutic Decision Points: An Overview of Issues, Concepts, and Clinical Strategies

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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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slide1

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

program contents
Program Contents
  • Definitions
  • Epidemiology
  • Pathophysiology
  • Clinical Features
  • Diagnosis
  • Therapy
definition
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.

key features of osteoporosis
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
slide6

Contents

  • Epidemiology
    • Prevalence
    • Incidence
    • Sites
    • Cost
    • Status of care
slide7

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
prevalence of osteoporosis will increase with an increasing aging population
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.

osteoporotic fracture incidence is high
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.

slide10

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.

high economic burden
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.

current status of care
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.

slide13

Content

  • Pathophysiology
    • Bone Remodeling
    • Types of Osteoporosis
slide14

Osteoblast

Osteoclast

Mineralization

Osteoid

Deposition

The Bone Remodeling Cycle

Osteoblast

Recruitment

Resorption

Courtesy: Dr. Mone Zaidi

disordered bone remodeling as the cause of osteoporosis
Disordered Bone Remodelingas the Cause of Osteoporosis
  • High Remodeling
      • Hypogonadal (including post-menopausal)
      • Hyperparathyroidism
      • Hyperthyroidism
      • Others
  • Low Remodeling
      • Involutional (Aging)
      • Glucocorticoids (high dose)
      • HIV
pathogenesis of osteoporoses resorption must exceed formation
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

slide17

Content

  • Clinical Features
    • Vertebral Fractures
    • Non-Vertebral Fractures
    • Risk Stratification
vertebral fractures
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
nonvertebral fractures
NonVertebral Fractures
  • Entire skeleton can be involved
    • Wrist
    • Ankle
    • Pelvis
    • Humerus
    • Rib
    • Others
  • Associated with significant disability
slide20

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.

slide21

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.

slide22

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.

fracture stratification key points
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
slide24

Content

  • Diagnosis
    • Clinical Assessment
    • Diagnostic Criteria
    • Bone Densitometry
slide25

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.

the kyphotic woman
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
diagnosis
Diagnosis

BMD Criteria: Low T-Score

Non-BMD Criteria: Fragility Fracture

who diagnostic criteria
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.

slide29
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.

slide30

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
slide31

Content

  • Therapeutic Considerations
    • Mode of Action
    • Anti-resorptive Agents
    • Anabolic Agents
    • Bisphosphonate Failure
    • Efficacy Testing
slide32

Goals for Therapy

  • Fracture prevention
  • Stabilize or increase bone mass
  • Provide tolerability and long-term safety
  • Ensure compliance and adherence
slide33

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
slide34

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.

osteoporosis therapeutics

Osteoporosis Therapeutics

Decrease Resorption

Enhance Formation

  • Parathyroid Hormone
  • Bisphosphonates
  • Estrogen
  • Raloxifene
  • Calcitonin
anti resorptive versus anabolic
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

slide37
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

pth anabolic action
PTH – Anabolic Action

Receptor Binding and

Signal Transduction

Increased Osteoblast

Survival

Enhanced Osteoblast

Differentiation

Net Increase in Number and

Activity of Bone-Forming

Osteoblasts

slide39

Calcitonin

Courtesy: Mone Zaidi, MD Mount Sinai School of Medicine

estrogen and raloxifene
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.

structure of bisphosphonates

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

bisphosphonate mechanism of action
Bisphosphonate Mechanism of Action

Courtesy: Mone Zaidi, MD Mount Sinai School of Medicine

possible causes of poor adherence
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?

adherence with osteoporosis medications is poor
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.

long term compliance reduces fracture risk
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.

slide47

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.

slide48

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.

slide49

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

slide50

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
conclusions
Conclusions
  • 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
fracture risk reporting
Fracture Risk Reporting
  • 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
selection of clinical risk factors
Selection of Clinical Risk Factors
  • 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.

clinical risk factors
Clinical Risk Factors

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.

intervention threshold
Intervention Threshold
  • 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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