Transcript Management of Vertebral Compression Fractures

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
and Risk Stratification: Principles for Approaching a
Broad Population of Patients at Risk for Osteoporosis
Program Contents
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Definitions
Epidemiology
Pathophysiology
Clinical Features
Diagnosis
Therapy
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
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Bone involution in both sexes
with aging and a superimposed
acceleration of bone loss in
women after the menopause
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Low bone mass coupled with
micro-architectural deterioration
leading to enhanced bone
fragility and ultimately fracture
Risk Factors You Can’t Change
Contents
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Epidemiology
Prevalence
Incidence
Sites
Cost
Status of care
Prevalence
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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
%
Projected
Population
>65 Years
15
1950
1985
2020
10
5
0
Paiement GD, Perrier L. In: Comprehensive Management of Menopause. 1994:32-38. US Census Bureau. 2000.
Osteoporotic Fracture Incidence Is High
1,600,000
Cases/Year
1,400,000
1,200,000
1,000,000
800,000
600,000
400,000
200,000
0
Breast
Cancer
Heart
Disease
Women’s Health Facts and Figures. Washington, DC: ACOG; 2000.
Osteoporotic
Fractures
Distribution of Fractures
Vertebral
46%
(700,000)
Hip
19%
(300,000)
Wrist
16%
(250,000)
Other
19%
(300,000)
NIH/ORBD National Resource Center. October 2000.
High Economic Burden
Estimated $13.8 billion/year
Hospitalization
($8.6)
Outpatient
($1.3)
Ray NF et al. J Bone Miner Res. 1997;12:24-35.
Nursing
Home
($3.9)
Current Status of Care
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3% to 5% of hip fracture patients are
diagnosed for osteoporosis and
treated
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3% of wrist fracture patients receive
BMD testing
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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.
Content
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Pathophysiology
Bone Remodeling
Types of
Osteoporosis
The Bone Remodeling Cycle
Osteoclast
Osteoblast
Osteoblast
Recruitment
Resorption
Mineralization
Osteoid
Deposition
Courtesy: Dr. Mone Zaidi
Disordered Bone Remodeling
as the Cause of Osteoporosis
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High Remodeling
Hypogonadal (including post-menopausal)
Hyperparathyroidism
Hyperthyroidism
Others
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Low Remodeling
Involutional (Aging)
Glucocorticoids (high dose)
HIV
Pathogenesis of Osteoporoses
Resorption 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
Content
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Clinical Features
Vertebral Fractures
Non-Vertebral
Fractures
Risk Stratification
Vertebral Fractures
► Most
common fractures (46%)
► Insidious
► Progressive
► Often
unrecognized
► Associated
with
– Deformity, height loss, back
pain
– Morbidity and mortality
► Predict
future vertebral and nonvertebral fractures
NonVertebral Fractures
► Entire
skeleton can be involved
– Wrist
– Ankle
– Pelvis
– Humerus
– Rib
– Others
► Associated
disability
with significant
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
NIH Consensus Development Panel. JAMA. 2001;285:785-795.
Risk of Fracture
All postmenopausal women with the following:
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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.
A Fracture Begets a Future Fracture
Future Fractures (Fold Increase)
Existing Fracture
Wrist
Vertebral
Hip
Wrist
3.3
1.7
1.9
Vertebral
1.4
4.4
2.3
-
2.5
2.3
Hip
Klotzbuecher CM et al. J Bone Miner Res. 2000;15:721-739.
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
Content
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Diagnosis
Clinical Assessment
Diagnostic Criteria
Bone Densitometry
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.
Kyphotic vs. Non-Kyphotic
The Kyphotic Woman
► Likely has
osteoporosis and
vertebral fractures
► Confirmatory
spinal
x-ray for diagnosis
► Baseline
BMD
The Non-Kyphotic Woman
► Spinal
x-ray or DXA
if height loss >1.5
inches
► Atraumatic
vertebral fractures =
osteoporosis a
Diagnosis
BMD Criteria: Low T-Score
Non-BMD Criteria: Fragility Fracture
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 mass
in young adults.
Techniques
Diagnosis
Risk Assessment/
Research
Central dual energy xray absorptiometry
(DXA)
► Gold standard
► WHO criteria
applied
►Peripheral
National Osteoporosis Foundation. Washington, DC; 1999.
DXA (pDXA)
►Ultrasound
►Quantitative computed
tomography (QCT)
Central vs Peripheral DXA
Central DXA
Peripheral DXA
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► Different
Establish or confirm
diagnosis
► Assess fracture risk
► Follow up
► Enhance patient
compliance
from WHO
T-score criteria
► Fracture
risk
assessment in elderly
with low T-scores
Content
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Therapeutic Considerations
Mode of Action
Anti-resorptive Agents
Anabolic Agents
Bisphosphonate Failure
Efficacy Testing
Goals for Therapy
► Fracture
prevention
► Stabilize or increase bone
mass
► Provide tolerability and longterm safety
► Ensure compliance and
adherence
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 musclestrengthening exercise (no weight lifting if
BMD in spine is low)
► Fall
prevention advice
► Home
safety evaluation
Medications
FDA-Approved
Prevention Treatment
Hormone replacement
Yes
No
Calcitonin (Miacalcin®)
Raloxifene (Evista®)
No
Yes
Yes
Yes
Alendronate (Fosamax®)
Risedronate (Actonel®)
Yes
Yes
Yes
Yes
Ibandronate (Boniva®)
Ibandronate Injection
(Boniva®)
Parathyroid hormone
(Forteo®)
Yes
Yes
Yes
Yes
*
Yes
*Not considered.
Osteoporosis Therapeutics
Decrease Resorption
► Bisphosphonates
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Estrogen
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Raloxifene
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Calcitonin
Enhance Formation
► Parathyroid
Hormone
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
PTH
Mode of Delivery = Bone Activity
Intermittent versus Continuous
=
Osteoblastic versus Osteoclastic
=
Formation versus Resorption
=
Bone Gain versus Bone Loss
Courtesy: Mone Zaidi, MD
Mount Sinai School of Medicine
PTH – Anabolic Action
Receptor Binding and
Signal Transduction
Increased Osteoblast
Survival
Enhanced Osteoblast
Differentiation
Net Increase in Number and
Activity of Bone-Forming
Osteoblasts
Calcitonin
Courtesy: Mone Zaidi, MD
Mount Sinai School of Medicine
Nasal Calcitonin: Efficacy
at the Spine and Hip
PROOF: Three Year Analysis
Estrogen and Raloxifene
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Reduce the birth (genesis) of new osteoclasts
from bone marrow
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Does not inhibit the activity of mature resorbing
osteoclasts
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Osteoclast birth increases exponentially to a
peak within the first few years of the
menopausal transition
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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
OH R1 OH
OH
OH
O=P–C–P=O O=P–O–P=O
OH R2 OH
Bisphosphonate
OH
OH
Polyphosphate
Bisphosphonate Mechanism of Action
Courtesy: Mone Zaidi, MD
Mount Sinai School of Medicine
Possible Causes of Poor Adherence?
Lack of positive
reinforcement?
Osteoporosis
eclipsed by
other chronic
conditions?
Poor patient
education?
POOR
ADHERENCE
Concern about
side effects?
Complex
dosing
guidelines?
Disruption to
daily routine?
(less frequent
dosing)
Adherence With Osteoporosis
Medications Is Poor
Patients Abandoning
Treatment (%)
30
25
26%
20
19%
19%
Bisphosphonate
(n=366)
Selective Estrogen
Receptor Modulator
(n=256)
15
10
5
0
Hormone Replacement
Therapy
(n=334)
Tosteson ANA, et al. Am J Med. 2003;115:209-216.
% Patients With Fracture
Long-term Compliance Reduces
Fracture Risk
14
12
12.6%
*
9.4%
10
8
6
4
2
0
†
Compliant
(n=3400)
Noncompliant
(n=3425)
Siris E, et al. Presented at: Sixth International Symposium on Osteoporosis. April 6-10, 2005; Washington, DC.
Daily vs. Weekly Bisphosphonates Has
Led To Increased Compliance
Daily
Patients on Therapy (%)
100
Weekly
90
80
70
60
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
Oct Nov
2002
Dec
Jan
Feb
Mar
Apr
May
Jun
Jul
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.
Aug
Sep
Oct
2003
BMD Changes: 30-Minute vs 60-Minute
Postdose Fast With Ibandronate-Sodium
Mean % Change in BMD (95% Cl)
7
30-minute postdose fast
60-minute postdose fast
6
5
4
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.
Efficacy Testing Of
Anti-osteoporosis Drugs
The FDA-mandated primary outcome measures
(end point) for all pivotal trials is the
demonstration of efficacy in reducing vertebral
fracture
Non-vertebral fractures, BMD and bone
remodeling markers are secondary end points
Secondary end points are never statistically
powered in terms of patient numbers to detect
differences between placebo and drug
Non-Vertebral Fractures
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Multiple non-vertebral sites, the definition
of which varies across clinical trials
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Heterogenous group of bones, with
different proportions of cortical and
cancellous bone
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Differences in non-vertebral fracture
incidence and disease severity in placebo
groups
Conclusions
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Characterized by a loss of bone mass and
architecture
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Inevitable consequence of aging in both sexes
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Accelerated following menopause, disease and
drugs
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Early detection and intervention is mandatory
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Fracture stratification allows identification beyond
BMD
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Bisphosphonates are the mainstay of therapy
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Ensuring compliance through less complex dosing
should lead to greater therapeutic benefit
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
► 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
Femoral neck T-score +
►
Age
►
Previous low trauma fracture
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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
►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