Transcript 2 vertebral fractures

Postmenopausal Osteoporosis
Overview
Bruce Ettinger, MD
Senior Investigator
Division of Research
Kaiser Permanente Medical Care Program
Oakland, California
Summary of Presentation
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Importance of Osteoporotic Fracture
Making the diagnosis
Drug Treatments
 what works
 who should be treated
 changing treatments
Incidence Rates for Vertebral, Wrist and
Hip Fractures in Women After Age 50
Annual
incidence/100
4.0
Vertebrae*
3.0
2.0
Hip
Wrist
1.0
50
60
Age (yrs)
70
80
* Morphometric 3SD deformities
Wasnich RD: Primer Metabolic Bone Diseases and Disorders of Mineral
Metabolism. 1999
Effect of Preexisting Vertebral Fracture
on Risk of Subsequent Vertebral
Fracture
15
% new
vertebral
fracture
RR = 7.3
10
RR = 2.6
5
0
0
1
2
Number baseline vertebral fractures
2725 postmenopausal women randomized to placebo.
R Lindsay, et al. JAMA 2001;285:320-23
Cumulative Hip Fracture
Probability
25
20
20.7
21.4
15
10
10.3
10.6
Hawaii
All Japan
5
0
Hawaii
Minnesota
Caucasian
Japanese
Relative Risk of Death Following
Fractures
Fracture Intervention Trial (FIT)*
Any Clinical
Non-spine
6.7
Hip
8.6
Spine
Forearm
Other
0
1.0
2.0
5.0
10.0
Age-Adjusted Relative Risk (95% CI)
JA Cauley, et al.
Osteoporos Int. 2000;11:556-61.
*6459 postmenopausal women, 55-81 yr,
followed for an average of 3.8 years.
Mortality Rates by Number of
Prevalent Vertebral Fractures
45
40
Age-adjusted
mortality
(per 1000
person-years)
35
30
25
20
15
10
5
0
p for trend <.001
0
1
2
3
4
5+
Number baseline vertebral fractures
DM Kado, et al. Arch Intern Med 1999;159:1215-20
Consequences of Vertebral Fractures
 Kyphosis
 Height loss
 Ribs compress
abdomen
 Acute and chronic pain
 Limited activity
 Breathing difficulties
 Indigestion
 Gastric reflux
 Depression
 Impaired quality of life
Vertebral Fractures Are Overlooked
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Radiologist fail to diagnose vertebral
deformities in routine x-rays
Physicians fail to diagnose vertebral
fractures clinically
 Back pain is common
 Painful vertebral fractures are
not common
 Height and stature are not assessed
Distinguishing Vertebral Fracture
From Other Back Problems
Symptoms:
• Acute and severe
• Mid-back
• Localized
• May radiate anteriorly
Signs:
• Point tenderness over specific vertebra
• Tender paravertebral muscles
• Pain increases with motion
40
Prevalence and Site of Vertebral
Fracture
Japanese in Hawaii
30
20
10
0
T4
T5
T6
T7
T8
T9
T10
T11
T12
L1
L2
L3
L4
L5
40
Japanese in Hiroshima
30
WEDGE
20
ENDPLATE
CRUSH
10
0
T4
T5
T6
T7
T8
T9
T10
T11
T12
L1
L2
L3
L4
L5
T11
T12
L1
L2
L3
L4
L5
40
Caucasian in Minnesota
30
20
10
0
T4
T5
T6
T7
T8
T9
T10
Case Finding
for Primary Care Physicians
History
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Thinness
Smoking
Family history
History of
fractures
Examination
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Height loss
Kyphosis
Lateral spine film
Bone density
Review of Clinical Trials of
Drugs for Treatment of
Osteoporosis
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Double-blind, placebo-controlled
Adequate power to detect effect
Fracture endpoint
 spine fractures
 non-spine fractures
Osteoporosis Drugs
Calcium with Vitamin D
 Hormone Therapy
 Raloxifene
 Bisphosphonates
 alendronate
 risedronate
 Parathyroid hormone-teriparatide

Effects of Calcium (500mg) Plus
Vitamin D (700 IU) on Fractures
in Elderly* Men and Women
Cumulative
fracture
incidence (%)
15
* All >65 yrs
mean 71 yrs
Placebo
10
5
0
Calcium +
vitamin D
0
6
12
18
24
Months
B Dawson Hughes, et al. NEJM 1997; 337:670
30
36
Effects of Vitamin D (800 IU) and Calcium
(1200 mg) in Elderly* Women
36 Months Follow-up
Treatment Placebo % Reduction
Fractures
n=872
n=893
in risk
Hip
109
155
29
Non-vertebral
218
284
24
*All in care centers
Mean age 84 yrs
MC Chapuy, et al. NEJM 1992;327:1637
MC Chapuy, et al. BMJ 1994;308:1081
Use Combination of Calcium and
Vitamin D in the Elderly
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After age 65, calcium intake is low
and absorption is inefficient.
Vitamin D alone does not reduce
fracture risk. *
Calcium with Vitamin D form the
cornerstone of treatment but may
not be enough.
* HE Meyer, et al. JBMR 2002;17:709
* P Lips, et al. Ann Intern Med 1996;124:400
MORE Study
Multiple Outcomes of Raloxifene Evaluation
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
Multicenter, double-blind, placebocontrolled- 4 year study
Raloxifene 60 mg, 120 mg, or placebo
(with calcium and vitamin D)
7705 women, mean age 67-68 years
Endpoints
 Primary: vertebral fracture BMD
 Secondary: non-vertebral fracture,
CVD, breast cancer, uterine safety,
cognitive function
Effect of Raloxifene in Women
With or Without Prevalent Fractures
Four Years
RR 0.54
RR 0.66
% Incident Fracture
25
20
15
Placebo
RLX 60
RLX120
RR 0.62
10
RR 0.51
5
0
No Prevalent Fractures
Prevalent Fractures
K Harper, ASBMR, 2000
Efficacy of Raloxifene Through 4 Years
Incidence of New
Vertebral Fractures
(%)
Placebo
RLX 60 mg/d
15
First Scheduled
Radiograph
P<0.001
10
5
0
0
12
24
36
Months of Exposure
PD Delmas, et al. JCEM 87: 3609-17, 2002
48
Design of the Fracture
Intervention Trial
Baseline visits
 BMD
 Eligibility
 Spinal radiograph
FIT-1
FIT-2
Vertebral fracture arm
n=2027
Clinical Fracture arm
n=4432
Follow-up: 3 years
Follow-up: 4.25 years
DM Black, et al. Lancet 348:1535, 1996
Effect of Alendronate* on Risk
of Vertebral Fractures
% Incident Fracture
FIT-1 & FIT-2
20
RR 0.54
15
Placebo
Alendronate
10
RR 0.56
5
* 5mg/day for 2 yr,
then 10mg/day
0
No Prevalent Fractures
Prevalent Fractures
DM Black,et al. Lancet 348:1535, 1996
SR Cummings, et al. JAMA 280:2077, 1998
VERT Study
Inclusion Criteria
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 5 years post-menopausal
 85 years of age
Multi-National (n = 1226)*
  2 vertebral fractures (T4-L4)
North American (n = 2458)**
  2 vertebral fractures (T4-L4), or
1
vertebral fracture and lumbar
spine T-score  -2
* J-Y Reginster, et al. Osteopor Int 11:83, 2000
** ST Harris, et al. JAMA 282:1344, 1999
Effect of Risedronate on Incident
Vertebral Fractures
% wtih fracture
VERT - North American
VERT - Multi-National
30
30
25
25
41%

20
15
65%

10
5
*
49%

20
*
61%

15
*
10
*
*
5
*
0
0
0
12
24
36
0
12
Months
24
36
Months
Placebo
ST Harris et al, JAMA 282: 1344, 1999
Risedronate 5 mg
*
5.0 mg vs. placebo
p < 0.01
J-Y Reginster et al, Osteopor Int 11:83, 2000
Secondary Endpoint:
Incident Non-Vertebral Fracture
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Ascertained by direct questioning
at each clinic visit
Excluded
 fractures due to severe trauma
 finger, toe, face, and skull
fractures
 pathologic fractures
Effect of Raloxifene on Risk of
Non-Vertebral Fractures
Four Years
RR=0.87
% Incident Fracture
14
RR=0.99
12
10
8
6
4
2
0
Placebo
PD Delmas, et al. JCEM 87: 3609-17, 2002
Raloxifene
60 mg
Raloxifene
120 mg
Risk of Nonvertebral* Fracture
in Women With Baseline SQ Grade 3
MORE Trial - 3 Years
% with 1
non-vertebral fracture
20
RH = 0.53
( 0.29-0.99)
15
10
5
0
Placebo
Raloxifene 60 mg/d
* Clavicle, humerus, wrist, pelvis, hip, leg
P Delmas, et al. Osteoporosis Int, 2002, Suppl.1 (presented at IOF)
Effect of Alendronate on Risk
of Non-vertebral Fractures
FIT-1 plus selected FIT-2
% Incident Fracture
16
14
Placebo
12
27%
10
8
Alendronate
6
4
2
0
0
6
12
18
24
30
Months
D Black, et al. JCEM 85:4118, 2000
36
Alendronate Fracture Risk Reduction
Depends on Degree of Osteoporosis
FIT-2
Relative risk vs. placebo
Femoral Neck t-score Vert. Fx Clinical Fx
-1.6 to - 2.0
-2.5 to - 2.0
below - 2.5
0.8
0.5
0.5
1.1
1.0
0.6
SR Cummings, et al. JAMA 280:2077, 1998
Effect of Risedronate on Risk of
Non-Vertebral Fractures
% with Fracture
20
20
North American
15
15
10
10
5
5
0
0
0
12
24
36
Multi-National
0
12
Months
Placebo
Harris et. al. JAMA. 1999;282(14):1344-52.
24
36
Months
Risedronate 5 mg
Reginster et al. Osteoporos Int. 2000;11:83-91.
Effect of Risedronate
on Incidence of Hip Fracture
Low Bone Density Group (Group 1)
% with fracture
6
5
4
3
Placebo
2
1
39%
Risedronate
0
0
6
12
18
24
30
36
Months
MR McClung, et al. NEJM 344:333, 2001
Risedronate May Not Reduce Hip Fracture
Risk in Non-Osteoporotic Women
Risk Reduction
Cohort
70-79 years with
t-score <3.0
80+ years
all
t-score <2.5
Hip Fracture
39%
18%
26%
M McClung, et al. NEJM 344:333, 2001
Fracture Risk Reductions
Observed
in Trials of Anti-resorptive
Therapies
Alendronate
Raloxifene
Risedronate
Spine
3 yr 1 yr
45% 60%
43% 68%*
45% 63%
Non-Spine
3 yr
12, 22, 27%
12, 48%
12, 33, 18, 39%
* M Maricic, et al. Arch Intern Med 162:1140-1143, 2002
Evista Versus Alendronate
EVA
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Outcome- any osteoporotic
fracture
3000 osteoporotic women
(hip t-score -2.5 to - 4.0)
Start 2002, Finish 2007
CASE 1
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50 year-old woman
Natural menopause 2 years ago
Vasomotor symptoms
Bone density: t-score -1.6
Tried HRT but stopped due to
breast tenderness and bloating
Not a candidate for raloxifene or alendronate
CASE 2
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65 year-old women
Concerned about memory
No menopausal symptoms
Wrist fracture 3 years ago
Bone density: t-score -3.0
High risk of fracture- requires treatment
Rationale for Raloxifene Use for
Postmenopausal Women with Osteoporosis
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To reduce risk of osteoporotic fracture
To reduce the risk of breast cancer
To reduce risk of CHD
To prevent cognitive decline
Long-term safety and acceptance
CASE 3
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75 year-old woman
prior wrist fracture
presents with a painful L-1 crush
fracture
X-ray shows wedging T-7 and T-8
Bone density t-score -3.5
Needs strong, rapidly acting osteoporosis drug
Antiresorptive Drugs Increase BMD
but Not Bone Volume
• Early BMD increase is due to filling in
•
•
of remodelling (resorption) space
Later BMD increase is due to
increased mineralization of BMU
Most of BMD effect can be explained
by mineralization
GY Boivin, et al. Bone 27:687-694, 2000
CJ Hernandez, et al. Bone 29:511-516, 2001
Relationship Between Excessive Suppression
Of Bone Turnover and Damage Accumulation
Excessive Suppression of Bone Turnover
Prolonged
Mineralization
Insufficient Repair
of Microdamage
Damage Accumulation
Decrease in Bone Toughness
Long-term Safety?
Hypothetical Effects of Increasing
Bone Mineralization
Force
x Hyper-mineralized
x Optimum
x Hypo-mineralized
Displacement
CH Turner Osteoporos Int 13:97-104, 2002
Hypothetical Effects of Increasing
Bone Mineralization
Improved resistance to
bending = stiffness
Resistance
to fracture
forces
Increasing brittleness
Percentage Mineralization
Safety Concerns Regarding
Long-term Alendronate
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Rate of clinical spine fractures during
years 5-7 was 3 times higher
than during years 1-3
Height loss (1.2mm/yr) during
years 5-7 tended to be higher
than during years 1-3 (1.0mm/yr)
RP Tonino, et al. JCEM 85:3109, 2000
Concept of Sustained vs.
Unsustained Efficacy
Drug A
Efficacy
Drug B
0
Time
For Severe Osteoporosis:
Prescribe Sequentially
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
Short-term “quick-fix” with a
strong bone-specific agent
Long-term bone maintenance with
a milder (and safer) effect:
 multipurpose drug - raloxifene
Key Messages for Primary
Care Physicians
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Osteoporosis is frequently overlooked
Osteoporosis is treatable
Drug treatment should be encouraged
for those at highest risk