Transcript Document 7458528

Estrogen plus Progestin, BMD and
Fractures:
Women’s Health Initiative
Jane A. Cauley
University of Pittsburgh
JAMA 2003; 290 (13) :1729-1738
Objectives
● To present final analysis of fracture endpoints,
thru July 7, 2002.
● To test the hypothesis that the effect of E+P on
fracture differed by risk factors for fracture.
● To report BMD results.
● To test whether the risk-benefit profile of E+P
differs in women at higher vs. lower risk of hip
fracture.
Outcomes
● All Fractures except ribs,
chest/sternum, skull/face, fingers, toes
and cervical vertebrae;
►Radiographically confirmed;
►Hip Fractures centrally adjudicated
● BMD : baseline, years 1 and 3
● Global Index
Statistical Analyses
● Intent to Treat
● Cox Proportional Hazard Models (95% CI)
● Hip Fractures: Adjusted CI
– 1 of 8 clinical outcomes monitored by DSMB
•
All other Fractures: Nominal CI
Summary FRACTURE Risk Score
Risk Factor
Age
Prior Fracture > age 55
Current Smoker
Low BMI
OR
1.14
2.22
2.31
1.91
Points
0-7*
2
2
1
ROC Curve AUC = 0.79 (95% CI 0.73-0.84)
* Age 50-53 = 0; age 54-57 = 1; age 58-61=2; age 62-64=3; age 65-68=4;
age 69-72=5; age 73-75=6; age 76-79=7
Black D et al, Osteoporosis Int 2001;12:519-529
Baseline Characteristics across Categories
of Summary FRACTURE Risk Score
(n)
Age (y)
BMI (kg/m2)
Caucasian (%)
Past HT (%)
Current HT (%)
Current Smoke (%)
Fracture History (%)
Osteoporotic (%) a
a = T-score <-2.5, n=1024
“Low” “Moderate” “High”
(4743)
(5871)
(3146)
56
30
77
19
10
3
24
12
65
29
85
19
5
13
28
23
72
27
90
22
3
16
59
41
Prevalence of Osteoporosis by DXA:
Femoral Neck T-scores (WHO) (n=1024)
Estrogen Plus Progestin
Placebo
12%
10%
32%
53%
58%
Normal
35%
Low Bone Mass
P = 0.29
Osteoporosis
Effects of Estrogen plus Progestin on
Hip and Total Fractures
Hip Fracture
35% Reduction
3.0
2.5
Total Fracture
24% Reduction
HR = 0.76
nCI=0.69 to 0.83
3.0
2.5
HR = 0.65
nCI=0.47 tp 0.96
aCI= 0.41 to 1.10
2.0
1.5
24%
2.0
1.99
1.5
1.52
1.0
1.0
35%
0.5
0.5
0.11
0.16
0.0
0.0
E+P
52 hip fx
Placebo
E+P
73 hip fx
733 fx
n= nominal 95% CI a= adjusted 95% CI
Placebo
986 fx
Effects of Estrogen plus Progestin on
Wrist and Vertebral Fractures
3.0
Wrist/Lower Arm
28% Reduction
2.5
2.0
Clinical Vertebral
31% Reduction
2.5
2.0
HR = 0.72
nC I= 0.60 to 0.87
1.5
3.0
HR = 0.66
1.5
nCI = 0.44 to 0.98
1.0
1.0
28%
0.59
0.5
0.43
0.5
31%
0.09
0.0
0.15
0.0
E+P
189 fx
n=nominal 95% CI
Placebo
E+P
Placebo
245 fx
41 fx
60 fx
Effects of Estrogen Plus Progestin
on Total Fractures by Age
Favors E&P
0.76*
Favors Placebo
Age (y)
50-54
55-59
60-64
65-69
70-74
75-79
.1
P(interaction) = 0.47
* Overall HR
1.0
Hazard Ratio (95% CI)
10
The Effect of Estrogen + Progestin on
Fractures was similar in different subgroups
● Years Since
● Parental History of
menopause
● Race/ethnicity
● BMI
● Smoking
● Falls
● Calcium Intake
Fracture
● Personal History Of
Fracture
● Past use of HT
● BMD
● Summary Fracture
risk score
All Interactions were Not Statistically Significant
Effects of Estrogen plus Progestin on
Total Fractures by Summary FRACTURE
Risk Score
0.85 (0.70, 1.03)
Annualized Incidence
of Fracture (Percent
3.0
2.74
2.5
0.68 (0.28, 0.81)
2.33
2.0
E+P
Placebo
1.99
0.82 (0.66, 1.02)
1.5
1.0
1.10
1.33
1.41
0.5
0.0
"L ow"
(341 fx)
p (interaction) = 0.54
"M od erate"
"Hig h "
(434 fx)
(672 fx)
Fracture Summary Score
Comparison of WHI E + P results on Non-Spine
Fractures with ORAG* report
Favors Placebo
Favors E&P
Greenspan 1998
Komulainen 1997
Wilalawansa 1998
Hulley 1998
Hosking 1998
Alexandersen 1999
Pooled Estimate (HR=0.87)
Cauley (WHI) (HR=0.75)
.01
*Wells
.1
1
G et al Endocrine Reviews 2002;23:529-539
10
100
Mean change from baseline in bone mineral density
(BMD) at the Lumbar Spine during 3 years of follow-up
Change in Spine BMD
from Baseline Value,
%
7
6
4.5%
Difference
5
4
E+P
Placebo
3
2
1
0
-1
0
1
2
Follow-up, years
3
Effects of Estrogen plus Progestin on the
Global Index by FRACTURE Risk Score
Tertiles
HR=1.03
(0.86 – 1.24)
Annualized (%)
Incidence of Global
Index Event
3.5
3.0
HR=1.23
(1.04, 1.46)
2.5
2.94 2.84
E+P
Placebo
2.0
1.5
HR=1.20
(0.93, 1.55)
1.89
1.55
1.0
0.96
0.5
0.81
0.0
"L ow"
p (interaction) = 0.54
"M od erate"
Summary Score
"Hig h "
Limitations
● One estrogen plus progestin regimen
● Fracture risk score: ratio of highest to
lowest risk was modest 2.0
 No BMD measurements
 No prevalent Vertebral fracture
 May have better benefit/risk profile in
women at higher risk.
● Clinical Vertebral Fractures
● Global Index: Potentially life threatening
illness
 Vertebral fractures
Summary
● Estrogen plus Progestin increases BMD and reduces
the risk of fracture in healthy pre-dominantly nonosteoporotic women.
● Decreased risk of fracture was present in all
subgroups of women examined
● The Effect of E+P on fracture is consistent with
recent Meta-analyses.
● The effect of E+P on the Global Index did not differ
across tertiles of fracture risk. There was no
evidence of a net benefit in women at high risk of
fracture.
Conclusion
 Given:
• Overall unfavorable risk- benefit ratio
• Availability of other agents for the prevention
and treatment of osteoporosis
 Estrogen plus progestin cannot be
recommended for the prevention or the treatment
of osteoporosis in asymptomatic women.
 Before the combination of estrogen and progestin
is considered for the purpose of fracture
prevention, women should be fully informed
about the potential adverse effects.
Extra Slides
Comparison of Osteoporosis
Therapies: ORAG
Intervention
No. of trials/patients
RR(95% CI)
Calcium
2(222)
0.86 (0.43,1.72)
0.54
Vit D
6(6187)
0.77 (0.57,1.04)
0.09
Alen.(5mg)
8(8603)
0.87 (0.73,1.02)
0.09
Alen. (10-40)
6(3723)
0.51 (0.38,0.69)
<0.01
Raloxifene
7(6961)
0.91 (0.79,1.06)
0.24
Calcitonin
1(1245)
0.80 (0.59,1.09)
0.16
Risedr.
7(12958)
0.73 (0.61,0.87)
<0.01
HT-pre WHI
6(3986)
0.87 (0.71,1.08)
0.10
HT WHI
1(16608)
0.75 (0.68,0.83)
<0.05
Cranney A et al Endocrine Reviews 2002; 23(4): 570
p
NNT for 2 years to prevent a non-vertebral
fracture: Low and High risk group
Low risk
High Risk
Vitamin D1
?
?
Alendronate1
?
24
Risedronate1
?
43
Raloxifene 1
?
?
E+P(WHI)
106
?
WHI : women considered “low” risk
1. Cranney et al, 2002
NNT for 2 years to prevent a vertebral
fracture: Low and High risk group
Low risk
High Risk
Vitamin D1
2252
94
Alendronate1
1790
72
Risedronate1
2252
94
Raloxifene1
2381
99
E+P(WHI)
833
---
WHI: Clinical Vertebral Fractures ; women considered
“low” risk.
1. Cranney et al, 2002
Mean Difference in Percent Change in Bone Density
after Treatment with E + P : ORAGa vs WHI
Lumbar spine Favors Placebo
ORAGa 1 year
2 year
WHI
1 year
3 year
Femoral Neck
ORAG 1 year
2 year
WHI
1 year
3 year
-5
Favors E & P
0
5
Weighted Mean Difference (95% CI)
aWells
G et al Endocrine Reviews 2002;23(4):529-539
10
Bone Mineral Density by
Randomized Group
BMD (g/cm2)
(n)
E+P
(n) Placebo
Total Hip
Lumbar Spine
546
528
0.83
0.94
478
461
0.84
0.95
0.77
0.87
T-score
Total Hip
Lumbar Spine
546
528
-0.94
-1.30
478
461
-0.91
-1.26
0.79
0.87
p
Distribution of Summary Fracture
Risk Score By Randomized Group
Summary Risk Score
(points)
E&P
n (%)
Placebo
n(%)
Low (0-2)
2393 (34.5)
2350 (34.4)
Moderate (3-5)
2691 (42.7)
2910 (42.6)
High (>5)
1575 (22.7)
1571 (23.0)
P=0.93