Estrogen plus Progestin, BMD and Fractures: Women’s Health Initiative Jane A. Cauley University of...
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Transcript of Estrogen plus Progestin, BMD and Fractures: Women’s Health Initiative Jane A. Cauley University of...
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
Age 1.14 0-7*
Prior Fracture > age 55 2.22 2
Current Smoker 2.31 2
Low BMI 1.91 1
Risk Factor OR Points
* 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
ROC Curve AUC = 0.79 (95% CI 0.73-0.84)
Baseline Characteristics across Categories of Summary FRACTURE Risk Score
“Low” “Moderate” “High”
(n) (4743) (5871) (3146)
Age (y) 56 65 72BMI (kg/m2) 30 29 27Caucasian (%) 77 85 90Past HT (%) 19 19 22Current HT (%) 10 5 3Current Smoke (%) 3 13 16Fracture History (%) 24 28 59Osteoporotic (%) a 12 23 41
a = T-score <-2.5, n=1024
Prevalence of Osteoporosis by DXA:Femoral Neck T-scores (WHO) (n=1024)
32%
58%
10%
53%
35%
12%
Normal
Low Bone Mass
Osteoporosis
P = 0.29
Estrogen Plus Progestin Placebo
0.0
0.5
1.0
1.5
2.0
2.5
3.0
E+P Placebo
0.0
0.5
1.0
1.5
2.0
2.5
3.0
E+P Placebo
Hip Fracture
0.11 0.16
35%
HR = 0.65
Total Fracture
24%
1.52
1.99nCI=0.47 tp 0.96aCI= 0.41 to 1.10
An
nu
aliz
ed I n
cid
ence
of
Fra
c tu
res
(%)
HR = 0.76nCI=0.69 to 0.83
24% Reduction35% Reduction
n= nominal 95% CI a= adjusted 95% CI
An
nu
aliz
ed I n
cid
ence
of
Fra
c tu
res
(%)
Effects of Estrogen plus Progestin on Hip and Total Fractures
52 hip fx
73 hip fx 733 fx
986 fx
Effects of Estrogen plus Progestin on Wrist and Vertebral Fractures
0.0
0.5
1.0
1.5
2.0
2.5
3.0
E+P Placebo0.0
0.5
1.0
1.5
2.0
2.5
3.0
E+P Placebo
Wrist/Lower Arm
0.430.59
28%
HR = 0.72
nC I= 0.60 to 0.87
n=nominal 95% CI
HR = 0.66
nCI = 0.44 to 0.98
Clinical Vertebral
31%
0.09 0.15
28% Reduction 31% Reduction
189 fx 245 fx 41 fx 60 fx
Age (y)
50-54
55-59
60-64
65-69
70-74
75-79
1.0 10.1
0.76*Favors E&PFavors E&P Favors PlaceboFavors Placebo
P(interaction) = 0.47* Overall HR Hazard Ratio (95% CI)
Effects of Estrogen Plus Progestin on Total Fractures by Age
The Effect of Estrogen + Progestin on
Fractures was similar in different subgroups
● Years Since menopause
● Race/ethnicity
● BMI
● Smoking
● Falls
● Calcium Intake
● Parental History of 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
0.0
0.5
1.0
1.5
2.0
2.5
3.0
"Low" "Moderate" "High"
Fracture Summary Score
0.85 (0.70, 1.03)
0.68 (0.28, 0.81)
0.82 (0.66, 1.02)
p (interaction) = 0.54
1.101.33
1.41
1.99
2.33
2.74
PlaceboE+P
An
nu
aliz
ed I
nci
den
ce
of
Fra
ctu
re (
Per
cen
t
(341 fx) (434 fx) (672 fx)
Greenspan 1998
Komulainen 1997
Wilalawansa 1998
Hulley 1998
Hosking 1998
Alexandersen 1999
Pooled Estimate (HR=0.87)
Cauley (WHI) (HR=0.75)1 100.01 .1 10
Favors E&PFavors E&P Favors PlaceboFavors Placebo
*Wells G et al Endocrine Reviews 2002;23:529-539
Comparison of WHI E + P results on Non-Spine Fractures with ORAG* report
Mean change from baseline in bone mineral density (BMD) at the Lumbar Spine during 3 years of follow-up
- 1
0
1
2
3
4
5
6
7
0 1 2 3
Follow-up, years
Ch
an
ge
in S
pin
e B
MD
fro
m B
ase
line
Va
lue
, %
E+PPlacebo
4.5% Difference
Effects of Estrogen plus Progestin on the Global Index by FRACTURE Risk Score
Tertiles
0.0
0.5
1.0
1.5
2.0
2.5
3.0
3.5
"Low" "Moderate" "High"Summary Score
p (interaction) = 0.54
PlaceboE+P
HR=1.20(0.93, 1.55)
0.960.81
1.55
1.89
HR=1.23(1.04, 1.46)
2.94 2.84
HR=1.03(0.86 – 1.24)
An
nu
aliz
ed (
%)
Inci
den
ce o
f G
lob
al
Ind
ex E
ven
t
Limitations
●One estrogen plus progestin regimen●Fracture risk score: ratio of highest to lowest
risk was modest 2.0No BMD measurementsNo prevalent Vertebral fractureMay 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 non-osteoporotic 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.
ConclusionGiven:
• 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) p
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
NNT for 2 years to prevent a non-vertebral fracture: Low and High risk group
Vitamin D1 ? ?
Alendronate1 ? 24
Risedronate1 ? 43
Raloxifene1 ? ?
E+P(WHI) 106 ?
Low risk High Risk
WHI : women considered “low” risk 1. Cranney et al, 2002
NNT for 2 years to prevent a vertebral fracture: Low and High risk group
Vitamin D1 2252 94
Alendronate1 1790 72
Risedronate1 2252 94
Raloxifene1 2381 99
E+P(WHI) 833 ---
Low risk High Risk
WHI: Clinical Vertebral Fractures ; women considered “low” risk. 1. Cranney et al, 2002
Lumbar spine
ORAGa 1 year
2 year
WHI 1 year
3 year
Femoral Neck
ORAG 1 year
2 year
WHI 1 year
3 year
0 10
Favors E & PFavors E & PFavors PlaceboFavors Placebo
aWells G et al Endocrine Reviews 2002;23(4):529-539
Weighted Mean Difference (95% CI)5-5
Mean Difference in Percent Change in Bone Density after Treatment with E + P : ORAGa vs WHI
Bone Mineral Density by Randomized Group
Total Hip 546 0.83 478 0.84 0.77
Lumbar Spine 528 0.94 461 0.95 0.87
T-score
Total Hip 546 -0.94 478 -0.91 0.79
Lumbar Spine 528 -1.30 461 -1.26 0.87
BMD (g/cm2) (n) E+P (n) Placebo p
Distribution of Summary Fracture Risk Score By Randomized Group
Summary Risk Score E&P Placebo(points) n (%) 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