Estrogen plus Progestin, BMD and Fractures: Womens Health Initiative

1
Estrogen plus Progestin, BMD and Fractures
Womens Health Initiative

• Jane A. Cauley
• University of Pittsburgh

JAMA 2003 290 (13) 1729-1738
2
Objectives

• To present final analysis of fracture endpoints,
  thru July 7, 2002.
• To test the hypothesis that the effect of EP on
  fracture differed by risk factors for fracture.
• To report BMD results.
• To test whether the risk-benefit profile of EP
  differs in women at higher vs. lower risk of hip
  fracture.

3
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

4
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

5
Summary FRACTURE Risk Score

Risk Factor OR Points

• Age 1.14 0-7
• Prior Fracture gt age 55 2.22 2
• Current Smoker 2.31 2
• Low BMI 1.91 1

ROC Curve AUC 0.79 (95 CI
0.73-0.84)
Age 50-53 0 age 54-57 1 age 58-612 age
62-643 age 65-684 age 69-725 age 73-756
age 76-797
Black D et al, Osteoporosis Int 200112519-529
6
Baseline Characteristics across Categories of
Summary FRACTURE Risk Score

• Low Moderate High
• (n) (4743) (5871) (3146)

Age (y) 56 65 72 BMI (kg/m2) 30 29 27 Caucasian
() 77 85 90 Past HT () 19 19 22 Current HT
() 10 5 3 Current Smoke () 3 13 16 Fracture
History () 24 28 59 Osteoporotic () a 12
23 41
a T-score lt-2.5, n1024
7
Prevalence of Osteoporosis by DXAFemoral Neck
T-scores (WHO) (n1024)
Estrogen Plus Progestin
Placebo

P 0.29
8
Effects of Estrogen plus Progestin on Hip and
Total Fractures
Hip Fracture
Total Fracture
24 Reduction
35 Reduction
HR 0.76 nCI0.69 to 0.83
24
HR 0.65
nCI0.47 tp 0.96

Annualized Incidence of Fractures ()
Annualized Incidence of Fractures ()
1.99
aCI 0.41 to 1.10
1.52
35
0.11
0.16
73 hip fx
733 fx
986 fx
52 hip fx
n nominal 95 CI a adjusted 95 CI
9
Effects of Estrogen plus Progestin on Wrist and
Vertebral Fractures
Wrist/Lower Arm
Clinical Vertebral
28 Reduction
31 Reduction
HR 0.72 nC I 0.60 to 0.87
HR 0.66 nCI 0.44 to 0.98
28
0.59
31
0.43
0.15
0.09
245 fx
189 fx
41 fx
60 fx
nnominal 95 CI
10
Effects of Estrogen Plus Progestin on Total
Fractures by Age
Favors EP
Favors Placebo
0.76
Age (y) 50-54 55-59 60-64 65-69 70-74 75-79

10
.1
1.0
P(interaction) 0.47
Overall HR
Hazard Ratio (95 CI)
11
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
12
Effects of Estrogen plus Progestin on Total
Fractures by Summary FRACTURE Risk Score
0.85 (0.70, 1.03)
2.74
0.68 (0.28, 0.81)
2.33
Annualized Incidence of Fracture (Percent
1.99
EP
0.82 (0.66, 1.02)
Placebo
1.41
1.33
1.10
(341 fx)
(434 fx)
(672 fx)
Fracture Summary Score
p (interaction) 0.54
13
Comparison of WHI E P results on Non-Spine
Fractures with ORAG report
Favors Placebo
Favors EP
Greenspan 1998 Komulainen 1997 Wilalawansa
1998 Hulley 1998 Hosking 1998 Alexandersen
1999 Pooled Estimate (HR0.87) Cauley (WHI)
(HR0.75)
100
.01
.1
1
10
Wells G et al Endocrine Reviews 200223529-539
14
Mean change from baseline in bone mineral density
(BMD) at the Lumbar Spine during 3 years of
follow-up
7
6
4.5 Difference
5
Change in Spine BMD from Baseline Value,
4
EP
3
Placebo
2
1
0
-
1
0
1
2
3
Follow-up, years
15
Effects of Estrogen plus Progestin on the Global
Index by FRACTURE Risk Score Tertiles
HR1.03
(0.86 1.24)
2.94
HR1.23
2.84
(1.04, 1.46)
EP
Annualized () Incidence of Global Index Event
Placebo
HR1.20
1.89
(0.93, 1.55)
1.55
0.96
0.81
Summary Score
p (interaction) 0.54
16
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

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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 EP on fracture is consistent with
  recent Meta-analyses.
• The effect of EP 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.

18
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.

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Extra Slides
20
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) lt0.01 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) lt0.01 HT-pre WHI 6(3986) 0.87
(0.71,1.08) 0.10 HT WHI 1(16608) 0.75
(0.68,0.83) lt0.05
Cranney A et al Endocrine Reviews 2002 23(4) 570
21
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
? ? EP(WHI) 106 ?
WHI women considered low risk 1. Cranney
et al, 2002
WHI women considered low risk
22
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 Ris
edronate1 2252 94 Raloxifene1 2381 99 EP(WH
I) 833 ---
WHI Clinical Vertebral Fractures women
considered low risk.
1. Cranney et al, 2002
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Mean Difference in Percent Change in Bone
Density after Treatment with E P ORAGa vs
WHI
Favors Placebo
Favors E P
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
5
-5
Weighted Mean Difference (95 CI)
aWells G et al Endocrine Reviews
200223(4)529-539
24
Bone Mineral Density by Randomized Group
BMD (g/cm2) (n) EP (n) Placebo p

• 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

25
Distribution of Summary Fracture Risk Score By
Randomized Group
Summary Risk Score EP
Placebo (points) n () n() Low
(0-2) 2393 (34.5) 2350 (34.4) Moderate
(3-5) 2691 (42.7) 2910 (42.6) High
(gt5) 1575 (22.7) 1571 (23.0)
P0.93