Estrogen plus Progestin, bmd and Fractures: Women’s Health Initiative



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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
  • 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
  • * 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 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 <-2.5, n=1024

Prevalence of Osteoporosis by DXA: Femoral Neck T-scores (WHO) (n=1024)

  • Normal
  • Low Bone Mass
  • Osteoporosis
  • P = 0.29
  • Estrogen Plus Progestin
  • Placebo
  • 0.11
  • 0.16
  • 35%
  • HR = 0.65
  • Total Fracture
  • 24%
  • 1.52
  • 1.99
  • nCI=0.47 tp 0.96
  • aCI= 0.41 to 1.10
  • Annualized Incidence
  • of Fractures (%)
  • HR = 0.76
  • nCI=0.69 to 0.83
  • 35% Reduction
  • n= nominal 95% CI a= adjusted 95% CI
  • Annualized Incidence
  • of Fractures (%)
  • 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

  • Wrist/Lower Arm
  • 0.43
  • 0.59
  • 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

Effects of Estrogen Plus Progestin on Total Fractures by Age

  • Age (y)
  • 50-54
  • 55-59
  • 60-64
  • 65-69
  • 70-74
  • 75-79
  • 1.0
  • 10
  • .1
  • 0.76*
  • Favors E&P
  • Favors Placebo
  • P(interaction) = 0.47
  • * Overall HR
  • Hazard Ratio (95% CI)

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

Effects of Estrogen plus Progestin on Total Fractures by Summary FRACTURE Risk Score

  • 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
  • 1.10
  • 1.33
  • 1.41
  • 1.99
  • 2.33
  • 2.74
  • Placebo
  • E+P
  • Annualized Incidence of Fracture (Percent
  • (341 fx)
  • (434 fx)
  • (672 fx)

Comparison of WHI E + P results on Non-Spine Fractures with ORAG* report

  • 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&P
  • Favors Placebo
  • *Wells G et al Endocrine Reviews 2002;23:529-539

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
  • Change in Spine BMD
  • from Baseline Value, %
  • E+P
  • Placebo
  • 4.5% Difference

Effects of Estrogen plus Progestin on the Global Index by FRACTURE Risk Score Tertiles

  • Summary Score
  • p (interaction) = 0.54
  • Placebo
  • E+P
  • HR=1.20
  • (0.93, 1.55)
  • 0.96
  • 0.81
  • 1.55
  • 1.89
  • HR=1.23
  • (1.04, 1.46)
  • 2.94
  • 2.84
  • HR=1.03
  • (0.86 – 1.24)
  • Annualized (%) Incidence of Global Index Event

Limitations

  • One estrogen plus progestin regimen
  • Fracture risk score: ratio of highest to lowest risk was modest 2.0
  • 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.

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) 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
  • Raloxifene 1 ? ?
  • E+P(WHI) 106 ?
  • WHI: women considered “low” risk
  • 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

Mean Difference in Percent Change in Bone Density after Treatment with E + P : ORAGa vs WHI

  • 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 & P
  • Favors Placebo
  • aWells G et al Endocrine Reviews 2002;23(4):529-539
  • Weighted Mean Difference (95% CI)
  • 5
  • -5

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


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