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

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.

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

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  1. Estrogen plus Progestin, BMD and Fractures: Women’s 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 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.

  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 otherFractures: Nominal CI

  5. 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 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

  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 <-2.5, n=1024

  7. Normal Low Bone Mass Osteoporosis Prevalence of Osteoporosis by DXA:Femoral Neck T-scores (WHO) (n=1024) 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 nCI=0.69 to 0.83 24% HR = 0.65 nCI=0.47 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 n=nominal 95% CI

  10. Effects of Estrogen Plus Progestin on Total Fractures by Age Favors E&P 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. 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 The Effect of Estrogen + Progestin on Fractures was similar in different subgroups 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 Incidenceof Fracture (Percent 1.99 E+P 0.82 (0.66, 1.02) Placebo 1.41 1.33 1.10 (341 fx) (434 fx) (672 fx) p (interaction) = 0.54 Fracture Summary Score

  13. 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) 100 .1 .01 10 1 *Wells G et al Endocrine Reviews 2002;23:529-539

  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 E+P 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 HR=1.03 (0.86 – 1.24) 2.94 HR=1.23 2.84 (1.04, 1.46) E+P Annualized (%)Incidence of Global Index Event Placebo HR=1.20 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

  17. 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.

  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.

  19. 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) <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

  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 ? ? E+P(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 Risedronate1 2252 94 Raloxifene1 2381 99 E+P(WHI) 833 --- WHI: Clinical Vertebral Fractures ; women considered “low”risk. 1. Cranney et al, 2002

  23. Mean Difference in Percent Change in Bone Density after Treatment with E + P : ORAGa vs WHI Favors Placebo Favors E & P Lumbar spine ORAGa1 year 2 year WHI 1 year 3 year Femoral Neck ORAG 1 year 2 year WHI 1 year 3 year 10 0 -5 5 Weighted Mean Difference (95% CI) aWells G et al Endocrine Reviews 2002;23(4):529-539

  24. 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

  25. 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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