Estrogen plus Progestin, BMD and Fractures: Women’s Health Initiative Jane A. Cauley University of Pittsburgh JAMA 2003; 290 (13) :

Objectives ● To present final analysis of fracture endpoints, thru July 7, ● 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 * Prior Fracture > age Current Smoker Low BMI Risk FactorOR Points * Age = 0; age = 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: ROC Curve AUC = 0.79 (95% CI )

Baseline Characteristics across Categories of Summary FRACTURE Risk Score “Low”“Moderate”“High” (n)(4743)(5871)(3146) Age (y) BMI (kg/m 2 ) Caucasian (%) Past HT (%) Current HT (%)1053 Current Smoke (%)31316 Fracture History (%) Osteoporotic (%) a a = T-score <-2.5, n=1024

Prevalence of Osteoporosis by DXA: Femoral Neck T-scores (WHO) (n=1024) NormalLow Bone MassOsteoporosis P = 0.29 Estrogen Plus ProgestinPlacebo

Hip Fracture % HR = 0.65 Total Fracture 24% nCI=0.47 tp 0.96 aCI= 0.41 to 1.10 Annualized Incidence of Fractures (%) HR = 0.76 nCI=0.69 to % Reduction 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 % 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% % Reduction 31% Reduction 189 fx 245 fx 41 fx60 fx

Age (y) * Favors E&P Favors 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 Fracture Summary Score 0.85 (0.70, 1.03) 0.68 (0.28, 0.81) 0.82 (0.66, 1.02) p (interaction) = Placebo E+P Annualized Incidence of Fracture (Percent (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) Favors E&P Favors Placebo * Wells G et al Endocrine Reviews 2002;23: 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 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) HR=1.23 (1.04, 1.46) 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  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 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 InterventionNo. of trials/patients RR(95% CI) p Calcium2(222)0.86 (0.43,1.72)0.54 Vit D6(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 Raloxifene7(6961)0.91 (0.79,1.06)0.24 Calcitonin1(1245)0.80 (0.59,1.09)0.16 Risedr.7(12958)0.73 (0.61,0.87)<0.01 HT-pre WHI6(3986)0.87 (0.71,1.08)0.10 HT WHI1(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 D 1 ?? Alendronate 1 ?24 Risedronate 1 ?43 Raloxifene 1 ?? E+P(WHI)106? WHI: women considered “low” risk 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 D Alendronate Risedronate Raloxifene E+P(WHI) Low risk High Risk WHI: Clinical Vertebral Fractures ; women considered “low” risk. 1. Cranney et al, 2002

Lumbar spine ORAG a 1 year 2 year WHI1 year 3 year Femoral Neck ORAG1 year 2 year WHI1 year 3 year 0 10 Favors E & P Favors Placebo a Wells G et al Endocrine Reviews 2002;23(4): Weighted Mean Difference (95% CI) 5 -5 Mean Difference in Percent Change in Bone Density after Treatment with E + P : ORAG a vs WHI

Bone Mineral Density by Randomized Group Total Hip Lumbar Spine T-score Total Hip Lumbar Spine BMD (g/cm 2 ) (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