1. New Data on Ultra Low-Dose Estradiol Therapy in Osteoporosis Prevention New Data on Ultra Low-Dose Estradiol Therapy in Osteoporosis Prevention Marie Foegh, MD, DSc VP, Medical Affairs Berlex Laboratories

2. Outline BackgroundBackground StudyStudy –Design –Efficacy –Safety ConclusionConclusion

3. Loss of Estrogen has Profound Effects on Bone Increased resorptionIncreased resorption Rapid bone lossRapid bone loss Apoptosis of osteocytesApoptosis of osteocytes Increased risk of hip & spine fractureIncreased risk of hip & spine fracture

4. Lowest effective dose “ for the individual patient ” Risk / BenefitRisk / Benefit Quality of LifeQuality of Life

5. Ultra Low Dose Transdermal Estrogen Replacement Assessment (ULTRA) UCSF Coordinating CenterUCSF Coordinating Center –Deborah Grady, Steven Cummings, Eric Vittinghoff, Judy Macer, Judy Quan, Lorie Denton InvestigatorsInvestigators –B. Ettinger (Kaiser Permanente), K. Ensrud (University of Minnesota), B. Wallace (University of Iowa), K. Johnson (University of Tennessee), P. Marx (Chicago Center for Clinical Research), S. Barbier (Seattle Women’s Clinical Research Center), J. Pinkerton (University of Virginia), M. Farmer (Meridien Research) and D. Rowe (Palm Beach Research Center)

6. Design Randomized, placebo-controlled, blinded trialRandomized, placebo-controlled, blinded trial 417 women (E2 n=208, placebo n=209)417 women (E2 n=208, placebo n=209) –60 to 80 years old with an intact uterus –More than 5 years post-menopausal –BMD z-score  - 2.0 Weekly transdermal E2 (0.014 mg/d) vs. placeboWeekly transdermal E2 (0.014 mg/d) vs. placebo –Goal to increase serum E2 to 10–15 pg/mL Daily calcium (800mg/d) and vitamin D (400 IU/d)Daily calcium (800mg/d) and vitamin D (400 IU/d) Duration of Study: 2 yearsDuration of Study: 2 years –Follow-up visits every 4 months

7. Effects of 0.014 mg E2 on BMD 2.5%

8. Effects of 0.014 mg E2 on BMD 1.5%

9. Patients with Clinical Fractures 62Other 32Wrist 00Hip 10SpinePlacebo(n=209) 0.014 mg Estradiol (n=208) Fracture Location

10. Pooling Both “Ultra Low” Trials Clinical Fractures 166Combined** 62 Prestwood et al* 104ULTRAPlacebo Ultra Low E2 * JAMA August 27, 2003 ** S. Cummings, RR = 0.4; p = 0.04

11. Adverse Events: Serious

12. Ultra Trial Conclusion Two years of unopposed ultra low dose transdermal estradiolTwo years of unopposed ultra low dose transdermal estradiol –Prevents bone loss in older post- menopausal women –Safe for the endometrium –Decrease in markers of bone turnover –No increase in breast tenderness, headache and other common estrogen-related adverse events –No effect on C-RP, SHBG, Lipids

13. Paradigm Shift: Changing the Risk/Benefit Profile Ultra low dose estradiol: Fracture reduction in osteopenic patientsFracture reduction in osteopenic patients Ultra low dose unopposed safe for the endometrium for up to two yearsUltra low dose unopposed safe for the endometrium for up to two years Adverse event profile similar to placeboAdverse event profile similar to placebo –No negative GI or vasomotor effects

14. Markers of Bone Turnover * Change in median

15. Cumulative Percent with Amenorrhea

16. Endometrial Evaluation after 24 Months 417 Randomized Tissue diagnosis269 normal267 atypical hyperplasia 1 uterine adenosarcoma 1 Dropped out 41 placebo24 estradiol17 No tissue diagnosis107 sample lost 1 refused or unable 68 insufficient 38 Refused TVUS 6 TVUS 101 Endometrium> 5mm11 normal tissue 6 nml hysterosalpingogram 1 No further work-up 4 Endometrium< 5mm90

17. Baseline Characteristics EstradiolPlaceboP (n=208)(n=209) Age, years66.866.71.0 White, %92.891.90.7 College Educ, %63.563.61.0 Current smoker, %7.76.20.6 Dietary calcium, mg/day7466910.2 Any alcohol64.467.00.8 BMI28.328.00.6 Age at menopause, yrs49.950.50.2

18. Adverse Events No significant difference of headache, nausea or genital discomfort reported (  2%)No significant difference of headache, nausea or genital discomfort reported (  2%)

19. Adverse Events over Two Years: N (%) 00 Death Death 0.70 20 ( 9.6) 22 (10.6) Hospitalization Hospitalization 0.50 5 ( 2.4) 3 ( 1.4) Cancer Cancer 1.00 24 (11.5) Serious Adverse Events P-valuePlacebo(n=209)Estradiol (n = 208)

20. 0.003 21 (10.0) 6 ( 2.9) Rash Rash 0.01 9 ( 4.3) 1 ( 0.5) Herpes Zoster Herpes Zoster 0.03 7 ( 3.3) 1 ( 0.5) Hernia Hernia 0.001 3 ( 1.4) 22 (10.6) Vaginal discharge Vaginal discharge 0.01 2 ( 0.9) 7 ( 3.4) Endometrial polyp Endometrial polyp 0.03 4 ( 1.0) 12 ( 5.8) Cervical polyp Cervical polyp P-valuePlacebo(n=209)Estradiol (n = 208) * incidence > 2% and statistical difference between estradiol and placebo Adverse Events over Two Years: N (%)

21. Individualizing Therapy