New Data on Ultra Low-Dose New Data on Ultra Low-Dose Estradiol Therapy in Estradiol Therapy in Osteoporosis Prevention Osteoporosis Prevention Marie Foegh, MD, DSc Marie Foegh, MD, DSc VP, Medical Affairs VP, Medical Affairs Berlex Laboratories Berlex Laboratories
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New Data on Ultra Low-Dose Estradiol Therapy in Osteoporosis Prevention New Data on Ultra Low-Dose Estradiol Therapy in Osteoporosis Prevention Marie Foegh,
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New Data on Ultra Low-Dose Estradiol New Data on Ultra Low-Dose Estradiol Therapy in Osteoporosis PreventionTherapy in Osteoporosis Prevention
Marie Foegh, MD, DScMarie Foegh, MD, DScVP, Medical AffairsVP, Medical Affairs
• UCSF Coordinating CenterUCSF Coordinating Center– Deborah Grady, Steven Cummings, Eric Vittinghoff, Deborah Grady, Steven Cummings, Eric Vittinghoff,
• InvestigatorsInvestigators– B. Ettinger (Kaiser Permanente), K. Ensrud (University of Minnesota), B. Ettinger (Kaiser Permanente), K. Ensrud (University of Minnesota),
B. Wallace (University of Iowa), K. Johnson (University of Tennessee), B. Wallace (University of Iowa), K. Johnson (University of Tennessee),
P. Marx (Chicago Center for Clinical Research), S. Barbier (Seattle P. Marx (Chicago Center for Clinical Research), S. Barbier (Seattle
Women’s Clinical Research Center), J. Pinkerton (University of Women’s Clinical Research Center), J. Pinkerton (University of
Virginia), M. Farmer (Meridien Research) and D. Rowe (Palm Beach Virginia), M. Farmer (Meridien Research) and D. Rowe (Palm Beach
• 417 women (E2 n=208, placebo n=209)417 women (E2 n=208, placebo n=209)– 60 to 80 years old with an intact uterus60 to 80 years old with an intact uterus– More than 5 years post-menopausalMore than 5 years post-menopausal
– BMD z-score BMD z-score - 2.0 - 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/mLGoal 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 monthsFollow-up visits every 4 months
Lumbar Spine BMD
0.5% 0.5%
2.3%
3.0%
0
0.5
1
1.5
2
2.5
3
3.5
12 months 24 months
Mean % change from
baseline
Placebo Ultra-low Estradiol
p<0.001
p< 0.001
Lumbar Spine BMD
0.5% 0.5%
2.3%
3.0%
0
0.5
1
1.5
2
2.5
3
3.5
12 months 24 months
Mean % change from
baseline
Placebo Ultra-low Estradiol
p<0.001
p< 0.001
Effects of 0.014 mg E2 on BMDEffects of 0.014 mg E2 on BMD
2.5%
Total Hip BMD
-0.2% -0.7%
0.9% 0.8%
-0.8
-0.6
-0.4
-0.2
0
0.2
0.4
0.6
0.8
1
1.2
Mean % change from
baseline
Placebo Ultra-low Estradiol
12 months 24 months
p< 0.001 p<0.001
Total Hip BMD
-0.2% -0.7%
0.9% 0.8%
-0.8
-0.6
-0.4
-0.2
0
0.2
0.4
0.6
0.8
1
1.2
Mean % change from
baseline
Placebo Ultra-low Estradiol
12 months 24 months
p< 0.001 p<0.001
Effects of 0.014 mg E2 on BMDEffects of 0.014 mg E2 on BMD
1.5%
Patients with Clinical FracturesPatients with Clinical Fractures
6622OtherOther
3322WristWrist
0000HipHip
1100SpineSpine
PlaceboPlacebo
(n=209)(n=209)
0.014 mg Estradiol0.014 mg Estradiol
(n=208)(n=208)
Fracture LocationFracture Location
Pooling Both “Ultra Low” TrialsPooling Both “Ultra Low” TrialsClinical FracturesClinical Fractures
161666Combined**Combined**
6622Prestwood et al*Prestwood et al*
101044ULTRAULTRA
PlaceboPlaceboUltra Low E2Ultra Low E2
* JAMA August 27, 2003** S. Cummings, RR = 0.4; p = 0.04
• Two years of unopposed ultra low dose Two years of unopposed ultra low dose transdermal estradioltransdermal estradiol–Prevents bone loss in older post-menopausal Prevents bone loss in older post-menopausal
womenwomen–Safe for the endometriumSafe for the endometrium–Decrease in markers of bone turnoverDecrease in markers of bone turnover–No increase in breast tenderness, headache and No increase in breast tenderness, headache and
other common estrogen-related adverse eventsother common estrogen-related adverse events–No effect on C-RP, SHBG, LipidsNo effect on C-RP, SHBG, Lipids
Paradigm Shift:Paradigm Shift:Changing the Risk/Benefit ProfileChanging the Risk/Benefit Profile
• Fracture reduction in osteopenic patientsFracture reduction in osteopenic patients
• Ultra low dose Ultra low dose unopposedunopposed safe for the safe for the endometrium for up to two yearsendometrium for up to two years
• Adverse event profile similar to placeboAdverse event profile similar to placebo– No negative GI or vasomotor effectsNo negative GI or vasomotor effects
Age at menopause, yrsAge at menopause, yrs 49.949.9 50.550.5 0.20.2
Adverse EventsAdverse Events
• No significant difference of headache, nausea or No significant difference of headache, nausea or genital discomfort reported (genital discomfort reported ( 2%) 2%)