New Data on Ultra Low-Dose Estradiol Therapy in Osteoporosis Prevention

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New Data on Ultra Low-Dose Estradiol Therapy
in Osteoporosis Prevention

• Marie Foegh, MD, DSc
• VP, Medical Affairs
• Berlex Laboratories

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Outline

• Background
• Study
• Design
• Efficacy
• Safety
• Conclusion

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Loss of Estrogen has Profound Effects on Bone

• Increased resorption
• Rapid bone loss
• Apoptosis of osteocytes
• Increased risk of hip spine fracture

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Lowest effective dosefor the individual
patient

• Risk / Benefit
• Quality of Life

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Ultra Low Dose TransdermalEstrogen Replacement
Assessment (ULTRA)

• UCSF Coordinating Center
• Deborah Grady, Steven Cummings, Eric Vittinghoff,
  Judy Macer, Judy Quan, Lorie Denton
• Investigators
• 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 Womens Clinical
  Research Center), J. Pinkerton (University of
  Virginia), M. Farmer (Meridien Research) and D.
  Rowe (Palm Beach Research Center)

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Design

• Randomized, placebo-controlled, blinded trial
• 417 women (E2 n208, placebo n209)
• 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. placebo
• Goal to increase serum E2 to 1015 pg/mL
• Daily calcium (800mg/d) and vitamin D (400 IU/d)
• Duration of Study 2 years
• Follow-up visits every 4 months

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Effects of 0.014 mg E2 on BMD
2.5
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Effects of 0.014 mg E2 on BMD
1.5
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Patients with Clinical Fractures
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Pooling Both Ultra Low TrialsClinical Fractures
JAMA August 27, 2003 S. Cummings, RR 0.4
p 0.04
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Adverse Events Serious
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Ultra Trial Conclusion

• Two 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

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Paradigm ShiftChanging the Risk/Benefit Profile

• Ultra low dose estradiol
• Fracture reduction in osteopenic patients
• Ultra low dose unopposed safe for the endometrium
  for up to two years
• Adverse event profile similar to placebo
• No negative GI or vasomotor effects

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Markers of Bone Turnover

• Change in median

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Cumulative Percent with Amenorrhea
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Endometrial Evaluation after 24 Months
417 Randomized
No tissue diagnosis 107 sample lost
1 refused or unable 68 insufficient 38
Tissue diagnosis 269 normal 267 atypical
hyperplasia 1 uterine adenosarcoma 1
Dropped out 41 placebo 24 estradiol 17
Refused TVUS 6
TVUS 101
Endometrium gt 5mm 11 normal tissue 6 nml
hysterosalpingogram 1 No further work-up 4
Endometrium lt 5mm 90
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Baseline Characteristics

• Estradiol Placebo P
• (n208) (n209)
• Age, years 66.8 66.7 1.0
• White, 92.8 91.9 0.7
• College Educ, 63.5 63.6 1.0
• Current smoker, 7.7 6.2 0.6
• Dietary calcium, mg/day 746 691 0.2
• Any alcohol 64.4 67.0 0.8
• BMI 28.3 28.0 0.6
• Age at menopause, yrs 49.9 50.5 0.2

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Adverse Events

• No significant difference of headache, nausea or
  genital discomfort reported (? 2)

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Adverse Events over Two Years N ()
P-value
Placebo (n209)
Estradiol (n 208)
1.00
24 (11.5)
24 (11.5)
Serious Adverse Events
0.50
5 ( 2.4)
3 ( 1.4)
Cancer
0.70
20 ( 9.6)
22 (10.6)
Hospitalization
0
0
Death
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Adverse Events over Two Years N ()
P-value
Placebo (n209)
Estradiol (n 208)
0.03
4 ( 1.0)
12 ( 5.8)
Cervical polyp
0.01
2 ( 0.9)
7 ( 3.4)
Endometrial polyp
0.001
3 ( 1.4)
22 (10.6)
Vaginal discharge
0.03
7 ( 3.3)
1 ( 0.5)
Hernia
0.01
9 ( 4.3)
1 ( 0.5)
Herpes Zoster
0.003
21 (10.0)
6 ( 2.9)
Rash
incidence gt 2 and statistical difference
between estradiol and placebo
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Individualizing Therapy