# Presentation: 689983

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

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

## Outline

**Background**
**Study**
**Design**
**Efficacy**
**Safety**
**Conclusion**

## Loss of Estrogen has Profound Effects on Bone

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

## Lowest effective dose“for the individual patient”

**Risk / Benefit **
**Quality of Life **

## Ultra Low Dose TransdermalEstrogen 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 Women’s Clinical Research Center), J. Pinkerton (University of Virginia), M. Farmer (Meridien Research) and D. Rowe (Palm Beach Research Center)**

## Design

**Randomized, placebo-controlled, blinded trial**
**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. placebo**
**Goal to increase serum E2 to 10–15 pg/mL**
**Daily calcium (800mg/d) and vitamin D (400 IU/d)**
**Duration of Study: 2 years**
**Follow-up visits every 4 months**

## Effects of 0.014 mg E2 on BMD

**Effects of 0.014 mg E2 on BMD**

**2.5%**

## Effects of 0.014 mg E2 on BMD

**Effects of 0.014 mg E2 on BMD**

**1.5%**

## Patients with Clinical Fractures

## Pooling Both “Ultra Low” TrialsClinical Fractures

** JAMA August 27, 2003*
*** S. Cummings, RR = 0.4; p = 0.04*

## Adverse Events: Serious

## 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**

## Paradigm Shift:Changing 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**

## Markers of Bone Turnover

***  Change in median**

## Cumulative Percent with Amenorrhea

**Cumulative Percent with Amenorrhea**

## Endometrial Evaluation after 24 Months

**417 Randomized**

**Tissue diagnosis****	****269**
**	****normal****	****267**
**	****atypical hyperplasia****	****    1**
**	****uterine adenosarcoma****	****  1**

**Dropped out 41**
**	****placebo****	****24**
**	****estradiol****	****17**

**No tissue diagnosis****	****107**
**	****sample lost****	****    1**
**	****refused or unable****	****  68**
**	****insufficient****	****  38**

**Refused   TVUS   6**

**TVUS     101**

**Endometrium****	**_**>**_** 5mm****	****11**
**	****normal tissue****	****	****	****  6**
**	****nml hysterosalpingogram****	****  1**
**	****No further work-up****	****	****  4**

**Endometrium****	****< 5mm****	****90**

## Baseline Characteristics

**	****	****	****	****	**_**Estradiol**__**	**__**Placebo**__**	**__**	**__**P**_
**	****	****	****	****	****(n=208)****	****	****(n=209)****	**
**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**

## Adverse Events

**No significant difference of headache, nausea or genital discomfort reported (******** 2%)**

## Adverse Events over Two Years: N (%)

**0**

**0**

**     ****Death**

**0.70**

**20 (  9.6)**

**22 (10.6)**

**     ****Hospitalization**

**0.50**

**5 (  2.4)**

**3 (  1.4)**

**     ****Cancer**

**1.00**

**24 (11.5)**

**24 (11.5)**

_**Serious Adverse Events**_

_**P-value**_

_**Placebo**_
**(n=209)**

_**Estradiol**_
**(n = 208)**

## Adverse Events over Two Years: N (%)

**21 (10.0)**

**6 (  2.9)**

**     ****Rash**

**0.01**

**9 (  4.3)**

**1 (  0.5)**

**     ****Herpes Zoster**

**0.03**

**7 (  3.3)**

**1 (  0.5)**

**     ****Hernia**

**0.001**

**3 (  1.4)**

**22 (10.6)**

**     ****Vaginal discharge**

**0.01**

**2 (  0.9)**

**7 (  3.4)**

**     ****Endometrial polyp**

**0.03**

**4 (  1.0)**

**12 (  5.8)**

**     ****Cervical polyp**

_**P-value**_

_**Placebo**_
**(n=209)**

_**Estradiol**_
**(n = 208)**

-  * incidence > 2% and statistical difference between estradiol and placebo

**Adverse Events over Two Years: N (%)**

## Individualizing Therapy

**Individualizing Therapy**