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

Berlex LaboratoriesBerlex Laboratories

OutlineOutline

• BackgroundBackground

• StudyStudy– DesignDesign– EfficacyEfficacy– SafetySafety

• ConclusionConclusion

Loss of Estrogen has Profound Effects Loss of Estrogen has Profound Effects on Boneon Bone

• Increased resorptionIncreased resorption

• Rapid bone lossRapid bone loss

• Apoptosis of osteocytesApoptosis of osteocytes

• Increased risk of hip & spine Increased risk of hip & spine fracturefracture

Lowest effective doseLowest effective dose““for the individual patientfor the individual patient””

• Risk / Benefit Risk / Benefit

• Quality of Life Quality of Life

Ultra Low Dose TransdermalUltra Low Dose TransdermalEstrogen Replacement Assessment (ULTRA)Estrogen Replacement Assessment (ULTRA)

• UCSF Coordinating CenterUCSF Coordinating Center– Deborah Grady, Steven Cummings, Eric Vittinghoff, Deborah Grady, Steven Cummings, Eric Vittinghoff,

Judy Macer, Judy Quan, Lorie DentonJudy Macer, Judy Quan, Lorie Denton

• 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

Research Center)Research Center)

DesignDesign

• 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 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

Adverse Events: SeriousAdverse Events: Serious

Adverse EventsType

Estradiol(n=208)

Placebo(n=209)

Total Serious AEs 24 (11.5) 23 (11.0)

Cancer 3 (1.4) 5 (2.4)Breast 1 (0.5) 2 (1.0)Other 2 (1.0) 3 (1.4)

Cardiovascular 3 (1.4) 5 (2.4)CHD 0 (0.0) 3 (1.4)Stroke/TIA 1 (0.5) 2 (1.0)VTE 0 (0.0) 0 (0.0)Other 2 (2.0) 0 (0.0)

Hospitalization 22 (10.6) 20 (9.6)Death 0 0

Ultra Trial ConclusionUltra Trial Conclusion

• 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

Ultra low dose estradiol:Ultra low dose estradiol:

• 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

Markers of Bone TurnoverMarkers of Bone Turnover

* Change in median* Change in median

12 months* P-value

sCTX -20% <0.001Osteocalcin -16% <0.001BsAP -15% <0.001

Cumulative Percent with Amenorrhea

Endometrial Evaluation after 24 MonthsEndometrial Evaluation after 24 Months

417 Randomized417 Randomized

Tissue diagnosis 269

normal 267

atypical hyperplasia 1

uterine adenosarcoma 1

Tissue diagnosis 269

normal 267

atypical hyperplasia 1

uterine adenosarcoma 1

Dropped out 41

placebo 24

estradiol 17

Dropped out 41

placebo 24

estradiol 17

No tissue diagnosis 107

sample lost 1

refused or unable 68

insufficient 38

No tissue diagnosis 107

sample lost 1

refused or unable 68

insufficient 38

Refused TVUS 6Refused TVUS 6TVUS 101TVUS 101

Endometrium > 5mm 11

normal tissue 6

nml hysterosalpingogram 1

No further work-up 4

Endometrium > 5mm 11

normal tissue 6

nml hysterosalpingogram 1

No further work-up 4

Endometrium < 5mm 90Endometrium < 5mm 90

Baseline CharacteristicsBaseline Characteristics

EstradiolEstradiol PlaceboPlacebo PP

(n=208)(n=208) (n=209)(n=209)

Age, yearsAge, years 66.866.8 66.766.7 1.01.0

White, %White, % 92.892.8 91.991.9 0.70.7

College Educ, %College Educ, % 63.563.5 63.663.6 1.01.0

Current smoker, %Current smoker, % 7.77.7 6.26.2 0.60.6

Dietary calcium, mg/dayDietary calcium, mg/day 746746 691691 0.20.2

Any alcoholAny alcohol 64.464.4 67.067.0 0.80.8

BMIBMI 28.328.3 28.028.0 0.60.6

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%)

Adverse EventsType

Estradiol(n=208)

Placebo(n=209)

Breast Tenderness 5 (2.4) 4 (1.0)Cervical polyp 12 (5.8) 4 (1.0)Endometrial polyp 7 (3.4) 2 (0.9)Endometrial hyperplasia 1 (0.5) 0 (0.0)Vaginal discharge 22 (10.6) 3 (1.4)Hernia 1 (0.5) 7 (3.3)Herpes Zoster 1 (0.5) 9 (4.3)Rash 6 (2.9) 21 (10.0)

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

0000 DeathDeath

0.700.7020 ( 9.6)20 ( 9.6)22 (10.6)22 (10.6) HospitalizationHospitalization

0.500.505 ( 2.4)5 ( 2.4)3 ( 1.4)3 ( 1.4) CancerCancer

1.001.0024 (11.5)24 (11.5)24 (11.5)24 (11.5)Serious Adverse EventsSerious Adverse Events

P-valueP-valuePlaceboPlacebo

(n=209)(n=209)

EstradiolEstradiol

(n = 208)(n = 208)

0.0030.00321 (10.0)21 (10.0)6 ( 2.9)6 ( 2.9) RashRash

0.010.019 ( 4.3)9 ( 4.3)1 ( 0.5)1 ( 0.5) Herpes ZosterHerpes Zoster

0.030.037 ( 3.3)7 ( 3.3)1 ( 0.5)1 ( 0.5) HerniaHernia

0.0010.0013 ( 1.4)3 ( 1.4)22 (10.6)22 (10.6) Vaginal dischargeVaginal discharge

0.010.012 ( 0.9)2 ( 0.9)7 ( 3.4)7 ( 3.4) Endometrial polypEndometrial polyp

0.030.034 ( 1.0)4 ( 1.0)12 ( 5.8)12 ( 5.8) Cervical polypCervical polyp

P-valueP-valuePlaceboPlacebo

(n=209)(n=209)

EstradiolEstradiol

(n = 208)(n = 208)

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

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

Standard HT (E+P)Ultra-Low Estrogen

(Transdermal)Bisphosphonates SERMs

Safety

VTE 2.141 1.04 NA 2.766

CHD/Stroke 1.29/1.412 ?? NA 0.86/0.98BCa 2.03 1.245 NA 1.0GI NA NA negative effect NA

Reversible yes yes 30 yrs in bone yes

Footnotes:1. Hazard Ratio (WHI)2. Hazard Ratio3. RR (Million Woman)

4. OR (ESTHER)5. RR (Million Woman)

6. RR (MORE)

Individualizing TherapyIndividualizing Therapy