Rhythmic Estradiol and Bone Health

Study Overview
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Brief Summary
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The goal of this randomized-controlled trial is to compare the effect of rhythmic estrogen treatment to continuous estrogen treatment on bone turnover in healthy postmenopausal women. The main question it aims to answer are: • Does rhythmic estrogen lead to increased bone formation in healthy postmenopausal women, compared to continuous estrogen? Participants will receive one of the following treatments for a duration of 16 weeks: - Rhythmic estradiol: Alternating 4-week cycles consisting of transdermal 17-β-estradiol 25μg/24hrs for two weeks, followed by two weeks of transdermal 17-β-estradiol 50μg/24hrs. Estradiol therapy will be combined with continuous oral micronized progesterone 100mg once daily. Low-dose continuous estradiol: Continuous transdermal 17-β-estradiol 25μg/24hrs, combined with continuous oral micronized progesterone 100mg daily once daily. Standard-dose continuous estradiol: Continuous transdermal 17-β-estradiol 50μg/24hrs, combined with continuous oral micronized progesterone 100mg daily once daily. If there is a comparison group: Researchers will compare rhythmic estradiol to continuous estradiol to see if rhythmic estradiol improves bone formation in postmenopausal women.

Official Title
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The Effect of Low-dose Rhythmic 17-β-estradiol Administration on Bone Turnover in Postmenopausal Women

Conditions
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Osteoporosis Risk, Menopause

Intervention / Treatment
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* Drug: Estradiol patch
* Drug: Progesterone


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Postmenopausal, defined as final menstrual cycle more than 1 years prior to inclusion and FSH>30 IU/L Final menstrual cycle < 10 years prior to inclusion Exclusion Criteria: Contra-indication for estrogen and/or progesterone therapy First-grade family member with inherited thrombophilia or history of venous thromboembolism under the age of 60 years Hysterectomy Premature menopause (menopause age <40 years) Known hypersensitivity to the excipients in the estradiol patch or progesterone capsule Hormonal contraception or hormone replacement therapy use (estradiol with or without progesterone) in the past 12 months Presence or history of any clinically relevant metabolic, endocrinological, hepatic, renal, cardiovascular, gastrointestinal, or respiratory conditions, history of bone disease or bone marrow disease, known vitamin D deficiency (25-OH vitamin D <30 nmol/L) Recent fracture (<12 months) BMI <20 or BMI ≥30 Use of drugs including herbal medicine known to affect bone metabolism (e.g. corticosteroids) or to interfere with cytochrome P450 enzyme (CYP) pathways. Exceptions are occasional use of paracetamol, ibuprofen, acetylsalicylic acid or topical medication

Ages Eligible for Study
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Minimum Age: 45 Years
Maximum Age: 60 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Continuous estradiol 50 mcg/day<br>The continuous standard-dose 17-β-estradiol group will receive the standard therapy for prevention of osteoporosis. A transdermal patch that releases 50ug/24 hrs of 17-β-estradiol will be administered continuously during the 16 weeks of treatment. | Drug: Estradiol patch<br>* Transdermal patch of estradiol<br>* Other names: transdermal17-beta-estradiol;Drug: Progesterone<br>* Oral progesterone capsules 100mg/day<br>* Other names: micronized progesterone;|
| Active Comparator: Continuous estradiol 25 mcg/day<br>The continuous low-dose 17-β-estradiol group will receive a transdermal patch that releases 25ug/24 hrs of 17-β-estradiol administered continuously during the 16 weeks of treatment. | Drug: Estradiol patch<br>* Transdermal patch of estradiol<br>* Other names: transdermal17-beta-estradiol;Drug: Progesterone<br>* Oral progesterone capsules 100mg/day<br>* Other names: micronized progesterone;|
| Experimental: Rhythmic estradiol 25-50 mcg/day<br>The rhythmic 17-β-estradiol group will receive a transdermal patch for two weeks that releases 25ug/24hrs of 17-β-estradiol, and a patch of 50ug/24hrs for 2 weeks in each 4-week cycle. | Drug: Estradiol patch<br>* Transdermal patch of estradiol<br>* Other names: transdermal17-beta-estradiol;Drug: Progesterone<br>* Oral progesterone capsules 100mg/day<br>* Other names: micronized progesterone;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Serum P1NP | The interaction between treatment and time on serum P1NP | The difference in P1NP between treatment arms after 2 weeks | 
| Serum P1NP | The interaction between treatment and time on serum P1NP | The difference in P1NP between treatment arms after 4 weeks | 
| Serum P1NP | The interaction between treatment and time on serum P1NP | The difference in P1NP between treatment arms after 6 weeks | 
| Serum P1NP | The interaction between treatment and time on serum P1NP | The difference in P1NP between treatment arms after 8 weeks | 
| Serum P1NP | The interaction between treatment and time on serum P1NP | The difference in P1NP between treatment arms after 10 weeks | 
| Serum P1NP | The interaction between treatment and time on serum P1NP | The difference in P1NP between treatment arms after 12 weeks | 
| Serum P1NP | The interaction between treatment and time on serum P1NP | The difference in P1NP between treatment arms after 14 weeks | 
| Serum P1NP | The interaction between treatment and time on serum P1NP | The difference in P1NP between treatment arms after 16 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Serum CTX | The interaction between treatment and time on serum CTX | The difference in CTX between treatment arms after 2 weeks | 
| Serum CTX | The interaction between treatment and time on serum CTX | The difference in CTX between treatment arms after 4 weeks | 
| Serum CTX | The interaction between treatment and time on serum CTX | The difference in CTX between treatment arms after 6 weeks | 
| Serum CTX | The interaction between treatment and time on serum CTX | The difference in CTX between treatment arms after 8 weeks | 
| Serum CTX | The interaction between treatment and time on serum CTX | The difference in CTX between treatment arms after 10 weeks | 
| Serum CTX | The interaction between treatment and time on serum CTX | The difference in CTX between treatment arms after 12 weeks | 
| Serum CTX | The interaction between treatment and time on serum CTX | The difference in CTX treatment arms after 14 weeks | 
| Serum CTX | The interaction between treatment and time on serum CTX | The difference in CTX between treatment arms after 16 weeks |