Rhythmic Estradiol and Bone Health (REBEL)

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

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.

Study Overview

• Status: Completed
• Conditions: Menopause; Osteoporosis Risk
• Intervention / Treatment: Drug: Estradiol patch; Drug: Progesterone

• Study Type: Interventional
• Enrollment (Actual): 48
• Phase: Phase 4

Contacts and Locations

Study Locations

• Netherlands
  • Amsterdam, Netherlands, 1105 AZ
    • Amsterdam UMC

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult
• Accepts Healthy Volunteers: Yes

Description

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

Study Plan

How is the study designed?

Design Details

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

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Continuous estradiol 50 mcg/day; 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; Transdermal patch of estradiol; Other Names: transdermal17-beta-estradiol; Drug: Progesterone; Oral progesterone capsules 100mg/day; Other Names: micronized progesterone
Active Comparator: Continuous estradiol 25 mcg/day; 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; Transdermal patch of estradiol; Other Names: transdermal17-beta-estradiol; Drug: Progesterone; Oral progesterone capsules 100mg/day; Other Names: micronized progesterone
Experimental: Rhythmic estradiol 25-50 mcg/day; 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; Transdermal patch of estradiol; Other Names: transdermal17-beta-estradiol; Drug: Progesterone; Oral progesterone capsules 100mg/day; Other Names: micronized progesterone

What is the study measuring?

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

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Fasting glucose	Change in fasting glucose	The difference between treatment arms in terms of change in fasting glucose after 16 weeks
Fasting insulin	Change in fasting insulin	The difference between treatment arms in terms of change in fasting insulin after 16 weeks
Fasting insulin insulin resistance (HOMA-IR), and post-OGTT outcomes from to baseline until 16 weeks of treatment.	Change in fasting insulin	The difference between treatment arms in terms of change in HOMA-IR after 16 weeks
Glucose levels after an oral glucose tolerance test (OGTT)	Change in glucose levels 2 hours after an oral glucose tolerance test (OGTT)	The difference between treatment arms in terms of change in post-OGTT glucose values after 16 weeks
Change in liver steatosis	Controlled Attenuation Parameter (CAP) scores, assessed with a Fibroscan	The difference between treatment arms in terms of change in CAP scores after 16 weeks

Collaborators and Investigators

• Sponsor: Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
• Investigators: Principal Investigator: Peter M Bisschop, Amsterdam UMC

Study record dates

Study Major Dates

• Study Start (Actual): July 19, 2023
• Primary Completion (Actual): October 21, 2024
• Study Completion (Actual): October 28, 2024

Study Registration Dates

• First Submitted: May 15, 2023
• First Submitted That Met QC Criteria: June 12, 2023
• First Posted (Actual): June 15, 2023

Study Record Updates

• Last Update Posted (Actual): March 25, 2025
• Last Update Submitted That Met QC Criteria: February 3, 2025
• Last Verified: July 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Bone Diseases; Musculoskeletal Diseases; Metabolic Diseases; Bone Diseases, Metabolic; Osteoporosis; Contraceptive Agents, Hormonal; Physiological Effects of Drugs; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Reproductive Control Agents; Contraceptive Agents, Female; Contraceptive Agents; Estrogens; Progestins; Estradiol 17 beta-cypionate; Estradiol 3-benzoate; Estradiol; Polyestradiol phosphate; Progesterone
• Other Study ID Numbers: NL83336.018.23

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No