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CompletedNCT05903820REBELUpdated Feb 5, 2025

Rhythmic Estradiol and Bone Health

A Phase 4 interventional study of Estradiol patch and Progesterone in Osteoporosis Risk and Menopause, sponsored by Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA). Completed at 1 site in Netherlands. Open to female participants aged 45 Years to 60 Years, including healthy volunteers. Per ClinicalTrials.gov, last updated 2025-02-05.

Sponsored by Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA) · Phase 4, Interventional, and Prevention

Phase
Phase 4
Study type
Interventional
Enrollment
48
Allocation
Randomized
Ages
45 Years to 60 Years
Sex
Female
01

Study summary

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.

02

Conditions studied

  • Osteoporosis Risk
  • Menopause

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03

In context

Osteoporosis

1,640 studies on the registry are indexed under Osteoporosis; 212 are open to participants now.

This study's enrollment of 48 is below the median of 95 across 1,133 interventional studies indexed under Osteoporosis.

Browse Osteoporosis studies →

Lead sponsor

Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA) is the lead sponsor of 512 studies on the registry; 178 are open to participants now.

Counted across the registry records on this site, refreshed daily.

04

Who can participate

Ages eligible
45 Years to 60 Years
Sexes eligible
Female
Accepts healthy volunteers
Yes

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

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
05

Study design

Phase
Phase 4
Primary purpose
Prevention
Allocation
Randomized
Intervention model
Parallel assignment
Masking
None (open label)
Enrollment
48 participants (actual)

Study arms

  • 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 · Drug: 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 · Drug: 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 · Drug: Progesterone

Interventions

  • DrugEstradiol patch

    Transdermal patch of estradiol

    Also known as: transdermal17-beta-estradiol

  • DrugProgesterone

    Oral progesterone capsules 100mg/day

    Also known as: micronized progesterone

06

What researchers measure

Primary outcomes

  1. Serum P1NP

    The interaction between treatment and time on serum P1NP

    Time frame: The difference in P1NP between treatment arms after 2 weeks

  2. Serum P1NP

    The interaction between treatment and time on serum P1NP

    Time frame: The difference in P1NP between treatment arms after 4 weeks

  3. Serum P1NP

    The interaction between treatment and time on serum P1NP

    Time frame: The difference in P1NP between treatment arms after 6 weeks

  4. Serum P1NP

    The interaction between treatment and time on serum P1NP

    Time frame: The difference in P1NP between treatment arms after 8 weeks

  5. Serum P1NP

    The interaction between treatment and time on serum P1NP

    Time frame: The difference in P1NP between treatment arms after 10 weeks

  6. Serum P1NP

    The interaction between treatment and time on serum P1NP

    Time frame: The difference in P1NP between treatment arms after 12 weeks

  7. Serum P1NP

    The interaction between treatment and time on serum P1NP

    Time frame: The difference in P1NP between treatment arms after 14 weeks

  8. Serum P1NP

    The interaction between treatment and time on serum P1NP

    Time frame: The difference in P1NP between treatment arms after 16 weeks

Secondary outcomes

  1. Serum CTX

    The interaction between treatment and time on serum CTX

    Time frame: The difference in CTX between treatment arms after 2 weeks

  2. Serum CTX

    The interaction between treatment and time on serum CTX

    Time frame: The difference in CTX between treatment arms after 4 weeks

  3. Serum CTX

    The interaction between treatment and time on serum CTX

    Time frame: The difference in CTX between treatment arms after 6 weeks

  4. Serum CTX

    The interaction between treatment and time on serum CTX

    Time frame: The difference in CTX between treatment arms after 8 weeks

  5. Serum CTX

    The interaction between treatment and time on serum CTX

    Time frame: The difference in CTX between treatment arms after 10 weeks

  6. Serum CTX

    The interaction between treatment and time on serum CTX

    Time frame: The difference in CTX between treatment arms after 12 weeks

  7. Serum CTX

    The interaction between treatment and time on serum CTX

    Time frame: The difference in CTX treatment arms after 14 weeks

  8. Serum CTX

    The interaction between treatment and time on serum CTX

    Time frame: The difference in CTX between treatment arms after 16 weeks

Other outcomes

  1. Fasting glucose

    Change in fasting glucose

    Time frame: The difference between treatment arms in terms of change in fasting glucose after 16 weeks

  2. Fasting insulin

    Change in fasting insulin

    Time frame: The difference between treatment arms in terms of change in fasting insulin after 16 weeks

  3. Fasting insulin insulin resistance (HOMA-IR), and post-OGTT outcomes from to baseline until 16 weeks of treatment.

    Change in fasting insulin

    Time frame: The difference between treatment arms in terms of change in HOMA-IR after 16 weeks

  4. Glucose levels after an oral glucose tolerance test (OGTT)

    Change in glucose levels 2 hours after an oral glucose tolerance test (OGTT)

    Time frame: The difference between treatment arms in terms of change in post-OGTT glucose values after 16 weeks

  5. Change in liver steatosis

    Controlled Attenuation Parameter (CAP) scores, assessed with a Fibroscan

    Time frame: The difference between treatment arms in terms of change in CAP scores after 16 weeks

07

Study locations

1 site
  • Amsterdam UMC
    Amsterdam, 1105 AZ, Netherlands
08

References and documents

Individual participant data

Plan to share: No

No publications or documents are linked to this record.

09

Updates

Tracking since Sep 25, 2026
No changes since tracking began. The registry record was last updated on Feb 5, 2025, before this site started recording changes on Sep 25, 2026. Its history is on ClinicalTrials.gov ↗
10

Registry details

Key details

Study ID
NCT05903820
Lead sponsor
Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)
Responsible party
Peter H. Bisschop (Principal Investigator, Amsterdam UMC, location AMC) — Principal investigator
First posted
Jun 15, 2023
Start date
Jul 19, 2023
Primary completion
Oct 21, 2024
Completion
Oct 28, 2024
Last update
Feb 5, 2025

Study contacts

Peter M Bisschop
principal investigator · Amsterdam UMC

Oversight

Data monitoring committee
No
FDA-regulated drug
No
FDA-regulated device
No
View the source record on ClinicalTrials.gov ↗

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