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.

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