Romosozumab as an Adjunct to Physiologic Estrogen Replacement in Functional Hypothalamic Amenorrhea

NCT ID: NCT06533865

Last Updated: 2025-10-20

Basic Information

• Recruitment Status: RECRUITING
• Clinical Phase: PHASE3
• Total Enrollment: 114 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2025-03-19
• Study Completion Date: 2029-04-30

Brief Summary

The goal of this study is to determine whether romosozumab will improve bone density in girls and women with functional hypothalamic amenorrhea (cessation of the menstrual period due to intense exercise, stress, or an eating disorder) who have low bone density. Participants will be randomly assigned to receive romosozumab or placebo for 6 months. All participants will receive one IV infusion of zoledronate at the 6 month visit. All participants will also receive transdermal estradiol and cyclic progesterone. We will investigate whether participants who receive active romosozumab will demonstrate greater improvements in bone density at one year than those who receive placebo. We will also compare bone density over a year with healthy controls (girls and women of similar age who have regular menstrual periods).

Conditions

FHA (Functional Hypothalamic Amenorrhea)

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: TRIPLE

Study Groups

Romosozumab

Participants with functional hypothalamic amenorrhea randomized to romosozumab.

Group Type: EXPERIMENTAL

Romosozumab

Intervention Type: DRUG

Six monthly subcutaneous injections. This group will also receive a 100-microgram transdermal estradiol patch applied twice weekly, and 200 mg of oral progesterone for the first 12 days of each month.

Zoledronic acid

Intervention Type: DRUG

One intravenous infusion

Placebo

Participants with functional hypothalamic amenorrhea randomized to placebo.

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: DRUG

Identical to romosozumab but inactive. This group will also receive a 100-microgram transdermal estradiol patch applied twice weekly, and 200 mg of oral progesterone for the first 12 days of each month.

Zoledronic acid

Intervention Type: DRUG

One intravenous infusion

Healthy Controls

Healthy controls (girls and women with regular menstrual periods)

Group Type: NO_INTERVENTION

No interventions assigned to this group

Interventions

Romosozumab

Six monthly subcutaneous injections. This group will also receive a 100-microgram transdermal estradiol patch applied twice weekly, and 200 mg of oral progesterone for the first 12 days of each month.

Intervention Type: DRUG

Placebo

Identical to romosozumab but inactive. This group will also receive a 100-microgram transdermal estradiol patch applied twice weekly, and 200 mg of oral progesterone for the first 12 days of each month.

Intervention Type: DRUG

Zoledronic acid

One intravenous infusion

Intervention Type: DRUG

Other Intervention Names

Evenity; Zoledronate, Reclast

Eligibility Criteria

Inclusion Criteria

For FHA and controls:

• Female, age 14-30 years, skeletally mature with bone age ≥ 14 years (only 2% of growth left)
• For women of reproductive age, agree to use an effective non-hormonal contraceptive method or a progestin releasing intrauterine device (no evidence of systemic skeletal effects) or implant for the study duration
• Biochemical criteria:
• Negative βHCG (pregnancy test)
• TSH within twice the upper limit of normal; potassium, magnesium within the normal range; prolactin <10 ng/mL above the upper limit of normal; FSH not elevated.
• Serum ALT ≤ 3 times upper limit of normal, LDL ≤ 190 mg/dl
• eGFR ≥ 30ml/minute
• If the diagnosis of FHA is unclear, we may check additional labs (e.g., testosterone and sex hormone binding globulin if there is a suspicion of PCOS based on clinical hyperandrogenism).

• Less than 3 menses in the preceding 6 months
• BMD Z-score ≤ -1.0 at ≥ 1 skeletal site (for subjects <18 years old, we will use the height Z-score-adjusted BMD Z-score using the pediatric bone density calculator developed by the National Institutes of Health and currently maintained by the Children's Hospital of Philadelphia)
• Dental check-up within the past year
• If the menstrual status of the subject is unclear due to the presence of a progestin-releasing IUD, serum estradiol levels will be checked twice, at least one week apart. Both estradiol levels must be < 50 pg/mL.

Exclusion Criteria

For FHA and controls

• Disease other than FHA known to affect bone, including untreated thyroid dysfunction, Cushing's disease, renal failure, diabetes mellitus
• Use of bisphosphonates
• Use of other medications known to affect bone metabolism within 3 months of the study (other than calcium and vitamin D supplementation).
• Current use of systemic corticosteroids
• Migraine with aura.
• Personal history of or first-degree relative with unprovoked thromboembolism (unless the subject has been tested and ruled out for a hypercoagulable state).
• Active substance use disorder; currently smokes or vapes
• History of malignancy or Paget disease of bone
• Pregnant, planning to become pregnant within 12 months after the end of treatment and/or breastfeeding

• Cardiovascular: History of myocardial infarction or stroke; history of hypertension or use of anti-hypertensive medications
• Immunodeficiency or taking immunosuppressive therapy
• Other conditions that can cause oligo-amenorrhea such as PCOS, primary ovarian insufficiency
• Dental: Osteonecrosis of the jaw (ONJ) or risk factor for ONJ, such as invasive dental procedures (tooth extraction, dental implants, oral surgery in the past 3 months), poor oral hygiene, periodontal and/or pre-existing dental disease
• Planned invasive dental procedure or other planned major surgery for 18 months after the baseline visit
• Known sensitivity or absolute contraindication to any of the products or components of the medications to be administered (romosozumab, zoledronic acid, transdermal estradiol, micronized progesterone, calcium or vitamin D supplements)
• Concerning EKG findings for ischemia

• BMD Z-score <-2.5 (who we will refer for evaluation)

• Minimum Eligible Age: 14 Years
• Maximum Eligible Age: 30 Years
• Eligible Sex: FEMALE
• Accepts Healthy Volunteers: No

Sponsors

Massachusetts General Hospital

OTHER

Sponsor Role: lead

Responsible Party

Karen Klahr Miller, MD

Chief, Neuroendocrine Unit, Massachusetts General Hospital

Responsibility Role: PRINCIPAL_INVESTIGATOR

Locations

Massachusetts General Hospital

Boston, Massachusetts, United States

Site Status: RECRUITING

University of Virginia Medical Center

Charlottesville, Virginia, United States

Site Status: RECRUITING

Countries

United States

Central Contacts

Karen K Miller, MD

Role: CONTACT

kkmiller@mgh.harvard.edu

617-726-3870

Melanie Haines, MD

Role: CONTACT

mshaines@mgh.harvard.edu

617-726-3897

Facility Contacts

Karen Miller, MD

Role: primary

kkmiller@mgh.harvard.edu

617-726-3870

Melanie Haines, MD

Role: backup

mshaines@mgh.harvard.edu

617-726-3897

Madhusmita Misra, MD, MPH

Role: primary

ABP6BD@uvahealth.org

434-924-9141

Andrea Marrs, MS

Role: backup

misralab@uvahealh.org

434-982-0871

Other Identifiers

2024P000273

Identifier Type: -

Identifier Source: org_study_id