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

Romosozumab as an Adjunct to Physiologic Estrogen Replacement in Adolescents and Young Adults With Functional Hypothalamic Amenorrhea

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).

Study Overview

• Status: Recruiting
• Conditions: FHA (Functional Hypothalamic Amenorrhea)
• Intervention / Treatment: Drug: Zoledronic acid; Drug: Romosozumab; Drug: Placebo

• Study Type: Interventional
• Enrollment (Estimated): 114
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Karen K Miller, MD; Phone Number: 617-726-3870; Email: kkmiller@mgh.harvard.edu
• Study Contact Backup: Name: Melanie Haines, MD; Phone Number: 617-726-3897; Email: mshaines@mgh.harvard.edu

Study Locations

• United States
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
      • Recruiting
      • Massachusetts General Hospital
      • Principal Investigator: Karen Miller, MD
      • Contact: Melanie Haines, MD; Phone Number: 617-726-3897; Email: mshaines@mgh.harvard.edu
      • Contact: Karen Miller, MD; Phone Number: 617-726-3870; Email: kkmiller@mgh.harvard.edu
  • Virginia
    • Charlottesville, Virginia, United States, 22903
      • Recruiting
      • University of Virginia Medical Center
      • Contact: Madhusmita Misra, MD, MPH; Phone Number: 434-924-9141; Email: ABP6BD@uvahealth.org
      • Principal Investigator: Madhusmita Misra, MD, MPH
      • Contact: Andrea Marrs, MS; Phone Number: 434-982-0871; Email: misralab@uvahealh.org

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

For FHA and controls:

• Female, age 14-30 years, skeletally mature with bone age ≥ 12 years

• For women of reproductive age, agree to use one of the following for the study duration:

  1. an effective non-hormonal contraceptive method
  2. a progestin releasing intrauterine device (no evidence of systemic skeletal effects)
  3. a progestin releasing implant
  4. does not have a history of sexual activity that could lead to pregnancy (i.e., same-sex partners only or total abstinence has been and is their preferred lifestyle)
• 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).

Additional inclusion criteria for FHA:

• 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.At the discretion of the study clinician, subjects with a diagnosis of PCOS may undergo one to two serum estradiol levels, at least one week apart. The estradiol level(s) 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 in the past year
• 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 as classified in IHS Classification ICHD-3.
• 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

Additional exclusion criteria for FHA

• 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. A participant with PCOS may be included if a study clinician determines that missed menstrual periods are more likely a consequence of FHA.
• 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 Additional exclusion criteria for normal-weight healthy controls
• BMD Z-score <-2.5 (who we will refer for evaluation)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Romosozumab; Participants with functional hypothalamic amenorrhea randomized to romosozumab.	Drug: Zoledronic acid; One intravenous infusion; Other Names: Zoledronate, Reclast; Drug: 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.; Other Names: Evenity
Placebo Comparator: Placebo; Participants with functional hypothalamic amenorrhea randomized to placebo.	Drug: Zoledronic acid; One intravenous infusion; Other Names: Zoledronate, Reclast; 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.
No Intervention: Healthy Controls; Healthy controls (girls and women with regular menstrual periods)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Lumbar spine bone density	6-month change in lumbar spine bone density	0 and 6 months
Tibial cortical thickness	6-month change in tibial cortical thickness	0 and 6 months
Tibial failure load	6-month change in tibial failure load	0 and 6 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Femoral neck and total hip bone density	6- and 12-month change in femoral neck and total hip bone density	0, 6, and 12 months
Lumbar spine bone density	12-month change in lumbar spine bone density	0 and 12 months
Radial cortical thickness	6- and 12-month change in radial cortical thickness	0, 6, and 12 months
Tibial cortical thickness	12-month change in tibial cortical thickness	0 and 12 months
P1NP and CTX	1-, 6-, and 12-month change in P1NP and CTX	0, 1, 6, and 12 months
Radial failure load	6- and 12-month change in radial failure load	0, 6, and 12 months
Tibial failure load	12-month change in change in tibial failure load	0 and 12 months
Lumbar spine, femoral neck, and total hip bone density	6- and 12-month in lumbar spine, femoral neck, and total hip bone density	0, 6, and 12 months
P1NP and CTX	1-, 6- and 12-month change in markers of bone metabolism	0, 1, 6 and 12 months
Tibial and radial cortical thickness	6- and 12-month change in tibial and radial cortical thickness	0, 6 and 12 months
Tibial and radial failure load	6- and 12-month change in tibial and radial failure load	0, 6 and 12 months

Collaborators and Investigators

• Sponsor: Massachusetts General Hospital

Study record dates

Study Major Dates

• Study Start (Actual): March 19, 2025
• Primary Completion (Estimated): October 1, 2028
• Study Completion (Estimated): April 1, 2029

Study Registration Dates

• First Submitted: July 30, 2024
• First Submitted That Met QC Criteria: July 30, 2024
• First Posted (Actual): August 1, 2024

Study Record Updates

• Last Update Posted (Actual): April 23, 2026
• Last Update Submitted That Met QC Criteria: April 22, 2026
• Last Verified: April 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Menstruation Disturbances; Amenorrhea; Organic Chemicals; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Azoles; Imidazoles; Organophosphorus Compounds; Organophosphonates; Diphosphonates; Zoledronic Acid; romosozumab
• Other Study ID Numbers: 2024P000273

Drug and device information, study documents

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