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

NCT06533865 | Recruiting Phase 3 DMC FDA Drug

• 1 other identifier: 2024P000273
• Study Type: interventional
• Target: 114
• Locations: 1 country
• Sites: 2

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)

Outcome Measures

Primary Outcomes (3)

• 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 Outcomes (11)

• Femoral neck and total hip bone density

  0, 6, and 12 months

• Lumbar spine bone density

  0 and 12 months

• Radial cortical thickness

  0, 6, and 12 months

• Tibial cortical thickness

  0 and 12 months

• P1NP and CTX

  0, 1, 6, and 12 months

Study Arms (3)

Romosozumab

EXPERIMENTAL

Participants with functional hypothalamic amenorrhea randomized to romosozumab.

Drug: Romosozumab; Drug: Zoledronic acid

Placebo

PLACEBO COMPARATOR

Participants with functional hypothalamic amenorrhea randomized to placebo.

Drug: Placebo; Drug: Zoledronic acid

Healthy Controls

NO INTERVENTION

Healthy controls (girls and women with regular menstrual periods)

Interventions

Romosozumab 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.

Also known as: Evenity

Romosozumab

Placebo 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.

Placebo

Zoledronic acid DRUG

One intravenous infusion

Also known as: Zoledronate, Reclast

Placebo; Romosozumab

Eligibility Criteria

• Age: 14 Years - 30 Years
• Sex: female
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• 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:
• an effective non-hormonal contraceptive method
• a progestin releasing intrauterine device (no evidence of systemic skeletal effects)
• a progestin releasing implant
• 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).
• 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)

You may not qualify if:

• 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
• 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

Sponsors & Collaborators

• Massachusetts General Hospital: lead

Study Sites (2)

Massachusetts General Hospital

Boston, Massachusetts, 02114, United States

RECRUITING

University of Virginia Medical Center

Charlottesville, Virginia, 22903, United States

RECRUITING

MeSH Terms

Interventions

romosozumab; Zoledronic Acid

Intervention Hierarchy (Ancestors)

Diphosphonates; Organophosphonates; Organophosphorus Compounds; Organic Chemicals; Imidazoles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds

Central Study Contacts

Karen K Miller, MD

CONTACT

617-726-3870; kkmiller@mgh.harvard.edu

Melanie Haines, MD

CONTACT

617-726-3897; mshaines@mgh.harvard.edu

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Chief, Neuroendocrine Unit, Massachusetts General Hospital

Study Record Dates

• First Submitted: July 30, 2024
• First Posted: August 1, 2024
• Study Start: March 19, 2025
• Primary Completion (Estimated): October 1, 2028
• Study Completion (Estimated): April 1, 2029
• Last Updated: April 23, 2026

Record last verified: 2026-04

Locations

US (2)