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

Mass General Brigham

Status and phase: Enrolling; Phase 3

Conditions: FHA (Functional Hypothalamic Amenorrhea)

Treatments: Drug: Placebo; Drug: Zoledronic acid; Drug: Romosozumab

Study type: Interventional

Funder types: Other

Identifiers

NCT06533865

2024P000273

Details and patient eligibility

About

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).

Enrollment: 114 estimated patients

Sex: Female

Ages: 14 to 30 years old

Volunteers: No Healthy Volunteers

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 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).

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.

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

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
• 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)

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: Triple Blind

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114 participants in 3 patient groups, including a placebo group

Romosozumab

Experimental group

Description:

Participants with functional hypothalamic amenorrhea randomized to romosozumab.

Treatment:

Drug: Romosozumab

Drug: Zoledronic acid

Placebo

Placebo Comparator group

Description:

Participants with functional hypothalamic amenorrhea randomized to placebo.

Treatment:

Drug: Zoledronic acid

Drug: Placebo

Healthy Controls

No Intervention group

Description:

Healthy controls (girls and women with regular menstrual periods)