Using romosozumab to improve bone density in women with functional hypothalamic amenorrhea

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

This study is testing if a medication called romosozumab can help improve bone density in girls and women aged 14-25 who have low bone density due to functional hypothalamic amenorrhea.

Quick facts

• Phase: PHASE3
• Study type: Interventional
• Enrollment: 114 (estimated)
• Ages: 14 Years to 30 Years
• Sex: Female
• Sponsor: Massachusetts General Hospital (other)
• Drugs / interventions: romosozumab
• Locations: 2 sites (Boston, Massachusetts and 1 other locations)
• Trial ID: NCT06533865 on ClinicalTrials.gov

What this trial studies

This study aims to evaluate the effectiveness of romosozumab in enhancing bone density among girls and women aged 14-25 who have functional hypothalamic amenorrhea (FHA) and low bone density. Participants will be randomly assigned to receive either romosozumab or a placebo for six months, alongside transdermal estradiol and cyclic progesterone. After six months, all participants will receive an IV infusion of zoledronate, and the study will assess bone density changes over one year compared to healthy controls. The goal is to determine if romosozumab leads to greater improvements in bone density than the placebo.

Who should consider this trial

Good fit: Ideal candidates are females aged 14-25 with a diagnosis of functional hypothalamic amenorrhea and low bone density.

Not a fit: Patients who do not have functional hypothalamic amenorrhea or those with normal bone density may not benefit from this study.

Why it matters

Potential benefit: If successful, this treatment could significantly improve bone health in young women suffering from FHA, reducing the risk of osteoporosis.

How similar studies have performed: While there have been studies on bone density treatments, the specific combination of romosozumab with estrogen replacement in FHA is relatively novel.

Eligibility criteria

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)

Where this trial is running

Boston, Massachusetts and 1 other locations

• Massachusetts General Hospital — Boston, Massachusetts, United States (RECRUITING)
• University of Virginia Medical Center — Charlottesville, Virginia, United States (RECRUITING)

Study contacts

• Study coordinator: Karen K Miller, MD

Conditions: FHA