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

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:

• 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).

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)