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

Inclusion Criteria:

For FHA and controls:

• Female, age 14-25 years, skeletally mature with bone age ≥ 14 years (only 2% ofgrowth left)

• For women of reproductive age, agree to use an effective non-hormonal contraceptivemethod or a progestin releasing intrauterine device (no evidence of systemicskeletal effects) for the study duration

• Biochemical criteria:

• Negative βHCG (pregnancy test)

• TSH, potassium, magnesium within the normal range; prolactin <10 ng/mL above theupper 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., testosteroneand sex hormone binding globulin if there is a suspicion of PCOS based on clinicalhyperandrogenism).

Additional inclusion criteria for FHA:

• Less than 3 menses in the preceding 6 months

• BMD Z-score < -1.0 at ≥ 1 skeletal site

• Dental check-up within the past year

Exclusion Criteria:

For FHA and controls

• Disease other than FHA known to affect bone, including untreated thyroiddysfunction, Cushing's disease, renal failure, diabetes mellitus

• Use of bisphosphonates

• Use of other medications known to affect bone metabolism within 3 months of thestudy (other than calcium and vitamin D supplementation).

• Migraine with aura.

• Personal history of or first-degree relative with unprovoked thromboembolism (unlessthe subject has been tested and ruled out for a hypercoagulable state).

• Active substance use disorder; current smoker

• History of malignancy or Paget disease of bone

• Pregnant, planning to become pregnant within 12 months after the end of treatmentand/or breastfeeding

Additional exclusion criteria for FHA

• Cardiovascular: History of myocardial infarction or stroke; history of hypertensionor use of anti-hypertensive medications

• Immunodeficiency or taking immunosuppressive therapy

• Other conditions that can cause oligo-amenorrhea such as PCOS, primary ovarianinsufficiency

• Dental: Osteonecrosis of the jaw (ONJ) or risk factor for ONJ, such as invasivedental procedures (tooth extraction, dental implants, oral surgery in the past 3months), poor oral hygiene, periodontal and/or pre-existing dental disease, andcurrent use of corticosteroids

• Planned invasive dental procedure or other planned major surgery over the next 12months (the duration of the study)

• Known sensitivity or absolute contraindication to any of the products or componentsof the medications to be administered (romosozumab, zoledronic acid, transdermalestradiol, micronized progesterone, calcium or vitamin D supplements)

• Concerning EKG findings for ischemia Additional exclusion criteria for normal-weighthealthy controls

• BMD Z-score <-2.5 (who we will refer for evaluation)