Mass General - Division of Clinical Research

For FHA and controls: - Female, age 14-25 years, skeletally mature with bone age ≥ 14 years (only 2% of growth left) - 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) for the study duration - Biochemical criteria: - Negative βHCG (pregnancy test) - TSH, 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 - Dental check-up within the past year

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). - 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; current smoker - 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, and current use of corticosteroids - Planned invasive dental procedure or other planned major surgery over the next 12 months (the duration of the study) - 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)