Abstract Low bone mass is a major co-morbid complication of functional hypothalamic amenorrhea (FHA) in adolescents and young adult women, including those with anorexia nervosa (AN) and exercise-induced amenorrhea (EIA). We propose to test in an 12-month randomized controlled trial the hypothesis that administration of romosozumab (vs. placebo) for 6 doses monthly followed by a single dose of zoledronic acid to amenorrheic adolescents and young women with FHA receiving transdermal estradiol replacement (with cyclic progesterone) and calcium and vitamin D supplementation who have not yet achieved peak bone mass will result in bone accrual that exceeds that of normal-weight controls without FHA with the potential to normalize bone endpoints. 84 participants with FHA will be randomized in a 2:1 ratio in a double-blind fashion to romosozumab or identical placebo injections monthly for 6 injections, to determine effects on bone mineral density (BMD), markers of bone metabolism, and bone geometry and bone strength at various skeletal sites using dual energy x-ray absorptiometry (DXA), high resolution peripheral quantitative computed tomography (HRpQCT) and microfinite element analysis (µFEA). This will be followed in all FHA subjects by a single zoledronic acid intravenous (IV) infusion at 6 months to consolidate gains from romosozumab therapy. All participants with FHA will also receive a 100 mcg transdermal estradiol patch (twice weekly) applied continuously, and 200 mg of oral micronized progesterone for the first 12 days of each month, which are known to improve, but not normalize, bone outcomes in FHA. In addition, 30 healthy controls will be followed prospectively for 12 months. All participants with FHA and healthy controls will receive at least 800 IU of vitamin D and 1000 mg of calcium daily (RDA) to avoid effects of suboptimal vitamin D concentrations on bone. There will be a one-month visit to determine whether romosozumab exerts the expected acute osteoanabolic effects in the FHA group vs. placebo, as studies have shown that the maximal anabolic effect of romosozumab is within the first month. We will determine whether romosozumab increases areal BMD (by DXA) and improves bone geometry (assessed by HRpQCT) and bone strength (assessed by microfinite element analysis) at 6 months in the FHA group compared with placebo. We will also compare the romosozumab group to healthy controls to determine whether the rate of improvement in bone endpoints exceeds that of healthy controls, resulting in catch-up and providing the anabolic boost necessary to set individuals with FHA on the path to normalization of bone endpoints. Moreover, we will determine whether 6 months of romosozumab followed by one IV zoledronic acid infusion improves BMD, bone geometry, and strength at 12 months in girls and women with FHA more than placebo followed by zoledronic acid and at a greater rate than in normal controls.