FHA (Functional Hypothalamic Amenorrhea)
Conditions
Brief summary
The goal of this study is to determine whether romosozumab will improve bone density in girls and women with functional hypothalamic amenorrhea (cessation of the menstrual period due to intense exercise, stress, or an eating disorder) who have low bone density. Participants will be randomly assigned to receive romosozumab or placebo for 6 months. All participants will receive one IV infusion of zoledronate at the 6 month visit. All participants will also receive transdermal estradiol and cyclic progesterone. We will investigate whether participants who receive active romosozumab will demonstrate greater improvements in bone density at one year than those who receive placebo. We will also compare bone density over a year with healthy controls (girls and women of similar age who have regular menstrual periods).
Interventions
DRUGRomosozumab
Six monthly subcutaneous injections. This group will also receive a 100-microgram transdermal estradiol patch applied twice weekly, and 200 mg of oral progesterone for the first 12 days of each month.
DRUGPlacebo
Identical to romosozumab but inactive. This group will also receive a 100-microgram transdermal estradiol patch applied twice weekly, and 200 mg of oral progesterone for the first 12 days of each month.
DRUGZoledronic acid
One intravenous infusion
Sponsors
Massachusetts General Hospital
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
FEMALE
Age
14 Years to 30 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Lumbar spine bone density | 0 and 6 months | 6-month change in lumbar spine bone density |
| Tibial cortical thickness | 0 and 6 months | 6-month change in tibial cortical thickness |
| Tibial failure load | 0 and 6 months | 6-month change in tibial failure load |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Femoral neck and total hip bone density | 0, 6, and 12 months | 6- and 12-month change in femoral neck and total hip bone density |
| Lumbar spine bone density | 0 and 12 months | 12-month change in lumbar spine bone density |
| Radial cortical thickness | 0, 6, and 12 months | 6- and 12-month change in radial cortical thickness |
| Tibial cortical thickness | 0 and 12 months | 12-month change in tibial cortical thickness |
| P1NP and CTX | 0, 1, 6, and 12 months | 1-, 6-, and 12-month change in P1NP and CTX |
| Radial failure load | 0, 6, and 12 months | 6- and 12-month change in radial failure load |
| Tibial failure load | 0 and 12 months | 12-month change in change in tibial failure load |
| Lumbar spine, femoral neck, and total hip bone density | 0, 6, and 12 months | 6- and 12-month in lumbar spine, femoral neck, and total hip bone density |
| Tibial and radial cortical thickness | 0, 6 and 12 months | 6- and 12-month change in tibial and radial cortical thickness |
| Tibial and radial failure load | 0, 6 and 12 months | 6- and 12-month change in tibial and radial failure load |
Countries
United States
Contacts
CONTACTKaren K Miller, MD
CONTACTMelanie Haines, MD
Outcome results
None listed