Effects of Anorexia Nervosa on Peak Bone Mass
Condition: Anorexia Nervosa
MeSH terms: Anorexia; Anorexia Nervosa
Intervention: RhIGF-1 with transdermal 17-beta estradiol; Placebo and transdermal 17-beta estradiol
Intervention description: RhIGF-1 will be started at a dose of 30mcg/k/dose twice daily, and will be titrated up or down in 25% dose increments to maintain IGF-1 levels in the upper half of the normal range.
Estradiol will be delivered transdermally using a 100 mcg patch (Vivelle Dot) changed twice weekly. Subjects will receive cyclic micronized progesterone (Prometrium) 100 mg daily for the first 10 days of each month. All subjects will receive supplemental calcium and vitamin D.; Placebo injections will be administered twice daily. Estradiol will be delivered transdermally using a patch (100 mcg) changed twice weekly. Subjects will receive cyclic micronized progesterone (Prometrium) 100 mg daily for the first 10 days of each month. All subjects will receive supplemental calcium and vitamin D.
Intervention MeSH terms: Estradiol 17 beta-cypionate; Estradiol 3-benzoate; Estradiol; Polyestradiol phosphate; Mecasermin
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Investigator)
Enrollment: 75.0
Sex: Female
Minimum age: 14 Years
Maximum age: 22 Years
Healthy volunteers: Accepts Healthy Volunteers
Keywords: Anorexia Nervosa; Estrogen; Teenagers; IGF-1

Summary:

      Teenage girls with anorexia nervosa (AN) are at risk for low bone density and low rates of
      bone accrual, raising concerns regarding acquisition of peak bone mass, an important
      determinant of future bone health and fracture risk. Important factors contributing to low
      bone density in AN include low levels of estrogen and insulin like growth factor-1 (IGF-1).
      While estrogen is important for preventing bone loss, IGF-1 is important for optimizing bone
      formation. We have shown in a previous study that replacement of estrogen is effective in
      increasing bone density in teenage girls with AN; however, this increase in bone density
      remains lower than that seen in normal-weight controls over the same duration, and residual
      deficits persist. Importantly, the impact of administering replacement doses of IGF-1 with
      estrogen replacement has not been studied in teenagers with AN.

      This study will examine the impact of administering recombinant human (rh) insulin like
      growth factor-1 (rhIGF-1) with estrogen (to mimic pubertal levels of these hormones) versus
      administration of estrogen alone on bone metabolism in adolescent girls with anorexia nervosa
      (AN).

      One aim of this proposal is to investigate whether co-administration of insulin like growth
      factor-1 (rhIGF-1) with physiologic estradiol replacement to adolescent girls with AN will
      increase BMD (bone mineral density) more than estrogen monotherapy, and whether bone mass
      will approach that seen in healthy adolescent girls. An additional aim is to determine
      whether co-administration of rhIGF-1 with estradiol to mimic the normal pubertal milieu
      stimulates bone formation through an IGF-1 mediated anabolic effect, increases bone density
      to a greater extent than estrogen monotherapy, and improves bone mass accrual to approach
      that in healthy controls. The impact of rhIGF-1 +estradiol versus estradiol alone on bone
      microarchitecture will also be assessed.
    

Eligibility criteria:

        Inclusion Criteria: AN:

          -  Age: 14-22 years old

          -  Bone age (BA): ≥14 years

          -  Should meet DSM IV criteria for AN

          -  Subjects at MGH will be evaluated by co-investigator Dr. David Herzog, Director of the
             Harris Center for Eating Disorders, at MGH, and by Dr. Debra Katzman, co-investigator,
             and the Hospital for Sick Children, Toronto who directs their Eating Disorders
             Program, respectively, before enrollment.

        Inclusion Criteria: Controls:

          -  Healthy adolescent girls 14-22 years

          -  BA of ≥14 years

          -  BMI between the 10th-90th percentiles for age

          -  Regular menstrual periods every 28-35 days for subjects ≥ 2 years post-menarche.

        Exclusion Criteria:

          -  Diseases known to affect bone metabolism including untreated thyroid disease,
             Cushing's syndrome, diabetes, pituitary disease, renal failure and prior bone fracture
             within six months of the study.

          -  Medications known to affect bone metabolism, including gonadal steroids, within three
             months.

          -  Evidence of suicidality, psychosis, or substance abuse.

          -  Premature ovarian failure, as demonstrated by an elevated FSH.

          -  Abnormal TSH.

          -  Hematocrit <30%, Potassium <3.0 mmol/L, Glucose <50 mg/dl

          -  Pregnancy

          -  History of malignancy

          -  Contraindications to estrogen therapy (for girls with AN)