Effects of Anorexia Nervosa on Peak Bone Mass
Condition: Anorexia Nervosa
MeSH terms: Anorexia; Anorexia Nervosa
Study type: Interventional
Phase: Phase 3

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.
    

Detailed description: 
      Given the increasing prevalence of AN, its profound consequences on bone health, and lack of
      optimal treatment interventions, these studies will provide critical data needed to identify
      optimal treatment strategies for this severe co-morbid disease using state- of- the- art
      endpoints of BMD, bone microarchitecture and strength. Although both low IGF-1 and
      hypogonadism are associated with increased skeletal fragility in AN, the mechanisms by which
      these factors interact are incompletely understood. Specifically, the increased skeletal
      fragility that is associated with AN is poorly reflected by DXA-derived BMD. Furthermore, the
      magnitude and mechanisms by which IGF-1 deficiency and hypogonadism influence bone
      microarchitecture are not defined. The growing incidence of eating disorders in adolescent
      girls and their long-term effects on skeletal health provide strong rationale for studies
      that will provide a better understanding of these issues and the evaluation of rational
      therapeutic approaches. The studies described in this proposal utilize both cross-sectional
      and RCT approaches to achieve this goal. Additionally, our utilization of sophisticated
      techniques such as high resolution peripheral QCT (HR-pQCT) will improve our understanding of
      the relationship between IGF-1, gonadal steroids and bone quality and will aid in the
      development of effective therapies in the treatment of skeletal fragility in Anorexia
      Nervosa.
    

Intervention name(s): RhIGF-1 with transdermal 17-beta estradiol; Placebo and transdermal 17-beta estradiol
Intervention type(s): Drug; Drug
Intervention description(s): 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.
Other intervention name(s): Mecasermin and Vivelle Dot patch; Vivelle Dot patch
Intervention MeSH terms: Estradiol 17 beta-cypionate; Estradiol 3-benzoate; Estradiol; Polyestradiol phosphate; Mecasermin
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary purpose: Treatment
Keywords: Anorexia Nervosa; Estrogen; Teenagers; IGF-1