Arimidex in children

[participant3]

Is there any data to support the use of Arimidex in patients with short stature or growth hormone deficiency?

[chantell.reagan]

The use of aromatase inhibitors in children with growth disorders is based on the premise of delaying estrogen-mediated skeletal maturation in order to prolong linear growth and to increase predicted adult height. Aromatase inhibitors have been studied in boys with constitutional delay of growth and puberty (CDGP), idiopathic short stature, and growth hormone deficiency; there is no data in female pediatric patients, possibly due to concerns for potential interference with pubertal development. Several studies show that anastrozole and letrozole can maintain growth velocity while decreasing bone age progression; however overall evidence is still limited. In addition, there are a number of safety considerations that still need to be evaluated, including increased testosterone levels, potential effects on BMD and other metabolic parameters. Anastrozole was evaluated in one randomized, placebo-controlled, multi-center trial evaluating use in growth hormone deficiency in boys for 1 to 3 years. In this study, 50 patients were randomized to 0.35 mg/kg/wk of anastrozole, had a diagnosis of short stature or significant growth deceleration, and were treated with a steady-dose of growth hormone for at least 6 months. Pubertal subjects had to have a bone age between 11.5-15 yrs at study entry. Study results showed a slower increase in bone age advancement from baseline in anastrozole+GH group vs. placebo+GH group after 2 and 3 years. This resulted in a net increase in predicted adult height of 6.7 cm after 3 years of treatment with anastrozole+GH versus a 1cm gain with placebo+GH. Safety was comparable between both groups.

Upon inquiry, AstraZeneca did not have any information as to whether they would be pursuing this additional indication with the FDA. Of note, aromatase inhibitors may be also used in other pediatric conditions, including male limited peripheral precocious puberty, congenital adrenal hyperplasia, and McCune-Albright Syndrome (in girls).

Additional sources:

Dunkel L. Update on the role of aromatase inhibitors in growth disorders. Horm Res. 2009;71 Suppl 1:57-63. (Pubmed abstract)

Kreher NC et al. Treatment of familial male-limited precocious puberty with bicalutamide and anastrozole. J Pediatr. 2006;149:416-20. (Pubmed abstract – case reports)

Shulman DI et al. Use of aromatase inhibitors in children and adolescents with disorders of growth and adolescent development. Pediatrics. 2008;121:e975-83. (Full-text article)

[Rander]

Hi,

Is anyone covering aromatase inhibitors for ISS?

We are getting more requests and the physicians are less satified with the denial reasons of limited to females and/or it is not FDA approved for this indication.

There is no data that shows it increases height only predicted adult height. No one know the long term side effects either.

Thanks,
Rander

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[chantell.reagan]

Since our initial inquiry in 4/09, there have been no additional published clinical trials evaluating the effectiveness of aromatase inhibitors (AIs) in idiopathic short stature (ISS). Few studies which have been published thus far, did focus on predicted adult height as the key objective – however, it seems as a more appropriate outcome than the actual height increase, considering that the primary objective is to reach adult height as close to the “normal” range as possible (as opposed to height increase after 1-2 years of treatment, while the adolescent is still growing).

One more randomized, placebo-controlled trial should be added to the list above - Hero et al evaluated letrozole in 31 males with ISS and found a statistically significant increase in predicted adult height (PAH) after 24 months of treatment. No adverse effects were found on bone mineralization during the study. However, in a follow-up cross-sectional study Hero et al evaluated whether letrozole was associated with detrimental skeletal effects in males with ISS - “mild vertebral body deformities were found in 5 of 11 (45%) letrozole-treated subjects” vs. none in the placebo group (p = 0.01). The investigators concluded that AI’s could “predispose to vertebral deformities, which probably reflect impaired vertebral body growth rather than impaired bone quality and compression fractures.” Based on these findings, the investigators recommended that if AI’s are used in growth disorders, there should be a “follow-up of vertebral morphology.”

Of note, a recent review article, notes that AIs offer “promise as an adjunct treatment of growth delay in pubertal patients [in ISS] if judiciously used for a window of time.” However, the author also notes that safety issues regarding bone health also require further study.

So, the bottom line is whether individual organizations will find the scope of existing data meeting their criteria for adequate/substantial evidence in order to effectively make coverage determination decisions.

Additional sources:
Maurus N. Strategies for maximizing growth in puberty in children with short stature. Endocrinol Metab Clin North Am. 2009 Sep;38(3):613-24. [Pubmed abstract]

Carel JC et al. Consensus Statement on the Use of Gonadotropin-Releasing Hormone Analogs in Children. Pediatrics. 2009 Apr;123(4): e752-e762 [full text]

Hero M et al. Impact of aromatase inhibitor therapy on bone turnover, cortical bone growth and vertebral morphology in pre- and peripubertal boys with idiopathic short stature. Horm Res. 2009;71(5):290-7. Epub 2009 Apr 1. [Pubmed abstract]

Hero M, Norjavaara E, Dunkel L. Inhibition of estrogen biosynthesis with a potent aromatase inhibitor increases predicted adult height in boys with idiopathic short stature: a randomized controlled trial. J Clin Endocrinol Metab 2005;90: 6396–402. [full-text]