Twice-daily IGF-I increased first-year height velocity in prepubertal children

Prepubertal children with short stature, low insulin-like growth factor I and normal growth hormone levels assigned to twice-daily insulin-like growth factor I experienced significant age- and dose-dependent increases in first-year height velocity and height standard deviation scores.

A one-year, open-label, observation-controlled, dose comparison trial was conducted to examine the effects of recombinant human IGF-I treatment (mecasermin) on short, prepubertal children aged 3 to 12 years. Researchers randomly assigned 136 children to three weight-based groups in a primary efficacy analysis: 80 mcg/kg (n=44), 120 mcg/kg (n=51) or untreated (n=25).

All children included in the study had an IGF-I SD score <–2, GH levels >7 ng/mL and normal nutritional history and thyroid function tests.

The researchers reported significant increases in first-year height velocity for children assigned to IGF-I 80 mcg/kg (7 cm per year) and 120 mcg/kg (7.9 cm per year) compared with the untreated group (5.2 cm per year; P<.0001). First-year height velocities were also increased for the 120 mcg/kg group vs. the 80 mcg/kg group (P=.0002).

“The most important predictors of first-year height velocity were age at baseline and dose,” the researchers wrote.

First-year height velocity was inversely related to age (P=.0003) and was not predicted by covariates such as sex, baseline height SD score or IGF-I SD score, antibody status, stimulated GH levels or IGF-I levels after an IGF-I generation test.

At one year, the mean changes in height SD score for the 80-mcg/kg (0.4) and 120-mcg/kg groups (0.5) were greater compared with the untreated group (0.02; P<.0001).

The mean change in bone age was similar between the 80 mcg/kg group (1.1 year) and 120 mcg/kg group (1.2 year) compared with the untreated group (0.8 year).

BMI SD score remained unchanged in the 80 mcg/kg group after one year, increased in the 120 mcg/kg group (0.3) and decreased in the untreated group (–0.3).

Thirteen children (12 treated and one untreated) entered puberty during the study; pubertal development occurred at appropriate ages in all children except one.

More than 90% of children reported at least one adverse event during the study. The most commonly reported adverse events associated with treatment included gastroenteritis (23% vs. 0%), headache (38% vs. 16%), vomiting (25% vs. 4%) and hypoglycemia (14% vs. 8%) compared with untreated patients. According to the researchers, “adverse events during treatment were less common than in previous studies and were generally transient, easily managed and without known sequelae.

“It is premature to state whether or not rhIGF-I treatment may alter adult height,” the researchers concluded. “A long-term extension trial is currently under way, which may provide some insight on this issue.”

Implications of off-label use

In an accompanying editorial, Arlan L. Rosenbloom, MD,of the department of pediatrics at University of Florida College of Medicine, and Scott A. Rivkees, MD, associate chair of pediatric research and director of the Yale Child Health Research Center, discussed the controversial, off-label use of IGF-I in children.

“The data provided by Midyett et al reinforce doubts about the concept of IGF-I deficiency due to partial GH resistance accounting for a substantial proportion of idiopathic short stature, the efficacy of treatment with rhIGF-I with its suppression of GH in children who are not GH resistant and safety of rhIGF-I,” they wrote.

Further, “the absence of evidence for GH insensitivity and for the diagnosis of IGF-I deficiency in children with ISS who have low IGF-I levels, the dubious efficacy of rhIGF-I in promoting growth in ISS, and the worrisome safety profile indicate that rhIGF-I use for growth promotion in children with ISS is not justified.” – by Matthew Brannon

Midyett LK. J Clin Endocrinol Metab. 2010;95:611-619.

Rosenbloom AL. J Clin Endocrinol Metab. 2010;95:505-508.

The paper by Midyett et al and the editorial by Rosenbloom and Rivkees summarized in this issue of Endocrine Today are emblematic of a major and still ongoing debate in pediatric endocrinology: Should all short but otherwise normal children, i.e. those with ISS, be treated with agents that enhance growth? If so, what is the best and safest agent to use in this condition? Do a subset of children with ISS who have normal GH secretion as currently defined but 'low' IGF-I levels based on current norms have IGF-I deficiency? If so, should this subset be treated with IGF-I, currently approved only for entities with IGF-I deficiency as a result of defects in the GH receptor signaling cascade or the IGF-I gene itself?

The paper demonstrates some benefit in enhancing growth with one year's treatment at a substantial cost of adverse events; an essential control group treated with GH only, the current 'gold standard,' is not included in this study. The editorial argues that IGF-I deficiency, as defined in this paper, is not a valid diagnostic entity and that IGF-I treatment is fraught with short- and long-term complications, whereas GH treatment is effective in most children with ISS. Only the results of well-designed, scientifically rigorous studies will, in time, resolve these issues.

- Mark A. Sperling, MD

Endocrine Today Editorial Board member