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Dosing of Growth Hormone Therapy According to IGF Levels« Back to Volume 24, Issue 1, May 2008 - Table of Contents Cohen and colleagues conducted a 2-year, open-label, randomized, insulin-like growth factor (IGF)-I concentration-controlled trial, administering varying doses of growth hormone (GH) to test whether IGF-I levels achieved during GH therapy are determinants of the growth responses to GH treatment. The 172 subjects (77% male) were pre-pubertal children (mean age 7.53 years) with short stature (mean height SDS –2.64, mean IGF-I SDS –3.56). Subjects were randomized to receive GH treatment following one of 3 regimens: (1) conventional GH dosing based on the patient’s weight (40 mcg/kg/d, n=34); (2) regularly adjusted GH doses to achieve an IGF-I SDS of –0.5 to +0.5 (IGF(low) group, n=70) or; (3) regularly adjusted GH doses to achieve an IGF-I SDS of +1.5 to +2.5 (IGF(high) group, n=68). Groups did not differ significantly on demographic or baseline variables such as height, IGF-I levels, peak GH, or bone age. Baseline data collected included concomitant illness and medications, physical examination, funduscopy, height, weight, determination of IGF-I, pubertal staging, checks for scoliosis and slipped capital femoral epiphysis (SCFE), blood sampling, and urinalysis. Study visits occurred at months 0, 1, 3, and every 3 months thereafter until 2 years. Adverse event reporting, height, weight, IGF-I, funduscopy, vital signs, and physical examinations for scoliosis and SCFE were conducted at all repeat visits. Laboratory evaluations performed at baseline were repeated annually, and bone age x-rays were obtained at baseline and year 2. Analysis of covariance was used to test for treatment effects, using baseline height-SDS (HT-SDS) as a covariate. Of the 172 enrolled participants, 147 completed the study. An intent-to-treat statistical analysis was performed including all randomized patients who received GH and at least one post-baseline height and IGF-I assessment. Dosage and Growth. All 3 treatment groups demonstrated increased HT-SDS scores at the end of the study (median of 24 months), with the IGF(high) group showing the greatest increase (1.58 SDS) compared with the IGF(low) group (1.08 SDS) and the conventional dosing group (1.00 SDS). Annualized growth velocities for the IGF(low), IGF(high), and conventional groups were 9.71, 11.20, and 9.01 cm/year at 12 months, and 8.38, 10.03, and 8.16 cm/year at 24 months, respectively. Mean IGF-I SDS showed a rapid increase in all 3 groups during the first month after initiation of GH treatment; the target IGF-I values were generally reached within 6 to 9 months. The IGF(high) group had a target IGF-I SDS value of 2.0 (1.5–2.5) and the IGF(low) 0 (–0.5 to 0.5). IGF-I SDS values for the IGF(high) group were significantly higher than for the IGF(low) and the conventional groups from 6 months onward; no differences were found between mean IGF-I SDS for IGF(low) and conventional groups. Mean daily GH doses for the 3 treatment groups were 110 (median 98, range 20 to 346) mcg/kg/day for the IGF(high) group, 33 (median 28, range 9 to 114) mcg/kg/d for the IGF(low) group, and 41 (median 41, range 34 to 45) mcg/kg/day for the weight-based GH dosing comparison group. The IGF(high) group received a substantially larger mean GH dose than the other 2 groups, but no significant differences in the mean dose between the IGF(low) group and the comparison group were found. For all participants, the change in HT-SDS from baseline was positively correlated with both the IGF-I SDS change from baseline and with the cumulative GH dose. Multivariate analysis revealed that height outcome was significantly related to treatment group (accounting for 42% of the variance), inversely related to baseline peak GH level (39%), and inversely related to baseline IGF-I SDS (15%). Safety. Over the 2-years, treatment-emergent adverse events were reported in 95.7% of participants in the IGF(low) group, 86.6% of patients in the IGF(high) group, and 82.4% in the conventional treatment group; most commonly, upper respiratory tract infection, headache, fever, coughing, and injection site hematomas. There was no occurrence of intracranial hypertension or malignancy. There was one case of SCFE in the IGF(high) group and 11 cases of worsening scoliosis (3 in the conventional, 4 in the IGF(low) group, and 4 in the IGF(high) group). Change in fasting serum insulin levels from baseline in the IGF(high) group was significantly greater than in the other groups, although mean serum insulin remained within the normal range for all groups. Bone age was delayed by approximately 2 years in all 3 groups at baseline, and after 2 years of treatment, bone age showed an increase of 2.45 to 2.82 years with no differences identified among the 3 groups. The authors concluded that the IGF(high) group, titrated to the upper portion of the normal range, demonstrated significantly greater height gains than the IGF(low) and conventional groups. Expressed in height benefit, the IGF(high) group gained approximately 3 cm more in height than the comparison groups after 24 months of GH treatment. The study lacked sufficient power to detect the safety of IGF-based dosing in terms of rare side effects. No information regarding the long-term safety of such a regimen, especially in terms of cancer risk, was provided. Cohen P, Rogol AD, Howard CP, Bright GM, Kappelgaard AM, Rosenfeld RG; American Norditropin Study Group.. Insulin growth factor-based dosing of growth hormone therapy in children: A randomized, controlled study. J Clin Endocrinol Metab. 2007;92:2480-6. Editor’s CommentThis study provides evidence for the feasibility of IGF-based GH dose titration; however, the increased height gains compared to the conventional treatment dosing were only significant for the IGF(high) group. The authors were circumspect by restricting interpretation of the findings to a demonstration of the feasibility of IGF-I GH dose titration and not as a recommendation for clinical practice. Important considerations to explore before implementing such a strategy in regular practice include: (1) GH doses administered to this group were as high as 346 mcg/kg/day (mean 110), compared to the mean conventional weight-based dose of 41 mcg/kg/day; this represents as high as a 9-fold increase compared to previously studied values; (2) given the lack of safety data beyond the length of 2-year study, movement toward increasing GH above the conventional dosing should be discouraged. An editorial by Baron accompanying this paper stressed that the principle of primum non nocere dictates that weight-based dosing remain the standard of care.1 Although there is a dearth of information to inform us about the possible negative side effects that may be associated with prolonged treatment with high doses of GH, there is certainly a theoretical basis for concern. A growing body of epidemiological data suggests that high levels of circulating IGF-I constitute a risk factor for the development of breast, prostate, colon, and lung cancer.2 This study by Cohen and colleagues demonstrated a height gain of 3 cm for the IGF(high) group compared to the IGF(low) and conventional weight-based dosing groups. Even if the substantial excess cost of the additional GH administration of higher dosages is not considered, does the potential (not guarantee) for taller adult height justify potentially increasing a child’s risk of developing cancer? Baron reminds the reader that “risk must be weighed against benefit” and states that “although short stature may be quite unpleasant for some individuals and carry social disadvantages, it generally does not cause death, serious physical dysfunction, or probably even serious psychological dysfunction.”1 This opinion is grounded in empirical evidence.3 Baron also encourages careful evaluation of the etiology of short stature before prescribing a costly and invasive procedure to which greater than 80% of children experienced some adverse side effects. Although Cohen et al used GH therapy in children with GH deficiency as well as in children with other categories of non-GH deficient short stature, the situation may be more complex and different among the various types of patients. As an example, it is well known that decreased IGF-I levels reflect nutritnal status, not necessarily GH deficits,4 yet no attempts were made to distinguish patients who may have had nutritional growth retardation, nor were the body weights of the patients defined. It has been shown that a subgroup of children with idiopathic short stature show decreased weight for height,5 which is not typical of GH deficiency, suggesting their decreased growth and IGF-I may reflect insufficient nutrition. In such cases, lifestyle and dietary changes would be a more expedient, safer, and cost-effective treatment for the child.6 David E. Sandberg, PhD References - (linked to
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Volume 25 Number 1
June 2009
www.GGHjournal.com
ISSN 1932-9032
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