GH Dose Reduction Maintains Normal Prepubertal Height Velocity After Initial Catch-Up Growth in Short Children

Ralph Decker; Kerstin Albertsson-Wikland; Berit Kriström; Maria Halldin; Jan Gustafsson; Nils-Östen Nilsson; Jovanna Dahlgren

Disclosures

J Clin Endocrinol Metab. 2019;104(3):835-844. 

In This Article

Abstract and Introduction

Abstract

Context: GH responsiveness guides GH dosing during the catch-up growth (CUG) period; however, little is known regarding GH dosing during the prepubertal maintenance treatment period.

Objective: To evaluate whether SD score (SDS) channel parallel growth with normal height velocity can be maintained after CUG by reducing the GH dose by 50% in children receiving doses individualized according to estimated GH responsiveness during the catch-up period.

Design and Settings: Prepubertal children (n = 98; 72 boys) receiving GH during CUG (GH deficient, n = 33; non–GH deficient, n = 65), were randomized after 2 to 3 years to either a 50% reduced individualized dose (GHRID; n = 27; 20 boys) or unchanged individualized dose (GHUID; n = 38; 27 boys). Another 33 children (25 boys) continued a standard weight-based dose [43 μg/kg/d (GHFIX)].

Main Outcome Measures: The primary endpoint was the proportion of children with ΔheightSDS within ±0.3 at 1 year after GH dose reduction compared with two control groups: GHUIDand GHFIX. The hypothesis was that heightSDS could be maintained within ±0.3 with a reduced individualized GH dose.

Results: For the intention-to-treat population at 1 year, 85% of the GHRIDgroup maintained ΔheightSDS within ±0.3 vs 41% in the GHUIDgroup (P = 0.0055) and 48% in the GHFIXgroup (P = 0.0047). The ΔIGF-ISDS in the GHRID group was −0.75 ± 1.0 at 3 months (P = 0.003) and −0.72 ± 1.2 at 1 year compared with the GHUID group (0.15 ± 1.2; P = 0.005) and GHFIX group (0.05 ± 1.0; P = 0.02).

Conclusions: Channel parallel growth (i.e., normal height velocity) and IGF-ISDS levels within ±2 were maintained after completed CUG using a 50% lower individualized dose than that used during the CUG period.

Introduction

Recombinant human GH is used to normalize height and body composition in short children, irrespective of GH secretion capacity. Both children with short stature owing to GH deficiency (GHD) and those with short stature not related to low GH secretion [i.e., born appropriate for gestational age with idiopathic short stature (ISS) or born small for gestational age (SGA)] are reported to benefit from GH treatment.[1–6] The growth response in both groups of children is GH dose-dependent.[3,4] However, on average, children with ISS or SGA will require higher GH doses than children with GHD to achieve the same growth response.[1] This indicates reduced GH responsiveness in the former groups, although considerable overlap exists among individuals.[1,2,7]

It is well-known that the responsiveness to GH varies among individuals, even among those with the same diagnosis.[8] Models and algorithms that predict the individual growth response from the start of treatment using readily observable pretreatment auxological and biochemical variables have been constructed and validated, making it possible to estimate individual GH responsiveness according to the predicted growth response associated with a particular GH dose.[1,9–11] The magnitude of the first-year growth response in relation to dose is a reliable sign of GH responsiveness,[8] with greater growth indicating greater responsiveness. However, as yet, no method is available to estimate individual GH responsiveness during the prepubertal maintenance treatment period. Considering that GH is often given to short children for a prolonged period, the ultimate goal would be to use the lowest effective dose for the individual after achieving complete catch-up growth (CUG) (i.e., during the maintenance growth part to maintain sufficient growth and ensure appropriate effects on metabolism, cognition, and psychological function).[2,12,13] Growth response is related to the age of the child; the younger the child at the start of treatment, the greater the response.[9–11,14] The first-year growth response is especially important considering that the magnitude of response decreases with subsequent years of treatment (known as the GH fading effect on growth). In the optimal situation, 2 to 3 years of CUG should be attained during midchildhood,[1,15,16] before the last part of the prepubertal childhood growth phase, because, during the latter, GH secretion is reduced compared with the earlier prepubertal phase.

In a previous clinical trial focusing on CUG in GH-deficient and non–GH-deficient prepubertal children, the goal of a predefined height SD score (heightSDS) close to the midparental height SDS (MPHSDS) was achieved by individualized GH dosing according to the estimated GH responsiveness and distance to MPHSDS for each individual child.[1] MPHSDS was selected as our treatment target in the CUG study for calculation of the estimated biological GH dose for each individual. By tailoring the GH dose from the treatment start during the CUG period, it is implicit that the children who were predicted to respond poorly (i.e., were estimated to have low GH responsiveness calculated using our model for the prediction of growth response to GH treatment) received higher GH doses than those predicted to be highly responsive.[1] By applying this compensation for different GH responsiveness, GH-deficient and non–GH-deficient children could both be included in the present study. However, it was apparent that this GH dose was likely to be unnecessarily high for some children during the maintenance treatment growth period; therefore, a dose-reduction trial was performed.

The aim of the present randomized trial, in which the same study group was followed up as in the previous catch-up trial,[1] was to investigate whether a reduced individualized GH dose could be used to maintain channel parallel growth. This meant following the achieved prepubertal heightSDS goal close to the MPHSDS,[17,18] after a 50% reduction in individualized GH dose once CUG had been achieved to neither overtreat the child with GH nor lose the height that had been attained during the CUG period. The hypothesis was that, after CUG, channel parallel growth with normal height velocity (defined as growth within ±0.3 ΔheightSDS) could be maintained using a 50% lower dose than that used during the CUG period. This could be evidenced based on a greater proportion of children maintaining channel parallel growth, despite randomization to the reduced dose compared with those continuing with the previous individualized dose.

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