Attaining genetic height potential: Analysis of height outcomes from the ANSWER Program in children treated with growth hormone over 5 years
Introduction
Recombinant human growth hormone (GH) is an effective growth-promoting therapy for children with short stature or growth failure due to a number of conditions causing either a deficiency of, or lack of responsiveness to, endogenous growth hormone. The US Food and Drug Administration has approved the use of GH replacement therapy for the treatment of children with growth hormone deficiency (GHD), which includes patients with isolated growth hormone deficiency (IGHD) and multiple pituitary hormone deficiency (MPHD); children born small for gestational age (SGA); children with short stature or growth failure associated with Turner syndrome (TS) or Noonan syndrome (NS); and children with idiopathic short stature (ISS), Prader–Willi syndrome, chronic kidney disease (CKD), or short stature homeobox (SHOX) gene haploinsufficiency [1].
Recombinant GH treatment improves short-term linear growth and adult height achieved in children with various disorders associated with short stature or growth failure; however, clinical studies have shown that treatment outcomes can be highly variable [1], [2], [3], [4]. Attainment of target height is an important treatment goal for GH therapy in children with growth disorders because of the positive benefits it has on health-related quality of life and on physical and psychosocial well-being [5], [6], [7], [8]. Analyses of large data sets from pediatric patient registries have consistently demonstrated that early initiation and longer duration of prepubertal GH treatment are significantly correlated with greater gains in height standard deviation score (HSDS) and achievement of HSDS consistent with the genetic height potential for children with IGHD, MPHD, and other causes of growth failure or short stature [3], [9], [10], [11], [12], [13], [14], [15], [16].
Norditropin® [somatropin (recombinant DNA origin) injection, Novo Nordisk A/S, Bagsvaerd, Denmark], hereafter referred to as GH, has been approved for the treatment of children with growth failure due to growth hormone deficiency (IGHD or MPHD) or with short stature associated with NS, TS, or SGA with no catch-up growth by 2 to 4 years of age; it has also been approved for the treatment of adults with adult- or childhood-onset GHD [17]. The American Norditropin Studies: Web-enabled Research (ANSWER) Program is a noninterventional, observational study to evaluate the long-term effectiveness and safety of Norditropin® in patients with growth disorders [18]. The ANSWER Program (utilizing NovoNet®, the Novo Nordisk Web-based research platform) also evaluates factors predictive of patient response to GH treatment. Data from the ANSWER Program have shown that children with IGHD, MPHD, ISS, TS, NS, or SGA exhibit increases from baseline height in HSDS (ΔHSDS) following 2 years of GH treatment [18], [19], [20]. Similar results have been reported in other registries, including the National Cooperative Growth Study (NCGS), the Pfizer International Growth Study (formerly Kabi International Growth Study [KIGS]), and the NordiNet® International Outcome Study (IOS) [21], [22]. Factors identified as positively correlated with ΔHSDS over 2 years of GH treatment in patients with GHD were height velocity (HV) after 4 months of treatment and pre-treatment body mass index (BMI) SDS. In contrast, age, HSDS, and serum insulin-like growth factor-I (IGF-I) SDS at baseline were negatively correlated with ΔHSDS, while no consistent effect of gender was observed [19], [23]. However, in the joint analysis of the IOS and ANSWER Program studies, gender was shown to have an effect on growth in prepubertal patients with GHD or SGA (significantly greater ∆HSDS was reported in boys compared with girls) [24].
The principal aim of the current analysis of data from the ANSWER Program was to evaluate the long-term effects of GH treatment in achieving genetic height potential in previously untreated pediatric patients with IGHD, MPHD, SGA, or ISS. Height outcomes were determined by auxologic assessment and by calculation of HSDS and corrected HSDS from baseline through year 5 of GH treatment. The expectation is that patients from all diagnostic groups will have shown improvement in HSDS and have attained corrected HSDS consistent with their genetic height potential.
Section snippets
Study design
The ANSWER Program is an ongoing observational study initiated in 2002 that has collected long-term effectiveness and safety information on more than 13,000 pediatric patients treated with Norditropin® [18]. Physicians participating in the ANSWER Program provide updated patient histories and physical examination data utilizing NovoNet®. Patients were enrolled in the study at the discretion of the participating physician investigators. Patients or their parents or guardians provided informed
Patient demographics and characteristics at baseline
A total of 4297 children who were GH-naïve with IGHD ( N= 2884), MPHD ( N= 200), SGA ( N= 481), and ISS ( N= 732) were included in the analysis. Demographics and baseline characteristics for each diagnostic patient cohort are presented in Table 1.
At baseline (Table 1), the lowest mean peak serum GH concentration (ng/mL) in response to stimulation was observed in patients with IGHD (6.0 ± 2.6, n = 2106) or MPHD (4.1 ± 3.8, n = 96) compared with patients with SGA (14.9 ± 10.0, n = 146) and ISS (17.6 ± 9.8, n = 486).
Discussion
Results of the current analyses have shown that continued GH treatment for up to 5 years provided positive effects on height and other measures of auxologic assessment in children who were GH-naïve with IGHD, MPHD, SGA, and ISS. Long-term GH therapy resulted in significant increases in mean HSDS and corrected HSDS from baseline to year 5. In addition, the increase in corrected HSDS indicated that the growth response to long-term (5 year) GH treatment approached the genetic height potential for
Conclusions
In conclusion, long-term GH therapy over 5 years was associated with increases in mean HSDS in previously untreated pediatric patients with IGHD, MPHD, ISS, or SGA. Additionally, GH treatment was associated with HSDS approaching genetic height potential based on patient target heights, with a statistically significant increase over time in corrected HSDS observed in patients across all diagnostic groups. Total height gains, however, will need to be evaluated at the attainment of final height.
Conflicts of interests
Judith L. Ross, MD is a consultant for Novo Nordisk and Eli Lilly and receives research support from Novo Nordisk and Eli Lilly.
Peter A. Lee, MD, PhD is a consultant for Novo Nordisk, Abbvie, and Ipsen and receives research support from Pfizer, Novo Nordisk, Eli Lilly, Tercica, and Abbvie.
Robert Gut, MD, PhD is an employee of Novo Nordisk, Inc., Princeton, NJ, USA.
John Germak, MD is an employee of Novo Nordisk, Inc., Princeton, NJ, USA.
Acknowledgments
Editorial and writing assistance were provided by Jeffrey M. Palmer, PhD, ETHOS Health Communications, Newtown, Pennsylvania, with financial assistance from Novo Nordisk Inc., Princeton, New Jersey, in compliance with international guidelines on Good Publication Practice. The ANSWER Program was sponsored by Novo Nordisk Inc., Plainsboro, New Jersey.
References (48)
rhGH safety and efficacy update
Adv. Pediatr.
(2011)- et al.
Clinical longitudinal standards for height and height velocity for North American children
J. Pediatr.
(1985) - et al.
Spontaneous growth hormone secretion and IGF1:IGFBP3 molar ratios in children born small for gestational age (SGA)
Growth Hormon. IGF Res.
(2004) - et al.
Management and interpretation of heterogeneous observational data: using insulin-like growth factor-I data from the NordiNet(R) International Outcome Study
Growth Hormon. IGF Res.
(2015) - et al.
Current indications for growth hormone therapy for children and adolescents
Endocr. Dev.
(2010) - et al.
Adult height in children with growth hormone deficiency: a randomized, controlled, growth hormone dose–response trial
Horm. Res. Paediatr.
(2010) - et al.
Dose-dependent effect of growth hormone on final height in children with short stature without growth hormone deficiency
J. Clin. Endocrinol. Metab.
(2008) - et al.
Growth response, near-adult height, and patterns of growth and puberty in patients with Noonan syndrome treated with growth hormone
J. Clin. Endocrinol. Metab.
(2009) - et al.
Adult height and health-related quality of life after growth hormone therapy in small for gestational age subjects
J. Med. Econ.
(2010) - et al.
Impact of growth hormone therapy on adult height of children with idiopathic short stature: systematic review
BMJ
(2011)
Quality of life in children and adolescents with growth hormone deficiency: association with growth hormone treatment
Horm. Res. Paediatr.
Psychological adaptation in children with idiopathic short stature treated with growth hormone or placebo
J. Clin. Endocrinol. Metab.
Adult height after long term treatment with recombinant growth hormone for idiopathic isolated growth hormone deficiency: observational follow up study of the French population based registry
BMJ
Recombinant human growth hormone for children born small for gestational age: meta-analysis confirms the consistent dose–effect relationship on catch-up growth
J. Endocrinol. Investig.
Efficacy and safety results of long-term growth hormone treatment of idiopathic short stature
J. Clin. Endocrinol. Metab.
Growth hormone (GH) dosing during catch-up growth guided by individual responsiveness decreases growth response variability in prepubertal children with GH deficiency or idiopathic short stature
J. Clin. Endocrinol. Metab.
Long-term outcome of growth hormone therapy in children and adolescents
Treat. Endocrinol.
Observed and predicted growth responses in prepubertal children with growth disorders: guidance of growth hormone treatment by empirical variables
J. Clin. Endocrinol. Metab.
Effect of growth hormone (GH) treatment on the near-final height of 1258 patients with idiopathic GH deficiency: analysis of a large international database
J. Clin. Endocrinol. Metab.
Consensus Guidelines for the Diagnosis and Treatment of Growth Hormone (GH) Deficiency in Childhood and Adolescence: Summary Statement of the GH Research Society
J. Clin. Endocrinol. Metab.
Norditropin Cartridges [Somatropin (rDNA Origin) Injection] for Subcutaneous Use [Prescribing Information]
The NordiNet(R) International Outcome Study and NovoNet(R) ANSWER Program(R): rationale, design, and methodology of two international pharmacoepidemiological registry-based studies monitoring long-term clinical and safety outcomes of growth hormone therapy (Norditropin(R))
Clin. Epidemiol.
Factors influencing the one- and two-year growth response in children treated with growth hormone: analysis from an observational study
Int. J. Pediatr. Endocrinol.
Impact of age and duration of growth hormone therapy in children with Turner syndrome
Horm. Res. Paediatr.
Cited by (27)
A genetic approach to evaluation of short stature of undetermined cause
2018, The Lancet Diabetes and EndocrinologyCitation Excerpt :Another study58 identified six pathological NPR2 mutations in a cohort of 95 patients with idiopathic short stature and 173 patients with suspected Leri-Weill dyschondrosteosis (all with no known defect in SHOX/PAR1).58 Given the role of the growth hormone–IGF axis in growth and the finding of low IGF-1 in patients with idiopathic short stature,27,28 several studies have sought mutations in genes encoding components of this axis in undiagnosed patients with short stature. An increased frequency of mutations in children with short stature compared to controls has been found for the growth hormone secretagogue receptor GHSR,59 IGF1,60,61 IGFALS,62 and IGF1R.31
Skeletal effects of growth hormone and insulin-like growth factor-I therapy
2016, Molecular and Cellular EndocrinologyCitation Excerpt :Thus, treatment with GH or IGF-I is a logical therapy for children with such conditions. In fact, long-term administration of GH in children with GH-deficient conditions including isolated GH deficiency and multiple pituitary hormone deficiency significantly improved age-adjusted height in a manner consistent with growth approaching the children's genetic height potential (Ross et al., 2015). GH has even been effectively used to promote growth in children without proven GH deficiencies, born small for gestational age or with idiopathic short stature.
Postnatal management of growth failure in children born small for gestational age
2019, Jornal de PediatriaCitation Excerpt :In a systematic review, Maiorana and Cianfarani found that final height of adults born SGA treated with GH was significantly higher than that of the untreated individuals, exceeding by 0.9 SDS, with a mean height gain of 1.5 SDS.63 Similar results were showed by Ross et al.64 and Tanaka et al.41 Less intense gains in adult height have been reported in individuals with SRS compared with non-syndromic subjects born SGA (−2.17 vs. −1.65 SDS, p = 0.002),65 and few reports have shown no beneficial effect of GH treatment in adult height.66 Long-term GH therapy for SGA children is safe and well tolerated.41,43
Efficacy and safety of recombinant human growth hormone in treating Chinese children with idiopathic short stature
2018, Growth Hormone and IGF ResearchCitation Excerpt :This suggests that rhGH treatment has a slight effect on BMI. Previous studies have revealed that a high dose of rhGH may lead to advanced bone age [19,20]. In the samples of the present study, it was revealed that short-term treatment (within one year of treatment) and bone age was equal to the chronological age, while after two years or more of treatment, the growth of bone age accelerated in 23 children (17%) and the annual growth rate of bone age was >2 years (ΔBA > 2 years), even this remained less than CA.
A Superlong-Acting Growth Hormone-Polypeptide Fusion for Growth Hormone Deficiency Treatment
2024, Advanced Healthcare Materials