Impact of growth hormone therapy on bone and body composition in prepubertal children with idiopathic short stature

Introduction

Growth hormone (GH) therapy is widely recognized for its primary role in promoting linear growth in children with growth hormone deficiencies [1], 2]. However, beyond its effects on height, GH has significant metabolic effects, influencing body composition and bone metabolism [3], 4]. These effects include promoting bone formation, reducing fat mass, and enhancing lean body mass (LBM), which are crucial for pediatric growth and development [5], 6].

Previous studies have reported that GH therapy increases bone density in children with growth hormone deficiency (GHD) [7]. Children with GHD often exhibit reduced bone mineral density (BMD) due to the essential role of GH in bone remodeling and mineralization [7], 8]. However, the effects of GH treatment on bone density and body composition in children with idiopathic short stature (ISS) remain underexplored [9], [10], [11], [12]. Unlike GHD, ISS is a heterogeneous condition without an identifiable cause, and the metabolic effects of GH in this population are not well-documented. Some studies have suggested that children with ISS may have reduced bone mineral density (BMD), underscoring the need for thorough bone health assessment in this population [11], 12]. Given the established role of GH in bone metabolism, its potential impact on bone health in ISS warrants further investigation.

This study aimed to investigate the effects of GH therapy on BMD and body composition in prepubertal children with ISS. Specifically, it compared the BMD and body composition in children with ISS and healthy controls and evaluated changes after 1 year of GH treatment.

Subjects and methods

Participants and study design

Participants included prepubertal children aged ≥4 years diagnosed with ISS between January 2010 and December 2023 at Ajou University Hospital. For ISS diagnosis, all of the following widely accepted conditions were required to be met: (i) height ≤3rd percentile for age and sex; and (ii) peak GH levels >7 ng/mL in response to at least two GH stimulation tests (clonidine, insulin, or levodopa) [13], 14]. Children with GH deficiency or other organic causes of short stature, such as genetic syndromes and small for gestational age, were excluded. Patients exhibiting signs of puberty were also excluded. The control group consisted of 20 healthy prepubertal children matched for age, sex, and body mass index (BMI). They had no growth-related diseases but voluntarily underwent growth evaluation, including DXA scanning, after receiving sufficient explanation and providing written informed consent.

Baseline data, including height, weight, bone age, insulin, serum glucose, lipid profile, and insulin-like growth factor 1 (IGF-1) levels, were collected from clinical charts. Height was measured using a Harpenden stadiometer (Holtain, Crosswell, Crymych, UK) and weight was measured using a digital scale. BMI was calculated as weight in kilograms divided by the square of the height in meters. The standard deviation scores (SDS) for height, weight, and BMI were based on the 2017 Korean National Growth Charts [15]. Pubertal status was assessed using the Tanner and Marshall method for genital development in male children and breast development in female children [16]. Insulin resistance was assessed using the homeostasis model assessment of insulin resistance (HOMA-IR). HOMA-IR was calculated using the formula: fasting insulin (μU/mL) × fasting glucose (mmol/L)/22.5.

Of the 53 participants, 11 underwent GH treatment for 1 year and remained in the prepubertal stage after GH treatment. The mean GH dose was 0.23 mg/kg/week. Height, weight, bone age, IGF-1 levels, bone density, and body composition were assessed after 1 year of GH treatment. The process of participant selection, including inclusion and exclusion criteria, is illustrated in Figure 1.

Figure 1:

Flowchart of inclusion and exclusion criteria in a retrospective study. DXA, dual-energy X-ray absorptiometry; GH, growth hormone; BMI, body mass index; GHD, growth hormone deficiency; NS, Noonan syndrome; PWS, Prader–Willi syndrome; TS, Turner syndrome.

Results

The baseline characteristics of the ISS group and healthy controls are summarized in Table 1. At baseline, the ISS group exhibited significantly lower height and weight Z-scores than control group did (p<0.001). Sex distribution and the BMI SDS were not significantly different between the two groups.

The BMAD Z-scores were significantly lower in the ISS group (p=0.004), with lower BMC and LBM (p<0.001 for both), compared with the control group (Table 2). However, the BMD Z-scores for LS and FN, adjusted for age, sex, height, and the BMI SDS, did not significantly differ between the patients and healthy controls.

After 1 year of GH treatment, significant improvements in body composition were observed. No significant changes in the height-adjusted BMD (BMD_ht) Z-scores for LS or FN were observed after 1 year of GH treatment (p=0.664 and p=0.710, respectively) nor were significant improvements in the BMAD Z-scores detected (p=0.568) (Figure 2). However, LBM Z-scores increased significantly from −4.37 ± 0.6 to −2.11 ± 0.7 (p=0.003), whereas fat mass Z-scores showed a trend toward reduction (from 0.35 ± 0.2 to −0.55 ± 0.3 kg, p=0.025) (Figure 3). Body fat percentage also significantly decreased, from 18.4 ± 3.1 % to 14.7 ± 10.8 % (p=0.012). Additionally, insulin resistance (HOMA-IR) significantly increased after 1 year of GH treatment. Lipid profiles – including total cholesterol, low- and high-density lipoprotein cholesterol, and triglycerides – did not differ significantly between baseline and 1 year after GH treatment (Table 3).

Figure 2:

Changes in parameters of bone mineral density for chronological age. BMD, bone mineral density; BMAD, bone mineral apparent density; LS, lumbar spine; FN, femur neck.

Figure 3:

Changes in parameters of body composition for chronological age. BMC, bone mineral content; LBM, lean body mass; FM, fat mass.

Discussion

In this study, the BMAD of the LS in prepubertal children with ISS was significantly lower than that in healthy controls. Furthermore, body composition parameters, including BMC, LBM, and fat mass, were all reduced in the ISS group. After 1 year of GH therapy, body composition improved significantly, with increased LBM and reduced fat mass. However, no significant changes in the BMD_ht at the LS or FN or BMAD were detected.

To date, studies evaluating bone density or the outcomes of GH therapy in patients with ISS remain limited. Lanes et al. [11] reported that, in 16 patients with ISS who exhibited decreased LS BMD before GH therapy, the BMD improved to levels comparable to those in healthy controls after 3 years of treatment. However, Ogle et al. [20] demonstrated that the bone density measured at L2–L4 showed a non-significant increase after 6 months of GH treatment in patients with short stature without GH deficiency. Another study by Hogler et al. [10] reported reduced volumetric BMD at the LS in prepubertal children with ISS compared with healthy controls, with no significant change observed after 2 years of GH therapy, consistent with our findings. These results suggest that the effects of GH on skeletal mineralization during short-term treatment are limited. This may reflect the body’s prioritization of growth and muscle accretion over changes in bone density [5]​.

GH plays a crucial role in bone density by stimulating IGF-1 production, which enhances osteoblast proliferation, promotes collagen synthesis, facilitates bone matrix mineralization, and modulates bone resorption, thereby increasing bone mass and strength [21], 22]. GH also regulates calcium and phosphate metabolism, which are essential for bone mineralization [23]. Through these mechanisms, GH therapy is expected to improve bone density not only in patients with GHD but also in those with ISS. However, it is essential to consider that the effects of GH on bone density might become more evident with prolonged treatment durations.

Although the exact mechanism underlying reduced bone density in prepubertal children with ISS is not well understood, accumulating clinical reports suggest that these children may be at increased risk of low BMD [10]. One hypothesis is that, despite normal GH secretion, some ISS patients may exhibit subtle impairments in GH signaling or IGF-1 generation, raising the possibility of a partial GH resistance phenotype that could contribute to reduced bone formation by impairing IGF-1-mediated osteoblast activation and subsequent bone matrix synthesis [11], 24].

Another possible explanation is that short stature is commonly associated with smaller bone size, which may reduce mechanical loading on the skeleton and contribute to lower BMD [25]. However, smaller bone size can also lead to lower areal BMD measurements due to the two-dimensional nature of DEXA assessments, making it difficult to distinguish true reductions in bone density from size-related measurement artifacts. The BMAD and height-adjusted BMD partially mitigate the confounding effects of short stature; however, they are not consistently effective across all age ranges [26]. Consequently, interpreting bone density in children with short stature remains challenging.

Although children with ISS are not traditionally classified as high risk for pediatric osteoporosis, assessing BMD in this population has important clinical relevance. Childhood and adolescence are critical periods for the acquisition of peak bone mass, a key predictor of long-term skeletal health. Inadequate bone accrual during this window has been associated with increased risks of osteoporosis and fractures in adulthood [27], 28]. Therefore, early assessment of BMD is important in patients with ISS to identify potential reductions in bone density and to support the maintenance of normal bone mineralization. In addition, decisions regarding GH therapy should not be based solely on linear growth potential but must also incorporate considerations of bone health.

In our study, body composition, including LBM, fat mass, and percent body fat, improved after 1 year of GH treatment in patients with ISS. Similar findings have been documented in other research. Hannon et al. [29] observed that short-term GH treatment in adolescents with ISS resulted in an increased LBM and fat reduction. Additionally, Decker et al. [9] demonstrated that, after 2 years of GH treatment, patients with ISS exhibited increased LBM and reduced fat mass. Among metabolic parameters, insulin resistance significantly increased after GH treatment, with higher insulin levels likely representing a physiological response to GH treatment [4]. Similar findings have been consistently reported in other large observational registries of GH treatment, such as the KIGS database and the NordiNet and ANSWER Program [2], [30], [31], [32].

This study has certain limitations that should be considered when interpreting the results. First, the sample size was relatively small, potentially limiting the statistical power to detect subtle effects of GH treatment on bone density and body composition. Larger studies with more participants are necessary to draw more robust conclusions about the impact of GH on bone health in children with ISS. In addition, the small number of GH-treated participants in this study may reflect financial barriers to GH therapy for ISS. Since GH treatment for ISS is often not covered by insurance in Korea, financial constraints may have contributed to the limited number of treated patients.

Second, bone turnover markers were not assessed in this study. These markers could have provided additional insights into the mechanisms of the effects of GH on bone metabolism and clarified the lack of significant changes in bone density despite improvements in body composition. Including biochemical markers of bone turnover, such as osteocalcin, alkaline phosphatase, and type I collagen markers, could have offered a more comprehensive evaluation of bone remodeling during GH therapy. Lastly, the duration of GH treatment in this study was relatively short, lasting only 1 year. As changes in bone density are typically gradual, longer follow-up periods may be required to observe the full effects of GH on bone mineralization. Despite these limitations, this study provides valuable insights into the effects of GH treatment on bone density and body composition in children with ISS. A notable strength of this research is its focus on ISS, a condition not extensively studied regarding bone health and body composition, particularly in the context of short-term GH therapy. Although numerous studies have investigated the effects of GH in GHD, research specifically addressing ISS is scarce. This study contributes to the understanding of ISS by offering clinical data on bone density and body composition in this patient population.

In conclusion, GH therapy in children with ISS improves body composition; however, its short-term effects on bone density are limited. Future studies, especially those with extended follow-up durations, are necessary to explore the role of GH in bone health further and clarify long-term skeletal outcomes in children with ISS.