ABSTRACT
Objective
Growth hormone deficiency (GHD) in children results in short stature and impaired bone health. While daily growth hormone (GH) injections are effective, they are associated with adherence challenges. Somatrogon, a long-acting, recombinant human GH (rhGH), allows weekly administration, potentially improving treatment compliance.
Methods
This retrospective cohort study included prepubertal children with GHD treated with weekly Somatrogon at Al Jalila Children’s Hospital, Dubai. Diagnosis was based on clinical, biochemical, and radiological criteria, including height standard deviation score (SDS) <-2.0, subnormal growth velocity, and subnormal peak GH in one stimulation test (<10 ng/mL), supported by low IGF-1 and/or abnormal cranial magnetic resonance imaging. Growth outcomes and bone health indices were assessed over 12 months using auxology, insulin-like growth factor 1 (IGF-1) levels, and BoneXpert-derived bone health index (BHI) SDS and Metacarpal Index (MCI) SDS.
Results
The study cohort consisted of 39 children with GHD. After 12 months of therapy, mean height SDS improved significantly from -2.16±0.80 to -1.65±0.71 (p<0.001). IGF-1 SDS rose from -1.38±1.02 to 0.88±1.57 (p<0.001). Adult predicted height and BHI SDS also improved significantly (p=0.005 and p<0.001, respectively). No significant changes were observed in bone age SDS or MCI SDS.
Conclusion
Weekly Somatrogon significantly improved linear growth, IGF-1 levels, and measures of cortical bone health without advancing bone age in children with GHD. These findings support the efficacy of this form of long-acting GH therapy and its potential to optimize growth and skeletal outcomes in clinical practice.
What is already known on this topic?
Daily growth hormone (GH) therapy is effective but often limited by poor adherence. Weekly Somatrogon offers a convenient alternative, with early data showing comparable growth outcomes. Effects on bone health as measured by bone age or bone health index (BHI) remain underreported.
What this study adds?
Weekly Somatrogon improved height and insulin-like growth factor 1 standard deviation score over 12 months in prepubertal patients with GH deficiency (GHD). Somatrogon increased BHI without advancing bone age or metacarpal index. Somatrogon appears to be a safe, effective, once-weekly GH-therapy option.
Introduction
Growth hormone deficiency (GHD) in children is characterized by short stature, reduced growth velocity, and failure to achieve normal adult height, negatively impacting quality of life and future outcomes (1, 2).
Growth hormone replacement has enabled children with GHD to achieve height within the normal accepted adult range (1). However, agents used for conventional daily growth hormone therapy have a short half-life (3) and require frequent injections (4), which contribute to caregiver burden (5) and poor adherence (6). This leads to frequent missed doses (7) and eventually a poorer clinical outcome (8).
Efforts have focused on developing long-acting GH formulations to improve convenience, reduce injection burden, and enhance clinical outcomes (9, 10). Somatrogon (Ngenla®) is a long-acting rhGH with three C-terminal peptide extensions, designed to extend half-life and enable weekly dosing. Clinical trials have demonstrated that Somatrogon achieves growth outcomes comparable to daily GH therapy (11, 12).
GHD also impairs bone health, leading to reduced bone mineral density (BMD), as shown by dual-energy X-ray absorptiometry (DXA) (13) and computed tomography studies (14). GH replacement promotes osteoblast activity, new bone formation, and improved BMD (15, 16).
The bone health index (BHI), derived from hand radiographs using the automated BoneXpert® software (Visiana ApS, Fremtidsvej 1, 2970 Hørsholm, Denmark), serves as a robust indicator of cortical bone strength in children (17). Prior studies have demonstrated that daily GH treatment is associated with significant improvements in BHI (18).
The metacarpal index (MCI), another parameter generated through radiogrammetry, estimates cortical thickness and has been validated as a predictor of fracture risk (19, 20). Both BHI and MCI are calculated from metacarpal dimensions: BHI is defined as the cortical area divided by width1.33 multiplied by length0.33, while MCI is calculated as cortical area divided by width². These indices correlate strongly with DXA findings and provide a reliable, non-invasive means of assessing skeletal integrity in growing children (21, 22).
The aim of the present study was to evaluate the real-world effects of weekly Somatrogon therapy on growth outcomes, including height velocity, adult predicted height (APH), and IGF-1 stability, as well as the bone health indices, BHI and MCI, in children with GHD.
We hypothesised that weekly Somatrogon would improve linear growth and bone health in prepubertal children with GHD.
Methods
This retrospective cohort study assessed pre- and post-treatment outcomes over 12 months in children diagnosed with GHD who received Somatrogon therapy at Al Jalila Children’s Hospital in Dubai, UAE. The Institutional Review Boards of Al Jalila Children’s Hospital and Mohammed Bin Rashid University approved the study. Participants were consecutively recruited from January 2023 to June 2024.
The study population included children who received Somatrogon therapy at a dose of 0.66 mg/kg/week (11), all patients remained on the same dose throughout the 12 months of the study. Their age was between 3.0 and 10.0 years for girls and 3.0 and 11.0 years for boys. All were prepubertal, defined as Tanner stage 1 on physical examination (23, 24). All patients remained prepubertal (Tanner stage 1) throughout the entire 12-month study period.
The diagnosis of GHD was established through an integrated approach combining clinical, radiological, and biochemical evidence. An auxological assessment was performed, with growth failure defined as a height standard deviation score (SDS) below -2.0 for age and sex or a growth velocity 1 SD below the mean for chronological age over the 12 months prior to treatment (25, 26).
Participants were included if they exhibited a peak GH <10 ng/mL in one stimulation test, supported by either: (1) height SDS <-2.0 + growth velocity <-1 SDS, or (2) low IGF-1/IGFBP-3 (insulin-like growth factor binding protein-3), or (3) abnormal cranial MRI. This approach is consistent with guidelines for severe phenotypes (27, 28).
Exclusion criteria included previous exposure to growth-promoting agents, abnormal thyroid function, or other significant medical conditions. Data was collected anonymously using medical record numbers to ensure confidentiality.
Auxologic Measurements
Height was measured using a wall-mounted stadiometer [Seca216® (Seca GmbH & Co. KG, Hammer Steindamm 9-25, 22089 Hamburg, Germany)]. Height SDS was calculated using CDC 2000 references (29).
Laboratory Investigations
GH measurements were performed using the Siemens Immulite® assay (Siemens Healthineers, Llanberis, Gwynedd, United Kingdom); (sensitivity: 0.01 ng/mL). Serum IGF-1 was measured at baseline and 96 hours after the most recent Somatrogon dose to reflect weekly pharmacokinetics (30) using the Roche Elecsys® ECLIA (Roche Diagnostics GmbH, Sandhofer Strasse 116, 68305 Mannheim, Germany); (range: 0.25-1600 ng/mL; CV<5%) (31). IGF-1 values were expressed as SDS based on age- and sex-specific norms; eligible patients had baseline IGF-1 at least 1 SD below the mean (11, 31).
Radiographic Assessments
An automated radiographic analysis of the left hand and wrist radiographs was performed using BoneXpert® software before the initiation of Somatrogon therapy and after 12 months of treatment. This automated analysis determined bone age, BHI, and MCI.
Bone age assessment using the BoneXpert® method is based on the Greulich-Pyle bone age standard, and it analyzes the image completely automatically using artificial intelligence (AI). It has been shown to provide accurate data on a patient’s bone age, in addition to analysis of BHI and MCI (32).
BoneXpert® offers an automated assessment of both bone age and cortical bone geometry using radiographic measurements. Specifically, it evaluates the width (W), cortical thickness (T), and length (L) of the second, third, and fourth metacarpal bones. From these parameters, it calculates key indices:
Cortical area (A): Computed using the formula A=π×W×T×(1-T/W), representing the area of the cortical bone cross-section.
Metacarpal index (MCI): Defined as MCI=A/W², this index expresses cortical bone thickness relative to the overall bone width.
Bone health index (BHI): Calculated as BHI=A/(W1.33×L0.33), this index integrates bone dimensions to reflect cortical bone robustness.
These indices provide a detailed profile of cortical bone structure and are interpreted against standardized reference values for bone age. Although BoneXpert’s normative dataset is based on Caucasian populations (33), it remains the most widely validated tool for pediatric skeletal assessment. To mitigate ethnic bias, we report results as SDS relative to each patient’s bone age rather than relying on raw values.
APH was calculated using BoneXpert® software, which applies the Bayley-Pinneau method to deliver accurate and standardized predictions of final adult height, minimizing variability associated with manual calculations (34).
Sample Size
The sample size was calculated based on Horikawa et al. (11) study, in which Somatrogon increased height SDS in children with GHD by 0.94 after 12 months of treatment. Therefore, at a significance level of 0.05 and power of 80%, a total of 30 subjects were required to test our hypothesis.
Ethical Considerations
This study was approved by the Dubai Scientific Research Ethics Committee (DSREC), Dubai Health Authority, and the Institutional Review Board of Mohammed Bin Rashid University of Medicine and Health Sciences (MBRU IRB-2024-562; Ref: DSREC-SR-11/2024_04). Given the retrospective design, the requirement for informed consent was waived.
Statistical Analysis
Statistical analysis was done using SPSS, version 29 (IBM, Armonk, NY, USA). Continuous variables were assessed for normality using Shapiro-Wilk tests. Paired t-tests compared pre/post outcomes for parametric data. Continuous variables were summarized as means with SDs and/or medians with minimum and maximum values, as appropriate. Categorical data were presented as frequencies and percentages within the study cohort. To assess the primary endpoint, annual height velocity, comparisons between baseline and the end of therapy were conducted using a t-test, with statistical significance set at a p-value of less than 0.05.
Results
The study included 39 patients with a mean age of 9.63 years, of whom 64% were male (Table 1). Height SDS improved significantly from a mean of -2.16±0.80 at baseline to -1.65±0.71 after 12 months of treatment (p<0.001) (Figure 1). When analysed separately by sex, both boys and girls demonstrated a similar and significant increase in absolute height over 12 months. In boys (n=27), mean height increased from 123.73±8.74 cm to 132.06±8.55 cm (mean change +8.33 cm, p<0.001). In girls (n=12), mean height increased from 122.23 ± 14.88 cm to 130.97±13.82 cm (mean change +8.73 cm, p<0.001).
APH improved from 161.86±7.2 cm to 164.88±6.4 cm (p<0.001) (Figure 2). Bone age SDS showed no change (p=0.269) (Table 2).
The IGF-1 SDS improved significantly from a mean of -1.38±1.02 at baseline to 0.88±1.57 after treatment (p<0.001) (Figure 3). BHI SDS improved from –1.29±1.50 to -0.83±1.41 (Δ= +0.46; p<0.001). MCI SDS showed no significant change (-1.33±1.18 to -1.16 ±1.07; Δ= +0.17; p=0.106) (Table 2).
Discussion
In our real-world setting, treatment with Somatrogon significantly increased height SDS, APH, and IGF-1 SDS levels after one year of treatment. In addition, Somatrogon treatment for one year was associated with improved BHI without significant change in bone age or MCI.
The significant height SDS gain observed aligns with findings from Deal et al. (12), where Somatrogon demonstrated non-inferiority to daily somatropin in terms of height velocity and height SDS with the least squares mean (LS mean) treatment difference: 0.06 (95% confidence interval, -0.01, 0.13). Horikawa et al. (11) similarly reported robust growth outcomes with Somatrogon in rhGH naïve prepubertal children where the LS mean change in height SDS from baseline to 12 months was greater in the Somatrogon group (0.94) compared to the daily GH group (0.52) (11). Our height SDS improvement (Δ0.51) closely mirrors daily GH outcomes in Deal et al. (12) (Δ0.52).
The observed increase in IGF-1 SDS in our cohort is consistent with previous findings. Deal et al. (12) reported similar findings, noting that IGF-1 profiles with Somatrogon were higher compared to daily GH regimens, where the mean IGF-1 SDS was -1.95 at baseline and increased to 0.65 at 12 months post-baseline. Similarly, Horikawa et al. (11) reported significant increase in IGF-1 SDS in Japanese children with GHD after treatment with Somatrogon (11).Improvements in BHI observed in our study with Somatrogon treatment are consistent with findings from Wydra et al. (35), which emphasized the anabolic effects of GH on bone mineralization. Another study showed that in short-statured children, daily GH treatment significantly improved BHI, where BHI SDS increased from -0.97 to -0.17 after 1 year of GH (p<0.001). The BHI increased initially with GH treatment and plateaued over time, suggesting sustained improvement in bone health (18).
The absence of significant bone age advancement in our study differs from results commonly observed with previous studies, where Deal et al. (12) in a phase 3 study comparing Somatrogon to daily rhGH found significant bone age progression after one year of treatment, which was comparable to bone age progression rates seen on daily rhGH. Similarly, Horikawa et al. (11) reported significant bone age advancement on Somatrogon treatment. This discrepancy may be explained by the different methods used to assess bone age. In our study, bone age was determined using an automated AI-based analysis, whereas the previous studies relied on manual evaluation.
However, the lack of significant improvement in the MCI was notable. This is consistent with findings from Bettendorf et al. (36) and Radetti et al. (37), which reported no substantial alteration in metacarpal proportions during GH therapy. However, the findings diverge from Martin et al. (38), who also used BoneXpert and observed significant improvement in MCI within the first year of daily GH therapy (22). The discrepancy with the results reported by Martin et al. (38) could stem from differences in GH regimens. Daily GH therapy may exert a more consistent anabolic effect on bone geometry compared to the intermittent stimulation provided by weekly Somatrogon.
While BoneXpert software represents a validated and widely-used automated tool for bone health assessment in pediatric populations, it is important to acknowledge that its reference standards are derived from a Dutch Caucasian population (33). To address this potential limitation in our ethnically diverse cohort, we employed SDS relative to bone age rather than absolute values, a recommended approach that helps normalize for population differences (39). Although ethnic variations in BMD and skeletal architecture have been documented in pediatric populations, BoneXpert has demonstrated acceptable performance and has undergone validation across diverse populations (40). The BHI provided by BoneXpert has been shown to reflect cortical BMD effectively in pediatric and adolescent patients (17), and the use of SDS values in our analysis provides a standardized approach that accounts for individual variation, allowing for meaningful clinical interpretation of bone health parameters (38). While population-specific reference data would be ideal for Middle Eastern children, BoneXpert remains the most extensively validated automated tool available for pediatric bone health assessment, and our findings using SDS-based analysis provide valuable real-world evidence of skeletal outcomes following Somatrogon therapy (41). In addition, the paired design of our analysis, where each participant served as their own control, further mitigates the influence of any systematic bias in the reference data.
The observed improvement in the BHI, despite the absence of significant changes in the MCI or bone age, suggests a nuanced shift in cortical bone geometry. Given that MCI is calculated as the ratio of cortical area (A) to the square of bone width (W²), its stability implies that any increase in cortical area occurred proportionally to changes in bone width. In contrast, BHI incorporates both width and bone length in the denominator with lower exponents (W1.33 and L0.33), making it more sensitive to subtle increases in cortical area. The improvement in BHI, therefore, likely reflects a disproportionate increase in cortical thickness relative to width, resulting in a net gain in cortical area that was not substantial enough to affect MCI. Moreover, the lack of advancement in bone age suggests that these structural changes occurred independently of accelerated skeletal maturation.
Study Limitations
This study has several limitations. Its retrospective cross-sectional design, absence of a daily GH control group, and relatively small sample size may restrict the generalizability of the results. DXA, the gold standard for assessing BMD, was not employed (42). Bone age assessments were conducted using BoneXpert, which, while the most practical and validated tool available in the absence of local reference data, may be less accurate in a cohort with diverse ethnic backgrounds (33). In addition, systematic safety data were not collected due to the retrospective nature of the study.
Conclusion
In a real-world setting, the results of our study add to the growing body of evidence showing that Somatrogon is an effective option for GHD treatment. Weekly Somatrogon therapy led to significant improvements in growth parameters and IGF-1 levels, as well as enhancements in the BHI. However, the nuanced effects on cortical bone geometry underscore the need for further research. Future studies should include the assessment of bone health using DXA to provide a more comprehensive evaluation of skeletal outcomes.
