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Context Somatrogon is a long-acting recombinant human growth hormone (rhGH) in development for once-weekly treatment of children with growth hormone deficiency (GHD). Objective We aimed to compare the efficacy and safety of once-weekly somatrogon with once-daily somatropin in prepubertal children with GHD. Methods In this 12-month, open-label, randomized, active-controlled, parallel-group, phase 3 study, participants were randomized 1:1 to receive once-weekly somatrogon (0.66 mg/kg/week) or once-daily somatropin (0.24 mg/kg/week) for 12 months. A total of 228 prepubertal children (boys aged 3-11 years, girls aged 3-10 years) with GHD, impaired height and height velocity (HV), and no prior rhGH treatment were randomized and 224 received ≥1 dose of study treatment (somatrogon: 109; somatropin: 115). The primary endpoint was annualized HV at month 12. Results HV at month 12 was 10.10 cm/year for somatrogon-treated subjects and 9.78 cm/year for somatropin-treated subjects, with a treatment difference (somatrogon-somatropin) of 0.33 (95% CI: −0.24, 0.89). The lower bound of the 2-sided 95% CI was higher than the prespecified noninferiority margin (−1.8 cm/year), demonstrating noninferiority of once-weekly somatrogon vs daily somatropin. HV at month 6 and change in height standard deviation score at months 6 and 12 were similar between both treatment groups. Both treatments were well tolerated, with a similar percentage of subjects experiencing mild to moderate treatment-emergent adverse events in both groups (somatrogon: 78.9%, somatropin: 79.1%). Conclusion The efficacy of once-weekly somatrogon was noninferior to once-daily somatropin, with similar safety and tolerability profiles. (ClinicalTrials.gov no. NCT02968004).

Objectives: Somatrogon (hGH-CTP) is a long acting recombinant human growth hormone, consisting of the amino acid sequence of hGH and three copies of the carboxy-terminal peptide (CTP) of human chorionic gonadotropin (hCG) being developed as a once weekly treatment for children with pGHD. This report summarizes data from the first year of the optional open-label extension (OLE) of the pivotal phase 3 global trial (ClinicalTrials. gov: NCT02968004), comparing the efficacy and safety of children switched from Genotropin (rhGH; somatropin) to somatrogon (Geno/Soma) and children maintained on somatrogon (Soma/Soma). Methods: During the main study, 224 children were randomized to receive either once weekly somatrogon (0.66 mg/kg, n=109) or once daily Genotropin (0.24 mg/kg/wk, n=115) for 12 months. Of these, 222 completed the 12-month main study, and 212 chose to enter the OLE study. By Sept 30, 2020, 161 children (including 76 Geno/Soma) had complete auxological data at month 12 of the OLE. Results: At the end of the main study, mean height velocity and gain in height SDS for the somatrogon cohort were 10.10 cm/year and 0.92; for the Genotropin cohort these were 9.78 cm/year and 0.87. Baseline values for the OLE (Soma/Soma group and Geno/Soma group, respectively): height SDS was -1.95 and -1.84, BMI was 17.03 and 15.48 kg/m2 while bone age was 6.54 and 6.40 years. At month 12 (of the OLE), the mean height velocity and the change in height SDS was 8.04 cm/year and 0.41 (Soma/Soma group) and 8.21 cm/year and 0.47 (Geno/Soma group); BMI was 18.07 and 17.49 kg/m2 and bone age was 8.48 and 8.41 years. IGF-1 SDS values were 1.15, and 1.28, while the IGFBP-3 SDS were 0.29 and 0.42, respectively. Dose reductions were required in 16.3% and 20.4% of patients due to IGF-1 SDS >2. Pubertal status changed from Tanner 1 (at OLE baseline) for 13.6% of Soma/Soma patients and 14.6% of Geno/Soma patients. Mean glucose, HbA1c, thyroid function (free T4 and TSH) and cholesterol (total, LDL and HDL) values remained similar to baseline in both groups across the 12 months OLE. The majority of adverse events in both cohorts were mild to moderate (Soma/Soma 94.2%, Geno/Soma 93.5%) and there were no clinically concerning safety observations. During the first 12 months of the OLE six patients discontinued in the Geno/Soma group due to AEs vs zero in the Soma/Soma group. Conclusions: Height velocities and change in height SDS in the OLE were similar between the Geno/Soma and Soma/Soma cohorts. The main phase of the global pivotal phase 3 trial demonstrated that somatrogon (hGH-CTP) given once weekly is non-inferior to Genotropin (hGH) while the OLE demonstrated that catch-up growth continued into the second year of treatment, with ‘switch’ from Genotropin to somatrogon non-inferior to somatrogon given for two years. Metabolic (glycemic, lipid and thyroid) parameters were similar between groups and not meaningfully different from the main study.

Background: Thyroid hormone exerts systemic actions mediated by its specific receptors. These actions encompass a wide array of functions, including energy homeostasis, skeletal growth, neural development, cardiac function, and gastrointestinal function. There are two thyroid hormone receptors, thyroid hormone receptor alpha (THRA) and thyroid hormone receptor beta (THRB) which are encoded by genes on two different chromosomes and with differing tissue distributions. Only mutations in THRB were known until recently with a reported incidence of 1 in ~40,000. Mutations in thyroid receptor THRA have recently been discovered and are exceedingly rare, with 14 cases documented in the past five years. We report a case of a patient with generalized thyroid hormone resistance due to THRA mutation. Clinical Case: Patient was born to non-consanguineous parents at term and was appropriate for gestational age. Prenatal ultrasound was suspect for shortened long bones. Congenital heart disease (ASD and VSD) were detected at birth. Genetics consultation confirmed ultrasound concern with finding of mild rhizomelia. Patient had coarse facial features, macroglossia, and dysmorphic appearance. Initial genetics work-up showed normal chromosomes, normal newborn screening, and normal metabolic studies. Genetics was concerned for possible mucopolysaccharidosis, but further testing ordered did not confirm this diagnosis. Patient exhibited post-natal growth failure after birth with length well below 3rd percentile by 18 months old. Delayed developmental milestones (verbal > motor) were noted. Thyroid function tests between birth and 11 months old were normal. Thyroid function testing at 11 months old were suspect for central hypothyroidism with free T4 0.6 ng/dl (0.6-1.3) and TSH 1.07 uIU/ml (0.71-5.81). Cranial MRI scan showed no abnormalities in hypothalamic-pituitary area. Levothyroxine 37.5 mcg was started, and thyroid function tests normalized. However, little change was seen clinically in patient’s growth pattern or development. Whole exome screening performed in 2013 demonstrated a heterozygous mutation in the THRA gene consistent with generalized thyroid hormone resistance from this mutation. Liothyronine treatment was added in 2014. Growth has continued to be extremely slow with current height standard deviation score of -4.2. Patient is developmentally delayed and non-verbal. Conclusions: A constellation of findings including post-natal growth failure, skeletal findings, and prominent verbal developmental delays are seen in generalized thyroid hormone resistance due to THRA mutation. The subtle presentation of this condition is different from congenital hypothyroidism or generalized thyroid hormone resistance due to THRB mutation. Presentation of this case will hopefully help pediatric specialist to recognize and test for this condition more promptly.

Objective: To report clinical characteristics and medical history data obtained retrospectively for a large cohort of pediatric patients with perinatal and infantile hypophosphatasia. Study design: Medical records from academic medical centers known to diagnose and/or treat hypophosphatasia were reviewed. Patients born between 1970 and 2011 with hypophosphatasia and any of the following signs/symptoms at age 70% of patients between birth and age 5 years. Vitamin B6–dependent seizures and respiratory distress and failure were associated significantly (P

Although severely low bone density is relatively rare in the pediatric population, it can be a significant problem in many patients with chronic illness. As peak bone formation occurs during adolescence, it is crucial that pediatricians and other care providers for this patient population recognize the significance of attainment of adequate bone. Dietary intake of vitamin D and calcium should be optimized, and correction of underlying causes of poor bone density should occur whenever possible. Assessment of bone density is difficult, as each technology available has problems, and none of the technologies are well-associated with fracture risk in pediatric patients. Once diagnosis of severely low bone density is established, treatment options are limited and poorly studied. The benefits of bisphosphonate therapy appear to outweigh the risks in patients with low bone density and frequent fragility fractures, and it appears that most improvement with bisphosphonates occurs within the first 2 to 4 years. Evidence, however, is emerging that once off therapy, bone turnover remains decreased for at least several years. During that time, improvements in bone density are decreased. Many questions remain regarding duration of therapy with bisphosphonate therapy and the long-term effects on the children who receive this medication. Anabolic therapies may become important in the future, but there is currently extremely limited information regarding their use in pediatrics.

1. Joel Steelman, MD* 2. Philip Zeitler, MD, PhD† 1. 2. *Pediatric Endocrine Fellow. 3. 4. †Assistant Professor of Pediatric Endocrinology, The Childern’s Hospital, Denver, CO. Dr Zeitler has received a supply of drugs from Novartis Pharmaceuticals for a research protocol. Objectives After completing this article, readers should be able to: 1. Identify determinants of bone mass. 2. Delineate pediatric populations at risk for osteoporosis. 3. Describe test procedures to measure parameters such as bone mineral density, bone formation, and bone resorption. 4. Describe methods to interpret pediatric DEXA scan results. 5. Identify measures to maximize peak bone mass in children and adolescents. 6. Identify osteoporosis treatments available for children and adolescents. Bone consists of a collagen matrix into which calcium, in the form of hydroxyapatite, is deposited. The accumulation and maintenance of the substance of bone is the result of a continuous process of formation, predominately mediated by osteoblasts, and resorption, facilitated by osteoclasts. During childhood and adolescence, the process of formation predominates, leading to a net increase in bone mass and size. Infancy and adolescence are periods of particularly rapid formation. Peak bone mass is achieved shortly after completion of puberty and normally remains stable until the third decade of life, when age-related (involutional) bone loss begins. Osteoporosis is defined as a systemic skeletal disease characterized by low bone mass and microarchitectural deterioration of bone tissue, with a consequent increase in bone fragility and susceptibility to fractures. It is the most common metabolic bone disorder in adults. Approximately 13.8 billion dollars were spent in 1995 in the United States for treatment of osteoporotic fractures. Osteoporosis incidence increases with age; an estimated 30% to 40% of adults older than age 60 years have osteoporosis. Genetics, age, and menopause are important, relatively unchangeable determinants of osteoporosis risk in adulthood. However, other factors, such as chronic illness, nutrition, medications, and lifestyle, clearly modify the rapidity and severity of bone loss in aging adults. Osteoporosis generally has been considered an adult disease, but there is increasing evidence that its roots lie in childhood. The loss in bone mass begins …

Background: Although high-dose inhaled glucocorticoids (GCs) with or without chronically administered oral GCs are often used in children with severe persistent asthma, the adverse effects associated with their use have not been well-described in this patient population. Objective: We sought to determine the GC-induced adverse effects profile of older children with severe persistent asthma. Methods: A chart review of 163 consecutive children 9 years of age or older admitted to National Jewish for difficult to control asthma was done. Results: The population studied consisted mostly of adolescents (mean ± SD age, 14.4 ± 2.1 years) with severe asthma receiving high-dose inhaled GC therapy (1675 ± 94 μg/d) and averaging 6 systemic GC bursts per year. 50% required chronic oral GC therapy. GC-associated adverse effects were common and included hypertension (88%), cushingoid features (66%), adrenal suppression (56%), myopathy (50%), osteopenia (46%), growth suppression (39%), obesity and hypercholesterolemia (30%), and cataracts (14%). Height standard deviation scores of –0.44, –1.22, and –0.93 for those receiving intermittent, alternate day, and daily oral GCs, respectively, were smaller (less suppressed) than published values from the same institution before inhaled GC therapy (standard deviation scores of –1.26, –1.91, and –1.95, respectively). Osteopenia was strongly associated with growth suppression (odds ratio, 5.6; confidence interval, 2.7-11.8; P < .0001) and was found to be more common in female than male subjects, even after correcting for short stature (42% vs 18%, P < .006). Conclusions: GC-associated adverse effects are still unacceptably common among children with severe asthma, even in those not receiving chronically administered oral GC therapy yet receiving high-dose inhaled GCs. Therefore close monitoring and proper intervention are warranted, especially in female subjects, who appear to be at greater risk for osteopenia. There is clearly a need to consider alternative therapy or earlier intervention. The magnitude of growth suppression, while still a problem, appeared to be less severe with the addition of inhaled GC therapy. This observation suggests that high-dose inhaled GC therapy, by affording better asthma control and allowing less use of systemic therapy, has attenuated the growth-suppressive effects of poorly controlled asthma. (J Allergy Clin Immunol 2000;106:651-9.)

The GHMonitor observational registry collates data on pediatric subjects receiving Saizen (recombinant human growth hormone (GH)) therapy. From January 2003 through August 2006, 1335 subjects were enrolled in the registry, approximately two-thirds of whom are male. The most common diagnosis in the registry is idiopathic growth hormone deficiency (58%). Most subjects in GHMonitor are receiving Saizen doses using a needle-free delivery device, the cool.click (73%). Mean height standard deviation scores show an improvement from -2.1 at screening to -1.1 following 3 years of Saizen therapy. To date, adverse events have been reported in 4% of subjects. Three serious adverse events were identified to be related to Saizen by the primary investigator: cellulitis at the injection site, behavioral problems/suicidal ideation, and enlargement of a craniopharyngioma. This article provides an update on data from the registry and briefly discusses topical and controversial issues in the treatment of pediatric patients requiring GH therapy.

The North American (US and Canada) GHMonitor was initiated to assess the safety and efficacy of Saizen (somatropin [recombinant human growth hormone for injection]) for growth disorders. Between 2003 and 2005, 1057 patients were enrolled in the registry; there were more males than females (67% vs 32%), the median age was 11.2 years, and most were Caucasian (80.9%). In the GHMonitor, the cool.click needle-free device (NFD) was the most widely used Saizen delivery device (73.8%), followed by needle and syringe (19.8%) and one.click (3.3%). At enrollment, most patients were recombinant human GH (rhGH) treatment-naïve (82.8%) and patients transitioning from prior rhGH therapy tended to choose cool.click NFD (67.1%), followed by needle and syringe (27.4%), and one.click(R) (1.8%). At screening, the most common diagnoses were idiopathic growth hormone deficiency (59%), idiopathic short stature (18%), neurosecretory dysfunction (6%), and Turner syndrome (3%). Patient characteristics included bone age that was delayed an average of one year relative to chronological age, a median BMI of 16.8 kg/m2, median height standard deviation score (SDS) -2.3, and median weight SDS -1.5. Eighteen of the forty reported adverse events (45%) were felt to be associated with Saizen. Most were mild and predominantly musculoskeletal complaints, although three were reported as serious.

This multicenter, randomized, controlled, crossover trial of prepubertal children with cystic fibrosis (CF) tests the hypotheses that recombinant human GH (rhGH) treatment 1) improves height, weight, lean mass, and bone content irrespective of baseline measures; 2) improves clinical status and quality of life; and 3) has continued effect after cessation after 1 yr of treatment.Sixty-one prepubertal subjects (or=25th percentile for height and weight) were randomized into two groups: daily rhGH treatment or no treatment groups for 1 yr. In yr 2, treatments were crossed over. Outcome measures included serial standardized height and weight, number of hospitalizations and antibiotic courses, random blood glucose levels, lean mass, bone mineral content, pulmonary function, nutritional intake, and CF quality of life questionnaires.Groups were similar at baseline and prepubertal during the entire study. After 1 yr, GH showed significantly greater gain in height, weight, lean mass, and bone mineral content. Gain in height was similar regardless of baseline. There were fewer hospitalizations in the rhGH-treated group and improvement in CF quality of life questionnaires measures of weight and body image. There was no difference in pulmonary function between groups. Results were similar in those treated with rhGH the second year. After cessation of rhGH treatment, there was sustained effect for increased height and weight velocity, as well as accrual of bone mineral.rhGH therapy improves height and weight, decreases the number of hospitalizations, and improves quality of life in prepubertal children with CF. These effects are sustained after rhGH is discontinued.

Objectives To examine the response to single-day intravenous pamidronate in a heterogeneous population with symptomatic osteoporosis. Study design Patients (n = 18) 6 to 21 years of age, meeting treatment criteria were offered treatment with a single-day infusion of pamidronate every 3 months. Baseline and follow-up data were recorded and compared between persons with risk factors of progressive chronic illness or ongoing glucocorticoid usage (group 1) and persons with neither risk factor (group 2). We also examined the association between changes in urinary N-telopeptide percentile and spinal bone mineral density (BMD). Results Spinal BMD Z score increased in all patients after 6 months of treatment. Although patients had an average of 1.9 fractures in the year preceding treatment, only 2 patients had fractures once treatment began. No significant differences in baseline data were noted between the two groups. However, group 1 had significantly less gain in BMD ( P =.04) than group 2. No evidence of growth impairment was seen, and no association between changes in urinary N-telopeptide percentile and changes in BMD were noted. Conclusions Single-day intravenous infusion of pamidronate is efficacious and well tolerated in a heterogeneous group of pediatric patients with symptomatic osteoporosis. (J Pediatr 2003;142:417-23)