Christof Land

Growth response to an individualized versus fixed dose GH treatment in short children born small for gestational age: the OPTIMA study

OBJECTIVE Initial GH-induced catch up growth is highly variable in short children born small for gestational age (SGA) and mainly influenced by age at start of therapy and GH dose. This study compared the first year growth-promoting effect of an individually adjusted GH dose (IAD) versus a fixed high GH dose (FHD) in pre-pubertal children born SGA with severe short stature. DESIGN This was a randomized, open-label, multi-center study. METHODS The FHD group received 0.067 mg/kg per day GH throughout the 12-month study. The IAD group initially received 0.035 mg/kg per day GH; at 3 months the Cologne growth-prediction model for first year change in height SDS was applied; if predicted change was <0.75, GH was increased to 0.067 mg/kg per day for the remaining 9 months, otherwise the initial dose was continued. RESULTS In the IAD group, 38 out of the 80 patients required the higher GH dose from month 3. From an ANCOVA for non-inferiority, mean difference in change in height SDS between IAD and FHD groups was -0.24 (95% confidence interval (CI) -0.35: -0.12), the CI for height SDS being above the pre-defined non-inferiority margin of -0.5. GH dose reductions due to IGF-I SDS >0.5 and IGFBP-3 SDS <-0.5 were performed in 4/99 FHD patients, but none of the IAD group patients. Safety data were similar between groups. CONCLUSION With a mean treatment group difference of 1 cm in 12-month growth response, although statistically significant, the IAD group was considered non-inferior compared with the FHD group. Early growth prediction can be used to tailor the dose to the individual patients needs, resulting in lower overall GH dose.

Do Bone Mineral Density, Bone Geometry and the Functional Muscle-Bone Unit Explain Bone Fractures in Healthy Children and Adolescents?

Background/Aims: Because the increasing fracture incidence has not been understood, the present study compares variables of the muscle-bone interaction to examine the hypothesis that an impaired adaptation of bone strength to muscle forces explains this phenomenon. Methods: The forearm of 220 individuals (mean age 11.1 ± 3.2 years; range 5.5–17.4 years) was analyzed by peripheral quantitative computed tomography. Bone mineral content (BMC), bone mineral density, periosteal circumference, cortical area, strength strain index (SSI) and muscle area (MA) were measured at the distal and proximal radius of the non-dominant forearm. Maximum isometric grip force was measured by a dynamometer. The fracture history was evaluated by a questionnaire after a period of 5 ± 1.7 years. Results: During the observational period at least one fracture appeared in 78 children and adolescents (35.5%). Individuals with and without fractures were not different in age, height, weight, and body mass index. Variables of bone mineral density, bone geometry and muscle force were not different between both groups. BMC, MA and SSI were dependent on age and sex. Conclusion: Fracture risk in healthy children and adolescents is not sufficiently explained by volumetric bone mineral density, the skeletal phenotype and indices of the functional muscle-bone unit.

Early differentiation between good and poor response to growth hormone therapy in short children born small for gestational age (SGA) to improve the outcome of poor responders.

Abstract Objective: The aim of this study was to examine height-gain response in relation to predicted good or poor response during first-year low or high growth hormone (GH) dose in short prepubertal children born small for gestational age. Patients and methods: The OPTIMA (Optimization of GH Treatment in Short Children Born Small for Gestational Age Based on a Growth Prediction Model) randomised study evaluated 12-month height standard deviation score (SDS) changes in patients receiving GH dose: fixed high (FH; 0.067 mg/kg/day) or 0.035 mg/kg/day individually adjusted (IA) after 3 months according to the Cologne early growth prediction. Results: Predicted 12-month height SDS gain was <0.75 for 21/89 FH-dose patients, considered poor responders; 11/21 reached a 12-month height SDS gain of ≥0.75. In IA-dose poor responders, increasing GH dose at 3 months maintained mean height velocity (HV), with 73.7% reaching a 12-month height SDS gain of ≥0.75 vs. 73.8% in IA-dose good responders who continued on low GH dose, where mean HV decreased after the initial 3-month period. Conclusion: GH dose increase at 3 months in patients with predicted poor response maintained catch-up growth. Even when on FH dose, some patients did not achieve a good response.

Growth Hormone Treatment for Short Stature in the USA, Germany and France: 15 Years of Surveillance in the Genetics and Neuroendocrinology of Short-Stature International Study (GeNeSIS)

Background/Aims: To describe characteristics, auxological outcomes and safety in paediatric patients with growth disorders treated with growth hormone (GH), for cohorts from the USA, Germany and France enrolled in GeNeSIS, a post-authorisation surveillance programme. Methods: Diagnosis and biochemical measurement data were based on reporting from, and GH treatment was initiated at the discretion of, treating physicians. Auxological outcomes during the first 4 years of GH treatment and at near-adult height (NAH) were analysed. Serious and treatment-emergent adverse events were described. Results: Children in the USA (n = 9,810), Germany (n = 2,682) and France (n = 1,667) received GH (dose varied between countries), most commonly for GH deficiency. Across diagnostic groups and countries, mean height velocity standard deviation score (SDS) was > 0 and height SDS increased from baseline during the first 4 years of treatment, with greatest improvements during year 1. Most children achieved NAH within the normal range (height SDS >−2). No new or unexpected safety concerns were noted. Conclusion: GH treatment improved growth indices to a similar extent for patients in all three countries despite variations in GH doses. Data from these three countries, which together contributed > 60% of patients to GeNeSIS, indicated no new safety signals and the benefit-risk profile of GH remains unchanged.