Potential for Optimization of Growth Hormone Treatment in Children with Growth Hormone Deficiency, Small for Gestational Age, and Turner Syndrome in Germany: Data from the PATRO® Children Study.

INTRODUCTION: Growth hormone (GH) treatment in children with growth hormone deficiency (GHD), short children born small for gestational age (SGA), and Turner syndrome (TS) is well established. However, a variety of parameters are still under discussion to achieve optimal growth results and efficiency of GH use in real-world treatment. METHODS: German GH-treatment naïve patients of the PATRO Children database were grouped according to their start of treatment into groups of 3 years from 2007 to 2018. Time trends in age, gender, GH dose, height standard deviation score (SDS), first-year growth response, and Index of Responsiveness (IoR) were investigated in children with GHD, short children born SGA, and TS starting GH treatment in the German patient population of the PATRO Children database from 2007 to 2018 to determine specific parameters for GH treatment optimization. RESULTS: All patient groups started GH treatment at a relatively high chronological age (2007-2009: GHD 8.33 ± 3.19, SGA 7.32 ± 2.52, TS 8.65 ± 4.39) with a slight but not significant trend towards younger therapy start up to 2016-2018 (GHD 8.04 ± 3.36, SGA 6.67 ± 2.65, TS 7.85 ± 3.38). In the GHD and SGA groups, female patients were underrepresented compared to male patients (GHD 32.3%, SGA 43.6%) with no significant change over the 4 time periods. Patients with GHD started GH treatment at a low dose (0.026 mg/kg/day). In SGA and TS patients, GH therapy was started below the registered dose recommendation (30.0 µg/kg/day and 33.7 µg/kg/day, respectively). In the first year of treatment, the mean GH dose was increased moderately (GHD: 30.7, SGA: 35.7, TS: 40.8 µg/kg/day). There was no significant change of GH dosing over time from 2007 to 2018. The IoR was comparable between time-groups for all 3 diagnoses. DISCUSSION: This study shows potential for improvement of GH treatment results in GHD, SGA, and TS patients in terms of early dose adjustment and younger age at the start of treatment. This is in accordance with important parameters used in prediction models.

Safety and Effectiveness of Omnitrope®, a Biosimilar Recombinant Human Growth Hormone: More Than 10 Years' Experience from the PATRO Children Study.

INTRODUCTION: Omnitrope® was approved as a biosimilar recombinant human growth hormone (rhGH) in 2006. OBJECTIVE: The purpose of this work was to evaluate the long-term safety and effectiveness of Omnitrope® in PATRO Children - an ongoing, international, longitudinal, non-interventional study in children who require rhGH treatment. METHODS: The study population includes infants, children, and adolescents receiving Omnitrope®. Adverse events (AEs) are monitored for safety and rhGH effectiveness is evaluated by calculation of the height standard deviation score (HSDS), height velocity (HV), and HVSDS using height measurements and country-specific references. RESULTS: As of November 2017, 6,009 patients from 298 centers across 14 countries were enrolled in PATRO Children. Overall, 57.7% of patients had growth hormone deficiency (GHD), 25.8% were born small for gestational age (SGA), and 4.8% had Turner syndrome (TS). In total, 84.1% were rhGH treatment naïve at study entry. The mean duration of Omnitrope® treatment in the study was 36.1 months (range 0-133.7). Overall, 10,360 AEs were reported in 2,750 patients (45.8%). Treatment-related AEs were reported in 396 patients (6.6%; 550 events), and serious AEs (SAE) in 636 patients (10.6%; 1,191 events); 50 SAEs in 37 patients (0.6%) were considered treatment related. Following 5 years of therapy in patients who were rhGH treatment naïve at study entry, improvement from baseline in mean HSDS was +1.85 in GHD, +1.76 in SGA, and +1.0 in TS patients. In total, 912 (17.9%) patients reached adult height (n = 577 GHD, n = 236 SGA, n = 62 TS). CONCLUSIONS: This analysis of PATRO Children indicates that biosimilar rhGH is well tolerated and effective in real-world clinical practice.

The relationship between body composition and the urinary excretion of deoxypyridinoline and galactosyl-hydroxylysine in children and adolescents.

The study intends to investigate the relationship of body composition (%fat, percent body fat; FM, fat mass; FFM, fat free mass; FA and MA cross-sectional fat and muscle area) to the urinary excretion of deoxypyridinoline (DPD) and galactosyl-hydroxylysine (Gal-Hyl). 231 healthy children and adolescents (age 5-19 years; 112 males) of the DONALD study were analyzed for FM and FFM by measuring 4 skinfold thicknesses, for DPD and Gal-Hyl in urine samples and for bone parameters, FA and MA at the forearm by peripheral quantitative computed tomography. In contrast to adrenarchal females, adrenarchal males with low %fat had low levels of DPD and Gal-Hyl. %fat was correlated with DPD in pre-adrenarchal males (r = 0.290) and females (r = 0.298). Cortical bone mineral density (BMDcort) was correlated with DPD (r = -0.351) in adrenarchal males. Controlled for BMDcort, FM was correlated with DPD in pre-adrenarchal males (r = 0.348), and FA was correlated with DPD in pre-adrenarchal females (r = 0.294). FFM was negatively correlated with Gal-Hyl in adrenarchal males (r = -0.436) and females (r = -0.338). Less than 40% of variance of excreted DPD and Gal-Hyl was explained by regression models based on parameters of body composition. The effect of body composition explains the minor part of variance of the urinary excretion of DPD and Gal-Hyl. The association of body composition to excreted DPD and Gal-Hyl was not explained by the effect of adipose tissue on bone formation and bone resorption.

Forearm length - a new tool to standardize bone parameters of the forearm measured with peripheral quantitative computed tomography in individuals with disproportional growth of forearm length and body height.

AIM: To investigate the relationship of forearm length (FL) or height to bone parameters of the forearm of a normal pediatric population in comparison to individuals with osteogenesis imperfecta (OI). METHODS: Data on FL, height and peripheral quantitative computed tomography measurements of the forearm were collected from participants of the DONALD study (140 males and 156 females; age 5-19 years) and from 73 patients with OI (53 males; mean age +/- SD: 11.7 +/- 3.3 years). Bone mineral content (BMC) was transformed into standard deviation score (SDS) according to height or FL. RESULTS: Height and Tanner stages significantly predicted FL in males (R(2)(adjusted) = 0.960) and females (R(2)(adjusted) = 0.934). Height was a stronger predictor of FL than Tanner stages. Compared to controls, patients with OI were characterized by lower BMC-SDS(FL) and lower BMC-SDS(height) (-0.37 +/- 1.77 vs. 0.00 +/- 0.97, p = 0.002, and -0.15 +/- 5.0 vs. -0.02 +/- 1.01, p = 0.011, respectively). BMC-SDS(FL) was not significantly lower than BMC-SDS(height) in controls, and also not lower in patients with OI (p = 0.865 and p = 0.809). The height/FL ratio was significantly decreased in patients with OI (mean +/- SD: 6.34 +/- 0.38 vs. 6.45 +/- 0.21, p = 0.001) compared with controls. CONCLUSION: Because of disproportional growth, BMC may be overestimated in OI patients.

Fetal and postnatal bone development: reviewing the role of mechanical stimuli and nutrition.

Fetal and postnatal bone development is by tradition viewed as a process of bone mineral accretion or an increase in bone mass. Accordingly, previous approaches to bone development in neonatology and early childhood have emphasized the determinants of peak bone mass and their relationship to osteopenia, osteoporosis and fractures in later life. This suggests that the neonatal period and early childhood is an important period for bone mineral accrual, and that peak bone mass may be correlated with subsequent skeletal health. Nevertheless, describing fetal and postnatal bone development just in terms of changes in mass or density means looking at bones as if they were amorphous heaps of calcium and phosphorus. In reality, of course, bones are complex three-dimensional structures. It is therefore important to create conditions that stimulate bones to become more stable. We suggest that functional bone physiology can be used to explain fetal and postnatal bone development and to devise strategies for improved bone development in both premature infants and neonates.

The 'functional muscle-cartilage unit': a reasonable approach to describe a putative relationship between muscle force and longitudinal growth at the forearm in children and adolescents?

BACKGROUND: Several reports give evidence that the perichondral ossificiation of bone tubes (modeling) strongly depends on muscular forces in children and adolescents. The present analyses intend to investigate the hypothesis that muscular forces also partly determine enchondral ossification and, therefore, longitudinal growth of bone tubes. SUBJECTS AND METHODS: Analyses were based on a single cross-sectional investigation with peripheral quantitative computed tomography in 296 individuals (age 5-19 years) participating in the Dortmund Nutritional and Anthropometric Longitudinally Designed (DONALD) study. RESULTS: Forearm length (FL) was correlated with body height in gender-related subgroups of prepubertal and pubertal individuals (rs between 0.76 and 0.86). Cross-sectional muscle area (MA) increased faster than FL and faster than cross-sectional bone area (BA) close to the distal growth plate in puberty. Close to the growth plate, longitudinal growth was faster than perichondral ossification in females. The ratio MA/BA (surrogate of pressure on the distal growth plate) was correlated with FL in prepubertal boys (r = -0.249, p = 0.043) and pubertal individuals (r = 0.153, p = 0.051). CONCLUSIONS: Results support the hypothesis that longitudinal growth precedes modeling at the distal forearm. Confounding variables such as puberty may modify the relationship between muscle forces and longitudinal growth at the forearm in boys.

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.

Osteogenesis imperfecta type VI in childhood and adolescence: effects of cyclical intravenous pamidronate treatment.

Cyclical intravenous treatment with pamidronate is of clinical benefit in children with moderate to severe osteogenesis imperfecta (OI) types I, III and IV, but there is no information on the effects of this treatment on the newly described OI type VI. Here, we report on the results of 3 years of pamidronate treatment in 10 children and adolescents with OI type VI (age range 0.8 to 14.5 years, three girls). Treatment effects were compared to those of 10 patients with OI types I, III, and IV, who were matched for age and disease severity (based on height and lumbar spine areal bone mineral density). During pamidronate therapy, lumbar spine areal bone mineral density z scores increased and lumbar spine vertebral bodies improved in shape. Iliac bone histomorphometry showed a tendency to higher cortical thickness (+53%, P=0.06) but the mineralization defect, a characteristic feature of OI type VI, did not change during pamidronate treatment. Annualized fracture incidence decreased from 3.1 per year before treatment to 1.4 fractures per year during treatment (P<0.05). Regarding mobility, the Pediatric Evaluation of Disability Inventory gross motor score increased by 42% during pamidronate treatment (P<0.005). Significant improvements were also found for age-related z scores of maximal isometric grip force. In comparison to the OI control group, the fracture incidence was higher and the gross motor scores were lower in OI type VI, both before and after pamidronate treatment (P<0.05 for each parameter). No differences were found between the groups for changes in densitometric measures and cortical thickness during pamidronate treatment. Our results suggest that 3 years of intravenous pamidronate therapy led to improvements in bone mineral mass, gross motor function, muscle force and fracture incidence in patients with OI type VI. However, the gains in mobility scores and reductions in fracture incidence during pamidronate treatment are less than in other OI types.

Predicting the growth response to growth hormone (GH) treatment in prepubertal and pubertal children with isolated GH deficiency--model validation in an observational setting (GeNeSIS).

AIM: Validation of a preexisting mathematical model for predicting height velocity in the first year of growth hormone (GH) treatment, using an independent cohort of pediatric patients with confirmed GH deficiency (GHD). DESIGN: 210 prepubertal and pubertal patients with isolated GHD were enrolled within the 'growth prediction module' of a prospective international postmarketing research program (GeNeSIS). METHODS: The patients were grouped as 'prepubertal', at 'start of puberty' and 'pubertal', and the performance of the model was validated by comparing predicted and observed height velocity (HV) in the first treatment year for each group. The operational characteristics of the model, when used as a screening method to predict poor and good growth response to GH, were calculated using the first year change in height standard deviation score as a cut-off for treatment response. RESULTS: Depending on pubertal stage, the growth prediction model explained 53-72% of the variability of the first year HV. The model fulfilled the statistical prerequisites to identify patients with poor and good responses to GH with sufficient reliability in individual patients. CONCLUSIONS: The growth prediction model was successfully validated in a large cohort of prepubertal and pubertal pediatric patients under field conditions.

Cyclical intravenous pamidronate treatment affects metaphyseal modeling in growing patients with osteogenesis imperfecta.

UNLABELLED: This analysis of 50 growing patients with osteogenesis imperfecta revealed that 2-4 years of pamidronate treatment lead to abnormalities in the shape of the distal femoral metaphyses. INTRODUCTION: Cyclical intravenous pamidronate therapy is of clinical benefit in children and adolescents with moderate to severe osteogenesis imperfecta (OI) but might interfere with the shaping of long bone metaphyses during growth. MATERIALS AND METHODS: We evaluated the distal femur in 50 growing children with moderate to severe OI (mean age, 6.7 +/- 3.4 years; 26 girls) who had received 2-4 years of pamidronate therapy (annual dose, 9 mg/kg body weight). The mediolateral width of the distal femoral growth plate and of the metaphysis, as well as the ratio between these two measures (called metaphyseal index), were determined on lower limb radiographs. RESULTS: Compared with untreated OI patients who were matched for OI type and age, pamidronate-treated patients had similar growth plate width but wider metaphyses, resulting in a 26% higher metaphyseal index (p < 0.001). Apart from the effect on bone shape, each pamidronate cycle induces a transverse line in metaphyses that are adjacent to active growth plates. Analyses of these transverse lines revealed that they persist for an average time of approximately 4 years, with a range from 2 to 8 years. CONCLUSIONS: Pamidronate interferes with the process of periosteal resorption that is normally responsible for shaping the distal femoral metaphysis. Pamidronate-induced transverse lines disappear with time, supporting the view that these lines represent horizontal trabeculae that undergo remodeling. There is no evidence at present that these treatment induced morphological changes have any clinical implications.

Pamidronate in children and adolescents with osteogenesis imperfecta: effect of treatment discontinuation.

CONTEXT: Cyclical iv pamidronate is a widely used symptomatic therapy of osteogenesis imperfecta (OI). What happens after treatment discontinuation is unknown. OBJECTIVE: The objective of this study was to assess the effect of pamidronate discontinuation in pediatric patients with moderate to severe OI types I, III, and IV. DESIGN: This was an open-label controlled and observational study in patients who had received pamidronate for more than 3 yr. SETTING: This study was performed at a pediatric metabolic bone research unit. PATIENTS: In the controlled study, 12 pairs of patients were matched for age, OI severity, and duration of pamidronate treatment. Pamidronate was stopped in one patient of each pair; the other continued to receive treatment. In the observational study, 38 OI patients were examined (mean age, 13.8 yr). INTERVENTION: The intervention was discontinuation of pamidronate treatment for 2 yr. MAIN OUTCOME MEASURES: The main outcome measures were lumbar spine bone mineral content and areal bone mineral density (aBMD), biochemical markers of bone metabolism, fracture incidence, and clinical evaluation. RESULTS: In the controlled study, bone resorption activity was higher after treatment discontinuation. Bone mineral content continued to increase in both groups. aBMD z-scores decreased in the untreated group, but increased in the continuation cohort. Fracture rates and functional status were similar between groups. In the observational study, bone resorption activity increased after treatment discontinuation, but remained significantly lower than in untreated OI patients. Bone mineral content and aBMD continued to increase, whereas aBMD z-scores decreased. Changes were faster in patients who continued growing. CONCLUSIONS: Bone metabolism is still suppressed 2 yr after pamidronate discontinuation. Bone mass gains continue after treatment is stopped, but lumbar spine aBMD increases less than in healthy subjects. The size of these effects is growth dependent.

Vertebral morphometry in children and adolescents with osteogenesis imperfecta: effect of intravenous pamidronate treatment.

Results in small patient series suggest that cyclical intravenous treatment with pamidronate can lead to reshaping of compressed vertebral bodies in children and adolescents with osteogenesis imperfecta (OI), but more detailed analyses are lacking. In this study of patients with moderate to severe OI (age range 0.1 to 16.7 years), we used vertebral morphometry to longitudinally assess changes in lumbar vertebral shape before (n = 17 patients) and during 2 to 4 years of pamidronate treatment (n = 72 patients). Anterior, posterior and midpoint vertebral heights of lumbar vertebrae L1 to L4 were determined on lateral lumbar spine X-rays and were related to vertebral body length in the antero-posterior direction. Before pamidronate treatment, vertebral body height ratios did not change significantly, but the mean concavity index (defined as the ratio between midpoint and posterior vertebral body heights) decreased by 22% (P = 0.002). Pamidronate treatment was associated with an increase in vertebral height ratio at each of the 12 sites that were analyzed. Consequently, patients who had received pamidronate for an average of 3 years had less compressed vertebrae than a historical control group of patients who had the same OI type, age and sex but who had not received pamidronate. Multiple regression analysis revealed that age was negatively and lumbar spine areal bone mineral density z score was positively associated with vertebral shape at baseline. The main determinant of treatment response was the severity of vertebral deformities at baseline. These results suggest that vertebral deformations worsen in patients with moderate to severe OI who do not receive medical treatment and that pamidronate helps to reverse this trend. In moderate to severe forms of OI, pamidronate should be started as early as possible to treat or to prevent vertebral deformations.

High and low density in the same bone: a study on children and adolescents with mild osteogenesis imperfecta.

Children and adolescents with osteogenesis imperfecta (OI) generally have low bone mineral density (BMD) at the lumbar spine and hip. However, the effects of the disease on diaphyseal bone have not been well characterized, even though long-bone fractures are common in such patients. In this study on 42 fully mobile children and adolescents with mild OI (age 6-19 years; 17 girls), lumbar spine, radius (metaphysis and diaphysis) and second metacarpal (diaphysis) were analyzed using dual-energy X-ray absorptiometry, peripheral quantitative computed tomography and radiogrammetry, respectively. Bone mineral content at the lumbar spine, radial metaphysis and radial diaphysis was between 25% and 31% lower than in age-matched healthy children and adolescents. At the lumbar spine and radial metaphysis, bone size (as estimated from projection area and cross-sectional area, respectively) was normal or only slightly below the results expected for healthy individuals, whereas bone size was very small at the diaphyseal sites of the radius and the second metacarpal. Total volumetric BMD is defined as the ratio between bone mineral content and bone volume. Therefore, these differences in bone size between skeletal locations led to markedly discrepant results for total volumetric BMD. Total volumetric BMD was low at the lumbar spine (23% below result expected for healthy subjects of the same age) and the radial metaphysis (-15%) but elevated at the radial diaphysis (+25%; all differences to controls significant at P < 0.001). Despite high volumetric BMD, estimated bending strength at the radial diaphysis was very low. These results demonstrate that volumetric BMD can be abnormally high and low within the same bone in the same individual and highlight the fact that volumetric BMD at diaphyseal sites does not provide a good estimate of bone strength when bone size is abnormal.

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.

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.

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.

Risedronate in the treatment of mild pediatric osteogenesis imperfecta: a randomized placebo-controlled study.

Intravenous pamidronate is the most widely used treatment for moderate to severe osteogenesis imperfecta (OI). Currently, there is no medical treatment for patients with mild OI. We conducted a single-center randomized double-blind placebo-controlled trial to examine the efficacy and safety of oral risedronate in the treatment of pediatric patients with mild OI. A total of 26 children and adolescents (age, 6.1-17.7 yr; 11 girls) with OI type I were randomized to either placebo (N = 13) or risedronate (N = 13) for 2 yr. Risedronate doses were 15 mg once per week in patients weighing <40 kg and 30 mg once per week in patients weighing >40 kg. After 2 yr of treatment, risedronate decreased serum levels of the bone resorption marker collagen type I N-telopeptide by 35% compared with a 6% reduction with placebo (p = 0.003). Risedronate increased lumbar spine areal BMD Z-scores by 0.65, whereas patients receiving placebo experienced a decrease of 0.15 (p = 0.002). In contrast, no significant treatment differences in bone mass and density were found at the radial metaphysis and diaphysis, the hip, and the total body. Histomorphometric analysis of transiliac bone biopsies at the end of the study period did not show a significant treatment difference in cortical width, trabecular bone volume, or parameters of bone turnover. Similarly, there was no detectable treatment effect on vertebral morphometry, second metacarpal cortical width, grip force, bone pain, or number of new fractures. Regarding safety, risedronate was generally well tolerated, and the incidence of clinical or laboratory adverse experiences was similar among treatment groups. These results suggest that the skeletal effects of oral risedronate are weaker than those that are commonly observed with intravenous pamidronate treatment but still lead to an increase in lumbar spine areal BMD. Future studies should investigate whether oral risedronate is effective in reducing fracture rates in children and adolescents with mild OI type I.

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 patient's needs, resulting in lower overall GH dose.

Subcutaneous fat and body fat mass have different effects on bone development at the forearm in children and adolescents.

The present study investigated whether subcutaneous fat differs in the impact on bone development from fat mass (FM). We analyzed 295 healthy children and adolescents (age 5-19 years, 139 males) for FM by measuring four skinfold thicknesses and for bone development and body composition at the forearm by peripheral quantitative computed tomography in a cross-sectional investigation. Relative cross-sectional fat area (FA) was a surrogate for relative subcutaneous FM at the forearm and was associated positively with percent fat in prepubertal individuals and pubertal females but negatively in pubertal males. Percent FM was associated with trabecular bone mineral density (BMDtrab) in prepubertal individuals (females r = 0.394, males r = 0.242) and pubertal individuals (females r = 0.215, males r = -0.275). Bone mineral count was correlated with percent FM in pubertal males (r = -0.287). FA was correlated with BMDtrab (r = 0.285) and with cortical bone mineral density (BMDcort, r = -0.296) in pubertal females. The ratio FA/ FM was negatively correlated with BMDcort (r = -0.299) in pubertal females. Pubertal females with relatively high subcutaneous fat area (high ratio FA/FM) were characterized by lower bone strength (P = 0.047). FM and the relative amount of subcutaneous fat have effects on bone formation and resorption that depend on gender and puberty. Especially in pubertal females, higher levels of subcutaneous fat may decrease bone strength due to increased cortical remodeling.

Effect of intravenous pamidronate therapy on functional abilities and level of ambulation in children with osteogenesis imperfecta.

OBJECTIVE: To evaluate the functional abilities and the level of ambulation during pamidronate therapy in children with moderate to severe osteogenesis imperfecta. STUDY DESIGN: Functional abilities, ambulation, and grip force were assessed in 59 patients (mean age, 6.1 years; range, 0.5-15.7 years; 30 girls) during 3 years of pamidronate treatment. Functional skills (mobility and self-care) were both assessed by using the Pediatric Evaluation of Disability Inventory. Ambulation level was assessed by using the modified Bleck score. For 48 patients, results after 3 years of pamidronate treatment could be matched to those of patients with similar age and disease severity who had not received pamidronate. RESULTS: Mobility and self-care scores increased during the study period (+43% and +30%, respectively). The average ambulation score changed from 0.8 to 1.9. Maximal isometric grip force increased by 63%. Mobility and ambulation scores and grip force measures were significantly higher than in patients who had not received pamidronate. The difference in self-care scores did not reach significance. CONCLUSION: This study suggests that cyclical pamidronate treatment improves mobility, ambulation level, and muscle force in children with moderate to severe osteogenesis imperfecta.

Effect of pamidronate treatment on vertebral deformity in children with primary osteoporosis. A pilot study using radiographic morphometry.

OBJECTIVE: Bisphosphonates are effectively used in treatment for primary osteoporosis in children. In the present study, we quantitatively evaluated the effect of pamidronate treatment on lumbar vertebrae in children with primary osteoporosis using radiographic morphometry. METHODS: Paired lateral radiographs of the lumbar spine were obtained before and after pamidronate treatment in 5 children with primary osteoporosis. To characterize vertebral deformities, specific morphometrical ratios were calculated for vertebral bodies L1-L4. RESULTS: Significant reshape of lumbar vertebrae was observed: the concavity index (middle-anterior ratio) decreased from 55 to 36% (p = 0.006), and the anterior-posterior ratio (used as a surrogate of wedge deformity) decreased from 25 to 11% (p = 0.001). CONCLUSIONS: Pamidronate treatment significantly influences the restoration of vertebral fractures in children with primary osteoporosis. The present study demonstrates that radiographic morphometry is a suitable tool for quantitative assessment of the vertebral deformities in childhood.