Bisphosphonate therapy is the mainstay of pharmacological intervention in young people with skeletal fragility. The evidence of its use in a variety of conditions remains limited despite over three decades of clinical experience. On behalf of the Australasian Paediatric Endocrine Group, this evidence-based consensus guideline presents recommendations and discusses the graded evidence (using the GRADE system) for these recommendations. Primary bone fragility disorders such as osteogenesis imperfecta are considered separately from osteoporosis secondary to other clinical conditions (such as cerebral palsy, Duchenne muscular dystrophy). The use of bisphosphonates in non-fragility conditions, such as fibrous dysplasia, avascular necrosis, bone cysts and hypercalcaemia, is also discussed. While these guidelines provide an evidence-based approach where possible, further research is required in all clinical applications in order to strengthen the recommendations made.

Most Australian children and adolescents with type 1 diabetes are not meeting the recognised HbA1c target. The prevalence of overweight and obesity is high. There is an urgent need to identify barriers to achieving optimal glycaemic control in this population.

CD is a common comorbidity in youth with type 1 diabetes. Differences in CD prevalence may reflect international variation in screening and diagnostic practices, and/or CD risk. Although glycemic control was not different, the lower height SDS supports close monitoring of growth and nutrition in this population.

Context Germline mutations in the aryl hydrocarbon receptor-interacting protein (AIP) gene are responsible for a subset of familial isolated pituitary adenoma (FIPA) cases and sporadic pituitary neuroendocrine tumors (PitNETs). Objective To compare prospectively diagnosed AIP mutation-positive (AIPmut) PitNET patients with clinically presenting patients and to compare the clinical characteristics of AIPmut and AIPneg PitNET patients. Design 12-year prospective, observational study. Participants & Setting We studied probands and family members of FIPA kindreds and sporadic patients with disease onset ≤18 years or macroadenomas with onset ≤30 years (n = 1477). This was a collaborative study conducted at referral centers for pituitary diseases. Interventions & Outcome AIP testing and clinical screening for pituitary disease. Comparison of characteristics of prospectively diagnosed (n = 22) vs clinically presenting AIPmut PitNET patients (n = 145), and AIPmut (n = 167) vs AIPneg PitNET patients (n = 1310). Results Prospectively diagnosed AIPmut PitNET patients had smaller lesions with less suprasellar extension or cavernous sinus invasion and required fewer treatments with fewer operations and no radiotherapy compared with clinically presenting cases; there were fewer cases with active disease and hypopituitarism at last follow-up. When comparing AIPmut and AIPneg cases, AIPmut patients were more often males, younger, more often had GH excess, pituitary apoplexy, suprasellar extension, and more patients required multimodal therapy, including radiotherapy. AIPmut patients (n = 136) with GH excess were taller than AIPneg counterparts (n = 650). Conclusions Prospectively diagnosed AIPmut patients show better outcomes than clinically presenting cases, demonstrating the benefits of genetic and clinical screening. AIP-related pituitary disease has a wide spectrum ranging from aggressively growing lesions to stable or indolent disease course.

Mean stool frequency decreased with age as did the variation. This is a combined effect of age and feed type. These data can be used as a guide to the bowel habit of healthy Australian children.

Tham E, Liu J, Innis S, Thompson D, Gaylinn BD, Bogarin R, Haim A, Thorner MO, Chanoine JP. Acylated ghrelin concentrations are markedly decreased during pregnancy in mothers with and without gestational diabetes: relationship with cholinesterase. Am J Physiol Endocrinol Metab 296: E1093-E1100, 2009. First published February 24, 2009 doi:10.1152 doi:10. /ajpendo.90866.2008 ghrelin stimulates food intake and growth hormone secretion and is deacylated into desacyl ghrelin by butyrylcholinesterase. Acylated and desacyl ghrelin both promote adipogenesis. Ghrelin concentrations decrease with hyperglycemia and hyperinsulinism. We hypothesized that 1) acylated ghrelin increases during pregnancy, contributing positively to energy balance, but is lower in women with gestational diabetes and 2) butyrylcholinesterase activity is inversely correlated with acylated ghrelin concentrations. In a first group of subjects, using two-site sandwich ghrelin assays that specifically detect full-length forms, we investigated women with and without gestational diabetes (n ϭ 14/group) during pregnancy and after delivery. We examined whether changes in ghrelin during a test meal were correlated with changes in pituitary growth hormone [assessed through calculation of the area under the curve (AUC) during the test meal]. In postpartum subjects, the percent of total ghrelin that is acylated was four to five times higher than previously observed using single antibody assays. During pregnancy, acylated ghrelin concentrations (mean Ϯ SE) were lower compared with the postpartum period throughout the meal (AUC 1.2 Ϯ 0.2 vs. 10.2 Ϯ 1.9 ng ⅐ ml Ϫ1 ⅐ 90 min Ϫ1 , P Ͻ 0.001). In the postpartum, acylated ghrelin and growth hormone were positively correlated (r ϭ 0.50, P ϭ 0.007). Desacyl (but not acylated) ghrelin was increased in subjects with gestational diabetes during and after pregnancy (AUC 15.4 Ϯ 1.9 vs. 8.6 Ϯ 1.2 ng ⅐ ml Ϫ1 ⅐ 90 min Ϫ1 , P ϭ 0.005). In a second group of subjects (n ϭ 13), acylated ghrelin was similarly suppressed during pregnancy. Circulating octanoate concentrations (3.1 Ϯ 0.5 vs. 4.5 Ϯ 0.6 g/ml, P ϭ 0.029) and cholinesterase activity (705 Ϯ 33 vs. 1,013 Ϯ 56 U/ml, P Ͻ 0.001) were lower during pregnancy compared with the postpartum period. In conclusion, acylated ghrelin markedly decreases during pregnancy, likely because of a decrease in the acylation process. Desacyl ghrelin increases in gestational diabetes, possibly reflecting resistance to the inhibitory effect of insulin on ghrelin secretion. In vitro studies suggest that, in humans, circulating ghrelin is deacylated rapidly, at least in part by the enzyme cholinesterase (also known as pseudocholinesterase or butyrylcholinesterase, EC 3.1.1.8) (9).Both AG and DG could potentially play a physiological role in energy balance. Exogenous administration of AG, but not DG, stimulates GH secretion (35) and has orexigenic effects (41) in humans. AG injection also causes hyperglycemia and a decrease in circulating insulin (2). In addition, in rodents, administration of both AG...

Hypoglycemia, but not glucose variability, during continuous glucose monitoring relates to impaired vascular endothelial function in children with type 1 diabetes. Hypoglycemia may be an additional risk factor for early cardiovascular disease, but the effect of glucose variability, independent of glycosylated hemoglobin, on vascular function remains uncertain.

IntroductionPerthes disease (PD) is an idiopathic disorder presenting with avascular necrosis to the femoral head, which frequently results in flattening. Long-term function is directly related to the subsequent femoral head sphericity. Current treatment includes mechanical modalities and surgical procedures, which are therapeutic but are not uniformly able to prevent collapse. The use of the nitrogen-containing bisphosphonate zoledronic acid (ZA) to inhibit osteoclastic bone resorption is aimed at preserving femoral head strength, reducing collapse and thus maintaining shape. The proposed multicentre, prospective, randomised controlled trial intends to evaluate the efficacy of ZA treatment in PD.Methods and analysisAn open-label randomised control trial recruiting 100 children (50 each treatment arm) 5 to 16 years old with unilateral PD. Subjects are randomly assigned to either (a) ZA and standard care or (b) Standard care. The primary outcome measure is deformity index (DI), a radiographic parameter of femoral head roundness assessed at 24 months, following 12 months of ZA treatment (3-monthly doses of ZA 0.025 mg/kg at baseline, 3, 6, 9 and 12 months) plus 12 months observation (group A) or 24 months of observation (group B). Secondary outcome measures are femoral head subluxation, Faces Pain scale, Harris hip score and quality of life. Assessments are made at baseline, 3 monthly during the first year of follow-up and then 6 monthly, until the 24th month.Ethics and disseminationThe study commenced following the written approval from the Human Research Ethics Committee. Safety considerations regarding the effects of ZA are monitored which include the subject’s symptomatology, mineral status, bone mass and turnover activity, and metaphyseal modelling. Data handling plan requires that all documents, clinical information, biological samples and investigation results will be held in strict confidence by study investigators to preserve its safety and confidentiality.Trial registration numberAustralian and New Zealand Clinical Trials ACTRN12610000407099, pre-results.