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Introduction: When expressed as a percentage of the average result in young adults, bone mineral content lags behind bone length before puberty. Even though this observation has led to speculation about bone fragility in children, such relationships could simply be due to scaling effects when measures with different geometrical dimensions are compared., Methods: The study population comprised 145 healthy subjects (6-25 years, 94 females). Magnetic resonance imaging and dual-energy X-ray absorptiometry were used to determine femur length, bone mineral content, cortical bone mineral density, cross-sectional bone geometry (bone diameter; cortical thickness; total, cortical and medullary areas; cross-sectional and polar moments of area; bone strength index) and muscle area at the proximal one-third site of the femur. Results were dimensionally scaled by raising two-, three- and four-dimensional variables to the power of 1/2, 1/3 and 1/4, respectively. Sex-differences were also assessed before and after functionally adjusting variables for femur length and weight or muscle size., Results: In prepubertal children, unscaled results expressed as percentages of adult values were lowest for variables with the highest dimensions (e.g., moments of area

Background: The insulin tolerance test (ITT) has become less popular in paediatrics because of the risks associated with hypoglycaemia. Human corticotrophin-releasing hormone (hCRH) test results correlate with the ITT and may be an acceptable method to test for central adrenal insufficiency (CAI). Simpler tests, such as the low dose Synacthen test (LDST) and 9am cortisol, have also been proposed., Objective: To compare the ability of the hCRH test, LDST, 9am cortisol level and 24-h cortisol profiles to diagnose CAI in a paediatric population., Design and Setting: A cross-sectional study in a tertiary paediatric endocrine clinic., Participants: Thirty-one children and adolescents (aged 2.3-18.3 years) with CAI risk factors had an hCRH test, LDST, 9am cortisol and 24-h cortisol profile performed., Results: Of 23 patients with confirmed CAI (hCRH peak cortisol < 400 nmol/), 19 failed the LDST (peak cortisol < 267 nmol/l, i.e. 10th percentile for controls). Nineteen would have failed based on the 10th percentile cut point for 9am cortisol (< 140 nmol/l). Using receiver operating characteristic (ROC) curve coordinates, a 9am cortisol < 108 nmol/l was sensitive (83%) and specific (99%) for CAI. The 9am cortisol levels measured on two occasions were repeatable (94%) and correlated (r = 0.83, P = 0.01). All eight adrenally sufficient patients (hCRH peak cortisol > or = 400 nmol/l) passed the LDST. Seven had normal 9am cortisol (> or = 140 nmol/l). The 24-h cortisol area under the curve (AUC) for these patients was within the 10th-90th percentiles for control subjects' AUC. The peak cortisol to hCRH and LDST were correlated (r = 0.88, P = 0.01), with no difference between the peaks (mean difference -5.3 nmol/l, P = 0.69)., Conclusions: In children with CAI risk factors, the diagnosis can be made if unstressed 9am cortisol is < 108 nmol/l. As cortisol levels > 381 nmol/l are highly suggestive of normal hypothalamic-pituitary-adrenal (HPA) function, stimulation testing need only be performed if 9am cortisol is 108-381 nmol/l. The LDST should be interpreted cautiously because mild CAI may be missed. When stimulation results are marginal, 24-h cortisol profiles can provide reassurance of normal cortisol status.

Unlabelled: There are few longitudinal data on bone development during puberty in children with low calcium intake. This 5-yr longitudinal study showed that, in Chinese girls, the mean apparent calcium retention efficiency during puberty was 40.9%, PHV occurred at 3-0 yr before menarche, and peak bone mineral accretion occurred 1 yr later than PHV. Chinese girls have high calcium retention efficiency during puberty., Introduction: There are few longitudinal data on bone development during puberty in children with low dietary calcium intake. The aim of this study was to examine the rate of growth and bone mineral accretion and study the predictors of total body BMC during puberty in a 5-yr longitudinal study with Chinese girls., Materials and Methods: Ninety-two girls, 9.5-10.5 yr of age at baseline, from the unsupplemented control group of a school milk intervention trial were included in this analysis. Data on anthropometric measurements, total body BMC as assessed by DXA, and calcium intake as assessed by a 3-day food record were obtained at baseline and 1, 2, 4, and 5 yr., Results: The mean age of menarche was 12.1 +/- 1.0 yr. The mean annual rate of bone mineral accretion was 197.4 g/yr during the follow-up period, representing a calcium accretion rate of 162.3 mg/d. This calcium retention rate and the average dietary calcium intake of 444.1 mg/d gave an apparent calcium retention efficiency of 40.9%. Peak height velocity (PHV) occurred at 3-0 yr before menarche. Peak bone mineral accretion occurred 1 yr later than PHV. There was a decrease in size-corrected BMD in the year before menarche. In the linear mixed-effects model analysis containing body size and lifestyle factors, we found that height, body weight, and calcium intake were significant independent predictors of total body BMC., Conclusions: Chinese girls with low habitual dietary calcium intake have high calcium retention efficiency during puberty. Because calcium intake is a significant predictor of total body BMC, increasing dietary calcium intake may have beneficial effects on bone mineral accretion in these girls.

Background: Body mass index (BMI) may not indicate the level of central adiposity associated with the clustering of cardiovascular disease (CVD) risk factors. Hence, it has been recommended that waist circumference be used as an alternative measure., Objective: The objective was to investigate whether waist circumference in midchildhood is more effective at predicting cardiovascular disease risk clustering in adolescence than is BMI., Design: Anthropometric measurements were made in 342 children aged 8 y. Seven years later, anthropometric measurements were made in 290 participants, and metabolic profiles were determined in 172 participants., Results: At 15 y, between 9.4% and 11.0% of adolescents were defined as having CVD risk clustering. Children who were overweight or obese at 8 y of age were 7 times (odds ratio: 6.9; 95% CI: 2.5, 19.0; P < 0.001) as likely to have CVD risk clustering in adolescence than were their peers who were not overweight or obese. Those with an increased waist circumference at 8 y were 4 times (3.6; 1.0, 12.9; P = 0.061) as likely to have CVD risk clustering in adolescence than were children with a smaller waist circumference. Neither BMI nor waist circumference were predictive of CVD risk clustering if adiposity was not included as a risk factor., Conclusions: The association between measures of adiposity in midchildhood and later adverse CVD risk is a result of the tracking of adiposity status. Our results do not support the need to measure waist circumference in children, in addition to BMI, to identify those at increased risk of CVD risk factor clustering in adolescence.

Introduction: Previous reports have shown a high frequency of hypocalcaemia and flu-like symptoms following an initial first zoledronic acid dose of 0.02-0.025 mg/kg in children., Methods: We systematically evaluated the mineral status and symptomatology of 63 children with a variety of bone disorders treated with an initial zoledronic acid dose of 0.0125 mg/kg. The Mann-Whitney U test, chi-squared test and Fisher's exact test were used as appropriate., Results: 0.0125 mg/kg zoledronic acid reduced the incidence and intensity of hypocalcaemia but not the incidence of the flu-like symptoms compared to higher doses. Within the low dose cohort, flu-like symptoms were associated with an acute inflammatory response. Children who became hypocalcaemic received a higher dose in relation to their body mass index and body surface area., Conclusion: Reducing the initial zoledronic acid dose in children decreased the incidence of hypocalcaemia and thus improved safety. Dosing on the basis of body mass index or body surface area instead of body weight may further reduce the incidence of hypocalcaemia.

Background: Femoral head osteonecrosis as a result of trauma in adolescents has a poor prognosis as a result of femoral head collapse and subsequent degenerative change of the hip. There are currently no satisfactory treatments for adolescents with this condition, although bisphosphonate therapy has improved the outcome in animal models of osteonecrosis. We evaluated bisphosphonate therapy for femoral head osteonecrosis following trauma in adolescents., Methods: We established a protocol for identifying adolescents with osteonecrosis of the femoral head with use of bone scans immediately after surgical treatment of hips at risk for the development of osteonecrosis following trauma. In a consecutive group of twenty-eight patients with an unstable slipped capital femoral epiphysis (twenty-two patients), femoral neck fracture (four), or traumatic hip dislocation (two), seventeen patients with osteonecrosis were identified. These patients (thirteen boys and four girls with a mean age of 12.7 years) and their families gave consent for the patients to receive treatment with intravenous bisphosphonates. The average duration of the bisphosphonate treatment was 20.3 months (range, seven to thirty-nine months). All patients were followed clinically and radiographically for a minimum of two years., Results: After a mean duration of follow-up of 38.7 months, fourteen patients were pain-free. Clinically, all seventeen patients had a good or excellent outcome. On the average, the Harris hip score was 91.2 points, the Iowa Hip Rating was 92.1 points, and the Global Pediatric Outcomes Data Collection Instrument (PODCI) score was 91.5 points. According to the radiographic classification system of Stulberg et al., nine hips were rated as Class I or II; six, as Class III; and two, as Class IV., Conclusions: Bisphosphonate therapy may play an adjunctive role in the treatment of adolescents with osteonecrosis of the femoral head following trauma.

Distraction osteogenesis is a powerful stimulus for new bone (and tissue) generation (anabolism). Biomechanical stimulation by distraction of the regenerate region results in a high rate of tissue and bone production. However, catabolism (bone resorption) can also occur, the process potentially accentuated in a stress-shielded environment of an external fixator. Regenerate insufficiency can result in regenerate bending or fracture after frame removal. Experimental evidence has demonstrated that bisphosphonates may mediate improved local limb bone mineral density (BMD) and regenerate strength in animal models. Seven patients who had undergone limb lengthening using an Ilizarov device were found to have regenerate insufficiency. Poor regenerate quality led to consideration for intervention. With informed consent, patients received a therapeutic regime of intravenous pamidronate (n = 3) or zoledronic acid (n = 4).The mean age was 13.8 years (SD, +/-3.6 years), with a minimum follow-up period of 4 months after fixator removal. The sites of regenerate insufficiency were the proximal tibia (n = 6) and the distal femur (n = 1). The mean time interval in the fixator before bisphosphonate treatment was 170 days (range, 124-252 days), with an average length increase of 4.8 cm (SD, +/-1.1 cm). At time of intravenous bisphosphonate treatment, dual-energy x-ray absorptiometry measurements demonstrated a reduced BMD (mean, 62.1%; SD, +/-12.6%) in the bone adjacent to the lengthening site of the nonoperated side. Mean healing index was high at 79.6 days/cm (range, 64.4-108.0 days/cm), reflecting the observed regenerate insufficiency. No significant systemic complications were encountered. Six of the patient's fixators were removed without requirement for other intervention, demonstrating a rapid and sustained improvement in local BMD, increasing to a mean of 85.6% (SD, +/-13.3%) of the healthy side. One patient did not respond and subsequently healed after percutaneous osteogenic protein 1 (bone morphogenetic protein 7) and bone marrow injection. Most failed regenerate cases maintain some underlying anabolic activity and can be treated successfully with bisphosphonate therapy, which reduces catabolism. Only 1 case required percutaneous administration of an anabolic therapy to achieve union. These minimally invasive approaches may lessen the need for surgery in a group where significant surgical reintervention could otherwise be required.

Neurofibromatosis type 1 (NF1) is a common genetic disorder affecting 1 in 3000 live births. It is well documented to be associated with bony deformities and other orthopaedic problems. Based on our observation that NF1 patients undergoing orthopaedic surgery often had osteopenic bone, we performed a study to assess the bone mineral density of a cohort of children with NF1 without orthopaedic defects.Twenty-three patients were recruited from the neurofibromatosis clinic. The bone mineral density of the total body, lumbar spine, and proximal femur was measured using dual-energy x-ray absorptiometry. Quantitative ultrasound was used to measure broadband ultrasonic attenuation at both heels. The group's mean dual-energy x-ray absorptiometry sex- and age-matched Z scores were below normal (-0.8 +/- 1.1, -0.8 +/- 1.2, -0.7 +/- 0.8, -0.6 +/- 1.1, -0.6 +/- 0.9, -0.6 +/- 1.1 for the total body, arms, legs, lumbar spine, and right and left femoral neck, respectively; all P < 0.01). Although some individuals had normal bone mass, 30% had total body Z scores below -1.5. The mean heel broadband ultrasonic attenuation Z score was also lower than normal (-0.8 +/- 0.6; P < 0.001). Children with NF1 have a general tendency toward osteopenia, suggesting an abnormal underlying bone phenotype. This may be relevant when considering operative intervention and, if better understood, may partially explain poor bone healing associated with NF1.

Objective: The aim of glucocorticoid replacement therapy in ACTH-deficient patients is to mimic the normal diurnal variation of cortisol. However, current hydrocortisone (HC) replacement results in prolonged episodes of hypocortisolaemia and supraphysiological peaks. Plasma cortisol profiles are an accurate yet labour-intensive method of assessing HC replacement. Salivary and bloodspot cortisol sampling methods are less invasive and may be useful tools for assessing glucocorticoid replacement, particularly in children. Therefore, we aimed to define normal salivary and bloodspot cortisol levels in children and their correlations with the gold standard (plasma cortisol)., Design: Cross-sectional study in a paediatric teaching hospital., Methods: Plasma, saliva and bloodspot cortisol profiles were performed on 30 ACTH-deficient children and 22 healthy siblings., Results: In ACTH-deficient patients taking oral HC, the bloodspot-plasma correlation (p=0.90) was stronger than the salivary-plasma correlation (p=0.49). Using target ranges for salivary and bloodspot cortisol levels based on normal data from control subjects, the less invasive sampling methods had low rates of agreement with plasma cortisol target ranges (saliva 65% and bloodspot 75%). Using the plasma-bloodspot correlation regression equation to convert bloodspot to calculated plasma cortisol, there was a high concordance between calculated and actual measured plasma cortisol (88%)., Conclusion: Bloodspot cortisol sampling is a feasible and accurate method for monitoring oral HC replacement in paediatric patients without necessitating hospital admission, but salivary sampling is not useful.

Purpose: To clarify the effect of chronological age, height, lean tissue mass, and menstrual status on standard reported DXA (dual-energy x-ray absorptiometry) measures., Methods: Growth and DXA data from a retrospective longitudinal cohort of 30 adolescent females with anorexia nervosa (AN) were examined. Areal bone mineral density (aBMD), total body bone mineral content (BMC) and total body bone area were measured and standardized for age, height, lean tissue mass, and total bone area. We then examined the changes in these parameters after 12 months of multidisciplinary treatment., Results: The subjects had lower BMC and aBMD than the age- and height-matched reference population at baseline, there were further decreases in these parameters with treatment. BMC adjusted for lean tissue mass and bone area were normal at baseline and there was no significant change with treatment. Bone area adjusted for height was low at baseline and decreased despite treatment., Conclusion: Our data suggest that the low age- and height-adjusted bone mineral content and bone mineral density in females with AN is secondary to poor bone growth leading to low bone area. These subjects had relatively normal bone mineral content for their bone size and lean tissue mass. Changes in bone size were proportional to changes in lean tissue mass.

Neonatal severe hyperparathyroidism is a rare condition that presents as striking hyperparathyroidism, hypercalcaemia, and metabolic bone disease. The aetiology needs to be determined soon after diagnosis to direct appropriate management and to determine an accurate prognosis. Taking a family history is a valuable clinical tool in paediatric medicine. Presented here is the case of a neonate presenting with severe hyperparathyroidism. Obtaining the family history, coupled with basic parental studies, enabled a rapid aetiological diagnosis, which allowed for conservative management.

Context and Objective: Menarche is a milestone of reproductive development, and its timing may be differentially influenced by the growth conditions before birth and those between birth and puberty. The present study explored the relationships among menarcheal timing and markers of prenatal and midchildhood growth in healthy Australian girls., Setting, Design, and Patients: A total of 156 girls aged 8 yr from a birth cohort of full-term babies had height, weight, and waist circumference measured. One hundred three girls had dual x-ray absorptiometry performed and blood analyzed for insulin, leptin, IGF-I, estradiol, and dehydroepiandrosterone sulfate levels. Girls were followed up at age 15 yr and their age of menarche was recorded., Main Outcome Measures: Measures included age of menarche; birth weight and birth length; height, weight, waist circumference, and body composition by dual x-ray absorptiometry; and plasma insulin, leptin, IGF-I, estradiol, and dehydroepiandrosterone sulfate at age 8 yr., Results: Girls with earlier menarche were light and long at birth and had higher total and central adiposity and IGF-I and estradiol levels in midchildhood, compared with those with later menarche. Age of menarche was best predicted by combining size at birth and body mass index z score at age 8 yr (r2 = 0.12; P < 0.001)., Conclusions: The timing of menarche appears to be influenced in opposing directions by pre- and postnatal growth. Menarche was found to occur earlier in girls who were long and light at birth and who had a higher fat mass and circulating IGF-I in childhood. These findings may partly explain ethnic differences and secular trends in the age of menarche.

Background: Few young people meet television viewing guidelines., Purpose: To determine the association between factors in the family and home environment and watching television, including videos and DVDs, in early adolescence., Methods: Cross-sectional, self-report survey of 343 adolescents aged 12-13 years (173 girls), and their parents (338 mothers, 293 fathers). Main measures were factors in the family and home environment potentially associated with adolescents spending >or= 2 hours per day in front of the television. Factors examined included family structure, opportunities to watch television/video/DVDs, perceptions of rules and regulations on television viewing, and television viewing practices., Results: Two-thirds of adolescents watched >or= 2 hours television per day. Factors in the family and home environment associated with adolescents watching television >or= 2 hours per day include adolescents who have siblings (Adjusted Odds Ratio [95%CI] AOR = 3.0 [1.2, 7.8]); access to pay television (AOR = 2.0 [1.1, 3.7]); ate snacks while watching television (AOR = 3.1 [1.8, 5.4]); co-viewed television with parents (AOR = 2.3 [1.3, 4.2]); and had mothers who watched >or= 2 hours television per day (AOR = 2.4 [1.3, 4.6])., Conclusion: There are factors in the family and home environment that influence the volume of television viewed by 12-13 year olds. Television plays a central role in the family environment, potentially providing a means of recreation among families of young adolescents for little cost. Interventions which target family television viewing practices and those of parents, in particular, are more likely to be effective than interventions which directly target adolescent viewing times.

Vitamin D deficiency has re-emerged as a significant paediatric health issue, with complications including hypocalcaemic seizures, rickets, limb pain and fracture. A major risk factor for infants is maternal vitamin D deficiency. For older infants and children, risk factors include dark skin colour, cultural practices, prolonged breastfeeding, restricted sun exposure and certain medical conditions. To prevent vitamin D deficiency in infants, pregnant women, especially those who are dark-skinned or veiled, should be screened and treated for vitamin D deficiency, and breastfed infants of dark-skinned or veiled women should be supplemented with vitamin D for the first 12 months of life. Regular sunlight exposure can prevent vitamin D deficiency, but the safe exposure time for children is unknown. To prevent vitamin D deficiency, at-risk children should receive 400 IU vitamin D daily; if compliance is poor, an annual dose of 150,000 IU may be considered. Treatment of vitamin D deficiency involves giving ergocalciferol or cholecalciferol for 3 months (1000 IU/day if < 1 month of age; 3000 IU/day if 1-12 months of age; 5000 IU/day if > 12 months of age). High-dose bolus therapy (300,000-500,000 IU) should be considered for children over 12 months of age if compliance or absorption issues are suspected.

Objective: To evaluate the response to recombinant GH treatment and adverse events in children with Prader-Willi syndrome (PWS) from KIGS, the Pfizer International Growth Database., Patients: A total of 328 children (274 prepubertal, median age 6.0 years; 54 pubertal, median age 12.7 years) were treated for 1 year and 161 children were treated for 2 years with GH., Results: Height standard deviation score (SDS) increased significantly during treatment; the response was greater in prepubertal (-0.7 vs.-1.8 pretreatment) compared with pubertal children (-1.5 vs.-1.8). Predictors of first-year height velocity in multiple regression analysis were GH dose, body weight (positively correlated), height SDS minus mid-parental height SDS and chronological age (negatively correlated), together accounting for 39% of the variation in response to GH. Body mass index (BMI) SDS did not change significantly during 2 years of treatment. Of all the 675 GH-treated PWS patients in KIGS, there were five cases of sudden death (age range 3-15 years). Three were obese (weight for height > 200%) and causes of death included bronchopneumonia, respiratory insufficiency and sleep apnoea. Scoliosis was the most commonly reported adverse event (n = 24), four children developed hyperglycaemia and six had presumptive diabetes (type 2 in five, and one case of type 1)., Conclusions: Short-term growth improved in response to conventional doses of GH in children with PWS. Prior to commencement of GH, examination of the upper airways and sleep studies should be performed in PWS patients. GH should be used with caution in those with extreme obesity or disordered breathing and all patients should be closely monitored for adverse events.

We studied the relation between soft drink/cordial (a sweet, flavoured, concentrated syrup that is mixed with water to taste), fruit juice/drink and milk consumption in mid-childhood, and body mass index (BMI) status in early adolescence in a contemporary Australian cohort. In 1996/7, 268 children (136 males) were recruited from western Sydney at baseline (mean+/-s.d.: 7.7+/-0.6 years), and at follow-up 5 years later (13.0+/-0.2 years). Height and weight were measured at both time periods and overweight and obesity defined using the International Obesity TaskForce criteria. Beverage consumption was calculated from a 3-day food record at baseline. Median carbohydrate intake from soft drink/cordial was 10 g higher (P=0.002) per day in children who were overweight/obese at follow-up compared to those who had an acceptable BMI at both baseline and follow-up. Intakes of soft drink/cordial in mid-childhood, but not fruit juice/fruit drink and milk, were associated with excess weight gain in early adolescence.

Context: Metformin therapy for adults and children with type 2 diabetes is well established. However, its role in the treatment of insulin resistance and obesity in children and adolescents is less clearly defined., Objective: We assessed the effect of metformin on body composition and insulin sensitivity in pediatric subjects with exogenous obesity., Design and Setting: Patients referred to a pediatric endocrine clinic were enrolled in a randomized, double-blind, crossover trial., Patients: Twenty-eight patients (13 males) aged 9-18 yr participated in the study., Intervention: Patients received metformin (1 g twice daily) and placebo for 6 months, each with a 2-wk washout period., Main Outcome Measures: Body composition (anthropometry, dual-energy x-ray absorptiometry, and abdominal magnetic resonance imaging), and insulin sensitivity (Si; minimal model, fasting insulin and glucose) were measured at baseline and 6 and 12 months., Results: Mean age of subjects at baseline was 12.5 +/- 2.2 yr, median body mass index z-score 2.54 (range, 1.93-2.85). Metformin had a greater treatment effect over placebo for weight (-4.35 kg, P = 0.02), body mass index (-1.26 kg/m(2), P = 0.002), waist circumference (-2.8 cm, P = 0.003), sc abdominal adipose tissue (-52.5 cm(2), P = 0.002), and fasting insulin (-2.2 mU/liter, P = 0.011). Si improved in 45% of subjects while on metformin and 27% of subjects while on placebo (P = 0.21)., Conclusions: Metformin therapy for obese insulin-resistant pediatric patients results in significant improvement in body composition and fasting insulin. Although improvement in Si was noted in many individuals, Si was a less useful parameter for analysis of group data, possibly because of effects of variable compliance and changing Si during puberty.

Background: A 2-y school milk intervention trial showed that 330 mL of a dietary milk supplement (fortified with calcium alone or with both calcium and vitamin D) enhanced the growth and bone mineral accretion of Chinese girls aged 10 y at baseline. Girls who received milk fortified with both calcium and vitamin D also had better vitamin D status than did girls who received nothing or girls who received milk fortified only with calcium., Objective: The aim was to evaluate whether these effects were sustained 3 y after supplement withdrawal., Design: Anthropometric measures and dietary intake were reassessed in 501 of the 698 girls whose data had been studied at the end of the intervention. As in the intervention phase, total-body bone mineral content and bone mineral density and serum 25-hydroxyvitamin D concentrations were measured in half of these subjects., Results: At follow-up, 99% of girls had reached menarche, at a mean (+/-SD) menarcheal age of 12.1 +/- 1.1 y. No significant differences in the timing of menarche were observed between the 3 groups (P = 0.6). No significant differences in the changes of total-body bone mineral content and bone mineral density since baseline were observed between the groups. The group receiving calcium-fortified milk had significantly greater gains in sitting height (0.9 +/- 0.3%; P = 0.02) than did the control group. The group that received calcium- and vitamin D-fortified milk had 17.1 +/- 6.7% lower serum 25-hydroxyvitamin D concentrations than did the control group (P = 0.04), but the difference was attenuated by additional adjustment for physical activity level (14.2 +/- 6.7%; P = 0.08)., Conclusion: Milk supplementation during early puberty does not have long-lasting effects on bone mineral accretion.

Background: Estimates of the prevalence of overweight and obesity in young people are typically based on body mass index (BMI). However, BMI may not indicate the level of central adiposity. Waist circumference has therefore been recommended to identify young people at risk of morbidity associated with central adiposity., Objective: To investigate (a) change in total and central adiposity between 7-8 and 12-13 y (b) agreement between classifying young people as overweight or obese based on total adiposity and central adiposity, and (c) risk factors associated with the development of total and central adiposity., Design: Anthropometric measurements were taken on 342 children in 1996/97 and 5 y later. Risk factors examined included birth weight, physical activity, TV viewing, pubertal status, parental adiposity, diet and socio-economic status., Results: Between 7-8 and 12-13 y indices of central adiposity increased more than total adiposity; waist circumference z-score increased by (mean+/-s.d.) 0.74+/-0.92 and BMI z-score increased by 0.18+/-0.67. At 12-13 y there was moderate agreement between the two measures of adiposity (weighted kappa=0.64). However, waist circumference identified a greater number of young people as overweight or obese compared to BMI (41.2 vs 29.3%, P<0.001). Adiposity status at 7-8 y, maternal obesity, and pubertal stage were the strongest predictors of BMI status at 12-13 y. Risk factors associated with increased central adiposity were similar., Conclusions: Overweight and obesity, as measured by waist circumference, is a bigger problem than is currently assessed by BMI. Targeting known risk factors for total adiposity may be an appropriate strategy for preventing increased central adiposity.

The state of bone health and the effect of growth hormone (GH) therapy on bone and body composition in children with idiopathic short stature (ISS) are largely unknown. A direct role of GH deficiency (GHD) on bone density is controversial. Using dual-energy X-ray absorptiometry, this study measured total body bone mineral content (TB BMC), body composition, and volumetric bone mineral density (vBMD) at the lumbar spine (LS) and femoral neck (FN) in 77 children (aged 3-17 years) with ISS (n = 57) and GHD (n = 20). Fifty-five children (GHD = 13) receiving GH were followed over 24 months including measurement of bone turnover. At diagnosis, size-corrected TB BMC SDS was greater (P

Osteoporosis secondary to chronic disease in children has emerged as a major health issue. As the severity of a child's illness increases, so too does the number of factors affecting their bone health. Determinants of bone health in children include level of mobility, exposure to osteotoxic medication, nutritional status, calcium and vitamin D intake, chronic inflammation and pubertal development.

There has been recent concern in the literature that the treatment with bisphosphonates in children can have an adverse effect on metaphyseal modeling leading to "drug-induced osteopetrosis". We created a normal database called metaphyseal index in the distal femur so that we could quantify the inwasting modeling process in children on bisphosphonates. Radiographs of the distal femur of 468 normal children who had presented to our institution for orthopedic trauma were examined. A measurement of the distal femoral growth plate width (GPW) was recorded. The femoral width at an interval of 0.5 GPW proximal to the distal femoral growth plate was also recorded (0.5 W). The metaphyseal index was defined as a ratio of 0.5 W/GPW. A graph of the means, one and two standard deviations from the mean, was constructed using the data obtained from this cohort. We found this ratio to be constant with minimal variability regardless of the age or sex of the child. We plotted 20 patients at our institution given bisphosphonates for localized orthopedic complaints. Z scores for girls averaged 0.68 and boys 0.13. Three patients had Z scores >2.0, with values of 2.2, 2.9, and 3.2. Metaphyseal modeling in the distal femur is constant, with slight variation between sexes, resulting in a similar shape of the distal femur throughout childhood. Clinically relevant doses of bisphosphonates given for appropriate indications do not necessarily disturb this process, while the beneficial clinical effect is maintained.

Background: We previously reported that increased milk consumption enhances growth and bone mineral accretion in Chinese girls aged 10-12 y., Objective: Our objective was to evaluate the effects of milk supplementation on cortical bone accretion and to study the physiologic mechanisms underlying the observed changes in bone., Design: Chinese girls aged 10 y were randomly assigned into calcium-fortified milk (Ca milk), calcium and vitamin D-fortified milk (CaD milk), and control groups according to their schools in a 24-mo school milk intervention trial. Periosteal and medullary diameters of metacarpal bone were measured at baseline and 24 mo in the Ca milk (n = 177), CaD milk (n = 210), and control (n = 219) groups. Insulin-like growth factor I (IGF-I), parathyroid hormone (PTH), bone alkaline phosphatase (BAP), osteocalcin, and deoxypyridinoline concentrations were measured at baseline and at 12 and 24 mo in the Ca milk (n = 43), CaD milk (n = 44), and control (n = 41) groups., Results: After adjustment for pubertal status and clustering by school, 24-mo supplementation led to greater increases in periosteal diameter (1.2%) and cortical thickness (5.7%) and to smaller gains in medullary diameter (6.7%) than did the control (P < 0.05). The CaD milk group had lower serum BAP at 12 mo (19.9%) and lower serum PTH at 12 (46.2%) and 24 (16.4%) mo than did the control group (P < 0.05). The effect of milk supplementation on increasing IGF-I concentrations at 24 mo (16.7-23.3%) was significant in individual analyses but not after adjustment for clustering by school., Conclusions: Milk supplementation showed positive effects on periosteal and endosteal apposition of cortical bone.

Objective: To investigate characteristics associated with body mass index (BMI) and waist circumference stability over a five-year period in women with school-age children., Methods: Women with 7-8 year-old children from western Sydney, Australia, had anthropometric measures taken in 1996/97 (n=436) and five years later (n=327). Socio-demographic characteristics examined at baseline included age, socioeconomic status, smoking, and number of children., Results: Over five years, less than half of the women maintained a stable BMI (38.8%) or waist circumference (31.5%), with the majority gaining in both indicators of adiposity. BMI and socio-demographic characteristics were not predictive of BMI or waist circumference stability or decrease., Conclusions and Implications: Total and abdominal adiposity increased in these Australian women who have children. The results support the need to develop effective weight gain prevention initiatives.

Background/aims: The beneficial effects of growth hormone (GH) therapy on statural growth in children are well established, but the effects on skeletal maturation are less clear. The progression of bone age (BA) was therefore studied during the first year of GH treatment in pre-pubertal children with idiopathic GH deficiency (GHD), Turner syndrome (TS) or idiopathic short stature (ISS), and in short pre-pubertal children born small for gestational age (SGA)., Methods: Cross-sectional data on 2,209 short children with idiopathic GHD, 694 with TS, 569 with ISS and 153 with SGA were analysed. Longitudinal data were also analysed from 308 children with idiopathic GHD, 99 with TS, 57 with ISS and 29 with SGA. All patients included in the study were enrolled in KIGS (Pfizer International Growth Database) and were being treated with recombinant human GH (Genotropin). BA was assessed using the Greulich and Pyle method at baseline and after 1 year of GH therapy., Results: In all groups of patients the mean progression of BA was 1 year during the year of GH therapy, although there was considerable individual variation. Progression of BA was not correlated with chronological age, BA, height SD score (SDS) or body mass index SDS at the onset of GH therapy. There was also no consistent effect of the GH dose on BA progression., Conclusion: Progression of BA appears to be normal in patients receiving GH in these diagnostic groups, at least over the first year of treatment in pre-puberty., (Copyright 2005 S. Karger AG, Basel.)

The clinical side effects of the potent new bisphosphonate zoledronic acid in children are unknown. In this study of 34 children with various bone disorders, the frequency of postinfusion flu-like illness, hypocalcemia, and hypophosphatemia was 85%, 74%, and 82%, respectively. No renal side effects were detected after up to 3 consecutive infusions.

Background: Sex differences in body composition exist before puberty, but the reason for this phenomenon is unknown. The physical changes that occur during puberty are mediated, in part, through sex steroids, insulin-like growth factor I (IGF-I), and leptin. However, data are lacking that address the extent to which concentrations of these hormones influence body composition, bone mass, and density in prepubertal children., Objective: We investigated the effects of IGF-I, dehydroepiandrosterone sulfate, and sex steroids on body composition and fat distribution and the effects of these hormones and leptin on total body bone mineral content (TBMC) and volumetric bone mineral density (vBMD) at the femoral neck and lumbar spine (LS) in 255 healthy children (137 girls), aged 7-8 y., Design: Body composition, fat distribution, TBMC, and vBMD were derived by using dual-energy X-ray absorptiometry. Association between variables was examined by using regression analysis., Results: No sex differences were found in age, height, or weight. However, girls had significantly more total body fat, trunk fat, and higher LS vBMD but significantly less fat-free soft tissue, TBMC, and femoral neck vBMD than did boys. Girls also had significantly (P < 0.001) higher IGF-I, estradiol, testosterone, and leptin concentrations than did boys. Estradiol concentrations predicted percentage body fat, which supported an effect of estrogen on fat storage. Leptin had an independent effect on LS vBMD, which suggests a positive effect for leptin on trabecular bone., Conclusions: The hormones examined explained 3-17% of the variations in body-composition measures, fat distribution, and bone density, which suggests that other factors are important predictors of prepubertal sexual dimorphism.

It is presently unclear whether men with a history of constitutional delay (CD) of puberty are osteopenic. This study compares auxology, bone mass, size, and density of 32 men (age, 21-33 yr) with previous CD with 45 controls. Using dual-energy x-ray absorptiometry, areal bone mineral density (aBMD) and volumetric bone mineral density at the lumbar spine (LS) and femoral neck (FN), hip strength analysis, and total-body and body segment (arms, legs, trunk) measurements were determined. Auxological variables, body composition, the muscle-bone relation, and the effect of prior androgen treatment were studied. Men with previous CD were shorter (P < 0.001) and had shorter height-adjusted arms compared with controls. Height-adjusted total-body bone mineral content (BMC) (P = 0.004), aBMD (P = 0.016), and bone area (P = 0.006) but not lean tissue mass (P = 0.507) were lower in CD men compared with controls; consequently, their BMC to lean tissue mass ratio was reduced (P < 0.001). Segment length-adjusted BMC and bone area of arms (P < 0.001) and legs (P < 0.03), but not trunk were lower in CD men than in controls. They had lower LS aBMD (P = 0.044) but normal LS and FN volumetric bone mineral density. Size-adjusted LS width and the hip cross-sectional area were lower than in controls. There was no difference in anthropometric or dual-energy x-ray absorptiometry results between untreated (n = 15) and androgen-treated (n = 17) CD men.We conclude that men with previous CD have normal LS and FN volumetric density but reduced total-body bone mass, which was explained by reduced limb bone mass and size. Together with the reduced LS bone width and hip crosssectional area, these skeletal characteristics suggest impaired periosteal expansion during puberty. The skeletal phenotype of CD males may be altered by their late onset of puberty.

Objectives: (i) To evaluate the benefits and adverse effects of a Diabetes Day Care Program (DDCP); and (ii) to compare outcomes in two cohorts diagnosed before and after implementing the DDCP ("pre-DDCP" and "post-DDCP")., Design: Outcomes from the pre-DDCP cohort were compared with those of the post-DDCP cohort., Setting: The study was conducted from March 2001 to October 2002 at the Children's Hospital at Westmead., Participants: The pre-DDCP cohort comprised all children newly diagnosed with type 1 diabetes from March 2000 to November 2000 (n = 49). The post-DDCP cohort were those diagnosed from November 2000 to August 2001 (n = 61)., Main Outcome Measures: Length of stay, adverse events, insulin requirement and glycohaemoglobin (HbA(1c)) level over the first year after diagnosis were ascertained from medical records. Questionnaires to measure parents' knowledge of diabetes, emotional adjustment to diabetes, and responsibility for and conflict over specific diabetes management tasks were completed by parents at 6-monthly intervals., Results: Median length of hospital stay decreased from 5.14 days (range, 2-10) to 1.70 days (range, 0-10) (P < 0.001). There were no differences between the two cohorts in insulin requirement at 12 months (pre-DDCP: 0.9 U/kg [95% CI, 0.8-1.0]; post-DDCP: 0.8 U/kg [95% CI, 0.7-0.9]; P = 0.22), HbA(1c) level at 12 months (pre-DDCP: 8.4% [95% CI, 8.0%-8.9%]; post-DDCP: 8.2% [95% CI, 7.9%-8.5%]; P = 0.37) and adverse events over the first year after diagnosis. Both groups reported similar scores for the parental questionnaires., Conclusions: Ambulatory stabilisation of children with type 1 diabetes provides similar metabolic outcomes for the child, and comparable levels of diabetes knowledge and similar psychosocial outcomes for the family, to inpatient stabilisation programs.

Gender differences in brain morphology have previously been reported in the temporal lobe and an 'X-chromosome dosage effect' has been described in Turner syndrome (45,X). To examine this further, we investigated temporal lobe morphology, metabolism and function in nine children with non-mosaic Turner syndrome using magnetic resonance imaging, (1)H magnetic resonance spectroscopy and neuropsychological testing and compared outcomes with results from nine age-matched control girls (46,XX). Turner subjects were found to have significantly larger superior temporal lobes (P = 0.004) and middle temporal lobes (P = 0.047) than controls. The size of the temporal lobe was found to correlate negatively with temporal lobe choline-containing compounds suggesting that increased temporal lobe size is associated with larger cells and/or decreased dendrites. This suggests a developmental failure to prune neurons. The degree of enlargement correlates negatively with functional performance on temporal-lobe associated tasks, suggesting that the enlargement may be a compensatory mechanism, or possibly causative in the case of semantic fluency performance. These temporal lobe abnormalities are discussed with reference to genes which are absent in Turner syndrome and to hormonal differences between Turner syndrome subjects and 46,XX controls.

Osteoporosis and fractures are features in adults with Turner syndrome (TS). Using dual-energy x-ray absorptiometry, correcting bone mineral content (BMC) for height and lean mass (LTM) avoids misclassification of short children as osteopenic. Total body (TB), lumbar spine (LS), and femoral neck (FN) dual-energy x-ray absorptiometry scans were performed on 83 patients with TS (aged 4-24 yr). A prepubertal subgroup (n = 17) receiving GH was followed for 24 months. Age z-scores for height, TB BMC, LTM, the BMC/LTM ratio, and LS volumetric bone mineral density (vBMD) decreased significantly (P < 0.001) with age in prepubertal subjects (n = 51) but were constant in the combined pubertal and postmenarchal group (n = 32). Osteopenia was found in 14.5% (TB), 15.8% (LS), and 28.4% (FN) of patients. In the longitudinal subgroup, TB BMC z-scores decreased by -0.28 (0.31) in subjects remaining prepubertal (n = 11) but increased by 0.71 (0.56) in subjects entering puberty (n = 6; P = 0.007). The z-scores for height and LTM increased in both groups. Our results show a height-independent prepubertal decrease in bone mass accrual, which ceased with puberty. Optimizing bone mass in TS may require earlier induction of puberty than currently recommended. However, reduced FN volumetric bone mineral density and a dissociation of bone and muscle measures were age independent, suggesting an additional intrinsic bone defect.

Obesity and multiple pituitary hormone deficiency are common complications after surgery for childhood craniopharyngioma. We hypothesized that post craniopharyngioma surgery, children are at high risk for the metabolic syndrome, including insulin resistance due to excess weight gain and GH deficiency. This study characterized body composition (anthropometry and dual energy x-ray absorptiometry) and metabolic outcomes in 15 children (10 males and 5 females; age, 12.2 yr; range, 7.2-18.5 yr) after surgical removal of craniopharyngioma. In 9 subjects, outcomes were compared with those of healthy age-, sex-, body mass index-, and pubertal stage-matched controls. Insulin sensitivity was measured by 40-min iv glucose tolerance test. Seventy-three percent of subjects were overweight or obese. Sixty-six percent had normal growth velocity without GH treatment. Subjects had increased abdominal adiposity (P = 0.008) compared with controls. However, there was no significant difference in total body fat. Subjects had higher fasting triglycerides (P = 0.02) and lower high density lipoprotein cholesterol to total cholesterol ratio (P = 0.015). Insulin sensitivity was equally reduced for subjects and controls (P = 0.86). After craniopharyngioma removal, patients had more features of the metabolic syndrome compared with controls. This could be a result of hypothalamic damage causing obesity and GH deficiency. Further studies exploring predictors of the metabolic syndrome after craniopharyngioma surgery are required.

In upper extremity bones, a sexual dimorphism exists in the development of periosteal and endocortical bone surfaces during growth. Little is known about developmental patterns of bone geometry at weight-bearing bones like the femur. Using MRI and dual energy X-ray absorptiometry (DXA), this study assessed the differences in mid-femoral total (TA), cortical (CA) and medullary areas (MA), cortical thickness, and cortical density (BMD(compartment)) between prepuberty and young adulthood in 145 healthy subjects (94 females) 6 to 25 years old. Additionally, agreement between mid-femoral total bone volume (TV) measurements by DXA and MRI were investigated. In both sexes, TA, CA, MA, and cortical thickness were significantly larger in adults compared to prepubertal subjects (P < 0.001), and males had greater values than females. This sex difference persisted for TA, CA, and cortical thickness (P < 0.05), but not MA, after adjusting for femur length and weight. Mean (SD) cortical BMD increased from 1.05 (0.07) and 1.09 (0.10) g/cm(3) in prepubertal children to 1.46 (0.14) and 1.42 (0.1) g/cm(3) in young adults, females and males, respectively (P < 0.001). TV measurements by DXA were significantly greater than by MRI (P < 0.001) in young adults. In conclusion, periosteal and endocortical expansion and increasing cortical BMD are the growth processes found at the mid-femur in both sexes. Our findings contrast to that in upper extremity bones, where MA is constant in females during growth. The difference in femoral bone development may be due to higher strains caused by weight bearing and genetic factors. DXA, in contrast to MRI, is inaccurate in the determination of mid-femoral TV measures.

The role of GH treatment during total pubertal growth (TPG) is still unclear. We developed a prediction model for TPG (centimeters) through a multiple regression analysis of various prepubertal parameters in 303 adolescents with idiopathic GH deficiency from the KIGS database. Prepubertal catch-up growth and near-adult height were achieved, and GH dose was kept constant at approximately 30 micro g/kg.d. The model was validated on a cohort of 36 patients from one center. Four TPG predictors explained 70% of the variability with an error SD of 4.2 cm: gender (TPG in males was >11.3 cm vs. that in females), age at onset of puberty (negative), height SD score minus midparental height SD score at puberty onset (negative), and mean GH dose during puberty (positive). Our analysis suggests that TPG in idiopathic GH deficiency is only moderately dependent on GH dose. The use of a higher GH dosage at the onset of puberty should thus depend on the individual's height development. The TPG model aids in the planning of individually optimized and cost-effective GH treatment.

Objective: Most studies that use total body dual energy x-ray absorptiometry (DEXA) in children rely on areal bone mineral density (BMD=bone mineral content [BMC]/bone area [BA]) and compare the output with age- and sex-specific normative data. Because this approach is prone to size-related misinterpretation, this study focuses on the interrelations among BMC, body size (height), and lean tissue mass (LTM)., Study Design: This cross-sectional study presents normative total body LTM data in relation to height and BMC for 459 healthy white subjects (249 female), 3 to 30 years of age. Guidelines for DEXA interpretation in children are provided and illustrated for patients with growth hormone deficiency (n=5) and anorexia nervosa (n=5)., Results: LTM/height tended to be greater in male than in girls. The BMC/LTM ratio was greater in female than in boys (P<.001), even after adjustment for age and height. Sex-specific reference curves were created for LTM/height, the BMC/LTM ratio, BA/height, and BMC/BA., Conclusions: We recommend that total body DEXA in children should be interpreted in 4 steps: (1) BMD or BMC/age, (2) height/age, (3) LTM/height, and (4) BMC/LTM ratio for height. This allows differentiation of the origin of a low BMD or BMC/age, for example, short stature and primary, secondary, and mixed bone defects.

Unlabelled: Prolonged healing times and stress-shielding osteopenia remain problematic in distraction osteogenesis. In this study of 30 rabbits, zoledronic acid increased regenerate volume, mineralization, and tibial strength and prevented osteopenia over a 6-week period. Translation to the clinical setting, if safe, could improve outcomes in distraction osteogenesis in children., Introduction: Because the external fixators for limb lengthening and reconstruction are designed to control the positions of bone fragments accurately, they also produce stress-shielding effects on the forming regenerate and surrounding bone. Osteopenia, leading to refracture and limitations on rehabilitation, are common consequences, potentially increasing morbidity and detracting from final clinical outcome., Materials and Methods: We examined the effect of zoledronic acid on distraction osteogenesis in 42 immature male NZW rabbits. The model chosen results in reliable regenerate formation and stress-shielding osteopenia. Fourteen animals received either Saline, zoledronic acid 0.1 mg/kg at surgery (ZOL), or another dose 2 weeks postoperatively (Redosed ZOL). Rabbits underwent DXA for bone mineral content and bone mineral density in regenerate and surrounding segments of operated and contralateral tibias. After death at 6 weeks, 30 pairs of tibias underwent quantitative computerized tomography (QCT) and four-point bend testing, and 12 were examined by histomorphometry. The study was powered at 0.8 to show differences of 1.3 SDs for mineral and mechanical parameters., Results: Osteopenia observed in tibias of the Saline group was absent in ZOL and Redosed ZOL tibias, the latter exhibiting higher bone mineral density and bone mineral content over contralateral regions (p < 0.01). Regenerate bone mineral content was higher in ZOL and Redosed ZOL versus Saline groups at 4 and 6 weeks (p < 0.01). Cross-sectional area was 49% and 59% greater at 6 weeks in ZOL and Redosed ZOL regenerates compared with the Saline group (p < 0.01). ZOL and Redosed ZOL tibias were 29% and 89% stronger by four-point bending than the Saline group (p < 0.01). Histomorphometry in the regenerate of ZOL and Redosed ZOL groups revealed higher trabecular bone volume and trabecular number compared with the Saline group (p < 0.001)., Conclusions: Zoledronic acid administration led to significantly greater bone area, mineral content, strength, and trabecular number with reduced stress-shielding osteopenia in this model of distraction osteogenesis. These data suggest that intraoperative and postoperative zoledronic acid administration could improve outcomes in children undergoing limb lengthening.

In 1988, new guidelines for growth hormone (GH) usage emphasizing auxological criteria were adopted in Australia. Currently, 1,250 children with the following diagnoses are being treated: idiopathic GH deficiency (IGHD), 23.4%; malignancy-related GHD, 7.9%; Turner's syndrome, 12.1%; nonendocrine disorders, 22.2%; idiopathic short stature, 26.0%; endocrine disorders, 3.2%; unknown, 5.3%. At onset of GH therapy, mean age remained lowest in patients with IGHD (8.6 years); mean height SDS was unchanged over time in all groups (-2.8 to -3.3); mean GH doses were lowest for patients with idiopathic and malignancy-related GHD (0.15-0.16 mg/kg/week) and highest for the Turner's syndrome group (0.22 mg/kg/week). Children with GHD demonstrated the best final height outcome (mean final height SDS -1.0 +/- 1.1 for boys and -1.4 +/- 1.2 for girls; improvements of 2.0 SDS for both genders). Mean final height SDS for the other etiologies were similar: -2 in malignancy-related GHD (no improvement), -2.3 in nonendocrine disorders (improvement of 0.7), -1.8 in idiopathic short stature (improvement of 1.1), and -2.3 for Turner's syndrome (improvement of 0.9). In 1993-94, when more stringent entry and exit criteria were introduced, patient numbers and expenditure were halved and have remained unchanged (US dollars 9-10 M per year). The use of auxology-based criteria continues to make possible rational, effective, and economical use of GH therapy in short children in Australia.

Inhaled corticosteroids (ICS) remain a vital part of the management of persistent asthma, but concerns have been raised about their potential adverse effects in children. This review examines the safety data on three new ICS - fluticasone propionate, mometasone, and extrafine beclomethasone in hydrofluoroalkane (HFA-134a) propellant (QVAR The use of tradenames is for product identification purposes only and does not imply endorsement. formulation) in relation to the older corticosteroids. Topical adverse effects such as thrush and dysphonia are rare, but dental erosion is a possibility with powder forms of ICS because of their low pH. Thus, it is important to stress mouth rinsing after administration and maintaining good dental hygiene to minimize this risk. Biochemical adrenal suppression can be readily demonstrated, particularly with high doses of all ICS. The clinical relevance of this was uncertain in the past, but there have now been >50 reported cases of acute adrenal crises in children receiving ICS, most of whom were on fluticasone propionate. In order to minimize the risk of symptomatic adrenal suppression, it is important to back-titrate the ICS dose and alert families of children receiving high-dose ICS of this potential adverse effect. A pediatric endocrine opinion should be sought if adrenal suppression is suspected. The older ICS cause temporary slowing of growth velocity, but the limited data available do not show any significant compromise of final adult height. The effect on growth of fluticasone propionate may not be as great as with the older ICS, but the studies have been short term and only used low doses of fluticasone propionate. There have been case reports of growth suppression in children receiving high doses of fluticasone propionate. The limited studies performed on the effect of ICS on bone mineral density in children did not show any adverse effects, but there may be an increased risk of fractures. Hydrofluoroalkane beclomethasone (QVAR) is essentially the same drug as chlorofluorocarbon beclomethasone, but with double the lung deposition owing to the smaller particle size. Thus, it could be expected that any adverse effects seen with chlorofluorocarbon beclomethasone would be the same with hydrofluoroalkane beclomethasone. However, some of the published data, particularly in adults, suggest that hydrofluoroalkane beclomethasone may be less systemically active than chlorofluorocarbon beclomethasone, even at equipotent doses. As yet, there are no long-term data on mometasone, but initial studies in adults suggest there may be less suppression of the hypothalamic-pituitary-adrenal axis, although further studies are required, particularly in children.ICS will remain a cornerstone in the management of persistent pediatric asthma, provided that the diagnosis of asthma is secure. It is very important to use ICS appropriately and to ensure the lowest possible doses are used to achieve symptom control, thus minimizing the risk of serious adverse effects.

Although recombinant techniques have enabled the production of limitless amounts of human growth hormone (GH), and clinical methods for diagnosis and treatment have been greatly enhanced, the mean final heights of children with idiopathic GH deficiency (IGHD) treated with GH remain in the range of -1.3 standard deviation scores (SDS) below normal height. One of the methods used to increase height outcomes is to delay the onset and progression of puberty to allow for a longer 'pre-pubertal' growth phase. We reviewed the KIGS (Pharmacia International Growth Database) data of patients with IGHD who had been treated with gonadotropin-releasing hormone agonists (GnRHa) in order to see if a greater gain in height could be achieved by altering the tempo of pubertal maturation. Near-final height data were analysed in 39 adolescents (out of a total of 249) who had received GH + GnRHa therapy and were compared with similar data from 1,893 patients with IGHD treated with GH alone. The total change in height SDS in boys who received GH alone was +1.6, in contrast to +1.1 in GH + GnRHa-treated boys; the total change in height SDS in girls who received GH alone was +1.4 in contrast to +1.1 in girls treated with GH + GnRHa. The near final height SDS in girls treated with GH + GnRHa was 1.0 below the mid-parental target height (MPH), whereas there was only a -0.5 SDS difference in girls treated with GH. Approximation to the MPH did not differ in boys between the two treatment groups. These data suggest that the attainment of a substantial height SDS by manipulating the tempo of puberty is limited, but that optimizing growth during the pre-pubertal phase is a more important factor., (Copyright 2003 S. Karger AG, Basel)

A model was developed that allows physicians to individualize GH treatment in children born short for gestational age (SGA) who fail to show spontaneous catch-up growth. Data from children (n = 613) in a large pharmacoepidemiological survey, the KIGS (Pharmacia International Growth Database), or who had participated in clinical trials were used to develop the model. Another group of similar children (n = 68) from KIGS was used for validation. In the first year of GH treatment, the growth response correlated positively with GH dose, weight at the start of GH treatment, and midparental height SD score and negatively with age at treatment start. Using this model, 52% of the variability of the growth response could be explained, with a mean error SD of 1.3 cm. GH dose was the most important response predictor (35% of variability), followed by age at treatment start. The second year growth response was best predicted by a three-parameter model (height velocity in yr 1 of treatment, age at start of treatment, and GH dose), which accounted for 34% of the variability, with an error SD of 1.1 cm. The first year response to GH treatment was the most important predictor of the second year response, accounting for 29% of the variability. No statistically significant differences between the predicted and observed growth responses were found when the models were applied to the validation groups. In conclusion, using simple variables, we have developed a model that can be used in clinical practice to adjust the GH dose to achieve the desired growth response in patients born SGA. Furthermore, this model can be used to provide patients with a realistic expectation of treatment and may help to identify compliance problems or other underlying causes of treatment failure.

Peak bone strength depends on bone mass, bone size (geometry), and bone material properties. Most studies to date have focused on bone mass as assessed with the use of dual-energy X-ray absorptiometry, with bone mineral content (BMC) and bone mineral density (BMD) being best described. Peak BMC accrual follows by 6 months the growth spurt of adolescent females, and there is good evidence for tracking of BMD during puberty, indicating genetic influence. The search for genes involved in the regulation of peak bone strength has revealed inconsistent findings. Weight-bearing exercise during the peripubertal years enhances BMD and bone geometry of the axial skeleton, but calcium intake is not predictive of peak BMD. Estrogen plays a critical role in the accrual of BMC, and nutrition is an important factor in both bone size and BMC.

We analyzed the GNAS1 gene in five patients with pseudohypoparathyroidism type 1a (PHP1a) by performing polymerase chain reaction, followed by sequencing all 13 exons of the gene, single-stranded conformational polymorphism (SSCP) or heteroduplex analysis (HD). Three novel mutations were discovered: (1) a de novo 3 bp insertion of CTG in codon 47 of exon 1; (2) a missense mutation 1103T in exon 4; and (3) a de novo mutation of Arg280Gly in exon 10. Two other mutations, previously described in the literature, include: (1) a de novo 4 bp deletion (deltaGACT) involving codons 189 and 190 in exon 7, and (2) a deletion of a cytosine nucleotide at codon 115 in exon 5. We conclude that mutational analysis of the GNAS1 gene is a strong supportive tool for the diagnosis of PHP1a, and is a useful adjunct to the synthetic parathyroid hormone infusion test for PTH resistance.

The cause of skeletal muscle insulin resistance is unclear, but high levels of intramyocellular lipids are often present in affected individuals. We aimed to establish the metabolic, familial, and anthropometric associations of intramyocellular lipid in a pediatric population. We studied 41 boys aged 6.9-9.9 y and 23 of their mothers by proton magnetic resonance spectroscopy. We related muscle lipid levels to important factors that define an increased risk of developing insulin resistance in adult life. There were significant associations between the boys' intramyocellular lipid and their waist circumference (r = 0.42, p = 0.007), body mass index SD score (r = 0.32, p = 0.04), weight SD score (r = 0.32, p = 0.04), glucose:insulin ratio (r= -0.59, p = 0.04), maternal log fasting insulin levels (r = 0.44, p = 0.04), maternal body mass index (r = 0.46, p = 0.03), and maternal intramyocellular lipid (r = 0.62, p = 0.003). In the 41 boys, waist circumference explained 19% of the variance in the boys' intramyocellular lipid. Maternal intramyocellular lipid explained 39% of the variance in the boys' intramyocellular lipid in the sub-group of 23 boys. Intramyocellular lipid levels have both metabolic and anthropometric associations in childhood. Before puberty, children develop or inherit muscle metabolic characteristics that are associated both with insulin resistance and risk factors for the development of insulin resistance syndrome in adult life.

We examined the effect on bone mineral density (BMD), bone mineral content (BMC) and mechanical properties of a single 1.0 mg/kg dose of the bisphosphonate pamidronate (Novartis), in a distraction osteogenesis model in immature rabbits. Twenty rabbits underwent a tibial osteotomy. Ten rabbits received pamidronate 1.0 mg/kg via ear vein intra-operatively while 10 received saline infusions only. After a 24 h latency, all underwent distraction of 0.375 mm twice daily for 15 days. The animals were culled at 42 days. After culling, the distracted and non-distracted tibiae were examined by quantitative computer tomography (QCT). The volumetric bone mineral density (vBMD, mg/cm(3)) in the bone proximal and distal to the regenerate in the operated limb was increased by a mean of 11 and 14%, respectively, compared to controls (P<0.05). The vBMD of the regenerate bone was increased by a mean of 8% over controls (NS, P=0.17). The bone mineral content (BMC, mg) was increased by 23% (proximal and distal) (P<0.05) in the bone surrounding the lengthening and there was a 17% trend towards an increase in the regenerate (NS, P=0.3). Four-point bending analysis documented that the load to failure was increased by 32% from 436 to 574 N (P<0.01) in the pamidronate group. The modulus of elasticity was not different between the control and pamidronate groups (P=0.3), and in both groups was only approximately one-third of the intact tibiae (P<0.001). The administration of a single dose of pamidronate can improve the bone mineral density, content and mechanical properties of a bone undergoing distraction osteogenesis.

Although macroscopic geometric architecture is an important determinant of bone strength, there is limited published information relating to the validation of the techniques used in its measurement. This study describes new techniques for assessing geometry at the midfemur using magnetic resonance imaging (MRI) and dual-energy X-ray absorptiometry (DXA) and examines both the repeatability and the accuracy of these and previously described DXA methods. Contiguous transverse MRI (Philips 1.5T) scans of the middle one-third femur were made in 13 subjects, 3 subjects with osteoporosis. Midpoint values for total width (TW), cortical width (CW), total cross-sectional area (TCSA), cortical cross-sectional area (CCSA), and volumes from reconstructed three-dimensional (3D) images (total volume [TV] and cortical volume [CVol]) were derived. Midpoint TW and CW also were determined using DXA (Lunar V3.6, lumbar software) by visual and automated edge detection analysis. Repeatability was assessed on scans made on two occasions and then analyzed twice by two independent observers (blinded), with intra- and interobserver repeatability expressed as the CV (CV +/- SD). Accuracy was examined by comparing MRI and DXA measurements of venison bone (and Perspex phantom for MRI), against "gold standard" measures made by vernier caliper (width), photographic image digitization (area) and water displacement (volume). Agreement between methods was analyzed using mean differences (MD +/- SD%). MRI CVs ranged from 0.5 +/- 0.5% (TV) to 3.1 +/- 3.1% (CW) for intraobserver and 0.55 +/- 0.5% (TV) to 3.6 +/- 3.6% (CW) for interobserver repeatability. DXA results ranged from 1.6 +/- 1.5% (TW) to 4.4 +/- 4.5% (CW) for intraobserver and 3.8 +/- 3.8% (TW) to 8.3 +/- 8.1% (CW) for interobserver variation. MRI accuracy was excellent for TV (3.3 +/- 6.4%), CVol (3.5 +/- 4.0%), TCSA (1.8 +/- 2.6%), and CCSA (1.6 +/- 4.2%) but not TW (4.1 +/- 1.4%) or CW (16.4 +/14.9%). DXA results were TW (6.8 +/- 2.7%) and CW (16.4 +/- 17.0%). MRI measures of geometric parameters of the midfemur are highly accurate and repeatable, even in osteoporosis. Both MRI and DXA techniques have limited value in determining cortical width. MRI may prove valuable in the assessment of surface-specific bone accrual and resorption responses to disease, therapy, and variations in mechanical loading.