Surgical Management and Denosumab for Aneurysmal Bone Cysts of the Spine in an Australian Tertiary Paediatric Centre.

Aneurysmal bone cysts (ABC) are rare osteolytic, benign but often locally aggressive tumours of the long bones or vertebrae. For spinal ABC, surgical management, embolisation or sclerotherapy alone often carry high morbidity and/or high recurrence rates. Interruption of receptor activator of nuclear factor-kappa B ligand (RANKL) signalling holds promise as an effective therapeutic strategy for these tumours. We aimed to review the approach to surgical management and evaluate the efficacy and safety of denosumab for ABC of the spine in children. Retrospective review of 7 patients treated with denosumab using a standardised protocol for ABC of the spine in a tertiary paediatric centre. Surgical intervention was only conducted if there was spinal instability or significant neurological impairment. Denosumab 70 mg/m2 was given 4-weekly for at least 6 months, followed by 2 doses of zoledronate 0.025 mg/kg, aiming to prevent rebound hypercalcaemia. All patients achieved stability of the spine and resolution of neurological impairment, if present. Six patients achieved metabolic remission and have ceased denosumab without recurrence to date; the other showed clinical and radiological improvement without complete metabolic remission. Three patients developed symptomatic hypercalcaemia 5-7 months after cessation of denosumab, requiring additional bisphosphonate treatment. We present our algorithm for the surgical and medical management of paediatric spinal ABC. Denosumab produced a radiological and metabolic response in all patients, with complete remission in most. Follow-up time was not long enough to evaluate the endurance of response after cessation in some patients. Incidence of rebound hypercalcaemia in this paediatric cohort was high, prompting a change to our protocol.

Childhood type 1 diabetes is associated with abnormal bone development.

OBJECTIVE: To describe bone mineral density (BMD), bone structure, and fracture prevalence in adolescents with type 1 diabetes (T1D) and explore their associations with glycemic control and microvascular complications. RESEARCH DESIGN AND METHODS: Cross sectional study of 64 adolescents (38 males) with T1D duration >10 years who underwent dual-energy X-ray absorptiometry (DXA), peripheral quantitative computed tomography (pQCT), fracture survey, plantar fascia thickness, and microvascular complications assessment. RESULTS: Mean age was 16.6 ± 2.1 years, diabetes duration 12.8 ± 2.2 years and HbA1c 8.9 ± 1.7% (74 mmol/mol). Fracture prevalence was 50%. DXA areal BMD (Z-score) was reduced for femoral neck (-0.5 ± 1.3, p = 0.008) and arm (-0.4 ± 1.0, p < 0.001), while total areal BMD and lumbar spine BMD were normal. In pQCT (Z-score), trabecular volumetric BMD (vBMD) was reduced for tibia (-0.4 ± 0.8, p < 0.001) and radius (-0.8 ± 1.4, p < 0.001) whereas cortical vBMD was increased at both sites (tibia: 0.5 ± 0.6, p < 0.001, radius: 0.7 ± 1.5, p < 0.001). Muscle cross-sectional area (CSA) was reduced for upper (-0.6 ± 1.2, p < 0.001) and lower (-0.4 ± 0.7, p < 0.001) limbs. DXA total areal BMD was positively correlated with BMI (p < 0.01) and age at T1D diagnosis (p = 0.04). Lower radial bone CSA, total and lumbar spine BMD were associated with autonomic nerve dysfunction. HbA1c, diabetes duration, fracture history and other microvascular complications were not significantly associated with bone parameters. CONCLUSIONS: Adolescents with childhood-onset T1D have site-specific bone deficits in upper and lower limbs but normal total and lumbar spine BMD. T1D appears to have differential effects on trabecular and cortical bone compartments. Future longitudinal analysis is warranted to examine whether these changes translate in to increased fracture risk.

Denosumab for central giant cell granuloma in an Australian tertiary paediatric centre.

BACKGROUND: Central giant cell granulomas (CGCG) are rare osteolytic, benign but often locally aggressive tumours of bone. Surgical curettage may not be possible in extensive lesions and resection carries high morbidity, especially in growing children, and previous medical therapies have had variable efficacy and high recurrence rates. Interruption of receptor activator of nuclear factor-kappa B ligand (RANKL) signalling holds promise as an effective therapeutic strategy for these tumours. AIMS: To evaluate the efficacy and safety of our protocol for denosumab treatment of CGCG in children. METHODS: Retrospective review of 4 patients treated with denosumab using a standardised protocol for CGCG in a tertiary paediatric centre. Denosumab 70 mg/m2 was given 4-weekly, followed by 2 doses of zoledronate 0.025 mg/kg, aimed at preventing rebound hypercalcaemia. RESULTS: Treatment of CGCG resulted in metabolic remission in all patients, but recurrence, detected by positron emission tomography (PET), occurred at 6 months in three patients and 12 months in one patient. Three patients developed symptomatic hypercalcaemia 4-5 months and one patient asymptomatic hypercalcaemia 7 months after cessation of denosumab, with 3 requiring additional bisphosphonate treatment. CONCLUSIONS: Denosumab produced a radiological and metabolic response in our patients, but metabolic recurrence occurred in all patients. PET imaging was effective for monitoring treatment response and early detection of recurrence. Incidence of rebound hypercalcaemia in this paediatric cohort was high. We present proposed changes to our protocol with the aim of producing sustained remission and preventing rebound hypercalcaemia.

Randomized Controlled Trial Evaluating the Use of Zoledronic Acid in Duchenne Muscular Dystrophy.

CONTEXT: Patients with glucocorticoid-dependent Duchenne muscular dystrophy (DMD) have increased fracture risk and reduced bone mineral density (BMD), often precipitating mobility loss. OBJECTIVE: To investigate use of zoledronic acid (ZA) in DMD in improving BMD. METHODS: Two arm, parallel, randomized controlled trial, set in pediatric hospitals across Australia and New Zealand. Sixty-two (31 per arm) boys with glucocorticoid-dependent DMD between 6 and 16 years were included. Five ZA infusions (0.025 mg/kg at months 0, and 3, and 0.05 mg/kg at months 6, 12, and 18), plus calcium and vitamin D, were compared with calcium and vitamin D alone. The main outcome measures were change in lumbar spine (LS) BMD raw and Z-score by dual energy absorptiometry x-ray (DXA) at 12 and 24 months, secondary outcomes assessing mobility, fracture incidence, bone turnover, peripheral quantitative computerized (pQCT) and pain scores. RESULTS: At 12 and 24 months, mean difference in changes of LS BMD Z-score from baseline was 1.2 SD (95% CI 0.9-1.5), higher by 19.3% (14.6-24.0) and 1.4 SD (0.9-1.9), higher by 26.0% (17.4-34.5) in ZA than control arms respectively (both P < .001). Five controls developed Genant 3 vertebral fractures, 0 in the ZA arm. Mobility, pain, and bone turnover markers were similar between arms at 12 and 24 months. Trabecular BMC and vBMD pQCT at radius and tibia were greater at 12 months in the ZA cohort than control; the evidence for this difference remained at 24 months for radius but not tibia. CONCLUSION: ZA improved BMD in glucocorticoid-dependent DMD boys. Although the small cohort precluded demonstrable fracture benefit, improved BMD might reduce incident vertebral fracture.

Long-term outcomes of warfarin versus aspirin after Fontan surgery.

OBJECTIVES: Because of the nature of the Fontan physiology, patients are at an increased risk of thromboembolic complications. As such, warfarin or aspirin is generally prescribed lifelong for thromboprophylaxis. This study aimed to compare long-term rates of cerebrovascular injury, thrombosis, bleeding, bone mineral density, and quality of life in people living with Fontan circulation receiving warfarin compared with aspirin. METHODS: This was a multicenter study of a selected cohort from the Australia and New Zealand Fontan population. Participants underwent cerebral magnetic resonance imaging to detect the presence of cerebrovascular injury (n = 84) and dual-energy X-ray absorptiometry to assess bone mineral density (n = 120). Bleeding (n = 100) and quality of life (n = 90) were assessed using validated questionnaires: Warfarin and Aspirin Bleeding assessment tool and Pediatric Quality of Life Inventory, respectively. RESULTS: Stroke was detected in 33 participants (39%), with only 7 (6%) being clinically symptomatic. There was no association between stroke and Fontan type or thromboprophylaxis type. Microhemorrhage and white matter injury were detected in most participants (96% and 86%, respectively), regardless of thromboprophylaxis type. Bleeding rates were high in both groups; however, bleeding was more frequent in the warfarin group. Bone mineral density was reduced in our cohort compared with the general population; however, this was further attenuated in the warfarin group. Quality of life was similar between the warfarin and aspirin groups. Home international normalized ratio monitoring was associated with better quality of life scores in the warfarin group. CONCLUSIONS: Cerebrovascular injury is a frequent occurrence in the Australia and New Zealand Fontan population regardless of thromboprophylaxis type. No benefit of long-term warfarin prophylaxis could be demonstrated over aspirin; however, consideration must be given to important clinical features such as cardiac function and lung function. Furthermore, the association of reduced bone health in children receiving warfarin warrants further mechanistic studies.

Impact of adiposity on clinical outcomes in people living with a Fontan circulation.

BACKGROUND: To assess the association between body composition and the risk of adverse outcomes in Fontan patients. METHODS: Participants from the Australian and New Zealand Fontan Registry with dual-energy X-ray absorptiometry scans were included. Appendicular lean mass (ALM), appendicular lean mass index (ALM divided by height squared; ALMI) and total body fat mass percentage (%BF) were calculated. ALMI and %BF z-scores were derived using age- and sex-matched reference ranges. The primary outcome was Fontan failure (death, transplantation, New York Heart Association functional class III/IV, protein-losing enteropathy, and plastic bronchitis) or moderate-or-severe ventricular dysfunction. RESULTS: 144 patients were included. Mean %BF was 29% (SD 10) with 50% having increased adiposity. Mean ALMI z-score was -1.4 (SD 1.1); one third of patients had skeletal muscle deficiency (ALMI z-score < -1 and -2) and another third had Fontan-associated myopaenia (ALMI z-score < -2). Age and %BF were associated with the risk of the endpoint in univariable regression (age: HR 1.09 per year, 95% CI 1.02-1.17, p = 0.01; %BF: HR 1.08, 95% CI 1.01-1.17, p = 0.03). On multivariable regression, every 1% increase in %BF was associated with a 10% increased risk of reaching the clinical endpoint (HR 1.10, 95% CI 1.01-1.19; p = 0.03). ALM was not associated with the endpoint (HR 1.02 per kg, 95% CI 0.88-1.20, p = 0.77). CONCLUSIONS: Increased adiposity is associated with higher risk for adverse outcomes. Prospective studies to assess lifestyle interventions to optimise body composition should be prioritised.

Exercise Intolerance, Benefits, and Prescription for People Living With a Fontan Circulation: The Fontan Fitness Intervention Trial (F-FIT)-Rationale and Design.

Background: Despite developments in surgical techniques and medical care, people with a Fontan circulation still experience long-term complications; non-invasive therapies to optimize the circulation have not been established. Exercise intolerance affects the majority of the population and is associated with worse prognosis. Historically, people living with a Fontan circulation were advised to avoid physical activity, but a small number of heterogenous, predominantly uncontrolled studies have shown that exercise training is safe-and for unique reasons, may even be of heightened importance in the setting of Fontan physiology. The mechanisms underlying improvements in aerobic exercise capacity and the effects of exercise training on circulatory and end-organ function remain incompletely understood. Furthermore, the optimal methods of exercise prescription are poorly characterized. This highlights the need for large, well-designed, multi-center, randomized, controlled trials. Aims and Methods: The Fontan Fitness Intervention Trial (F-FIT)-a phase III clinical trial-aims to optimize exercise prescription and delivery in people with a Fontan circulation. In this multi-center, randomized, controlled study, eligible Fontan participants will be randomized to either a 4-month supervised aerobic and resistance exercise training program of moderate-to-vigorous intensity followed by an 8-month maintenance phase; or usual care (control group). Adolescent and adult (≥16 years) Fontan participants will be randomized to either traditional face-to-face exercise training, telehealth exercise training, or usual care in a three-arm trial with an allocation of 2:2:1 (traditional:telehealth:control). Children (<16 years) will be randomized to either a physical activity and exercise program of moderate-to-vigorous intensity or usual care in a two-arm trial with a 1:1 allocation. The primary outcome is a change in aerobic exercise capacity (peak oxygen uptake) at 4-months. Secondary outcomes include safety, and changes in cardiopulmonary exercise testing measures, peripheral venous pressure, respiratory muscle and lung function, body composition, liver stiffness, neuropsychological and neurocognitive function, physical activity levels, dietary and nutritional status, vascular function, neurohormonal activation, metabolites, cardiac function, quality of life, musculoskeletal fitness, and health care utilization. Outcome measures will be assessed at baseline, 4-months, and 12-months. This manuscript will describe the pathophysiology of exercise intolerance in the Fontan circulation and the rationale and protocol for the F-FIT.

High Bone Mineral Density Osteogenesis Imperfecta in a Family with a Novel Pathogenic Variant in COL1A2.

Osteogenesis imperfecta (OI) is a heterogenous group of heritable bone dysplasias characterized by bone fragility, typically low bone mass, joint laxity, easy bruising, and variable short stature. Classical OI is caused by autosomal dominant pathogenic variants in COL1A1 or COL1A2 that result in either reduced production of normal type 1 collagen or structurally abnormal collagen molecules. Pathogenic variants in these genes generally result in low bone mass. Here, we report a family that had 2 affected individuals who presented with minimal trauma fractures and were found to have elevated bone mineral density (BMD) and a previously unreported variant in COL1A2 c.3356C>T p.(Ala1119Val). We report the change in BMD using dual-energy X-ray and peripheral quantitative computed tomography over a 2.3-year period in the proband. This case report highlights the importance of BMD studies and genetic testing in the diagnostic process for brittle bone disorders.

Body Composition in Young Adults Living With a Fontan Circulation: The Myopenic Profile.

Background We sought to characterize body composition abnormalities in young patients living with a Fontan circulation and explore potential pathophysiologic associations. Methods and Results Twenty-eight patients with a Fontan circulation were prospectively recruited in this cross-sectional study. Participants underwent cardiopulmonary exercise testing, dual-energy X-ray absorptiometry, echocardiography, and biochemical assessment. Mean age was 26±7 years. Skeletal muscle mass, estimated by appendicular lean mass index Z score, was reduced compared with reference data (-1.49±1.10, P<0.001). Percentage body fat Z score overall was within normal range (0.23±1.26, P=0.35), although 46% had elevated adiposity. Those with reduced skeletal muscle mass (appendicular lean mass index Z score of -1 or lower) had lower percent predicted oxygen pulse (55±15 versus 76±16%, P=0.002). Overall agreement between body mass index and dual-energy X-ray absorptiometry to assess adiposity was fair only (weighted [linear] κ coefficient: 0.53; 95% CI, 0.34-0.73) and slight in the setting of muscle mass deficiency (weighted κ coefficient: 0.32; 95% CI, 0.13-0.50). Appendicular lean mass was independently associated with absolute peak VO2 (ß=70.6 mL/min, P=0.001). Appendicular lean mass index Z score was inversely associated with hemoglobin (r=-0.4, P=0.04), and the degree of muscle deficit was associated with ventricular systolic impairment. Conclusions Young patients with a Fontan circulation have a body composition characterized by reduced skeletal muscle mass, which is associated with peak exercise capacity. Increased adiposity is common despite a normal body mass index. Low skeletal muscle mass is associated with systolic dysfunction and compensatory erythrocytosis.

Abnormal Cortical and Trabecular Bone in Youth With Type 1 Diabetes and Celiac Disease.

OBJECTIVE: This study compared bone health in youth with type 1 diabetes and celiac disease (CD) versus type 1 diabetes alone. RESEARCH DESIGN AND METHODS: This was a case-control study of 42 youth with coexisting type 1 diabetes and CD and 40 with type 1 diabetes matched for age, sex, diabetes duration, and HbA1c. Bone mineral density (BMD), bone mineral content (BMC), and BMC-to-lean tissue mass (LTM) ratio were measured using DXA and reported as z-scores for height. Total, trabecular, and cortical bone and muscle parameters were measured using peripheral quantitative computed tomography (pQCT) and reported as z-scores for age. RESULTS: Mean age at assessment was 14.3 ± 3.1 years; diabetes duration, 8.0 ± 3.5 years; HbA1c, 8.2 ± 1.5% (66 ± 5 mmol/mol); and 25-hydroxy vitamin D, 71 ± 21 nmol/L. Comparing youth with coexisting CD versus type 1 diabetes alone, DXA showed lower BMC-to-LTM ratio (0.37 ± 1.12 vs. 0.73 ± 2.23, P = 0.007) but no difference in total BMD. Youth with coexisting CD also had lower BMC-to-LTM ratio versus the general population (P = 0.04). Radial pQCT showed lower total BMC (-0.92 ± 1.40 vs. -0.26 ± 1.23, P = 0.03) despite similar bone and muscle cross-sectional area. In multivariable linear regression, lower BMC was associated with higher insulin dose (P = 0.03) but not HbA1c. CONCLUSIONS: Youth with both type 1 diabetes and CD have lower BMC relative to LTM and lower BMC, indicating abnormal trabecular and cortical bone development despite similar bone and muscle size. These findings suggest that the two conditions confer a lower bone turnover state. We recommend further examination of bone health in this population; future research should examine early interventions to improve bone health.

Long-term Outcomes of Adolescent Anorexia Nervosa on Bone.

PURPOSE: Anorexia nervosa (AN) is a chronic and life-threatening eating disorder that can have a considerable negative impact on the growing skeleton. We hypothesized that the long-term impact on bone health may persist even after normalization of body weight. METHODS: 41 females (mean age 21.2 ± 2.9 years) with a history of adolescent-onset AN attended a follow-up bone health assessment at 5 years (T5, n = 28) or 10 years (T10, n = 13) after their first AN-related hospital admission. Assessment included dual-energy x-ray absorptiometry measurements of the total body, lumbar spine, and proximal femur, peripheral quantitative computed tomography at the radius and tibia, anthropometric measurements, serum biochemistry, fracture history, and a patient questionnaire. RESULTS: A recovery in body weight and BMI was seen for both the T5 and T10 cohorts (BMI at intake 16.6, BMI at T5-T10 21.2-21.3). Dual-energy x-ray absorptiometry body composition indicated a recovery of fat mass and lean tissue mass. Total BMD was unaffected, but reductions were seen at the femoral neck and arms. Peripheral quantitative computed tomography showed reduced trabecular and cortical bone in the radius, and cortical thinning in the tibia. AN patients showed a statistically significant reduction in measures of radiographic bone health at follow up, although not to a degree that necessitated clinical intervention. Serum insulin-like growth factor 1 was also positively correlated with total BMD and BMC measures. While fracture risk was not increased, a subset of participants (8%) showed multiple (>4) fractures. CONCLUSION: A longitudinal study of adolescent AN showed persisting negative effects on bone health.

Incomplete total body protein recovery in adolescent patients with anorexia nervosa.

Background: Bone health and growth during adolescence require adequate total body protein (TBPr). Renutrition for patients with anorexia nervosa (AN) should aim to normalize body composition and to recover both fat mass and TBPr. Objective: We intended to analyze predictors of protein status, including exercise status, in adolescents with AN and to investigate whether weight gain would replenish body protein deficits. Methods: We assessed TBPr in a longitudinal, observational study as height-adjusted nitrogen index (NI) using in vivo neutron activation analysis in 103 adolescents with AN [mean ± SD age, 15.6 ± 1.4 y; body mass index (BMI, in kg/m2), 16.5 ± 1.6] at the commencement of inpatient refeeding (T0), in 56 of these patients 7 mo thereafter as outpatients (T1), and in age-matched controls (C; n = 51, 15.5 ± 2.1 y, BMI 20.7 ± 1.9). Lean tissue and fat mass were assessed by dual-energy X-ray absorptiometry. BMI, BMI standard deviation score, and lean tissue mass were tested as predictors of protein status using receiver operating characteristic analysis. Results: At T0, NI was decreased in AN (AN, 0.88 ± 0.10 compared with C, 1.00 ± 0.08, P < 0.001). In 34%, the patients showed protein depletion. Patients classified as ``exercisers'' had a higher NI than did ``nonexercisers'' (0.89 ± 0.11 compared with 0.85 ± 0.08, P = 0.045). BMI, BMI standard deviation score, and lean tissue mass did not show potential as predictors of protein status. Despite increases in weight (+6.9 ± 4.5 kg), and BMI (+2.5 ± 1.7), protein status did not improve (TBPr T0, 8.0 ± 1.1 kg; T1, 8.1 ± 1.0 kg, P = 0.495). In an AN subgroup at 7 mo matched with controls in age (AN, 16.5 ± 1.1 y; C, 16.2 ± 1.8 y) and BMI (AN, 20.5 ± 1.4; C, 20.7 ± 1.3), protein status was still not normalized in AN (NI: AN, 0.89 ± 0.09 compared with C, 1.00 ± 0.07, P < 0.001). Conclusions: Adolescents recovering from AN remained protein depleted at 7 mo after baseline assessment, even though they were weight restored.

Novel variant in Sp7/Osx associated with recessive osteogenesis imperfecta with bone fragility and hearing impairment.

Osteogenesis imperfecta (OI) is a connective tissue disorder characterized by low bone density and recurrent fractures with a wide genotypic and phenotypic spectrum. Common features include short stature, opalescent teeth, blue sclerae and hearing impairment. The majority (>90%) of patients with OI have autosomal dominant variants in COL1A1/COL1A2, which lead to defects in type 1 collagen. More recently, numerous recessive variants involving other genes have also been identified. Sp7/Osx gene, is a protein coding gene that encodes a zinc finger transcription factor, osterix, which is a member of the Sp subfamily of sequence-specific DNA-binding proteins. Osterix is expressed primarily by osteoblasts and has been shown to be vital for bone formation and bone homeostasis by promoting osteoblast differentiation and maturation. In animal models, Sp7/Osx has also been shown to regulate biomineralization of otoliths, calcium carbonate structures found in the inner ear of vertebrates. Until recently, only one report of a boy with an Sp7/Osx pathogenic variant presenting with bone fragility, limb deformities and normal hearing has been described in the literature. We have identified a novel Sp7/Osx variant in another sibship that presented with osteoporosis, low-trauma fractures and short stature. Progressive moderate-to-severe and severe-to-profound hearing loss secondary to otospongiosis and poor mineralization of ossicles and petrous temporal bone was also noted in two of the siblings. A homozygous pathogenic variant in exon 2 of the Sp7/Osx gene was found in all affected relatives; c.946C>T (p.Arg316Cys). Bone biopsies in the proband and his male sibling revealed significant cortical porosity and high trabecular bone turnover. This is the second report to describe children with OI associated with an Sp7/Osx variant. However, it is the first to describe the bone histomorphometry associated with this disorder and identifies a significant hearing loss as a potential feature in this OI subtype. Early audiology screening in these children is therefore warranted.

ABCD: Anthropometry, Body Composition, and Crohn Disease.

BACKGROUND: Young individuals with Crohn disease (CD) are at risk of poor bone mineral density (BMD) and reduced lean tissue mass (LTM). The importance of LTM for maintaining skeletal health, in both incident and established CD, is evidenced. We used dual-energy x-ray absorptiometry assessment to identify areal BMD and LTM in individuals with CD. METHODS: In 57 patients with CD (15F; 12.99-14.16 years) anthropometric, disease activity, bone age assessment, and total body dual-energy x-ray absorptiometry measurements were acquired. A 4-step algorithm was used to assess simultaneous bone and body composition data: areal BMD and height z scores, and LTM for height and bone mineral content (BMC) for LTM z scores were calculated. Low z score cut-off values were defined as ≤1 standard deviations below the population means. RESULTS: The CD cohort showed: low areal BMD z scores (P = 0.00); and low LTM for height (P = 0.00) according to defined cut-off values. BMC appeared to be adapting for the lower amount of LTM. Correcting for bone age eliminated the low areal BMD z scores. As expected, LTM for height and BMC for LTM z scores remained unchanged. CONCLUSIONS: We present a useful clinical algorithm to show significant LTM for height deficits, regardless of chronological or bone age, in this CD cohort. BMC seemed to adapt to the reduced LTM, indicating clinically "normal" areal BMD for age when considered for height. The ongoing deficits in LTM may, however, create chronic long-term consequences for bone health. Improving LTM should be a focus of clinical treatment in individuals with CD.

Cystic fibrosis-related bone disease in children: Examination of peripheral quantitative computed tomography (pQCT) data.

BACKGROUND: The investigation of skeletal health data beyond dual X-ray absorptiometry (DXA) is limited in young individuals with CF. We assessed volumetric bone mineral densities (BMD), and bone and muscle parameters using peripheral quantitative computed tomography (pQCT) in individuals with CF and controls, 7.00-17.99 years. METHODS: Peripheral QCT (XCT 3000, Stratec) measurements were made in 53 individuals with CF and 53 controls. Bone mineral content (BMC), total volumetric BMD (vBMD) and cross sectional area (CSA) of the bone were measured at the 4% and 66% sites of the non-dominant tibia and radius. Additionally, trabecular vBMD and bone strength index (BSIc) were measured at the 4% sites, and cortical vBMD, muscle CSA (mCSA) and strength strain index (SSI) were measured at the 66% sites. RESULTS: Pre-pubertal males with CF had greater trabecular vBMD (p=0.01) and total vBMD (p=0.00) at 4% tibia, and greater total vBMD (p=0.02) at 4% radius. Pre-pubertal females with CF had greater total vBMD at 66% tibia (p=0.02) and radius (p=0.04), and cortical vBMD (p=0.04) at the radius. At puberty, the CF cohort had less BMC at 4% tibia (males, p=0.02; females, p=0.01), and smaller mCSA at 66% tibia (males, p=0.02; females, p=0.01). Pubertal CF females had a smaller bone CSA (p=0.01) at 4% tibia, and lower bone strength (SSI) at the tibia (p=0.00) and radius (p=0.05) sites. CONCLUSIONS: Bone strength parameters were not compromised prior to puberty in this CF cohort. At puberty, the bone phenotype changed for this CF cohort, showing several deficits compared to the controls. However, bone strength was adapting to the mechanical demands of the muscle. Altered bone parameters and their implications for lowered bone strength with increased age may be greatly influenced by: the CF cohort remaining smaller for age and/or a reduced bone strain, secondary to reduced muscle force.

The long-term effects of switching from active intravenous bisphosphonate treatment to low-dose maintenance therapy in children with osteogenesis imperfecta.

BACKGROUND/AIMS: Intravenous bisphosphonate therapy is the first-line treatment in moderate-to-severe osteogenesis imperfecta (OI), but there are varied treatment protocols with little data on long-term efficacy. This study evaluates the clinical outcomes when transitioning from active bisphosphonate treatment to maintenance therapy. METHODS: A retrospective review was conducted on 17 patients before treatment, following active treatment (zoledronate 0.05 mg/kg 6-monthly or pamidronate 6-9 mg/kg/year) and after establishment on maintenance treatment for more than 2 years (zoledronate 0.025 mg/kg 6-monthly or pamidronate <4 mg/kg/year). RESULTS: There was a significant reduction in mean fracture rate from 1.5 ± 1.1 fractures/year at baseline to 0.7 ± 0.7 fractures/year on active treatment. Z-scores for lumbar spine bone mineral density, bone mineral content, volumetric bone mineral density and bone mineral content for lean tissue mass increased during active treatment. These improvements were maintained during the period of maintenance treatment. Vertebral height improved in fractured thoracic vertebrae from pre-treatment to active therapy and improved further during maintenance treatment. Metacarpal cortical thickness and relative cortical area also increased over the treatment periods. CONCLUSION: Maintenance intravenous bisphosphonate therapy preserved the beneficial effects of active treatment at the doses stated above. Further studies are required to determine the optimal bisphosphonate treatment regimen in the management of children with OI.

Cystic fibrosis-related bone disease explored using a four step algorithm.

BACKGROUND: A suboptimal bone accrual in young individuals with cystic fibrosis (CF) may be related to the development of a premature CF-related bone disease. Dual energy X-ray absorptiometry (DXA) is the mainstream measure of bone health; however, the influence of body size and lean tissue mass (LTM) on bone data is poorly interpreted. METHODS: Total body dual-energy X-ray absorptiometry (DXA) measurements of bone mineral content (BMC) and LTM in 53 individuals with CF (7.00-17.99years) were compared to 53 sex-matched controls. BMC, height, and LTM in relation to height and BMC Z-scores were calculated and used in a 4-step algorithm. RESULTS: Pubertal females with CF had less total body BMC for age (p=0.02); pre-pubertal males (p=0.05) and pubertal females with CF (p=0.03) were shorter; and pubertal females with CF showed less total body BMC for LTM (p=0.01). CONCLUSIONS: The algorithm showed the following: (1) prior to puberty lowered total body BMC was primarily due to short stature, (2) LTM was appropriate for body size, and (3) pubertal females with CF had significantly less total body BMC for their LTM. Longer controlled trials are needed to clinically interpret CF-related bone disease using DXA derived data that considers patient size and body composition.

Improved insulin sensitivity and body composition, irrespective of macronutrient intake, after a 12 month intervention in adolescents with pre-diabetes; RESIST a randomised control trial.

BACKGROUND: A higher protein to carbohydrate ratio in the diet may potentiate weight loss, improve body composition and cardiometabolic risk, including glucose homeostasis in adults. The aim of this randomised control trial was to determine the efficacy of two structured lifestyle interventions, differing in dietary macronutrient content, on insulin sensitivity and body composition in adolescents. We hypothesised that a moderate-carbohydrate (40-45% of energy), increased-protein (25-30%) diet would be more effective than a high-carbohydrate diet (55-60%), moderate-protein (15%) diet in improving outcomes in obese, insulin resistant adolescents. METHODS: Obese 10-17 year olds with either pre-diabetes and/or clinical features of insulin resistance were recruited at two hospitals in Sydney, Australia. At baseline adolescents were prescribed metformin and randomised to one of two energy restricted diets. The intervention included regular contact with the dietician and a supervised physical activity program. Outcomes included insulin sensitivity index measured by an oral glucose tolerance test and body composition measured by dual-energy x-ray absorptiometry at 12 months. RESULTS: Of the 111 adolescents recruited, 85 (77%) completed the intervention. BMI expressed as a percentage of the 95th percentile decreased by 6.8% [95% CI: -8.8 to -4.9], ISI increased by 0.2 [95% CI: 0.06 to 0.39] and percent body fat decreased by 2.4% [95% CI: -3.4 to -1.3]. There were no significant differences in outcomes between diet groups at any time. CONCLUSION: When treated with metformin and an exercise program, a structured, reduced energy diet, which is either high-carbohydrate or moderate-carbohydrate with increased-protein, can achieve clinically significant improvements in obese adolescents at risk of type 2 diabetes. TRIAL REGISTRATION: Australian New Zealand Clinical Trail Registry ACTRN12608000416392 . Registered 25 August 2008.

Bioelectrical impedance analysis to estimate body composition, and change in adiposity, in overweight and obese adolescents: comparison with dual-energy x-ray absorptiometry.

BACKGROUND: There is a need for a practical, inexpensive method to assess body composition in obese adolescents. This study aimed to 1) compare body composition parameters estimated by a stand-on, multi-frequency bioelectrical impendence (BIA) device, using a) the manufacturers' equations, and b) published and derived equations with body composition measured by dual-energy x-ray absorptiometry (DXA) and 2) assess percentage body fat (%BF) change after a weight loss intervention. METHODS: Participants were 66 obese adolescents, mean age (SD) 12.9 (2.0) years. Body composition was measured by Tanita BIA MC-180MA (Tanita BIA8) and DXA (GE-Lunar Prodigy). BIA resistance and reactance data at frequencies of 5, 50, 250 and 500 kHz, were used in published equations, and to generate a new prediction equation for fat-free mass (FFM) using a split-sample method. Approximately half (n = 34) of the adolescents had their body composition measured by DXA and BIA on two occasions, three to nine months apart. RESULTS: The correlations between FFM (kg), fat mass (kg) and %BF measured by BIA and DXA were 0.92, 0.93 and 0.78, respectively. The Tanita BIA8 manufacturers equations significantly (P < 0.001) overestimated FFM (4.3 kg [-5.3 to 13.9]) and underestimated %BF (-5.0% [-15 to 5.0]) compared to DXA. The mean differences between BIA derived equations and DXA measured body composition parameters were small (0.4 to 2.1%), not significant, but had large limits of agreements (~ ±15% for FFM). After the intervention mean %BF loss was similar by both methods (~1.5%), but with wide limits of agreement. CONCLUSION: The Tanita BIA8 could be a valuable clinical tool to measure body composition at the group level, but is inaccurate for the individual obese adolescent.

Fracture during intravenous bisphosphonate treatment in a child with osteogenesis imperfecta: an argument for a more frequent, low-dose treatment regimen.

BACKGROUND/AIMS: Intravenous bisphosphonate therapy is the mainstay of medical treatment in osteogenesis imperfecta (OI) and has been shown to increase bone mass, decrease bone pain, improve mobility, and reduce the incidence of fractures. Sclerotic metaphyseal lines parallel to the growth plate are seen on long bone radiographs following cyclical intravenous therapy. These areas create stress risers within the bone that may act as foci for subsequent fractures as exemplified in this clinical case. METHODS: An 8-year-old girl with OI sustained a distal radial fracture following 3 years of treatment with 6-monthly intravenous zoledronate. Her diagnosis, response to treatment, and subsequent fracture at a sclerotic metaphyseal line is described. RESULTS: Peripheral quantitative computer tomography was used to characterise the presence of multiple stress risers at the distal forearm. Trabecular bone mineral density fluctuated from 34 to 126% compared to neighbouring 2-mm regions. CONCLUSION: There remain many unanswered questions about optimal bisphosphonate treatment regimens in children with OI. The formation of stress risers following intravenous bisphosphonate treatment raises the hypothesis that a more frequent and low-dose bisphosphonate regimen would provide more uniform dosing of bone in the growing child and reduce the likelihood of fractures compared to current treatment practices.