Evaluation of Body Composition in Paediatric Osteogenesis Imperfecta.

Osteogenesis Imperfecta (OI) is a skeletal disorder characterised by a predisposition to recurrent fractures and bone deformities. Clinically OI is defined by features such as short stature, however, less is known regarding body composition. Assess body composition, both lean mass and fat mass, in a paediatric OI population. Children with OI attending the Bone service at the Royal Hospital for Children Glasgow were included; who had a dual-energy x-ray absorptiometry (DXA) scan performed 2015-2018. Height and body-mass-index (BMI) were converted to standard-deviation scores (SDS) using UK population references. DXA-derived lean mass and fat mass were used to generate lean-mass-index (LMI) and fat-mass-index (FMI) by dividing the covariates by height squared. LMI and FMI were converted to age-and-gender-adjusted SDS using DXA data from 198 local healthy children. Thirty-eight children (20 males) with median age 11.95 (range: 4.8, 18.3) years were included. Median height SDS was -1.08 (-3.64, 1.62) and was significantly lower than the healthy population (p<0.0001). Median BMI SDS was -0.10 (-2.31, 2.95), and not significantly different from the healthy population (p = 0.53). Median LMI SDS was -2.52 (-6.94, 0.77), and significantly lower than healthy controls (p<0.0001); 61% (23/38) had an SDS below -2.0. Median FMI SDS was 0.69 (-0.45, 2.72), significantly higher than healthy controls (p < 0.0001). BMI SDS cut-offs of -0.15 and 1.33, from ROC analysis, identified children with LMI SDS <-2, with a positive predictive value of 95% and a negative predictive value of 70%; and FMI SDS >2 with a positive predictive value of 44% and a negative predictive value of 100%. A contemporary population of children with ranging severities of OI present with significant reduction in height and lean mass, and relatively high fat mass. Standard BMI SDS cut-offs for identifying children with malnutrition and obesity have poor prognostic validity in OI.

Skeletal Fragility and Its Clinical Determinants in Children With Type 1 Diabetes.

CONTEXT: Type 1 diabetes (T1D) is associated with an increased fracture risk at all ages. OBJECTIVE: To understand the determinants of bone health and fractures in children with T1D. DESIGN: Case-control study of children with T1D on bone-turnover markers, dual-energy X-ray absorptiometry, and 3 Tesla-MRI of the proximal tibia to assess bone microarchitecture and vertebral marrow adiposity compared with age- and sex-matched healthy children. RESULTS: Thirty-two children with T1D at a median (range) age of 13.7 years (10.4, 16.7) and 26 controls, aged 13.8 years (10.2, 17.8), were recruited. In children with T1D, serum bone-specific alkaline phosphatase (BAP) SD score (SDS), C-terminal telopeptide of type I collagen SDS, and total body (TB) and lumbar spine bone mineral density (BMD) SDS were lower (all P < 0.05). Children with T1D also had lower trabecular volume [0.55 (0.47, 0.63) vs 0.59 (0.47, 0.63); P = 0.024], lower trabecular number [1.67 (1.56, 1.93) vs 1.82 (1.56, 1.99); P = 0.004], and higher trabecular separation [0.27 (0.21, 0.32) vs 0.24 (0.20, 0.33); P = 0.001] than controls. Marrow adiposity was similar in both groups (P = 0.25). Bone formation, as assessed by BAP, was lower in children with poorer glycemic control (P = 0.009) and who were acidotic at initial presentation (P = 0.017) but higher in children on continuous subcutaneous insulin infusion (P = 0.025). Fractures were more likely to be encountered in children with T1D compared with controls (31% vs 19%; P< 0.001). Compared with those without fractures, the T1D children with a fracture history had poorer glycemic control (P = 0.007) and lower TB BMD (P < 0.001) but no differences in bone microarchitecture. CONCLUSION: Children with T1D display a low bone-turnover state with reduced bone mineralization and poorer bone microarchitecture.

Skeletal disproportion in glucocorticoid-treated boys with Duchenne muscular dystrophy.

We aimed to compare body segment and bone lengths in glucocorticoid-treated boys with Duchenne muscular dystrophy (DMD) with healthy controls using dual-energy absorptiometry (DXA) images. Total height (Ht), sitting height (SH), leg length (LL) and bone lengths (femur, tibia) in boys with DMD and age-matched control boys were measured using DXA. Thirty boys with DMD (median age 10.0 years (6.1, 16.8)) were compared with 30 controls. SH in DMD was 3.3 cm lower (95% CI - 6.1, - 0.66; p = 0.016). LL in DMD was 7.3 cm lower (95% CI - 11.2, - 3.4; p < 0.0001). SH:LL of boys with DMD was higher by 0.08 (95% CI 0.04, 0.12; p < 0.0001). Femur length in DMD was 2.4 cm lower (95% CI - 4.6, - 0.12; p = 0.04), whereas tibial length in DMD was 4.8 cm lower (95% CI - 6.7, - 2.9; p < 0.0001). SH:LL was not associated with duration of glucocorticoid use (SH:LL ß = 0.003, 95% CI - 0.01 to 0.002, p = 0.72).Conclusion: Glucocorticoid-treated boys with DMD exhibit skeletal disproportion with relatively shorter leg length and more marked reduction of distal long bones. As glucocorticoid excess is not associated with such disproportion, our findings raise the possibility of an intrinsic disorder of growth in DMD. What is Known • Severe growth impairment and short stature are commonly observed in boys with Duchenne muscular dystrophy (DMD), especially those treated with long-term glucocorticoids (GC). • In other groups of children with chronic conditions and/or disorders of puberty, skeletal disproportion with lower spinal length has been reported. What is New • Growth impairment in GC-treated boys with DMD was associated with skeletal disproportion in relation to age, with lower limbs and distal long bones affected to a greater degree.

Growth hormone prescribing patterns in the UK, 2013-2016.

INTRODUCTION: Prescribing of recombinant human growth hormone (rhGH) for growth failure in UK children is based on guidance from the National Institute for Health and Care Excellence. In 2013, the British Society for Paediatric Endocrinology and Diabetes initiated a national audit of newly prescribed rhGH treatment for children and adolescents. In this review, we have examined prescribing practices between 2013 and 2016. METHODS: All patients ≤16.0 years of age starting rhGH for licensed and unlicensed conditions in the UK were included. Anonymised data on indication and patient demographics were analysed. RESULTS: During the 4 years, 3757 patients from 76 of 85 (89%) centres started rhGH. For each licensed indication, proportions remained stable over this period: 56% growth hormone deficiency (GHD), 17% small for gestational age (SGA), 10% Turner syndrome, 6% Prader-Willi syndrome (PWS), 3% chronic renal insufficiency (CRI) and 2% short stature homeobox deficiency (SHOXd). However, the unlicensed category decreased from 10% (n=94) in 2013 to 5% (n=50) in 2016. The median age of patients starting rhGH was 7.6 years (range 0.1-16.0). Patients with PWS were significantly younger (median 2.2 years, range 0.2-15.1) compared with other indications (p<0.0001) and were followed by the SGA group (median 6.2 years, range 1.3-15.6, p<0.0001). Boys predominated in all groups except for PWS and SHOXd. CONCLUSION: We demonstrate significant engagement of prescribing centres in this audit and a decline in unlicensed prescribing by half in this 4-year period. Patients in the PWS group were younger at initiation of rhGH compared with other indications and had no male predominance unlike GHD, SGA and CRI.

Effects of Recombinant Human Growth Hormone in Children with Crohn's Disease on the Muscle-Bone Unit: A Preliminary Study.

BACKGROUND/AIMS: There is limited information on the impact of recombinant human growth hormone (rhGH) on the muscle-bone unit in children with Crohn's disease (CD). In this pilot study, we report on the effects of rhGH on bone formation, dual-energy X-ray absorptiometry (DXA) total body (TB) bone mineral density adjusted for height and lumbar spine (LS) bone mineral apparent density (BMAD), and body composition. METHODS: Prospective study of 8 children with CD (6 male), aged 14.8 years (9.0-16.4), who received rhGH for 24 months. Serum procollagen type 1 N-terminal propeptide (P1NP) was measured at baseline and at 6 months. DXA was performed every 6 months. RESULTS: Six months of rhGH led to improvement in P1NP SDS adjusted for bone age from -3.6 (-7.9 to -0.9) to -2.4 (-3.7 to 0.4) (p = 0.01). At baseline, reduction in LS-BMAD and TB lean mass SDS was observed being -1.2 (-3.6 to 0.8) (p = 0.01 vs. zero) and -0.8 (-2.4 to 3.0) (p = 0.11 vs. zero), respectively. No significant changes were seen in DXA bone and muscle parameters over the 24 months. CONCLUSION: Twenty-four months of therapy with rhGH in CD did not lead to an improvement in DXA BMD and lean mass, despite improvement in P1NP and linear growth.

Persistence of Muscle-bone Deficits Following Anti-tumour Necrosis Factor Therapy in Adolescents With Crohn Disease.

OBJECTIVES: The aim of the study is to assess change in the muscle-bone unit in adolescents with Crohn disease (CD) on anti-tumour necrosis factor (anti-TNFα). METHODS: Prospective study following anti-TNFα in 19 adolescents with CD with a median age (range) of 15.1 years (11.2, 17.2). At baseline, 6 and 12 months, subjects had a biochemical assessment of insulin growth factor axis, bone turnover and muscle-bone health by dual energy absorptiometry (DXA), peripheral quantitative computed tomography (pQCT), and dynamic isometry. RESULTS: Significant clinical improvement in disease activity was observed by 2 weeks (P = 0.004 vs baseline) and maintained at 12 months (P = 0.038 vs baseline). Median bone specific alkaline phosphatase standard deviation score (SDS) increased from -1.7 (-3.6 to -1.0) to -1.2 (-3.6 to -0.5) by 6 weeks (P = 0.01). At baseline, DXA total body and lumbar spine bone mineral density (BMD) SDS was -0.9 (-2.3 to 0.5) and -1.1 (-2.9 to 0.4), respectively. At baseline, pQCT trabecular BMD SDS at 4% tibia and muscle cross-sectional area SDS at 66% radius was -1.6 (-3.2 to 1.1) and -2.4 (-4.3 to -0.3), respectively. At baseline, maximal isometric grip force (MIGF) of the non-dominant hand adjusted for height was -1.5 (-4.5 to 0.49). All these deficits in muscle-bone persisted at 6 and 12 months. CONCLUSIONS: Despite improvement in disease and osteoblast activity, bone and muscle deficits, as assessed by DXA, pQCT, and grip strength in adolescents with CD did not improve following twelve months of anti-TNFα.

Longitudinal changes in bone parameters in young girls with anorexia nervosa.

BACKGROUND: Anorexia nervosa (AN) during childhood and adolescence has been reported to adversely affect bone health, but few studies have investigated longitudinal changes. METHOD: DXA-derived bone parameters and body composition were retrospectively assessed in 111 young girls with AN with a median age of 15.4 years (10.9, 19.8). In 68 (61%) vertebral fracture assessment (VFA) was performed and in 31 (28%), a follow-up DXA was performed. Correlations with growth, changes in body composition and effects of illness duration and menstruation were examined. Size adjusted DXA standard deviation scores were calculated for total body (TB) less head bone mineral content (TBLH-BMC) and lumbar spine bone mineral apparent density (LS-BMAD). RESULTS: Mean (range) bone area (BA) for height centile was 27.1 (0-97), and mean lean mass for height centile was 28.8 (0-95) at baseline. Mean (range) LS BMAD was -1.0 (-2.6, 0.8) SDS at first and - 1.2 (-3.0, -0.2) at second DXA (p = 0.023). On follow up, lean mass for height increased from 27th centile (0, 75) to 40th centile (0, 70) (p = 0.006), and fat mass for height increased from 55 g/cm to 67 g/cm (11.3, 124.2) (p < 0.001). Duration of illness was the only negative predictor of LS BMAD (p < 0.0001). Change in height SDS was the only positive predictor of change in TBLH-BMC (r = 0.384, p = 0.037), and change in LS BMAD (r-0.934, p < 0.0001). Of 68 patients who had VFA, 4 (5.9%) had a mild vertebral fracture. CONCLUSION: Bones are smaller and less dense in childhood/adolescent AN compared to healthy adolescents. Although there are significant gains in lean mass and fat mass, over time, BMAD SDS decreases slightly. Improvement in BMAD SDS is related to improvement in height SDS.

A retrospective analysis of longitudinal changes in bone mineral content in cystic fibrosis.

BACKGROUND: We aimed to describe the longitudinal changes in bone mineral content and influencing factors, in children with cystic fibrosis (CF). METHODS: One hundred children (50 females) had dual X-ray absorptiometry (DXA) performed. Of these, 48 and 24 children had two to three scans, respectively over 10 years of follow-up. DXA data were expressed as lumbar spine bone mineral content standard deviation score (LSBMCSDS) adjusted for age, gender, ethnicity and bone area. Markers of disease, anthropometry and bone biochemistry were collected retrospectively. RESULTS: Baseline LSBMCSDS was >0.5 SDS in 13% children, between -0.5; 0.5 SDS, in 50% and ≤-0.5 in the remainder. Seventy-eight percent of the children who had baseline LSBMCSDS >-0.5, and 35% of the children with poor baseline (LSBMCSDS<-0.5), showed decreasing values in subsequent assessments. However, mean LS BMC SDS did not show a significant decline in subsequent assessments (-0.51; -0.64; -0.56; p=0.178). Lower forced expiratory volume in 1 s percent (FEV1%) low body mass index standard deviation scores (BMI SDS) and vitamin D were associated with reduction in BMC. CONCLUSIONS: Bone mineral content as assessed by DXA is sub-optimal and decreases with time in most children with CF and this study has highlighted parameters that can be addressed to improve bone health.

Prevalence of Vertebral Fractures in Children with Suspected Osteoporosis.

OBJECTIVES: To explore the prevalence and anatomic distribution of vertebral fractures in disease groups investigated for primary and secondary osteoporosis, using vertebral fracture assessment (VFA). STUDY DESIGN: VFA was performed independently by 2 nonradiologists, in 165 children (77 males, 88 females) as part of their investigation for osteoporosis. Vertebral bodies from T6 to L4 were assessed for vertebral fractures using the Genant scoring system. The common readings for the presence of vertebral fractures were used for evaluating the prevalence and anatomic distribution of vertebral fractures. RESULTS: The median age of the subjects was 13.4 years (range, 3.6, 18). Of the 165 children, 24 (15%) were being investigated for primary bone disease, and the remainder had a range of chronic diseases known to affect bone health. Vertebral fractures were identified in 38 (23%) children. The distribution of the vertebral fractures was bimodal, with vertebral fractures peaks centered at T9 and L4. Conditions associated with increased odds for vertebral fractures were inflammatory bowel disease (OR, 3.3; 95% CI, 1.4, 8.0; P = .018) and osteogenesis imperfecta (OR, 2.3; 95% CI, 1.04, 5.8; P = .022). Among children with vertebral fractures, those with Duchenne muscular dystrophy (P = .015) and osteogenesis imperfecta (P = .023) demonstrated higher number of vertebral fractures than the other disease groups. CONCLUSIONS: VFA identified the presence of vertebral fractures, in a bimodal distribution, in both primary bone disease and chronic disease groups. VFA is a practical screening tool for identification of vertebral fractures in children and adolescents at risk of fragility fractures.

An Unbalanced Rearrangement of Chromosomes 4:20 is Associated with Childhood Osteoporosis and Reduced Caspase-3 Levels.

The purpose of this study was to investigate the association of a chromosome 4:20 imbalance with osteoporosis in three related children. Bone biochemistry, bone turnover markers, and dual-energy X-ray absorptiometry (DXA) scanning were performed in all three cases and bone biopsy and histomorphometry in one. The chromosome imbalance was delineated by array comparative genomic hybridization (aCGH) and analyzed for candidate genes. A potential candidate gene within the deleted region is caspase-3, previously linked to low bone mineral density (BMD) in heterozygous mice thus caspase-3 activity was measured in cases and controls. Routine bone biochemistry and markers of bone turnover did not reveal any abnormality. DXA showed reduced total and lumbar spine bone mineral content. aCGH showed an 8 megabase (Mb) deletion of terminal chromosome 4q incorporating a region previously linked to low BMD and a 15 Mb duplication of terminal chromosome 20p. Bone biopsy showed a high bone turnover state, trabecularisation of cortical bone and numerous small osteoclasts coupled with normal bone formation. Basal serum caspase-3 activity was lower in cases compared with controls. We conclude that the early-onset osteoporosis with low basal levels of caspase-3 and abnormal osteoclasts is a feature of this chromosomal translocation. Further investigation of the role of the deleted and duplicated genes and especially caspase-3 is required.

A critical appraisal of vertebral fracture assessment in paediatrics.

PURPOSE: There is a need to improve our understanding of the clinical utility of vertebral fracture assessment (VFA) in paediatrics and this requires a thorough evaluation of its readability, reproducibility, and accuracy for identifying VF. METHODS: VFA was performed independently by two observers, in 165 children and adolescents with a median age of 13.4 years (range, 3.6, 18). In 20 of these subjects, VFA was compared to lateral vertebral morphometry assessment on lateral spine X-ray (LVM). RESULTS: 1528 (84%) of the vertebrae were adequately visualised by both observers for VFA. Interobserver agreement in vertebral readability was 94% (kappa, 0.73 [95% CI, 0.68, 0.73]). 93% of the non-readable vertebrae were located between T6 and T9. Interobserver agreement per-vertebra for the presence of VF was 99% (kappa, 0.85 [95% CI, 0.79, 0.91]). Interobserver agreement per-subject was 91% (kappa, 0.78 [95% CI, 0.66, 0.87]). Per-vertebra agreement between LVM and VFA was 95% (kappa 0.79 [95% CI, 0.62, 0.92]) and per-subject agreement was 95% (kappa, 0.88 [95% CI, 0.58, 1.0]). Accepting LVM as the gold standard, VFA had a positive predictive value (PPV) of 90% and a negative predictive value (NPV) of 95% in per-vertebra analysis and a PPV of 100% and NPV of 93% in per-subject analysis. CONCLUSION: VFA reaches an excellent level of agreement between observers and a high level of accuracy in identifying VF in a paediatric population. The readability of vertebrae at the mid thoracic region is suboptimal and interpretation at this level should be exercised with caution.

Group and individual agreement between field and dual X-ray absorptiometry-based body composition techniques in children from standard schools and a sports academy.

Percentage fat (%FM) and fat-free mass (FFM) were measured in 37 children from a sports academy and in 71 children from standard schools with dual x-ray absorptiometry (DXA) and bioelectrical impedance analysis (BIA) using the manufacturer's equation (Tanita) and an ethnic-specific prediction equation (Haroun). In the standard school, BIA overestimated FFM and underestimated %FM by a mean of 2.5 kg and 5.2%, respectively, using the Tanita equation. In girls from the sports academy, the Tanita equation underestimated FFM and overestimated %FM compared with DXA (mean difference BIA-DXA; FFM: -1.3 kg; %FM: 1.8%). The Haroun equation improved mean agreement between BIA and DXA in children (11 to 15 years) from the sports academy and for boys from standard schools, but reduced accuracy on individual assessments. These results have important practice implications for dietetics practitioners specializing in sports nutrition and exercise trainers.

Activity, body composition and bone health in children.

OBJECTIVE: To examine relationships among daily activity levels, body composition and bone outcomes in children aged 6.7 years who were born at term with birth weights <20th centile. METHODS: Activity data collected using accelerometers were correlated with body composition and bone outcome z-scores from dual-energy X-ray absorptiometry in 36 children. RESULTS: Activity levels were related to body composition outcomes; for example, lean mass index (lean mass/height(2)) was positively associated with time spent in moderate activity (r=0.40, p=0.02) and negatively with time spent in sedentary activity (r=-0.50, p=0.002). Per cent time spent in sedentary activity correlated negatively with whole body bone mineral density z-score (r=-0.44, p=0.01) and hip bone mineral content (r=-0.38, p=0.03). CONCLUSIONS: Moderate and vigorous activity levels were associated with increased lean and bone mass in this population but not with conventional measures of adiposity such as weight and body mass index z-scores. Standard measures of adiposity may mask potential benefits of regular activity.