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.

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.

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.

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.