Bone Abstracts

Background: Osteogenesis imperfecta (OI), the commonest inherited bone fragility disorder, affects 1/15,000 live births resulting in frequent fractures and reduced mobility, with significant impact on quality of life. Early diagnosis is important, as therapeutic advances can lead to improved clinical outcomes.Methodology and results: Trio whole exome sequencing in patients with OI identified, in two patients, compound heterozygous mutations in NBAS</...

PHP1B -iPPSD3 per the new proposed classification- is a rare disorder characterized in most patients by proximal tubular resistance to PTH resulting in hypocalcemia, hyperphosphatemia and elevated PTH. Loss-of-methylation (LOM) at the Differentially Methylated Region (DMR) at GNAS exon A/B occurs in all PHP1B patients, but methylation changes at other DMRs within GNAS occur in some familial and most sporadic PHP1B cases. All patients with autosomal dominant PHP1B (AD-...

Objectives: To determine if genetic variants associated with principal component-derived areal bone mineral density (aBMD) loading scores.Methods: Our sample comprised 1,293 children of European ancestry enrolled in the longitudinal Bone Mineral Density in Childhood Study (52% female). The participants completed up to 7 annual study visits. From dual energy X-ray absorptiometry scans, sex and age-specific aBMD Z-scores were calculated for total hip, femo...

Objectives: Single nucleotide polymorphisms (SNP) in genes related to vitamin D metabolism have been associated with 25-hydroxyvitamin D (25(OH)D) status, but these relationships have not been examined in pregnancy or following antenatal vitamin D supplementation. We assessed whether SNPs in DHCR7 (7-dehydrocholesterol reductase), CYP2R1 (25-hydroxylase), CYP24A1 (24-hydroxylase) and GC (Vitamin D binding protein) were associated with the re...

Objectives: Conventional wisdom suggests that bone is most responsive to physical activity during the growing the years, especially the period just before puberty. Few studies have addressed the entire period of adolescence and even fewer have done so using bone imaging techniques to capture structural outcomes which contribute to bone strength. Using a well-defined cohort (The Iowa Bone Development Study, IBDS), this report examined the magnitude and consistency of the associ...

The relationship between vitamin D status and lean mass accretion in young children is not well understood.Objective: To explore vitamin D status in relation to lean mass outcomes over 12 mo in children 2–8 years.Methods: This was a secondary analysis of trial data (clinicaltrials.gov: NCT02097160, NCT02387892) in Montreal, Canada. Children consumed their normal vitamin D intake for 6 mo (Apr–Oct 2014, n=39) and ...

Objectives: Murine studies have shown that iron deficiency during pregnancy can cause abnormal phosphate and bone metabolism in offspring by elevating concentrations of fibroblast growth factor-23 (FGF23). FGF23 exists in plasma as an intact phosphate- and vitamin D-regulating hormone and its C-terminal fragment, a cleavage product that possibly antagonises the intact hormone. These findings are pertinent to low-income countries, where the prevalence of iron deficiency in preg...

Objectives: Adolescent Idiopathic Scoliosis (AIS) is associated with low bone mass. This study aimed at evaluating the therapeutic effect and its determinants of Ca+Vit-D supplementation in improving bone strength and preventing curve progression in AIS.Methods: This was a randomized double-blinded placebo-controlled trial recruiting AIS girls (11–14 years old, Tanner stage<IV) with femoral neck BMDZ-scores<0 and Cobb angle≥15°. 3...

Objective: We have observed sex-specific effects of pregnancy calcium carbonate supplementation in 8–12 year old Gambian children, indicating slower growth after infancy in girls born to calcium-supplemented mothers but faster in boys.1,2 IGF-1 is a key driver of growth and is responsive to calcium supplementation.3 The aim of this study was to determine whether the pregnancy supplement had resulted in sex-specific effects on mid-childhood IGF1 of th...

We have previously shown a high prevalence of vitamin D inadequacy (serum 25-hydroxyvitamin D (S25(OH)D) <50 nmol/l) in adolescents (14–18 years) in the UK (51°N)(1). It is well recognised that vitamin D deficiency (S25(OH)D <25 nmol/l) increases the risk of rickets and impaired growth in adolescents, however the optimal vitamin D status for bone health is debated. The aim of this study was to investigate the effects of vitamin D status on bone hea...

Objectives: Osteogenesis imperfecta (OI) is a bone fragility disorder associated with reduced muscle size, dynamic muscle function and mobility. This paired randomised controlled pilot study assessed the effect of whole body vibration (WBV) training on bone density and geometry, muscle size and function, mobility, and balance in children with OI.Methods: Twenty-four children (5–16 years) with OI types 1,4 and limited mobility (defined as a Childhood...

Background: Fracture incidence rate and growth according to different glucocorticoid (GC) regimen in Duchenne Muscular Dystrophy (DMD) is currently unknown.Objective: To determine the extent of skeletal morbidity and the influence of GC regimen on fracture incidence rate and growth in a contemporary cohort of DMD in the UK.Method: Clinical details of 832 boys with DMD in the North Star database (2006–2015) from 23 centres were...

Aim: Human gut microbiota is an important determinant of health and disease. Discoveries from recent microbiome studies have been postulated as actionable targets to treat malnutrition, diabetes, obesity among other conditions. The role of the gut microbiome on the development of the human musculoskeletal system is yet to be established. The aim of our study was to investigate the association between bacterial operational taxonomic units (OTUs) of the gut in relation to bone m...

Background and objectives: Lean mass (LM) has been positively associated with bone mineral density (BMD), but the impact of increased adiposity on bone especially in children is controversial. Several biomarkers, secreted by adipose tissue, skeletal muscle, or bone, may have important roles in the bone health. Our aim was to study the association of body composition, adipokines, myokines, inflammation-related cytokines, growth factors, and serum 25-hydroxyvitamin D (S-25(OH)D)...

Objectives: Previous studies indicate that about half of boys and one fourth of girls suffer a fracture before the age of 16 years. Similarly, children of European descent are more prone to fracture. Here we aimed to investigate at the population level the influence of sex, ethnic background and bone mineral density (BMD) on the occurrence of bone fractures in children of school age.Methods: This study (n=3,633 children with complete information...

Objectives: Hypophosphatasia (HPP) is a rare, inherited metabolic disorder caused by loss-of-function mutations in the ALPL gene that encodes the tissue-nonspecific alkaline phosphatase TNAP (ORPHA 436). Its clinical presentation is highly heterogeneous with a remarkably wide-ranging severity. HPP affects patients of all age. Therefor diagnosis is often difficult and delayed. To improve the understanding of HPP in children and in order to shorten the diagnostic time span in th...

Objectives: The SNAP study is a prospective fracture study of children with chronic inflammatory and/or disabling conditions. The overall study aim is to assess causal links between body-size adjusted bone density and low trauma fracture.Methods: 330 children aged 5–18 years were recruited from seven disease groups namely; acute lymphoblastic leukaemia (ALL), rheumatological disease, inflammatory bowel disease, cystic fibrosis, coeliac disease, Duch...

Survival of chronic diseases in childhood is often achieved utilizing glucocorticoids. However, the survival comes at a cost to the growing skeleton, resulting in impairment in the acquisition of peak bone mass and is the major etiology of secondary osteoporosis in children. We recently found that preosteoclasts secrete platelet derived growth factor type BB (PDGF-BB) to promote angiogenesis and osteogenesis during both modeling and remodeling. As glucocorticoid therapy affect...

Introduction: Conventional therapy of osteosarcoma, a primary malignant bone tumor, includes surgical excision with wide resection, which leads to physical and aesthetic defects. Allografts for reconstruction of bone and joints and adipose tissue autologous grafts for soft tissue defects can be supplemented with mesenchymal stromal/stem cells (MSCs). Additionally MSCs may be used in tumor-targeted cell therapy. However MSCs may have adverse effects on osteosarcoma development,...

Background: Hyperphosphatemic familial tumoral calcinosis (HFTC)/hyperostosis-hyperphosphatemia syndrome (HHS) is an autosomal recessive disorder due to deficiency of or resistance to intact fibroblast growth factor 23 (FGF23). This leads to hyperphosphatemia, increased renal reabsorption of phosphorus (TRP), and elevated or inappropriately normal 1,25-dihydroxyvitamin D (1,25D). Affected individuals may develop ectopic calcifications and/or diaphyseal hyperostosis. Mutations ...

Objectives: Fibrous dysplasia is a rare bone and endocrine disorder resulting from somatic activating mutations in GNAS. In the skeleton, proliferation of undifferentiated stromal cells results in osseous lesions that are prone to deformity, fracture, and pain. Lesions may affect one bone or many, and may occur in isolation or in association with hyperfunctioning endocrinopathies, termed McCune-Albright syndrome (MAS). Scoliosis is a potentially serious, even lethal c...

High Bone Mass (HBM) osteogenesis imperfecta (OI) is caused by dominant mutations in the C-propeptide cleavage site of COL1A1 or COL1A2, characterized by bone hypermineralization. To elucidate the role of C-propeptide processing in bone mineralization and development, we generated heterozygous HBM mice with both residues (Ala-Asp) of the COL1A1 cleavage site substituted (Thr-Asn) to prevent processing by BMP1. Two, 6- and 12-month WT and HBM bones were examin...

Objective: Children with hypophosphatasia (HPP) treated with asfotase alfa in a Phase 2 study (NCT00952484) and its open-label extension (NCT01203826) experienced significant improvements in skeletal mineralization and physical function that were sustained through 5 years of treatment (1). Herein, we report data from these studies with a maximum of 7 years of treatment.Methods: Children with HPP aged 6–12 years at baseline received asfotase alfa (3 ...

Objectives: XLH features renal phosphate (Pi) wasting, hypophosphatemia, rickets, and skeletal deformities from elevated circulating levels of fibroblast growth factor 23 (FGF23). KRN23, an investigational fully human monoclonal antibody, binds FGF23 and inhibits its action. Our Phase 2 study of KRN23 in XLH children (ages 5–12 years) is demonstrating improvements in serum Pi and rickets. Here we present our Phase 2 trial evaluating the efficacy and safety of KRN23 in you...

Objective: To evaluate safety and efficacy after 5 years of treatment with asfotase alfa in adolescents and adults with hypophosphatasia (HPP) in a Phase 2, open-label, randomized, dose-ranging study (NCT01163149).Methods: Treatment with subcutaneous asfotase alfa 0.3 or 0.5 mg/kg per d was compared with no treatment (control) for 6 months in patients aged 13–66 years. After 6 months, all patients (treatment and control groups) received active treat...

Objectives: In XLH, FGF23-mediated hypophosphatemia leads to defective bone mineralization and rickets. Investigational product KRN23 binds FGF23 and inhibits its activity. The objective of this Phase 2 study was to evaluate the safety and efficacy of KRN23 in 52 children with XLH (ages 5–12 years, ≤Tanner 2).Methods: Patients were randomized to receive KRN23 biweekly (Q2W) or monthly (Q4W) by SC injection. KRN23 dose was titrated (maximum 2 m...