Searchable abstracts of presentations at key conferences on calcified tissues
Previous issue | Volume 7 | ICCBH2019

9th International Conference on Children's Bone Health

ba0007oc1 | (1) | ICCBH2019

Association between age at puberty and bone accrual up to 25 years-old

Elhakeem Ahmed , Frysz Monika , Tilling Kate , Tobias Jon H , Lawlor Debbie A

Objectives: Studies indicate that later puberty is associated with lower bone mineral density (BMD) in childhood. Less is known about effects of puberty timing on long-term bone accrual. We examined association between age at puberty and BMD accrual rate from 10 to 25 years.Methods: This was a prospective birth cohort of healthy largely European people born in southwest England in 1991–1992 and regularly follow-up from birth to mean age 25 years. Ag...

ba0007oc2 | (1) | ICCBH2019

Adolescent pregnancy and bone density in premenopausal women

Palande Sonal , Padidela Raja , Khadilkar Anuradha , Mughal Zulf , Chiplonkar Shashi , Khadilkar Vaman , Chauthmal Sujata , Kajale Neha

Objectives: High prevalence (20%) of adolescent pregnancy (AP) (1) is observed in India. Reports suggest that pregnancy during adolescence may have deleterious effects on peak bone mass (2). Few reports have described the long-term effects of history of AP on bone. The objective of this study was to compare bone density and geometry of premenopausal women having delivered first child during adolescence (before age of 19 years) or after 19 years.Methods: ...

ba0007oc3 | (1) | ICCBH2019

Osteocyte lacunae characteristics in healthy children

Blouin Stephane , Hartmann Markus A , Klaushofer Klaus , Glorieux Francis H. , Rauch Frank , Zwerina Jochen , Roschger Paul

Objectives: Osteocytes play a major role in bone metabolism as mechanosensors, key regulators of osteoblast and osteoclast activity and of the mineral homeostasis. Therefore the assessment of osteocytes characteristics is important to understand bone pathology. We propose to study indirectly the osteocytes by performing quantitative backscattered electron imaging to quantify the sectioned osteocyte lacunae density and size in 2D on bone samples.Methods: ...

ba0007oc4 | (1) | ICCBH2019

Early life vitamin D depletion and mechanical loading determine methylation changes in the RXRA, Runx2 and osterix promoters in mice

Borg Stephanie , Krstic Nevena , Buckley Harriet , Curtis Elizabeth , Cooper Cyrus , Lillycrop Karen , Harvey Nick , Skerry Tim , Bishop Nick

Objectives: Maternal vitamin D status in pregnancy is associated with neonatal bone mass, and altered DNA methylation. Mice exposed to early life vitamin D deficiency have lower bone mass and reduced bone accrual in response to mechanical loading. Using tibias from these mice we assessed DNA methylation of promoters of genetic loci important for bone growth and development.Methods: C57/BL6 mice received a vitamin D replete or deplete diet for 6 weeks per...

ba0007oc5 | (1) | ICCBH2019

Low birthweight is associated with poorer limb muscle mass and grip strength in middle age: findings from the UK Biobank Imaging Enhancement

Curtis Elizabeth , Liu Justin , Ward Kate , Jameson Karen , Raisi-Estabragh Zahra , Bell Jimmy , Petersen Steffen , Cooper Cyrus , Harvey Nicholas

Objectives: Low birthweight has been shown to be associated with poorer musculoskeletal health in later life in a variety of epidemiological studies. We investigated relationships between birthweight, and grip strength or magnetic resonance imaging (MRI) measures of muscle volume in UK Biobank.Methods: UK Biobank is a large prospective cohort of men and women aged 40–69 years, including a detailed baseline assessment in which birthweight was collect...

ba0007oc6 | (1) | ICCBH2019

Anthropometric characteristics of pediatric patients with hypophosphatasia: data from the Global Hypophosphatasia Patient Registry

Hogler Wolfgang , Linglart Agnes , Petryk Anna , Kishnani Priya , Seefried Lothar , Fang Shona , Rockman-Greenberg Cheryl , Ozono Keiichi , Martos-Moreno Gabriel Angel

Objectives: Limited data exist on growth parameters in children with hypophosphatasia (HPP), a rare metabolic disease characterized by impaired bone mineralization. We aimed to describe growth characteristics in untreated children with HPP enrolled in the Global HPP Patient Registry.Methods: Children (<18 years old) with a diagnosis of HPP who were not receiving enzyme replacement therapy with asfotase alfa at the time of evaluation were identified f...

ba0007oc7 | (1) | ICCBH2019

Comparison of zoledronate and pamidronate in children with skeletal disorders: Short term safety experience from a single institution

Tosi Laura , Estrada Andrea , Floor Marianne , Kim Mirini , Weigley Lindsay , Dollar Christina , Gillies Austin , Roberts Mary Scott , Gafni Rachel , Boyce Alison

Objectives: Bisphosphonates are frequently used in children with skeletal disorders, however optimal dosing and regimens are unknown. Early treatment focused on pamidronate (PAM), a second-generation formulation, however use of zoledronate (ZOL), a more potent third-generation bisphosphonate, has recently increased due to shorter and less frequent infusions. The objective of this study is to compare short-term safety of ZOL and PAM in a pediatric population.<p class="abste...

ba0007oc8 | (1) | ICCBH2019

Bisphosphonate improves hip range of motion and pain but not femoral head sphericity: A multicentre, randomized clinical trial of children with Perthes disease

Jamil Kamal , Zacharin Margaret , Foster Bruce , Donald Geoffrey , Hassall Timothy , Siafarikas Aris , Johnson Michael , Tham Elanie , Whitehead Colin , Gebski Val , Barnes Liz , Cowell Chris , Little David , Munns Craig

Introduction: Perthes disease (PD), idiopathic femoral head avascular necrosis, often results in deformity. The underlying cause is unclear and long-term function is directly related to the roundness of femoral head. Current treatment include mechanical treatments and various surgical procedures, which are therapeutic but can’t prevent collapse. A multicentre, prospective, randomised controlled trial of 12 months zoledronic acid (ZA) in children with PD was conducted. We ...

ba0007oc9 | (1) | ICCBH2019

Efficacy and safety of intravenous zoledronic acid for the treatment of pediatric glucocorticoid-induced osteoporosis: An international, randomized placebo-controlled trial

Ward Leanne M , Alos Nathalie , Cabral David A , Rodd Celia , Sbrocchi Anne Marie , Padidela Raja , Shaw Nick , Kostik Mikhail , Alexeeva Ekaterina , Thandrayen Kebashni , Aftring Paul , Choudhury Anup , Sunkara Gangadhar , Sayyed Sarfaraz , Munns Craig F.

Objectives: We evaluated the efficacy and safety of intravenous zoledronic acid (IV ZA) in children with glucocorticoid-induced osteoporosis (GIOP) through a randomized, placebo (PBO)-controlled trial.Methods: In this multi-national Phase 3 trial (NCT00799266), children 5–17 years of age with GIOP and low-trauma vertebral fractures (VF) were randomized 1:1 to IV ZA 0.05 mg/kg or IV PBO every six months for one year. Changes in lumbar spine areal bon...

ba0007oc10 | (1) | ICCBH2019

Next-generation antibody-guided enzyme replacement therapy for lysosomal storage diseases

Baik Andrew , Aaron Nina , Birnbaum Matthew , Calafati Philip , Schoenherr Christopher , Economides Aris , Cygnar Katherine

Objectives: Lysosomal diseases (LDs) are a heterogenous group of 40+ genetic disorders that can affect virtually all organs and systems, including the skeletal system. They are often caused by the loss of an enzyme critical for the breakdown of macromolecules in the lysosome, leading to accumulation of these substrates and subsequent lysosomal dysfunction. Enzyme replacement therapy (ERT) is the primary treatment option for many LDs, but several issues hinder the efficacy of t...

ba0007oc11 | (1) | ICCBH2019

Targeting adeno-associated viral vectors to fractures and the skeleton

Lee Lucinda , Peacock Lauren , Lisowski Leszek , Little David , Munns Craig , Schindeler Aaron

Objectives: While local gene therapy for bone applications has shown some success in preclinical models, systemic delivery of transgenes to the skeleton remains a considerable challenge. Viral vectors such as adeno-associated viruses (AAVs) have great potential as vectors for systemic transgene delivery and may be adapted for emerging gene editing technologies. Furthermore, AAV vectors can have high efficiency, low immunogenicity, and selective tropism towards different tissue...

ba0007oc12 | (1) | ICCBH2019

Combination treatment of a novel activin receptor IIB ligand trap and zoledronate improves muscle and bone proprieties in a mouse model of osteogenesis imperfecta

Boraschi-Diaz Iris , Rauch Frank

Osteogenesis imperfecta (OI) is not only characterized by fragile bones but also impaired muscle mass and function. Inhibition of signaling through the activin receptor IIB has the potential to improve both muscle and bone mass. Here we investigated the effect of a soluble activin receptor IIB ligand, ACE-2494 (10 mg/kg twice a week), in 4-week old Col1a1Jrt/+ male mice, a model of severe dominant OI caused by a Col1a1 splice site mutation. Four weeks of treatment with ACE-249...

ba0007oc13 | (1) | ICCBH2019

Analysis of osteogenesis imperfecta in pathology and the effects of 4-phenylbutyric acid using patient-derived fibroblasts and induced pluripotent stem cells

Takeyari Shinji , Ohata Yasuhisa , Kubota Takuo , Taga Yuki , Mizuno Kazunori , Ozono Keiichi

Objectives: Osteogenesis Imperfecta (OI) is a heritable brittle bone disease mainly caused by mutation of COL1A1 or COL1A2. Treatment with bisphosphonate is not effective enough in patients with severe OI. 4-phenylbutyric acid (4-PBA) may become a new medicine, which was reported to ameliorate the phenotype of an OI zebrafish model. In the present study, we aimed to analyze the pathology of OI and the effects of 4-PBA on patient-derived fibroblasts and induced pluripotent stem...

ba0007oc14 | (1) | ICCBH2019

Burosumab resulted in greater improvement in clinical outcomes than continuation with conventional therapy in younger (1-4 years-old) and older (5-12 years-old) children with X-linked hypophosphatemia

Ward Leanne , Imel Erik , Whyte Michael , Munns Craig , Portale Anthony , Hogler Wolfgang , Simmons Jill , Padidela Raja , Namba Noriyuki , Cheong Hae , Nilsson Ola , Mao Meng , Skrinar Alison , Chen Chao-Yin , Martin Javier San , Glorieux Francis

Objective: We compared the efficacy and safety of burosumab, a monoclonal antibody against FGF23, to conventional therapy [oral phosphate and active vitamin D (Pi/D)] in children with X-linked hypophosphatemia (XLH).Methods: In this Phase 3 trial (NCT02915705), 61 children with XLH (1-12 years-old) were randomized 1:1 after a 7-day Pi/D washout to receive burosumab starting at 0.8 mg/kg SC Q2W or reinitiate Pi/D optimally titrated by investigators. Eligi...

ba0007oc15 | (1) | ICCBH2019

Sustained efficacy and safety of burosumab, a fully human anti-FGF23 monoclonal antibody, in children and early adolescents with X-linked hypophosphatemia

Hogler Wolfgang , Carpenter Thomas , Imel Erik , Portale Anthony , Boot Annemieke , Linglart Agnes , Padidela Raja , Hoff William van't , Mao Meng , Skrinar Alison , Martin Javier San , Whyte Michael

Objective: We evaluated the long-term efficacy of burosumab, a monoclonal antibody against FGF23, in a Phase 2 Study (NCT02163577) in children with XLH.Methods: Fifty-two children with XLH (5-12 years-old, Tanner ≤ 2) were randomized 1:1 to receive subcutaneous burosumab Q2W or Q4W for 64 weeks. Doses were titrated up to 2 mg/kg/dose targeting serum phosphorus levels within 1.1–1.6 mmol/l. All subjects entered the long-term extension at Week 6...

ba0007oc16 | (1) | ICCBH2019

A natural history study of generalized arterial calcification of infancy (GACI) and autosomal recessive hypophosphatemic rickets (ARHR2) due to ENPP1 or ABCC6 deficiency: interim analysis

Nitschke Yvonne , Kintzinger Kristina , Hackbarth Mary , Botschen Ulrike , Wang Sisi , Gafni Rachel I , Mueller Kerstin , Ahmed Ruhi , Yuen Eric , Gahl William A , Ferreira Carlos R , Rutsch Frank

Introduction: ENPP1 Deficiency manifests as GACI type 1 in infants, a disorder characterized by extensive arterial calcifications and stenoses, often fatal in utero or in early infancy. Beyond six months, the mortality rate significantly decreases among survivors, who may later develop ARHR2, characterized clinically by short stature, bone deformities and pain. ABCC6 Deficiency also manifests as GACI type 2 in infants and is clinically indistinguishable from GACI type 1. Anima...

ba0007oc17 | (1) | ICCBH2019

Growth curves for children with X-linked hypophosphatemia

Mao Meng , Carpenter Thomas , Whyte Michael , Skrinar Alison , Chen Chao-Yin , Martin Javier San , Rogol Alan

Objective: We constructed height growth curves for children with XLH from birth to early adolescence, a majority of whom received conventional therapy consisting of multiple daily doses of oral phosphate and active vitamin D.Methods: Growth data from four clinical studies were pooled to construct the growth curves. UX023-CL002 was an observational, retrospective chart review of 103 children with XLH, 1–14 years of age. Pre-treatment data were collec...

ba0007oc18 | (1) | ICCBH2019

Developing a human-mouse hybrid model of osteogenesis imperfecta for investigating new therapies for children

Arshad Fawaz , Lefley Diane , Madan Sanjeev , Fernandes James , Bishop Nick , Ottewell Penelope

Objectives: Osteogenesis imperfecta (OI) displays a heterozygous phenotype even amongst similar genotypes. It has therefore been difficult to establish a mouse model which represents clinical OI in children. By engrafting human OI bone into mice we have developed a hybrid model enabling us to investigate the efficacy of new treatments for this phenotypically diverse condition.Methods: Bone chips, that would otherwise be discarded, were collected from chi...

ba0007oc19 | (1) | ICCBH2019

Altered 3 hydroxylation complex in bone homeostasis

Tonelli Francesca , Leoni Laura , Cotti Silvia , Giannini Gabriella , Daponte Valentina , Gioia Roberta , Fiedler Imke , Besio Roberta , Rossi Antonio , Busse Bjorn , Witten Eckhard , Forlino Antonella

Objectives: Osteogenesis imperfecta (OI) is a heritable disorder characterized by bone deformity and skeletal fragility. Cartilage associated protein (CRTAP), proline 3-Hydroxylase 1 (P3H1) and Cyclophylin B (PPIB) are components of the endoplasmic reticulum (ER)-resident complex involved in the 3-hydroxylation of specific proline residues in collagen type I α chains. Mutations in these proteins are responsible for recessive OI type VII, VIII and IX, respectively. Murine ...

ba0007oc20 | (1) | ICCBH2019

Identifying the role of NBAS in bone fragility using zebrafish and exploring therapeutic targets to reverse NBAS activity

Balasubramanian Meena , Baxendale Sarah , Roehl Henry

Background: We discovered that variants in NBAS (Neuroblastoma Amplified Sequence Gene) known to be associated with acute liver failure are also responsible for skeletal abnormalities. This work was published as a novel cause of bone fragility [Balasubramanian et al., 2017]. NBAS role in bone fragility provides an opportunity to use tractable animal research to advance understanding of mechanism and identify potential new treatments. This would be beneficial to patien...

ba0007oc21 | (1) | ICCBH2019

New mouse model with IFITM5 S42L for atypical type VI osteogenesis imperfecta

Guterman Ram Gali , Hedjazi Ghazal , Stephan Chris , Blouin Stephane , Roschger Paul , Klaushofer Klaus , Kozloff Ken , Fratzl-Zelman Nadja , Marini Joan

Objectives: Osteogenesis Imperfecta (OI) is a collagen-related disorder. Type V OI, caused by a recurrent dominant mutation in the plasma membrane protein IFITM5/BRIL, and type VI OI, caused by recessive null mutations in the anti-angiogenic factor PEDF, have distinct features. IFITM5 S40L, reported in six patients, causes severe dominant OI with phenotype and bone histology similar to type VI, rather than Type V, OI. Our objective is to understand the pathway connecting IFITM...

ba0007oc22 | (1) | ICCBH2019

Bone tissue phenotyping reveals increased matrix mineralization, elevated osteocyte lacunar density and altered vascularity in a new OI mouse model carrying a leucine substitution for the BRIL p.Serine42 residue

Hedjazi Ghazal , Guterman-Ram Gali , Blouin Stephane , Roschger Paul , Klaushofer Klaus , Fratzl-Zelman Nadja , Marini Joan C

Objectives: A common feature of nearly all forms of osteogenesis imperfecta (OI) is a hypermineralized bone matrix. Null mutations in SERPINF1, encoding the potent antiangiogenic factor PEDF, lead to type VI OI with excessive osteoid formation, abnormal osteoblast-osteocyte development and increased matrix mineralization. Recently, atypical type VI OI has been delineated, caused by a loss-of-function mutation (p.S40L) in IFITM5 the causative gene for type V OI. The 6 cases rep...

ba0007oc23 | (1) | ICCBH2019

Effects of the FGF2 aptamer on growth plate cartilage development of achondroplasia patient-specific iPS cells in a xenograft model

Kimura Takeshi , Yasuda Kie , Nakano Yukako , Takeyari Shinji , Kitabatake Yasuji , Kubota Takuo , Miyoshi Yoko , Ozono Keiichi , Nonaka Yosuke , Fujiwara Masatoshi , Nakamura Yoshikazu

Objectives: Endochondral ossification in the growth plate cartilage (GPC) plays a crucial role in the determination of the length and shape of long bones. Many skeletal dysplasias are caused by GPC dysfunction, associated with short stature. We have already reported that human iPS cell-derived cartilage (hiPSC-Cart), when implanted into the subcutaneous spaces of the SCID mice for 4 weeks, formed skeletal tissue like GPC. This model could also recapitulate the pathology of FGF...

ba0007oc24 | (1) | ICCBH2019

TA-46, a recombinant soluble FGFR3 receptor for the treatment of achondroplasia, is safe and well-tolerated in healthy volunteers

Collins Samuel , Greig Gerard , Porter Richard , Stavenhagen Jeff , Santarelli Luca , Meyer Christian

Objectives: To assess the safety, tolerability and pharmacokinetic (PK) profile of single and multiple doses of TA-46 administered subcutaneously to healthy volunteers.Methods: This was a double-blind, randomized, placebo-controlled trial in a total of 72 subjects. Cohorts of 8 subjects were randomised to receive either TA-46 or placebo in a 3:1 ratio in single ascending dose (SAD) and multiple ascending dose (MAD) cohorts. SAD doses were 0.3, 1, 3, 10 a...

ba0007oc25 | (1) | ICCBH2019

TransCon CNP: Potential for a once weekly novel therapy in children with achondroplasia

Bharucha Kamal , Ota Sho , Christoffersen Eva Dam , Mygind Per , Viuff Dorthe , Leff Jonathan

Objectives: Achondroplasia (ACH), the most common form of human dwarfism, is caused by a gain-of-function mutation in the fibroblast growth factor receptor 3 (FGFR3) gene, a key negative regulator of endochondral ossification. C-type natriuretic peptide (CNP) inhibits the FGFR3 pathway and thereby promotes proliferation and differentiation of chondrocytes to promote bone growth. TransCon CNP is a prodrug designed to provide continuous exposure to CNP to optimize efficacy with ...

ba0007oc26 | (1) | ICCBH2019

[18F] NaF PET/CT the first tool to diagnose chronic activity in FOP at all ages?

Netelenbos Coen , Botman Esmee , Raijmakers Pieter GHM , Lammertsma Adriaan A , Eekhoff Marelise W

Fibrodysplasia ossificans progressiva (FOP) is a rare, autosomal dominant disorder characterized by heterotopic ossification (HO) in muscles, ligaments and tendons. Flare-ups often precede formation of HO, resulting in immobilized joints. Recently, it has been shown that [18F]NaF PET/CT could identify early ossifying disease activity during flare-ups. HO may progress without signs of flare-up, but its underlying physiology is not understood. We wondered whether [18F]NaF PET/CT...

ba0007oc27 | (1) | ICCBH2019

Palovarotene inhibits the development of new heterotopic ossification in fibrodysplasia ossificans progressiva (FOP)

Kaplan Frederick , Hsiao Edward C , Baujat Genevieve , Keen Richard , De Cunto Carmen , Di Rocco Maja , Brown Matthew A , Al Mukaddam Mona M , Grogan Donna R , Pignolo Robert J

Objective: FOP is a rare, severely disabling disease characterized by episodic flare-ups and accumulation of heterotopic ossification (HO) leading to restricted movement, physical disability, and early death. Data from two Phase 2 interventional studies and one natural history study (NHS) were used to evaluate whether palovarotene could reduce HO following an FOP flare-up.Methods: HO volume at the flare-up site was determined by CT at baseline and 12 wee...