Bone Health

The EATC4Children Bone Health workstream focuses on three areas of bone health: metabolic bone disorders, bone inflammation disorders, and orthopaedic surgery.

Metabolic bone disorders include Osteogenesis imperfecta (OI). OI is a rare, genetic condition characterised by fractures, usually caused by minimal impact. It is estimated that approximately 1 in 15,000 people are born with it.

Chronic Nonbacterial Osteomyelitis (CNO), and its severe presentation Chronic Recurrent Multifocal Osteomyelitis (CRMO), are autoinflammatory bone disorders resulting in chronic inflammation in the bone. The exact cause of CNO is not known. There are treatments available but there have not been any clinical trials of drugs specifically for CNO.

Children requiring orthopaedic surgery can have a number of conditions including, but not limited to, Perthes’ disease, slipped epiphysis, and hip dysplasia. There are no well-established treatments for these diseases, which is in part because there are no well-established outcome measures.


Metabolic bone disorders

The EATC4Children is currently involved in two major intervention studies related to osteogenesis imperfecta:

Multicenter, Single-arm Study to Evaluate Efficacy, Safety, & Pharmacokinetics of Denosumab in Children w/ OI

The aim of this study is to evaluate the effect of denosumab on lumbar spine bone mineral density (BMD) Z-score at 12 months, as assessed by dual-energy X-ray absorptiometry (DXA), in children 2 to 17 years of age with osteogenesis imperfecta. (CI: N. Bishop). 

ASTEROID

A multicentre, multinational prospective study of the effect of an anti-sclerostin antibody on bone mass and fracture risk in children with osteogenesis imperfecta – due to start Q2 2019 (CI N Bishop).

The EATC4Children is also involved in studies relating to the role of vitamin D in bone health:

MAVIDOS follow up

The MAVIDOS study focused on maternal gestational vitamin D supplementation and offspring bone health. This study is currently in the follow up phase, and we are leading on the determination of the response of bone to mechanical stimulation as part of a series of evaluations coordinated by the University of Southampton  (PI: N. Bishop).

The EATC4Children has also led on the development of a bone biomarker-response system, assessing the acute response to vibration in children with fracture, children from the MAVIDOS cohort whose mothers did or did not receive vitamin D supplementation, and children with osteogenesis imperfecta before and after exposure to a short course of bisphosphonate treatment; the BAMES study ClinicalTrials.gov reg. no. NCT03208582. These studies are all complete and in the write-up phase. (PI N Bishop).


Bone inflammation disorders

The EATC4Children is working to identify disease biomarkers and determine what causes CNO so we can use new targets to treat this condition.

The molecular pathophysiology of CNO

Though the exact molecular pathophysiology of CNO/CRMO remains unclear, we provided evidence suggesting that variable defects in the TLR4/MAPK/inflammasome signaling cascade result in an imbalance between pro- and anti-inflammatory cytokine expressions in monocytes from CNO/CRMO patients. The resulting inflammatory microenvironment in the bone likely contributes to osteoclast activation, inflammatory remodelling and bone loss. This study will genotype 200 CNO patients and perform functional testing of mutations identified (CI: C. Hedrich).

Responses and outcomes in CNO patients

We are involved in international studies monitoring responses and outcomes in CNO patients, following various treatment options (CARRA CHOIR study). As part of this study, clinical data will be collected together with biological samples. These will be used to improve our understanding of the molecular pathophysiology of CNO and develop reliable disease biomarkers and safe and target directed treatments (CIs: C. Hedrich, K. Mahmood).

Classification criteria

Classification criteria are necessary to make results comparable and reliable in order to include defined patient groups in clinical trials. We are involved in international initiatives delivering classification criteria for CNO (CI: C. Hedrich).


Orthopaedic surgery

The EATC4Children is currently supporting a number of orthopaedic paediatric trials:

The BOSS Study

The British Orthopaedic Surgery Surveillance (BOSS) Study is a flagship study, which recruits Perthes’ Disease and Slipped Epiphysis across 143 hospitals in the UK. It aims to determine the epidemiology and outcomes in rare orthopaedic diseases. (CI: D. Perry).

ORCHID study

The Outcome Research in Children’s Hip Disease (ORCHID) study aims to develop a system to accurately measure the bones in the hip joint using X-ray images. It will focus on children with two common hip diseases, Perthes’ Disease of the Hip and Slipped Capital Femoral Epiphysis (SCFE). Using measurements of the hip and clinical symptoms methods to predict likely outcomes of the disease, and to choose the most appropriate treatment, will be developed (CI: D. Perry).

SHINE (Sensing Hips in Newborns) study

This study is working to develop a new sensor for the detection of hip dysplasia in children that does not involve a specialist with an ultrasound machine (CI: D. Perry).

The TOP (The Outcomes of Perthes Disease) Study

This study aims to develop a Core Outcome Set, following the COMET methodology, to identify the most important outcomes to measure in all Perthes’ Disease studies. This is an essential precursor to the development of clinical trials (CI: D. Perry).

SCIENCE (Surgery or Cast for Injuries of the EpicoNdyle in Children’s Elbows) study

This is a nationwide trauma RCT to identify the best way to manage this injury. The aim of the trial is to determine the clinical and cost-effectiveness of operative fixation versus non-operative treatment for medial epicondyle fractures of the elbow in children (CI: D. Perry).

FORCE (Forearm fracture Recovery in Children Evaluation) study

This is a nationwide trauma RCT to identify the best management of this injury. The aim is to evaluate the clinical and cost-effectiveness of soft bandage immobilisation and immediate discharge, compared to rigid splint immobilisation (CI: D. Perry).

BOSS-CP (Cerebral Palsy in the British Orthopaedic Surgery Surveillance Study)

nationwide cohort of multilevel surgery for children with ambulant cerebral palsy (Co-CI: D. Perry).

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