Title: Developing normative standards for vertebral morphology in children: A feasibility study
Funder: Department of Health and Social Care

Abstract: In adults, osteoporosis is conventionally defined based on bone mineral density (BMD) as measured by dual energy x-ray absorptiometry (DXA pronounced &ldquo;dexa&rdquo;). In children however, for various reasons including technical, BMD doesn t predict fracture; children with a normal BMD may sustain low energy fractures, while those with reduced BMD may not. BMD cannot therefore be used to diagnose osteoporosis in children. Recognising this, in 2013 the International Society for Clinical Densitometry updated their official position statements, such that the recognition of vertebral fractures (VF) is central to the diagnosis (and therefore treatment) of childhood osteoporosis. There are numerous causes of osteoporosis in children, with a rate of VF ranging from 16% (e.g. leukaemia) to over 75% (e.g. Duchenne muscular dystrophy), depending on the condition. If untreated, mild VF will tend to progress, with significant loss of vertebral body height, pain and deformity. Therefore, early detection and treatment (e.g. with bisphosphonates) is important. However, mild VF may be asymptomatic and hard to distinguish from physiological variation. Significant work is on-going developing methods of VF detection in the elderly, particularly those with osteoporosis. Our group has previously shown that diagnostic accuracy of VF in children is low, whether by subjective or semi-quantitative methods. We have also shown that semi-automated software developed for use in adults is unreliable when applied to children. There is a clear need for the development of paediatric-specific grading scales and software tools, particularly for the detection of mild fractures. If they are to be reliable, then such diagnostic tools must consider the age-related physiological changes in vertebral morphometry seen in children and young people, but not in adults. In order to develop such a tool, we aim to: 1. Document the natural variation in shape and height of vertebral bodies that occurs in healthy children 2. Produce an atlas of normal vertebral morphology in male and female children 3. Derive lambda-mu-sigma curves of normal vertebral morphology in male and female children 4. Harness the capabilities of artificial intelligence to develop an automated tool for VF diagnosis in children A definitive study is estimated to require 1,400 healthy children aged 5 to 18 years. For the current feasibility study, we will recruit 70 healthy children (male and female); 35 aged 7 to 8 years and 35 aged 14 to 15 years. We have chosen these ages to represent periods of rapid growth and puberty, when there is likely to be the largest variation in vertebral body height and shape. This degree of variation will inform a power calculation for the development of robust lambda-mu-sigma curves in the definitive study. Healthy children from 2 schools in Sheffield will attend Sheffield Children's Hospital for lateral spine DXA, while healthy children from 2 schools in Newmarket will be scanned at school on a mobile DXA scanner. Specific software will be developed to allow semi-automatic capture of size and shape of the vertebral bodies. Recruitment rate and child/parental preference for location of scanning will inform the design of the definitive study.

Lay abstract: Our long-term goal is to improve the diagnosis and treatment of childhood osteoporosis by improving the detection of back bone fractures. To achieve this, we must understand the natural variation in shape and height of the back bones that occurs in healthy growing children. Osteoporosis is thinning of the bones. There are over 25 inherited and acquired disorders (e.g. osteogenesis imperfecta, cystic fibrosis, Duchenne muscular dystrophy) and numerous drugs (e.g. steroids, anti-cancer drugs) associated with childhood osteoporosis, all predisposing affected children to fracture, pain and deformity. Furthermore, an adolescent with osteoporosis is likely to become an adult with osteoporosis. Early detection and treatment are important to prevent fracture/deformity progression. The International Society for Clinical Densitometry's definition of childhood osteoporosis is either 1) the presence of back bone fractures or 2) the presence of long bone fractures (supported by reduced bone density). This highlights the importance of identifying back bone fractures in children. If missed, a mild fracture of one back bone may &ldquo;cascade&rdquo; into multiple severe fractures, yet there is currently no reliable way of diagnosing mild childhood back bone fractures. Diagnosis depends on recognising loss of height and change in shape of the back bones either on spine x-ray or another type of imaging called DXA. There is no difficulty once changes are severe; the challenge lies in differentiating &ldquo;normal&rdquo; from &ldquo;mild back bone fracture&rdquo; especially because there are no normal standards in existence. Taking advantage of the low-radiation dose of DXA, we aim to document the normal variation in shape of the back bones that occurs in healthy children. To obtain reliable results, up to 1,400 healthy children may need to be recruited. This current smaller feasibility study will recruit 70 children (35 aged 7 to 8 years and 35 aged 14 to 15 years) from four schools. Children in Newmarket will have DXA on a mobile scanner sited on or nearby the school grounds. Sheffield children will attend Sheffield Children s Hospital for DXA. We will document recruitment rate and volunteer preferences for scanner location (school or hospital). We will develop specific software to help us outline and document the normal shape of back bones in the two age groups. Two adolescents and two parents from each city will be study collaborators; the adolescents and one adult helped with this application and all will assist with developing study material, recruitment and dissemination of results. Results will tell us how many children we actually need for the larger study, for which we shall apply for further funding. The final outcome will be the first and only software tool designed specifically for children, to improve fracture detection and therefore to improve diagnosis and treatment of childhood osteoporosis.

Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES;4.2 EVALUATION OF MARKERS AND TECHNOLOGIES
Health categories: MUSCULOSKELETAL