Title: Lifecourse Determinants of Bone and Joint Disease
Funder: Medical Research Council

Abstract: Objectives: To (a) understand better the mechanisms which underlie the developmental origins of osteoporosis and other musculoskeletal disorders; and (b) develop intervention studies aimed at modifying later disease risk through nutritional and other interventions targeted at critical periods of development. Research proposals: The programme will address the developmental origins of osteoporotic fracture from molecule to population, using observational as well as interventional studies. Follow-up of participants in the Hertfordshire and Helsinki cohort studies will determine the growth trajectories of individuals at later risk of fracture, and explore the impact of these trajectories on bone size, geometry, mineral content, and volumetric density; the genetic contribution to these aspects of fracture risk will be studied through genome-wide screening as part of large international consortia. Further follow-up of children included in the Southampton Womens Survey will elucidate the parental influences on skeletal development during peri-conception, pregnancy and early postnatal life. Follow-up of these children through ages 6 and 8 years will extend our understanding of the relationship between maternal 25-hydroxyvitamin D status during pregnancy and childhood skeletal size, geometry and volumetric density. Our studies will permit exploration of interactions between prenatal and postnatal environmental influences such as physical activity (assessed using accelerometry), and diet (using questionnaires and biomarkers). Epigenetic mechanisms underlying the observed relationships between early environment and later bone health will be explored using samples of umbilical cord and placenta obtained from deliveries within SWS; DNA methylation status of key genes engaged in calcium transport, and maternal stress, will be related to childhood bone mass. A centrepiece of the programme will be the first randomised controlled trial to investigate whether supplementation of vitamin D during pregnancy serves to optimise skeletal development in the offspring (MAVIDOS). This aetiological trial will encompass sub-studies addressing intermediary outcome measures and the impact of vitamin D supplementation on other systems (body composition, immune function and respiratory development). Interventions to prevent osteoporotic fracture later in the lifecourse will be evaluated as part of the programme. Thus, in the MRC SCOOP trial, we test a novel methodology for risk stratification developed by the WHO in a large (n=11,500), pragmatic, randomised controlled trial. Finally, linkage with the NIHR Biomedical Research Unit in Musculoskeletal Science, University of Oxford, will permit development of a research theme addressing the lifecourse epidemiology of osteoarthritis; we shall study determinants of initiation and progression of this disorder, risk factors for arthroplasty failure, and the role of vitamin D in retarding the progression of OA. Impact: Musculoskeletal disorders have enormous health and economic impacts on society. Our research programme will permit the development of novel public health strategies to improve skeletal health throughout the lifecourse, and reduce osteoporotic fractures in future generations. Greater understanding of the epidemiology of osteoarthritis (the commonest joint disorder worldwide) will contribute to parallel strategies that reduce the incidence and morbidity associated with this disorder.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS;2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT;3.1 PRIMARY PREVENTION INTERVENTIONS TO MODIFY BEHAVIOURS OR PROMOTE WELL-BEING
Health categories: MUSCULOSKELETAL