Programme 3: Early development and risk of adult musculoskeletal disease

The aim of this programme is to integrate observational epidemiology and mechanistic understanding to inform novel interventions in early life to reduce the risk of later diseases such as osteoporosis and sarcopenia. Whilst our results have already informed national guidelines (DH, NICE, Public Health England and the Scientific Advisory Committee on Nutrition), the programme will advance this work by generating discovery science to delineate underlying mechanisms and to establish the wider relevance of the findings in order to inform the successful implementation of resulting public health strategies.

Scientific abstract (around 400 words – max. 3,500 characters including spaces) Summary: This programme integrates observational epidemiology and mechanistic understanding to inform novel interventions in early life and thereby to reduce the risk of later diseases such as osteoporosis and sarcopenia.
Objectives: To (a) elucidate risk factors for reduced bone and muscle accrual during growth and development; (b) thus identify potential early interventions aimed at optimizing musculoskeletal development, so maximising peak bone and muscle mass, and; (c) test these
interventions, identifying mechanisms underlying, and markers of, factors which modify efficacy.
Research plan: Our future work will therefore focus on three key areas. First, study of Southampton Women’s Survey (SWS) children in late childhood/adolescence will enable us to characterise patterns of early nutrition and growth in relation to bone mass and body composition, and specifically the potential modifying effect on the pubertal transition of the earlier growth trajectory. Where potential interventions are identified and instruments are available, studies of causal inference may be undertaken using the UK Biobank cohort to inform new randomised controlled trials. We will use novel DXA image-derived phenotypes as part of our Wellcome Trust AUGMENT Award to investigate early life influences on novel indices of adult bone health in UK Biobank. With Programmes 1 and 2, this work will be complemented by novel intergenerational studies in the Hertfordshire Cohort and SWS, assessing phenotype and health across generations. Secondly, we will investigate the replication and persistence of the finding that maternal gestational vitamin D supplementation leads to improved offspring neonatal bone mass amongst winter births, using the SPRING trial (replication) and later childhood follow-up in MAVIDOS (persistence), together with adjunctive analyses in other populations, for example in novel trials such as NiPPeR and HeLTI trials in South Africa, India and China. Lastly, using experimental medicine approaches nested within our larger intervention studies, we will delineate mechanisms by which the impact of our interventions might be maximised, in a precision medicine approach, for example elucidating the influence of genetic polymorphisms on response to vitamin D supplementation and associated bone turnover, and markers of response using epigenetic profiles.
Impact: This programme will enable us to identify new public health approaches to optimise musculoskeletal development into adulthood, and characterise mechanisms underlying/modifying these early developmental influences, to ultimately reduce the burden of musculoskeletal diseases such as osteoporosis and sarcopenia in older age.