Early life influences on skeletal growth - effects of vitamin D and mechanical loading

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I propose to determine whether early life vitamin D deficiency alters later skeletal responsiveness to loading in a model system.Fractures in childhood are common and their incidence is increasing. Fractures are more common in children with smaller, narrower bones and lower bone mass for body size. Tracking of fracture risk would be a logical consequence of bone size tracking into adult life. Some studies show evidence of earlier fracture being associated with later bone size and mass. Other studies based on adult recall of childhood fracture do not support the tracking of fracture risk, but those studies recalled rates of fracture are much lower (4-5 fold) than those now reported in the UK in children. Regular loading of bone during childhood, particularly before puberty, has been shown to produce a sustained increase in bone mass and may reduce the risk of fracture both in childhood and in later life. Studies in both those participating in regular sporting activities such as gymnastics that create large strains, and in school-based exercise programmes, have shown biologically relevant increases in bone size and mass at the hip, in the spine and in the whole body. Such increases persist from childhood into post-pubertal life and have biological relevance in the prevention of adult osteoporotic disease.The contribution of vitamin D to fracture rates during childhood has been difficult to assess; a recent study of vitamin D supplementation in infancy showed a trend towards increased bone volume with higher vitamin D doses up to age 3 months. Current Department of Health advice is targeted at the prevention of rickets, rather than altering fracture risk either during childhood or later. The traditional view of vitamin D in relation to skeletal health is that it enhances the absorption of calcium. Lower calcium intake is associated with an increased risk of fracture. The roles of both diet and mechanical loading are therefore of considerable interest in respect of determining their likely contribution to skeletal health and the prevention of fracture in childhood. The timing of loading interventions is thought to be important - prepubertal loading may result in post-pubertal benefit for bone size and mass. What has not been addressed is the impact of the timing of interventions in respect of vitamin D.The suggestion that early life events could influence later growth and development was first advanced by McCance in the early 1960s. The concept has developed further and is now an established field of investigation - the Developmental Origins of Adult Health and Disease. Observational studies in humans suggest that infants of mothers with lower vitamin D levels during pregnancy may have narrower bones, and that this alteration in bone size persists into later childhood, increasing their risk of fracture. The persistence of the effects of lower vitamin D in pregnancy on the skeleton at least to age 8-9 years suggests that the normal response of the skeleton to factors likely to influence its size and shape post-natally is abrogated to some extent. The periods of pregnancy and early post-natal life represent an important opportunity for intervention that could improve skeletal health across the life course.I therefore propose to study the effect of reducing vitamin D intake during pregnancy and early life on the skeleton's response to mechanical loading using an animal model system. The study will help us understand the extent to which diet in early life affects our body's ability to respond appropriately later on, and if successful, may help us reduce the risk of fractures both in childhood and later years.