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

我建议在模型系统中确定生命早期维生素D缺乏是否会改变后来骨骼对负荷的反应。儿童期骨折是常见的，其发病率正在增加。骨折更常见于骨骼较小、较窄、骨量相对于体型较低的儿童。对骨折风险的追踪是成年后骨骼尺寸追踪的必然结果。一些研究表明，早期骨折与后来的骨大小和质量有关。其他基于成人回忆童年骨折的研究不支持追踪骨折风险，但这些研究回忆的骨折率远低于英国目前报道的儿童骨折率（4-5倍）。在儿童时期，特别是青春期之前，定期的骨骼负荷已被证明可以产生骨量的持续增加，并可能降低儿童时期和以后生活中骨折的风险。对参加常规体育活动（如体操）和学校运动项目的人进行的研究表明，从生物学角度看，臀部、脊柱和全身的骨骼大小和质量都有所增加。这种增加从童年一直持续到青春期后，在预防成人骨质疏松症方面具有生物学意义。维生素D对儿童期骨折率的影响一直难以评估；最近一项关于婴儿补充维生素D的研究表明，直到3个月大时，高剂量的维生素D有增加骨量的趋势。目前卫生部的建议是针对佝偻病的预防，而不是改变儿童时期或以后的骨折风险。关于维生素D与骨骼健康的传统观点是，它能促进钙的吸收。较低的钙摄入量与骨折风险增加有关。因此，饮食和机械负荷的作用在确定它们对骨骼健康和预防儿童骨折的可能贡献方面具有相当大的意义。加载干预的时间被认为是重要的-青春期前的加载可能导致青春期后的骨大小和质量的好处。干预时间对维生素d的影响尚未得到解决。早期生活事件可能影响后来的生长和发育的建议最早是由麦坎斯在20世纪60年代初提出的。这一概念得到进一步发展，现已成为一个既定的研究领域——成人健康和疾病的发展起源。对人类的观察性研究表明，怀孕期间维生素D水平较低的母亲所生的婴儿骨骼可能较窄，并且这种骨骼大小的改变会持续到童年后期，增加他们骨折的风险。怀孕期间维生素D含量较低对骨骼的影响至少持续到8-9岁，这表明骨骼对可能影响其出生后大小和形状的因素的正常反应在某种程度上被取消了。怀孕期和产后早期是进行干预的重要机会，可以改善整个生命过程中的骨骼健康。因此，我建议使用动物模型系统研究在怀孕和生命早期减少维生素D摄入量对骨骼对机械负荷反应的影响。这项研究将帮助我们了解生命早期的饮食在多大程度上影响了我们身体后来的适当反应能力，如果成功的话，可能会帮助我们减少童年和晚年骨折的风险。

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.