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

我建议在一个模型系统中确定早期维生素D缺乏是否会改变后期骨骼对负荷的反应。儿童时期的骨折很常见，而且其发生率正在增加。骨折在儿童中更常见，他们的骨骼更小、更窄，与身体大小相比骨量更低。对骨折风险的跟踪将是骨大小跟踪到成年生活的合乎逻辑的结果。一些研究表明，较早的骨折与较晚的骨骼大小和质量有关。其他基于成人童年骨折回忆的研究不支持追踪骨折风险，但这些研究回忆起的骨折发生率比英国目前报告的儿童骨折发生率低得多(4-5倍)。在儿童时期，特别是在青春期之前，有规律的骨骼负荷已被证明会导致骨量的持续增加，并可能降低儿童时期和以后生活中骨折的风险。对那些经常参加体操等产生大拉伤的体育活动和学校锻炼计划的人的研究表明，髋部、脊柱和全身的骨骼大小和质量都有生物学意义的增加。这种增加从儿童期持续到青春期后，在预防成人骨质疏松症方面具有生物学意义。维生素D对儿童时期骨折发生率的贡献一直难以评估；最近一项关于婴儿补充维生素D的研究表明，随着维生素D剂量增加到3个月，骨量有增加的趋势。卫生部目前的建议是针对预防软骨病，而不是改变儿童时期或以后的骨折风险。关于维生素D与骨骼健康关系的传统观点是，它能促进钙的吸收。钙摄入量较低与骨折风险增加有关。因此，饮食和机械负荷在确定它们对骨骼健康和预防儿童骨折的可能贡献方面的作用是相当有意义的。负荷干预的时机被认为是重要的-青春期前负荷可能导致青春期后对骨骼大小和质量的益处。关于维生素D干预时机的影响尚未得到解决。20世纪60年代初，麦克坎斯首次提出早期生活事件可能会影响后来的生长和发育。这一概念得到了进一步发展，现已成为一个既定的研究领域--成人健康和疾病的发育起源。对人类的观察研究表明，母亲在怀孕期间维生素D水平较低的婴儿可能骨骼较窄，这种骨骼大小的变化会持续到儿童后期，增加他们骨折的风险。较低的维生素D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一定程度上被取消了。妊娠期和出生后早期是一个重要的干预机会，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来研究怀孕和早期减少维生素D摄入量对骨骼对机械负荷的反应的影响。这项研究将帮助我们了解早期饮食在多大程度上影响我们身体后来做出适当反应的能力，如果成功，可能会帮助我们降低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.