EARLY GROWTH AND LATER BONE HEALTH : A PROJECT BASED ON TWO RANDOMISED INTERVENTION TRIALS

Osteoporosis is a major public health problem which is set to increase over the next 50 years. It is estimated to cost the NHS #1.73 billion per year - close to the estimated cost of treating heart disease (#1.75 billion). The lifetime risk for clinically diagnosed osteoporotic fractures in women is around 40%, similar to the risk of heart disease. The MRC has highlighted research in this field as a key priority area. Our research will build on evidence from animals and humans that infant nutrition and growth may influence or ?program? the risk of later osteoporosis and fractures. We will investigate this in two randomised trials of early nutrition, set up to test whether early diet in infants who are born small for their gestational age (SGA) has long-term effects on health. SGA infants are an ideal group for this study since they show great variation in early growth rates. Current practice is to encourage them to grow fast. However, there is now evidence to suggest that while this catch-up growth may be good for some outcomes such as bone health, it could be bad for others, such as heart disease. It is important to clarify this balance of risks and benefits in order to make sensible feeding recommendations. Although this study focuses on the smallest term infants, we believe that the findings may also be relevant to larger infants. We will study subjects from our two trials during childhood and adolescence, using a variety of techniques to measure their bone size, structure, mineral content and strength. We will also measure the rate at which bone is formed and broken down, using markers in blood. The planned research will be conducted by Dr Mary Fewtrell with Professor Alan Lucas, based at the MRC Childhood Nutrition Research Centre at the Institute of Child Health, London. Our overall aim is to test infant nutrition strategies to help improve later bone health and reduce the risk of osteoporosis, and to help provide a scientific basis for the nutritional management of infants in order to improve their later health.

IMPORTANCE: Osteoporosis and associated fractures are a significant cause of morbidity and mortality with major public health implications, costing the NHS ? #1.73 billion per year. MRC has highlighted research in this field as a key priority area. Data increasingly support the concept that factors operating in fetal life, infancy and childhood may influence or program later bone health and, consequently, osteoporosis risk. Previous studies raised the hypothesis that faster growth during infancy and childhood is associated with higher later bone mass, improved bone structure and reduced fracture risk. Our PROPOSED RESEARCH investigates in an experimental manner the primary hypothesis that an early nutritional intervention which promoted infant growth results in improved bone health later in childhood and adolescence; and the secondary hypothesis that the timing and pattern of linear growth during infancy and childhood influences bone size and bone mass. Embedded within the research is mechanistic work to investigate: (1) IGF-1 as a potential coupling mechanism; (2) the role of nutrient-gene interactions in determining the response to nutritional intervention. Our STUDY POPULATION consists of 714 subjects born small-for-gestational-age (SGA) at term, and therefore prone to marked variability in post-natal growth rates, who were enrolled in two nutritional intervention trials (539 randomised to either standard or nutrient-enriched infant formula; 175 breast-fed for ?6 weeks). They will be studied at 8-9 or 15 years. The interventions promoted more rapid infant growth, notably in length. OUTCOMES will be: (1) bone size, geometry and bone mass measured using Dual Energy X-ray Absorptiometry (DXA), peripheral Quantitative Computed Tomography (pQCT) and Quantitative Ultrasound (QUS): (2) biochemical markers of bone turnover (formation: plasma osteocalcin, P1NP and bone ALP. Resorption: plasma CTX). Other explanatory variables or confounders include anthropometry, fat and lean mass, muscle strength, calcium intake, physical activity. OVERALL OBJECTIVE: We aim to provide evidence on the effects of promoting early growth on bone health in this large group (10-20% of the population) most prone to catch-up growth and thus susceptible to later health effects. The data will add to the evidence for the risks and benefits of promoting infant growth, and will therefore help to underpin practice. Whilst this study is in smaller term infants, they reflect a large subgroup of major importance it its own right. The proposed work, which may prove applicable with further study to the whole population, is a step towards establishing evidence-based practices for primary prevention of osteoporosis.