Osteoporosis causes considerable morbidity and mortality in later life, and the risk of the disease is strongly determined by peak bone mass, which is achieved in early adulthood. Poor intrauterine and early childhood growth are associated with reduced peak bone mass, and increased risk of osteoporotic fracture in older age. In this review we describe the regulatory aspects of intrauterine bone development, and then summarize the evidence relating early growth to later fracture risk. Physiological systems include vitamin D, parathyroid hormone, leptin, GH/IGF-1; finally the potential role of epigenetic processes in the underlying mechanisms will be explored. Thus factors such as maternal lifestyle, diet, body build, physical activity, and vitamin D status in pregnancy all appear to influence offspring bone mineral accrual. These data demonstrate a likely interaction between environmental factors and gene expression, a phenomenon ubiquitous in the natural world (developmental plasticity), as the potential key process. Intervention studies are now required to test the hypotheses generated by these epidemiological and physiological findings, to inform potential novel public health interventions aimed at improving childhood bone health and reducing the burden of osteoporotic fracture in future generations.

MAVIDOS is a randomised, double-blind, placebo-controlled trial (ISRCTN82927713, registered 2008 Apr 11), funded by Arthritis Research UK, MRC, Bupa Foundation and NIHR.

Background

Osteoporosis is a major public health problem as a result of associated fragility fractures. Skeletal strength increases from birth to a peak in early adulthood. This peak predicts osteoporosis risk in later life. Vitamin D insufficiency in pregnancy is common (31% in a recent Southampton cohort) and predicts reduced bone mass in the offspring. In this study we aim to test whether offspring of mothers supplemented with vitamin D in pregnancy have higher bone mass at birth than those whose mothers were not supplemented.

Methods/Design

Women have their vitamin D status assessed after ultrasound scanning in the twelfth week of pregnancy at 3 trial centres (Southampton, Sheffield, Oxford). Women with circulating 25(OH)-vitamin D levels 25-100 nmol/l are randomised in a double-blind design to either oral vitamin D supplement (1000 IU cholecalciferol/day, n = 477) or placebo at 14 weeks (n = 477). Questionnaire data include parity, sunlight exposure, dietary information, and cigarette and alcohol consumption. At 19 and 34 weeks maternal anthropometry is assessed and blood samples taken to measure 25(OH)-vitamin D, PTH and biochemistry. At delivery venous umbilical cord blood is collected, together with umbilical cord and placental tissue. The babies undergo DXA assessment of bone mass within the first 14 days after birth, with the primary outcome being whole body bone mineral content adjusted for gestational age and age. Children are then followed up with yearly assessment of health, diet, physical activity and anthropometric measures, with repeat assessment of bone mass by DXA at age 4 years.

Discussion

As far as we are aware, this randomised trial is one of the first ever tests of the early life origins hypothesis in human participants and has the potential to inform public health policy regarding vitamin D supplementation in pregnancy. It will also provide a valuable resource in which to study the influence of maternal vitamin D status on other childhood outcomes such as glucose tolerance, blood pressure, cardiovascular function, IQ and immunology.

Osteoporotic fracture has a major impact upon health, both in terms of acute and long term disability and economic cost. Peak bone mass, achieved in early adulthood, is a major determinant of osteoporosis risk in later life. Poor early growth predicts reduced bone mass, and so risk of fracture in later life. Maternal lifestyle, body build and 25(OH) vitamin D status predict offspring bone mass. Recent work has suggested epigenetic mechanisms as key to these observations. This review will explore the role of the early environment in determining later osteoporotic fracture risk.

Background

Valid measures of physical activity correlates in preschool children are lacking. This study aimed to assess the validity, factor structure and internal consistency of a maternal questionnaire on potential correlates of four-year-old children's physical activity.

Methods

The questionnaire was designed to measure the following constructs: child personal factors; parental support and self-efficacy for providing support; parental rules and restrictions; maternal attitudes and perceptions; maternal behaviour; barriers to physical activity; and the home and local environments. Two separate studies were conducted. Study I included 24 mothers of four-year-old children who completed the questionnaire then participated in a telephone interview covering similar items to the questionnaire. To assess validity, the agreement between interview and questionnaire responses was assessed using Cohen's kappa and percentage agreement. Study II involved 398 mothers of four-year-old children participating in the Southampton Women's Survey. In this study, principal components analysis was used to explore the factor structure of the questionnaire to aid future analyses with these data. The internal consistency of the factors identified was assessed using Cronbach's alpha.

Results

Kappa scores showed 30% of items to have moderate agreement or above, 23% to have fair agreement and 47% to have slight or poor agreement. However, 89% of items had fair agreement as assessed by percentage agreement (≥ 66%). Limited variation in responses to variables is likely to have contributed to some of the low kappa values. Six questions had a low kappa and low percentage agreement (defined as poor validity); these included questions from the child personal factors, maternal self-efficacy, rules and restrictions, and local environment domains. The principal components analysis identified eleven factors and found several variables to stand alone. Eight of the composite factors identified had acceptable internal consistency (α ≥ 0.60) and three fell just short of achieving this (0.60 > α > 0.50).

Conclusion

Overall, this maternal questionnaire had reasonable validity and internal consistency for assessing potential correlates of physical activity in young children. With minor revision, this could be a useful tool for future research in this area. This, in turn, will aid the development of interventions to promote physical activity in this age group.

Objective:

To investigate whether exposure to high maternal concentrations of 25(OH)-vitamin D in pregnancy poses any risk to the child.

Design:

Prospective study.

Setting:

Princess Anne Maternity Hospital, Southampton, UK.

Subjects:

596 pregnant women were recruited. 466 (78%) children were examined at birth, 440 (74%) at age 9 months and 178 (30%) at age 9 years.

Methods:

Maternal (OH)-vitamin D concentrations were measured in late pregnancy. Anthropometry of the child was recorded at birth, 9 months and 9 years. At 9 months, atopic eczema was assessed. At 9 years, children had an echocardiogram and a DXA scan, blood pressure, arterial compliance and carotid intima-media thickness were measured and intelligence and psychological function assessed.

Results:

There were no associations between maternal 25(OH)-vitamin D concentrations and the child's body size or measures of the child's intelligence, psychological health or cardiovascular system. Children whose mothers' concentration of 25(OH)-vitamin D in pregnancy was >75 nmol/l had an increased risk of eczema on examination at 9 months (OR 3.26, 95% CI 1.15-9.29, p=0.025) and asthma at age 9 years (OR 5.40, 95% CI, 1.09-26.65, p=0.038) compared to children whose mothers' concentration was <30 nmol/l.

Conclusion:

Exposure to maternal concentrations of 25(OH)-vitamin D in pregnancy in excess of 75 nmol/l does not appear to influence the child's intelligence, psychological health or cardiovascular system; there could be an increased risk of atopic disorders, but this needs confirmation in other studies.

Objectives To estimate fracture risk in patients receiving bariatric surgery versus matched controls.

Design Population based, retrospective cohort study.

Setting Use of records from the United Kingdom General Practice Research Database, now known as the Clinical Practice Research Datalink (from January 1987 to December 2010).

Participants Patients with a body mass index of at least 30, with a record of bariatric surgery (n=2079), and matched controls without a record (n=10 442). Each bariatric surgery patient was matched to up to six controls by age, sex, practice, year, and body mass index. Patients were followed from the date of bariatric surgery for the occurrence of any fracture. We used time dependent Cox regression to calculate relative rates of fracture, adjusted for disease and previous drug treatment, and time-interaction terms to evaluate fracture timing patterns.

Main outcome measure Relative rates of any, osteoporotic, and non-osteoporotic fractures.

Results Mean follow-up time was 2.2 years. Overall, there was no significantly increased risk of fracture in patients who underwent bariatric surgery, compared with controls (8.8 v 8.2 per 1000 person years; adjusted relative risk 0.89, 95% confidence interval 0.60 to 1.33). Bariatric surgery also did not affect risk of osteoporotic and non-osteoporotic fractures. However, we saw a trend towards an increased fracture risk after three to five years following surgery, as well as in patients who had a greater decrease in body mass index after surgery, but this was not significant.

Conclusion Bariatric surgery does not have a significant effect on the risk of fracture. For the first few years after surgery, these results are reassuring for patients undergoing such operations, but do not exclude a more protracted adverse influence on skeletal health in the longer term.

Among primates, human neonates have the largest brains but also the highest proportion of body fat. If placental nutrient supply is limited, the fetus faces a dilemma: should resources be allocated to brain growth, or to fat deposition for use as a potential postnatal energy reserve? We hypothesised that resolving this dilemma operates at the level of umbilical blood distribution entering the fetal liver. In 381 uncomplicated pregnancies in third trimester, we measured blood flow perfusing the fetal liver, or bypassing it via the ductus venosus to supply the brain and heart using ultrasound techniques. Across the range of fetal growth and independent of the mother's adiposity and parity, greater liver blood flow was associated with greater offspring fat mass measured by dual-energy X-ray absorptiometry, both in the infant at birth (r = 0.43, P<0.001) and at age 4 years (r = 0.16, P = 0.02). In contrast, smaller placentas less able to meet fetal demand for essential nutrients were associated with a brain-sparing flow pattern (r = 0.17, p = 0.02). This flow pattern was also associated with a higher degree of shunting through ductus venosus (P = 0.04). We propose that humans evolved a developmental strategy to prioritize nutrient allocation for prenatal fat deposition when the supply of conditionally essential nutrients requiring hepatic inter-conversion is limited, switching resource allocation to favour the brain if the supply of essential nutrients is limited. Facilitated placental transfer mechanisms for glucose and other nutrients evolved in environments less affluent than those now prevalent in developed populations, and we propose that in circumstances of maternal adiposity and nutrient excess these mechanisms now also lead to prenatal fat deposition. Prenatal developmental influences play important roles in the human propensity to deposit fat.