Nicholas C. Harvey

Maternal vitamin D status during pregnancy and childhood bone mass at age 9 years: a longitudinal study.

BACKGROUND Vitamin D insufficiency is common in women of childbearing age and increasing evidence suggests that the risk of osteoporotic fracture in adulthood could be determined partly by environmental factors during intrauterine and early postnatal life. We investigated the effect of maternal vitamin D status during pregnancy on childhood skeletal growth. METHODS In a longitudinal study, we studied 198 children born in 1991-92 in a hospital in Southampton, UK; the body build, nutrition, and vitamin D status of their mothers had been characterised during pregnancy. The children were followed up at age 9 years to relate these maternal characteristics to their body size and bone mass. FINDINGS 49 (31%) mothers had insufficient and 28 (18%) had deficient circulating concentrations of 25(OH)-vitamin D during late pregnancy. Reduced concentration of 25(OH)-vitamin D in mothers during late pregnancy was associated with reduced whole-body (r=0.21, p=0.0088) and lumbar-spine (r=0.17, p=0.03) bone-mineral content in children at age 9 years. Both the estimated exposure to ultraviolet B radiation during late pregnancy and the maternal use of vitamin D supplements predicted maternal 25(OH)-vitamin D concentration (p<0.0001 and p=0.0110, respectively) and childhood bone mass (p=0.0267). Reduced concentration of umbilical-venous calcium also predicted reduced childhood bone mass (p=0.0286). INTERPRETATION Maternal vitamin D insufficiency is common during pregnancy and is associated with reduced bone-mineral accrual in the offspring during childhood; this association is mediated partly through the concentration of umbilical venous calcium. Vitamin D supplementation of pregnant women, especially during winter months, could lead to longlasting reductions in the risk of osteoporotic fracture in their offspring.

Secular trends in the incidence of hip and other osteoporotic fractures

Osteoporosis constitutes a major public health problem through its association with age-related fractures, most notably those of the proximal femur. Substantial geographic variation has been noted in the incidence of hip fracture throughout the world, and estimates of recent incidence trends have varied widely. Studies in the published literature have reported an increase, plateau, and decrease in age-adjusted incidence rates for hip fracture among both men and women. Accurate characterisation of these temporal trends is important in predicting the health care burden attributable to hip fracture in future decades. We therefore conducted a review of studies worldwide, addressing secular trends in the incidence of hip and other fractures. Studies in western populations, whether in North America, Europe or Oceania, have generally reported increases in hip fracture incidence through the second half of the last century, but those continuing to follow trends over the last two decades have found that rates stabilise with age-adjusted decreases being observed in certain centres. In contrast, some studies suggest that the rate is rising in Asia. This synthesis of temporal trends in the published literature will provide an important resource for preventing fractures. Understanding the reasons for the recent declines in rates of hip fracture may help understand ways to reduce rates of hip fracture worldwide.

Osteoporosis: impact on health and economics

Osteoporosis is a major public health problem through associated fragility fractures. The most common sites of fracture are the hip, spine and wrist, and these have an enormous health and economic impact. All fractures result in some degree of morbidity, but fractures at the hip are associated with the worst outcomes. The worldwide direct and indirect annual costs of hip fracture in 1990 were estimated at US

Epidemiology of hip fracture: Worldwide geographic variation

34.8 billion, and are expected to increase substantially over the next 50 years. Fracture incidence varies between populations, and is set to increase over coming decades as the global population becomes more elderly. This effect will be particularly marked in the developing world, which is additionally assuming more-westernized lifestyles that predispose to increased fracture risk. Strategies to target those at high risk of fracture have been developed, but preventative measures at the public health level are also urgently needed to reduce the burden of this devastating disease.

Vitamin D supplementation in pregnancy: a systematic review.

Osteoporosis is a major health problem, especially in elderly populations, and is associated with fragility fractures at the hip, spine, and wrist. Hip fracture contributes to both morbidity and mortality in the elderly. The demographics of world populations are set to change, with more elderly living in developing countries, and it has been estimated that by 2050 half of hip fractures will occur in Asia. This review conducted using the PubMed database describes the incidence of hip fracture in different regions of the world and discusses the possible causes of this wide geographic variation. The analysis of data from different studies show a wide geographic variation across the world, with higher hip fracture incidence reported from industrialized countries as compared to developing countries. The highest hip fracture rates are seen in North Europe and the US and lowest in Latin America and Africa. Asian countries such as Kuwait, Iran, China, and Hong Kong show intermediate hip fracture rates. There is also a north–south gradient seen in European studies, and more fractures are seen in the north of the US than in the south. The factors responsible of this variation are population demographics (with more elderly living in countries with higher incidence rates) and the influence of ethnicity, latitude, and environmental factors. The understanding of this changing geographic variation will help policy makers to develop strategies to reduce the burden of hip fractures in developing countries such as India, which will face the brunt of this problem over the coming decades.

A Meta‐Analysis of Trabecular Bone Score in Fracture Risk Prediction and Its Relationship to FRAX

BACKGROUND It is unclear whether or not the current evidence base allows definite conclusions to be made regarding the optimal maternal circulating concentration of 25-hydroxyvitamin D [25(OH)D] during pregnancy, and how this might best be achieved. OBJECTIVES To answer the following questions: (1) What are the clinical criteria for vitamin D deficiency in pregnant women? (2) What adverse maternal and neonatal health outcomes are associated with low maternal circulating 25(OH)D? (3) Does maternal supplementation with vitamin D in pregnancy lead to an improvement in these outcomes (including assessment of compliance and effectiveness)? (4) What is the optimal type (D2 or D3), dose, regimen and route for vitamin D supplementation in pregnancy? (5) Is supplementation with vitamin D in pregnancy likely to be cost-effective? METHODS We performed a systematic review and where possible combined study results using meta-analysis to estimate the combined effect size. Major electronic databases [including Database of Abstracts of Reviews of Effects (DARE), Centre for Reviews and Dissemination (CRD), Cochrane Database of Systematic Reviews (CDSR) and the Health Technology Assessment (HTA) database] were searched from inception up to June 2012 covering both published and grey literature. Bibliographies of selected papers were hand-searched for additional references. Relevant authors were contacted for any unpublished findings and additional data if necessary. Abstracts were reviewed by two reviewers. INCLUSION AND EXCLUSION CRITERIA SUBJECTS pregnant women or pregnant women and their offspring. EXPOSURE either assessment of vitamin D status [dietary intake, sunlight exposure, circulating 25(OH)D concentration] or supplementation of participants with vitamin D or food containing vitamin D (e.g. oily fish). OUTCOMES offspring - birthweight, birth length, head circumference, bone mass, anthropometry and body composition, risk of asthma and atopy, small for gestational dates, preterm birth, type 1 diabetes mellitus, low birthweight, serum calcium concentration, blood pressure and rickets; mother - pre-eclampsia, gestational diabetes mellitus, risk of caesarean section and bacterial vaginosis. RESULTS Seventy-six studies were included. There was considerable heterogeneity between the studies and for most outcomes there was conflicting evidence. The evidence base was insufficient to reliably answer question 1 in relation to biochemical or disease outcomes. For questions 2 and 3, modest positive relationships were identified between maternal 25(OH)D and (1) offspring birthweight in meta-analysis of three observational studies using log-transformed 25(OH)D concentrations after adjustment for potential confounding factors [pooled regression coefficient 5.63 g/10% change maternal 25(OH)D, 95% confidence interval (CI) 1.11 to 10.16 g], but not in those four studies using natural units, or across intervention studies; (2) offspring cord blood or postnatal calcium concentrations in a meta-analysis of six intervention studies (all found to be at high risk of bias; mean difference 0.05 mmol/l, 95% CI 0.02 to 0.05 mmol/l); and (3) offspring bone mass in observational studies judged to be of good quality, but which did not permit meta-analysis. The evidence base was insufficient to reliably answer questions 4 and 5. LIMITATIONS Study methodology varied widely in terms of study design, population used, vitamin D status assessment, exposure measured and outcome definition. CONCLUSIONS The evidence base is currently insufficient to support definite clinical recommendations regarding vitamin D supplementation in pregnancy. Although there is modest evidence to support a relationship between maternal 25(OH)D status and offspring birthweight, bone mass and serum calcium concentrations, these findings were limited by their observational nature (birthweight, bone mass) or risk of bias and low quality (calcium concentrations). High-quality randomised trials are now required. STUDY REGISTRATION This study is registered as PROSPERO CRD42011001426. FUNDING The National Institute for Health Research Health Technology Assessment programme.

Trabecular bone score (TBS) as a new complementary approach for osteoporosis evaluation in clinical practice

Trabecular bone score (TBS) is a gray‐level textural index of bone microarchitecture derived from lumbar spine dual‐energy X‐ray absorptiometry (DXA) images. TBS is a bone mineral density (BMD)‐independent predictor of fracture risk. The objective of this meta‐analysis was to determine whether TBS predicted fracture risk independently of FRAX probability and to examine their combined performance by adjusting the FRAX probability for TBS. We utilized individual‐level data from 17,809 men and women in 14 prospective population‐based cohorts. Baseline evaluation included TBS and the FRAX risk variables, and outcomes during follow‐up (mean 6.7 years) comprised major osteoporotic fractures. The association between TBS, FRAX probabilities, and the risk of fracture was examined using an extension of the Poisson regression model in each cohort and for each sex and expressed as the gradient of risk (GR; hazard ratio per 1 SD change in risk variable in direction of increased risk). FRAX probabilities were adjusted for TBS using an adjustment factor derived from an independent cohort (the Manitoba Bone Density Cohort). Overall, the GR of TBS for major osteoporotic fracture was 1.44 (95% confidence interval [CI] 1.35–1.53) when adjusted for age and time since baseline and was similar in men and women (p > 0.10). When additionally adjusted for FRAX 10‐year probability of major osteoporotic fracture, TBS remained a significant, independent predictor for fracture (GR = 1.32, 95% CI 1.24–1.41). The adjustment of FRAX probability for TBS resulted in a small increase in the GR (1.76, 95% CI 1.65–1.87 versus 1.70, 95% CI 1.60–1.81). A smaller change in GR for hip fracture was observed (FRAX hip fracture probability GR 2.25 vs. 2.22). TBS is a significant predictor of fracture risk independently of FRAX. The findings support the use of TBS as a potential adjustment for FRAX probability, though the impact of the adjustment remains to be determined in the context of clinical assessment guidelines.

Risk of fracture after bariatric surgery in the United Kingdom: population based, retrospective cohort study

Trabecular bone score (TBS) is a recently-developed analytical tool that performs novel grey-level texture measurements on lumbar spine dual X-ray absorptiometry (DXA) images, and thereby captures information relating to trabecular microarchitecture. In order for TBS to usefully add to bone mineral density (BMD) and clinical risk factors in osteoporosis risk stratification, it must be independently associated with fracture risk, readily obtainable, and ideally, present a risk which is amenable to osteoporosis treatment. This paper summarizes a review of the scientific literature performed by a Working Group of the European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis. Low TBS is consistently associated with an increase in both prevalent and incident fractures that is partly independent of both clinical risk factors and areal BMD (aBMD) at the lumbar spine and proximal femur. More recently, TBS has been shown to have predictive value for fracture independent of fracture probabilities using the FRAX® algorithm. Although TBS changes with osteoporosis treatment, the magnitude is less than that of aBMD of the spine, and it is not clear how change in TBS relates to fracture risk reduction. TBS may also have a role in the assessment of fracture risk in some causes of secondary osteoporosis (e.g., diabetes, hyperparathyroidism and glucocorticoid-induced osteoporosis). In conclusion, there is a role for TBS in fracture risk assessment in combination with both aBMD and FRAX.

Maternal vitamin D status in pregnancy is associated with adiposity in the offspring: findings from the Southampton Women's Survey

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.

Maternal plasma polyunsaturated fatty acid status in late pregnancy is associated with offspring body composition in childhood

BACKGROUND Low vitamin D status has been linked to adiposity, but little is known of the effects of low status in pregnancy on offspring body composition. OBJECTIVE The objective was to determine how maternal vitamin D status relates to lean and fat mass of the offspring. DESIGN The offspring of 977 pregnant women, who had serum 25-hydroxyvitamin D [25(OH)D] measured at 34 wk gestation, were followed up within 3 wk of birth and at 4 and 6 y of age for dual-energy X-ray absorptiometry assessment of lean and fat mass. RESULTS The median maternal serum 25(OH)D concentration was 62 nmol/L (IQR: 43-89 nmol/L); 35% of the women studied had values <50 nmol/L. Lower vitamin D status was associated with lower fat mass in the offspring at birth but with greater fat mass at ages 4 and 6 y. It was not associated with lean mass at any of the ages studied. The opposing associations seen between maternal 25(OH)D (SDs) and fat mass (SDs) in the offspring at birth and at age 6 y were robust to adjustment for a range of confounding factors, including maternal BMI and weight gain in pregnancy [β (95% CI): 0.08 (0.02, 0.15) and -0.10 (-0.17, -0.02), respectively]. The key independent predictors of higher maternal vitamin D status were season of assessment and use of vitamin D supplements. CONCLUSIONS Lower maternal vitamin D status may be linked to programmed differences in offspring fat mass. The findings require replication but add to a growing evidence base for a role of vitamin D in the origins of adiposity.