Zoe Cole

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.

Vitamin D supplementation in pregnancy: a systematic review.

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.

Maternal dietary patterns during pregnancy and childhood bone mass: a longitudinal study.

Maternal nutrition is a potentially important determinant of intrauterine skeletal development. Previous studies have examined the effects of individual nutrients, but the pattern of food consumption may be of greater relevance. We therefore examined the relationship between maternal dietary pattern during pregnancy and bone mass of the offspring at 9 yr of age. We studied 198 pregnant women 17–43 yr of age and their offspring at 9 yr of age. Dietary pattern was assessed using principal component analysis from a validated food frequency questionnaire. The offspring underwent measurements of bone mass using DXA at 9 yr of age. A high prudent diet score was characterized by elevated intakes of fruit, vegetables, and wholemeal bread, rice, and pasta and low intakes of processed foods. Higher prudent diet score in late pregnancy was associated with greater (p < 0.001) whole body and lumbar spine BMC and areal BMD in the offspring, after adjustment for sex, socioeconomic status, height, arm circumference, maternal smoking, and vitamin D status. Associations with prudent diet score in early pregnancy were weaker and nonsignificant. We conclude that dietary patterns consistent with current advice for healthy eating during pregnancy are associated with greater bone size and BMD in the offspring at 9 yr of age.

Diagnosis and epidemiology of osteoporosis

Purpose of reviewOsteoporosis remains a major public health problem through its association with fragility fractures. Recent data suggest that the annual cost in Europe is 13 billion euros, mainly accounted for by hospitalisation after fracture. Understanding the epidemiology of osteoporosis is an essential step in developing strategies to reduce the burden of osteoporotic fracture in the population. Recent findingsThis article will review recent advances surrounding the epidemiology of osteoporosis, the burden of fracture in children and adults in this country and abroad, morbidity associated with such fractures, associations of disease and medication with fragility fracture, and advances in diagnostic techniques and identification of at-risk groups. SummaryThe papers studied highlight the wealth of high-quality research in this field, and they help in the visualisation of strategies to identify individuals at high risk of fragility fracture and to quantify fracture risk by measurement of bone density, bone quality, and risk factor algorithms.

Increased fat mass is associated with increased bone size but reduced volumetric density in pre pubertal children

Recent studies have shown that obesity is associated with an increased risk of fracture in both adults and children. It has been suggested that, despite greater bone size, obese individuals may have reduced true volumetric density; however this is difficult to assess using two dimensional techniques such as DXA. We evaluated the relationship between fat mass, and bone size and density, in a population cohort of children in whom DXA and pQCT measurements had been acquired. We recruited 530 children at 6 years old from the Southampton Womens Survey. The children underwent measurement of bone mass at the whole body, lumbar spine and hip, together with body composition, by DXA (Hologic Discovery, Hologic Inc., Bedford, MA, USA). In addition 132 of these children underwent pQCT measurements at the tibia (Stratec XCT2000, Stratec Biomedical Systems, Birkenfeld, Germany). Significant positive associations were observed between total fat mass and both bone area (BA) and bone mineral content (BMC) at the whole body minus head, lumbar spine and hip sites (all p<0.0001). When true volumetric density was assessed using pQCT data from the tibia, fat mass (adjusted for lean mass) was negatively associated with both trabecular and cortical density (β=-14.6 mg/mm(3) per sd, p=0.003; β=-7.7 mg/mm(3) per sd, p=0.02 respectively). These results suggest that fat mass is negatively associated with volumetric bone density at 6 years old, independent of lean mass, despite positive associations with bone size.

Developmental origins of osteoporosis: the role of maternal nutrition

Osteoporosis is a major cause of morbidity and mortality through its association with age-related fractures. Although most effort in fracture prevention has been directed at retarding the rate of age-related bone loss, and reducing the frequency and severity of trauma among elderly people, evidence is growing that peak bone mass is an important contributor to bone strength during later life. The normal patterns of skeletal growth have been well characterised in cross-sectional and longitudinal studies. It has been confirmed that boys have higher bone mineral content, but not volumetric bone density, than girls. Furthermore, there is a dissociation between the peak velocities for height gain and bone mineral accrual in both genders. Puberty is the period during which volumetric density appears to increase in both axial and appendicular sites. Many factors influence the accumulation of bone mineral during childhood and adolescence, including heredity, gender, diet, physical activity, endocrine status, and sporadic risk factors such as cigarette smoking. In addition to these modifiable factors during childhood, evidence has also accrued that fracture risk might be programmed during intrauterine life. Epidemiological studies have demonstrated a relationship between birthweight, weight in infancy, and adult bone mass. This appears to be mediated through modulation of the set-point for basal activity of pituitary-dependent endocrine systems such as the hypothalamic-pituitary-adrenal (HPA) and growth hormone/insulin-like growth factor-1 (GH/IGF-1) axes. Maternal smoking, diet (particularly vitamin D deficiency) and physical activity also appear to modulate bone mineral acquisition during intrauterine life; furthermore, both low birth size and poor childhood growth, are directly linked to the later risk of hip fracture. The optimisation of maternal nutrition and intrauterine growth should also be included within preventive strategies against osteoporotic fracture, albeit for future generations.

INTRAUTERINE GROWTH AND POSTNATAL SKELETAL DEVELOPMENT: FINDINGS FROM THE SOUTHAMPTON WOMEN'S SURVEY

We have previously demonstrated associations between fetal growth in late pregnancy and postnatal bone mass. However, the relationships between the intrauterine and early postnatal skeletal growth trajectory remain unknown. We addressed this in a large population-based mother-offspring cohort study. A total of 628 mother-offspring pairs were recruited from the Southampton Womens Survey. Fetal abdominal circumference was measured at 11, 19 and 34 weeks gestation using high-resolution ultrasound with femur length assessed at 19 and 34 weeks. Bone mineral content was measured postnatally in the offspring using dual-energy X-ray absorptiometry at birth and 4 years; postnatal linear growth was assessed at birth, 6, 12, 24, 36 and 48 months. Late pregnancy abdominal circumference growth (19-34 weeks) was strongly (P < 0.01) related to bone mass at birth, but less robustly associated with bone mass at 4 years. Early pregnancy growth (11-19 weeks) was more strongly related to bone mass at 4 years than at birth. Postnatal relationships between growth and skeletal indices at 4 years were stronger for the first and second postnatal years, than the period aged 2-4 years. The proportion of children changing their place in the distribution of growth velocities progressively reduced with each year of postnatal life. The late intrauterine growth trajectory is a better predictor of skeletal growth and mineralisation at birth, while the early intrauterine growth trajectory is a more powerful determinant of skeletal status at age 4 years. The perturbations in this trajectory which influence childhood bone mass warrant further research.

The impact of methods for estimating bone health and the global burden of bone disease

Osteoporosis constitutes a major public health problem through its association with age related fractures. Fracture rates are generally higher in caucasian women than in other populations. Important determinants include estrogen deficiency in women, low body mass index, cigarette smoking, alcohol consumption, poor dietary calcium intake, physical inactivity, certain drugs and illnesses. Thus, modification of physical activity and dietary calcium/vitamin D nutrition should complement high risk approaches. In addition, the recently developed WHO algorithm for evaluation of 10-year absolute risk of fracture provides a means whereby various therapies can be targeted cost-effectively to those at risk. Risk factors, together with bone mineral density (BMD) and biochemical indices of bone turnover, can be utilised to derive absolute risks of fracture and cost-utility thresholds at which treatment is justified. These data will provide the basis for translation into coherent public health strategies aiming to prevent osteoporosis both in individuals and in the general population.

Inhibition by glucocorticoids of the mast cell-dependent weal and flare response in human skin in vivo.

This study examines the relative contributions made by inhibition of mast cell degranulation, reduction of mast cell recruitment and maturation, and lowering the responsiveness of the vasculature to histamine, in the inhibition by glucocorticoids of the weal and flare in human skin. One forearm of healthy human volunteers was treated for 24 h (n=6) or daily for 21 days (n=10) with 0.05% clobetasol propionate. The other arm served as control. Weal and flare responses were elicited by intradermal injection of 20 μl of 0.3 mM codeine. The areas of the responses were measured using scanning laser Doppler imaging. Microdialysis was used to assess histamine release. Mast cell numbers and tissue histamine content were assessed in 4‐mm punch biopsies. Histamine (20 μl of 1 μM i.d.) was used to assess the status of the vasculature. No significant effects were seen at 24 h. At 21 days, clobetasol reduced the areas of the codeine‐induced weal and flare responses by 59 and 58% respectively (both P=0.006). Mast cell numbers were reduced by 47%, (P=0.014) and total tissue histamine content by 52% (P=0.006). Codeine‐induced histamine release was reduced by 44% (P=0.022). The weal, but not the flare, induced by histamine was significantly inhibited (P=0.019). Echography revealed a 15% thinning of the skin by clobetasol. These results demonstrate that reduction of the weal and flare responses to codeine following clobetasol treatment, results primarily from reduced mast cell numbers and tissue histamine content rather than inhibition by corticosteroids of mast cell degranulation.

Early development and osteoporosis and bone health

Osteoporosis is a skeletal disorder characterized by low bone mass and micro-architectural deterioration of bone tissue with a consequent increase in bone fragility and susceptibility to fracture. Evidence is now accumulating from human studies that programming of bone growth might be an important contributor to the later risk of osteoporotic fracture. Body weight in infancy is a determinant of adult bone mineral content, as well as of the basal levels of activity of the growth hormone/insulin-like growth factor-1 (GH/IGF-1) and hypothalamo-pituitary-adrenal (HPA) axes, and recent work has suggested a central role for vitamin D. Epidemiological studies have shown that maternal smoking and nutrition during pregnancy influence intrauterine skeletal mineralization. Childhood growth rates have been directly linked to the risk of hip fracture many decades later, and now evidence is emerging from experimental animal studies that support these observational data. Recent studies have also highlighted epigenetic phenomena as potential mechanisms underlying the findings from epidemiological studies.