Direct healthcare resource utilisation, health-related quality of life, and work productivity in patients with moderate rheumatoid arthritis: an observational study.

BACKGROUND: The aim was to describe the population of patients with moderate rheumatoid arthritis (RA) in the United Kingdom and the burden of disease from the perspectives of the patient, caregiver, and health service. METHODS: In this descriptive study, retrospective patient-level data were extracted from hospital medical records to assess healthcare resource utilisation and validated outcome measures were administered via questionnaire to patients with moderate RA (Disease Activity Score [DAS28] between 3.2 and 5.1) from eight secondary care centres, and their caregivers. Patient-reported outcome instruments were scored according to licensed manuals. RESULTS: Outcome measures were completed by 102 patients and 38 caregivers. The mean EuroQoL-5 dimension-5 level crosswalk index value for patients was 0.62 (SD 0.24) compared to an England population norm of 0.82. Mean pain VAS score was 37.7 (SD 24.0) and mean Health Assessment Questionnaire Disability Index was 1.1 (SD 0.8). In employed patients who completed the Work Productivity and Activity Impairment questionnaire (n = 26), a mean 29% (SD 26%) reduction in work productivity was recorded. Patients experienced significant fatigue as a result of their RA (median Functional Assessment of Chronic Illness Therapy fatigue score 17.2 of a possible 52, interquartile range [IQR] 11.0-28.8). Over 50% of caregivers reported providing > 7 h of support care per week to the patient with RA, and 16 and 11% took paid/unpaid leave or reduced working hours, respectively. Mean Caregiver Reaction Assessment subscale scores were 1.9 (SD 0.9) for finance, 1.7 (SD 0.8) for health, 2.3 (SD 1.0) for schedule disruption, and 1.9 (SD 0.8) for family support. Patients had a mean 5.5 (SD 4.1) outpatient attendances and a median 9.0 (IQR 2.0-20.0) diagnostic and monitoring tests in the 12 months prior to enrolment. CONCLUSIONS: This study shows that moderate RA has a considerable impact on healthcare resources and on patients' and caregivers' lives. There is scope to improve the management of patients with moderate RA.

Fetal and infant growth predict hip geometry at 6 y old: findings from the Southampton Women's Survey.

BACKGROUND: We investigated relationships between early growth and proximal femoral geometry at age 6 y in a prospective population-based cohort, the Southampton Women's Survey. METHODS: In 493 mother-offspring pairs, we assessed linear size using high-resolution ultrasound at 11, 19, and 34 wk gestation (femur length) and at birth and 1, 2, 3, 4, and 6 y (crown-heel length/height). SD scores were created and conditional regression modeling generated mutually independent growth variables. Children underwent hip dual-energy X-ray absorptiometry (DXA) at 6 y; hip structure analysis software yielded measures of geometry and strength. RESULTS: There were strong associations between early linear growth and femoral neck section modulus (Z) at 6 y, with the strongest relationships observed for femur growth from 19 to 34 wk gestation (ß = 0.26 cm(3)/SD, P < 0.0001), and for height growth from birth to 1 y (ß = 0.25 cm(3)/SD, P < 0.0001) and 1 to 2 y (ß = 0.33 cm(3)/SD, P < 0.0001), with progressively weaker relationships over years 3 (ß = 0.23 cm(3)/SD, P = 0.0002) and 4 (ß = 0.10 cm(3)/SD, P = 0.18). CONCLUSION: These results demonstrate that growth before age 3 y predicts proximal femoral geometry at 6 y old. These data suggest critical periods in which there is capacity for long-term influence on the later skeletal growth trajectory.

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 Women's 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.

Breast-feeding and adherence to infant feeding guidelines do not influence bone mass at age 4 years.

The impact of variations in current infant feeding practice on bone mineral accrual is not known. We examined the associations between duration of breast-feeding and compliance with infant dietary guidelines and later bone size and density at age 4 years. At total of 599 (318 boys) mother-child pairs were recruited from the Southampton Women's Survey. Duration of breast-feeding was recorded and infant diet was assessed at 6 and 12 months using FFQ. At 6 and 12 months the most important dietary pattern, defined by principal component analysis, was characterised by high consumption of vegetables, fruits and home-prepared foods. As this was consistent with infant feeding recommendations, it was denoted the 'infant guidelines' pattern. At age 4 years, children underwent assessment of whole-body bone size and density using a Hologic Discovery dual-energy X-ray absorptiometry instrument. Correlation methods were used to explore the relationships between infant dietary variables and bone mineral. There was no association between duration of breast-feeding in the first year of life and 4-year bone size or density. 'Infant guidelines' pattern scores at 6 and 12 months were also unrelated to bone mass at age 4 years. We observed wide variations in current infant feeding practice, but these variations were not associated with differences in childhood bone mass at age 4 years.

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.

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.

Update on the treatment of post-menopausal osteoporosis.

BACKGROUND: Osteoporosis has a huge impact on public health, through the increased morbidity, mortality and economic costs associated with resultant fractures. The goal is to evaluate and identify those that are at risk of osteoporotic fracture in order to start preventative and therapeutic measures to reduce their risk of fracture. SOURCES OF DATA: This article reviews the data from randomized controlled trials for the current therapeutic agents available in the UK. It also reviews new trial data for promising osteoporosis therapies, in particular Denosumab, a monoclonal antibody against RANK ligand. AREAS OF AGREEMENT: Bisphosphonates are the current recommended first-line treatments for patients with osteoporosis. AREAS OF CONTROVERSY/GROWING POINTS: There are a number of patients where bisphosphonates are contraindicated. Under these circumstances, it is important that clinicians have access to alternative treatments. The long-awaited National Institute for Health and Clinical Excellence (NICE) technology appraisals for both primary and secondary prevention and the clinical guidelines will clarify this. Treatment decisions should be based on risk factors and pharmaceutical intervention given to those with the highest risks. AREAS TIMELY FOR DEVELOPING RESEARCH: Future studies are required to look at these agents in combination to see whether anti-fracture efficacy can be improved.

Osteoporosis epidemiology update.

Osteoporosis remains a major public health problem through its association with fragility fractures. Despite the availability of preventative therapeutic agents, the incidence and its associated costs continue to rise globally. Understanding osteoporosis epidemiology is essential to developing strategies to reduce the burden of osteoporotic fracture in the population. This article reviews the epidemiology of osteoporosis globally, highlighting recent advances. It describes the burden of common osteoporotic fractures, the associated morbidity and mortality, the clustering of fractures in individuals, and the identification of at-risk groups. It also highlights the development of new algorithms to identify individuals at high risk of fracture, enabling the implementation of appropriate treatment strategies.

Longitudinal changes in lean mass predict pQCT measures of tibial geometry and mineralisation at 6-7 years.

BACKGROUND: Studies in childhood suggest that both body composition and early postnatal growth are associated with bone mineral density (BMD). However, little is known of the relationships between longitudinal changes in fat (FM) and lean mass (LM) and bone development in pre-pubertal children. We therefore investigated these associations in a population-based mother-offspring cohort, the Southampton Women's Survey. METHODS: Total FM and LM were assessed at birth and 6-7 years of age by dual-energy x-ray absorptiometry (DXA). At 6-7 years, total cross-sectional area (CSA) and trabecular volumetric BMD (vBMD) at the 4% site (metaphysis) of the tibia was assessed using peripheral quantitative computed tomography [pQCT (Stratec XCT-2000)]. Total CSA, cortical CSA, cortical vBMD and strength-strain index (SSI) were measured at the 38% site (diaphysis). FM, LM and bone parameters were adjusted for age and sex and standardised to create within-cohort z-scores. Change in LM (ΔLM) or FM (ΔFM) was represented by change in z-score from birth to 7 years old and conditioned on the birth measurement. Linear regression was used to explore the associations between ΔLM or ΔFM and standardised pQCT outcomes, before and after mutual adjustment and for linear growth. The ß-coefficient represents SD change in outcome per unit SD change in predictor. RESULTS: DXA at birth, in addition to both DXA and pQCT scans at 6-7 years, were available for 200 children (48.5% male). ΔLM adjusted for ΔFM was positively associated with tibial total CSA at both the 4% (ß=0.57SD/SD, p<0.001) and 38% sites (ß=0.53SD/SD, p<0.001), cortical CSA (ß=0.48SD/SD, p<0.001) and trabecular vBMD (ß=0.30SD/SD, p<0.001), but not with cortical vBMD. These relationships persisted after adjustment for linear growth. In contrast, ΔFM adjusted for ΔLM was only associated with 38% total and cortical CSA, which became non-significant after adjustment for linear growth. CONCLUSION: In this study, gain in childhood LM was positively associated with bone size and trabecular vBMD at 6-7 years of age. In contrast, no relationships between change in FM and bone were observed, suggesting that muscle growth, rather than accrual of fat mass, may be a more important determinant of childhood bone development.

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. 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.

Session 2: Other diseases: Dietary management of osteoporosis throughout the life course.

Osteoporosis-related fractures have a major impact on health at the individual and societal levels, through associated morbidity and increased mortality. Up to 50% of women and 20% of men at age 50 years may have a fragility fracture in their remaining lifetimes. Nutrition is important throughout the life course. Thus, adequate Ca and vitamin D intake has been shown to reduce risk of fracture in old age. Other factors such as protein and vitamin K may also be important, although the evidence here is less strong. In childhood Ca or vitamin D supplementation trials have demonstrated modest short-term increases in bone mass, but the long-term implications have not been established. Over recent years it has become apparent that maternal nutrition may have critical and far-reaching persistent consequences for offspring health. Thus, reduced maternal fat stores and low levels of circulating 25-hydroxyvitamin D in pregnancy are associated with reduced bone mass in the offspring; placental Ca transport may be key to these relationships. Wider maternal dietary patterns have also been shown to predict offspring bone mass. These data suggest that an interventional approach aimed at specific micronutrients, such as vitamin D, should be complemented by general optimisation of the mother's diet and lifestyle in order to maximise intrauterine bone mineral accrual and postnatal skeletal growth and thus reduce the burden of osteoporotic fractures in future generations.

Weight gain in pregnancy and childhood body composition: findings from the Southampton Women's Survey.

BACKGROUND: Intrauterine life may be a critical period for the programming of later obesity, but there is conflicting evidence about whether pregnancy weight gain is an important determinant of offspring adiposity. OBJECTIVE: The purpose of this study was to examine the relation of pregnancy weight gain with neonatal and childhood body composition. DESIGN: The participants (n = 948) were children born to women in the Southampton Women's Survey who had dual-energy X-ray absorptiometry measurements of body composition at birth, 4 y, or 6 y. Pregnancy weight gain was derived from the mothers' measured weights before pregnancy and at 34 wk gestation and analyzed by using 2009 Institute of Medicine categories (inadequate, adequate, or excessive) and as a continuous measure. RESULTS: Almost one-half (49%) of the children were born to women who gained excessive weight in pregnancy. In comparison with children born to women with adequate weight gain, they had a greater fat mass in the neonatal period (SD: 0.17; 95% CI: 0.02, 0.32; P = 0.03), at 4 y (SD: 0.17; 95% CI: 0.00, 0.34; P = 0.05), and at 6 y (SD: 0.30; 95% CI: 0.11, 0.49; P = 0.002). Greater pregnancy weight gain, as a continuous measure, was associated with greater neonatal fat mass (SD: 0.10 per 5-kg weight gain; 95% CI: 0.04, 0.15; P = 0.0004) and was weakly associated with fat mass at 6 y (SD: 0.07 per 5-kg weight gain; 95% CI: 0.00, 0.14; P = 0.05) but not at 4 y (SD: 0.02 per 5-kg weight gain; 95% CI: -0.04, 0.08; P = 0.55). CONCLUSION: Appropriate pregnancy weight gain, as defined by 2009 Institute of Medicine recommendations, is linked to lower levels of adiposity in the offspring.

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 REVIEW: Osteoporosis 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 FINDINGS: This 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. SUMMARY: The 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.

The impact of methods for estimating bone health and the global burden of bone disease: [review] / Impacto de los métodos para medir la salud ósea y la carga global de enfermedades óseas: [revisión]

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.

La osteoporosis constituye un importante problema de salud pública debido a su asociación con fracturas relacionadas con la edad. Las tasas de fractura generalmente son más altas en mujeres caucásicas que en otros grupos poblacionales. Los principales determinantes incluyen deficiencia de estrógeno en mujeres, bajo índice de masa corporal, consumo de tabaco y alcohol, escaso consumo de calcio, inactividad física y algunas drogas y enfermedades. De este modo, la modificación de la actividad física y el consumo de nutrimentos con calcio y vitamina D deben complementar los tratamientos en alto riesgo. Además, el recientemente desarrollado algoritmo de la OMS para la evaluación de riesgo de fractura absoluto a 10 años constituye una herramienta que permite plantear eficientemente diversas terapias a aquellos que están en riesgo. Los factores de riesgo, junto con la densidad mineral ósea y los índices bioquímicos de regeneración ósea pueden utilizarse para obtener riesgos de fractura absolutos así como umbrales costo-utilidad que justifiquen el tratamiento. Estos datos proveerán una base para su traducción en estrategias de salud pública con la finalidad de prevenir la osteoporosis tanto en los individuos como en la población en general.