Determinants of circulating 25-hydroxyvitamin D concentration and its association with musculoskeletal health in midlife: Findings from the Hertfordshire Cohort Study.

INTRODUCTION: Several studies have reported the importance of vitamin D status to musculoskeletal health in populations of older adults. Here we report relationships between circulating serum 25(OH)D and musculoskeletal health in a community cohort of UK adults in midlife and investigate whether environmental (dietary intake, use of supplements) and/or genetic factors (4 SNPs previously related to vitamin D status) play more significant roles in determining vitamin D status in this population. METHODS: Participants were recruited from the Hertfordshire Cohort Study, an established longitudinal cohort study of community dwelling adults and were seen at baseline and follow up 9-12 years later. Lumbar spine and total femur BMD were measured at baseline using a Hologic QDR 4500 instrument. Osteoarthritis (OA) was defined by radiographs of the knees graded according to Kellgren & Lawrence at both time points. Serum 25(OH)D concentrations were measured using a DiaSorin Liaison chemiluminescent assay. Genotyping of 4 SNPs previously associated with 25(OH)D values were assessed: (rs12785878 (DHCR7), rs10741657 (CYP2R1) and rs6013897 (CYP24A1)) and a fourth SNP (rs4588), described as "a near-perfect proxy (i.e. substitute) for rs2282679 on the GC gene". RESULTS: 820 subjects (397 men, 423 women) participated at baseline, and 339 of these 820 subjects (164 men; 175 women) participated in a follow up study of OA progression. The median (IQR) age of participants at baseline was 64.0 (61.8-66.5) and 65.5 (63.3-67.6) for men and women respectively. Median circulating levels of 25(OH)D were 44.6 (35.0-63.0) nmol/L and 41.3 (29.8-53.5) nmol/L in men and women respectively. Circulating 25(OH)D was strongly associated with season of blood testing (p < 0.001). The greatest variance in a model of vitamin D status that included the four SNPs measured, season, and whether participants reported taking vitamin D supplements was explained by season of assay (17.9% men; 15.8% women). Higher femoral neck BMD was observed in men with higher baseline vitamin D status, after adjustment for age, season, BMI, smoker status, alcohol consumption, physical activity and social class (p = 0.01). Associations between 25(OH)D and BMD in women were not statistically significant in this population. There were no associations between circulating 25(OH)D and radiographic knee OA at either time point after adjustment for confounders and for duration of follow-up. CONCLUSION: Circulating 25(OH)D levels were generally lower than is recommended in community dwelling adults in midlife, with marked seasonal variation observed, but relationships with reported vitamin D supplementation were weaker. Circulating 25(OH)D was directly associated with hip BMD in men but relationships with BMD in women and radiographic OA were not seen in this sample.

Variation and implications of treatment decisions in early rheumatoid arthritis: results from a nationwide cohort study.

OBJECTIVES: Trial data have provided an evidence base to guide early treatment in RA. Few studies have investigated rheumatologists' adherence to guidelines, and subsequent impact on outcomes. The objectives of this study are to characterize baseline prescribing for patients with RA across the National Health Service, identifying treatment decisions that associate with patient outcomes. METHODS: A nationwide audit of RA collected information on treatment choices, DAS and sociodemographic factors at baseline. Treatment response was assessed at 3 months. Multilevel regression models were used to characterize departmental variations in prescribing. Heat maps were used to visualize geographical variation. Mixed effects regression models were constructed to assess the relationship between treatment decisions and disease outcomes, adjusting for patient and department level covariates. RESULTS: A total of 7154 patients with a diagnosis of RA were recruited from 136 departments. There was broad variation in prescribing choices, even between departments close to one another, with evidence of substantial deviation from guidelines. Over 75% of patients received glucocorticoids, fewer than half received combination conventional DMARDs. Early glucocorticoid therapy associated with achieving a good treatment response [odds ratio 1.93 (95% CI 1.31, 2.84), P-value = 0.001]. The association was maintained following propensity modelling and imputation. CONCLUSION: Guideline adherence varies between departments and cannot be explained by case-mix alone. Departments that prescribe early adjunctive steroid achieve better short-term outcomes. Further research should work to ensure that the early arthritis evidence base translates into better outcomes for patients.

Inappropriate claims from non-equivalent medications in osteoarthritis: a position paper endorsed by the European Society for Clinical and Economic Aspects of Osteoporosis, Osteoarthritis and Musculoskeletal Diseases (ESCEO).

Osteoarthritis (OA) is a progressive joint disease, that occurs frequently in the aging population and is a major cause of disability worldwide. Both glucosamine and chondroitin are biologically active molecules that are substrates for proteoglycan, an essential component of the cartilage matrix. Evidence supports the use of glucosamine and chondroitin as symptomatic slow-acting drugs for osteoarthritis (SYSADOAs) with impact on OA symptoms and disease-modifying effects in the long term. Glucosamine and chondroitin are administered in exogenous form as a sulfate salt and multiple formulations of these agents are available, both as prescription-grade products and nutritional supplements. However, while all preparations may claim to deliver a therapeutic level of glucosamine or chondroitin not all are supported by clinical evidence. Only patented crystalline glucosamine sulfate (pCGS) is shown to deliver consistently high glucosamine bioavailability and plasma concentration in humans, which corresponds to demonstrated clinical efficacy. Similarly, clinical evidence supports only the pharmaceutical-grade chondroitin sulfate. The European Society for Clinical and Economic Aspects of Osteoporosis, Osteoarthritis and Musculoskeletal Diseases (ESCEO) advocates, through careful consideration of the evidence base, that judicious choice of glucosamine and chondroitin formulation is essential to maximize clinical benefit, patient adherence and satisfaction with treatment. In future, the ESCEO recommends that complex molecules with biological activity such as pCGS may be treated as "biosimilars" akin to the European Medicines Agency guidance on biological medicinal products. It seems likely that for all other complex molecules classed as SYSADOAs, the recommendation to use only formulations clearly supported by the evidence-base should apply.

Barriers to sexually transmitted infection testing in New Zealand: a qualitative study.

OBJECTIVE: To investigate the barriers that prevent or delay people seeking a sexually transmitted infection (STI) test. METHODS: Qualitative in-depth interviews were conducted with 24 university students, who are a group prone to behaviours putting them at risk of STIs, to understand the factors that had prevented or delayed them from going for an STI test in the past. Resulting data were thematically analysed employing a qualitative content analysis method, and a final set of themes identified. RESULTS: There were three main types of barrier to STI testing. These were: personal (underestimating risk, perceiving STIs as not serious, fear of invasive procedure, self-consciousness in genital examination and being too busy); structural (financial cost of test and clinician attributes and attitude); and social (concern of being stigmatised). Conclusions and implications for public health: These data will help health providers and policy-makers provide services that minimise barriers and develop effective strategies for improving STI testing rates. The results of this study suggest a holistic approach to encouraging testing is required, which includes addressing personal beliefs, working with healthcare providers to minimise structural barriers and developing initiatives to change social views about STIs.

Determinants of the Maternal 25-Hydroxyvitamin D Response to Vitamin D Supplementation During Pregnancy.

CONTEXT: Current approaches to antenatal vitamin D supplementation do not account for interindividual differences in 25-hydroxyvitamin D (25(OH)D) response. OBJECTIVE: We assessed which maternal and environmental characteristics were associated with 25(OH)D after supplementation with cholecalciferol. DESIGN: Within-randomization-group analysis of participants in the Maternal Vitamin D Osteoporosis Study trial of vitamin D supplementation in pregnancy. SETTING: Hospital antenatal clinics. PARTICIPANTS: A total of 829 pregnant women (422 placebo, 407 cholecalciferol). At 14 and 34 weeks of gestation, maternal anthropometry, health, and lifestyle were assessed and 25(OH)D measured. Compliance was determined using pill counts at 19 and 34 weeks. INTERVENTIONS: 1000 IU/d of cholecalciferol or matched placebo from 14 weeks of gestation until delivery. MAIN OUTCOME MEASURE: 25(OH)D at 34 weeks, measured in a single batch (Diasorin Liaison). RESULTS: 25(OH)D at 34 weeks of gestation was higher in the women randomized to vitamin D (mean [SD], 67.7 [21.3] nmol/L) compared with placebo (43.1 [22.5] nmol/L; P < .001). In women randomized to cholecalciferol, higher pregnancy weight gain from 14 to 34 weeks of gestation (kg) (ß = -0.81 [95% confidence interval -1.39, -0.22]), lower compliance with study medication (%) (ß = -0.28 [-0.072, -0.48]), lower early pregnancy 25(OH)D (nmol/L) (ß = 0.28 [0.16, 0.40]), and delivery in the winter vs the summer (ß = -10.5 [-6.4, -14.6]) were independently associated with lower 25(OH)D at 34 weeks of gestation. CONCLUSIONS: Women who gained more weight during pregnancy had lower 25(OH)D in early pregnancy and delivered in winter achieved a lower 25(OH)D in late pregnancy when supplemented with 1000 IU/d cholecalciferol. Future studies should aim to determine appropriate doses to enable consistent repletion of 25(OH)D during pregnancy.

Maternal gestational vitamin D supplementation and offspring bone health (MAVIDOS): a multicentre, double-blind, randomised placebo-controlled trial.

BACKGROUND: Maternal vitamin D status has been associated with bone mass of offspring in many, but not all, observational studies. However, maternal vitamin D repletion during pregnancy has not yet been proven to improve offspring bone mass in a randomised controlled trial. We aimed to assess whether neonates born to mothers supplemented with vitamin D during pregnancy have greater whole-body bone mineral content (BMC) at birth than those of mothers who had not received supplementation. METHODS: The Maternal Vitamin D Osteoporosis Study (MAVIDOS) was a multicentre, double-blind, randomised, placebo-controlled trial that recruited pregnant women from three study sites in the UK (Southampton, Oxford, and Sheffield). Eligible participants were older than 18 years, with a singleton pregnancy, gestation of less than 17 weeks, and a serum 25-hydroxyvitamin D (25[OH]D) concentration of 25-100 nmol/L at 10-17 weeks' gestation. P'articipants were randomly assigned (1:1), in randomly permuted blocks of ten, to either cholecalciferol 1000 IU/day or matched placebo, taken orally, from 14 weeks' gestation (or as soon as possible before 17 weeks' gestation if recruited later) until delivery. Participants and the research team were masked to treatment allocation. The primary outcome was neonatal whole-body BMC, assessed within 2 weeks of birth by dual-energy x-ray absorptiometry (DXA), analysed in all randomly assigned neonates who had a usable DXA scan. Safety outcomes were assessed in all randomly assigned participants. This trial is registered with the International Standard Randomised Controlled Trial registry, ISRCTN 82927713, and the European Clinical Trials Database, EudraCT 2007-001716-23. FINDINGS: Between Oct 10, 2008, and Feb 11, 2014, we randomly assigned 569 pregnant women to placebo and 565 to cholecalciferol 1000 IU/day. 370 (65%) neonates in the placebo group and 367 (65%) neonates in the cholecalciferol group had a usable DXA scan and were analysed for the primary endpoint. Neonatal whole-body BMC of infants born to mothers assigned to cholecalciferol 1000 IU/day did not significantly differ from that of infants born to mothers assigned to placebo (61·6 g [95% CI 60·3-62·8] vs 60·5 g [59·3-61·7], respectively; p=0·21). We noted no significant differences in safety outcomes, apart from a greater proportion of women in the placebo group with severe post-partum haemorrhage than those in the cholecalciferol group (96 [17%] of 569 mothers in the placebo group vs 65 [12%] of 565 mothers in the cholecalciferol group; p=0·01). No adverse events were deemed to be treatment related. INTERPRETATION: Supplementation of women with cholecalciferol 1000 IU/day during pregnancy did not lead to increased offspring whole-body BMC compared with placebo, but did show that 1000 IU of cholecalciferol daily is sufficient to ensure that most pregnant women are vitamin D replete, and it is safe. These findings support current approaches to vitamin D supplementation in pregnancy. Results of the ongoing MAVIDOS childhood follow-up study are awaited. FUNDING: Arthritis Research UK, Medical Research Council, Bupa Foundation, and National Institute for Health Research.

Tracking of 25-hydroxyvitamin D status during pregnancy: the importance of vitamin D supplementation.

BACKGROUND: The role of maternal 25-hydroxyvitamin D [25(OH)D] in fetal development is uncertain, and findings of observational studies have been inconsistent. Most studies have assessed 25(OH)D only one time during pregnancy, but to our knowledge, the tracking of an individual's 25(OH)D during pregnancy has not been assessed previously. OBJECTIVE: We determined the tracking of serum 25(OH)D from early to late pregnancy and factors that influence this. DESIGN: The Southampton Women's Survey is a prospective mother-offspring birth-cohort study. Lifestyle, diet, and 25(OH)D status were assessed at 11 and 34 wk of gestation. A Fourier transformation was used to model the seasonal variation in 25(OH)D for early and late pregnancy separately, and the difference between the measured and seasonally modeled 25(OH)D was calculated to generate a season-corrected 25(OH)D. Tracking was assessed with the use of the Pearson correlation coefficient, and multivariate linear regression was used to determine factors associated with the change in season-corrected 25(OH)D. RESULTS: A total of 1753 women had 25(OH)D measured in both early and late pregnancy. There was a moderate correlation between season-corrected 25(OH)D measurements at 11 and 34 wk of gestation (r = 0.53, P < 0.0001; n = 1753). Vitamin D supplementation was the strongest predictor of tracking; in comparison with women who never used supplements, the discontinuation of supplementation after 11 wk was associated with a reduction in season-corrected 25(OH)D (ß = -7.3 nmol/L; P < 0.001), whereas the commencement (ß = 12.6 nmol/L; P < 0.001) or continuation (ß = 6.6 nmol/L; P < 0.001) of supplementation was associated with increases in season-corrected 25(OH)D. Higher pregnancy weight gain was associated with a reduction in season-corrected 25(OH)D (ß = -0.4 nmol · L(-1) · kg(-1); P = 0.015), whereas greater physical activity (ß = 0.4 nmol/L per h/wk; P = 0.011) was associated with increases. CONCLUSIONS: There is a moderate tracking of 25(OH)D status through pregnancy; factors such as vitamin D supplementation, weight gain, and physical activity are associated with changes in season-corrected 25(OH)D from early to late gestation. These findings have implications for study designs and analyses and approaches to intervention studies and clinical care.

Prenatal calcium and vitamin D intake, and bone mass in later life.

The aging population will result in an increasing burden of osteoporotic fractures, necessitating the identification of novel strategies for prevention. There is increasing recognition that factors in utero may influence bone mineral accrual, and, thus, osteoporosis risk. The role of calcium and vitamin D has received much attention in recent years, and in this review, we will survey available studies relating maternal calcium and vitamin D status during pregnancy to offspring bone development. The evidence base supporting a positive influence on intrauterine skeletal growth appears somewhat stronger for maternal 25(OH)-vitamin D concentration than for calcium intake, and the available data point toward the need for high-quality randomized controlled trials in order to inform public health policy. It is only with such a rigorous approach that it will be possible to delineate the optimal strategy for vitamin D supplementation in pregnancy in relation to offspring bone health.

Programming of hypertension: associations of plasma aldosterone in adult men and women with birthweight, cortisol, and blood pressure.

Animal models suggest that explanations for the association of low birthweight with adult hypertension may include chronic activation of the hypothalamic-pituitary-adrenal or renin-angiotensin-aldosterone axes. In humans, low birthweight predicts elevated plasma cortisol, but associations with aldosterone have not been reported. We measured aldosterone in serum samples from 205 men and 106 women from 67 to 78 years of age, from Hertfordshire, UK, for whom birthweight was recorded. Participants underwent an overnight low-dose (0.25 mg) dexamethasone suppression test and a low-dose (1 mug) ACTH (corticotropin) stimulation test and were genotyped for the -344 C/T polymorphism of the CYP11B2 gene encoding aldosterone synthase. Median aldosterone was 6.22 ng/dL (range 0.15 to 38.74) and was higher in men than women (P<0.0001). Higher aldosterone levels after both dexamethasone and ACTH stimulation were associated with higher blood pressure (r=0.20, P=0.001; r=0.33, P<0.0001, respectively) and with lower birthweight (r=-0.16, P=0.008; r=-0.21, P=0.001, respectively). These associations remained significant after adjusting for age, gender, obesity, and genotype. Our findings supplement previous evidence that aldosterone is an important regulator of blood pressure and suggest that factors in early life that retard fetal growth and program activation of the hypothalamic-pituitary-adrenal axis in humans result not only in higher glucocorticoid activity but also in increased mineralocorticoid activity.

Diet and its relationship with grip strength in community-dwelling older men and women: the Hertfordshire cohort study.

OBJECTIVES: To examine relationships between diet and grip strength in older men and women and to determine whether prenatal growth modifies these relationships. DESIGN: Cross-sectional and retrospective cohort study. SETTING: Hertfordshire, United Kingdom. PARTICIPANTS: Two thousand nine hundred eighty-three men and women aged 59 to 73 who were born and still living in Hertfordshire, United Kingdom. MEASUREMENTS: Weight at birth recorded in Health Visitor ledgers; current food and nutrient intake assessed using an administered food frequency questionnaire; and grip strength measured using a handheld dynamometer. RESULTS: Grip strength was positively associated with height and weight at birth and inversely related to age (all P<.001). Of the dietary factors considered in relation to grip strength, the most important was fatty fish consumption. An increase in grip strength of 0.43 kg (95% confidence interval (CI)=0.13-0.74) in men (P=.005) and 0.48 kg (95% CI=0.24-0.72) in women (P<.001) was observed for each additional portion of fatty fish consumed per week. These relationships were independent of adult height, age, and birth weight, each of which had additive effects on grip strength. There was no evidence of interactive effects of weight at birth and adult diet on grip strength. CONCLUSION: These data suggest that fatty fish consumption can have an important influence on muscle function in older men and women. This raises the possibility that the antiinflammatory actions of omega-3 fatty acids may play a role in the prevention of sarcopenia.