Alexandra Mavroeidi

Vitamin D3 supplementation has no effect on conventional cardiovascular risk factors: a parallel-group, double-blind, placebo-controlled RCT.

CONTEXT Observational studies show an association between low vitamin D status assessed by circulating 25-hydroxyvitamin D and cardiovascular events and mortality. Data from randomized controlled trials are limited. OBJECTIVE The aim of this study was to test whether daily doses of vitamin D(3) at 400 or 1000 IU/d for 1 yr affected conventional markers of cardiovascular disease (CVD) risk. DESIGN We conducted a parallel-group, double-blind, placebo-controlled randomized controlled trial. Randomization was computer generated. Participants and study investigators were blinded to intervention groupings throughout the trial. SETTING The study was conducted at the Clinical Research Facility, University of Aberdeen, United Kingdom. PARTICIPANTS A total of 305 healthy postmenopausal women aged 60-70 yr were recruited for the study. INTERVENTION Each woman received a daily capsule of 400 or 1000 IU vitamin D(3) or placebo randomly allocated. MAIN OUTCOME MEASURES Primary outcomes were serum lipid profile [total, high-density lipoprotein, and low-density lipoprotein cholesterol; triglycerides; and apolipoproteins A-1 and B100], insulin resistance (homeostatic model assessment), inflammatory biomarkers (high-sensitivity C-reactive protein, IL-6, soluble intracellular adhesion molecule-1), and blood pressure. RESULTS A total of 265 (87%) participants completed all study visits. Small differences between groups for serum apolipoprotein B100 change [repeated measures ANOVA, P=0.04; mean (sd), -1.0 (10.0) mg/dl (400 IU); -1.0 (10.0) mg/dl (1000 IU); and +0.02 (10.0) mg/dl (placebo)] were not considered clinically significant. Other systemic markers for CVD risk remained unchanged. There was significant seasonal variation in systolic and diastolic blood pressure independent of vitamin D dose (P<0.001, linear mixed model). Mean (sd) reduction in systolic blood pressure from winter to summer was -6.6 (10.8) mm Hg. CONCLUSIONS Improving vitamin D status through dietary supplementation is unlikely to reduce CVD risk factors. Confounding of seasonality should be recognized and addressed in future studies of vitamin D.

Vitamin D status in postmenopausal women living at higher latitudes in the UK in relation to bone health, overweight, sunlight exposure and dietary vitamin D

For 5 months a year the UK has insufficient sunlight for cutaneous synthesis of vitamin D and winter requirements are met from stores made the previous summer. Although there are few natural dietary sources, dietary intake may help maintain vitamin D status. We investigated the relationship between 25-hydroxyvitamin D (25(OH)D), bone health, overweight, sunlight exposure and dietary vitamin D in 3113 women (age 54.8 [SD 2.3] years) living at latitude 57 degrees N between 1998-2000. Serum 25(OH)D was measured by high performance liquid chromatography (HPLC), dietary intakes (food frequency questionnaire, n=2598), sunlight exposure (questionnaire, n=2402) and bone markers were assessed. Bone mineral density (BMD) was measured by dual x-ray absorptiometry in all women at the sampling visit and 6 years before. Seasonal variation in 25(OH)D was not substantial with a peak in the autumn (23.7 [9.9] ng/ml) and a nadir in spring (19.7 [7.6] ng/ml). Daily intake of vitamin D was 4.2 [2.5] mug from food only and 5.8 [4.0] mug including vitamin D from cod liver oil and multivitamins. The latter was associated with 25(OH)D at each season whereas vitamin D simply from food was associated with 25(OH)D in winter and spring only. Sunlight exposure was associated with 25(OH)D in summer and autumn. 25(OH)D was negatively associated with increased bone resorption and bone loss (P<0.05) remaining significant after adjustment for confounders (age, weight, height, menopausal status/HRT use, physical activity and socio-economic status). Using an insufficiency cut-off of <28 ng/ml 25(OH)D, showed lower concentrations of bone resorption markers in the upper category (fDPD/Cr 5.1 [1.7] nmol/mmol compared to 5.3 [2.1] nmol/mmol, P=0.03) and no difference in BMD or bone loss. 25(OH)D was lower (P<0.01) and parathyroid hormone higher (P<0.01) in the top quintile of body mass index. In conclusion, low vitamin D status is associated with greater bone turnover, bone loss and obesity. Diet appears to attenuate the seasonal variation of vitamin D status in early postmenopausal women at northerly latitude where quality of sunlight for production of vitamin D is diminished.

Hip bone loss is attenuated with 1000 IU but not 400 IU daily vitamin D3: a 1-year double-blind RCT in postmenopausal women.

Few year‐long vitamin D supplementation trials exist that match seasonal changes. The aim of this study was to determine whether daily oral vitamin D3 at 400 IU or 1000 IU compared with placebo affects annual bone mineral density (BMD) change in postmenopausal women in a 1‐year double‐blind placebo controlled trial in Scotland. White women aged 60 to 70 years (n = 305) were randomized to one of two doses of vitamin D or placebo. All participants started simultaneously in January/February 2009, attending visits at bimonthly intervals with 265 (87%) women attending the final visit and an additional visit 1 month after treatment cessation. BMD (Lunar iDXA) and 1,25‐dihydroxyvitamin D[1,25(OH)2D], N‐terminal propeptide of type 1 collagen [P1NP], C‐terminal telopeptide of type I collagen [CTX], and fibroblast growth factor‐23 [FGF23] were measured by immunoassay at the start and end of treatment. Circulating PTH, serum Ca, and total 25‐hydroxyvitamin D [25(OH)D] (latter by tandem mass spectrometry) were measured at each visit. Mean BMD loss at the hip was significantly less for the 1000 IU vitamin D group (0.05% ± 1.46%) compared with the 400 IU vitamin D or placebo groups (0.57% ± 1.33% and 0.60% ± 1.67%, respectively) (p < 0.05). Mean (± SD) baseline 25(OH)D was 33.8 ± 14.6 nmol/L; comparative 25(OH)D change for the placebo, 400 IU, and 1000 IU vitamin D groups was −4.1 ± 11.5 nmol/L, +31.6 ± 19.8 nmol/L, and +42.6 ± 18.9 nmol/L, respectively. Treatment did not change markers of bone metabolism, except for a small reduction in PTH and an increase in serum calcium (latter with 1000 IU dose only). The discordance between the incremental increase in 25(OH)D between the 400 IU and 1000 IU vitamin D and effect on BMD suggests that 25(OH)D may not accurately reflect clinical outcome, nor how much vitamin D is being stored.

The Functional ACTN3 577X Variant Increases the Risk of Falling in Older Females: Results From Two Large Independent Cohort Studies

BACKGROUND Falls among elderly people is a major issue in public health, causing debilitating outcomes including fracture. The identification of genetic risk factors for falling may provide a strategy for effectively targeting falls prevention programs. We investigated whether a common functional variant of skeletal muscle α-actinin-3 (ACTN3 p. R577X) previously associated with impairments in muscle strength, power, and physical functioning represents a risk factor for falls. METHODS Case-control analysis was conducted using two large cohorts of Caucasian postmenopausal women--the North of Scotland Osteoporosis Study (n = 1,245) and the Aberdeen Prospective Osteoporosis Screening Study (n = 2,918)--for whom self-reported falls status and DNA samples were available. Cross-sectional analysis of fallers versus nonfallers at baseline and follow-up was performed. In addition, individuals who reported having fallen at more than one timepoint (recurrent fallers) were compared with those who reported not falling at any timepoint. RESULTS Association between R577X genotype and falls was identified and validated. Carriage of 577X (one or two copies) was significantly associated with a 33% (10%-61%) increased risk of falling, with the effect apparent at both baseline and follow-up assessments (meta-analysis p = .003 and p = .02, respectively). No significant effect on recurrent falls was observed. CONCLUSION This study reports for the first time that the functional ACTN3 R577X genotype represents a genetic risk factor for falling in older females.

Seasonal 25-hydroxyvitamin D changes in British postmenopausal women at 57°N and 51°N: A longitudinal study

The UK has insufficient intensity of sunlight at wavelengths 290-315 nm to enable cutaneous synthesis of vitamin D from October to April. There are regional differences in UVB strength throughout the UK but whether this translates to differences in vitamin D status is not known. We have reported seasonal variations in a cross-sectional study of over 3000 Scottish women in Aberdeen. The aim of this longitudinal study was to compare the seasonal variation of serum 25-hydroxyvitamin D [25(OH)D] in postmenopausal women residing in Aberdeen (57 degrees N) and Surrey (51 degrees N). Women attended 3-monthly visits over 12 months, starting summer 2006. In Aberdeen, 338 Caucasian women (mean age+/-SD, 61.7+/-1.5 years); and at Surrey, 138 Caucasian women (61.4+/-4.5 years) and 35 Asian women (59.9+/-6.4 years) had serum 25(OH)D measured by IDS enzyme immunoassay. In winter/spring none of the Caucasian women living in Surrey had 25(OH)D<20 nmol/L, but nearly a quarter of women in Aberdeen were vitamin D-deficient. This number decreased to 4.2% in summer/autumn. For the Asian women 17.1% were vitamin D-deficient in summer, increasing to 58.1% in winter. Using higher 25(OH)D deficiency cut-offs, the percentage of women affected was much higher. These longitudinal data show clear differences in vitamin D status between the north and south of the UK, and marked ethnic differences. They are consistent with our previous data and with cross-sectional data from the 1958 birth cohort. The low vitamin D status may have implications for bone health and other health outcomes, which is currently being investigated in this publication group. The extent of vitamin D deficiency in Asian women residing in the South of England is of concern.

Seasonal 25-hydroxyvitamin D changes in British postmenopausal women at 57 degrees N and 51 degrees N: a longitudinal study.

The UK has insufficient intensity of sunlight at wavelengths 290-315 nm to enable cutaneous synthesis of vitamin D from October to April. There are regional differences in UVB strength throughout the UK but whether this translates to differences in vitamin D status is not known. We have reported seasonal variations in a cross-sectional study of over 3000 Scottish women in Aberdeen. The aim of this longitudinal study was to compare the seasonal variation of serum 25-hydroxyvitamin D [25(OH)D] in postmenopausal women residing in Aberdeen (57 degrees N) and Surrey (51 degrees N). Women attended 3-monthly visits over 12 months, starting summer 2006. In Aberdeen, 338 Caucasian women (mean age+/-SD, 61.7+/-1.5 years); and at Surrey, 138 Caucasian women (61.4+/-4.5 years) and 35 Asian women (59.9+/-6.4 years) had serum 25(OH)D measured by IDS enzyme immunoassay. In winter/spring none of the Caucasian women living in Surrey had 25(OH)D<20 nmol/L, but nearly a quarter of women in Aberdeen were vitamin D-deficient. This number decreased to 4.2% in summer/autumn. For the Asian women 17.1% were vitamin D-deficient in summer, increasing to 58.1% in winter. Using higher 25(OH)D deficiency cut-offs, the percentage of women affected was much higher. These longitudinal data show clear differences in vitamin D status between the north and south of the UK, and marked ethnic differences. They are consistent with our previous data and with cross-sectional data from the 1958 birth cohort. The low vitamin D status may have implications for bone health and other health outcomes, which is currently being investigated in this publication group. The extent of vitamin D deficiency in Asian women residing in the South of England is of concern.

Skin color change in Caucasian postmenopausal women predicts summer-winter change in 25-hydroxyvitamin D: findings from the ANSAViD cohort study.

CONTEXT UV radiation is responsible for vitamin D synthesis and skin tanning. Longitudinal data relating skin color to vitamin D status are lacking. OBJECTIVE Our objective was to determine whether seasonal facial skin color changes are related to changes in 25-hydroxyvitamin D [25(OH)D]. DESIGN AND SETTING We conducted a prospective observational cohort study (Aberdeen Nutrition Sunlight and Vitamin D) with five visits over 15 months, starting spring 2006 with an additional visit in spring 2008 at a university medical research center in Scotland, 57° N. PARTICIPANTS Participants included 314 Caucasian postmenopausal women, age 60-65 yr. MAIN OUTCOME MEASURES Facial skin color was assessed by skin reflectance and expressed as the individual typology angle (ITA) (higher number indicates paler skin). 25(OH)D was measured by immunoassay. RESULTS Most women (43%) reported Fitzpatrick skin type III (always burns, always tans), 32% type II, and 25% type I (always burns, never tans). Overall, mean (sd) ITA in degrees were 36.6 (7.7), 38.2 (6.5), and 42.8 (5.3), respectively, for summer, autumn, and winter (P < 0.001). Linear regression showed that a 5° summer-winter change in ITA, was associated with a 15 nmol/liter change in 25(OH)D (P < 0.001) but did not predict winter 25(OH)D. Reported sunscreen use was associated with higher 25(OH)D. Mean (SD) 25(OH)D (nanomoles per liter) but not skin color was lower for the top body mass index quartile (Q4) compared with the other quartiles (summer: Q1, 57.1(19.9); Q4, 49.7 (20.4); P = 0.010). CONCLUSIONS Skin color change between summer and winter predicts seasonal 25(OH)D change. Low vitamin D status in obese women was not due to reduced sun exposure, suggesting that increased requirements or inaccessibility of vitamin D stores may be responsible.

Sunlight or diet: what is the answer for providing sufficient vitamin D in the U.K.?

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Seasonal variation in 25(OH)D at Aberdeen (57°N) and bone health indicators--could holidays in the sun and cod liver oil supplements alleviate deficiency?

Vitamin D has been linked with many health outcomes. The aim of this longitudinal study, was to assess predictors of seasonal variation of 25-hydroxy-vitamin D (25(OH)D) (including use of supplements and holidays in sunny destinations) at a northerly latitude in the UK (57°N) in relation to bone health indicators. 365 healthy postmenopausal women (mean age 62.0 y (SD 1.4)) had 25(OH)D measurements by immunoassay, serum C-telopeptide (CTX), estimates of sunlight exposure (badges of polysulphone film), information regarding holidays in sunny destinations, and diet (from food diaries, including use of supplements such as cod liver oil (CLO)) at fixed 3-monthly intervals over 15 months (subject retention 88%) with an additional 25(OH)D assessment in spring 2008. Bone mineral density (BMD) at the lumbar spine (LS) and dual hip was measured in autumn 2006 and spring 2007 (Lunar I-DXA). Deficiency prevalence (25(OH)D<25 nmol/L) was reduced in women who went on holiday to sunny destinations 3 months prior to their visit, compared to women who did not go on holidays [5.4% vs. 24.6% in Spring (p<0.001) and 3.8% vs. 25.6% in Winter (p = 0.001), respectively]. Similarly deficiency was lower amongst those who took CLO supplements compared to women that did not consume these supplements [2.0% vs. 23.7% in Spring (p = 0.001) and 4.5% vs. 24.8% in winter (p = 0.005), respectively]. There was no seasonal variation in CTX; 25(OH)D predicted a small proportion (1.8% variation) of LS BMD in spring 2007 [unstandardized β (SE): 0.039 (0.016), p = 0.017]. Seasonal variation of 25(OH)D had little effect on BMD and no effect on CTX. It appears that small increments in vitamin D (e.g. those that can be achieved by cod liver oil supplements of 5 µg/day) are sufficient to ensure that 25(OH)D is above 25 nmol/L for most people throughout the year. Similarly, holidays in sunny destinations show benefit.

Seasonal comparison of energy and nutrient intakes from food diaries completed for a longitudinal study

Kim Giles, Alexandra Mavroeidi, Fiona O’Neill, Antonia Hardcastle, David Reid and Helen Macdonald Osteoporosis Research Unit, School of Medicine, University of Aberdeen, Aberdeen, UK, School of Medical Sciences, University of Aberdeen, Aberdeen, UK and Twin Research and Genetic Epidemiology Unit, King’s College London 1st Floor South Wing, St Thomas’ Hospital Campus, Westminster Bridge Road, London, UK