Reduced Prediagnostic 25-Hydroxyvitamin D Levels in Women with Breast Cancer: A Nested Case-Control Study Genetic variants and associations of 25-hydroxyvitamin D concentrations with major clinical outcomes. Plasma 25-Hydroxyvitamin D Levels and Risk of Incident Hypertension Associations between 25-hydroxyvitamin D and weight gain in elderly women. Maternal plasma 25-hydroxyvitamin D concentration and birthweight, growth and bone mineral accretion of Gambian infants Association of low serum 25-hydroxyvitamin D levels and high arterial blood pressure in the elderly. Plasma 25-Hydroxyvitamin D and 1,25-Dihydroxyvitamin D and Risk of Breast Cancer Pretreatment Serum Concentrations of 25-Hydroxyvitamin D and Breast Cancer Prognostic Characteristics: A Case-Control and a Case-Series Study Distribution and correlates of serum 25-hydroxyvitamin D levels in a sample of patients with hip fracture. Plasma free 25-hydroxyvitamin D, vitamin D binding protein, and risk of breast cancer in the Nurses’ Health Study II Vitamin d and physical activity status: associations with five-year changes in body composition and muscle function in community-dwelling older adults. Effect of vitamin D supplement on depression scores in people with low levels of serum 25-hydroxyvitamin D: nested case-control study and randomised clinical trial. The Effect of High-Dose Vitamin D Supplementation on Calciotropic Hormones and Bone Mineral Density in Obese Subjects with Low Levels of Circulating 25-Hydroxyvitamin D: Results from a Randomized Controlled Study Serum 25-Hydroxyvitamin D Concentrations and Risk for Hip Fractures The serum 25-hydroxyvitamin D response to vitamin D supplementation is related to genetic factors, BMI, and baseline levels. Plasma 25-Hydroxyvitamin D and Its Genetic Determinants in Relation to Incident Myocardial Infarction and Stroke in the European Prospective Investigation into Cancer and Nutrition (EPIC)-Germany Study 25-hydroxyvitamin D, 1,25-dihydroxyvitamin D and postoperative outcome in cardiac surgery.
Vitamin  D status may affect risk of cancer . In a cross-sectional study with a nested case-control analysis , we determined whether risk of breast cancer is associated with prediagnostic plasma 25-hydroxyvitamin D ( 25OHD ) levels and the effects of lifestyle characteristics known to influence vitamin D status on risk of breast cancer . We studied women without a prior history of breast cancer referred to a diagnostic mammography examination ( n = 2,465 ) . Cases were women diagnosed with an incident breast cancer ( n = 142 ) . Controls were women not diagnosed with a breast cancer matched to cases on age , menopausal status , and time of year of blood sampling ( n = 420 ) . Characteristics of cases and controls were assessed by a self-administrated question naire . Blood sample s were collected prior to the diagnostic mammography examination . Cases had lower plasma 25OHD levels than controls . Compared with the lowest tertile of 25OHD levels , risk of breast cancer was significantly reduced among women in the highest tertile ( relative risk , 0.52 ; 95 % confidence interval , 0.32 - 0.85 ) . Risk estimates were similar in women with an estrogen receptor – positive and estrogen receptor – negative breast cancer . Use of vitamin D supplements , sunbathing frequency , and fish intake was associated with 25OHD levels , but did not affect the risk of breast cancer . Accordingly , risk of breast cancer was inversely associated with 25OHD levels . R and omized controlled trials are warranted in order to assess whether a causal relationship exists . ( Cancer Epidemiol Biomarkers Prev 2009;18(10):2655–60 CONTEXT Lower serum 25-hydroxyvitamin D concentrations are associated with greater risks of many chronic diseases across large , prospect i ve community-based studies . Substrate 25-hydroxyvitamin D must be converted to 1,25-dihydroxyvitamin D for full biological activity , and complex metabolic pathways suggest that interindividual variability in vitamin D metabolism may alter the clinical consequences of measured serum 25-hydroxyvitamin D. OBJECTIVE To investigate whether common variation within genes encoding the vitamin D-binding protein , megalin , cubilin , CYP27B1 , CYP24A1 , and the vitamin D receptor ( VDR ) modify associations of low 25-hydroxyvitamin D with major clinical outcomes . DESIGN , SETTING , AND PARTICIPANTS Examination of 141 single-nucleotide polymorphisms in a discovery cohort of 1514 white participants ( who were recruited from 4 US regions ) from the community-based Cardiovascular Health Study . Participants had serum 25-hydroxyvitamin D measurements in 1992 - 1993 and were followed up for a median of 11 years ( through 2006 ) . Replication meta-analyses were conducted across the independent , community-based US Health , Aging , and Body Composition ( n = 922 ; follow-up : 1998 - 1999 through 2005 ) , Italian Invecchiare in Chianti ( n = 835 ; follow-up : 1998 - 2000 through 2006 ) , and Swedish Uppsala Longitudinal Study of Adult Men ( n = 970 ; follow-up : 1991 - 1995 through 2008 ) cohort studies . MAIN OUTCOME MEASURE Composite outcome of incident hip facture , myocardial infa rct ion , cancer , and mortality over long-term follow-up . RESULTS Interactions between 5 single-nucleotide polymorphisms and low 25-hydroxyvitamin D concentration were identified in the discovery phase and 1 involving a variant in the VDR gene replicated in independent meta- analysis . Among Cardiovascular Health Study participants , low 25-hydroxyvitamin D concentration was associated with hazard ratios for risk of the composite outcome of 1.40 ( 95 % CI , 1.12 - 1.74 ) for those who had 1 minor allele at rs7968585 and 1.82 ( 95 % CI , 1.31 - 2.54 ) for those with 2 minor alleles at rs7968585 . In contrast , there was no evidence of an association ( estimated hazard ratio , 0.93 [ 95 % CI , 0.70 - 1.24 ] ) among participants who had 0 minor alleles at this single-nucleotide polymorphism . CONCLUSION Known associations of low 25-hydroxyvitamin D with major health outcomes may vary according to common genetic differences in the vitamin D receptor Hydroxylation of 25(OH)D to 1,25-dihydroxyvitamin D and signaling through the vitamin D receptor occur in various tissues not traditionally involved in calcium homeostasis . Laboratory studies indicate that 1,25-dihydroxyvitamin D suppresses renin expression and vascular smooth muscle cell proliferation ; clinical studies demonstrate an inverse association between ultraviolet radiation , a surrogate marker for vitamin D synthesis , and blood pressure . We prospect ively studied the independent association between measured plasma 25-hydroxyvitamin D [ 25(OH)D ] levels and  risk of incident hypertension  and also the association between predicted plasma 25(OH)D levels and risk of incident hypertension .  Two prospect i ve cohort studies including 613 men from the Health Professionals ’ Follow-Up Study and 1198 women from the Nurses ’ Health Study with measured 25(OH)D levels were followed for 4 to 8 years . In addition , 2 prospect i ve cohort studies including 38 388 men and 77 531 women with predicted 25(OH)D levels were followed for 16 to 18 years . During 4 years of follow-up , the multivariable relative risk of incident hypertension among men whose measured plasma 25(OH)D levels were < 15 ng/mL ( ie , vitamin D deficiency ) compared with those whose levels were ≥30 ng/mL was 6.13 ( 95 % confidence interval [ CI ] : 1.00 to 37.8 ) . Among women , the same comparison yielded a relative risk of 2.67 ( 95 % CI : 1.05 to 6.79 ) . The pooled relative risk combining men and women with measured 25(OH)D levels using the r and om-effects model was 3.18 ( 95 % CI : 1.39 to 7.29 ) . Using predicted 25(OH)D levels in the larger cohorts , the multivariable relative risks comparing the lowest to highest deciles were 2.31 ( 95 % CI : 2.03 to 2.63 ) in men and 1.57 ( 95 % CI : 1.44 to 1.72 ) in women . Plasma 25(OH)D levels are inversely associated with risk of incident hypertension BACKGROUND 25-Hydroxyvitamin D [ 25(OH)D ] levels are lower in obese individuals . Determining whether low vitamin D status can predispose weight gain requires a longitudinal study . METHODS From a community-based multicenter U.S. prospect i ve cohort of 9704 ( Study of Osteoporotic Fractures [ SOF ] ) , 4659 women aged ≥65 with baseline 25(OH)D measurement were followed for 4.5 years . They were weighed at baseline and follow-up visits , and a subset ( n=1054 ) had 25(OH)D levels remeasured at follow-up . RESULTS Women with 25(OH)D levels ≥30 ng/mL had lower baseline weight ( 141.6 pounds ) compared to women with 25(OH)D levels < 30 ng/mL ( 148.6 pounds ) ( p<0.001 ) . Overall , 25(OH)D status was not associated with weight change over 4.5 years , although there was a significant interaction between 25(OH)D status and weight change category ( loss , gain , stable ) ( p<0.0001 ) . In women who gained ≥5 % weight , those with baseline 25(OH)D levels ≥30 ng/mL gained 16.4 pounds ( 12.2 % of baseline weight ) over 4.5 years compared to 18.5 pounds ( 13.9 % of baseline weight ) in women with levels < 30 ng/mL ( p=0.04 ) . In women who lost ≥5 % weight or remained stable ( < 5 % weight change ) , there was no association between 25(OH)D status at baseline and weight change . Among women who gained weight and had 25(OH)D measured at both visits , having sustained or developing 25(OH)D levels ≥30 ng/mL was associated with less weight gain between visits ( 14.81 vs. 16.34 pounds , p=0.04 ) . CONCLUSIONS Higher 25(OH)D levels are associated with lower weight gains , suggesting low vitamin D status may predispose to fat accumulation Maternal vitamin D deficiency during pregnancy is a recognized risk factor for rickets and osteomalacia in infancy ( 1 ) . The circulating plasma concentration of 25-hydroxyvitamin D ( 25OHD ) , a long-lived metabolite of vitamin D , is used to judge vitamin D status ; values below 25 nmol/L are associated with an increased risk of rickets and osteomalacia ( 1 ) . There is evidence that a low maternal plasma 25OHD in pregnancy may influence the growth and bone mineral accrual of the offspring during foetal life , infancy and childhood . Positive associations have been reported between maternal  vitamin D  status in pregnancy and birthweight , birth length , length at 1 year and bone mineral accretion at 9 years ( 2–6 ) , although evidence is conflicting ( 7,8 ) . These relationships have been observed at concentrations of 25OHD higher than those associated with rickets and osteomalacia , and there are calls to raise the accepted lower threshold of vitamin D sufficiency for pregnant women , most recently to 80 nmol/L ( 9 ) . On a population basis , plasma 25OHD concentrations above 80 nmol/L are relatively uncommon in countries at temperate latitudes but are more common among people living in the tropics who have abundant skin sunshine exposure ( 10 ) . To contribute to the debate on the definition of vitamin D sufficiency in pregnancy , we have investigated the influence of maternal plasma 25OHD concentration on foetal and infant growth in a rural area of The Gambia , West Africa ( 13 ° N ) . In this region , there is tropical sunshine all year , the women are farmers who work out-of-doors for much of each day , and local female dress does not restrict regular sunshine exposure to the face , neck , shoulders , arms and feet , especially during farm work and gardening . The study was a secondary analysis of biochemical , anthropometric and bone data from a subset of 125 women and infants collected during a calcium supplementation study of blood pressure in pregnant Gambian women ( International Trial Registry : IS RCT N96502494 ) . No significant benefits for foetal and infant growth of maternal calcium supplementation were identified despite the low customary calcium intake in The Gambia ( 11 ) . The protocol , methods , maternal characteristics and infant data from the detailed study have been published ( 11 ) . Briefly , women from the rural villages of Keneba and M and uar , West Kiang , The Gambia were recruited at 20 weeks of pregnancy ( P20 ) and r and omized to a daily calcium supplement or a matching placebo tablet until parturition ( 1500 mg Ca as calcium carbonate and microcellulose-lactose , respectively ; Nycomed Pharma AS , Asker , Norway ) . Fasting , early morning blood was collected and anthropometry performed at P20 and 36 weeks of pregnancy ( P36 ) . The mean ( ± SD ) age , weight , height and dietary calcium intake of the women at P20 were 27.4 ± 7.5 years , 56.3 ± 6.7 kg , 1.61 ± 0.05 m and 356 ± 190 mg/day , respectively . The median parity ( range ) was 3 ( 0–10 ) . Infant birthweight was measured within 24 h of delivery . Weight , crown-heel length and head circumference were measured at 2 , 13 and 52 weeks postpartum . In addition , infant bone mineral content ( BMC ) , bone mineral density ( BMD ) and bone width ( BW ) or bone area ( BA ) , were measured by single photon absorptiometry of the midshaft radius ( Lunar SP2 , Lunar Corporation , Madison , WI , USA ) and , for a subset ( n = 44 , 47 and 52 at 2 , 13 and 52 weeks , respectively ) , by whole-body dual-energy X-ray absorptiometry ( Lunar DPX+ , software version 4.7b , Lunar Corporation ) . Plasma 25OHD was measured a using radioimmunometric assay ( Diasorin Ltd , Wokingham , Berks , UK ) , with assay performance monitored through the Vitamin D External Quality Assessment Scheme ( DEQAS ; Endocrine/Oncology Laboratory , Charing Cross Hospital , London , UK ) . The intra- and inter-assay coefficients of variation were 4 % and 100 ) ; possible trends in the data with p = 0.01–0.1 were noted . The analysis was conducted on 123 mother – infant pairs ; blood sample s from two subjects were not available . Mean ± SD 25OHD ( range ) was : P20 = 103 ± 25 ( 53–167 ) nmol/L ; P36 = 111 ± 27 ( 51–189 ) nmol/L. No subject had a 25OHD value < 50 nmol/L , 20 % and 16 % had 25OHD < 80 nmol/L , at P20 and P36 , respectively . There was a high degree of within-subject consistency in 25OHD at P20 and P36 ( 25OHDP36 = 33.2 + [ 0.79 ± 0.07] × 25OHDP20 , p ≤ 0.001 , R2 adjusted 51.5 % , n = 121 ) ; 11 % of women had 25OHD < 80 nmol/L at both P20 and P36 . The mean birthweight of the infants was 2.99 ± 0.36 kg . The infant anthropometric and bone measures during the first year are given in Table 1 . No significant relationships or trends in the data were observed between maternal 25OHD concentration using the values at P20 , P36 or the mean of the two and any of the following infant measures : birthweight , infant weight , length , head circumference , BMC , BW ( or BA ) , BMD and size-adjusted BMC of the midshaft radius and whole body at any time postpartum . This is illustrated in Figure 1 for birthweight as a function of maternal 25OHD concentration at P20 . Comparing the results for mothers with 25OHD above and below 80 nmol/L did not alter this finding . Table 1 Anthropometric and bone measures  of Gambian infants Figure 1 Lack of a significant relationship between infant birthweight and maternal vitamin D status at 20 weeks of pregnancy ( p = 0.8 ) . Multiple regression model included season , maternal height , weight , weight gain , supplement group and sex of the infant . No significant interaction between supplement group and maternal 25OHD concentration was observed for any infant variable . Trends in the data were observed in a few instances for a supplement group × 25OHD interaction among the bone measures but no consistent picture emerged and they were considered to have arisen by chance . We conclude that there is no evidence for an influence of vitamin D status during pregnancy on infant growth and bone mineral accrual in the conditions prevailing in The Gambia . The children in this study , as is common in this region of The Gambia ( 13 ) , were born small , grew well for the first months of life but experienced growth faltering during later infancy compared to Western children ( 11,14 ) , as demonstrated by their weight and length SDS . The 25OHD concentrations of the women were > 50 nmol/L in the second half of pregnancy , and no distinction could be drawn in infant outcomes between mothers with concentrations above or below 80 nmol/L. Thus , our study suggests that , for women with regular , adventitious UVB sunshine exposure and in situations where foetal and infant growth may be constrained by multiple factors , there would be no benefit for foetal and infant growth or bone mineral accrual in aim ing to increase the vitamin D status of individual mothers during pregnancy above 50 or 80 BACKGROUND Vitamin D and calcium metabolism are involved in vascular smooth muscle cell proliferation , endothelial function and blood pressure ( BP ) regulation . Their physiopathology has been a matter of intensive clinical investigation with variable and sometimes contradictory results . Vitamin D insufficiency is highly prevalent in the general population , particularly among the elderly . We evaluated the association between serum 25(OH)-D levels and arterial BP in this population . METHODS An epidemiological cross-sectional study was design ed to analyse the prevalence of hypovitaminosis D ( ' D'AVIS ' study ) in our reference area . The study was performed on a representative r and om sample of the population over 64 years of age obtained from five primary health care areas . A medical record , arterial BP and biological analysis : serum 25(OH)-D , iPTH , creatinine , urea , calcium , albumin were obtained . RESULTS A total of 237 subjects ( 53 % women ) , aged between 64 and 93 ( mean 71.7 + /- 5.3 ) , were evaluated . The mean serum 25(OH)-D levels were 17.21 + /- 7.57 ng/ml ( interval 5 - 54 ; 86 % had < 25 ng/ml ) . The mean BP was 138.8 + /- 14/80 + /- 7.4 mmHg , and 46 % were on antihypertensive treatment . A significant negative association was observed between serum 25(OH)-D levels and systolic ( r = -0.153 , P = 0.018 ) and diastolic BP ( r = -0.152 , P = 0.019 ) . This association persisted after controlling for possible confounders in the multivariate analyses . CONCLUSIONS Low serum 25(OH)-D levels were inversely and independently associated with BP . Supplemental measures to prevent hypovitaminosis D in this population would be important , not only to protect the skeletal system but also for the possible beneficial effects on the cardiovascular system and the BP regulation Several lines of evidence suggest that vitamin D may reduce incidence of breast cancer , but few epidemiologic studies have addressed the relation of plasma vitamin D metabolites to the risk of this disease . We prospect ively examined the relationship between plasma levels of 25-hydroxyvitamin D [ 25(OH)D ] and 1,25-dihydroxyvitamin D [ 1,25(OH)2D ] and  risk of breast cancer  in a case-control study nested within the Nurses ' Health Study cohort .  Blood sample s were collected from study participants in 1989 - 1990 . Breast cancer cases developing between blood collection and June 1 , 1996 , were matched to cancer-free controls on the basis of age , menopausal status , and other factors . Stored plasma sample s from 701 cases and 724 controls were available for metabolite analysis . Cases had a lower mean 25(OH)D level than controls ( P = 0.01 ) , but mean 1,25(OH)2D levels were similar ( P = 0.49 ) . High levels of both metabolites were associated with a nonsignificant lower risk of breast cancer . Women in the highest quintile of 25(OH)D had a relative risk of 0.73 ( 95 % confidence interval = 0.49 - 1.07 ; Ptrend = 0.06 ) compared with those in the lowest quintile . For 1,25(OH)2D , the comparable relative risk was 0.76 ( 95 % confidence interval = 0.52 - 1.11 ; Ptrend = 0.39 ) . For both metabolites , the association was stronger in women ages 60 years and older , but results were not statistically significant . Our findings suggest that high levels of 25(OH)D , and perhaps 1,25(OH)2D , may be modestly associated with reduced risk of breast cancer Background Results from epidemiologic studies on the relationship between vitamin D and breast cancer risk are inconclusive . It is possible that vitamin D may be effective in reducing risk only of specific subtypes due to disease heterogeneity . Methods and Findings In case-control and case-series analyses , we examined serum concentrations of 25-hydroxyvitamin D ( 25OHD )  in relation to breast cancer prognostic characteristics , including histologic grade , estrogen receptor ( ER ) , and molecular subtypes defined by ER , progesterone receptor ( PR ) and HER2 , among 579 women with incident breast cancer and 574 controls matched on age and time of blood draw enrolled in the Roswell Park Cancer Institute from 2003 to 2008 . We found that breast cancer cases had significantly lower 25OHD concentrations than controls ( adjusted mean , 22.8 versus 26.2 ng/mL , p<0.001 ) . Among premenopausal women  , 25OHD concentrations were lower in those with high- versus low- grade tumors , and ER negative versus ER positive tumors ( p≤0.03 ) . Levels were lowest among women with triple-negative cancer ( 17.5 ng/mL ) , significantly different from those with luminal A cancer ( 24.5 ng/mL , p = 0.002 ) . In case-control analyses , premenopausal women with 25OHD concentrations above the median had significantly lower odds of having triple-negative cancer ( OR = 0.21 , 95 % CI = 0.08–0.53 ) than those with levels below the median ; and every 10 ng/mL increase in serum 25OHD concentrations was associated with a 64 % lower odds of having triple-negative cancer ( OR = 0.36 , 95 % CI = 0.22–0.56 ) . The differential associations by tumor subtypes among premenopausal women were confirmed in case-series analyses . Conclusion In our analyses , higher serum levels of 25OHD were associated with reduced risk of breast cancer , with associations strongest for high grade , ER negative or triple negative cancers in premenopausal women . With further confirmation in large prospect i ve studies , these findings could warrant vitamin D supplementation for reducing breast cancer risk , particularly those with poor prognostic characteristics among premenopausal women BACKGROUND Vitamin D deficiency is common in older population s , particularly during the winter months due to low levels of ultraviolet light exposure , and in nursing home residents . OBJECTIVE The main objective of the current study was to assess the distribution of serum 25-hydroxyvitamin D and its correlates in a sample of men and women with recent hip fractures who were part of a large clinical trial . METHODS This was a cross-sectional exploratory study of screened and ultimately r and omized patients with hip fractures . They were part of a multinational ( 115 clinical centers in 20 countries ) , r and omized , placebo-controlled , double-blind study testing the efficacy of a yearly IV bisphosphonate ( zoledronic acid ) in the prevention of new clinical fractures in patients with recent hip fracture repair .  Levels of 25-hydroxyvitamin D , calcium , alkaline phosphatase , creatinine clearance , and albumin were measured at a screening visit using blood serum . Demographic variables were assessed by patient self-report . Bone mineral density ( BMD ) was assessed by dual-energy x-ray absorptiometry of the nonfractured hip . RESULTS This report included 1174 screened patients ( 526 with vitamin D measured ) and 655 ( 385 with vitamin D measured ) patients r and omized before the protocol amendment . In screened patients , levels of 25-hydroxyvitamin D were low ( median , 14.7 ng/mL ; interquartilc range , 7.6 , 21.65 ) . Overall , 51 % were at or below the clinical ly meaningful threshold of 15 ng/mL. Among those patients r and omized , the level of 25-hydroxyvitamin D was significantly positively related to male sex ( rho , 0.13 ; P < 0.05 ) , serum calcium ( rho , 0.16 ; P < 0.01 ) , and BMD at the femoral neck ( rho , 0.22 ; P < 0.01 ) in bivariate analyses . Low serum 25-hydroxyvitamin D ( < 15 ng/mL ) was related only to low serum calcium ( odds ratio , 0.16 ; 95 % CI , 0.05 - 0.52 ) in multivariable logistic models controlling for sex , age , race , body mass index , living at home , alkaline phosphatase , and creatinine clearance . CONCLUSIONS We concluded that vitamin D insufficiency was a common problem in this population of elderly patients who had recently suffered a hip fracture . This insufficiency was related only to serum calcium in multivariable controlled models but can not be reliably identified or excluded by measuring serum calcium alone . Physicians should be encouraged to check and monitor patients ' serum levels of 25-hydroxyvitamin Purpose Prior prospect i ve studies , including our own , have evaluated total plasma 25-hydroxyvitamin D [ 25(OH)D ] and breast cancer risk with inconsistent results . However , recent studies suggest that some vitamin D functions may be more relevant to the unbound ( free ) fraction of 25(OH)D. Vitamin D binding protein ( DBP ) influences the free 25(OH)D levels and thus possibly the biological activities of vitamin D. Methods We conducted a case – control study nested within the Nurses ’ Health Study II to evaluate the association of plasma free 25(OH)D and DBP with breast cancer risk in predominantly premenopausal women .  Plasma sample s were assayed for 25(OH)D and DBP in 584 case – control pairs .  Free 25(OH)D levels were calculated based on plasma levels of total 25(OH)D , DBP , and a constant value representing average albumin levels . Conditional logistic regression was used to estimate relative risks ( RRs ) and 95 % confidence intervals ( CIs ) . Results We found no association between plasma calculated free 25(OH)D and risk of breast cancer overall ( highest vs. lowest quartile RR 1.21 , 95 % CI 0.83–1.77 , trend test p value = 0.50 ) . No association was observed for plasma DBP as well ( highest vs. lowest quartile RR 0.95 , 95 % CI 0.67–1.36 , trend test p value = 0.96 ) . Results were similar by tumor hormone receptor status . Neither the total nor the calculated free 25(OH)D and breast cancer association substantially varied by plasma DBP levels . Conclusions Our study does not support an important role of either calculated circulating free 25(OH)D or circulating DBP levels in breast cancer risk among predominantly premenopausal women CONTEXT High vitamin D and physical activity ( PA ) levels are independently associated with improved body composition and muscle function in older adults . OBJECTIVE The objective of this study was to investigate the interaction of 25-hydroxyvitamin D ( 25OHD ) and PA status in maintenance of body composition and muscle function in older adults . DESIGN AND SETTING This was a 5-year prospect i ve population -based study of Australian community-dwelling older adults . PARTICIPANTS Participants in the study included 615 community-dwelling volunteers aged 50 years old or older [ 61.4 ± 6.9 ( mean ± SD ) y ; 48 % female ] r and omly selected from electoral rolls and categorized according to baseline serum 25OHD ( ≥ or < 50 nmol/L ) and PA ( ≥ or < 10,000 pedometer determined steps/d ) levels as follows : high 25OHD and high PA ( VitD+PA+ ) ; high 25OHD and low PA ( VitD+PA- ) ; low 25OHD and high PA ( VitD-PA+ ) ; and low 25OHD and low PA ( VitD-PA- ) . A subset of 518 participants completed accelerometer assessment s during follow-up . MAIN OUTCOME MEASURES Changes in dual-energy X-ray absorptiometry-assessed body composition and lower-limb muscle function were measured . RESULTS VitD+PA+ had significantly smaller increases in body fat over 5 years compared with other groups ( all P < .05 ) . Higher baseline pedometer-determined PA result ed in declines in total body fat ( β = -.23 kg per 100 steps/d , P = .001 ) over 5 years for participants with high 25OHD but not those with low 25OHD ( P > .05 ) . Among participants with accelerometer data , these associations were generally mediated by higher levels of moderate/vigorous PA . CONCLUSIONS High vitamin D status appears to enhance PA-related declines in body fat during aging , but the mechanism may be greater amounts of outdoor moderate/vigorous PA rather than a direct effect of 25OHD AIMS To compare depressive symptoms in participants with low and high serum 25-hydroxyvitamin D ( 25(OH)D ) levels and to examine whether supplementation with vitamin D(3 ) would improve symptoms in those with low serum 25(OH)D levels . METHOD Participants with low 25(OH)D levels were r and omised to either placebo or 40 000 IU vitamin D(3 ) per week for 6 months . Individuals with high serum 25(OH)D levels were used as nested controls . Depressive symptoms were evaluated with the Beck Depression Inventory , Hospital Anxiety and Depression Scale , Seasonal Pattern Assessment Scale and Montgomery-Åsberg Depression Rating Scale . The study was registered at Clinical Trials.gov ( NCT00960232 ) . RESULTS Participants with low 25(OH)D levels ( n = 230 ) at baseline were more depressed ( P<0.05 ) than participants with high 25(OH)D levels ( n = 114 ) . In the intervention study no significant effect of high-dose vitamin D was found on depressive symptom scores when compared with placebo . CONCLUSIONS Low levels of serum 25(OH)D are associated with depressive symptoms , but no effect was found with vitamin D supplementation Low levels of 25-hydroxyvitamin D ( 25OHD ) are associated with increased bone turnover and risk of fractures . Plasma 25OHD is inversely related to body mass index , and vitamin D deficiency is common in obesity . We aim ed to determine whether vitamin D supplementation affects bone turnover and bone mineral density ( BMD ) in obese subjects . Fifty-two healthy obese men and women aged 18–50 years with plasma 25OHD levels below 50 nmol/L were r and omized to 7,000 IU of cholecalciferol daily or placebo for 26 weeks . We measured plasma levels of 25OHD , parathyroid hormone ( PTH ) , and markers of bone turnover , as well as BMD at the hip , spine , forearm , and whole body . Compared with placebo , treatment with cholecalciferol  increased mean plasma 25OHD from 35 to 110 nmol/L ( p < 0.00001 ) and significantly decreased PTH ( p < 0.05 ) . BMD increased significantly at the forearm by 1.6 ± 0.7 % ( p = 0.03 ) . The bone resorption marker C-terminal telopetide of type 1 collagen ( CTX ) decreased borderline significantly in the cholecalciferol group compared with the placebo group ( p = 0.07 ) . Changes in plasma 25OHD correlated inversely with changes in plasma levels of bone-specific alkaline phosphatase ( r = −0.38 , p = 0.01 ) and CTX ( r = −0.33 , p = 0.03 ) . Changes in CTX correlated inversely with changes in spine BMD ( r = −0.45 , p = 0.04 ) . Increasing circulating 25OHD levels by cholecalciferol treatment is of importance to bone health in young obese subjects as increased levels of 25OHD are associated with a decrease in both PTH and bone turnover and with an increase in BMD at the forearm Context Vitamin D supplementation may help prevent fractures , but the relationship between blood vitamin D concentrations and fracture risk is unclear . Contribution These authors observed an increased risk for hip fracture among women with lower serum 25-hydroxyvitamin D [ 25(OH ) vitamin D ] concentrations that was independent of measures of frailty , body mass index , physical function , and falls . Caution The authors did not measure bone mineral density ( BMD ) , so they could not determine whether 25(OH ) vitamin D concentrations give different information about fracture risk than that offered by BMD . Implication Low serum 25(OH ) vitamin D concentrations seem to be associated with a higher hip fracture risk . The Editors Vitamin  D deficiency is common in older adults , especially during the winter ( 1 ) and in homebound population s ( 2 ) , general medical in patients ( 3 ) , and community-dwelling women admitted to the hospital with acute hip fracture ( 4 ) . A recently published evidence -based report on vitamin D and bone health ( 5 ) found the level of evidence for an association between serum 25-hydroxyvitamin D [ 25(OH ) vitamin D ] concentrations and fracture risk to be inconsistent ( 5 ) . Since publication of that review , 1 prospect i ve study ( 6 ) reported no relationship between serum 25(OH ) vitamin D concentrations and fractures , whereas another ( 7 ) reported a significantly lower risk for hip fracture with 25(OH ) vitamin D concentrations greater than 60 nmol/L. Vitamin D concentration could be associated with fractures in several ways . It could influence muscle strength and balance , both of which contribute to falls and disability ( 810 ) . The association between 25(OH ) vitamin D concentrations and fracture may also be influenced by renal function , because renal insufficiency has been linked to fracture ( 11 ) and to vitamin D deficiency ( 12 ) . Several interactions between vitamin D and estrogen receptors have been described ( 13 ) ; hormone therapy has been shown to reverse abnormalities in vitamin D metabolism ( 14 ) , and low vitamin D concentrations have also been linked to higher bone turnover ( 15 , 16 ) . Thus , sex-steroid hormones and bone turnover could contribute to the association between 25(OH ) vitamin D concentration and fractures . We conducted a nested casecontrol study within the WHI-OS ( Women 's Health Initiative Observational Study ) among 400 case- patients with adjudicated incident hip fracture and 400 control participants . We tested whether low serum 25(OH ) vitamin D concentrations are associated with a higher risk for hip fractures in community-dwelling women and whether this relationship may be mediated by poor physical functioning , frailty , falls , sex-steroid hormones , renal function , or bone turnover . Methods Study Population Our study population came from the WHI-OS , a prospect i ve cohort study that enrolled 93676 women between 1994 and 1998 at 40 U.S. clinical centers ( age range , 50 to 79 years ) . Study methods are described in detail elsewhere ( 17 ) . In brief , women were eligible if they were postmenopausal , were unlikely to move or die within 3 years , were not enrolled in the WHI clinical trials , and were not currently participating in any other clinical trial . The human subjects review committees from each participating institution approved the study . Follow-up and Outcome Ascertainment We sent women question naires annually to report any hospitalization and other outcomes , including fractures . As of August 2004 , median follow-up duration was 7.1 years ( range , 0.7 to 9.3 years ) . At that time , 3.7 % of participants had withdrawn or were lost to follow-up and 5.3 % had died . We review ed medical records to verify cases of hip fracture , and blinded central adjudicators confirmed the cases ( 18 ) . We excluded patients with pathologic hip fractures . Nested CaseControl Study Design The present study is a casecontrol study nested within the prospect i ve design of WHI-OS . We excluded women who had a history of hip fracture ; were receiving hormone therapy up to 1 year before enrollment ; or were currently receiving and rogens , selective estrogen receptor modulators , antiestrogens , or other osteoporosis treatments ( bisphosphonates , calcitonin , or parathyroid hormone ) . We also excluded women with insufficient serum stored or of unknown ethnicity , leaving 39793 eligible participants . Of these , 404 women had a hip fracture . We r and omly selected 400 of these women to form the incident hip fracture group . For each case-patient , we selected 1 control participant who was within 1 year of the case-patient 's age at screening , was of matching race or ethnicity , and had their blood drawn within 120 days of the case-patient 's blood draw date ; 99 % of case- patients and control participants were matched within 30 days . Baseline Clinical Variables We divided clinical centers into 3 geographic regions on the basis of latitude : northern ( > 40 N ) , middle ( 35 to 40 N ) , and southern ( < 35 N ) . We ascertained all covariates at baseline . Clinic interviewers recorded current use of prescription medications by direct inspection of medicine containers . We entered prescription names into the WHI data base and assigned drug codes by using Medispan software ( First Data Bank , San Bruno , California ) . Average amounts of elemental calcium and vitamin D preparations were entered directly from supplement containers . Dietary intakes of calcium and vitamin D were assessed by using a semiquantitative food-frequency question naire ( 19 ) . Total calcium and vitamin D intake was defined as the sum of diet and supplements . We used question naires to ascertain date of birth , race or ethnicity , age at menopause , history of any fracture after age 55 years , smoking , parental history of hip fracture , self-rated health status , and alcohol consumption . We classfied physical activity on the basis of frequency and duration of walking and mild , moderate , and strenuous activities in the previous week . We calculated kilocalories of energy expended in 1 week as the metabolic equivalent ( kcal hours/week per kg ) ( 20 ) . We measured physical function by using the R AND Short Form-36 physical function scale , which comprises 10 items measuring whether health now limits physical function in moderate or vigorous activity ( 2 items ) ; strength to lift , carry , stoop , bend , or stair climb ( 4 items ) ; ability to walk various distances without difficulty ( 3 items ) ; and self-care ( 1 item ) ( 21 ) . The scale is scored from 0 to 100 , with higher scores indicating better physical function . We compared women with a score greater than 90 versus those with a score less than or equal to 90 , a cutoff value corresponding to the median score . We computed a frailty score , which included self-reported muscle weakness and impaired walking speed ( R AND Short Form-36 physical function scale score < 75 ) , exhaustion ( R AND Short Form-36 vitality scale score < 55 ) , low physical activity ( lowest quartile of physical activity ) , and unintended weight loss between baseline and 3 years of follow-up ( 22 ) . A woman was considered frail if she reported 3 or more of these indicators . Weight was measured on a balance-beam scale with the participant dressed in indoor clothing without shoes . Height was measured by using a wall-mounted stadiometer . Body mass index was calculated as weight ( in kg ) divided by height ( in m2 ) . Laboratory Procedures Laboratory personnel blinded to casecontrol status obtained a 12-hour fasting blood sample at the baseline visit , which was processed and stored at 80C according to strict quality control procedures ( 23 ) . Serum 25(OH ) vitamin D concentrations and sex-steroid hormone levels were measured at the Reproductive Endocrine Research Laboratory at the University of Southern California .  25-Hydroxyvitamin vitamin D was measured by using a radioimmunoassay with DiaSorin reagents ( DiaSorin , Stillwater , Minnesota ) . The sensitivity of the assay was 3.75 nmol/L. The interassay coefficients of variation were 11.7 % , 10.5 % , 8.6 % , and 12.5 % at 14.0 , 56.8 , 82.5 , and 122.5 nmol/L , respectively . Estradiol and testosterone concentrations were quantified by using sensitive and specific radioimmunoassays after organic solvent extraction and celite column partition chromatography ( 2427 ) . The intra- and interassay coefficients of variation were 7.9 % and 8 % to 12 % , respectively , for estradiol and 6 % and 10 % to 12 % , respectively , for testosterone . We calculated bioavailable hormone concentrations by using mass action equations ( 2830 ) . We measured sex hormonebinding globulin by using a solid-phase , 2-site chemiluminescent immunoassay . The intra- and interassay coefficients of variation were 4.1 % to 7.7 % and 5.8 % to 13 % , respectively . Serum cystatin C , a marker of renal function that is independent of age and weight , was measured at Medical Research Laboratories International , Highl and Heights , Kentucky , by using the Dade Behring BN-II nephelometer and Dade Behring reagents ( Dade Behring , Ramsey , Minnesota ) in a particle-enhanced immunonepholometric assay . Serum C-terminal telopeptide of type I collagen and aminoterminal procollagen extensions propeptide were measured by immunoassay ( Synarc , Lyon , France ) . Statistical Analysis We used chi-square and t tests to compare baseline characteristics between case- patients with hip fracture and matched control participants . We assigned 25(OH ) vitamin D concentrations to quartile categories defined on the basis of the distribution in the control participants . To further assess confounding , we compared baseline characteristics across quartiles of 25(OH ) vitamin D concentrations in case- patients and control participants combined . We calculated the P values for trend by using logistic regression and coding the variable of interest as a continuous variable . We assessed the association between serum 25(OH ) vitamin D concentrations and incident hip fracture in conditional logistic regression models that retained the matched casecontrol design . We first examined the unadjusted associations and then adjusted for age , OBJECTIVE The serum 25-hydroxyvitamin D ( 25(OH)D ) level is not only dependent on vitamin D intake and production in the skin but also dependent on genetic factors . Thus , in large genome-wide association studies , it has been shown that single nucleotide polymorphisms ( SNPs ) in the vitamin D binding protein ( DBP ) , as well as in enzymes related to activation or degradation of vitamin D and its metabolites , are as important for the serum 25(OH)D level as the effect of season . How these SNPs affect the serum 25(OH)D response to vitamin D supplementation is uncertain . DESIGN AND METHODS Data were pooled from three r and omized controlled trials where 40 , 000 IU vitamin D/week was given for 6 months . Serum 25(OH)D was measured before and at the end of the intervention , and the subjects were genotyped for SNPs related to the serum 25(OH)D level . RESULTS Baseline 25(OH)D levels were significantly related to SNPs in the DBP and CYP2R1 genes . Those with SNPs associated with the lowest baseline 25(OH)D levels also had the smallest increase ( delta ) after supplementation . Those with the lowest baseline serum 25(OH)D ( without regard to genotypes ) had the highest increase ( delta ) after supplementation . Subjects with high BMI had lowest baseline 25(OH)D levels and also the smallest increase ( delta ) after supplementation . CONCLUSIONS The serum 25(OH)D response to supplementation depends on genes , baseline level , and BMI . However , whether this is clinical ly important or not depends on the therapeutic window of vitamin D , an issue that is still not settled Circulating 25-hydroxyvitamin D ( 25(OH)D ) has been associated with cardiovascular disease ( CVD ) risk in observational studies . Also , SNPs to explain variation in 25(OH)D have been identified by genome-wide association studies . Detection of direct associations between SNPs that significantly affect 25(OH)D and CVD risk would indicate a causal role of vitamin D , as reverse causation could be excluded and confounding could be better controlled . Thus , a combined analysis of c and i date SNPs in relation to circulating 25(OH)D and CVD risk was carried out . A case-cohort study within the EPIC-Germany study was conducted comprising a r and omly drawn subcohort of 2,132 subjects ( 57.9 % women , mean age : 50.6 years ) and incident cases of myocardial infa rct ion ( n=559 ) and stroke ( n=471 ) that occurred during a mean follow-up duration of 7.6 years .  25(OH)D concentrations were measured by LC-MS/MS in baseline plasma sample s. Additionally , eight c and i date SNPs were assayed . Associations between 25(OH)D , SNPs and the risks of myocardial infa rct ion and stroke were assessed by multivariable regression analyses . Mean 25(OH)D level was 47.2 nmol/L in the subcohort . Four SNPs were associated with 25(OH)D ( p<0.05 ) . In subjects with 25(OH)D levels < 25 nmol/L , the risks of CVD as composite endpoint ( Hazard Ratio : 1.53 , 95 % confidence interval : 1.12–2.09 ) , myocardial infa rct ion , and stroke were significantly increased compared to subjects with levels ≥50 nmol/L , while no significant linear associations were observed . A SNP score was not related to the risks of total CVD ( Hazard Ratio : 1.0 , 95 % confidence interval : 0.71–1.42 ) , myocardial infa rct ion , or stroke . The same was true concerning single SNPs . Given the lack of association between SNPs and the risks of stroke and myocardial infa rct ion , the present findings do not point to a major causal role of vitamin D in the development of these diseases . However , a detection of modest associations between genetic markers and CVD risk in larger consortia can not be ruled out CONTEXT Several cohort studies have reported U-shaped or inverse J-shaped associations between circulating 25-hydroxyvitamin D [ 25OHD ] and clinical outcomes . OBJECTIVE We aim ed to investigate in cardiac surgical patients the association of preoperative 25OHD and 1,25-dihydroxyvitamin D3 [ 1,25(OH)2D3 ] levels with the risk of major adverse cardiac and cerebrovascular events ( MACCE ) . DESIGN A prospect i ve cohort study of adult cardiac surgical patients in 2012 - 2013 was used . SETTING The study was conducted at the Heart and Diabetes Center North Rhine-Westphalia , Germany . PATIENTS A total of 3371 adult patients participated in the study . INTERVENTION None Measurements : The main outcome measure was MACCE until discharge . We categorized vitamin D metabolite levels into subgroups and performed multivariable-adjusted logistic regression analysis to estimate odds ratios ( ORs ) of MACCE . Moreover , we performed multiple regression analysis to assess the association of 25OHD and circulating 1,25(OH)2D3 with preoperative parameters . RESULTS As compared with patients in the 25OHD reference category ( 75 - 100 nmol/L ) , the multivariable-adjusted odds ratios ( OR ) of MACCE was significantly higher in patients with deficient 25OHD levels ( < 30 nmol/L ) ( OR = 2.06 [ 95%CI : 1.24 - 3.43 ] ) , but was comparable in patients with 25OHD levels > 100 nmol/L ( OR = 1.16 [ 95 % CI : 0.56 - 2.37 ] ) . Poor kidney function was an important predictor of high 25OHD ( > 100 nmol/L ) and low 1,25(OH)2D3 levels . 1,25(OH)2D3 was not independently associated with the incidence of MACCE . CONCLUSIONS In cardiac surgical patients , deficient but not high 25OHD levels are independently associated with the risk of MACCE . Cohort studies should consider potential interrelationships between kidney function , circulating vitamin D metabolite levels , and clinical outcome
The fact that most MAs on results from RCTs did not show a beneficial effect does not disprove the hypothesis suggested by observational findings on adverse health outcomes of low 25OHD levels
Background A large number of observational studies have reported harmful effects of low 25-hydroxyvitamin D ( 25OHD ) levels on non-skeletal outcomes .
We performed a systematic quantitative review on characteristics of r and omized clinical trials ( RCTs ) included in meta-analyses ( MAs ) on non-skeletal effects of vitamin D supplementation .