Calcium and vitamin D supplementation is associated with decreased abdominal visceral adipose tissue in overweight and obese adults. Efficacy of vitamin D supplementation in depression in adults: a systematic review protocol Effect of vitamin D supplementation on inflammation: protocol for a systematic review Vitamin D and calcium intakes and breast cancer risk in pre- and postmenopausal women. Incidence of hypercalciuria and hypercalcemia during vitamin D and calcium supplementation in older women Vitamin D, calcium supplementation, and colorectal adenomas: results of a randomized trial. Long-term follow-up for mortality and cancer in a randomized placebo-controlled trial of vitamin D(3) and/or calcium (RECORD trial). Effects of Calcium Supplementation on Body Weight and Adiposity in Overweight and Obese Adults Association Between Vitamin D Supplementation During Pregnancy and Offspring Growth, Morbidity, and Mortality Calcium and vitamin d supplementation in postmenopausal women. The Women's Health Initiative calcium-vitamin D trial: overview and baseline characteristics of participants. Interaction of estrogen therapy with calcium and vitamin D supplementation on colorectal cancer risk: reanalysis of Women's Health Initiative randomized trial. Randomised controlled trial of vitamin D supplementation in sarcoidosis Effect of vitamin K supplementation on bone loss in elderly men and women. Type of dietary fat is associated with the 25-hydroxyvitamin D3 increment in response to vitamin D supplementation. Independent and combined effects of calcium-vitamin D3 and exercise on bone structure and strength in older men: an 18-month factorial design randomized controlled trial. A systematic review protocol examining the effect of vitamin D supplementation on endothelial function Intakes of calcium and vitamin D and risk of colorectal cancer in women. Pharmacologic Treatment of Low Bone Density or Osteoporosis to Prevent Fractures: A Clinical Practice Guideline from the American College of Physicians Calcium and vitamin D supplements and health outcomes: a reanalysis of the Women's Health Initiative (WHI) limited-access data set. Calcium-vitamin D cosupplementation influences circulating inflammatory biomarkers and adipocytokines in vitamin D-insufficient diabetics: a randomized controlled clinical trial. Calcium, vitamin D supplementation, and physical function in the Women's Health Initiative. Vitamin D and Calcium Supplementation and One-Year Change in Mammographic Density in the Women's Health Initiative Calcium and Vitamin D Trial
BACKGROUND Several studies suggest that calcium and vitamin D ( CaD ) may play a role in the regulation of abdominal fat mass . OBJECTIVE This study investigated the effect of CaD-supplemented orange juice ( OJ ) on weight loss and reduction of visceral adipose tissue ( VAT ) in overweight and obese adults ( mean ± SD age : 40.0 ± 12.9 y ) . DESIGN Two parallel , double-blind , placebo-controlled trials were conducted with either regular or reduced-energy ( lite ) orange juice . For each 16-wk trial , 171 participants were r and omly assigned to 1 of 2 groups . The treatment groups consumed three 240-mL glasses of OJ ( regular or lite ) fortified with 350 mg Ca and 100 IU vitamin D per serving , and the control groups consumed either unfortified regular or lite OJ .  Computed tomography scans of VAT and subcutaneous adipose tissue were performed by imaging a single cut at the lumbar 4 level . RESULTS After 16 wk , the average weight loss ( ∼2.45 kg ) did not differ significantly between groups . In the regular OJ trial , the reduction of VAT was significantly greater ( P = 0.024 ) in the CaD group ( -12.7 ± 25.0 cm(2 ) ) than in the control group ( -1.3 ± 13.6 cm(2 ) ) . In the lite OJ trial , the reduction of VAT was significantly greater ( P = 0.039 ) in the CaD group ( -13.1 ± 18.4 cm(2 ) ) than in the control group ( -6.4 ± 17.5 cm(2 ) ) after control for baseline VAT . The effect of calcium and vitamin D on VAT remained highly significant when the results of the 2 trials were combined ( P = 0.007 ) . CONCLUSIONS The findings suggest that calcium and /or vitamin D supplementation contributes to a beneficial reduction of VAT . This trial is registered at clinical trial.gov as NCT00386672 , NCT01363115 Background The role of vitamin D in management of depression is unclear . Results from observational and emerging r and omized controlled trials ( RCTs ) investigating the efficacy of vitamin D in depression lack consistency - with some suggesting a positive association while others show a negative or inconclusive association . Methods / Design The primary aim of this study is to conduct a systematic review of RCTs to assess the effect of oral vitamin D supplementation versus placebo on depression symptoms measured by scales and the proportion of patients with symptomatic improvement according to the authors ’ original definition . Secondary aims include assessing the change in quality of life , adverse events and treatment discontinuation . We will conduct the systematic review and meta- analysis according to the recommendations of the Cochrane H and book for Systematic Review s of Interventions . We will search the Cochrane Central Register of Controlled Trials ( CENTRAL ) , MEDLINE ( 1966 to present ) , EMBASE ( 1980 to present ) , CINAHL ( 1982 to present ) , PsychINFO ( 1967 to present ) and Clinical Trials.gov . Unpublished work will be identified by search ing two major conferences : the International Vitamin Conference , the Anxiety Disorders and Depression Conference , while grey literature will be acquired by contacting authors of included studies . We will use the r and om-effects meta- analysis to synthesize the data by pooling the results of included studies . Discussion The results of this systematic review will be helpful in clarifying the efficacy of vitamin D supplementation and providing evidence to establish guidelines for implementation of vitamin D for depression in general practice and other relevant setting s. Study registration Unique identifier : CRD42013003849 Introduction The extraskeletal role of vitamin D is being increasingly recognised . This has important clinical implication s , as vitamin D deficiency has reached epidemic proportions worldwide . Vitamin D has proposed anti-inflammatory properties , yet the role of vitamin D supplementation in reducing inflammation remains largely unknown . The purpose of this review is to investigate the impact of vitamin D supplementation on inflammation , and to identify relevant knowledge gaps in the field . Methods and analysis Medline , CINAHL , EMBASE and All EBM will be systematic ally search ed for r and omised controlled trials ( RCTs ) and systematic review s of RCTs , comparing vitamin D supplementation with placebo , usual care or other pharmacological or non-pharmacological interventions . One review er will assess articles for eligibility according to prespecified selection criteria , after which 2 independent review ers will perform data extraction and quality appraisal . Meta-analyses will be conducted where appropriate . Ethics and dissemination Formal ethical approval is not required as no primary data is collected . This systematic review will identify potential clinical implication s of vitamin D deficiency and supplementation , and will be disseminated through a peer- review ed publication and at conference meetings , to inform future research on the efficacy of vitamin D supplementation for inflammation and inflammatory diseases . PROSPERO registration number CRD42016037104 BACKGROUND Some evidence suggests that vitamin D may reduce  breast cancer risk . Despite the biological interaction between vitamin D and calcium , few studies have evaluated their joint effects on breast cancer risk . OBJECTIVE The objective was to evaluate the associations and potential interaction between vitamin D and calcium ( from food and supplements ) and breast cancer risk in a population -based case-control study . DESIGN Breast cancer cases aged 25 - 74 y ( diagnosed 2002 - 2003 ) were identified through the Ontario Cancer Registry . Controls were identified by using r and om digit dialing ; 3101 cases and 3471 controls completed epidemiologic and food-frequency question naires . Adjusted odds ratios ( ORs ) and 95 % CIs were estimated by using multivariate logistic regression . RESULTS Vitamin D and calcium intakes from food only and total combined intakes ( food and supplements ) were not associated with breast cancer risk , although the mean intake of vitamin D was low . Vitamin D supplement intake > 10 microg/d ( 400 IU/d ) compared with no intake was associated with a reduced risk of breast cancer ( adjusted OR : 0.76 ; 95 % CI : 0.59 , 0.98 ) . No categories of calcium supplement intake were significantly associated with reduced breast cancer risk , but a significant inverse trend was observed ( P = 0.04 ) . There were no significant interactions involving vitamin D , calcium , or menopausal status . CONCLUSIONS No associations were found between overall vitamin D or calcium intake and breast cancer risk .  Vitamin D from supplements was independently associated with reduced breast cancer risk . Further research is needed to investigate the effects of higher doses of vitamin D and calcium supplements Objective This study aims to prospect ively assess the incidence of hypercalciuria and hypercalcemia with different doses of vitamin D and with a calcium intake of approximately 1,200 mg/day . Methods This was a 1-year r and omized placebo-controlled study of vitamin D ( 400 - 4,800 IU/d ) in 163 white women aged 57 to 90 years .  Calcium citrate tablets ( 200 mg ) were added to the diet to achieve a total calcium intake of approximately 1,200 mg/day in all groups . All women had vitamin D insufficiency at baseline , with serum 25-hydroxyvitaminD levels lower than 20 ng/mL ( 50 nmol/L ) . Serum and 24-hour urine calcium were collected every 3 months on supplementation , any test result above the upper reference range represented an episode of hypercalcemia or hypercalciuria . Mixed-effects models and multivariate logistic regression were used in the analysis . Results Hypercalcemia ( > 10.2 mg/dL [ 2.55 mmol/L ] ) occurred in 8.8 % of white women .  Hypercalciuria ( > 300 mg/d [ 7.5 mmol ] ) occurred in 30.6 % of white women . Episodes of hypercalciuria were transient in half of the group and recurrent in the other half . No relationship between hypercalcemia or hypercalciuria and vitamin D dose was found , and hypercalciuria was equally common in the placebo group . Conclusions Hypercalciuria and hypercalcemia commonly occur with vitamin D and calcium supplements . Whether hypercalciuria and hypercalcemia are caused by calcium , vitamin D , or both is unclear . These findings may have relevance to the reported increase in kidney stones in the Women ’s Health Initiative trial . Because calcium 1,200 mg and vitamin D 800 IU/day are widely recommended in postmenopausal women , systematic evaluation of the safety of supplements is warranted in clinical management and in future studies BACKGROUND Calcium and vitamin D both appear to have antineoplastic effects in the large bowel . Although these nutrients are inter-related metabolically in bone and in the normal intestine , their potential interactions in large-bowel carcinogenesis are not well understood . METHODS We assessed independent and joint effects of calcium supplementation and vitamin D status on  adenoma recurrence in 803 subjects in a multi-center , placebo-controlled r and omized clinical trial of calcium supplementation for the prevention of colorectal adenoma recurrence . Serum levels of 25-hydroxy [ 25-(OH ) ] vitamin D and 1,25-dihydroxy [ 1,25-(OH)2 ] vitamin D levels were determined , and the Taq I and Fok I polymorphisms in the vitamin D receptor ( VDR ) gene were analyzed by polymerase chain reaction . Risk ratios ( RRs ) for any adenoma recurrence were computed for calcium supplementation within groups defined by serum vitamin D levels and for serum vitamin D levels within treatment groups . Associations of VDR polymorphisms with recurrence risk were also evaluated . All statistical tests were two-sided . RESULTS Among subjects with baseline 25-(OH ) vitamin D levels at or below the median ( 29.1 ng/mL ) , calcium supplementation was not associated with adenoma recurrence , whereas among those with levels above the median , calcium supplementation was associated with a reduced risk ( RR = 0.71 , 95 % confidence interval [ CI ] = 0.57 to 0.89 , P for interaction = .012 ) . Conversely , serum 25-(OH ) vitamin D levels were associated with a reduced risk only among subjects receiving calcium supplements ( RR per 12 ng/mL increase of vitamin D = 0.88 , 95 % CI = 0.77 to 0.99 , P for interaction = .006 ) . VDR polymorphisms were not related to adenoma recurrence and did not modify the associations with vitamin D or calcium . CONCLUSIONS Calcium supplementation and vitamin D status appear to act largely together , not separately , to reduce the risk of colorectal adenoma recurrence . VDR genotype does not appear to be associated with risk CONTEXT Vitamin D or calcium supplementation may have effects on  vascular disease and cancer .  OBJECTIVE Our objective was to investigate whether vitamin D or calcium supplementation affects mortality , vascular disease , and cancer in older people . DESIGN AND SETTING The study included long-term follow-up of participants in a two by two factorial , r and omized controlled trial from 21 orthopedic centers in the United Kingdom . PARTICIPANTS Participants were 5292 people ( 85 % women ) aged at least 70 yr with previous low-trauma fracture . INTERVENTIONS Participants were r and omly allocated to daily vitamin D(3 ) ( 800 IU ) , calcium ( 1000 mg ) , both , or placebo for 24 - 62 months , with a follow-up of 3 yr after intervention . MAIN OUTCOME MEASURES All-cause mortality , vascular disease mortality , cancer mortality , and cancer incidence were evaluated . RESULTS In intention-to-treat analyses , mortality [ hazard ratio ( HR ) = 0.93 ; 95 % confidence interval ( CI ) = 0.85 - 1.02 ] , vascular disease mortality ( HR = 0.91 ; 95 % CI = 0.79 - 1.05 ) , cancer mortality ( HR = 0.85 ; 95 % CI = 0.68 - 1.06 ) , and cancer incidence ( HR = 1.07 ; 95 % CI = 0.92 - 1.25 ) did not differ significantly between participants allocated vitamin D and those not . All-cause mortality ( HR = 1.03 ; 95 % CI = 0.94 - 1.13 ) , vascular disease mortality ( HR = 1.07 ; 95 % CI = 0.92 - 1.24 ) , cancer mortality ( HR = 1.13 ; 95 % CI = 0.91 - 1.40 ) , and cancer incidence ( HR = 1.06 ; 95 % CI = 0.91 - 1.23 ) also did not differ significantly between participants allocated calcium and those not . In a post hoc statistical analysis adjusting for compliance , thus with fewer participants , trends for reduced mortality with vitamin D and increased mortality with calcium were accentuated , although all results remain nonsignificant . CONCLUSIONS Daily vitamin D or calcium supplementation did not affect mortality , vascular disease , cancer mortality , or cancer incidence Context Some data suggest that body weight is inversely associated with calcium intake , increasing the possibility that supplemental calcium might facilitate weight loss or prevent weight gain . Contribution Research ers r and omly assigned overweight and obese patients to supplemental calcium or placebo and found no between-group differences in measures of weight change . Caution Trial participants were almost all women . Implication Calcium supplementation is unlikely to prevent weight gain in persons who are overweight or obese . The Editors The high prevalence of overweight and obesity in the United States ( 1 ) has stimulated great interest in identifying approaches that may help to prevent weight gain or improve ability to lose weight . Increasing calcium intake is a potential means of weight management that has received much attention from both lay press ( 24 ) and the medical community ( 57 ) . This interest has been stimulated by a series of cross-sectional studies ( 817 ) reporting that children and adults with low reported consumption of dietary ( primarily dairy ) calcium  have greater body weight , a higher degree of adiposity , and greater risk for having components of the metabolic syndrome than those who report that they consume more calcium . Some ( 1824 ) , although not all ( 2534 ) , longitudinal investigations have also suggested that children and adults who consume a lower calcium diet tend to gain more weight than those with greater dietary or supplemental calcium intake . These data , together with some small clinical trials suggesting that weight loss during dieting may be augmented by supplemental ( 35 ) or dairy calcium ( 3538 ) , have led to expectations that substantially augmenting calcium intake might diminish body weight by 0.5 kg or more each year ( 5 , 18 , 22 , 39 ) . Two possible mechanisms for an effect of dietary calcium on body weight have been suggested . First , calcium can combine with fatty acids in the intestine to form insoluble soaps that are therefore not absorbed ( 40 , 41 ) . Second , some research ers ( 4246 ) have proposed that low dietary calcium leads to increased adipocyte triglyceride deposition ( 4749 ) . If calcium substantially affects fat accumulation , calcium supplementation could prevent additional weight and fat gain among people with high body weight . To test this hypothesis , we measured the effect of calcium carbonate supplementation for 2 years on the weight and body fat of overweight and obese adults . Methods Setting and Participants We recruited participants through advertisements posted in Bethesda , Maryl and , and spontaneous reply to newspaper and radio advertising in the Washington , DC , metropolitan area seeking healthy adult volunteers for a project to study the health effects of calcium supplementation . Men and women age 18 to 80 years were eligible to enroll if they had a body mass index ( BMI ) of 25 kg/m2 or more and did not have cerebrovascular , cardiovascular , pulmonary , renal , hepatic , endocrinologic , or other substantial medical disease . Women were ineligible if they were pregnant , were breastfeeding , or had received a recommendation from a health care professional to take calcium supplements for any condition . We excluded persons who regularly used medications known to affect body weight , had a weight loss of 3 % or more in the preceding 3 months , reported total calcium intake in excess of 3.5 g/d , used supplemental calcium in excess of 300 mg/d , used vitamin D supplements in excess of 400 IU/d , or had a history of renal stones . The institutional review board of the National Institute of Child Health and Human Development , National Institutes of Health , approved the research protocol . Each participant provided signed consent . We provided financial compensation for participants ' time and inconvenience . Design Overview We conducted a single-center , r and omized , double-blind , placebo-controlled trial from March 2002 to April 2006 . After an outpatient visit to determine eligibility and obtain initial assessment s , participants entered a 2-year , double-blind treatment period . R and omization and Interventions We r and omly assigned participants , in a 1:1 ratio , to receive either elemental calcium , 1500 mg/d ( calcium carbonate , purchased from Particle Dynamics , St. Louis , Missouri ) , or placebo , administered as 2 divided doses with meals . Investigators assigned consecutive code numbers to participants from prespecified lists stratified by race or ethnicity , sex , and BMI ( 25 to 26.99 , 27 to 29.99 , 30 to 34.99 , and 35 kg/m2 ) . The National Institutes of Health Clinical Center Pharmaceutical Development Section used permuted blocks with stratification to generate the allocations that translated code numbers into study group assignments by using a pseudo-r and om number program . The Pharmaceutical Development Section prepared placebo and calcium capsules to appear identical . Pharmacy personnel , not otherwise involved with the conduct of the study , dispensed study capsules with medication placed in containers that appeared identical and differed only by the individual participant code number . No participant , investigator , or other medical or nursing staff interacting with participants was aware of study group assignments for the duration of the trial . Initial Assessment At their prer and omization evaluation , participants reported after an overnight fast and were weighed in hospital gowns by using a digital scale ( Life Measurement Instruments , Concord , California ) that was calibrated with a known weight before each participant 's measurement . We measured height by using a stadiometer calibrated before each measurement ( Holtain , Crymych , United Kingdom ) . Research dietitians assessed abdominal and hip circumferences in triplicate to the nearest 0.1 cm , as recommended ( 50 , 51 ) , and measured triceps skinfold thickness to the nearest 0.5 mm by using Lange calipers ( Cambridge Scientific Industries , Cambridge , Maryl and ) . We measured blood pressure , obtained after a 5-minute rest period , 3 times at 5-minute intervals from seated participants by using an automated sphygmomanometer ( Dinamap-Plus , Critikon , Tampa , Florida ) . We did whole-body dual-energy x-ray absorptiometry to estimate total body fat mass ( Delphi A , software version 11.2 , Hologic , Bedford , Massachusetts ) . We measured intact parathyroid hormone concentrations with 2-site immunochemiluminometric assays ( 52 ) , and serum 25-hydroxy vitamin D levels by using a competitive binding assay ( Nichols Advantage , Nichols Diagnostic , San Clemente , California ) ( 53 ) . We asked participants with substantial vitamin D deficiency ( serum 25-hydroxy vitamin D level < 25.0 nmol/L ) to take vitamin D , 400 IU/d ( ergocalciferol ) , in a multivitamin . We assessed baseline dietary calcium intake by using a 7-day food record that a registered dietitian review ed with each participant to maximize accuracy and completeness , and analyzed for dietary calcium intake by using the Nutrition Data System for Research software , versions 4.04_32 and 4.05_33 ( University of Minnesota , Minneapolis , Minnesota ) ( 54 ) . We measured calcium intake from multivitamins or calcium supplements with a vali date d calcium question naire ( 55 ) that was review ed for completeness through an interview with a registered dietitian . We recorded the calcium content as it was listed on the label of each multivitamin or calcium supplement . We measured dietary and supplemental vitamin D intakes in the same manner . We estimated energy intake at baseline and at 2 years by using a food-frequency question naire that assessed total diet ( 5557 ) . We measured socioeconomic status by using the Hollingshead score ( 58 ) . Outcomes and Follow-up Primary efficacy end points were change in body weight and body fat mass at the end of 2 years of treatment . Secondary outcomes were fasting anthropometric measurements , body composition by dual-energy x-ray absorptiometry , and change in blood pressure , assessed yearly , along with question naire data on dietary and supplemental calcium intake ( 55 ) . In addition , we contacted participants every 3 months to complete question naires about their adherence to the medication regimen ; assess their general health ; and obtain self-reports of mood , stress , physical activity , and hunger . Every 6 months , participants returned to the clinic to exchange their unused study medication for a new supply . We used the tally of returned capsules to assess adherence . To examine adequacy of the masking procedure , participants completed a question naire at the end of the study that requested they report their best guess about their study group assignment . Statistical Analysis All reported primary data analyses were prespecified . On the basis of our previous study of observed yearly changes in body weight over time ( 59 ) , we needed a total sample size of 256 participants to detect a 0.35-kg difference per year in weight change ( that is , 0.7 kg over 2 years ) between groups with 80 % power . Participant accrual was set at 340 participants to allow 25 % loss to follow-up . We analyzed data by using SPSS for Windows , version 14.0 ( SPSS , Chicago , Illinois ) . We assessed efficacy in the intention-to-treat sample of all r and omly assigned participants . We did 2 efficacy analyses . The primary analysis used a multiple imputation model for missing data under a missing-at-r and om assumption ( 60 ) . By using NORM , version 2.03 ( The Pennsylvania State University , State College , Pennsylvania ) ( 61 , 62 ) , we included all available baseline , 1-year , and 2-year outcome measures in an imputation model along with age , sex , race , baseline serum 25-hydroxy vitamin D concentration , baseline calcium intake , and study group . We then combined the coefficients from analyses of 20 imputed data sets into a single set of estimates according to Shafer ( 62 ) and the Rubin rules ( 63 ) . To assess sensitivity of these results to the missing-at-r and om assumption , we conducted 3 additional analyses : assuming that all participants who withdrew from the study had major weight gain ( Importance Whether vitamin D supplementation during pregnancy is beneficial and safe for offspring is unclear . Objective To systematic ally review studies of the effects of vitamin D supplementation during pregnancy on offspring growth , morbidity  , and mortality . Data Sources Search es of Medline , Embase , and the Cochrane Data base of Systematic Review s were conducted up to October 31 , 2017 . Key search terms were vitamin D , pregnancy , r and omized controlled trials , and offspring outcomes . Study Selection R and omized clinical trials of vitamin D supplementation during pregnancy and offspring outcomes . Data Extraction and Synthesis Two authors independently extracted data , and the quality of the studies was assessed . Summary risk ratio ( RR ) , risk difference ( RD ) or mean difference ( MD ) , and 95 % CI were calculated using fixed-effects or r and om-effects meta- analysis . Main Outcomes and Measures Main outcomes were fetal or neonatal mortality , small for gestational age ( SGA ) , congenital malformation , admission to a neonatal intensive care unit , birth weight , Apgar scores , neonatal 25-hydroxyvitamin D ( 25[OH]D ) and calcium concentrations , gestational age , preterm birth , infant anthropometry , and respiratory morbidity during childhood . Results Twenty-four clinical trials involving 5405 participants met inclusion criteria . Vitamin D supplementation during pregnancy was associated with a lower risk of SGA ( RR , 0.72 ; 95 % CI , 0.52 to 0.99 ; RD , −5.60 % ; 95 % CI , −0.86 % to −10.34 % ) without risk of fetal or neonatal mortality ( RR , 0.72 ; 95 % CI , 0.47 to 1.11 ) or congenital abnormality ( RR , 0.94 ; 95 % CI , 0.61 to 1.43 ) . Neonates with prenatal vitamin D supplementation had higher 25(OH)D levels ( MD , 13.50 ng/mL ; 95 % CI , 10.12 to 16.87 ng/mL ) , calcium levels ( MD , 0.19 mg/dL ; 95 % CI , 0.003 to 0.38 mg/dL ) , and weight at birth ( MD , 75.38 g ; 95 % CI , 22.88 to 127.88 g ) , 3 months ( MD , 0.21 kg ; 95 % CI , 0.13 to 0.28 kg ) , 6 months ( MD , 0.46 kg ; 95 % CI , 0.33 to 0.58 kg ) , 9 months ( MD , 0.50 kg ; 95 % CI , 0.01 to 0.99 kg ) , and 12 months ( MD , 0.32 kg ; 95 % CI , 0.12 to 0.52 kg ) . Subgroup analysis by doses showed that low-dose vitamin D supplementation ( ⩽2000 IU/d ) was associated with a reduced risk of fetal or neonatal mortality ( RR , 0.35 ; 95 % CI , 0.15 to 0.80 ) , but higher doses ( > 2000 IU/d ) did not reduce this risk ( RR , 0.95 ; 95 % CI , 0.59 to 1.54 ) . Conclusions and Relevance Vitamin D supplementation during pregnancy is associated with a reduced risk of SGA and improved infant growth without risk of fetal or neonatal mortality or congenital abnormality . Vitamin D supplementation with doses of 2000 IU/d or lower during pregnancy may reduce the risk of fetal or neonatal mortality CONTEXT Bone health is influenced by the intake of both calcium and vitamin D. OBJECTIVE Our objective was to evaluate the influence of calcium and vitamin D supplementation on PTH and bone turnover . SETTING , PATIENTS , AND DESIGN : At an ambulatory research center , 159 postmenopausal healthy white women participated in this double-blind , placebo-controlled parallel , longitudinal factorial study that was 6 months in duration . INTERVENTIONS Subjects were r and omly allocated to 4 groups : 1 ) double placebo , 2 ) calcium ( 1200 mg daily ) plus placebo , 3 ) vitamin D3 ( 100 μg ) plus placebo , and 4 ) vitamin D3 and calcium . Serum and urine were collected fasting and 2 hours after a calcium load at baseline and at 3 and 6 months . MAIN OUTCOME MEASURES Serum PTH , cross-linked C-telopeptide ( CTX ) , and procollagen type I N-terminal propeptide ( P1NP ) were measured . RESULTS Before study medication , a calcium load result ed in a decline in PTH and CTX and an increase in urinary calcium excretion . Serum CTX and P1NP declined over time with calcium supplementation but did not change with increased vitamin D intake . There was a decline in PTH in the vitamin D groups in the fasting state compared with placebo . Suppression of PTH was greater after a calcium load in the vitamin D groups . A calcium load decreased PTH and CTX and raised urinary calcium . CONCLUSIONS Fasting PTH  declines with vitamin D supplementation . PTH declines after calcium intake . Supplementation of the diet with 1200 mg calcium/d reduces bone turnover markers , whereas supplementation with up to100 μg vitamin D3/d does not Osteoporosis is a major public health issue leading to significant morbidity , loss of independence and excess loss of life . It has been estimated that 13 to 17 million postmenopausal women have low bone mass or osteoporosis ( 1 , 2 ) . This is associated with almost 1.5 million fractures annually , including 300,000 hip fractures ( 2 , 3 ) . A review of the evidence by Cumming in 1990 ( 4 ) and subsequently published r and omized clinical trials have shown that calcium and /or vitamin D supplements may play a role in the prevention and treatment of osteoporosis by slowing the rates of bone loss in postmenopausal and elderly women ( 5–9 ) . However , there are a limited number of calcium and /or vitamin D trials ( 10–13 ) and observational studies [ review of evidence by Cumming and Nevitt ( 14 ) and Kanis ( 15 ) ] , to support a role for calcium and vitamin D supplementation in the reduction of hip and other fractures . It has also been suggested that calcium and vitamin D supplementation may play a role in the reduction of colorectal cancer incidence ( 16–21 ) . To address these major health concerns of postmenopausal women , the Calcium-Vitamin D ( CaD ) trial of the Women ’s Health Initiative ( WHI ) was design ed to test the primary hypothesis that women who are r and omized to receive calcium and vitamin D supplementation will have a lower risk of hip fracture and secondarily , a lower risk of all fractures and colorectal cancer than women receiving corresponding placebo . The objective of this paper is Although calcium and vitamin-D intake were consistently shown to be inversely associated with  colorectal cancer risk  in several large prospect i ve studies and protective against adenoma and cancer in multiple r and omized trials , the Women 's Health Initiative ( WHI ) of calcium and low-dose vitamin-D supplementation trial found no overall effects on colorectal cancer . However , the previous report did not recognize an important biologic interaction with estrogen therapy . We investigated the treatment interaction of estrogen with calcium and vitamin-D on risk of colorectal cancer via a re analysis of primary data results from the WHI calcium and vitamin-D supplementation trial ( 1,000 mg elemental calcium , 400 IU of vitamin-D3 , or placebo ) , reanalyzing results from women concurrently r and omized to estrogen interventions  and placebo . Results indicate that concurrent estrogen therapy was a strong effect modifier of calcium and vitamin-D supplementation on colorectal cancer risk . While calcium plus vitamin-D supplementation among women concurrently assigned to estrogen therapies suggested increased risk ( Hazard Ratio = 1.50 , 95 % CI : 0.96 - 2.33 ) , among women concurrently assigned to placebos arms of the estrogen trials , calcium plus vitamin-D indicated suggestive benefits ( HR = 0.71 , 95 % CI : 0.46 - 1.09 ) ( p-for-estrogen-interaction = 0.018 ) . Consistent interaction was also found by reported estrogen use ( p interaction = 0.037 ) . Results indicate contrasting effects of calcium and vitamin-D by concurrent estrogen therapy on colorectal cancer risk . Although further clinical and mechanistic studies are warranted , the potential clinical implication s of the apparent interaction of estrogen therapy with calcium and vitamin-D supplementation should be recognized . Important biological mechanisms related to the key membrane receptor megalin and estrogen-dependent protein calbindin are discussed Objectives The role vitamin D intake/production plays in sarcoidosis-associated hypercalcaemia is uncertain . However , authoritative review s have recommended avoiding sunlight exposure and vitamin D supplements , which might lead to adverse skeletal outcomes from vitamin D insufficiency . We investigated the effects of vitamin D supplementation on surrogate measures of skeletal health in patients with sarcoidosis and vitamin D insufficiency . Design R and omised , placebo-controlled trial . Setting Clinical research centre . Participants 27 normocalcaemic patients with sarcoidosis and 25-hydroxyvitamin D ( 25OHD ) < 50 nmol/L. Intervention 50 000 IU weekly cholecalciferol for 4 weeks , then 50 000 IU monthly for 11 months or placebo . Primary and secondary outcome measures The primary endpoint was the change in serum calcium over 12 months , and secondary endpoints included measurements of calcitropic hormones , bone turnover markers and bone mineral density ( BMD ) . Results The mean age of participants was 57 years and 70 % were women . The mean ( SD ) screening 25OHD was 35 ( 12 ) and 38 ( 9 ) nmol/L in the treatment and control groups , respectively . Vitamin D supplementation increased 25OHD to 94 nmol/L after 4 weeks , 84 nmol/L at 6 months and 78 nmol/L at 12 months , while levels remained stable in the control group . 1,25-Dihydroxy vitamin D levels were significantly different between the groups at 4 weeks , but not at 6 or 12 months . There were no between-groups differences in albumin-adjusted serum calcium , 24 h urine calcium , markers of bone turnover , parathyroid hormone or BMD over the trial . One participant developed significant hypercalcaemia after 6 weeks ( total cholecalciferol dose 250 000 IU ) . Conclusions In patients with sarcoidosis and 25OHD < 50 nmol/L  , vitamin D supplements did not alter average serum calcium or urine calcium , but had no benefit on surrogate markers of skeletal health and caused one case of significant hypercalcaemia . Trial registration This trial is registered at the Australian New Zeal and Clinical Trials Registry ( http://www.anzctr.org.au ) . The registration number is ACTRN12607000364471 , date of registration 5/7/2007 CONTEXT Vitamin K has been implicated in bone health , primarily in observational studies . However , little is known about the role of phylloquinone supplementation on prevention of bone loss in men and women . OBJECTIVE The objective of this study was to determine the effect of 3-yr phylloquinone supplementation on change in bone mineral density ( BMD ) of the femoral neck bone in older men and women who were calcium and vitamin D replete . DESIGN , PARTICIPANTS , AND INTERVENTION In this 3-yr , double-blind , controlled trial , 452 men and women ( 60 - 80 yr ) were r and omized equally to receive a multivitamin that contained either 500 mug/d or no phylloquinone plus a daily calcium ( 600 mg elemental calcium ) and vitamin D ( 400 IU ) supplement . MAIN OUTCOME MEASURES Measurements of the femoral neck , spine ( L2-L4 ) , and total-body BMD , bone turnover , and vitamins K and D status were measured every 6 - 12 months . Intent-to-treat analysis was used to compare change in measures in 401 participants who completed the trial . RESULTS There were no differences in changes in BMD measurements at any of the anatomical sites measured between the two groups . The group that received the phylloquinone supplement had significantly higher phylloquinone and significantly lower percent undercarboxylated osteocalcin concentrations compared with the group that did not receive phylloquinone . No other biochemical measures differed between the two groups . CONCLUSIONS Phylloquinone supplementation in a dose attainable in the diet does not confer any additional benefit for bone health at the spine or hip when taken with recommended amounts of calcium and vitamin CONTEXT Mono- and polyunsaturated fats may have opposing effects on vitamin D absorption . OBJECTIVE The purpose of this study was to determine whether intakes of different dietary fats are associated with the increase in serum 25-hydroxyvitamin D ( 25OHD ) after supplementation with vitamin D(3 ) . DESIGN , SETTING , AND PARTICIPANTS This analysis was conducted in the active treatment arm of a r and omized , double-blind , placebo-controlled trial of vitamin D and calcium supplementation to prevent bone loss and fracture . Subjects included 152 healthy men and women age 65 and older who were assigned to 700 IU/d vitamin D(3 ) and 500 mg/d calcium .  Intakes of monounsaturated fatty acids ( MUFA ) , polyunsaturated fatty acids ( PUFA ) , and saturated fatty acids ( SFA ) were estimated by food frequency question naire . MAIN OUTCOME MEASURE The change in plasma 25OHD during 2 yr  vitamin D and calcium supplementation was assessed . RESULTS The change in plasma 25OHD ( nanograms per milliliter ) during vitamin D supplementation was positively associated with MUFA , ( β = 0.94 ; P = 0.016 ) , negatively associated with PUFA , ( β = -0.93 ; P = 0.038 ) , and positively associated with the MUFA/PUFA ratio ( β = 6.46 ; P = 0.014 ) . CONCLUSION The fat composition of the diet may influence the 25OHD response to supplemental vitamin D(3 ) . Diets rich in MUFA may improve and those rich in PUFA may reduce the effectiveness of vitamin D(3 ) supplements in healthy older adults . More studies are needed to confirm these findings CONTEXT Exercise and calcium-vitamin D are independently recognized as important strategies to prevent osteoporosis , but their combined effects on bone strength and its determinants remain uncertain . OBJECTIVE To assess whether calcium-vitamin D(3 ) fortified milk could enhance the effects of exercise on bone strength , structure , and mineral density in middle-aged and older men . DESIGN , SETTING , PARTICIPANTS An 18-month factorial design r and omized controlled trial in which 180 men aged 50 - 79 years were r and omized to the following : exercise + fortified milk ; exercise ; fortified milk ; or controls . Exercise consisted of progressive resistance training with weight-bearing impact activities performed 3 d/week . Men assigned to fortified milk consumed 400 ml/d of 1 % fat milk containing 1000 mg/d calcium and 800 IU/d vitamin D(3 ) . MAIN OUTCOME MEASURES Changes in bone mineral density ( BMD ) , bone structure , and strength at the lumbar spine ( LS ) , proximal femur , mid-femur , and mid-tibia measured by dual energy x-ray absorptiometry and /or quantitative computed tomography . RESULTS There were no exercise-by-fortified milk interactions at any skeletal site . Main effect analysis showed that exercise led to a 2.1 % ( 95 % confidence interval , 0.5 - 3.6 ) net gain in femoral neck section modulus , which was associated with an approximately 1.9 % gain in areal BMD and cross-sectional area .  Exercise also improved LS trabecular BMD [ net gain 2.2 % ( 95 % confidence interval , 0.2 - 4.1 ) ] , but had no effect on mid-femur or mid-tibia BMD , structure , or strength . There were no main effects of the fortified milk at any skeletal site . CONCLUSION A community-based multi-component exercise program successfully improved LS and femoral neck BMD and strength in healthy older men , but providing additional calcium-vitamin D(3 ) to these replete men did not enhance the osteogenic response Introduction Vitamin D has potential benefits for extraskeletal health . These could include an anti-inflammatory effect as well as a reduction in endothelial dysfunction . We aim to provide quality evidence for the hypothesis that supplementation with vitamin D will improve endothelial function ( EF ) , possibly through the abrogation of systemic inflammation . Methods and analysis We will conduct a systematic review of all r and omised controlled trials on  vitamin D supplementation and EF lasting 12 weeks or more . The search will cover the period 2000–2015 and include studies that describe direct measures of EF  , markers of endothelial cell ( EC ) activation  and if concurrently reported , indicators of systemic inflammation  . Study selection will follow the Preferred Reporting Items for Systematic Review s and Meta-Analyses ( PRISMA ) guidelines and study quality will be assessed by the Jadad score in addition to an evaluation of allocation concealment and data analysis . If sufficient data are available , a meta- analysis will be conducted . The effect sizes will be generated using Hedges ’ g score , for both fixed and r and om effect models . I2 statistics and Galbraith plots will be used to assess heterogeneity and identify their potential sources . Potential publication and small sample size bias will be assessed by visual inspections of funnel plots and also Egger 's test . Meta-regression analysis ( if feasible ) will be conducted with restricted maximum likelihood ( REML ) estimation method , controlling for potential confounders ( demographics , study methods , location , etc ) . A backward elimination process will be applied in the regression modelling procedure . Subgroup analysis , conditional on number of studies retrieved and their sample size , will be stratified on participant disease category , total dose administered , degree of 25(OH)D change and type of supplement used . Ethics and dissemination Formal ethical approval is not required as primary data will not be collected . The results will be disseminated through a peer- review ed publication , conference presentation and the popular press . Trial registration number International Prospect i ve Register for Systematic Review s ( PROSPERO ) number CRD42014013523 In vivo and in vitro studies have suggested a protective role of calcium and vitamin D in the development of colorectal cancer . However , epidemiologic data have been inconclusive . The authors prospect ively assessed intakes of calcium and vitamin D in relation to risk of colorectal cancer in a large , prospect i ve , female cohort from the US Women 's Health Study . In 1993 , 39,876 women aged > or = 45 years and free of cardiovascular disease and cancer were enrolled in the study . During an average follow-up of 10 years , 223 of 36,976 women eligible for the present study developed colorectal cancer . Intakes of calcium and vitamin D from dietary sources and supplements were assessed with a baseline food frequency question naire . Cox proportional hazards regression was used to estimate relative risks and 95 % confidence intervals . Intakes of total calcium and vitamin D  were not associated with risk of colorectal cancer ; multivariate relative risks comparing the highest with the lowest quintile were 1.20 ( 95 % confidence interval : 0.79 , 1.85 ; p for trend = 0.21 ) for total calcium and 1.34 ( 95 % confidence interval : 0.84 , 2.13 ; p for trend = 0.08 ) for total vitamin D. Intakes of both nutrients from specific types of sources , including diet and supplements , were also not significantly associated with colorectal cancer risk . Data provide little support for an association of calcium and vitamin D intake with colorectal cancer risk The National Institutes of Health 's consensus conference ( 1 ) defined osteoporosis as a skeletal disorder characterized by compromised bone strength predisposing to an increased risk for fracture . Bone strength reflects the integration of two main features : bone density and bone quality .Bone quality refers to architecture , turnover , damage accumulation ( e.g. , microfractures ) , and mineralization . Although osteoporosis can affect any bone , the hip , spine , and wrist are most likely to be affected . Osteoporosis affects an estimated 44 million Americans or 55 % of people 50 years of age or older . Another 34 million Americans are estimated to have low bone mass , meaning that they are at an increased risk for osteoporosis . Osteoporosis can be diagnosed by the occurrence of fragility fracture . In patients without fragility fracture , osteoporosis is often diagnosed by low bone density .  Dual x-ray absorptiometry ( DXA ) is the current gold st and ard test for diagnosing osteoporosis in people without an osteoporotic fracture .  Dual x-ray absorptiometry results are scored as st and ard deviations ( SDs ) from a young healthy norm ( usually female ) and reported as T-scores . For example , a T-score of 2 indicates a bone mineral density that is 2 SDs below the comparative norm . The international reference st and ard for the description of osteoporosis in postmenopausal women and in men age 50 years or older is a femoral neck bone mineral density of 2.5 SD or more below the young female adult mean ( 2 ) . Low bone density , as measured by DXA , is an imperfect predictor of fracture risk , identifying fewer than half the people who go on to have an osteoporotic fracture . Screening guidelines for women are well established ( 3 ) , and the American College of Physicians ( ACP ) recently published guidelines on screening for men ( 4 ) . This guideline presents the available evidence on various pharmacologic treatments to prevent fractures in men and women with low bone density or osteoporosis . Medications used to treat osteoporosis may affect different parts of the skeletal system differently , and efficacy for vertebral fractures does not necessarily imply efficacy for nonvertebral fractures . The target audience for this guideline is all clinicians and the target patient population is all adult men and women with low bone density or osteoporosis . These recommendations are based on the systematic evidence review by MacLean and colleagues ( 5 ) and the Agency for Healthcare Research and Quality sponsored Southern California Evidence -Based Practice Center evidence report ( 6 ) . The drugs currently approved for prevention of osteoporosis include alendronate , ib and ronate , risedronate , zoledronic acid , estrogen , and raloxifene . The drugs currently approved for treatment of osteoporosis include alendronate , ib and ronate , risedronate , calcitonin , teriparatide , zoledronic acid ( in postmenopausal women ) , and raloxifene . Testosterone , pamidronate , and etidronate are not approved by the U.S. Food and Drug Administration for the treatment or prevention of osteoporosis . Methods The literature search done by MacLean and colleagues for the systematic review ( 5 ) included studies from MEDLINE ( 1966 to December 2006 ) , the ACP Journal Club data base , the Cochrane Central Register of Controlled Trials ( no date limits ) , the Cochrane Data base of Systematic Review s ( no date limits ) , Web sites of the United Kingdom National Institute of Health and Clinical Excellence ( no date limits ) , and the United Kingdom Health Technology Assessment Program ( January 1998 to December 2006 ) . The review ers limited their search to English- language publications and human studies . They derived evidence for comparative benefits of various treatments exclusively from r and omized , controlled trials , whereas they included evidence from other types of studies for short- and long-term harms . Two physicians independently abstract ed data about study population s , interventions , follow-up , and outcome ascertainment by using a structured form . For each group within a r and omized trial , a statistician extracted the sample size and number of persons reporting fractures . Two review ers , under the supervision of the statistician , independently abstract ed information about adverse events . The statistician or the principal investigator resolved disagreements . This guideline is based on an evaluation of 76 r and omized , controlled trials , 4 of which were identified in the up date d search , and 24 meta-analyses that were included in the efficacy analyses . The analyses of adverse events included 491 articles , representing 417 r and omized trials , 25 other controlled clinical trials , 11 open-label trials , 31 large observational studies , and 9 case reports of osteonecrosis among bisphosphonate users . MacLean and colleagues ' background article ( 5 ) includes details about the methods used for the systematic evidence review . The ACP rates the evidence and recommendations by using the Grading of Recommendations , Assessment , Development , and Evaluation ( GRADE ) system with minor modifications ( Table 1 ) . In addition , the evidence review ers used predefined criteria to assess the quality of systematic review s and r and omized trials , based on internal and external validity assessment s detailed in the Quality of Reporting of Meta-Analyses ( QUOROM ) statement ( 7 ) . Table 1 . The American College of Physicians ' Guideline Grading System The objective of this guideline is to synthesize the evidence for the following questions : What are the comparative benefits in fracture reduction among and also within the following treatments for low bone density :  bisphosphonates , specifically alendronate , risedronate , etidronate , ib and ronate , pamidronate , and zoledronic acid ; calcitonin ; estrogen for women ; teriparatide ; selective estrogen receptor modulators ( SERMs ) , specifically raloxifene and tamoxifen ; testosterone for men ; vitamins and minerals , specifically vitamin D and calcium ; and the combination of calcium plus vitamin D ? How does fracture reduction result ing from treatments vary among individuals with different risks for fracture as determined by bone mineral density ( borderline , low , or severe ) , previous fractures ( prevention vs. treatment ) , age , sex , glucocorticoid use , and other factors ( such as community-dwelling vs. institutionalized or vitamin Ddeficient vs. not ) ? What are the short- and long-term harms ( adverse effects ) of these therapies , and do these vary by specific sub population s ? Comparative Benefits of Drugs versus Placebo in Fracture Reduction Evidence from 24 meta-analyses ( 830 ) and 35 additional r and omized trials published after the meta-analyses ( 3165 ) described the effect of 9 of the 14 agents ( alendronate , etidronate , risedronate , calcitonin , estrogen , teriparatide , raloxifene , calcium , and vitamin D ) on fracture incidence . For 4 agents ( ib and ronate , pamidronate , zoledronic acid , and tamoxifen ) , the review ers found no meta-analyses and instead gathered the evidence from 14 r and omized trials ( 6679 ) . No studies were found that reported fracture rates for testosterone . Three r and omized trials ( 35 , 80 , 81 ) and 1 meta- analysis ( 82 ) evaluated the combination of calcium plus vitamin D  on fractures .  Bisphosphonates Good- quality evidence showed that alendronate , etidronate , ib and ronate , and risedronate prevent vertebral fractures . In addition , evidence from good- quality studies demonstrated that both alendronate and risedronate prevent nonvertebral and hip fractures . Two large r and omized trials showed that zoledronic acid prevents vertebral and nonvertebral fractures in high-risk population s and reduces the risk for hip fracture ( 67 , 74 ) . Ib and ronate has not been shown to reduce nonvertebral fractures ( 68 ) . Of the 6 fairly small trials that looked at vertebral fractures , 1 demonstrated a statistically significant reduction in fractures with pamidronate relative to placebo ( 0.14 [ 95 % CI , 0.03 to 0.72 ] ) ( 73 ) . However , after these data were pooled , the pooled risk estimate for fractures for pamidronate relative to placebo was not significant ( 0.52 [ CI , 0.21 to 1.24 ] ) ( 6 ) . Calcitonin Fair- quality evidence shows that calcitonin reduces vertebral fractures ( 83 , 84 ) . Good- quality evidence indicates that calcitonin does not reduce nonvertebral fractures ( 13 , 16 ) . Estrogen Good- quality evidence shows that estrogen reduces the incidence of vertebral ( 29 , 85 ) , nonvertebral ( 86 ) , and hip fractures ( 85 ) . Teriparatide Good- quality evidence shows that teriparatide prevents vertebral fractures . The evidence related to teriparatide preventing nonvertebral fractures is mixed ; 1 large r and omized trial showed a reduction in nonvertebral fractures ( 34 ) but 2 small trials did not ( 87 , 88 ) . SERMs Good- quality evidence shows that raloxifene prevents vertebral fractures , but that tamoxifen has no effect on vertebral fractures ( 8991 ) . In addition , both raloxifene and tamoxifen had no effect on hip fractures ( 91 ) . Tamoxifen is not approved by the U.S. Food and Drug Administration for the treatment or prevention of osteoporosis . Testosterone No studies reported fracture rates for testosterone . Calcium and Vitamin D In the studies evaluated by MacLean and colleagues ( 5 ) , the evidence for the effect of calcium alone on reduction of fractures is complex . Most studies of pharmacologic agents for osteoporosis include calcium and vitamin D as part of the treatment regimen . Evidence from 1 meta- analysis ( 27 ) and several r and omized trials ( 35 , 48 , 51 , 92 ) showed no significant difference between calcium and placebo in preventing vertebral , nonvertebral , and hip fractures in postmenopausal women . However , nonadherence to therapy may influence this result , and 1 trial with a prespecified analysis of adherent patients found a reduction in fracture risk ( 48 ) . A recent meta- analysis ( 82 ) concluded that the relative risk ( RR ) for fracture with calcium alone was 0.90 ( CI , 0.80 to 1.00 ) , but it did not include a modestly large trial with negative results ( 35 ) . MacLean and colleagues ( 5 ) BACKGROUND Frequent use of personal , non protocol calcium supplements obscured an adverse effect of coadministered calcium and vitamin D ( CaD ) on cardiovascular risk in the Women 's Health Initiative ( WHI ) . OBJECTIVE We investigated the effects of the use of personal calcium or vitamin D supplements on other outcomes in the WHI CaD Study ( WHI CaD ) by using the WHI limited-access clinical trials data set . DESIGN The WHI CaD was a 7-y , r and omized , placebo-controlled trial of CaD ( 1 g Ca/400 IU vitamin D daily ) in 36,282 community-dwelling , postmenopausal women . The incidence of total cancer ( excluding nonmelanoma skin cancers ) , breast and colorectal cancers , hip and total fracture , and mortality was assessed by using Cox proportional hazards models . RESULTS In the WHI CaD , interactions between the use of either personal calcium or vitamin D supplements and CaD were found for total , breast , and colorectal cancers but not for fracture or mortality .  In 15,646 women ( 43 % ) who were not taking personal calcium or vitamin D supplements at r and omization , CaD significantly decreased the risk of total , breast , and invasive breast cancers by 14 - 20 % and nonsignificantly reduced the risk of colorectal cancer by 17 % . In women taking personal calcium or vitamin D supplements , CaD did not alter cancer risk ( HR : 1.06 - 1.26 ) . CONCLUSIONS For women in the WHI CaD who were not taking personal calcium or vitamin D supplements at r and omization , CaD decreased the risk of total , breast , and colorectal cancers and did not change the risk of fractures or total mortality . The nonskeletal effects of CaD may be more important than the skeletal effects and should be considered when evaluating these supplements . The WHI CaD trial is registered at clinical trials.gov as NCT00000611 CONTEXT To the best of our knowledge , no study has examined the effects of vitamin D-calcium cosupplementation on inflammatory biomarkers and adipocytokines in vitamin D-insufficient type 2 diabetics . OBJECTIVE This study was performed to assess the effects of vitamin D and calcium supplementation on inflammatory biomarkers and adipocytokines in vitamin D-insufficient people with type 2 diabetes . METHODS Totally , 118 diabetic patients were enrolled in this r and omized , placebo-controlled clinical trial . After matching for age , sex , body mass index , type and dose of hypoglycemic agents , and duration of diabetes , subjects were r and omly assigned into 4 groups receiving the following : 1 ) 50000 IU/wk vitamin D + calcium placebo ; 2 ) 1000 mg/d calcium + vitamin D placebo ; 3 ) 50 000 IU/wk vitamin D + 1000 mg/d calcium ; or 4 ) vitamin D placebo + calcium placebo for 8 weeks . Blood sampling was done for the quantification of inflammatory biomarkers and adipocytokines at the study baseline and after 8 weeks of intervention . RESULTS Calcium ( changes from baseline : -75 ± 19 ng/ml , P = .01 ) and vitamin D alone ( -56 ± 19 ng/mL , P = .01 ) and joint calcium-vitamin D supplementation ( -92 ± 19 ng/mL , P = .01 ) result ed in a significant reduction in serum leptin levels compared with placebo ( -9 ± 18 ng/mL ) . This was also the case for serum IL-6 , such that calcium ( -2 ± 1 pg/mL , P < .001 ) and vitamin D alone ( -4 ± 1 pg/mL , P < .001 ) and their combination ( -4 ± 1 pg/mL , P < .001 ) led to significant reductions compared with placebo ( 3 ± 1 pg/mL ) . After adjustment for potential confounders , individuals in the calcium ( -3.1 ± 1.3 , P < .05 ) , vitamin D ( -3.1 ± 1.3 , P < .05 ) , and joint calcium-vitamin D groups ( -3.4 ± 1.3 , P < .05 ) had greater reductions in serum TNF-α concentrations compared with placebo ( 0.1 ± 1.2 ) . Individuals who received joint calcium-vitamin D supplements tended to have a decrease in serum high-sensitivity C-reactive protein levels compared with placebo after controlling for baseline levels ( -1.14 ± 0.25 vs 0.02 ± 0.24 ng/mL , P = .09 ) . CONCLUSION Joint calcium-vitamin D supplementation might improve systemic inflammation through decreasing IL-6 and TNF-α concentrations in vitamin D-insufficient people with type 2 diabetes OBJECTIVES The Women 's Health Initiative ( WHI ) r and omized trial of calcium/vitamin D supplementation found reduced bone loss with active treatment compared to placebo . Now we examine whether the treatment affected self-reported physical functioning and objective measures of physical functioning . DESIGN A r and omized , double-blind , placebo-controlled trial of 1,000 mg calcium carbonate plus 400 IU vitamin D(3 ) per day or matching placebo pills . SUBJECTS/ SETTING The study included 33,067 women ( 50 to 79 years old ) at 40 US study centers . MAIN OUTCOME MEASURES Physical functioning was assessed by question naire at enrollment in WHI , 1 year prior to calcium/vitamin D trial r and omization and at study close-out ( average follow-up 7.1 years ) . Objective physical performance and self-reported exercise measures were collected at WHI baseline ( 1 year prior to calcium/vitamin D enrollment ) and 2 years and 4 years after calcium/vitamin D trial enrollment in a sub sample ( n=3,137 ) . STATISTICAL ANALYSES PERFORMED Calcium/vitamin D effects were tested in unadjusted and interaction linear models for each of the physical function measures . Covariates were baseline total calcium intake , fracture risk score , treatment arm in the hormone therapy and dietary modification trials ( ie , active drug or placebo , low-fat diet intervention or usual diet , respectively ) and age . RESULTS Neither intention to treat nor high adherence analyses produced substantial effects of calcium/vitamin D  compared to placebo on physical functioning or performance . The interaction analyses also did not result in differences because of calcium/vitamin D. CONCLUSIONS As the first long-term r and omized trial to examine the effectiveness of calcium and vitamin D in protecting against decline of physical functioning in older women , the results did not support benefit Background : Calcium and vitamin D may be inversely related to breast cancer risk , in part by affecting mammographic density . However , results from previous , mostly cross-sectional studies have been mixed , and there have been few r and omized clinical trials of the effect of calcium and vitamin D supplementation on change in mammographic density . Methods : We assessed the effect of one year of supplementation on mammographic density in 330 postmenopausal women enrolled in the Women 's Health Initiative hormone therapy ( HT ) and calcium and vitamin D ( CaD ) trials . Women were r and omized to receive 1,000 mg/d of elemental calcium carbonate plus 400 IU/d of vitamin D3 or placebo . Results : After approximately one year , mammographic density decreased 2 % in the CaD supplementation group and increased 1 % in the placebo group ( ratio of means = 0.97 ; 95 % CI = 0.81–1.17 ) . Results suggested potential interaction by HT use ( P = 0.08 ) . Among women r and omized to HT placebo , the ratio of mean density comparing CaD supplementation and placebo groups was 0.82 ( 95 % CI = 0.61–1.11 ) vs. 1.16 ( 95 % CI = 0.92–1.45 ) in women r and omized to active HT . In sensitivity analyses limited to women taking ≥80 % of study supplements , ratios were 0.67 ( 95 % CI = 0.41–1.07 ) in women not assigned to HT and 1.07 ( 95 % CI = 0.79–1.47 ) women assigned to HT . Conclusions : We observed no overall effect of vitamin D and calcium supplementation  on mammographic density after one year . Impact : Potential interaction between these nutrients and estrogen as related to mammographic density warrants further study . Cancer Epidemiol Biomarkers Prev ; 21(3 ) ; 462–73 . © 2012 AACR
CONCLUSIONS Supplementation with vitamin D showed no effect on adiposity measures in adults
CONTEXT The independent or interactive effects of vitamin D and calcium on adiposity remain inconclusive .
OBJECTIVE The objective of this systematic review and meta- analysis was to assess whether vitamin D and calcium supplements cause changes in adiposity .