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Effect of vitamin D, calcium and multiple micronutrient supplementation on vitamin D and bone status in Bangladeshi premenopausal garment factory workers with hypovitaminosis D: a double-blinded, randomised, placebo-controlled 1-year intervention. Pretreatment Serum Concentrations of 25-Hydroxyvitamin D and Breast Cancer Prognostic Characteristics: A Case-Control and a Case-Series Study Calcium Absorption Varies within the Reference Range for Serum 25-Hydroxyvitamin D The 2011 Report on Dietary Reference Intakes for Calcium and Vitamin D from the Institute of Medicine: What Clinicians Need to Know High-dose oral vitamin D3 supplementation in the elderly Optimal vitamin D status: a critical analysis on the basis of evidence-based medicine. 25-Hydoxyvitamin D levels among healthy Saudi Arabian women. A randomized study on the effect of vitamin D₃ supplementation on skeletal muscle morphology and vitamin D receptor concentration in older women. The Efficacy of Vitamin D Supplementation During a Prolonged Submarine Patrol Pharmacologic Treatment of Low Bone Density or Osteoporosis to Prevent Fractures: A Clinical Practice Guideline from the American College of Physicians How to write an evidence-based clinical review article. Vitamin D3 supplementation using an oral spray solution resolves deficiency but has no effect on VO2 max in Gaelic footballers: results from a randomised, double-blind, placebo-controlled trial Vitamin D intervention in preschoolers with viral-induced asthma (DIVA): a pilot randomised controlled trial The Effects of Vitamin D Supplementation on Physical Function and Quality of Life in Older Patients With Heart Failure: A Randomized Controlled Trial Effects of vitamin D supplementation on strength, physical function, and health perception in older, community-dwelling men. Serum 25-hydroxyvitamin D levels in vitamin D-insufficient hip fracture patients after supplementation with ergocalciferol and cholecalciferol. Vitamin D supplementation improves neuromuscular function in older people who fall. Milk fortified with the current adequate intake for vitamin D (5 microg) increases serum 25-hydroxyvitamin D compared to control milk but is not sufficient to prevent a seasonal decline in young women. Large Doses of Vitamin D Fail to Increase 25-Hydroxyvitamin D Levels or to Alter Cardiovascular Risk Factors in Obese Adolescents: A Pilot Study. How Quickly Do Systematic Reviews Go Out of Date? A Survival Analysis Randomized controlled trials of aprotinin in cardiac surgery: could clinical equipoise have stopped the bleeding? Skeletal Effects of Vitamin D Supplementation in Postmenopausal Black Women Concordance of randomized and nonrandomized studies was unrelated to translational patterns of two nutrient-disease associations. 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Vitamin D Supplementation and Hemoglobin Levels in Hypertensive Patients: A Randomized Controlled Trial Effect of free vitamin D2 drops on serum 25-hydroxyvitamin D in infants with immigrant origin: a cluster randomized controlled 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 Single photon emission computed tomography for the diagnosis of coronary artery disease: an evidence-based analysis. The impact of outcome reporting bias in randomised controlled trials on a cohort of systematic reviews Sources of evidence for systematic reviews of interventions in diabetes. 25-hydroxyvitamin D, 1,25-dihydroxyvitamin D and postoperative outcome in cardiac surgery. A systematic review protocol examining the effect of vitamin D supplementation on endothelial function Alveolar bone changes after rapid maxillary expansion with tooth-born appliances: a systematic review Effect of pregnancy on gingival inflammation in systemically healthy women: a systematic review. Chronic kidney disease, hypovitaminosis D, and mortality in the United States. High-dose vitamin d intervention in infants--effects on vitamin d status, calcium homeostasis, and bone strength. Reduced Prediagnostic 25-Hydroxyvitamin D Levels in Women with Breast Cancer: A Nested Case-Control Study Role of Vitamin D in Insulin Secretion and Insulin Sensitivity for Glucose Homeostasis Type of dietary fat is associated with the 25-hydroxyvitamin D3 increment in response to vitamin D supplementation. Maternal plasma 25-hydroxyvitamin D concentration and birthweight, growth and bone mineral accretion of Gambian infants A global study of vitamin D status and parathyroid function in postmenopausal women with osteoporosis: baseline data from the multiple outcomes of raloxifene evaluation clinical trial. Low-Dose Vitamin D Prevents Muscular Atrophy and Reduces Falls and Hip Fractures in Women after Stroke: A Randomized Controlled Trial Circulating 25OHD, dietary vitamin D, PTH, and calcium associations with incident cardiovascular disease and mortality: the MIDSPAN Family Study. EFFECT OF HIGH-DOSE VITAMIN D REPLETION ON GLYCEMIC CONTROL IN AFRICAN-AMERICAN MALES WITH PREDIABETES AND HYPOVITAMINOSIS D. Maternal vitamin D in pregnancy may influence not only offspring bone mass but other aspects of musculoskeletal health and adiposity. 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Introduction Optimal vitamin D status promotes skeletal health and is recommended with specific treatment in individuals at high risk for fragility fractures . A growing body of literature has provided indirect and some direct evidence for possible extraskeletal vitamin D-related effects . Purpose and Methods Members of the European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis have review ed the main evidence for possible proven benefits of vitamin D supplementation in adults at risk of or with overt chronic extra-skeletal diseases , providing recommendations and guidelines for future studies in this field . Results and conclusions Robust mechanistic evidence is available from in vitro studies and in vivo animal studies , usually employing cholecalciferol , calcidiol or calcitriol in pharmacologic rather than physiologic doses . Although many cross-sectional and prospect i ve association studies in humans have shown that low 25-hydroxyvitamin D levels ( i.e. , < 50 nmol/L ) are consistently associated with chronic diseases , further strengthened by a dose-response relationship , several meta-analyses of clinical trials have shown contradictory results . Overall , large r and omized controlled trials with sufficient doses of vitamin D are missing , and available small to moderate-size trials often included people with baseline levels of serum 25-hydroxyvitamin D levels  > 50 nmol/L , did not simultaneously assess multiple outcomes , and did not report overall safety ( e.g. , falls ) . Thus , no recommendations can be made to date for the use of vitamin D supplementation in general , parental compounds , or non-hypercalcemic vitamin D analogs in the prevention and treatment of extra-skeletal chronic diseases . Moreover , attainment of serum 25-hydroxyvitamin D levels well above the threshold desired for bone health can not be recommended based on current evidence , since safety has yet to be confirmed . Finally , the promising findings from mechanistic studies , large cohort studies , and small clinical trials obtained for autoimmune diseases ( including type 1 diabetes , multiple sclerosis , and systemic lupus erythematosus ) , cardiovascular disorders , and overall reduction in mortality require further confirmation 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 The Institute of Medicine Committee to Review Dietary Reference Intakes for Calcium and Vitamin D comprehensively review ed the evidence for both skeletal and nonskeletal health outcomes and concluded that a causal role of calcium and vitamin D in skeletal health provided the necessary basis for the 2011 Estimated Average Requirement ( EAR ) and Recommended Dietary Allowance ( RDA ) for ages older than 1 year . For nonskeletal outcomes , including cancer , cardiovascular disease , diabetes , infections , and autoimmune disorders , r and omized clinical trials were sparse , and evidence was inconsistent , inconclusive as to causality , and insufficient for Dietary Reference Intake ( DRI ) development . The EAR and RDA for calcium range from 500 to 1,100 and 700 to 1,300 mg daily , respectively , for ages 1 year and older . For vitamin D ( assuming minimal sun exposure ) , the EAR is 400 IU/day for ages older than 1 year and the RDA is 600 IU/day for ages 1 to 70 years and 800 IU/day for 71 years and older , corresponding to serum 25-hydroxyvitamin D ( 25OHD ) levels of 16 ng/mL ( 40 nmol/L ) for EARs and 20 ng/mL ( 50 nmol/L ) or more for RDAs . Prevalence of vitamin D inadequacy in North America has been overestimated based on serum 25OHD levels corresponding to the EAR and RDA . Higher serum 25OHD levels were not consistently associated with greater benefit , and for some outcomes U-shaped associations with risks at both low and high levels were observed . The Tolerable Upper Intake Level for calcium ranges from 1,000 to 3,000 mg daily , based on calcium excretion or kidney stone formation , and from 1,000 to 4,000 IU daily for vitamin D , based on hypercalcemia adjusted for uncertainty result ing from emerging risk relationships . Urgently needed are evidence -based guidelines to interpret serum 25OHD levels relative to vitamin D status and intervention 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 Introduction Maternal vitamin D status in pregnancy has been linked to many health outcomes in mother and offspring . A wealth of observational studies have reported on both obstetric outcomes and complications , including pre-eclampsia , gestational diabetes , mode and timing of delivery . Many foetal and childhood outcomes are also linked to vitamin D status , including measures of foetal size , body composition and skeletal mineralization , in addition to later childhood outcomes , such as asthma . Sources of data Synthesis of systematic and narrative review s. Areas of agreement and controversy The findings are generally inconsistent in most areas , and , at present , there is a lack of data from high- quality intervention studies to confirm a causal role for vitamin D in these outcomes . In most areas , the evidence tends towards maternal vitamin D being of overall benefit , but often does not reach statistical significance in meta-analyses . Growing points and areas timely for developing research The most conclusive evidence is in the role of maternal vitamin D supplementation in the prevention of neonatal hypocalcaemia ; as a consequence the UK department of health recommends that pregnant women take 400 IU vitamin D daily . High- quality r and omized placebo-controlled trials , such as the UK-based MAVIDOS trial , will inform the potential efficacy and safety of vitamin D supplementation in pregnancy across a variety of outcomes INTRODUCTION Ovarian cancer is the leading cause of death among gynecological malignancies . Its usual clinical manifestation is at advanced stages , with nutritional impairment , weight loss , and a consequent decline in skeletal muscle mass and strength ( defined as sarcopenia ) . The relationship between sarcopenia and decreased survival was demonstrated not only in ovarian cancer but also in other cancer types , such as hepatocellular , pancreatic , lung , colon , cervical , metastatic breast , and renal cancer . The aim of this study is to review the current evidence regarding the relationship between sarcopenia and the surgical and oncological outcomes in ovarian cancer patients . METHODS The systematic search was performed according to the Preferred Reporting Items for Systematic Review s and Meta-Analyses ( PRSIMA ) statement . The terms " SARCOPENIA " AND " OVARIAN CANCER " were systematic ally used to search PubMed and Scopus data bases . Original reports in English language were identified , with the purpose to include all relevant papers regarding the role of sarcopenia and indicators of skeletal muscle quality assessment in gynecological ovarian cancer . RESULTS A total of 9 studies were considered eligible for the present review . The strength of recommendation was moderate and the level of evidence was low in all selected articles . No prospect i ve studies were conducted and most of the papers were case-control series comparing ovarian cancer sarcopenic population vs. non sarcopenic population . CONCLUSIONS Sarcopenia appears to have an important role in oncological outcomes of ovarian cancer patients . However , sarcopenia occurrence during disease history and mechanisms underlying the possible impairment in prognosis should be better investigated . Prospect i ve trials are awaited in order to obtain a better insight in this topic OBJECTIVE Suboptimal mitochondrial function has been implicated in several disorders in which fatigue is a prominent feature . Vitamin D deficiency is a well-recognized cause of fatigue and myopathy . The aim of this study was to examine the effects of cholecalciferol therapy on skeletal mitochondrial oxidative function in symptomatic , vitamin D-deficient individuals . DESIGN This longitudinal study assessed mitochondrial oxidative phosphorylation in the gastrosoleus compartment using phosphorus-31 magnetic resonance spectroscopy measurements of phosphocreatine recovery kinetics in 12 symptomatic , severely vitamin D-deficient subjects before and after treatment with cholecalciferol .  All subjects had serum assays before and after cholecalciferol therapy to document serum 25-hydroxyvitamin D ( 25OHD ) and bone profiles . Fifteen healthy controls also underwent (31)P-magnetic resonance spectroscopy and serum 25OHD assessment . RESULTS The phosphocreatine recovery half-time ( τ1/2PCr ) was significantly reduced after cholecalciferol therapy in the subjects indicating an improvement in maximal oxidative phosphorylation ( 34.44 ± 8.18 sec to 27.84 ± 9.54 sec , P < .001 ) . This was associated with an improvement in mean serum 25OHD levels ( 8.8 ± 4.2 nmol/L to 113.8 ± 51.5 nmol/L , P < .001 ) . There was no difference in phosphate metabolites at rest . A linear regression model showed that decreasing serum 25OHD levels was associated with increasing τ1/2PCr ( r = -0.41 , P = .009 ) . All patients reported an improvement in fatigue  after cholecalciferol therapy . CONCLUSIONS Cholecalciferol therapy augments muscle mitochondrial maximal oxidative phosphorylation after exercise in symptomatic , vitamin D-deficient individuals . This finding suggests that changes in mitochondrial oxidative phosphorylation in skeletal muscle could at least be partly responsible for the fatigue experienced by these patients . For the first time , we demonstrate a link between vitamin D and the mitochondria in human skeletal muscle Due to little outdoor activity and low dietary intake of vitamin D ( VD ) , Bangladeshi low-income women are at risk for osteoporosis at an early age . The present study assessed the effect of VD , Ca and multiple micronutrient supplementation on VD and bone status in Bangladeshi young female garment factory workers . This placebo-controlled 1-year intervention r and omly assigned 200 apparently healthy subjects ( aged 16 - 36 years ) to four groups : VD group , daily 10 microg VD ; VD and Ca ( VD-Ca ) group , daily 10 microg VD+600 mg Ca ; multiple micronutrient and Ca ( MMN-Ca ) group , 10 microg VD and other micronutrients+600 mg Ca ; a placebo group .  Serum 25-hydroxyvitamin D ( S-25OHD ) , intact parathyroid hormone ( S-iPTH ) , Ca , phosphate and alkaline phosphatase were measured . Bone mineral density and bone mineral content were measured by dual-energy X-ray absorptiometry . All measurements were made at baseline and at 12 months . Significantly ( P < 0.001 ) higher S-25OHD concentrations were observed in the supplemented groups than in the placebo group after the intervention . Supplementation had an effect ( P < 0.001 ) on S-iPTH in the VD-Ca and MMN-Ca groups compared with the placebo group . Bone mineral augmentation increased at the femur in the supplemented groups . Supplementation with VD-Ca should be recommended as a strategic option to reduce the risk of osteomalacia and osteoporosis in these subjects . MMN-Ca may have analogous positive health implication s with additional non-skeletal benefits 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 : Calcium absorption is generally considered to be impaired under conditions of vitamin D deficiency , but the vitamin D status that fully normalizes absorption is not known for humans . Objective : To quantify calcium absorption at two levels of vitamin D repletion , using pharmacokinetic methods and commercially marketed calcium supplements . Design : Two experiments performed in the spring of the year , one year apart . In the first , in which participants were pretreated with 25-hydroxyvitamin D ( 25OHD )  , mean serum 25OHD concentration was 86.5 nmol/L ; and in the other , with no pretreatment , mean serum concentration was 50.2 nmol/L. Participants received 500 mg oral calcium loads as a part of a st and ard low calcium breakfast . A low calcium lunch was provided at mid-day . Blood was obtained fasting and at frequent intervals for 10 to 12 hours thereafter . Methods : Relative calcium absorption at the two 25OHD concentrations was estimated from the area under the curve ( AUC ) for the load-induced increment in serum total calcium . Results : AUC9 ( ± SEM ) , was 3.63 mg hr/dL ± 0.234 in participants pretreated with 25OHD  and 2.20 ± 0.240 in those not pretreated ( P < 0.001 ) . In brief , absorption was 65 % higher at serum 25OHD levels averaging 86.5 nmol/L than at levels averaging 50 nmol/L ( both values within the nominal reference range for this analyte ) . Conclusions : Despite the fact that the mean serum 25OHD level in the experiment without supplementation was within the current reference ranges , calcium absorptive performance at 50 nmol/L was significantly reduced relative to that at a mean 25OHD level of 86 nmol/L. Thus , individuals with serum 25-hydroxyvitamin D levels at the low end of the current reference ranges may not be getting the full benefit from their calcium intake . We conclude that the lower end of the current reference range is set too low This article summarizes the new 2011 report on dietary requirements for calcium and vitamin D from the Institute of Medicine ( IOM ) . An IOM Committee charged with determining the population needs for these nutrients in North America conducted a comprehensive review of the evidence for both skeletal and extraskeletal outcomes . The Committee concluded that available scientific evidence supports a key role of calcium and vitamin D in skeletal health , consistent with a cause- and -effect relationship and providing a sound basis for determination of intake requirements . For extraskeletal outcomes , including cancer , cardiovascular disease , diabetes , and autoimmune disorders , the evidence was inconsistent , inconclusive as to causality , and insufficient to inform nutritional requirements . R and omized clinical trial evidence for extraskeletal outcomes was limited and generally uninformative . Based on bone health , Recommended Dietary Allowances ( RDAs ; covering requirements of ≥97.5 % of the population ) for calcium range from 700 to 1300 mg/d for life-stage groups at least 1 yr of age . For vitamin D , RDAs of 600 IU/d for ages 1–70 yr and 800 IU/d for ages 71 yr and older , corresponding to a serum 25-hydroxyvitamin D level of at least 20 ng/ml ( 50 nmol/liter ) , meet the requirements of at least 97.5 % of the population . RDAs for vitamin D were derived based on conditions of minimal sun exposure due to wide variability in vitamin D synthesis from ultraviolet light and the risks of skin cancer . Higher values were not consistently associated with greater benefit , and for some outcomes U-shaped associations were observed , with risks at both low and high levels . The Committee concluded that the prevalence of vitamin D inadequacy in North America has been overestimated . Urgent research and clinical priorities were identified , including re assessment of laboratory ranges for 25-hydroxyvitamin D , to avoid problems of both undertreatment and overtreatment Summary Daily dosing with vitamin D often fails to achieve optimal outcomes , and it is uncertain what the target level of 25-hydroxyvitamin D should be . This study found that large loading doses of vitamin D3 rapidly and safely normalize 25OHD levels , and that monthly dosing is similarly effective after 3–5 months . With baseline 25OHD > 50 nmol/L , vitamin D supplementation does not reduce PTH levels . Introduction There is concern that vitamin D supplementation doses are frequently inadequate , and that compliance with daily medication is likely to be suboptimal . Methods This r and omized double-blind trial compares responses to three high-dose vitamin D3 regimens and estimates optimal 25-hydroxyvitamin D ( 25OHD ) levels , from changes in parathyroid hormone ( PTH ) , and procollagen type I amino-terminal propeptide ( P1NP ) in relation to baseline 25OHD . Sixty-three elderly participants were r and omized to three regimens of vitamin D supplementation : a 500,000-IU loading dose ; the loading dose plus 50,000 IU/month ; or 50,000 IU/month . Results The Loading and Loading + Monthly groups showed increases in 25OHD of 58 ± 28 nmol/L from baseline to 1 month . Thereafter , levels gradually declined to plateaus of 69 ± 5 nmol/L and 91 ± 4 nmol/l , respectively . In the Monthly group , 25OHD reached a plateau of ~80 ± 20 nmol/L at 3–5 months . There were no changes in serum calcium concentrations . PTH and P1NP were only suppressed by vitamin D treatment in those with baseline 25OHD levels < 50 and < 30 nmol/L , respectively . Conclusions Large loading doses of vitamin D3 rapidly and safely normalize 25OHD levels in the frail elderly . Monthly dosing is similarly effective and safe , but takes 3–5 months for plateau 25OHD levels to be reached CONTEXT Public health authorities around the world recommend widely variable supplementation strategies for adults , whereas several professional organizations , including The Endocrine Society , recommend higher supplementation . METHODS We analyzed published r and omized controlled clinical trials to define the optimal intake or vitamin D status for bone and extraskeletal health . CONCLUSIONS The extraskeletal effects of vitamin D are plausible as based on pre clinical data and observational studies . However , apart from the beneficial effects of 800 IU/d of vitamin D3 for reduction of falls in the elderly , causality remains yet unproven in r and omized controlled trials ( RCTs ) . The greatest risk for cancer , infections , cardiovascular and metabolic diseases is associated with 25-hydroxyvitamin D ( 25OHD ) levels below 20 ng/mL. There is ample evidence from RCTs that calcium and bone homeostasis , estimated from serum 1,25-dihydroxyvitamin D and PTH , calcium absorption , or bone mass , can be normalized by 25OHD levels above 20 ng/mL. Moreover , vitamin D supplementation ( 800 IU/d ) in combination with calcium can reduce fracture incidence by about 20 % . Such a dose will bring serum levels of 25OHD above 20 ng/mL in nearly all postmenopausal women . Based on calculations of the metabolic clearance of 25OHD , a daily intake of 500 - 700 IU of vitamin D3 is sufficient to maintain serum 25OHD levels of 20 ng/mL. Therefore , the recommendations for a daily intake of 1500 - 2000 IU/d or serum 25OHD levels of 30 ng or higher for all adults or elderly subjects , as suggested by The Endocrine Society Task Force , are premature . Fortunately , ongoing RCTs will help to guide us to solve this important public health question OBJECTIVE To assess the serum level of 25 hydroxyvitamin D 25OHD  among healthy Saudi Arabian women living in the eastern province . METHODS A cross-sectional r and omized study was conducted between February 1st 2008 and May 31st 2008 at the King Fahd University Hospital , Al-Khobar , Kingdom of Saudi Arabia in 200 Saudi women between 25 - 35 years group 1 and women of > or = 50 years group 2 .  Clinical examination , laboratory tests , a complete blood picture , serum calcium , phosphorous , alkaline phosphatase , parathormone , and the serum levels of 25OHD levels were carried out . Data on lifestyle , dietary , and demographic question naires were collected . Vitamin D was defined as deficient with serum level < 50 nmol/L , insufficient between 52 - 72 nmol/L , and normal as 75nmol/L. RESULTS In group 1 , 70 % of women had normal 25OHD , and in women of group 2 , 45 % had normal levels of 25OHD . Alkaline phosphatase and parathormone levels were significantly higher in women with low vitamin D levels . Sun exposure and consumption of dairy products were minimal . CONCLUSION Vitamin D deficiency among healthy young Saudi women of 25 - 35 years was 30 % and 55 % in women of > or = 50 years . This study indicates that hypovitaminosis D is common in young and postmenopausal women . Efforts are require to augment and encouraged women for adequate exposure to sunlight and increased intake of fortified vitamin D products to maintain skeletal health CONTEXT Studies examining whether vitamin D supplementation increases muscle mass or muscle-specific vitamin D receptor ( VDR ) concentration are lacking . OBJECTIVE Our objective was to determine whether vitamin D₃ 4000 IU/d alters muscle fiber cross-sectional area ( FCSA ) and intramyonuclear VDR concentration over 4 months . DESIGN AND SETTING This was a r and omized , double-blind , placebo-controlled study in a single center . PARTICIPANTS Participants were 21 mobility-limited women ( aged ≥ 65 years ) with serum 25-hydroxyvitamin D ( 25OHD ) levels of 22.5 to 60 nmol/L. MAIN OUTCOME MEASURES Baseline and 4-month FCSA and intramyonuclear VDR were measured from vastus lateralis muscle cross-sections probed for muscle fiber type ( I/IIa/IIx ) and VDR using immunofluorescence . RESULTS At baseline , mean ( ±SD ) age was 78 ± 5 years ; body mass index was 27 ± 5 kg/m² , 25OHD was 46.3 ± 9.5 nmol/L , and  a short physical performance battery score was 7.95 ± 1.57 out of 12 . At 4 months , 25OHD level was 52.5 ± 17.1 ( placebo ) vs 80.0 ± 11.5 nmol/L ( vitamin D [ VD ] ; P < .01 ) , and change in 25OHD level was strongly associated with percent change in intramyonuclear VDR concentration-independent of group ( r = 0.87 , P < .001 ) . By treatment group , percent change in intramyonuclear VDR concentration was 7.8 % ± 18.2 % ( placebo ) vs 29.7 % ± 11.7 % ( VD ; P = .03 ) with a more pronounced group difference in type II vs I fibers . Percent change in total ( type I/II ) FCSA was -7.4 % ± 18.9 % ( placebo ) vs 10.6 % ± 20.0 % ( VD ; P = .048 ) . CONCLUSION Vitamin D₃ supplementation  increased intramyonuclear VDR concentration by 30 % and increased muscle fiber size by 10 % in older , mobility-limited , vitamin D-insufficient women . Further work is needed to determine whether the observed effect of vitamin D on fiber size is mediated by the VDR and to identify which signaling pathways are involved Submariners spend prolonged periods submerged without sunlight exposure and may benefit from vitamin D supplementation to maintain vitamin D status . The primary objective of this study was to determine the efficacy of daily vitamin D supplementation on maintenance of 25-hydroxyvitamin D ( 25(OH)D ) during a 3-month submarine patrol . Submariners were r and omly divided into three groups : placebo ( n = 16 ) , 1,000 IU/day ( n = 20 ) , or 2,000 IU/day ( n = 17 ) . Anthropometrics , self-reported dietary calcium and vitamin D intake , serum markers of vitamin D and bone metabolism , and peripheral quantitative computed tomography ( pQCT ) parameters of the tibia were determined before and after the patrol . Prior to departure , 49 % of the subjects were vitamin D insufficient ( < 50 nmol/L ) . Following the patrol , 25(OH)D increased in all groups ( p < 0.001 ) : 3.3 ± 13.1 ( placebo ) , 4.6 ± 11.3 ( 1,000 IU/day ) , and 13 ± 14 nmol/L ( 2,000 IU/day ) . The changes in 25(OH)D levels were dependent upon the baseline concentration of 25(OH)D and body mass ( p < 0.001 ) . Osteocalcin increased by 38 % ( p < 0.01 ) , and pQCT analyses revealed small , yet significant increases in indices of tibial structure and strength ( p < 0.05 ) that were independent of supplementation . These data suggest that vitamin D status was low prior to the patrol , and the subsequent changes in vitamin D status were dependent on the baseline 25(OH)D levels and body mass . Furthermore , short-term skeletal health does not appear to be negatively affected by 3 months of submergence in spite of a suboptimal response to vitamin D supplementation 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 ) Traditional clinical review articles , also known as up date s , differ from systematic review s and meta-analyses . Up date s selectively review the medical literature while discussing a topic broadly . Non-quantitative systematic review s comprehensively examine the medical literature , seeking to identify and synthesize all relevant information to formulate the best approach to diagnosis or treatment . Meta-analyses ( quantitative systematic review s ) seek to answer a focused clinical question , using rigorous statistical analysis of pooled research studies . This article presents guidelines for writing an evidence -based clinical review article for American Family Physician . First , the topic should be of common interest and relevance to family practice . Include a table of the continuing medical education objectives of the review . State how the literature search was done and include several sources of evidence -based review s , such as the Cochrane Collaboration , BMJ 's Clinical Evidence , or the InfoRetriever Web site . Where possible , use evidence based on clinical outcomes relating to morbidity , mortality , or quality of life , and studies of primary care population s. In articles su bmi tted to American Family Physician , rate the level of evidence for key recommendations according to the following scale : level A ( r and omized controlled trial [ RCT ] , meta- analysis ) ; level B ( other evidence ) ; level C ( consensus/expert opinion ) . Finally , provide a table of key summary points Purpose Vitamin D inadequacy is a global health concern in athletes as well as the general population . Whilst the role of vitamin D in skeletal health is well defined , there remains uncertainty over whether vitamin D supplementation has an added benefit beyond bone health . Methods This r and omised placebo-controlled trial in healthy male and female Gaelic footballers ( n = 42 ) investigated the effect of vitamin D3 supplementation [ 3000 IU ( 75 µg ) daily for 12 weeks , via an oral spray solution ] on VO2 max which was the primary outcome measure . Secondary outcomes included skeletal muscle and lung function . Results Supplementation significantly increased total 25-hydroxyvitamin D concentrations compared to the placebo group ( mean ± SD change from baseline , 36.31 ± 32.34 vs. 6.11 ± 23.93 nmol/L , respectively ; P = 0.006 ) . At baseline , 50 and 22 % of footballers presented with vitamin D insufficiency ( 31–49 nmol/L ) and deficiency ( < 30 nmol/L ) , respectively . Total 25-hydroxyvitamin D concentration did not significantly correlate with any measure of physical performance . Analysis of covariance ( ANCOVA ) models demonstrated that vitamin D supplementation over 12 weeks had no significant effect on VO2 max ( P = 0.375 ) , vertical jump height ( P = 0.797 ) , left and right h and grip strength ( P = 0.146 and P = 0.266 , respectively ) , forced vital capacity ( P = 0.573 ) or forced expiratory volume at 1 s ( P = 0.665 ) , after adjusting for confounders . The high prevalence of vitamin D inadequacy observed in this cohort of collegiate Gaelic footballers supports the need for vitamin D supplementation during wintertime to avoid being at risk of poor bone health . Conclusions Twelve-week daily supplementation with 3000 IU ( 75 µg ) vitamin D3 successfully resolved deficiency but did not have any significant effect on VO2 max , skeletal muscle or lung function Background Trials in school-aged children suggest vitamin D supplementation reduces asthma exacerbations . Primary aim : to examine whether vitamin D3 ( 100,000 IU ) rapidly raises serum 25-hydroxyvitamin D ( 25OHD ) ≥75 nmol/L in asthmatic preschoolers . Methods In a double-blind , r and omised , placebo-controlled trial , preschool-aged children with asthma received 100,000 IU vitamin D3 ( intervention ) or placebo ( control ) , followed by 400 IU vitamin D3 daily for 6 months . Serum 25OHD was measured at baseline , 10 days , 3 and 6 months . Outcomes included the group difference in 25OHD change from baseline at 3 months ( Δ25OHD ) ; the proportion of children with 25OHD ≥75 nmol/L at 3 months ; the pattern in serum vitamin D over 6 months ; the proportion of children with hypercalciuria at any time point ( safety ) ; and group rates for oral corticosteroids . Continuous outcomes were analysed using generalised linear mixed models and group rate ratios of events per child were assessed using a Poisson distribution model . Results Twenty-two children were r and omised ( intervention:11 ; control:11 ) during winter . At 3 months , the group difference in Δ25OHD ( 7.2 nmol/L ; 95 % CI : -13.7 , 28.1 ) was not significant ; yet , 100 % versus 54.5 % ( intervention versus control ) had serum 25OHD ≥75 nmol/L. There was a significant group difference in Δ25OHD at 10 days ( 110.3 nmol/L ; 95 % CI : 64.0 , 156.6 ) . One child in each group had transient hypercalciuria at 10 days . Group oral corticosteroids rates were 0.82 and 1.18/child , intervention versus control ( rate ratio = 0.68 ; 95 % CI : 0.30 , 1.62 ; non-significant ) . Conclusions Following 100,000 IU vitamin D3 , all children reached serum 25OHD ≥75 nmol/L , compared with half who received placebo . Daily supplementation , sun exposure and insufficient power may explain the absence of a significant 3-month group difference in Δ25OHD . No clinical ly important alterations in bone metabolism biomarkers occurred . Group oral corticosteroid rates will inform sample size calculations for the larger trial . ( NCT01999907 , 25 November 2013 ) Background —Low 25-hydroxyvitamin D levels , commonly found in older patients with heart failure , may contribute to the chronic inflammation and skeletal myopathy that lead to poor exercise tolerance . We tested whether vitamin D supplementation of patients with heart failure and vitamin D insufficiency can improve physical function and quality of life . Methods and Results —In a r and omized , parallel group , double-blind , placebo-controlled trial , patients with systolic heart failure aged ≥70 years with 25-hydroxyvitamin D levels < 50 nmol/L ( 20 ng/mL ) received 100000 U of oral vitamin D2 or placebo at baseline and 10 weeks . Outcomes measured at baseline , 10 weeks , and 20 weeks were 6-minute walk distance , quality of life ( Minnesota score ) , daily activity measured by accelerometry , Functional Limitations Profile , B-type natriuretic peptide , and tumor necrosis factor-&agr;. Participants in the vitamin D group had an increase in their 25-hydroxyvitamin D levels compared with placebo at 10 weeks ( 22.9 versus 2.3 nmol/L [ 9.2 versus 0.9 ng/mL ] ; P<0.001 ) and maintained this increase at 20 weeks . The 6-minute walk did not improve in the treatment group relative to placebo . No significant benefit was seen on timed up and go testing , subjective measures of function , daily activity , or tumor necrosis factor . Quality of life worsened by a small , but significant amount in the treatment group relative to placebo . B-type natriuretic peptide decreased in the treatment group relative to placebo ( −22 versus + 78 pg/mL at 10 weeks ; P=0.04 ) . Conclusions —Vitamin D supplementation did not improve functional capacity or quality of life in older patients with heart failure with vitamin D insufficiency . Clinical Trial Registration —www.controlled-trials.com . Identifier : IS RCT N51372896 OBJECTIVES To study the effects of vitamin D supplementation in healthier population s of men . DESIGN : R and omized , controlled trial . SETTING General clinical research center . PARTICIPANTS Sixty-five healthy , community-dwelling men ( mean age+/-st and ard deviation=76+/-4 , range 65 - 87 ) . INTERVENTION Cholecalciferol ( 1,000 IU/d ) or placebo supplementation for 6 months ; all received 500 mg supplemental calcium . MEASUREMENTS Upper and lower extremity muscle strength and power , physical performance and activity , health perception , calcium and vitamin D intake , and biochemical assessment , including 25-hydroxyvitamin D ( 25OHD ) , parathyroid hormone ( PTH ) , and ionized calcium levels . RESULTS The levels of 25OHD increased and PTH decreased in the cholecalciferol group , whereas there were no significant changes in the control group ( P<.001 ) . Baseline 25OHD levels correlated with baseline single-leg stance time and physical activity score . Baseline PTH levels correlated with baseline 8-foot walk time and physical activity score . No significant difference in strength , power , physical performance , or health perception was found between groups . CONCLUSION The 25OHD or PTH levels correlated with physical activity and physical performance in older , community-dwelling men with normal 25OHD status . Vitamin D supplementation increased 25OHD levels and decreased PTH levels but did not increase muscle strength or improve physical performance or health perception in this group of healthy , older men . Further investigations of the effects of vitamin D supplementation should focus on individuals with low levels of vitamin Vitamin D insufficiency is commonly associated with hip fracture . However , the equipotency of ergocalciferol and cholecalciferol supplementation in this patient group has not been studied in a r and omized trial using high-performance liquid chromatography ( HPLC ) measurement of serum 25-hydroxyvitamin D ( 25OHD ) . The objective of this study was to determine if ergocalciferol and cholecalciferol are equipotent therapies in vitamin D-insufficient hip fracture patients . Ninety five hip fracture in patients with vitamin D insufficiency ( 25OHD<50 nmol/L ) were r and omized , double-blind , to treatment with ergocalciferol 1000 IU/day ( n=48 ) or cholecalciferol 1000 IU/day ( n=47 ) for three months . All participants were also given a placebo matching the alternative treatment to maintain blinding of treatment allocation . The primary endpoint was total serum 25OHD measured by HPLC . Secondary endpoints included 25OHD measured by radioimmunoassay ( RIA ) , intact parathyroid hormone ( iPTH ) , and bioactive ( 1 - 84 ) whole PTH ( wPTH ) .  Seventy patients ( 74 % ) completed the study with paired sample s for analysis . Cholecalciferol supplementation result ed in a 31 % greater increase in total HPLC-measured 25OHD ( p=0.010 ) and 52 % greater rise in RIA-measured 25OHD ( p<0.001 ) than supplementation with an equivalent dose of ergocalciferol . Changes in iPTH and wPTH were not significantly different between calciferol treatments ( p>0.05 ) . In vitamin D-insufficient hip fracture patients , supplementation with cholecalciferol 1000 IU/day for three months was more effective in increasing serum 25OHD than an equivalent dose of ergocalciferol . However , the lack of difference in PTH lowering between calciferol treatments raises questions about the biological importance of this observation BACKGROUND vitamin D supplementation reduces the incidence of fractures in older adults . This may be partly mediated by effects of vitamin D on neuromuscular function . OBJECTIVE to determine the effects of vitamin D supplementation on aspects of neuromuscular function known to be risk factors for falls and fractures . DESIGN r and omised , double-blind , placebo-controlled study . SETTING falls clinic taking referrals from general practitioners and accident and emergency department . SUBJECTS 139 ambulatory subjects ( > /=65 years ) with a history of falls and 25-hydroxyvitamin D ( 25OHD ) < /=12 microg/l . INTERVENTION patients were r and omised to receive a single intramuscular injection of 600,000 i.u . ergocalciferol or placebo . OUTCOME MEASURES assessment s including biochemistry , postural sway , choice reaction time ( CRT ) , aggregate functional performance time ( AFPT ) , and quadriceps strength were carried out at baseline and 6 months post-intervention . RESULTS baseline characteristics were comparable between both groups . 25OHD in the treatment group increased significantly at 6 months . AFPT deteriorated in the control group and improved in the intervention group , representing a significant difference between groups ( + 6.6 s versus -2.0 s , t = 2.80 , P < 0.05 ) . Similar changes were observed for CRT ( -0.06 s versus + 0.41 s , t = -2.52 , P < 0.01 ) and postural sway ( + 0.0025 versus -0.0138 , t = 2.35 , P < 0.02 ) . There was no significant difference in muscle strength change between groups ( -10 N versus -2 N , t = -1.26 , ns ) . A significant correlation between change in AFPT and change in 25OHD levels was observed ( r = 0.19 , P = 0.03 ) . There was no significant difference in the number of falls ( 0.39 versus 0.24 , t = 1.08 , P = 0.28 ) or fallers ( 14 versus 11 , P = 0.52 ) between two groups . CONCLUSIONS vitamin D supplementation , in fallers with vitamin D insufficiency , has a significant beneficial effect on functional performance , reaction time and balance , but not muscle strength . This suggests that vitamin D supplementation improves neuromuscular or neuroprotective function , which may in part explain the mechanism whereby vitamin D reduces falls and fractures Low vitamin D status in women of childbearing age may have implication s for health . Vitamin D status of New Zeal and ers ( NZ ) , based on low serum 25-hydroxyvitamin D ( 25OHD ) is suboptimal . Vitamin D status may be improved with supplements and /or fortified foods . Recently an Adequate Intake ( AI ) for Australia and NZ was set at 5 microg/d vitamin D. We aim ed to determine the effect of daily consumption of milk powder fortified with 5 microg vitamin D3 on serum 25OHD concentration over 12 wks . 73 non-pregnant women ( 18 - 47 y ) living in Dunedin , NZ ( 46 degrees S ) were r and omised to receive either unfortified ( control ) or fortified ( 5 microg vitamin D3 ) milk for 12 wks from January to April . Mean 25OHD was similar between groups at week 0 ( control 74 vs 76 nmol/L ) and fell significantly in both groups over the 12 weeks ( control 53 nmol/L , fortified 65 nmol/L ; p < 0.001 ) . After 12 wks the fortified milk group had a serum 25OHD 19 % ( 95 % CI ; 7 , 32 % ) higher ( 10 nmol/L ) than the control group after adjusting for baseline levels ( p < 0.001 ) . Daily consumption of fortified milk providing the current AI of 5 microg day vitamin D3 for 12 weeks result ed in higher 25OHD concentrations than control milk . This dose was not sufficient to prevent the seasonal decline in 25OHD . This study suggests an AI of 5 microg may be inadequate for New Zeal and ers to allow for seasonal changes in sunlight exposure , and is unlikely sufficient for other population s with low sunlight exposure PURPOSE Vitamin D deficiency and cardiometabolic risk factors are common in obese adolescents . Observational studies demonstrate an inverse relationship among serum 25-hydroxyvitamin D ( 25OHD ) and obesity , insulin resistance , and inflammatory cytokines . This pilot study explores if vitamin D supplementation could reduce serum concentrations of inflammatory cytokines ( interleukin [ IL ] 6 , IL-10 , tumor necrosis factor α ) , adiponectin , lipids , hemoglobin A1C , and high-sensitivity C-reactive protein ( hs-CRP ) . A secondary aim was to determine the associations between baseline serum 25OHD concentrations and body mass index ( BMI ) , hs-CRP , inflammatory cytokines , and lipids . METHODS Overweight and obese adolescents enrolled in this 24-week , r and omized , double-blind study were given 150,000 IU ergocalciferol or placebo at baseline and 12 weeks . Outcome measurements included serum 25OHD , inflammatory cytokines , adiponectin , hs-CRP , lipids , hemoglobin A1C , and BMI at baseline , 12 , and 24 weeks . RESULTS Of 40 participants , 31 ( 78 % ) completed the study . Mean ± st and ard error 25OHD levels were similar in vitamin D and placebo groups at baseline ( 19.6 ± 5.3 vs. 25.8 ± 10.8 ng/mL ) and 24 weeks ( 20.1 ± 3.4 vs. 24.6 ± 8.4 ng/mL ) . Inflammatory and cardiovascular markers were not significantly different between groups at 24 weeks . Serum 25OHD at baseline was associated with BMI ( r = -.44 [ 95 % confidence interval , -.66 to -.15 ] ) but not with other outcome measures . CONCLUSIONS Supplementation with vitamin D at 150,000 IU every 3 months failed to increase serum 25OHD or alter inflammatory markers and lipids in overweight and obese youth . Further studies are needed to establish the dose of vitamin D required to increase 25OHD and determine potential effects on metabolic risk factors in obese teens Context Clinicians rely on systematic review s for current , evidence -based information . Contribution This survival analysis of 100 meta-analyses indexed in ACP Journal Club from 1995 to 2005 found that new evidence that substantively changed conclusions about the effectiveness or harms of therapies arose frequently and within relatively short time periods . The median survival time without substantive new evidence for the meta-analyses was 5.5 years . Significant new evidence was already available for 7 % of the review s at the time of publication and became available for 23 % within 2 years . Implication Clinical ly important evidence that alters conclusions about the effectiveness and harms of treatments can accumulate rapidly . The Editors Systematic review s have become increasingly common in recent years ( 1 ) and are recommended by many as the best sources of evidence to guide both clinical decisions ( 2 ) and health care policy ( 3 ) . For systematic review s to fulfill these roles , their findings must remain relatively stable for at least several years or effective mechanisms must exist for alerting end users to important changes in evidence . Yet , surprisingly little research has assessed the extent to which systematic review s become out of date or the rate at which this occurs ( 47 ) . Some organizations , such as the Cochrane Collaboration , recommend updating systematic review s every 2 years , but few empirical data guide this or other recommendations about updating . We sought to determine how quickly systematic review s meet explicitly defined criteria for changes in evidence of sufficient importance to warrant updating . We also sought to identify predictors of survival time , the time to such important changes in evidence . Survival time might vary depending on many factors , including the type of question posed by the original review ( for example , therapeutic or diagnostic ) , the types of studies included ( for example , r and omized trials or observational studies ) , and whether the systematic review provided quantitative synthesis . To limit such variation , we focused on systematic review s of r and omized , controlled trials that evaluated therapeutic benefit or harm by providing quantitative synthesis ( meta- analysis ) for at least 1 outcome . Methods Study Design and Sample We used a quasi-r and om process ( alphabetical sort order by author ) to select 100 systematic review s that were indexed in ACP Journal Club with an accompanying commentary between January 1995 and December 2005 ( with a search date no later than 31 December 2004 to ensure at least 1 full year for new evidence to appear ) . We chose this sampling frame because ACP Journal Club selects systematic review s that meet explicit quality st and ards and are deemed directly relevant to clinical practice ( 8) . We regarded the sample size of 100 as sufficiently large to achieve suitably narrow confidence intervals and to permit evaluation of up to 5 potential predictors of survival . Eligibility Criteria Eligible review s evaluated the benefit or harm of a specific drug , class of drug , device , or procedure ( invasive procedure or surgery ) and included r and omized or quasi-r and omized , controlled trials . We excluded evaluations of alternative and complementary medicines because the stability of review s of such therapies might differ substantially from review s of conventional therapies . We required that review s provide a point estimate and 95 % confidence interval for at least 1 outcome in the form of a relative risk , odds ratio , or absolute risk difference for binary outcomes and weighted mean differences for continuous outcomes . We excluded meta-analyses of individual-patient data , meta-regressions , and indirect meta-analyses because of the difficulty of determining whether new data would alter previous quantitative results . Two team members independently assessed eligibility , with disagreements resolved by consensus involving a third review er . When more than 1 review on the same topic was identified , only the earliest was included . Search ing For each review , search es for new trials included identifying new systematic review s on the same topic , su bmi tting relevant content terms to the Clinical Queries function in Ovid , applying the Related Articles function in PubMed to the 3 largest and the 3 most recent trials in the original review ( up to 6 trials in total ) , and using Scopus ( www . scopus .com/ scopus /home.url ) to identify new r and omized trials that cited the original review . When these search strategies yielded no eligible new trials , we conducted more comprehensive electronic search es and review ed relevant chapters in such sources as Clinical Evidence and UpTo Date to ensure that we had not missed new trials . Team members who had background s in both medicine and clinical research screened citations retrieved by the preceding methods to identify trials that would have met the inclusion criteria in the original review . Retrieved articles were screened in chronological order to ascertain quantitative or qualitative signals for the need for updating . The review protocol stopped when any criteria for updating were met . Each systematic review was discussed in detail , with the final statussignal for updating was or was not detectedadjudicated by consensus ( Figure 1 ) . Figure 1 . Overall process for determining updating status . ACP Journal Club Signals for the Need to Up date Systematic Review s In design ing criteria for comparing new findings with those in a previous review , we adapted methods used by other investigators to address similar problems with comparing 2 sets of results relating to the same question ( 913 ) , such as r and omized and nonr and omized studies of the same intervention . These investigators identified conflicting findings among different publications using a combination of quantitative thresholds for differences in effect magnitude and qualitative judgments about the language used to describe the results . We have similarly conceptualized quantitative and qualitative signals of potential changes in evidence that are sufficiently important to warrant updating previous systematic review s. Quantitative Signals Quantitative signals consisted of a change in statistical significance or relative change in effect magnitude of at least 50 % . We restricted these changes to those involving 1 of the primary outcomes of the original review or any mortality outcome . We also ignored trivial changes in statistical significance when the original and up date d meta-analytic results both had P values between 0.04 and 0.06so that quantitative signals of changes in evidence would represent robust indicators of the need to up date previous review s. Quantitative signals were detected by combining data from eligible new trials with the previous results using a fixed-effects approach . Use of fixed-effect models allowed pooling of the new trials with the previous meta-analytic result , as opposed to having to obtain original data from all of the included trials in each of 100 systematic review s. Although r and om-effects models are usually preferred to avoid spurious precision in the face of heterogeneity , our goal was to detect potential changes in evidence that would warrant a formal up date , not produce exact estimates of the up date d results . Qualitative Signals Qualitative signals included new information about harm sufficient to affect clinical decision making , important caveats to the original results , emergence of a superior alternate therapy , and important changes in certainty or direction of effect . Qualitative signals were detected by using explicit criteria for comparing the language in the original review with descriptions of findings in new systematic review s that addressed the same topic , pivotal trials , clinical practice guidelines , or recent editions of major textbooks ( for example , UpTo Date ) . Pivotal trials were defined as trials that had a sample size at least 3 times larger than that of the previous largest trial or were published in 1 of the 5 highest-impact general medical journals ( The New Engl and Journal of Medicine , Lancet , Journal of the American Medical Association , Annals of Internal Medicine , and the British Medical Journal ) . We defined 2 levels of importance for qualitative signals : potentially invalidating changes in evidence , which would make one no longer want clinicians or policymakers to base decisions on the original findings ( such as a pivotal trial that characterized treatment effectiveness in terms opposite of those in the original systematic review ) , and major changes in evidence , which would affect clinical decision making in important ways without invalidating the previous results ( such as the identification of patient population s for whom treatment is more or less beneficial ) . Major changes also included differing characterizations of effectiveness that were less extreme than those for potentially invalidating signals but that would still affect clinical decision making ( for example , a change from possibly beneficial to definitely beneficial ) . Of importance , such characterizations as possibly effective , probably effective , and promising , were all categorized as possibly effective . Thus , qualitative signals for changes in evidence captured substantive differences in the characterization of treatment effects , not merely semantic differences . Full definitions for each of the specific signals can be found at www.ohri.ca/UpdatingSystRevs . Data Collection For each review , we characterized the clinical content area , eligibility criteria for included trials , definitions of reported outcomes , number of included trials and participants , meta-analytic result for each outcome , identification of statistical heterogeneity , and excerpted quotations of the authors ' characterizations of the main results . We also abstract ed whether a given outcome was explicitly identified as 1 of the primary or main outcomes . We discounted identification of more than 3 such outcomes as inconsistent with the Background Aprotinin is a serine protease inhibitor used to limit perioperative bleeding and reduce the need for donated blood transfusions during cardiac surgery . R and omized controlled trials of aprotinin evaluating its effect on the outcome of perioperative transfusion have been published since 1987 , and systematic review s were conducted in 1992 and 1997 . Methods A systematic search was conducted for all RCTs of aprotinin  that used placebo controls or were open-label with no active control treatment . Data collected included the primary outcome , objective of each study , whether a systematic review was cited or conducted as part of the background and /or rationale for the study and the number of previously published RCTs cited . Cumulative meta-analyses were performed . Results Sixty-four r and omized , controlled trials of aprotinin were found , conducted between 1987 and 2002 , reporting an endpoint of perioperative transfusion .  Median trial size was 64 subjects , with a range of 20 to 1784 . A cumulative meta- analysis indicated that aprotinin greatly decreased the need for perioperative transfusion , stabilizing at an odds ratio of 0.25 ( p , 10 2 6 ) by the 12th study , published in June of 1992 . The upper limit of the confidence interval never exceeded 0.65 and results were similar in all subgroups . Citation of previous RCTs was extremely low , with a median of 20 % of prior trials cited . Only 7 of 44 ( 15 % ) of subsequent reports referenced the largest trial ( N 1/4 1784 ) , which was 28 times larger than the median trial size . Conclusions This study demonstrates that investigators evaluating aprotinin were not adequately citing previous research , result ing in a large number of RCTs being conducted to address efficacy questions that prior trials had already definitively answered . Institutional review boards and journals could reduce the number of redundant trials by requiring investigators to conduct adequate search es for prior evidence and conducting systematic review Black women have lower serum 25-hydroxyvitamin D ( 25[OH]D ) levels and higher parathyroid hormone ( PTH ) levels than white peers but lower bone turnover , suggesting skeletal resistance to PTH . Our objective was to determine if vitamin D supplementation ( 1,000 IU/day ) would prevent bone loss and whether vitamin D receptor ( VDR ) polymorphisms modify the response . We performed a 2-year r and omized , controlled , double-blind study of 1,000 IU vitamin D3 vs. placebo in postmenopausal black women with serum 25(OH)D levels < 20 ng/mL ( n = 103 ) .  Measurements of 25(OH)D , PTH , and bone turnover were evaluated at baseline and 3 , 6 , 12 , 18 , and 24 months . DNA was extracted from peripheral blood leukocytes , and genotyping was conducted using st and ard techniques . Spine and hip bone mineral density ( BMD ) was measured at baseline and every 6 months . Serum 25(OH)D increased 11 ng/mL with vitamin D supplementation ( p < 0.001 ) , with no change in the placebo group . Vitamin D supplementation produced a significant decline in PTH at 3 months only , with no differences in bone turnover between placebo and vitamin D at any time point . Two-year changes in BMD were not significantly different between placebo- and vitamin D-treated black women at any skeletal site . Despite similar elevations in 25(OH)D , femoral neck BMD was only responsive to vitamin D supplementation in FF subjects ( n = 47 ) , not Ff/ff subjects ( n = 31 ) . Vitamin D supplementation does not appear to influence  bone loss in black women . However , in the FF polymorphism of the VDR gene group , vitamin D supplementation may retard the higher rate of bone loss OBJECTIVE There are several examples in nutrition of discordance between the results of observational studies and r and omized controlled trials ( RCTs ) . We hypothesized that this discordance is attributable to differences in the translational paths of nutrient-disease associations . Translational paths can be assessed using citation analysis . STUDY DESIGN AND SETTING We compared the characteristics of citation networks using examples , where RCTs and observational studies agreed ( long-chain n-3 polyunsaturated fatty acids [ n-3 PUFA ] ) or disagreed ( vitamin E ) . We performed systematic review s in each example , constructed citation networks , and compared them with respect to the number of articles and citation relationships between them , as well as the distribution of articles ' hub and authority scores . RESULTS For n-3 PUFA , meta-analyses of 14 RCTs and 10 observational studies both suggested that higher intake was associated with lower cardiovascular mortality . For vitamin E , the meta- analysis of 14 RCTs excluded a clinical ly significant effect , whereas 14 observational studies reported a significant inverse association . The respective citation networks consisted of 392 ( n-3 PUFA ) and 351 ( vitamin E ) articles . No differences between the characteristics of the two networks were identified . There was no evidence that the observational studies pre date d RCTs in the translational process in either example . CONCLUSION In the two examples , citation network characteristics do not predict concordance in the results of observational studies and RCTs BACKGROUND Low vitamin D status in pregnancy was proposed as a risk factor of  preeclampsia  . METHODS We assessed the effect of vitamin D supplementation ( 4,400 vs. 400 IU/day ) , initiated early in pregnancy ( 10 - 18 weeks ) , on the development of preeclampsia . The effects of serum vitamin D ( 25-hydroxyvitamin D [ 25OHD ] ) levels on preeclampsia incidence at trial entry and in the third trimester ( 32 - 38 weeks ) were studied . We also conducted a nested case-control study of 157 women to investigate peripheral blood vitamin D-associated gene expression profiles at 10 to 18 weeks in 47 participants who developed preeclampsia . RESULTS Of 881 women r and omized , outcome data were available for 816 , with 67 ( 8.2 % ) developing preeclampsia . There was no significant difference between treatment ( N = 408 ) or control ( N = 408 ) groups in the incidence of preeclampsia ( 8.08 % vs. 8.33 % , respectively ; relative risk : 0.97 ; 95 % CI , 0.61 - 1.53 ) . However , in a cohort analysis and after adjustment for confounders , a significant effect of sufficient vitamin D status ( 25OHD ≥30 ng/ml ) was observed in both early and late pregnancy compared with insufficient levels ( 25OHD < 30 ng/ml ) ( adjusted odds ratio , 0.28 ; 95 % CI , 0.10 - 0.96 ) . Differential expression of 348 vitamin D-associated genes ( 158 upregulated ) was found in peripheral blood of women who developed preeclampsia ( FDR < 0.05 in the Vitamin D Antenatal Asthma Reduction Trial [ VDAART ] ; P < 0.05 in a replication cohort ) . Functional enrichment and network analyses of this vitamin D-associated gene set suggests several highly functional modules related to systematic inflammatory and immune responses , including some nodes with a high degree of connectivity . CONCLUSIONS Vitamin D supplementation initiated in weeks 10 - 18 of pregnancy did not reduce preeclampsia incidence in the intention-to-treat paradigm . However , vitamin D levels of 30 ng/ml or higher at trial entry and in late pregnancy were associated with a lower risk of preeclampsia . Differentially expressed vitamin D-associated transcriptomes implicated the emergence of an early pregnancy , distinctive immune response in women who went on to develop preeclampsia . TRIAL REGISTRATION Clinical Trials.gov NCT00920621 . FUNDING Quebec Breast Cancer Foundation and Genome Canada Innovation Network . This trial was funded by the National Heart , Lung , and Blood Institute . For details see Acknowledgments BACKGROUND Systematic review s may be compromised by selective inclusion and reporting of outcomes and analyses . Selective inclusion occurs when there are multiple effect estimates in a trial report that could be included in a particular meta- analysis ( e.g. from multiple measurement scales and time points ) and the choice of effect estimate to include in the meta- analysis is based on the results ( e.g. statistical significance , magnitude or direction of effect ) . Selective reporting occurs when the reporting of a subset of outcomes and analyses in the systematic review is based on the results ( e.g. a protocol -defined outcome is omitted from the published systematic review ) . OBJECTIVES To summarise the characteristics and synthesis e the results of empirical studies that have investigated the prevalence of selective inclusion or reporting in systematic review s of r and omised controlled trials ( RCTs ) , investigated the factors ( e.g. statistical significance or direction of effect ) associated with the prevalence and quantified the bias . SEARCH METHODS We search ed the Cochrane Methodology Register ( to July 2012 ) , Ovid MEDLINE , Ovid EMBASE , Ovid PsycINFO and ISI Web of Science ( each up to May 2013 ) , and the US Agency for Healthcare Research and Quality ( AHRQ ) Effective Healthcare Program 's Scientific Re source Center ( SRC ) Methods Library ( to June 2013 ) . We also search ed the abstract books of the 2011 and 2012 Cochrane Colloquia and the article alerts for method ological work in research synthesis published from 2009 to 2011 and compiled in Research Synthesis Methods . SELECTION CRITERIA We included both published and unpublished empirical studies that investigated the prevalence and factors associated with selective inclusion or reporting , or both , in systematic review s of RCTs of healthcare interventions . We included empirical studies assessing any type of selective inclusion or reporting , such as investigations of how frequently RCT outcome data is selectively included in systematic review s based on the results , outcomes and analyses are discrepant between protocol and published review or non-significant outcomes are partially reported in the full text or summary within systematic review s. DATA COLLECTION AND ANALYSIS Two review authors independently selected empirical studies for inclusion , extracted the data and performed a risk of bias assessment . A third review author resolved any disagreements about inclusion or exclusion of empirical studies , data extraction and risk of bias . We contacted authors of included studies for additional unpublished data . Primary outcomes included overall prevalence of selective inclusion or reporting , association between selective inclusion or reporting and the statistical significance of the effect estimate , and association between selective inclusion or reporting and the direction of the effect estimate . We combined prevalence estimates and risk ratios ( RRs ) using a r and om-effects meta- analysis model . MAIN RESULTS Seven studies met the inclusion criteria . No studies had investigated selective inclusion of results in systematic review s , or discrepancies in outcomes and analyses between systematic review registry entries and published systematic review s. Based on a meta- analysis of four studies ( including 485 Cochrane Review s ) , 38 % ( 95 % confidence interval ( CI ) 23 % to 54 % ) of systematic review s added , omitted , up grade d or down grade d at least one outcome between the protocol and published systematic review . The association between statistical significance and discrepant outcome reporting between protocol and published systematic review was uncertain . The meta-analytic estimate suggested an increased risk of adding or upgrading ( i.e. changing a secondary outcome to primary ) when the outcome was statistically significant , although the 95 % CI included no association and a decreased risk as plausible estimates ( RR 1.43 , 95 % CI 0.71 to 2.85 ; two studies , n = 552 meta-analyses ) . Also , the meta-analytic estimate suggested an increased risk of downgrading ( i.e. changing a primary outcome to secondary ) when the outcome was statistically significant , although the 95 % CI included no association and a decreased risk as plausible estimates ( RR 1.26 , 95 % CI 0.60 to 2.62 ; two studies , n = 484 meta-analyses ) . None of the included studies had investigated whether the association between statistical significance and adding , upgrading or downgrading of outcomes was modified by the type of comparison , direction of effect or type of outcome ; or whether there is an association between direction of the effect estimate and discrepant outcome reporting . Several secondary outcomes were reported in the included studies . Two studies found that reasons for discrepant outcome reporting were infrequently reported in published systematic review s ( 6 % in one study and 22 % in the other ) . One study ( including 62 Cochrane Review s ) found that 32 % ( 95 % CI 21 % to 45 % ) of systematic review s did not report all primary outcomes in the abstract . Another study ( including 64 Cochrane and 118 non-Cochrane review s ) found that statistically significant primary outcomes were more likely to be completely reported in the systematic review abstract than non-significant primary outcomes ( RR 2.66 , 95 % CI 1.81 to 3.90 ) . None of the studies included systematic review s published after 2009 when reporting st and ards for systematic review s ( Preferred Reporting Items for Systematic review s and Meta-Analyses ( PRISMA ) Statement , and Method ological Expectations of Cochrane Intervention Review s ( MECIR ) ) were disseminated , so the results might not be generalisable to more recent systematic review s. AUTHORS ' CONCLUSIONS Discrepant outcome reporting between the protocol and published systematic review is fairly common , although the association between statistical significance and discrepant outcome reporting is uncertain . Complete reporting of outcomes in systematic review abstract s is associated with statistical significance of the results for those outcomes . Systematic review outcomes and analysis plans should be specified prior to seeing the results of included studies to minimise post-hoc decisions that may be based on the observed results . Modifications that occur once the review has commenced , along with their justification , should be clearly reported . Effect estimates and CIs should be reported for all systematic review outcomes regardless of the results . The lack of research on selective inclusion of results in systematic review s needs to be addressed and studies that avoid the method ological weaknesses of existing research are also needed Aims : With the increase in the number of systematic review s available , a logical next step to provide decision makers in healthcare with the evidence they require has been the conduct of review s of existing systematic review s. Syntheses of existing systematic review s are referred to by many different names , one of which is an umbrella review . An umbrella review allows the findings of review s relevant to a review question to be compared and contrasted . An umbrella review 's most characteristic feature is that this type of evidence synthesis only considers for inclusion the highest level of evidence , namely other systematic review s and meta-analyses . A methodology working group was formed by the Joanna Briggs Institute to develop method ological guidance for the conduct of an umbrella review , including diverse types of evidence , both quantitative and qualitative . The aim of this study is to describe the development and guidance for the conduct of an umbrella review . Methods : Discussion and testing of the elements of methods for the conduct of an umbrella review were held over a 6-month period by members of a methodology working group . The working group comprised six participants who corresponded via teleconference , e-mail and face-to-face meeting during this development period . In October 2013 , the methodology was presented in a workshop at the Joanna Briggs Institute Convention . Workshop participants , review authors and method ologists provided further testing , critique and feedback on the proposed methodology . Results : This study describes the methodology and methods developed for the conduct of an umbrella review that includes published systematic review s and meta-analyses as the analytical unit of the review . Details are provided regarding the essential elements of an umbrella review , including presentation of the review question in a Population , Intervention , Comparator , Outcome format , nuances of the inclusion criteria and search strategy . A critical appraisal tool with 10 questions to help assess risk of bias in systematic review s and meta-analyses was also developed and tested . Relevant details to extract from included review s and how to best present the findings of both quantitative and qualitative systematic review s in a reader friendly format are provided . Conclusions : Umbrella review s provide a ready means for decision makers in healthcare to gain a clear underst and ing of a broad topic area . The umbrella review methodology described here is the first to consider review s that report other than quantitative evidence derived from r and omized controlled trials . The methodology includes an easy to use and informative summary of evidence table to readily provide decision makers with the available , highest level of evidence relevant to the question posed BACKGROUND Subjects with atopic dermatitis ( AD ) have defects in antimicrobial peptide ( AMP ) production possibly contributing to an increased risk of infections . In laboratory models , vitamin D can alter innate immunity by increasing AMP production . OBJECTIVE To determine if AD severity correlates with baseline vitamin D levels , and to test whether supplementation with oral vitamin D alters AMP production in AD skin . METHODS This was a multi-centre , placebo-controlled , double-blind study in 30 subjects with AD , 30 non-atopic subjects , and 16 subjects with psoriasis . Subjects were r and omized to receive either 4000 IU of cholecalciferol or placebo for 21 days . At baseline and day 21 , levels of 25-hydroxyvitamin D ( 25OHD ) , cathelicidin , HBD-3 , IL-13 , and Eczema Area and Severity Index ( EASI ) and Rajka-Langel and scores were obtained . RESULTS At baseline , 20 % of AD subjects had serum 25OHD below 20 ng/mL. Low serum 25OHD correlated with increased Fitzpatrick Skin Type and elevated BMI , but not AD severity . After 21 days of oral cholecalciferol , mean serum 25OHD increased , but there was no significant change in skin cathelicidin , HBD-3 , IL-13 or EASI scores . CONCLUSIONS This study illustrated that darker skin types and elevated BMI are important risk factors for vitamin D deficiency in subjects with AD , and highlighted the possibility that seasonality and locale may be potent contributors to cathelicidin induction through their effect on steady state 25OHD levels . Given the molecular links between vitamin D and immune function , further study of vitamin D supplementation in subjects with AD is warranted Falls are a serious health problem in the aging population . Because low levels of vitamin D have been associated with increased fall rates , many trials have been performed with vitamin D ; two meta-analyses showed either a small effect or no effect of vitamin D on falls . We conducted a study of the effect of vitamin D on serum 25 hydroxyvitamin D ( 25OHD ) and data on falls was collected as a secondary outcome . In a 12-month double blind r and omized placebo trial , elderly women , mean age 66 years , were r and omized to one of seven daily oral doses of vitamin D or placebo . The main inclusion criterion for study was a baseline serum 25OHD<20ng/ml ( 50nmol/L ) . A history of falls was collected at baseline and fall events were collected every 3 months . Results showed that the effect of vitamin D on falls followed a U-shaped curve whether analyzed by dose or serum 25OHD levels . There was no decrease in falls on low vitamin D doses 400 , 800 IU , a significant decrease on medium doses 1600 , 2400,3200 IU ( p=0.020 ) and no decrease on high doses 4000 , 4800 IU compared to placebo ( p=0.55 ) . When compared to 12-month serum 25OHD quintiles , the faller rate was 60 % in the lowest quintile < 25ng/ml ( < 50nmol/L ) , 21 % in the low middle quintile 32 - 38ng/ml ( 80 - 95nmo/L ) , 72 % in the high middle quintile 38 - 46ng/ml ( 95 - 115nmo/L ) and 45 % in the highest quintile 46 - 66ng/ml ( 115 - 165nmol/L ) . In the subgroup with a fall history , fall rates were 68 % on low dose , 27 % on medium doses and 100 % on higher doses . Fall rates on high doses were increased compared to medium doses ( Odds Ratio 5.6.95 % CI : 2.1 - 14.8 ) . In summary , the maximum decrease in falls corresponds to a 12- month serum 25OHD of 32 - 38ng/ml ( 80 - 95nmol/L ) and faller rates increase as serum 25OHD exceed 40 - 45ng/ml ( 100 - 112.5nmol/L ) . The Tolerable upper limit ( TUL ) recently increased in 2010 from 2000 to 4000 IU/day may need to be reduced in elderly women especially in those with a fall history 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 CONTEXT R and omized control trials ( RCT ) of the effect of vitamin D/calcium supplementation on skeletal muscle strength have not shown promising effect in the elderly . OBJECTIVE Our objective was to assess the effect of vitamin D and /or calcium on muscle strength in young adults with vitamin D deficiency . DESIGN AND SETTING We conducted a RCT using a factorial design at a tertiary-care center from September 2010 to April 2011 . SUBJECTS A total of 173 healthy females with mean age , body mass index , and 25-hydroxyvitamin D [ 25(OH)D ] of 21.7 ± 4.4 yr , 20.8 ± 2.96 kg/m(2 ) , and 9.3 ± 3.37 ng/ml , respectively , were block r and omized to 1 ) double placebo , 2 ) calcium/placebo , 3 ) cholecalciferol/placebo , and 4 ) cholecalciferol/calcium for 6 months . Cholecalciferol was given at 60,000 IU/wk for 8 wk followed by 60,000 IU/fortnight . Elemental calcium was given in doses of 500 mg twice per day for 6 months . METHODS Assessment included h and grip ( primary outcome ) and pinch grip strength , distance walked in 6 min , dyspnea score , quality of life by Short Form ( 36 ) Health Survey ( SP-36 ) , serum 25(OH)D , 1,25-dihydroxyvitamin D , and intact PTH . RESULTS The serum 25(OH)D increased significantly to 29.9 ± 8.35 and 27.0 ± 9.54 ng/ml in two groups on cholecalciferol . The mean h and grip strength ( 19.4 ± 3.92 , 21.1 ± 3.31 , 20.6 ± 3.92 , and 20.1 ± 4.00 kg ) and its increase from baseline ( 0.3 ± 2.25 , 0.3 ± 2.64 , -0.3 ± 2.41 , and 0.6 ± 2.30 kg ) were comparable in four groups at 6 months . Quality of life , urinary calcium/creatinine ratio , and adverse effects were also comparable in groups . CONCLUSION Oral cholecalciferol/calcium supplementation in the dose/schedule used is effective and safe in increasing and maintaining serum 25(OH)D. However , this does not lead to improved skeletal muscle strength in young females INTRODUCTION There is emerging evidence on the widespread tissue effects of vitamin D. AIMS To formulate a position statement on the role of vitamin D in postmenopausal women . MATERIAL S AND METHODS Literature review and consensus of expert opinion . RESULTS AND CONCLUSIONS Epidemiological and prospect i ve studies have related vitamin D deficiency with not only osteoporosis but also cardiovascular disease , diabetes , cancer , infections and neurodegenerative disease . However the evidence is robust for skeletal but not nonskeletal outcomes where data from large prospect i ve studies are lacking . The major natural source of vitamin D is cutaneous synthesis through exposure to sunlight with a small amount from the diet in animal-based foods such as fatty fish , eggs and milk . Vitamin D status is determined by measuring serum 25-hydroxyvitamin D [ 25(OH)D ] levels . Optimal serum 25(OH)D levels are in the region of 30 - 90 ng/mL ( 75 - 225 nmol/L ) though there is no international consensus . Levels vary according to time of the year ( lower in the winter ) , latitude , altitude , air pollution , skin pigmentation , use of sunscreens and clothing coverage . Risk factors for low serum 25(OH)D levels include : obesity , malabsorption syndromes , medication use ( e.g. anticonvulsants , antiretrovirals ) , skin aging , low sun exposure and those in residential care . Fortified foods do not necessarily provide sufficient amounts of vitamin D. Regular sunlight exposure ( without sunscreens ) for 15 min , 3 - 4 times a week , in the middle of the day in summer generate healthy levels . The recommended daily allowance is 600 IU/day increasing to 800 IU/day in those aged 71 years and older . Supplementation can be undertaken with either vitamin D2 ( ergocalciferol ) or vitamin D3 ( cholecalciferol ) with monitoring depending on the dose used and the presence of concomitant medical conditions such as renal disease Epidemiological evidence suggests that circulating 25-hydroxyvitamin D ( 25OHD ) levels are inversely associated with hemoglobin ( Hb ) levels and anemia risk . We evaluated whether vitamin D supplementation improves Hb levels and reduces anemia risk in hypertensive patients . Two hundred patients with 25OHD levels < 75 nmol/L who attended the Styrian Vitamin D Hypertension Trial were included , of whom 188 completed the trial . Patients r and omly received 2800 IU vitamin D3 daily or a matching placebo for eight weeks . Initially , the prevalence of anemic status ( Hb levels < 12.5 g/dL ) and deficient 25OHD levels ( < 30 nmol/L ) was 6.5 % and 7.5 % , respectively . All anemic patients had 25OHD levels > 50 nmol/L. The mean ( 95 % confidence interval ) vitamin D effect on Hb levels was 0.04 ( −0.14 to 0.22 ) g/dL ( P = 0.661 ) . Moreover , vitamin D treatment did not influence anemic status significantly ( P > 0.999 ) . Likewise , vitamin D had no significant effect on Hb levels in the subgroups of anemic patients or in patients with initial 25OHD levels < 30 nmol/L. In conclusion , a daily vitamin D supplement of 2800 IU for eight weeks did not improve Hb levels or anemic status  in hypertensive patients . Future trials should focus on anemic patients with deficient 25OHD levels ( e.g. , < 30 nmol/L ) . This trial is registered with clinical trials.gov [ NCT02136771 ] Background / Objective : To study whether a free supply of vitamin D2 drops to 6-week-old infants together with tailor-made information h and outs improves the vitamin D status after 7 weeks in the intervention group compared to a control group . Subjects/ Methods : In this cluster r and omized controlled trial in eight child health clinics in Oslo , Norway , 66 healthy infants with Pakistani , Turkish or Somali background were included . The intervention group received daily supplementation of vitamin D drops containing 10 μg ( 400 IU ) of ergocalciferol ( vitamin D2 ) with a tailor-made information brochure about vitamin D and its sources , and instruction on how to administer the drops . They were compared to a control group receiving usual care . The principal outcome measure was increase in serum 25-hydroxyvitamin D ( S-25OHD ) 7 weeks later . S-25OHD was analyzed by high-performance liquid chromatography-ultraviolet-mass spectrometry . Results : Total 78 % ( n=51 ) of the included infants completed the study . At follow-up , S-25OHD was significantly higher in the intervention group than in the control group ( 93.5 versus 72.7 nmol l−1 , P=0.03 ) . The mean increase in S-25OHD adjusted for baseline was 28 nmol l−1 ( 95 % confidence interval 10.9–45.2 , P=0.002 ) higher in the intervention group than in the control group . Among exclusively breastfed infants at baseline , S-25OHD increased by 32.3 nmol l−1 ( P=0.035 ) in the intervention group compared to control group . Conclusion : Free supply of vitamin D drops to 6-week-old infants together with tailor-made information h and outs significantly improved the vitamin D status of infants with immigrant background compared to usual care 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 UNLABELLED In July 2009 , the Medical Advisory Secretariat ( MAS ) began work on Non-Invasive Cardiac Imaging Technologies for the Diagnosis of Coronary Artery Disease ( CAD ) , an evidence -based review of the literature surrounding different cardiac imaging modalities to ensure that appropriate technologies are accessed by patients suspected of having CAD . This project came about when the Health Services Branch at the Ministry of Health and Long-Term Care asked MAS to provide an evidentiary platform on effectiveness and cost-effectiveness of non-invasive cardiac imaging modalities . After an initial review of the strategy and consultation with experts , MAS identified five key non-invasive cardiac imaging technologies for the diagnosis of CAD . Evidence -based analyses have been prepared for each of these five imaging modalities : cardiac magnetic resonance imaging , single photon emission computed tomography , 64-slice computed tomographic angiography , stress echocardiography , and stress echocardiography with contrast . For each technology , an economic analysis was also completed ( where appropriate ) . A summary decision analytic model was then developed to encapsulate the data from each of these reports ( available on the OHTAC and MAS website).The Non-Invasive Cardiac Imaging Technologies for the Diagnosis of Coronary Artery Disease series is made up of the following reports , which can be publicly accessed at the MAS website at : www.health.gov.on.ca/mas or at www.health.gov.on.ca/english/providers/program/mas/mas_about.htmlSINGLE PHOTON EMISSION COMPUTED TOMOGRAPHY FOR THE DIAGNOSIS OF CORONARY ARTERY DISEASE : An Evidence -Based Analysis STRESS ECHOCARDIOGRAPHY FOR THE DIAGNOSIS OF CORONARY ARTERY DISEASE : An Evidence -Based Analysis STRESS ECHOCARDIOGRAPHY WITH CONTRAST FOR THE DIAGNOSIS OF CORONARY ARTERY DISEASE : An Evidence -Based Analysis 64-Slice Computed Tomographic Angiography for the Diagnosis of Coronary Artery Disease : An Evidence -Based Analysis CARDIAC MAGNETIC RESONANCE IMAGING FOR THE DIAGNOSIS OF CORONARY ARTERY DISEASE : An Evidence -Based Analysis Pease note that two related evidence -based analyses of non-invasive cardiac imaging technologies for the assessment of myocardial viability are also available on the MAS website : POSITRON EMISSION TOMOGRAPHY FOR THE ASSESSMENT OF MYOCARDIAL VIABILITY : An Evidence -Based Analysis MAGNETIC RESONANCE IMAGING FOR THE ASSESSMENT OF MYOCARDIAL VIABILITY : an Evidence -Based Analysis The Toronto Health Economics and Technology Assessment Collaborative has also produced an associated economic report entitled : The Relative Cost-effectiveness of Five Non-invasive Cardiac Imaging Technologies for Diagnosing Coronary Artery Disease in Ontario [ Internet ] . Available from : http://theta.utoronto.ca/reports/?id=7 OBJECTIVE The objective of the analysis is to determine the diagnostic accuracy of single photon emission tomography ( SPECT ) in the diagnosis of coronary artery disease ( CAD ) compared to the reference st and ard of coronary angiography ( CA ) . The analysis is primarily meant to allow for indirect comparisons between non-invasive strategies for the diagnosis of CAD , using CA as a reference st and ard . SPECT : Cardiac SPECT , or myocardial perfusion scintigraphy ( MPS ) , is a widely used nuclear , non-invasive image acquisition technique for investigating ischemic heart disease . SPECT is currently appropriate for all aspects of detecting and managing ischemic heart disease including diagnosis , risk assessment /stratification , assessment of myocardial viability , and the evaluation of left ventricular function . Myocardial perfusion scintigraphy was originally developed as a two-dimensional planar imaging technique , but SPECT acquisition has since become the clinical st and ard in current practice . Cardiac SPECT for the diagnosis of CAD uses an intravenously administered radiopharmaceutical tracer to evaluate regional coronary blood flow usually at rest and after stress . The radioactive tracers thallium ( 201Tl ) or technetium-99 m ( 99mTc ) , or both , may be used to visualize the SPECT acquisition . Exercise or a pharmacologic agent is used to achieve stress . After the administration of the tracer , its distribution within the myocardium ( which is dependent on myocardial blood flow ) is imaged using a gamma camera . In SPECT imaging , the gamma camera rotates around the patients for 10 to 20 minutes so that multiple two-dimensional projections are acquired from various angles . The raw data are then processed using computational algorithms to obtain three-dimensional tomographic images . Since its inception , SPECT has evolved and its techniques/applications have become increasingly more complex and numerous . Accordingly , new techniques such as attenuation correction and ECG gating have been developed to correct for attenuation due to motion or soft-tissue artifact and to improve overall image clarity . RESEARCH QUESTIONS What is the diagnostic accuracy of SPECT for the diagnosis of CAD compared to the reference st and ard of CA?Is  SPECT cost-effective compared to other non-invasive cardiac imaging modalities for the diagnosis of CAD?What are the major safety concerns with SPECT when used for the diagnosis of CAD ? METHODS A preliminary literature search was performed across OVID MEDLINE , MEDLINE In-Process and Other Non-Indexed Citations , EMBASE , the Cochrane Library , and the International Agency for Health Technology Assessment ( INAHTA ) for all systematic review s/meta- analysis published between January 1 , 2004 and August 22 , 2009 . A comprehensive systematic review was identified from this search and used as a basis for an up date d search . A second comprehensive literature search was then performed on October 30 , 2009 across the same data bases for studies published between January 1 , 2002 and October 30 , 2009 . Abstract s were review ed by a single review er and , for those studies meeting the eligibility criteria , full-text articles were obtained . Reference lists were also h and - search ed for any additional studies . Inclusion Criteria Exclusion Criteria Systematic review s , meta-analyses , controlled clinical trials , and observational studies Minimum sample size of 20 patients who completed coronary angiographyUse of CA as a reference st and ard for the diagnosis of CAD Data available to calculate true positives ( TP ) , false positives ( FP ) , false negatives ( FN ) and true negatives (TN)Accuracy data reported by patient not by segmentEnglish language Non- systematic review s , case reportsGrey literature and abstract sTrials using planar imaging onlyTrials conducted in patients with non-ischemic heart disease Studies done exclusively in special population s ( e.g. , patients with left branch bundle block , diabetics , minority population s ) unless insufficient data available SUMMARY OF FINDINGS Eighty-four observational studies , one non-r and omized , single arm controlled clinical trial , and one poorly reported trial that appeared to be a r and omized controlled trial ( RCT ) met the inclusion criteria for this review . All studies assessed the diagnostic accuracy of myocardial perfusion SPECT  for the diagnosis of CAD using CA as a reference st and ard . Based on the results of these studies the following conclusions were made : According to very low quality evidence , the addition of attenuation correction to traditional or ECG-gated SPECT greatly improves the specificity of SPECT  for the diagnosis of CAD although this improvement is not statistically significant . A trend towards improvement of specificity was also observed with the addition of ECG gating to traditional SPECT.According to very low quality evidence , neither the choice of stress agent ( exercise or pharmacologic ) nor the choice of radioactive tracer ( technetium vs. thallium ) significantly affect the diagnostic accuracy of SPECT  for the diagnosis of CAD although a trend towards accuracy improvement was observed with the use of pharmacologic stress over exercise stress and technetium over thallium . Considerably heterogeneity was observed both within and between trials . This heterogeneity may explain why some of the differences observed between accuracy estimates for various subgroups were not statistically significant . More complex analytic techniques such as meta-regression may help to better underst and which study characteristics significantly influence the diagnostic accuracy of SPECT Objective To examine the prevalence of outcome reporting bias — the selection for publication of a subset of the original recorded outcome variables on the basis of the results — and its impact on Cochrane review s. Design A nine point classification system for missing outcome data in r and omised trials was developed and applied to the trials assessed in a large , unselected cohort of Cochrane systematic review s. Research ers who conducted the trials were contacted and the reason sought for the non-reporting of data . A sensitivity analysis was undertaken to assess the impact of outcome reporting bias on review s that included a single meta- analysis of the review primary outcome . Results More than half ( 157/283 ( 55 % ) ) the review s did not include full data for the review primary outcome of interest from all eligible trials . The median amount of review outcome data missing for any reason was 10 % , whereas 50 % or more of the potential data were missing in 70 ( 25 % ) review s. It was clear from the publications for 155 ( 6 % ) of the 2486 assessable trials that the research ers had measured and analysed the review primary outcome but did not report or only partially reported the results . For reports that did not mention the review primary outcome , our classification regarding the presence of outcome reporting bias was shown to have a sensitivity of 88 % ( 95 % CI 65 % to 100 % ) and specificity of 80 % ( 95 % CI 69 % to 90 % ) on the basis of responses from 62 trialists . A third of Cochrane review s ( 96/283 ( 34 % ) ) contained at least one trial with high suspicion of outcome reporting bias for the review primary outcome . In a sensitivity analysis undertaken for 81 review s with a single meta- analysis of the primary outcome of interest , the treatment effect estimate was reduced by 20 % or more in 19 ( 23 % ) . Of the 42 meta-analyses with a statistically significant result only , eight ( 19 % ) became non-significant after adjustment for outcome reporting bias and 11 ( 26 % ) would have overestimated the treatment effect by 20 % or more . Conclusions Outcome reporting bias is an under-recognised problem that affects the conclusions in a substantial proportion of Cochrane review s. Individuals conducting systematic review s need to address explicitly the issue of missing outcome data for their review to be considered a reliable source of evidence . Extra care is required during data extraction , review ers should identify when a trial reports that an outcome was measured but no results were reported or events observed , and contact with trialists should be encouraged AIMS To analyse the effect on systematic review s in diabetes interventions of including only trials that are indexed in medline , and to assess the impact of adding trials from other data bases and the grey literature . METHODS All systematic review s of diabetes interventions which included a meta- analysis of r and omized controlled trials , and were published since 1996 , were selected . The impact on the meta- analysis of including only those trials indexed in medline , and the effect of then adding trials from other sources , was assessed . Where possible this was measured quantitatively , by redoing the meta- analysis , otherwise a qualitative estimate was made . RESULTS Forty-four systematic review s met our inclusion criteria . There were 120 articles reporting trial data which were not indexed in medline . These came from 52 % of the review s. In 34 % of the review s , basing a meta- analysis on a search of only medline would miss trials that could affect the result . Sources of non- medline data which had the biggest effect on the meta-analyses were journal articles from central and embase ( mainly in Diabetes , Nutrition and Metabolism ) and unpublished data ( mainly from industry ) . The exceptions were journal articles on herbal medicine , mostly indexed in Chinese language data bases . CONCLUSIONS A search of only the medline data base is insufficient for systematic review s of diabetes , because in about 34 % of review s the missed trials could affect the results of the meta- analysis . It is recommended that central ( on the Cochrane Library ) also be search ed . Scanning meeting abstract s , and seeking unpublished data are also recommended if the intervention has only recently been introduced 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 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 Background During rapid maxillary expansion ( RME ) , heavy forces are transmitted to the maxilla by the anchored teeth causing buccal inclination and buccal bone loss of posterior teeth . Objective To systematic ally review the literature in order to investigate whether RME causes periodontal sequelae , assessed by cone-beam computed tomography ( CBCT ) . Search methods Fifteen electronic data bases and reference lists of studies were search ed up to March 2017 . Selection criteria To be included in the systematic review , articles must be human studies on growing subjects , with transversal maxillary deficiency treated with RME and with assessment of buccal bone loss by CBCT images . Only r and omized and non-r and omized trials were included . Data collection and analysis Two authors independently performed study selection , data extraction , and risk of bias assessment . Study characteristics ( study design , sample size , age , sex , skeletal maturity , type of appliance , daily activation , evaluated linear measurements , observation period , CBCT setting s ) , and study outcomes ( loss of buccal bone thickness and marginal bone ) were reported according to the PRISMA statement . Results On the basis of the applied inclusion criteria , only six articles , three r and omized clinical trials and three controlled clinical trials were included . An individual analysis of the selected articles was undertaken . The risks of bias of the six trials were scored as medium to low . Limitations The results of the present systematic review are based on a limited number of studies and only one study included a control group . Conclusions and implication s In all considered studies , significant loss of buccal bone thickness and marginal bone level were observed in anchored teeth , following RME . Further prospect i ve studies correlating the radiological data of bone loss to the periodontal soft tissues reaction after RME are required . A preliminary evaluation of the patient-related risk factors for RR may be advisable when considering to administering RME . Registration This systematic review was registered in the National Institute of Health Research data base with an appropriate protocol number ( http://www.crd.york.ac.uk/ PROSPERO Protocol : CRD42017062645 ) . Funding The present study has not received any contributions from private or public funding agencies AIM To obtain an overall quantitative estimate of the association between pregnancy and gingival inflammation . MATERIAL AND METHODS Medline and EMBASE data bases were search ed through August 2011 . Prospect i ve cohort or cross-sectional studies assessing the effect of pregnancy on gingival inflammation evaluated by the gingival index ( GI ) and /or bleeding on probing were included . Meta-analyses were performed if possible . RESULTS Forty-four articles representing 33 studies ( 14 cohort and 19 cross-sectional ) were included . Meta-analyses , performed whenever possible , revealed ( 1 ) a significantly lower GI in pregnant women in the first term compared with those in their second or third term of pregnancy ; ( 2 ) a lower mean GI score in post-partum women compared with women in their second [ WMD = 0.143 ; 95 % CI ( 0.031 ; 0.255 ) ; p = 0.012 ] or third term [ WMD = 0.256 ; 95 % CI ( 0.151 ; 0.360 ) ; p < 0.001 ] of pregnancy , when considering cohort studies ; ( 3 ) Non-pregnant women had lower mean GI values than women in their second or third term of pregnancy . Small changes in plaque levels were reported . CONCLUSION Despite the limited number of studies included in the meta-analyses , the present systematic review confirms the existence of a significant increase in GI throughout pregnancy and between pregnant versus post-partum or non-pregnant women , without a concomitant increase in plaque levels Low serum 25-hydroxy vitamin D ( 25OHD ) predicts a higher cardiovascular risk in the general population . Because patients with chronic kidney disease are more likely to have low serum 25OHD , we determined the relationship between hypovitaminosis D and death in this group . Analysis was done using a cohort composed of 3011 patients from the Third National Health and Nutrition Examination Survey who had chronic kidney disease but were not on dialysis and who had a mean follow-up of 9 years . In analyses adjusted for demographics , cardiovascular risk factors , serum phosphorus , albumin , hemoglobin , stage of chronic kidney disease , albuminuria , and socioeconomic status , individuals with serum 25OHD levels less than 15 ng/ml had an increased risk for all-cause mortality when compared to those with levels over 30 ng/ml . This significantly higher risk for death with low serum 25OHD was evident in 15 of the 23 subgroups . The higher risk for cardiovascular and non-cardiovascular mortality became statistically nonsignificant on multivariable adjustment . The trend for higher mortality in patients with 25OHD levels 15 - 30 ng/ml was not statistically significant . Our results indicate there is a grade d relationship between serum 25OHD and the risk for death among subjects with chronic kidney disease who are not undergoing dialysis . R and omized , controlled trials are needed to conclusively determine whether vitamin D supplementation reduces mortality CONTEXT Guidelines in Finl and recommend 10 μg of vitamin D3 daily for all infants . Recent observations suggest that this may be insufficient to maintain optimal serum 25-hydroxyvitamin D ( S-25-OHD ) . OBJECTIVE The aim of the study was to evaluate effects of various vitamin D doses and determine a dose ensuring S-25-OHD of at least 80 nmol/liter in infants without signs of vitamin D excess . DESIGN We conducted a r and omized double-blind intervention study . Cord blood was obtained at birth for S-25-OHD ; 113 infants were r and omized to receive vitamin D3 10 , 30 , or 40 μg/d from age 2 wk to 3 months . SETTING An investigator-initiated study was performed in a single maternity hospital in Helsinki , Finl and . MAIN OUTCOME MEASURES S-25-OHD , calcium homeostasis , and skeletal characteristics were evaluated with peripheral quantitative computed tomography at age 3 months . RESULTS Baseline S-25-OHD was similar in all three groups ( median , 53 nmol/liter ) . At 3 months , the mean S-25-OHD values were 88 , 124 , and 153 nmol/liter , and the minimum values were 46 , 57 , and 86 nmol/liter in the groups receiving 10 , 30 , and 40 μg ( ANOVA ; P < 0.001 ) . No hypercalcemia occurred ; plasma calcium , serum PTH , and urine calcium excretion was similar between the groups . Peripheral quantitative computed tomography showed a trend toward larger tibial total bone and cortical bone area with higher vitamin D doses . CONCLUSION Vitamin D3 supplementation with up to 40 μg/d from age 2 wk to 3 months was safe and caused no hypercalcemia or hypercalciuria . The 40-μg dose maintained S-25-OHD above 80 nmol/liter in all infants . More extensive and longer intervention studies are necessary to assess long-term effects 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 Vitamin D functions are not limited to skeletal health benefits and may extend to preservation of insulin secretion and insulin sensitivity . This review summarizes the literature related to potential vitamin D influences on glucose homeostasis and insulin sensitivity . Cross-sectional data provide some evidence that circulating 25-hydroxyvitamin D ( 25(OH)D ) is inversely associated with insulin resistance , although direct measurements of insulin sensitivity are required for confirmation . Reported associations with insulin secretion , however , are contradictory . Available prospect i ve studies support a protective influence of high 25(OH)D concentrations on type 2 diabetes mellitus risk . There is a general lack of consistency in vitamin D intervention outcomes on insulin secretion and sensitivity , likely due to differences in subject population s , length of interventions , and forms of vitamin D supplementation . Vitamin D receptor gene polymorphisms and vitamin D interactions with the insulin like growth factor system may further influence glucose homeostasis . The ambiguity of optimal vitamin D dosing regimens and optimal therapeutic concentrations of serum 25(OH)D limit available intervention studies . Future studies , including cross-sectional and prospect i ve , should be performed in population s at high risk for both vitamin D deficiency and type 2 diabetes mellitus . Well- design ed , placebo-controlled , r and omized intervention studies are required to establish a true protective influence of  vitamin D on glucose homeostasis 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 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 Vitamin D deficiency leads to secondary hyperparathyroidism , increased bone turnover , and bone loss and , when severe , to osteomalacia . Vitamin D deficiency is common in elderly people , especially the institutionalized . The definition of vitamin D deficiency is hampered by the fact that large interlaboratory differences exist in assays for serum 25-hydroxyvitamin D ( 25OHD ) , the main circulating metabolite . The international Multiple Outcomes of Raloxifene Evaluation study , a large prospect i ve intervention trial in postmenopausal women with osteoporosis , offered the opportunity to compare vitamin D status and parathyroid function throughout many countries over the world . For this study , baseline data were available from 7564 postmenopausal women from 25 countries on 5 continents . All women had osteoporosis , i.e. bone mineral density ( BMD ) at femoral neck or lumbar spine was lower than t-score -2.5 , or they had 2 vertebral fractures .  Serum 25OHD was measured by RIA , and  serum PTH  was measured by immunoradiometric assay .  BMD was measured by dual x-ray absorptiometry . The mean ( + /-SD ) serum 25OHD was 70.8 + /- 30.9 nmol/L. A low serum 25OHD ( < 25 nmol/L ) was observed in 4.1 % of all women in the Multiple Outcomes of Raloxifene Evaluation study , ranging from 0 % in south east Asia ( very few patients ) to 8.3 % in southern Europe . Serum 25OHD was between 25 - 50 nmol/L in 24.3 % of the women . Serum 25OHD showed a significant seasonal relationship , with lower values in all regions in winter . Serum PTH correlated negatively with serum 25OHD ( r = -0.25 ; P < 0.001 ) . This significant negative correlation was observed in all regions . When serum 25OHD was less than 25 , 25 - 50 , or more than 50 nmol/L , respectively , mean serum PTH levels were 4.8 , 4.1 , and 3.5 pmol/L , respectively ( by ANOVA , P < 0.001 ) . Similarly , mean alkaline phosphatase levels were 83.7 , 79.1 , and 75.7 U/L ( P < 0.001 ) , respectively , with increasing serum 25OHD . The effect of serum 25OHD on BMD was only significant for the BMD of the trochanter where a serum 25OHD level less than 25 nmol/L was associated with a 4 % lower BMD . After 6 months of treatment with vitamin D(3 ) ( 400 - 600 IU/day ) and calcium ( 500 mg/day ) , serum 25OHD increased from 70.8 + /- 29.8 to 92.3 + /- 28.6 nmol/L. Serum PTH decreased significantly after 6 months of treatment , and this decrease depended on baseline serum 25OHD . When baseline serum 25OHD was less than 25 , 25 - 50 , or more than 50 nmol/L , respectively , serum PTH decreased by 0.8 , 0.5 , or 0.2 pmol/L , respectively ( P < 0.001 ) . In conclusion , serum 25OHD was less than 25 nmol/L in 4 % of the women , and this was associated with a 30 % higher serum PTH . In 24 % of the women  serum 25OHD was between 25 - 50 nmol/L , associated with a 15 % higher level of serum PTH compared with women with a serum 25OHD greater than 50 nmol/L. A low serum 25OHD level was also associated with higher serum alkaline phosphatase and lower BMD of the trochanter . Treatment with vitamin D(3 ) and calcium increased serum 25OHD and decreased serum PTH significantly ; the effect was greater for lower baseline serum 25OHD OBJECTIVE Vitamin D supplementation is suggested to reduce the risk of falls among ambulatory or institutionalized elderly subjects . The present study was undertaken to address the reduced risk of falls and hip fractures in patients with long-st and ing stroke by vitamin D supplementation . METHODS Ninety-six elderly women with poststroke hemiplegia were followed for two years . Patients were r and omly assigned to one of the two groups , and 48 patients received 1,000 IU ergocalciferol daily , and the remaining 48 received placebo . The number of falls per person and incidence of hip fractures were compared between the two groups . Strength and tissue ATPase of skeletal muscles on the nonparetic side were assessed before and after the study . RESULTS At baseline , serum 25-hydroxyvitamin D levels were in the deficient range ( < 10 ng/ml ) in all patients ; and vitamin D treatment enhanced serum 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D levels .  Vitamin D treatment accounted for a 59 % reduction in falls ( 95 % CI , 28 - 81 % ; p = 0.003 ) . There were increases in the relative number and size of type II muscle fibers and improved muscle strength in the vitamin D-treated group . Hip fractures occurred in 4 of 48 placebo group and 0 in 48 vitamin D2 group during the 2-year study period ( log-rank , p = 0.049 ) . CONCLUSION Vitamin D may increase muscle strength by improving atrophy of type II muscle fibers , which may lead to decreased falls and hip fractures CONTEXT Observational studies relating circulating 25-hydroxyvitamin D ( 25OHD ) and dietary vitamin D intake to cardiovascular disease ( CVD ) have reported conflicting results . OBJECTIVE Our objective was to investigate the association of 25OHD , dietary vitamin D , PTH , and adjusted calcium  with  CVD and mortality in a Scottish cohort . DESIGN AND SETTING The MIDSPAN Family Study is a prospect i ve study of 1040 men and 1298 women from the West of Scotl and recruited in 1996 and followed up for a median 14.4 yr . PARTICIPANTS Locally resident adult offspring of a general population cohort were recruited from 1972 - 1976 . MAIN OUTCOME MEASURES CVD events ( n = 416 ) and all-cause mortality ( n = 100 ) were evaluated . RESULTS 25OHD was measured using liquid chromatography-t and em mass spectrometry in available plasma ( n = 2081 ) . Median plasma 25OHD was 18.6 ng/ml , and median vitamin D intake was 3.2 μg/d ( 128 IU/d ) . Vitamin D deficiency ( 25OHD < 15 ng/ml ) was present in 689 participants ( 33.1 % ) . There was no evidence that dietary vitamin D intake , PTH , or adjusted calcium were associated with CVD events or with mortality . Vitamin D deficiency was not associated with CVD ( fully adjusted hazard ratio = 1.00 ; 95 % confidence interval = 0.77 - 1.31 ) . Results were similar after excluding patients who reported an activity-limiting longst and ing illness at baseline ( 18.8 % ) and those taking any vitamin supplements ( 21.7 % ) . However , there was some evidence vitamin D deficiency was associated with all-cause mortality ( fully adjusted hazard ratio = 2.02 ; 95 % confidence interval = 1.17 - 3.51 ) . CONCLUSION Vitamin D deficiency was not associated with risk of CVD in this cohort with very low 25OHD . Future trials of vitamin D supplementation in middle-aged cohorts should be powered to detect differences in mortality outcomes as well as CVD OBJECTIVE This double-blind , r and omized , controlled trial evaluated whether 12 months of high-dose vitamin D2 supplementation improved insulin sensitivity and secretion and glycemic status . METHODS African-American males ( AAM ) with prediabetes ( glycosylated hemoglobin [ A1C ] 5.7 - 6.4 % ) , hypovitaminosis D ( 25-hydroxyvitamin D [ 25OHD ] 5 - 29 ng/mL ) , and prevalent medical problems were supplemented with vitamin D3 ( 400 IU/day ) and then r and omized to weekly placebo or vitamin D2 ( 50,000 IU ) . The primary outcome was the change in oral glucose insulin sensitivity ( OGIS , from an oral glucose tolerance test [ OGTT ] ) after 12 months of treatment . Secondary outcomes included other glycemic indices , A1C , and incident diabetes . RESULTS Baseline characteristics were similar in vitamin D-supplemented ( n = 87 ) and placebo ( n = 86 ) subjects completing the trial with average concentrations 14.4 ng/mL , 362 mL × min(-1 ) × m(-2 ) , and 6.1 % for 25OHD , OGIS and A1C , respectively . After 12 months , the vitamin D-supplemented group had a change in serum 25OHD + 35 versus + 6 ng/mL for placebo , P<.001 ; OGIS + 7.8 versus -16.0 mL × min(-1 ) × m(-2 ) for placebo , P = .026 ; and A1C -0.01 versus + 0.01 % for placebo , P = .66 . Ten percent of subjects in both groups progressed to diabetes . A posthoc analysis of participants with baseline impaired fasting glucose ( IFG ) showed that more subjects in the vitamin D subgroup ( 31.6 % ) than placebo ( 8.3 % ) returned to normal glucose tolerance , but the difference did not reach significance ( P = .13 ) . CONCLUSION The trial does not provide evidence that 12 months of high-dose D2 repletion improves clinical ly relevant glycemic outcomes in subjects with prediabetes and hypovitaminosis D ( NCT01375660 ) Osteoporotic fractures , falls and obesity are major health problems in developed nations . Evidence suggests that there are antenatal factors predisposing to these conditions . Data are emerging from Australia and elsewhere to suggest that maternal vitamin D status in pregnancy affects intrauterine skeletal mineralisation and skeletal growth together with muscle development and adiposity . Given that low levels of vitamin D have been documented in many urbanised population s , including those in countries with abundant sunlight , an important issue for public health is whether maternal vitamin D insufficiency during pregnancy has adverse effects on offspring health . The developing fetus may be exposed to low levels of vitamin D during critical phases of development as a result of maternal hypovitaminosis D. We hypothesise that this may have adverse effects on offspring musculoskeletal health and other aspects of body composition . Further research focused on the implication s of poor gestational vitamin D nutrition is warranted as these developmental effects are likely to have a sustained influence on health during childhood and in adult life . We suggest that there is a clear rationale for r and omised clinical trials to assess the potential benefits and harmful effects of vitamin D supplementation during pregnancy Background Low serum 25-hydroxyvitamin D [ 25(OH)D ] levels have been associated with higher risk of many diseases that affect mortality , including cardiovascular disease ( CVD ) and cancer . The inverse association between serum 25(OH)D and mortality may be modified by excess circulating vitamin A , due to interactions of vitamin A at the level of the vitamin D nuclear receptor . In this prospect i ve cohort study , we investigated whether the association of 25(OH)D with all-cause , cancer , and CVD mortality  was modified by circulating vitamin A or preformed vitamin A intake from supplements . Methods We analyzed 15,998 adults in the Third National Health and Nutrition Examination Survey ( NHANES III ) , 1988–1994 . Mortality data for all-cause ( n = 3890 ) , cancer ( n = 844 ) , and CVD mortality ( n = 1715 ) were assessed through December 2006 .  Serum 25(OH)D was measured using a radioimmunoassay kit , vitamin A biomarkers were measured by HPLC , and information on supplement use was obtained by self-report . Multivariable hazard ratios ( HRs ) and corresponding 95 % confidence intervals ( CI ) were estimated by proportional hazards regression . Results Serum 25(OH)D was significantly inversely associated with all-cause mortality ( HR 0.93 , 95 % CI 0.89 , 0.97 , per 10 ng/mL increase ) and also with CVD mortality and mortality due to non-cancer/non-cardiovascular causes , but not with cancer mortality . The observed inverse associations remained statistically significant only among participants with serum retinyl esters < 7.0 μg/dL. High intake ( > 5000 IU/day ) of preformed vitamin A from supplements attenuated the inverse association of 25(OH)D with overall mortality . The observed interactions were not statistically significant . Conclusions 25(OH)D was inversely associated with overall mortality , CVD mortality , and mortality due to non-cancer/non-CVD causes , but not with cancer mortality . A possible interaction between vitamin A exposure and 25(OH)D concentration appears to be associated with an attenuation of the inverse association between risk of death and quartile of 25(OH)D concentration CONTEXT The findings of systematic review s ( SRs ) and meta-analyses ( MAs ) are used for clinical decision making . The European Association of Urology has committed increasing re sources into the development of high quality clinical guidelines based on such SRs and MAs . OBJECTIVE In this paper , we have summarised the process of conducting SRs for underpinning clinical practice guidelines under the auspices of the European Association of Urology Guidelines Office . EVIDENCE ACQUISITION The process involves explicit methods and the findings should be reproducible . When conducting a SR , the essential first step is to formulate a clear and answerable research question . An extensive literature search lays the foundation for evidence synthesis . Data are extracted independently by two review ers and any disagreements are resolved by discussion or arbitration by a third review er . EVIDENCE SYNTHESIS In SRs , data for particular outcomes in individual r and omised controlled trials may be combined statistically in a meta- analysis to increase power when the studies are similar enough . Biases in studies included in a SR/MA can lead to either an over estimation or an under estimation of true intervention effect size , result ing in heterogeneity in outcome between studies . A number of different tools are available such as Cochrane Risk of Bias assessment tool for r and omised controlled trials . In circumstances where there is too much heterogeneity , or when a review has included nonr and omised comparative studies , it is more appropriate to conduct a narrative synthesis . The GRADE tool for assessing quality of evidence strives to be a structured and transparent system , which can be applied to all evidence , regardless of quality . A SR not only identifies , evaluates , and summarises the best available evidence , but also the gaps to be targeted by future studies . CONCLUSIONS SRs and MAs are integral in developing sound clinical practice guidelines and recommendations . PATIENT SUMMARY Clinical practice guidelines should be evidence based , and systematic review s and meta-analyses are essential in their production . We have discussed the key steps of conducting systematic review s and meta-analyses in this paper BACKGROUND Vitamin D insufficiency was shown to be associated with adverse musculoskeletal and nonskeletal outcomes in numerous observational studies . However , some studies did not control for confounding factors such as age or seasonal variation of 25-hydroxyvitamin D [ 25(OH)D ] . OBJECTIVE We sought to determine the effect of vitamin D status on health outcomes . DESIGN Healthy community-dwelling women ( n = 1471 ) with a mean age of 74 y were followed in a 5-y trial of calcium supplementation .  25(OH)D was measured at baseline in all women .  Skeletal and nonskeletal outcomes were evaluated according to seasonally adjusted vitamin D status at baseline . RESULTS Fifty percent of women had a seasonally adjusted 25(OH)D concentration < 50 nmol/L. These women were significantly older , heavier , and less physically active and had more comorbidities than women with a seasonally adjusted 25(OH)D concentration > or = 50 nmol/L. Women with a seasonally adjusted 25(OH)D concentration < 50 nmol/L had an increased incidence of stroke and cardiovascular events that did not persist after adjustment for between-group differences in age or comorbidities . Women with a seasonally adjusted 25(OH)D concentration < 50 nmol/L were not at increased risk of adverse consequences for any musculoskeletal outcome , including fracture , falls , bone density , or grip strength or any nonskeletal outcomes , including death , myocardial infa rct ion , cancer , heart failure , diabetes , or adverse changes in blood pressure , weight , body composition , cholesterol , or glucose . CONCLUSIONS Vitamin D insufficiency is more common in older , frailer women . Community-dwelling older women with a seasonally adjusted 25(OH)D concentration < 50 nmol/L were not at risk of adverse outcomes over 5 y after control for comorbidities . R and omized placebo-controlled trials are needed to determine whether vitamin D supplementation in individuals with vitamin D insufficiency influences health outcomes . This trial was registered at www.anzctr.org.au as ACTRN 012605000242628 Background Musculoskeletal disorders ( MSDs ) are the leading cause of work disability and sickness absence worldwide . The prevalence of MSDs increases with age , consequently challenging sustainable employability among the growing ageing workforce . Knowledge of feasible and efficient workplace-based interventions to rehabilitate MSD or prevent its consequences is therefore warranted . This systematic review will evaluate the effectiveness of workplace-based interventions on MSDs and its consequences among adult workers with physical and sedentary work tasks , respectively . Methods We will search the following bibliographic data bases : PubMed ( including the data base ‘ MEDLINE ’ ) and Web of Science Core Collection ( including the data bases ‘ Science Citation Index Exp and ed ’ , ‘ Social Sciences Citation Index ’ and ‘ Arts & Humanities Citation Index ’ ) . Manual search es will also be performed . We will include r and omised controlled trials ( RCTs ) and non- RCTs reported in English in which ( 1 ) participants are adult workers with MSD , ( 2 ) interventions are aim ing at rehabilitating pain symptoms of MSD or preventing the consequences of MSD and ( 3 ) interventions are initiated and /or carried out at the workplace . The review will adhere to the ‘ Preferred Reporting Items for Systematic review s and Meta-Analyses ’ ( PRISMA ) guidelines for reporting systematic review s and the Institute for Work and Health ( IWH ) guidelines for workplace-based interventions . For the primary evaluation of the review , the quality assessment and evidence synthesis will conform to the IWH guidelines . Secondary evaluation will include a meta- analysis ( unless the included studies do not allow this due to heterogeneity ) and employ the risk of bias domains recommended by Cochrane along with the Grading of Recommendations , Assessment , Development and Evaluations ( GRADE ) approach on the studies with pain intensity as an outcome . Discussion This systematic review will provide knowledge on effective workplace-based interventions among physical and sedentary workers with MSD . RCTs are considered the most powerful experimental design in clinical trials , but solely including these may be too restrictive to underst and effective workplace-based interventions where r and omised and carefully controlled trials ( RCTs ) are not always possible . In order to maximize practical relevance , the selection process will , therefore , include both RCTs and non- RCTs and the quality assessment and evidence synthesis will conform to IWH guidelines focusing on developing practical guidelines for stakeholders . The result of this work will form the basis for industry-specific evidence -based recommendations on effective workplace-based interventions for rehabilitation of MSDs and its consequences that will later be operationalised into concrete and user-friendly practical tools for workplaces . Systematic review registration International Prospect i ve Register of Systematic Review s ( PROSPERO ) number CRD42018116752 PURPOSE Health interventions based on theory may be more effective than those that are not . This review of review s synthesizes all published r and omized controlled trial ( RCT ) meta-analytic evidence from the last decade to examine whether theory-based interventions were found to be associated with more effective  adult health behaviour change interventions . METHODS Systematic review s including meta-analyses were identified by search ing Medline , CINAHL , PsycINFO , and CDSR . A narrative synthesis was used to summarize and analyse the evidence . Only review s including RCTs of health behaviour change interventions with adults aged 18 + published from 2007 to 2017 were included . RESULTS Of 8,659 articles , nine systematic review s met inclusion criteria . The majority of review s ( n = 8) suggested no increased effectiveness for theory-based compared to non-theory-based interventions for effectiveness of outcomes relating to health behaviour . Less than half of the RCTs included in the review s reported the use of theory ( 85/183 ) . Two review s suggested interventions based on control theory , motivational interviewing , or self-determination theory were associated with greater effectiveness for physical activity and /or dietary interventions and outcomes . Method ological and reporting issues limit the conclusions . CONCLUSIONS Theory-based interventions as currently operationalized in systematic review s were not found to be more effective than non-theory-based interventions . Method ological and reporting issues at study and review level may not reflect the true utility of theory use within health behaviour interventions . The promotion of theory use may benefit from using a multifaceted argument , rather than a narrow focus of increased effectiveness . Statement of contribution What is already known on this subject ? Theory use is regularly promoted by cl aim ing that it will lead to more effective behaviour change interventions . Theory use has been frequently linked to effectiveness within systematic review s of behaviour change interventions . The theory-effectiveness hypothesis has not been systematic ally examined at the systematic review level . What does this study add ? Theory use as operationalized by systematic review authors was not associated with increased effectiveness within systematic review s examining r and omized controlled trials of behaviour change interventions in adults . Interventions based on control theory , motivational interviewing , or self-determination theory were associated with greater effectiveness for physical activity and /or dietary interventions and outcomes . Theory use should be promoted using a multifaceted argument , and assertions for increased effectiveness of theory-based interventions should only be used in domains where specific evidence exists to support this cl aim BACKGROUND Adequate intakes of calcium and vitamin D reduce bone loss and fracture risk in the elderly . Other nutrients also affect bone health , and adequate intakes may influence bone turnover and balance . OBJECTIVE We compared the long-term effects on bone turnover markers and calciotropic hormones of a multinutrient supplement , a calcium and vitamin D supplement , and dietary instruction aim ed at increasing calcium intake through foods . DESIGN Ninety-nine healthy postmenopausal women participated in a 3-y , r and omized trial , receiving either 1 ) supplemental calcium ( 1450 mg/d ) and vitamin D [ 10 microg ( 400 IU)/d ] , 2 ) calcium , vitamin D , and other nutrients ( multinutrient supplement ) , or 3 ) dietary instruction ( dietary control group ) . Data are from 83 subjects who completed the trial . RESULTS Increases over baseline in calcium intakes and serum 25-hydroxyvitamin D concentrations were sustained over 3 y in all treatment groups . Circulating parathyroid hormone concentrations were reduced at year 1 in all treatment groups but trended toward baseline thereafter . Bone turnover markers followed a similar pattern , and none of the changes in biochemical concentrations differed significantly between groups . CONCLUSIONS All 3 interventions offer long-term feasibility for increasing calcium intake and serum 25-hydroxyvitamin D concentrations . The dietary addition of micronutrients implicated in skeletal physiology confers no obvious bone-sparing effect in healthy postmenopausal women beyond that of calcium and vitamin D alone . The attenuation over time in suppression of parathyroid hormone and bone turnover might help explain why nutrient intervention tends to have less of a bone-sparing effect than do skeletally active medications such as estrogen or bisphosphonates At an orthodontic meeting in recent years , a colleague recounted to me that when a presenter had finished their presentation on a systematic review , the person beside leaned over and said to my colleague ‘ not another systematic review where it ’s not possible to draw any firm conclusions ’ . So an element of frustration was clear based on the screening of a large volume of evidence to arrive at such a low point for a conclusion . This , however , is now a familiar outcome for many orthodontic systematic review s. In this short editorial , I have attempted to give a brief outline of the proposed benefits of systematic review s but more importantly , to highlight , some issues we all need to bear in mind in their regard . The increasing focus on evidence -based healthcare , including orthodontics , has shunned the narrative review and spawned the systematic review . Aim ing to identify , evaluate and summarize the findings of all relevant studies on a specific topic , its exacting systematic approach should minimize bias and provide conclusions based on reliable findings . Meta-analyses of r and omized clinical trials with low risk of bias are considered the highest level of evidence available for evaluating the effects of an intervention . Systematic review s are also important tools in setting the research agenda via their recommendations for future research and authors can alert research ers to the most pertinent outcomes in clinical practice . But systematic review s like any other study type are not without their variability , both in dentistry in general and specifically in orthodontics . Large differences have also been observed in the quality of reporting of several characteristics between Cochrane and non-Cochrane systematic review s. A key question that must be asked when looking at all Cochrane review s is whether the review has been undertaken in a way to avoid bias and whether the data and results from the included studies are valid . Conclusions may be distorted if bias is introduced to the review process at any stage . For example , incomplete search ing for all relevant studies may lead to publication bias ; there is strong association between publication and studies reporting significant or positive findings in medicine and also within orthodontics . With regard to studies included within the review , these need to be assessed to ensure that they are undertaken and reported in a manner that is free of bias ( systematic error ) . Outcome reporting bias ( ORB ) may also be relevant , e.g. in a study identified as relevant to a review , where data exist on the outcome of interest but only selected findings have been given based on the results . Although systematic review s have emphasized ‘ assessment of method ological quality ’ of included studies , the Cochrane h and book recommends a focus on ‘ risk of bias assessment ’ instead . The justifications are four-fold : it targets whether the results of included studies should be credible ; despite being carried out to the highest st and ards , a study may have risk of bias due to , e.g. impracticality/impossibility of blinding of participants / study personnel ; some quality markers , e.g. a power calculation is unlikely to directly affect risk of bias ; it overcomes ambiguity between quality of reporting and quality of the underlying research Introduction : The aim of this quantitative systematic review /meta- analysis was to compare the treatment outcomes of mineral trioxide aggregate ( MTA ) and calcium hydroxide ( CH ) in pulpotomy of human primary molars . The focused PICO question was “ in case of pulp exposure in vital primary molars , how does MTA pulpotomy compare to CH in terms of clinical /radiographic success ? ” Methods and Material s : We retrieved published r and omized clinical trials ( RCTs ) of at least 6-month duration ; our search included articles published up to March 2013 in five following data bases : PubMed ( Medline ) , Cochrane data base of systematic review s , Science Citation Index , EMBASE , and Google Scholar . Mantel Haenszel and Inverse Variance-weighted methods were applied by STATA ; the relative risk ( RR ) was calculated with 95 % confidence intervals ( CI ) . Results : A total of 282 English articles were collected . Two authors independently screened the articles and five RCTs were selected ; data extraction and quality assessment were then carried out . Four RCTs were appropriate for meta- analysis according to their follow-up times by Mantel Haenszel method . Statistically significant difference was found between success rate of MTA compared to CH , with RR=0.08 ( 95 % CI , 0.02 - 0.39 ) , RR=0.19 ( 95 % CI , 0.08 - 0.46 ) , and RR=0.38 ( 95 % CI , 0.21 - 0.68 ) for 6- , 12- , and 24-month follow-ups , respectively . A significant difference was also observed for all included RCTs after analyses using the Inverse Variance-weighted method ( RR=0.44 ; 95 % CI , 0.27 - 0.72 ) . Conclusions : Systematic review /meta- analysis of included RCTs revealed that for pulpotomy of vital primary molars , MTA has better treatment outcomes compared to CH 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
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 .