Vitamin D supplementation in the prevention and management of major chronic diseases not related to mineral homeostasis in adults: research for evidence and a scientific statement from the European society for clinical and economic aspects of osteoporosis and osteoarthritis (ESCEO) Randomised controlled trial of vitamin D supplementation in sarcoidosis The 2011 Dietary Reference Intakes for Calcium and Vitamin D: what dietetics practitioners need to know. Effect of vitamin D supplementation on inflammation: protocol for a systematic review Maternal vitamin D supplementation during pregnancy Sarcopenia in ovarian cancer patients, oncologic outcomes revealing the importance of clinical nutrition: review of literature. Improving the vitamin D status of vitamin D deficient adults is associated with improved mitochondrial oxidative function in skeletal muscle. 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.
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
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 .