Background
Ecological and observational studies suggest that low vitamin D status could be associated with higher mortality from life-threatening conditions including cancer, cardiovascular disease, and diabetes mellitus that account for 60% to 70% of total mortality in high-income countries. We examined the risk of dying from any cause in subjects who participated in randomized trials testing the impact of vitamin D supplementation (ergocalciferol [vitamin D2] or cholecalciferol [vitamin D3]) on any health condition.
Methods
The literature up to November 2006 was searched without language restriction using the following databases: PubMed, ISI Web of Science (Science Citation Index Expanded), EMBASE, and the Cochrane Library.
Results
We identified 18 independent randomized controlled trials, including 57 311 participants. A total of 4777 deaths from any cause occurred during a trial size–adjusted mean of 5.7 years. Daily doses of vitamin D supplements varied from 300 to 2000 IU. The trial size–adjusted mean daily vitamin D dose was 528 IU. In 9 trials, there was a 1.4- to 5.2-fold difference in serum 25-hydroxyvitamin D between the intervention and control groups. The summary relative risk for mortality from any cause was 0.93 (95% confidence interval, 0.87-0.99). There was neither indication for heterogeneity nor indication for publication biases. The summary relative risk did not change according to the addition of calcium supplements in the intervention.
Conclusions
Intake of ordinary doses of vitamin D supplements seems to be associated with decreases in total mortality rates. The relationship between baseline vitamin D status, dose of vitamin D supplements, and total mortality rates remains to be investigated. Population-based, placebo-controlled randomized trials with total mortality as the main end point should be organized for confirming these findings.
Ecological studies in North America have suggested that mortality from several potentially life-threatening chronic health conditions such as cancer, cardiovascular diseases, and diabetes mellitus would increase with increasing latitude, that is, with residence increasingly distant from the equator.1,2 Other studies have shown that the survival of patients with cardiovascular disease or with some cancer (eg, lung, colorectal, and breast cancer) was greater if the diagnosis was made during summer as compared with the winter.3,4 Increasing distance from the equator and winter period were equated to decreasing exposure to sunlight, especially to UV-B radiation (280-315 nm) because with increasing latitude, amounts of UV-B radiation reaching the earth surface decrease faster than amounts of UV-A radiation (315-400 nm).5 Also, seasonal variations are more pronounced for UV-B radiation than for the UV-A radiation.5 Because UV-B radiation is necessary for the synthesis of vitamin D in the skin, it has been hypothesized that associations found between latitude or seasonality and mortality from several chronic conditions could be owing to variations in vitamin D status.6-10Some food products may also represent a source of vitamin D, although of highly variable content (eg, fortified foods, oily fish, eggs, and butter). Hence, low vitamin D status could proceed from the conjunction of insufficient intakes (exogenous source) and of insufficient skin synthesis (endogenous source) of vitamin D. Biological findings have reinforced the likelihood of the vitamin D hypothesis. First, vitamin D receptors have been found in various organs, and activation of these receptors by 1α,25 dihydroxyvitamin D3 (calcitriol), the physiologically active form of vitamin D, induces cell differentiation and inhibits proliferation, invasiveness, angiogenesis, and metastatic potential.11,12 These biological phenomena are typical of cancer genesis and some of them (eg, differentiation and proliferation) are also involved in cardiovascular ischemic diseases. Second, many tissues express the 1α-hydroxylase enzyme.11 So, after 25-hydroxylation of vitamin D in the liver, many cell types are able to convert the circulating 25-hydroxyvitamin D into 1α,25-dihydroxyvitamin D, and autocrine or paracrine production of 1α,25-dihydroxyvitamin D would depend on serum concentration of 25-hydroxyvitamin D.
In industrialized countries, cancer, cardiovascular diseases, and metabolic disorders such as diabetes mellitus account for 60% to 70% of deaths among subjects 50 years or older.13,14 If the associations made between vitamin D and these conditions were consistent, then interventions effectively strengthening vitamin D status should result in reduced total mortality. In this meta-analysis, we examined the risk of dying from any cause in subjects who participated in randomized trials testing the impact of vitamin D supplementation (ergocalciferol [vitamin D2] or cholecalciferol [vitamin D3]) on any health condition.
The study design was the quantitative synthesis of randomized controlled trials that could contribute to evaluating the impact of vitamin D supplementation on death from any cause.
The outcome of this analysis was total mortality;the supplementation evaluated was vitamin D2 (ergocalciferol) or vitamin D3 (cholecalciferol). Calcitriol and other vitamin D analogues have seldom been tested for prevention purposes. The few small trials that used these compounds for fracture prevention reported a total of 20 deaths from all causes and demonstrated their toxic effects, mainly hypercalcemia.15 We did not include trials that evaluated treatment with 1α-hydroxyvitamin D3 (alfacalcidol), the physiologically active form of vitamin D (1α,25-dihydroxyvitamin D3 [calcitriol]), or other vitamin D analogues in patients with advanced prostate cancer, chronic renal disease, or end-stage renal disease or in patients undergoing renal dialysis.
The search was carried out for clinical trials, and no language or time restrictions were applied. The literature up to November 2006 was searched using the following databases: PubMed, ISI Web of Science (Science Citation Index Expanded), EMBASE, and the Cochrane Library. For intervention, the following keywords or corresponding MeSH terms were used: vitamin D, cholecalciferol, and ergocalciferol. For methods, the following keywords and or corresponding MeSH terms used were randomized controlled trial and placebo. A first general search was done using combinations of keywords for intervention and for method. After that, we made searches using combinations of intervention keywords with the following outcome keywords (and their corresponding MeSH terms): congestive heart failure, coronary heart disease, cardiovascular disease, fracture, bone mineral density, and bone turnover. Mortality was not a helpful keyword because none of the trials with vitamin D supplements, except for 1 trial in the United Kingdom,16 had mortality as an end point.
The search for keywords in the title and in the abstract was done systematically. A manual search was done of references cited in the selected articles and in selected reviews or books. Any abstract or article whose title or summary contained at least 1 intervention keyword and 1 method keyword or 1 intervention keyword and 1 outcome keyword was retrieved and read.
For an article to be included in our analysis, it must have met the following criteria:
To represent the principal published report on a randomized controlled trial evaluating an intervention with vitamin D. The addition of calcium supplements in the intervention group and the absence of a placebo for vitamin D in the control group (ie, an open-label trial) were not exclusion criteria.
To be independent from other studies to avoid giving double weight to estimates derived from the same trial.
To have deaths from any cause reported separately for the intervention and the control groups. If in an article the number of all-cause deaths was not reported by treatment group, we tried to contact corresponding authors to obtain the missing information.
To have subjects randomized to the intervention and control groups on an individual basis. Cluster randomization (eg, a nursing home taken as a randomization unit) was not valid because mortality in a specific cluster could be increased by a health event (eg, an influenza epidemic) affecting this cluster and not the others.
To have sufficient information to allow adequate estimation of the relative risks (RRs) and 95% confidence intervals (CIs) (ie, crude data or adjusted RRs and standard errors, 95% CIs, or P values) to estimate mortality risk after vitamin D intake vs placebo or control.
Description of studies retrieved
A total of 992 articles or abstracts were retrieved and checked for relevance in terms of intervention, design, and reporting of mortality data. This process resulted in retrieving a total of 27 articles or abstracts that published information on randomized clinical trials evaluating effects of vitamin D supplementation on any end point and reporting data on deaths. Of these 27 articles, 9 were not included in the meta-analysis for the following reasons: (1) Two articles referred to the same trial.17,18 (2) Three did not report deaths by treatment arm (16 deaths overall) and this information could not be retrieved.19-21 (3) In 2 trials, the intervention consisted of a set of drugs including vitamin D.22,23 (4) Two trials were based on cluster randomization,24,25 and 1 of them did not report deaths by trial groups.25 A trial in England24 randomized 118 homes for elderly people, including 3717 participants with a mean age of 85 years. The intervention was equivalent to a daily dose of 1100 IU of ergocalciferol. (5) A placebo-controlled randomized trial was excluded because it was impossible to relate numbers of reported deaths (about 17 deaths) with numbers of subjects in randomization groups.26
One article27 compared an open-label trial with a subgroup of the placebo-controlled RECORD (Randomised Evaluation of Calcium Or vitamin D) trial.28 We used the data from the open-label trial and not from the subgroup of the RECORD trial to have independent studies. For the open-label trial, we took the numbers of deaths at the end of the follow-up that were mentioned in another report.15Table 1 summarizes the 18 studies that were used for the meta-analysis.
Denominators used for calculating death rates in each randomization group were all participants randomized to that group (intent-to-treat analysis). Some trials, such as the RECORD trial,28 had a factorial design (eg, calcium and vitamin D supplementation and vitamin D supplementation alone compared with calcium supplementation alone or with placebo). In such cases, in the meta-analyses, data related to groups receiving vitamin D were considered as coming from the “intervention group” and data related to groups not receiving vitamin D were considered as coming from the “control group.”
In most of the selected studies, mortality was a relatively rare event, and we therefore ignored the distinction between the various measures of relative risk (ie, odds ratio, rate ratio, and risk ratio). We transformed the RR estimates and their CIs into log RR, and we calculated the corresponding variance using the formula proposed by Greenland44 in 1987. When estimates were not given, we calculated them from tabular data, and we used the Woolf formula to evaluate the standard error of the log odds ratio.44 Logit estimators were used for a correction of 0.5 in every cell of those tables that contained a zero (Proc Freq with SAS [SAS Windows version 8.02; SAS Institute Inc, Cary, North Carolina; 1999]).
The association between intake of vitamin D supplements and all-cause mortality across selected trials was computed as a summary RR (SRR) with 95% CIs. The SRR was considered statistically significant if the 95% CI did not include 1.0.
We assessed the homogeneity of the effect across studies using the large sample test based on the χ2 statistic. Since the χ2 test has limited power, we considered that statistically significant heterogeneity existed when the P value was ≤.10.45 Subgroup analyses and meta-regressions were carried out to investigate between-study heterogeneity focusing on type of study, type of control, length of follow-up, vitamin D dose, use of calcium, year of publication, and country. Heterogeneity was compared among subgroup analyses by using the I2 parameter, which represents the percentage of total variation across studies that is attributable to heterogeneity rather than to chance.46 The SRR was estimated pooling the study-specific estimates by random effects models fitted using SAS (Proc Mixed) with maximum likelihood estimate. Two funnel plot–based approaches were used for assessing publication bias: the sensitivity analysis of Copas and Shi47 and the funnel plot regression of ln(RR) on the sample size, weighted by the inverse of the pooled variance.48
The main meta-analysis was carried out on 18 independent randomized controlled trials with individual randomization (Table 1): 12 placebo-controlled and 6 open-label trials. The numbers of trial participants varied from 55 to 36 282. Mean follow-up varied between 6 months to 7 years, with a mean of 5.7 years after adjustment for trial sizes.
The mean daily dose of vitamin D supplements varied from 300 IU18 to 2000 IU,41 but most of the daily doses were between 400 IU and 833 IU. When taking trial sizes into account, the mean daily vitamin D dose was 528 IU. Table 2 indicates a substantial increase from baseline levels of serum 25-hydroxyvitamin D levels in intervention groups, while levels tended to decrease in control groups, translating to a 1.4- to 5.2-fold difference in serum 25-hydroxyvitamin D level between intervention and control groups. However, increases from baseline levels and in-study differences between intervention and control groups seemed unrelated to daily dose taken. Compliance with taking vitamin D supplements in the largest trials (see “Trials With Decent Statistical Power” in the Figure) was 48% in the RECORD Trial,28 59% in the Women's Health Initiative trial,42,43 63% in the trial by Porthouse et al,39 68% in the trial by Ficker et al,40 79% in the trial by Meyer et al,34 80% in the trial by Trivedi et al,16 83% in the trial by Chapuy et al33 in 2002, 85% in the trial by Lips et al,30 and 95% in the trial by Chapuy et al29 in 1992.
The 18 trials included 57 311 participants, and 4777 deaths for any cause occurred during follow-up. The Figure shows for each selected trial the RRs of dying from any cause associated with taking vitamin D supplements. The SRR synthesizing results of the 18 trials indicated a significant decrease in the risk of all-cause mortality with using vitamin D supplements (SRR, 0.93; 95% CI, 0.87-0.99). There was no indication for heterogeneity (P = .52) or of publication bias (P = .37 with the method of Copas and Shi47 and P = .77 with the method of Macaskill et al48).
A subgroup analysis (Table 3) shows no appreciable change in SRR according to trial duration and dose of vitamin D supplements.Calcium supplements seemed not to be involved in the total mortality decrease, as the SRRs remained similar in trials with or without calcium supplements as part of the intervention. Exclusion of the quasirandomized trial34 did not affect results. Inclusion of 1 cluster-randomized trial25 increased the SRR but also brought substantial heterogeneity. In this respect, exclusion of this trial was justified.
Results of this meta-analysis of randomized controlled trials suggest that intake of vitamin D supplements may decrease total mortality during trial duration. Publication bias toward concealment of trial results showing no impact of vitamin D supplements on all-cause mortality is not likely because total mortality did not constitute a main end point for any of the 18 trials included in the meta-analysis except 1.16 Timing of deaths during trials was never reported, and we thus could not assess whether exclusion of deaths occurring during the first year of follow-up would have modified the SRRs.
The effect on mortality was not likely to be due to calcium supplements, since the 5 trials that did not include calcium supplements in the intervention group16,29,34,35,40 had an SRR similar to those found with trials that included both vitamin D and calcium supplements. No relationship was found with dose of vitamin D supplements, but in most trials, the daily dose range was relatively narrow (ie, 400-830 IU), and large variations in size of trials and in compliance to interventions preclude any conclusion on optimal vitamin D daily dose associated with mortality reduction.
Most trials included in the meta-analysis were conducted in frail elderly people who are at high risk of fall or of low-energy fracture, who often have low serum 25-hydroxyvitamin D levels. Vitamin D is known to increase postural stability and to reduce fall incidence by 22% in elderly subjects, but about 15 elderly people must take vitamin D supplements for avoiding 1 person from falling.49 Such an effect cannot translate to a 7% decrease in total mortality. Also, the Women's Health Initiative,42,43 which accounted for nearly half of the participants considered in this meta-analysis, included younger women with a low probability to die because of falls.
Vitamin D regimens used in trials ranged from 300 to 833 IU, and most vitamin D supplements publicly available include a daily dose of 400 IU to 600 IU that entailed no toxic effects. Serum concentration of 25-hydroxyvitamin D is considered as a good reflection of skin synthesis and food intakes of vitamin D.50 Data from 9 trials showed that the intake of vitamin D supplements resulted in increases in serum 25-hydoxyvitamin D levels. Such data were not available for the other trials, including the Women's Health Initiative.42,43 It was thus not possible to assess from this meta-analysis whether a correlation exists between the magnitude of mortality reduction and the difference in circulating 25-hydroxyvitamin D.
Of the 18 randomized trials, 2 included in this meta-analysis (a trial in the United Kingdom16 and the Women's Health Initiative43) reported the association of vitamin D supplements with incidence and mortality of some cancers and of cardiovascular diseases. In the United Kingdom trial, the rate ratios (95% CIs) between the intervention and control groups for the incidence of cardiovascular diseases, cancers, and colorectal cancer were 0.90 (0.77-1.06), 1.11 (0.86-1.42), and 1.02 (0.60-1.74), respectively.16 For mortality, these ratios were 0.84 (0.65-1.10), 0.86 (0.61-1.20), and 0.62 (0.24-1.60), respectively. In the Women's Health Initiative trial, rate ratios (95% CIs) for incidence of cancer and of colorectal cancer were 0.98 (0.91-1.05) and 1.08 (0.86-1.34), respectively, and rate ratios (95% CIs) for mortality were 0.89 (0.77-1.03) and 0.82 (0.52-1.29), respectively.43 Hence, although none of these results reached statistical significance, incidence rate ratios were always close to 1.0, while mortality rate ratios were always lower, suggesting that vitamin D supplementation would affect mortality associated with cancers and cardiovascular diseases, but would probably have less of an effect (or not at all) on their incidence. This hypothesis is reinforced by recent observations: one prospective cohort study among adult Finish male smokers showed an increasing incidence of pancreas cancer with increasing serum 25-hydroxyvitamin D level.51 In contrast, another prospective study showed that women diagnosed as having advanced breast cancer had lower serum 25-hydroxyvitamin D concentrations than women diagnosed as having less advanced breast cancer.52 In a prospective study in which serum 25-hydoxyvitamin D concentration was estimated using an indirect method based on questions, the influence of decreasing concentrations was more manifest for cancer mortality than for cancer incidence.53
A meta-analysis of randomized trials on supplementation with beta carotene, vitamins A and E, ascorbic acid, and selenium found an increased RR for all-cause mortality of 1.06 (95% CI, 1.02-1.10) associated with the taking of these supplements.54 A randomized controlled trial of the Women's Health Study found no effect of supplementation with 600 IU/d of vitamin E on total mortality.55 These results are contrasting with the results from our meta-analysis on vitamin D supplements. Our results also provide reassurance that at ordinary doses, long-term vitamin D supplementation does not seem to be associated with an overall adverse effect.
Mechanisms by which vitamin D supplementation would decrease all-cause mortality are not clear. The physiologically active form of vitamin D (1α,25 dihydroxyvitamin D [calcitriol]) acts as a hormone that has pleiotropic skeletal and extra skeletal effects on, among other things, calcium homeostasis, bone formation, cellular proliferation and differentiation, immune system, bile acid transport, rennin production, the endothelium and vascular walls, and the endocrine system.11,56 Some effects mediated through the activation of the vitamin D receptor, such as inhibition of cellular proliferation and activation of cellular differentiation,12,57 could reduce aggressiveness of cancerous processes and expansion of atheromatous lesions. Interestingly, the ability of strong cholesterol reducers, the statins, to decrease all-cause mortality could partly be due to increases in vitamin D levels they would provoke or though acting as vitamin D analogues on vitamin D receptors.10,58 The biological mechanism by which vitamin D would prevent and possibly reduce the severity of type 2 diabetes mellitus59 remains unknown.60
In conclusion, the intake of ordinary doses of vitamin D supplements seems to be associated with decreases in total mortality rates. The relationship between baseline vitamin D status, dose of vitamin D supplements, and total mortality rates remains to be investigated. Population-based, placebo-controlled randomized trials in people 50 years or older for at least 6 years with total mortality as the main end point should be organized to confirm these findings.
Correspondence: Philippe Autier, MD, International Agency for Research on Cancer, 150 cours Albert Thomas, F-69372 Lyon CEDEX 08, France (autierp@iarc.fr).
Accepted for Publication: April 18, 2007.
Author Contributions: Drs Autier and Gandini had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: Autier. Acquisition of data: Autier and Gandini. Analysis and interpretation of data: Autier and Gandini. Drafting of the manuscript: Autier. Statistical analysis: Gandini. Administrative, technical, and material support: Autier. Study supervision: Autier.
Financial Disclosure: None reported.
Additional Contributions: The librarians William Russel-Edu of the European Institute of Oncology and Sharon Grant from the International Agency for Research on Cancer retrieved the literature. John Daniels of the International Agency for Research on Cancer provided editorial help.
This article was corrected for typographical errors on 9/17/2007.
1.Grant
WB Ecologic studies of solar UV-B radiation and cancer mortality rates.
Recent Results Cancer Res 2003;164371- 377
PubMedGoogle Scholar 2.Zittermann
ASchleithoff
SSKoerfer
R Putting cardiovascular disease and vitamin D into perspective.
Br J Nutr 2005;94
(4)
483- 492
PubMedGoogle ScholarCrossref 3.Scragg
R Seasonality of cardiovascular disease mortality and the possible protective effect of ultra-violet radiation.
Int J Epidemiol 1981;10
(4)
337- 341
PubMedGoogle ScholarCrossref 4.Lim
HSRoychoudhuri
RPeto
JSchwartz
GBaade
PMoller
H Cancer survival is dependent on season of diagnosis and sunlight exposure.
Int J Cancer 2006;119
(7)
1530- 1536
PubMedGoogle ScholarCrossref 5.IARC, Solar and Ultraviolet Radiation. 55 Lyon, France International Agency for Research on Cancer1992;IARC Monographs on the Evaluation of Carcinogenic Risks to Humans
6.Giovannucci
E The epidemiology of vitamin D and cancer incidence and mortality: a review (Unites States).
Cancer Causes Control 2005;16
(2)
83- 95
PubMedGoogle ScholarCrossref 7.Kricker
AArmstrong
B Does sunlight have a beneficial influence on certain cancers?
Prog Biophys Mol Biol 2006;92
(1)
132- 139
PubMedGoogle ScholarCrossref 8.Garland
CFGarland
FCGorham
ED
et al. The role of vitamin D in cancer prevention.
Am J Public Health 2006;96
(2)
252- 261
PubMedGoogle ScholarCrossref 11.Ordonez-Moran
PLarriba
MJPendas-Franco
N
et al. Vitamin D and cancer: an update of in vitro and in vivo data.
Front Biosci 2005;102723- 2749
PubMedGoogle ScholarCrossref 12.Banerjee
PChatterjee
M Antiproliferative role of vitamin D and its analogs—a brief overview.
Mol Cell Biochem 2003;253
(1-2)
247- 254
PubMedGoogle ScholarCrossref 13.National Center for Health Statistics, Health, United States, 2006, With Chart Book on Trends in the Health of Americans. Hyattsville, MD National Center for Health Statistics2006;
14.Niederlaender
E Causes of Death in the EU. Luxembourg City, Luxembourg Eurostat October2006;Population and Social Conditions—Statistics in Focus 10/2006
15.Avenell
AGillespie
WJGillespie
LDO'Connell
DL Vitamin D and vitamin D analogues for preventing fractures associated with involutional and post-menopausal osteoporosis.
Cochrane Database Syst Rev 2005;
(3)
CD000227
PubMedGoogle Scholar 16.Trivedi
DPDoll
RKhaw
KT Effect of four monthly oral vitamin D3 (cholecalciferol) supplementation on fractures and mortality in men and women living in the community: randomized double blind controlled trial.
BMJ 2003;326
(7387)
469- 472
PubMedGoogle ScholarCrossref 17.Komulainen
MHKroger
HTuppurainen
MT
et al. HRT and Vit D in prevention of non-vertebral fractures in postmenopausal women: a 5 year randomized trial.
Maturitas 1998;31
(1)
45- 54
PubMedGoogle ScholarCrossref 18.Komulainen
MKroger
HTuppurainen
MT
et al. Prevention of femoral and lumbar bone loss with hormone replacement therapy and vitamin D3 in early postmenopausal women: a population based 5-year randomized trial.
J Clin Endocrinol Metab 1999;84
(2)
546- 552
PubMedGoogle Scholar 19.Bischoff
HAStahelin
HBDick
W
et al. Effects of vitamin d and calcium supplementation on falls: a randomized controlled trial.
J Bone Miner Res 2003;18
(2)
343- 351
PubMedGoogle ScholarCrossref 20.Graafmans
WCOoms
MEHofstee
HMBezemer
PDBouter
LMLips
P Falls in the elderly: a prospective study of risk factors and risk profiles.
Am J Epidemiol 1996;143
(11)
1129- 1136
PubMedGoogle ScholarCrossref 21.Keane
EMHealy
MO'Moore
RCoakley
DWalsh
JB Vitamin D–fortified liquid milk: benefits for the elderly community-based population.
Calcif Tissue Int 1998;62
(4)
300- 302
PubMedGoogle ScholarCrossref 22.Hedström
MSjoberg
KBrosjo
EAstrom
KSjoberg
HDalen
N Positive effects of anabolic steroids, vitamin D and calcium on muscle mass, bone mineral density and clinical function after a hip fracture: a randomised study of 63 women.
J Bone Joint Surg Br 2002;84
(4)
497- 503
PubMedGoogle ScholarCrossref 23.Sato
YKanoko
TSatoh
KIwamoto
J The prevention of hip fracture with risedronate and ergocalciferol plus calcium supplementation in elderly women with Alzheimer disease: a randomized controlled trial.
Arch Intern Med 2005;165
(15)
1737- 1742
PubMedGoogle ScholarCrossref 24.Law
MWithers
HMorris
JAnderson
F Vitamin D supplementation and the prevention of fractures and falls: results of a randomised trial in elderly people in residential accommodation.
Age Ageing 2006;35
(5)
482- 486
PubMedGoogle ScholarCrossref 25.Larsen
ERMosekilde
LFoldspang
A Vitamin D and calcium supplementation prevents osteoporotic fractures in elderly community dwelling residents: a pragmatic population-based 3-year intervention study.
J Bone Miner Res 2004;19
(3)
370- 378
PubMedGoogle ScholarCrossref 26.Corless
DDawson
EFraser
F
et al. Do vitamin D supplements improve the physical capabilities of elderly hospital patients.
Age Ageing 1985;14
(2)
76- 84
PubMedGoogle ScholarCrossref 27.Avenell
AGrant
AMMcGee
MMcPherson
GCampbell
MKMcGee
MARECORD Trial Management Group, The effects of an open design on trial participant recruitment, compliance and retention—a randomized controlled trial comparison with a blinded, placebo-controlled design.
Clin Trials 2004;1
(6)
490- 498
PubMedGoogle ScholarCrossref 28.Grant
AMAvenell
ACampbell
MK
et al. RECORD Trial Group, Oral vitamin D3 and calcium for secondary prevention of low-trauma fractures in elderly people: a randomised placebo-controlled trial.
Lancet 2005;365
(9471)
1621- 1628
PubMedGoogle ScholarCrossref 29.Chapuy
MCArlot
MEDuboeuf
F
et al. Vitamin D3 and calcium to prevent hip fractures in elderly women.
N Engl J Med 1992;327
(23)
1637- 1642
PubMedGoogle ScholarCrossref 30.Lips
PGraafmans
WCOoms
MEBezemer
PDBouter
LM Vitamin D supplementation and fracture incidence in elderly persons.
Ann Intern Med 1996;124
(4)
400- 406
PubMedGoogle ScholarCrossref 31.Baeksgaard
LAndersen
KPHylstrup
L Calcium and vitamin supplementation increases spinal BMD in healthy, postmenopausal women.
Osteoporos Int 1998;8
(3)
255- 260
PubMedGoogle ScholarCrossref 32.Krieg
MAJacquet
AFBremgartner
MCuttelod
SThiebaud
DBurckhardt
P Effect of supplementation with vitamin D3 and calcium on quantitative ultrasound of bone in elderly institutionalized women: a longitudinal study.
Osteoporos Int 1999;9
(6)
483- 488
PubMedGoogle Scholar 33.Chapuy
MCPamphile
RParis
E
et al. Combined calcium and vitamin D3 supplementation in elderly women: confirmation of reversal of secondary hyperparathyroidism and hip fracture risk: the Decalyos II Study.
Osteoporos Int 2002;13
(3)
257- 264
PubMedGoogle ScholarCrossref 34.Meyer
HESmedshaug
GBKvaavik
EFalch
JATverdal
APedersen
JI Can vitamin D supplementation reduce the risk of fracture in the elderly? a randomized controlled trial.
J Bone Miner Res 2002;17
(4)
709- 715
PubMedGoogle ScholarCrossref 35.Latham
NKAnderson
CSLee
A
et al. A randomized, controlled trial of quadriceps resistance exercise and vitamin D in frail older people: the Frailty Interventions Trial in Elderly Subjects.
J Am Geriatr Soc 2003;51
(3)
291- 299
PubMedGoogle ScholarCrossref 36.Harwood
RHSahota
OGaynor
K
et al. A randomised, controlled comparison of different calcium and vitamin D supplementation regimens in elderly women after hip fracture: the Nottingham Neck of Femur (NoNOF) Study.
Age Ageing 2004;33
(1)
45- 51
PubMedGoogle ScholarCrossref 37.Meier
CWoitge
HWWitte
KLemmer
BSeibel
MJ Supplementation with oral vitamin D3 and calcium during winter prevents seasonal bone loss: a randomized controlled open-label prospective trial.
J Bone Miner Res 2004;19
(8)
1221- 1230
PubMedGoogle ScholarCrossref 38.Brazier
MGrados
FKamel
S
et al. Clinical and laboratory safety of one year's use of a combination calcium + vitamin D tablets in ambulatory elderly women with vitamin D insufficiency: results of a multicenter, randomized, double-blind, placebo-controlled study.
Clin Ther 2005;27
(12)
1885- 1893
PubMedGoogle ScholarCrossref 39.Porthouse
JCockayne
SKing
C
et al. Randomised controlled trial of calcium and supplementation with cholecalciferol (vitamin D3) for prevention of fractures in primary care.
BMJ 2005;330
(7498)
1003
PubMedGoogle ScholarCrossref 40.Flicker
LMacInnis
RStein
M
et al. Should all older people in residential care receive vitamin D to prevent falls? results of a randomised trial [abstract].
J Bone Miner Res 2004;19
((suppl 1))
S99
Google Scholar 41.Schleithoff
SSZittermann
ATenderich
GBerthold
HKStehle
PKoerfer
R Vitamin D supplementation improves cytokine profiles in patients with congestive heart failure: a double-blind, randomized, placebo-controlled trial.
Am J Clin Nutr 2006;83
(4)
754- 759
PubMedGoogle Scholar 42.Jackson
RDLaCroix
AZGass
M
et al. Women's Health Initiative Investigators, Calcium plus vitamin D supplementation and the risk of fractures.
N Engl J Med 2006;354
(7)
669- 683
PubMedGoogle ScholarCrossref 43.Wactawski-Wende
JKotchen
JMAnderson
GL
et al. Women's Health Initiative Investigators, Calcium plus vitamin D supplementation and the risk of colorectal cancer.
N Engl J Med 2006;354
(7)
684- 696
PubMedGoogle ScholarCrossref 44.Greenland
S Quantitative methods in the review of epidemiologic literature.
Epidemiol Rev 1987;91- 30
PubMedGoogle Scholar 45.Sterne
JAJuni
PSchulz
KFAltman
DGBartlett
CEgger
M Statistical methods for assessing the influence of study characteristics on treatment effects in “meta-epidemiological” research.
Stat Med 2002;21
(11)
1513- 1524
PubMedGoogle ScholarCrossref 48.Macaskill
PWalter
SDIrwig
L A comparison of methods to detect publication bias in meta-analysis.
Stat Med 2001;20
(4)
641- 654
PubMedGoogle ScholarCrossref 49.Bischoff-Ferrari
HADawson-Hughes
BWillett
WC
et al. Effect of vitamin D on falls: a meta-analysis.
JAMA 2004;291
(16)
1999- 2006
PubMedGoogle ScholarCrossref 50.Bouillon
RMoody
TSporn
MBarrett
JCNorman
AW NIH deltanoids meeting on vitamin D and cancer: conclusion and strategic options.
J Steroid Biochem Mol Biol 2005;97
(1-2)
3- 5
PubMedGoogle ScholarCrossref 51.Stolzenberg-Solomon
RZVieth
RAzad
A
et al. A prospective nested case-control study of vitamin D status and pancreatic cancer risk in male smokers.
Cancer Res 2006;66
(20)
10213- 10219
PubMedGoogle ScholarCrossref 52.Palmieri
CMacGregor
TGirgis
SVigushin
D Serum 25 hydroxyvitamin D levels in early and advanced breast cancer.
J Clin Pathol 2006;59
(12)
1334- 1336
PubMedGoogle ScholarCrossref 53.Giovannucci
ELiu
YRimm
EB
et al. A prospective Study of predictors of vitamin D status and cancer incidence and mortality in men.
J Natl Cancer Inst 2006;98
(7)
451- 459
PubMedGoogle ScholarCrossref 54.Bjelakovic
GNikolova
DSimonetti
RGGluud
C Antioxidant supplements for prevention of gastrointestinal cancers: a systematic review and meta-analysis.
Lancet 2004;364
(9441)
1219- 1228
PubMedGoogle ScholarCrossref 55.Lee
IMCook
NRGaziano
JM
et al. Vitamin E in the primary prevention of cardiovascular disease and cancer: the Women's Health Study: a randomized controlled trial.
JAMA 2005;294
(1)
56- 65
PubMedGoogle ScholarCrossref 56.Bouillon
REelen
GVerlinden
LMathieu
CCarmeliet
GVerstuyf
A Vitamin D and cancer.
J Steroid Biochem Mol Biol 2006;102
(1-5)
156- 162
PubMedGoogle ScholarCrossref 57.Pendás-Franco
NGonzalez-Sancho
JMSuarez
Y
et al. Vitamin D regulates the phenotype of human breast cancer cells.
Differentiation 2007;75
(3)
193- 207
PubMedGoogle ScholarCrossref 58.Pérez-Castrillón
JLVega
GAbad
L
et al. Effects of atorvastatin on vitamin D levels in patients with acute ischemic heart disease.
Am J Cardiol 2007;99
(7)
903- 905
PubMedGoogle ScholarCrossref 59.Pittas
AGDawson-Hughes
BLi
T
et al. Vitamin D and calcium intake in relation to type 2 diabetes in women.
Diabetes Care 2006;29
(3)
650- 656
PubMedGoogle ScholarCrossref 60.Barbeau
WEBassaganya-Riera
JHontecillas
R Putting the pieces of the puzzle together—a series of hypotheses on the etiology and pathogenesis of type 1 diabetes.
Med Hypotheses 2007;68
(3)
607- 619
PubMedGoogle ScholarCrossref