In recent years, the scientific evidence linking vitamin D status or supplementation to breast cancer has grown notably. To investigate the role of vitamin D supplementation on breast cancer incidence, we conducted a systematic review and meta-analysis of randomized controlled trials comparing vitamin D with placebo or no treatment. We used OVID to search MEDLINE (R), EMBASE and CENTRAL until April 2012. We screened the reference lists of included studies and used the “Related Article” feature in PubMed to identify additional articles. No language restrictions were applied. Two reviewers independently extracted data on methodological quality, participants, intervention, comparison and outcomes. Risk Ratios and 95% Confident Intervals for breast cancer were pooled using a random-effects model. Heterogeneity was assessed using the I2 test. In sensitivity analysis, we assessed the impact of vitamin D dosage and mode of administration on treatment effects. Only two randomized controlled trials fulfilled the pre-set inclusion criteria. The pooled analysis included 5372 postmenopausal women. Overall, Risk Ratios and 95% Confident Intervals were 1.11 and 0.74–1.68. We found no evidence of heterogeneity. Neither vitamin D dosage nor mode of administration significantly affected breast cancer risk. However, treatment efficacy was somewhat greater when vitamin D was administered at the highest dosage and in combination with calcium (Risk Ratio 0.58, 95% Confident Interval 0.23–1.47 and Risk Ratio 0.93, 95% Confident Interval 0.54–1.60, respectively). In conclusions, vitamin D use seems not to be associated with a reduced risk of breast cancer development in postmenopausal women. However, the available evidence is still limited and inadequate to draw firm conclusions. Study protocol code: FARM8L2B5L.
Citation: Sperati F, Vici P, Maugeri-Saccà M, Stranges S, Santesso N, et al. (2013) Vitamin D Supplementation and Breast Cancer Prevention: A Systematic Review and Meta-Analysis of Randomized Clinical Trials. PLoS ONE 8(7): e69269. doi:10.1371/journal.pone.0069269
Editor: German Malaga, Universidad Peruana Cayetano Heredia, Peru
Received: March 6, 2013; Accepted: June 6, 2013; Published: July 22, 2013
Copyright: © 2013 Sperati et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Funding: This project was supported by grant code FARM8L2B5L from the Italian Medicines Agency (AIFA). The content is solely the responsibility of the authors and does not necessarily represent the official views of the financing institution. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Competing interests: The authors have declared that no competing interests exist.
In recent years, the scientific evidence linking vitamin D (vit D) to breast cancer has grown notably. Garland and Garland first hypothesized a role of exposure to solar radiation in explaining geographic variation in breast cancer incidence. Accordingly, lower levels of vit D resulting from weaker UV-B radiation were suggested to explain higher breast cancer rates at higher latitudes. However, this ecological observation was only partially substantiated by subsequent epidemiological studies –.
Several observational studies have focused on the association between breast cancer risk and circulating levels of 25 (OH) hydroxyvitamin D (25-OH vit D), which is the precursor of the active hormone 1,25 (OH)2 vit D and the most commonly used biomarker of vit D status. Results from case-control studies have consistently revealed an inverse association between 25-OH vit D and breast cancer –. Conversely, evidence from prospective studies tend to be inconsistent. No significant inverse association between 25-OH vit D levels and breast cancer risk was observed in a meta-analysis including four prospective studies in 2010 , while in a subsequent meta-analysis including two additional prospective studies a significant inverse association was found . Since negative findings emerged from three further prospective studies published after these latter meta-analyses –, the evidence from prospective studies focused on the association between 25-OH vit D levels and breast cancer risk remains substantially unclear.
Several systematic reviews including randomized controlled trials (RCTs) have recently focused on vit D and health outcomes. Autier investigated the impact of vit D supplementation on death from any cause including cancer. Vit D was associated with a slight reduction in death from any cause [summary relative risk and 95% Confident Interval (CI) were 0.93, 0.87–0.99]. Eighteen RCTs were included, but only two of them reported on cancer incidence and mortality, overall and for colorectal cancer –. Chung has addressed the role of vit D supplementation in prevention of cancer and fractures. Nineteen RCTs were included, but only three focused on cancer outcomes and two reported on breast cancer –. Though limited, the available data seemed to suggest a role of vit D in reducing the risk for total cancer . More recently, an individual patient data meta-analysis of eight RCTs has confirmed a 7% reduction in overall mortality for participants allocated to vit D (0.93, 95% CI 0.88–0.99). The authors did not report on cancer outcomes .
So far, no systematic review has specifically addressed the role of vit D supplementation in breast cancer prevention. We aimed to investigate risk of breast cancer development in a systematic review of women participating in RCTs of vit D supplementation compared with placebo/no treatment.
Materials and Methods
This systematic review was performed in full agreement with an ad-hoc study protocol which was submitted to the Italian Agency of Drugs (AIFA) in 2008 (study protocol code: FARM8L2B5L).
Data Sources and Search
In April 2012, a qualified librarian used OVID to electronically search MEDLINE (R) (January 1950 onward), EMBASE (January 1980 onward), and the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library, latest issue). We designed and applied the search strategy using sensitivity criteria potentially capturing RCTs of vit D use in both breast cancer prevention and treatment. To this aim, we combined terms for vit D and cancer (Appendix 1) with search filters for RCTs . We also screened the references of included studies and used the “Related Article” feature in PubMed to identify additional articles.
No language restrictions were applied.
Study Selection and Outcomes of Interest
Included studies were RCTs of vit D in breast cancer. Studies suitable for inclusion were RCTs of vit D in breast cancer. We considered RCTs if vit D was administered as a single agent compared with placebo/no treatment or as part of combined regimens including supplements and lifestyle modifications as long as the administration of the co-intervention was planned to be the same in all groups. For multi-arm RCTs, we included all pairwise comparisons with arms differing by vit D use only. Breast cancer incidence and mortality were the outcomes of interest in RCTs focused on breast cancer prevention. We planned to consider survival, time to recurrence, risk of ipsilateral and/or contralateral disease, health related quality of life and toxicity as outcomes of interest in RCTs of vit D in breast cancer treatment. However, only trials of vit D in breast cancer prevention were included. RCTs involving pregnant or lactating women were excluded.
Data Extraction and Assessment of Risk of Bias
Two reviewers independently completed title and abstract screening and full text review. Disagreements were solved through discussion or consultation of a third reviewer. A pilot-tested form was used for data extraction. Collected data related to methodological quality, participants, intervention, comparison and outcomes. In regards to outcome data, Risk Ratios (RRs) were calculated by treatment arm for breast cancer incidence. For mortality, we planned to abstract the log hazard ratio [log(HR)] and its variance .
Risk of bias was assessed using the Cochrane risk of bias tool. Two reviewers independently assessed methodological quality and resolved disagreements by discussion. Their evaluation focused on randomization, blinding, percentage of lost to follow-up, early stop for benefit or harm, intention-to-treat (ITT) principle, incomplete outcome data, selective reporting. In order to assess reporting bias, we compared the list of outcomes from the protocol to the outcomes reported in the published paper . We planned to assess publication bias by mean of funnel plots and visual inspection for asymmetry –. However, the very low number of RCTs included did not allow such an evaluation.
Data Synthesis and Analysis
We calculated the agreement between the two reviewers for the assessment of eligibility using kappa statistic.
Heterogeneity was assessed using the I2 test and judged considerable if ≥75% . We tested the effect of vit D dosage in meta-regression analysis. In subgroup analyses, we assessed whether vit D administration as a single agent or combined with calcium had an impact on treatment effects. We used Revman 5.0 and Stata version 8.2 (Stata Coro., College Station, Tx, USA) for statistical analysis.
Results of the Search
The flow diagram of the trial selection process appears in figure 1.
Figure 1. Flow diagram of the trial selection process.doi:10.1371/journal.pone.0069269.g001
The April 2012 search identified 5690 unique citations. Based on the title and abstract screening, we rejected 5597 citations. Among the remaining 93 unique citations, 91 were excluded for the following reasons: 1. Eight did not report on cancer outcomes -; 2. Twenty four did not report on breast cancer outcomes –; 3.Twenty eight were not RCTs –; 4. Eighteen did not fulfill the inclusion criterion related to the intervention , –; 5. Thirteen were excluded because combining at least 2 among the previously described features (1 to 5) , , – (Figure 1). Only two trials fulfilled the inclusion criteria , . Agreement between reviewers for study eligibility was excellent (kappa = 0.99).
Table 1 lists the characteristics of the two studies included.
Table 1. Characteristics of the included Randomized Clinical Trials (RCTs).doi:10.1371/journal.pone.0069269.t001
The first study was a randomized factorial-design trial of cholecalciferol and calcium supplementation for the secondary prevention of fragility fractures in 5292 people aged 70 years and older. Women represented about 85% of the overall sample. Participants were randomized to daily cholecalciferol (800 IU), calcium (1000 mg), both, or placebo for 24–62 months, with a minimum follow up for long term outcomes of three years. Cancer incidence and mortality were listed among the secondary outcomes along with overall mortality and mortality from vascular diseases. Overall, the study did not rule out a significant role of vit D or calcium on cancer incidence and mortality (HR: 1.06, 95% CI: 0.91–1.24, and HR: 1.03, 95% CI: 0.94–1.13, respectively) .
Lappe and co-authors carried out a 4-year, placebo-controlled, randomized trial to assess the impact of calcium and cholecalciferol supplementation on the skeletal status and calcium homeostasis in healthy postmenopausal women aged 55 years and older. The 1180 participants were randomized to placebo, consisting of both a vit D placebo and calcium placebo, calcium (1400 mg/day of calcium citrate or 1500 mg/day of calcium carbonate) and a vit D placebo, calcium and 1000 IU cholecalciferol/day. Cancer incidence was a secondary outcomes. The study results showed a decreased risk of cancer development in women randomized to calcium and cholecalciferol as well as in participants taking calcium compared with placebo (RR: 0.402, p = 0.001 and RR: 0.532, p = 0.06, respectively) .
Risk of Bias in Included Studies
Overall results of risk of bias assessment appear in figure 2.
Figure 2. Risk of bias summary.
Legend to Figure 2. Reviewers’ judgment on each “Risk of bias” item within each included study.doi:10.1371/journal.pone.0069269.g002
In both RCTs, randomization was centralized, computer-generated. Participating women were blind to treatment assignment due the use of placebo. No specific details are reported on whether blinding was extended to caregivers, data collectors, outcome assessors and analysts.
In the study from Lappe and co-authors, about 13.2% of the study participants (156 out of 1180) were lost to follow up. Reasons for drop out and droppers’ distribution across the study arms are not reported. Incomplete outcome data are not addressed by Avenell et al.
We found no evidence of selective reporting for the two studies included. In both the RCTs, the outcomes listed in the methods section of the cited manuscripts fully matched with those reported by the original protocols –.
None of the two RCTs was stopped earlier. Authors from both RCTs reported conducting ITT analyses. However, in Lappe and co-authors the number of participants randomized to treatment assignment does not exactly match with the number of participants followed up due to the exclusion of one woman after randomization. Reasons for exclusion are described in details. We could not identify further potential sources of bias for the studies included.
Effects of Intervention
Breast cancer incidence.
Both the included trials contributed patients to this outcome.
All the 4481 women participating in the trial from Avenell were included. By pre-set inclusion criteria calling for comparison of study groups differing by vit D use only, participants allocated to cholecalciferol and calcium were compared to participants taking calcium (Avenell A 2012-1st), while women in the vit D arm were compared to participants randomized to placebo (Avenell A 2012-2nd). Conversely, the study from Lappe et al contributed only partly to the quantitative synthesis on breast cancer incidence. Indeed, we included participants randomized to cholecalciferol and calcium (446/1180) and compared them to women allocated to calcium only (445/1180). Study participants assigned to placebo were not considered (288/1180). Women participating in this trial tended to be significantly younger and with higher serum concentration of 25-OH vit D at baseline (i.e. 71±20.3 nmol/liter) compared to those participating in the trial from Avenell and colleagues (Table 1). The most significant risk reduction was observed in women randomized to vit D and calcium compared with placebo (0.402, p = 0.01). This was the only subgroup with a significant change in circulating levels of 25-OH vit D at 12 months compared to baseline concentrations (i.e. absolute change 23.9±17.8).
The pooled analysis included 5372 women. Overall, RRs and 95% CI were 1.11 and 0.74–1.68, respectively. We found no evidence of significant heterogeneity (p = 0.59, I2: 0%) (figure 3). Meta-regression analysis of vit D dosage performed on the basis of a random effects model methodology showed non-significant results. However, there was a suggestion for greater treatment efficacy with higher vit D dosage (RR 0.58, 95% CI 0.23–1.47). In analysis of mode of administration, women taking vit D and calcium appeared somewhat less likely to develop breast cancer compared with subjects receiving calcium and placebo, though at a non significant extent (0.93, 0.54–1.59; I2: 0%) (figure 4).
Figure 3. Forest plot of vitamin D supplementation and breast cancer incidence.
Legend to Figure 3. M–H, Mantel-Haenszel; 95% CI, 95% confidence interval; df, degrees of freedom.doi:10.1371/journal.pone.0069269.g003
Figure 4. Forest plot of vitamin D supplementation and breast cancer incidence.
Administration mode on treatment effects. Legend to Figure 4. M–H, Mantel-Haenszel; 95% CI, 95% confidence interval; df, degrees of freedom.doi:10.1371/journal.pone.0069269.g004
Breast cancer mortality.
The number of breast cancer-related fatal events was available for one single study at three years of follow up. Deaths from breast cancer out of the total events due to cancer by study arm were as it follows: 7/78, 7/73, 9/95 and 4/83 in women allocated to vit D and calcium, vit D and (calcium) placebo, (vit D) placebo and calcium or placebo, respectively. The lack of point-in-time data refrained us from extracting the log HR and its variance for breast cancer mortality. However, since mortality data were provided exclusively by one trial , the meta-analytical approach was substantially not feasible.
We conducted a systematic review of RCTs focused on vit D supplemenation in breast cancer prevention. Based on pre-stated selection criteria, only two trials were included. Results from the pooled analysis do not support a role of vit D in reducing breast cancer risk in postmenopausal women. When compared to controls allocated to calcium and/or placebo, healthy women taking vitamin D either as a single agent or part of a combined treatment did not show a reduced risk of breast cancer development. In sensitivity analysis, vit D dosage and mode of administration did not affect the outcome of interest at a significant extent, although treatment efficacy appeared somewhat greater when vit D was administered at the highest dosage and in combination with calcium.
This systematic review has the following strengths. We followed the Cochrane Collaboration methods for the conduct of systematic reviews of intervention trials. A qualified librarian designed an extensive search strategy, which was applied with sensitivity criteria to the first phase of the reference screening. The search of three major databases, use of the related tools and other reference sources, along with the lack of language restrictions, increase our confidence in the identification of all relevant trials.
There are some limitations to this review. Our efforts to identify published trials were not paralleled by the systematic attempt to locate unpublished studies. Moreover, we could not assess publication bias by funnel plots due to the restricted number of RCTs included. On this basis, publication bias cannot be excluded. Among unpublished trials, those with non-significant results represent the vast majority . It is plausible to hypothesize that, if existing, unpublished studies on the effects of vit D in breast cancer prevention would not have added significant evidence in support of a beneficial effect of the intervention of interest, thus eventually strengthening our conclusions.
In addition, all women participating in the included studies were postmenopausal. This limits our ability to make inference regarding vit D use for breast cancer prevention in healthy premenopausal women. The number of studies judged eligible was particularly low. This result, along with the relatively low number of women included (i.e. 5372) and the paucity of breast cancer events (i.e. 48 and 43 breast cancers in women allocated to the intervention and control group, respectively), might have conferred to our meta-analysis an insufficient power to detect the effects of interest. Moreover, when singularly considered, none of the included studies was primarily tailored to detect incident cancers, either overall or by primitive cancer site. Our results were largely driven by the RCT from Avenell and co-authors. Women participating in this trial were older and had poorer vit D status at recruitment than those participating in the other trial. However, baseline, circulating levels of 25-OH vit D were assessed in only a very small subgroup of 60 participants and might not be representative of the wider trial population. In this same group, supplementation was associated with an increase in circulating 25-OH vit D from 38 to 62 nmol/liter, which could still be suboptimal .
Dose adequacy represents a further, critical issue. Adults aged 50–70 and 70 years and older require at least 600 and 800 IU of vit D daily, respectively. However, to raise the blood level of 25-OH vit D above 75 nmol/liter requires at least 1500–2000 IU daily . In the trial from Avenell, participants received 800 IU of vit D for 24–62 months, with a minimum follow up for long term outcomes of three years. Lappe and co-authors set up the daily supplementation of vit D at 1100 IU. Only in this latter study, the circulating 25-OH vit D levels raised to recommended values. Furthermore, the duration of the included studies could be questionable for long-term outcomes. The 4- and 5-year duration of the trials from Lappe and Avenell might be insufficient to the detection of incident cancer cases.
When combined with calcium, vit D showed a slight, not significant protective role towards breast cancer development compared with calcium alone (RR 0.93, 95% CI: 0.54–1.59, I2 0%). This could suggest that the reduced risk of cancer development is due to the effect of calcium rather than vit D. However, the inclusion of RCTs with co-interventions balanced across the compared groups should have minimized the differential contribution of calcium to the overall treatment effects.
To our knowledge, this is the first systematic review specifically conceived to provide the reader with a comprehensive appraisal of RCTs focused on vit D supplementation in breast cancer prevention. Breast cancer-related outcomes were not included in the systematic review from Autier and Gandini, neither did ReJnmark report on cancer mortality , . Conversely, two trials on vit D in breast cancer prevention were considered eligible by Chung and co-authors –. Our systematic review does not include the trial carried out by the Women’s Health Initiative Investigators because of unbalanced co-interventions between the study arms. In this study, postmenopausal women were randomized to 1000 milligrams of elemental calcium and 400 IU of daily cholecalciferol or placebo. This study findings do not support a role of vit D supplementation in reducing breast cancer incidence (HR: 0.96, 95% CI: 0.85–0.96) . Critics have been fueled by the low vit D dose along with poor treatment adherence and off study use of additional vit D and calcium supplements , –. The inclusion of the trial from Avenell represents a further distinctive feature of our work, since results from this trial were not available at the time of the previous systematic reviews’ conduct and publication .
In summary, our work contributes a systematic appraisal of the currently available randomized controlled evidence on vit D supplementation for breast cancer prevention. Based on our results and limited trial evidence, vit D supplementation seems not to be associated with a reduced risk of breast cancer development in postmenopausal women. However, the scientific panorama related to the association of interest is still limited and inadequate to draw firm conclusions. The lack of systematic assessment of vit D status applied to the entire study population in the widest trial included, along with the documented potentialities for dose inadequacy and insufficient study length relatively to cancer-related outcomes, represent major limitations of the literature examined. New trials specifically tailored on the vit D-cancer- binomious are in progress and should provide additional information in a few years’ time –. Methodological tools and key tenets of vit D metabolism and biological activities will help interpret the upcoming results.
We thank Dr. Francesca Servoli, Dr. Fabio D’Orsogna and Dr. Tania Merlino for their support.
Conceived and designed the experiments: MB M. Mottolese. Analyzed the data: FS. Contributed reagents/materials/analysis tools: FS. Wrote the paper: FS PV MB. Designed search strategy, performed and updated search: NS. Screened reference files and extracted data: NS DS LP AC. Provided methodological advice and critically revised the manuscript: MM-S SS LM AG LDL M. Montella.
- 1. Grant WB (2003) Ecologic studies of solar UV-B radiation and cancer mortality rates. Recent Results. Cancer Res 164: 371–377. doi: 10.1007/978-3-642-55580-0_27
- 2. Zittermann A, Schleithoff SS, Koerfer R (2005) Putting vitamin D and cardiovascular diseases into perspective. Br J Nutr 94(4): 483–492. doi: 10.1079/bjn20051544
- 3. Holick MF (2004) Vitamin D: importance in the prevention of cancers, type 1 diabetes, heart disease, and osteoporosis. Am J Clin Nutr 79: 362–71.
- 4. Giovannucci E (2005) The epidemiology of vitamin D and cancer incidence and mortality: a review (United States). Cancer Causes Control 16: 83–95. doi: 10.1007/s10552-004-1661-4
- 5. Garland CF, Grant W, Mohr SB, Gorham ED, Garland FC (2007) What is the dose-response relationship between vitamin D and cancer risk? Nutr Rev 65: S91–5. doi: 10.1111/j.1753-4887.2007.tb00349.x
- 6. Garland FC, Garland CF, Gorham ED, Young JF (1990) Geographic variation in breast cancer mortality in the United States: a hypothesis involving exposure to solar radiation. Prev Med 19: 614–22. doi: 10.1016/0091-7435(90)90058-r
- 7. Gorham ED, Garlkand FC, Garland CF (1990) Sunlight and breast cancer incidence in the USSR. Int J Epidemiol 19: 820–4. doi: 10.1093/ije/19.4.820
- 8. Grant WB (2002) An ecologic study of dietary and solar ultraviolet-B links to breast carcinoma mortality rates. Cancer Causes Control 94: 272–81. doi: 10.1002/cncr.10196
- 9. Boscoe FP, Schymura MJ (2006) Solar ultraviolet-B exposure and cancer incidence and mortality in the United States 1993–2002. BMC Cancer 6: 264. doi: 10.1186/1471-2407-6-264
- 10. Van der Wielen LM, van den Berg H, de Groot LCPGM, van Staveren WA, Löwik MRH, et al. (1995) Serum vitamin D concentrations among elderly people in Europe. Lancet 346(8969): 207–10. doi: 10.1016/s0140-6736(95)91266-5
- 11. Lips P, Duong T, Oleksik A, Black D, Cummings,S et al (2001) 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. 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. J Clin Endocrinol Metab 86(3): 1212–21. doi: 10.1210/jcem.86.3.7327
- 12. Yin L, Grandi N, Raum E, Haug U, Arndt V, et al. (2010) Meta-analysis: serum vitamin D and breast cancer risk. Eur J Cancer 46: 2196–205. doi: 10.1016/j.ejca.2010.03.037
- 13. Mohr SB, Gorham E, Alcaraz JE, Kane CJ, Macera CA, et al. (2011) Serum 25-hydroxyvitamin D and prevention of breast cancer: pooled analysis. Anticancer Res 31: 2939–48.
- 14. Fedirko V, Torres-Mejía G, Ortega-Olvera C, Biessy C, Angeles-Llerenas A, et al. (2012) Serum 25-hydroxyvitamin D and risk of breast cancer: results of a large population-based case-control study in Mexican women. Cancer Causes Control 23: 1149–62. doi: 10.1007/s10552-012-9984-z
- 15. Amir E, Cecchini R, Ganz PA, Costantino JP, Beddows S, et al. (2012) 25-Hydroxy vitamin-D, obesity, and associated variables as predictors of breast cancer risk and tamoxifen benefit in NSABP-P1. Breast Cancer Res Treat 133: 1077–88. doi: 10.1007/s10549-012-2012-x
- 16. Eliassen AH, Spiegelman D, Hollis BW, Horst RL, Willett W, C et al (2011) Plasma 25-hydroxyvitamin D and risk of breast cancer in the Nurses’ Health Study II. Breast Cancer Res Treat 13: R50. doi: 10.1186/bcr2880
- 17. Kühn T, Kaaks R, Becker S, Eomois PP, Clavel-Chapelon F, et al.. (2013) Plasma 25-hydroxyvitamin D and the risk of breast cancer in the European prospective investigation into cancer and nutrition: A nested case-control study. Int J Cancer doi: 10.1002/ijc.28172. 2013.
- 18. Autier P, Gandini S (2007) Vitamin D Supplementation and Total Mortality. Arch Intern Med 167(16): 1730–1737. doi: 10.1001/archinte.167.16.1730
- 19. Trivedi DP, Doll R, Khaw KT (2003) 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 326 (7387): 469–472. doi: 10.1136/bmj.326.7387.469
- 20. Wactawski-Wende J, Kotchen J, Anderson GL, Assaf AR, Brunner RL, et al.. (2006) Women’s Health Initiative Investigators. Calcium plus vitamin D supplementation and the risk of colorectal cancer. N Engl J Med 354 (7) 684–696.
- 21. Lappe J, Travers-Gustafson D, Davies KM, Recker RR, Heaney RP (2007) Vitamin D and calcium supplementation reduces cancer risk: results of a randomized trial. Am J Clin Nutr 85(6): 1586–91.
- 22. Chlebowski RT, Johnson K, Kooperberg C, Pettinger M, Wactawski-Wende J, et al. (2008) Calcium plus vitamin D supplementation and the risk of breast cancer. J Natl Cancer Inst 19 100(22): 1581–91. doi: 10.1093/jnci/djn360
- 23. Chung M, Lee J, Terasawa T, Lau J, Trikalinos TA (2011) Vitamin D with or without calcium supplementation for prevention of cancer and fractures: an updated meta-analysis for the U.S. Preventive Services Task Force. Ann Intern Med 155(12): 827–38. doi: 10.7326/0003-4819-155-12-201112200-00005
- 24. Rejnmark L, Avenell A, Masud T, Anderson F, Meyer HE, et al. (2012) Vitamin d with calcium reduces mortality: patient level pooled analysis of 70,528 patients from eight major vitamin d trials. J Clin Endocrinol Metab 97(8): 2670–81. doi: 10.1210/jc.2011-3328
- 25. Wong SS, Wilczynski N, Haynes RB (2006) Comparison of top-performing search strategies for detecting clinically sound treatment studies and systematic reviews in MEDLINE and EMBASE. J Med Libr Assoc 94(4): 451–5.
- 26. Parmar M, Torri V, Stewart L (1998) Extracting summary statistics to perform meta-analyses of the published literature for survival endpoints. Stat Med 17: 2815–34. doi: 10.1002/(sici)1097-0258(19981230)17:24<2815::aid-sim110>3.0.co;2-8
- 27. Higgins JP, Altman D, Gøtzsche PC, Jüni P, Moher D, et al. (2011) The Cochrane Collaboration’s tool for assessing risk of bias in randomised trials. BMJ 343: d5928 doi: 10.1136/bmj.d5928.
- 28. Sutton AJ, Abrams R, Jones DR, Sheldon TA, Song F (2000) Methods for Meta-Analysis in Medical Research. Chichester, UK: Wiley.
- 29. Higgins JPT, Green S (2011) Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0. Collaboration C. Wiley-Blackwell.
- 30. Avenell A, ManLennan G, Jenkinson DJ, McPherson GC, McDonald AM, et al. (2012) Long-term follow-up for mortality and cancer in a randomized placebo-controlled trial of vitamin D(3) and/or calcium (RECORD trial). J Clin Endocrinol Metab 97(2): 614–22. doi: 10.1210/jc.2011-1309
- 31. Jorde R, Sneve M, Hutchinson M, Emaus N, Figenschau Y, et al. (2010) Tracking of serum 25-hydroxyvitamin D levels during 14 years in a population-based study and during 12 months in an intervention study. American Journal of Epidemiology 171(8): 903–8. doi: 10.1093/aje/kwq005
- 32. Roh JL, Park JY, Park CI (2009) Prevention of postoperative hypocalcemia with routine oral calcium and vitamin D supplements in patients with differentiated papillary thyroid carcinoma undergoing total thyroidectomy plus central neck dissection. Cancer 115(32): 251–258. doi: 10.1002/cncr.24027
- 33. Witham MD, Crighton LJ, Gillespie ND, Struthers AD, McMurdo ME (2010) The effects of vitamin D supplementation on physical function and quality of life in older patients with heart failure: a randomized controlled trial. Circulation: Heart Failure 3(2): 195–201. doi: 10.1161/circheartfailure.109.907899
- 34. Zhou W, Suk R, Liu G, Park S, Neuberg DS, et al. (2005) Vitamin D is associated with improved survival in early-stage non-small cell lung cancer patients. Cancer Epidemiol Biomarkers Prev 14(10): 2303–9. doi: 10.1158/1055-9965.epi-05-0335
- 35. Zhou FL, Zhang WG, Cao XM, Chen YX, He AL, et al. (2008) Retrospective observation of curative effects on MDS refractory anemia with combination of all-trans retinoic acid, 1, 25-dihydroxyvitamin D3 and androgen. [Chinese]. Journal of experimental hematology 13(5): 8961–6.
- 36. Hollis BW, Wagner CL (2004) Vitamin D requirements during lactation: high-dose maternal supplementation as therapy to prevent hypovitaminosis D for both the mother and the nursing infant. Am J Cli Nutr 1752S-8S.
- 37. Inanir A, Ozoran K, Tutkak H, Mermerci B (2004) The effects of calcitriol therapy on serum interleukin-1, interleukin-6 and tumour necrosis factor-alpha concentrations in post-menopausal patients with osteoporosis. Journal of International Medical Research 32(6): 570–582. doi: 10.1177/147323000403200602
- 38. Harvey JA, Holm MK, Ranganath R, Guse PA, Trott EA, et al. (2009) The effects of bazedoxifene on mammographie breast density in postmenopausal women with osteoporosis. Menopause 16(6): 1193–1196. doi: 10.1097/gme.0b013e3181a7fb1e
- 39. Fedirko V, Bostick RM, Flanders WD, Long Q, Shaukat A, et al. (2009) Effects of vitamin D and calcium supplementation on markers of apoptosis in normal colon mucosa: A randomized, double-blind, placebo-controlled clinical trial. Cancer Prevention Research 2(3): 212–23. doi: 10.1158/1940-6207.capr-08-0157
- 40. Freedman DM, Tangrea JA, Virtamo J, Albanes D (1999) The effect of beta-carotene supplementation on serum vitamin D metabolite concentrations.Cancer Epidemiol Biomarkers Prev. 8(12): 1115–6.
- 41. Freedman DM, Looker AC, Abnet CC, Linet MS, Graubard BI (2010) Serum 25-hydroxyvitamin D and cancer mortality in the NHANES III study (1988–2006). Cancer Research 70(21): 8587–97. doi: 10.1158/0008-5472.can-10-1420
- 42. Hartman JJ (2000) Vitamin D deficiency rickets in children: prevalence and need for community education. Orthop Nurs 19(1): 63–7. doi: 10.1097/00006416-200019010-00013
- 43. Hartman AL, Benjamin JT (2002) An 18-month-old who could not walk: a case report. Clin Pediatr (Phila) 41(9): 731–2; discussion 732–4.
- 44. Hartman TJ, Albert PS, Snyder K, Slattery ML, Caan B, et al. (2005) The association of calcium and vitamin D with risk of colorectal adenomas. J Nutr 135(2): 252–9.
- 45. Stern PH, Lucas RC, Seidenfeld J (1991) Alpha-difluoromethylornithine inhibits bone resorption in vitro without decreasing beta-glucuronidase release. Mol Pharmacol 39(4): 557–62.
- 46. Sidelnikov E, Bostick RM, Flanders WD, Long Q, Fedirko V, et al. (2010) Effects of calcium and vitamin D on MLH1 and MSH2 expression in rectal mucosa of sporadic colorectal adenoma patients. Cancer Epidemiology Biomarkers and Prevention 19 (4): 1022–1032. doi: 10.1158/1055-9965.epi-09-0526
- 47. Van Veldhuizen PJ, Taylor SA, Williamson S, Drees BM (2000) Treatment of vitamin D deficiency in patients with metastatic prostate cancer may improve bone pain and muscle strength. Journal of Urology 163(1): 187–190. doi: 10.1097/00005392-200001000-00044
- 48. Verner AM, McGuire W, Craig JS (2007) Effect of taurine supplementation on growth and development in preterm or low birth weight infants. Cochrane Database of Systematic Reviews: Reviews 4(10).
- 49. Attia S, Eickhoff J, Wilding G, McNeel D, Blank J, et al. (2008) Randomized, double-blinded phase II evaluation of docetaxel with or without doxercalciferol in patients with metastatic, androgen-independent prostate cancer. Clinical Cancer Research 14(8): 2437–2443. doi: 10.1158/1078-0432.ccr-07-4274
- 50. Beer TM, Garzotto M, Katovic NM (2004) High-dose calcitriol and carboplatin in metastatic androgen-independent prostate cancer. American Journal of Clinical Oncology: Cancer Clinical Trials 27(5): 535–541. doi: 10.1097/01.coc.0000136020.27904.9c
- 51. Beer TM, Javle M, Lam GN, Henner WD, Wong A, et al. (2005) Pharmacokinetics and tolerability of a single dose of DN-101, a new formulation of catcitriol, in patients with cancer. Clinical Cancer Research 11(21): 7794–7799. doi: 10.1158/1078-0432.ccr-05-0552
- 52. Beer TM, Javle MM, Ryan CW, Garzotto M, Lam GN, et al. (2007) Phase I study of weekly DN-101, a new formulation of calcitriol, in patients with cancer. Cancer Chemotherapy and Pharmacology 59(5): 581–587. doi: 10.1007/s00280-006-0299-1
- 53. Beer TM, Lalani AS, Lee S, Mori M, Eilers KM, et al. (2008) C-reactive protein as a prognostic marker for men with androgen-independent prostate cancer: Results from the ASCENT trial. Cancer 112(11): 2377–2383. doi: 10.1002/cncr.23461
- 54. Glinghammar B, Venturi M, Rowland IR, Rafter JJ (1997) Shift from a dairy product-rich to a dairy product-free diet: influence on cytotoxicity and genotoxicity of fecal water–potential risk factors for colon cancer. The American journal of clinical nutrition 66(5): 1277–82.
- 55. Grau MV, Baron JA, Sandler RS, Haile RW, Beach ML, et al. (2003) Vitamin D, calcium supplementation, and colorectal adenomas: results of a randomized trial. J Natl Cancer Inst 3 95(23): 1765–71. doi: 10.1093/jnci/djg110
- 56. Gross C, Stamey T, Hancock S, Feldman D (1998) Treatment of early recurrent prostate cancer with 1,25-dihydroxyvitamin D3 (calcitriol). Journal of Urology 159(6): 2035–2040. doi: 10.1016/s0022-5347(01)63236-1
- 57. Hager ED, Birkenmeier J (2006) Stage IV malignant melanoma: Use of deep regional hyperthermia, tamoxifen, interferon-alpha and complementary therapies. Deutsche Zeitschrift fur Onkologie 38(1): 32–34. doi: 10.1055/s-2006-932313
- 58. Hellstrom E, Robert KH, Samuelsson J (1990) Treatment of myelodysplastic syndromes with retinoic acid and 1alpha-hydroxy-vitamin D3 in combination with low-dose ara-C is not superior to ara-C alone. Results from a randomized study. European Journal of Haematology 45(5): 255–261. doi: 10.1111/j.1600-0609.1990.tb00470.x
- 59. Henriksen DB, Alexandersen P, Hartmann B, Adrian CL, Byrjalsen I, et al. (2009) Four-month treatment with GLP-2 significantly increases hip BMD. A randomized, placebo-controlled, dose-ranging study in postmenopausal women with low BMD. Bone 45(5): 833–842. doi: 10.1016/j.bone.2009.07.008
- 60. Kulbersh JS, Day TA, Gillespie MB, Young MR (2009) 1alpha,25-Dihydroxyvitamin D3 to skew intratumoral levels of immune inhibitory CD34+ progenitor cells into dendritic cells. Otolaryngology Head and Neck Surgery 140(2): 235–240. doi: 10.1016/j.otohns.2008.11.011
- 61. Jacobs ET, Jurutka PW, Martinez ME, Alberts DS (2009) Vitamin D, calcium, and colorectal neoplasia: New insights on mechanisms of action. Cancer Prevention Research 2(3): 197–199. doi: 10.1158/1940-6207.capr-09-0019
- 62. Yoshida Y, Oguma S, Uchino H, Maekawa T, Nomura T (1993) A randomized study of alfacalcidol in the refractory myelodysplastic anaemias. A Japanese cooperative study. International Journal of Clinical Pharmacology Research 13(1): 21–7. doi: 10.1016/0145-2126(92)90156-2
- 63. Lin J, Manson JE, Lee IM, Cook NR, Buring JE, et al. (2007) Intakes of calcium and vitamin D and breast cancer risk in women 2007. Archives of Internal Medicine 167 (10): 1050–9. doi: 10.1001/archinte.167.10.1050
- 64. Neuhouser ML, Kristal AR, Patterson RE, Goodman PJ, Thompson IM (2001) Dietary supplement use in the Prostate Cancer Prevention Trial: implications for prevention trials. Nutr Cancer 39(1): 12–8. doi: 10.1207/s15327914nc391_2
- 65. Bjelakovic G, Nikolova D, Gluud LL, Simonetti RG, Gluud C (2008) Antioxidant supplements for prevention of mortality in healthy participants and patients with various diseases. Cochrane Database of Systematic Reviews 4(10).
- 66. Grober U (2009) Preventing chronic diseases with vitamin D3. [German]. Deutsche Apotheker Zeitung 149 (25): 62–69.
- 67. Kerst A (2007) Vitamin D supplementation reduces the incidence of cancer - A randomized study. [Dutch]. Geneesmiddelenbulletin 41(12): 133–134.
- 68. Ingraham BA, Bragdon B, Nohe A (2008) Molecular basis of the potential of vitamin D to prevent cancer. Current Medical Research and Opinion 24(1): 139–149. doi: 10.1185/030079907x253519
- 69. Jacobs TP, Bilezikian JP (2005) Clinical review: Rare causes of hypercalcemia. Journal of Clinical Endocrinology and Metabolism 90(11): 6316–6322. doi: 10.1210/jc.2005-0675
- 70. Lehmann B, Querings K, Reichrath J (2004) Vitamin D and skin: New aspects for dermatology. Experimental Dermatology 13S(4): 11–5. doi: 10.1111/j.1600-0625.2004.00257.x
- 71. Millen AE, Wactawski-Wende J, Pettinger M, Melamed ML, Tylavsky FA, et al. (2010) Predictors of serum 25-hydroxyvitamin D concentrations among postmenopausal women: the Women’s Health Initiative Calcium plus Vitamin D clinical trial. American Journal of Clinical Nutrition 91: 1324–1335. doi: 10.3945/ajcn.2009.28908
- 72. Raimondi S, Johansson H, Maisonneuve P, Gandini S (2009) Review and meta-analysis on vitamin D receptor polymorphisms and cancer risk. Carcinogenesis 30(7): 1170–1180. doi: 10.1093/carcin/bgp103
- 73. Ryan CW, Huo D, Stallings JW, Davis RL, Beer TM, et al. (2007) Lifestyle Factors and Duration of Androgen Deprivation Affect Bone Mineral Density of Patients with Prostate Cancer During First Year of Therapy. Urology 70(1): 122–126. doi: 10.1016/j.urology.2007.03.026
- 74. Schumann SA, Ewigman B (2007) Double-dose vitamin D lowers cancer risk in women over 55. J Fam Pract 56(11): 907–10.
- 75. Schwartz GG, Skinner HG (2007) Vitamin D status and cancer: New insights. Current Opinion in Clinical Nutrition and Metabolic Care 10(1): 6–11. doi: 10.1097/mco.0b013e328011aa60
- 76. Schwartz GG, Blot WJ (2006) Vitamin D status and cancer incidence and mortality: Something new under the sun. Journal of the National Cancer Institute 98(7): 428–430. doi: 10.1093/jnci/djj127
- 77. Spina CS, Tangpricha V, Uskokovic M, Adorinic L, Maehr H, et al.. (2006) Vitamin D and cancer. Anticancer Res 26(4A): 2515–24. Review.
- 78. Williamson CS (2006) Vitamin D, sunlight and cancer. Nutrition Bulletin 31(2): 77–80. doi: 10.1111/j.1467-3010.2006.00558.x
- 79. Dizdar O, Bulut N, Altundag K (2007) Vitamin D supplementation and response to aromatase inhibitors in postmenopausal women with hormone-receptor positive breast cancer. Breast 17(2): 120. doi: 10.1016/j.breast.2007.10.013
- 80. Fakih MG, Trump DL, Muindi JR, Black JD, Bernardi RJ, et al. (2007) A phase I pharmacokinetic and pharmacodynamic study of intravenous calcitriol in combination with oral gefitinib in patients with advanced solid tumors. Clinical Cancer Research 13(4): 1216–1223. doi: 10.1158/1078-0432.ccr-06-1165
- 81. Frost P, D’Anglure BS (2009) Black-white differences in cancer risk and the vitamin D hypothesis. Journal of the National Medical Association 101(12): 1310–1312.
- 82. Galan P, Favier A, Preziosi P, Bertrais S, Arnault N, et al. (2003) [The bank of biological material in the SU.VI.MAX study]. Rev Epidemiol Sante Publique 51(1 Pt 2): 147–50.
- 83. Goodwin PJ (2009) Vitamin D in cancer patients: Above all, do no harm. Journal of Clinical Oncology 27(13): 2117–2119. doi: 10.1200/jco.2008.20.8629
- 84. Grant WB (2009) Commentary: Ecologic studies in identifying dietary risk factors for coronary heart disease and cancer. International Journal of Epidemiology 37(6): 1209–1211. doi: 10.1093/ije/dyn172
- 85. Grant WB (2008) Vitamin D may reduce prostate cancer metastasis by several mechanisms including blocking Stat3. 1 Am J Pathol 173(5): 1589–90. doi: 10.2353/ajpath.2008.080579
- 86. Harstrick A, Perschl A (2000) Tumor angiogenesis - Therapeutic implications. Inhibition with integrin antagonists - A new therapeutic approach. [German]. Onkologe 6(5): 443–449.
- 87. Holick MF (2006) Calcium plus vitamin D and the risk of colorectal cancer. New England Journal of Medicine 354(21): 2287–8; author reply 2287–8.
- 88. Holt PR, Arber N, Halmos B, Forde K, Kissileff H, et al. (2002) Colonic epithelial cell proliferation decreases with increasing levels of serum 25-hydroxy vitamin D. Cancer Epidemiology Biomarkers and Prevention. 11(1): 113–119.
- 89. Glen H, Cassidy J (2006) Vitamin D (and its analogs) in the treatment and prevention of cancer. Expert Review of Anticancer Therapy 6(3): 305–308. doi: 10.1586/14737220.127.116.115
- 90. Price N, D’Orazio A, Jain VK, Sartor O (2004) The Development of Vitamin D-Based Therapies for ProstateCancer. Clinical Prostate Cancer 2(4): 202–205. doi: 10.1016/s1540-0352(11)70044-0
- 91. Ji Y, Kutner A, Verstuyf A, Verlinden L, Studzinski GP (2002) Derivatives of vitamins D2 and D3 activate three MAPK pathways and upregulate pRb expression in differentiating HL60 cells. Cell Cycle 1(6): 410–5. doi: 10.4161/cc.1.6.269
- 92. Perez EA, Josse RG, Pritchard KI, Ingle JN, Martino S, et al. (2006) Effect of letrozole versus placebo on bone mineral density in women with primary breast cancer completing 5 or more years of adjuvant tamoxifen: a companion study to NCIC CTG MA.17. Journal of clinical oncology: official journal of the American Society of Clinical Oncology 24(22): 3629–35. doi: 10.1200/jco.2005.05.4882
- 93. Prentice RL, Anderson GL (2008) The women’s health initiative: Lessons learned. Annual Review of Public Health 29: 131–50. doi: 10.1146/annurev.publhealth.29.020907.090947
- 94. Qiao S, Pennanen P, Nazarova N, Lou YR, Tuohimaa P (2003) Inhibition of fatty acid synthase expression by 1alpha,25-dihydroxyvitamin D3 in prostate cancer cells J Steroid Biochem Mol Biol. 85(1): 1–8. doi: 10.1016/s0960-0760(03)00142-0
- 95. Rohan TE, Negassa A, Caan B, Chlebowski RT, Curb JD, et al. (2008) Low-fat dietary pattern and risk of benign proliferative breast disease: a randomized, controlled dietary modification trial. Cancer Prevention Research 1(4): 275–284. doi: 10.1158/1940-6207.capr-08-0003
- 96. Hercberg S, Preziosi P, Galan P, Faure H, Arnaud J, et al. (1999) “The SU.VI.MAX Study”: a primary prevention trial using nutritional doses of antioxidant vitamins and minerals in cardiovascular diseases and cancers. Supplementation on Vitamines et Minéraux AntioXydants. Food Chem Toxicol 37(9–10): 925–30. doi: 10.1016/s0278-6915(99)00078-2
- 97. Hercberg S, Galan P, Preziosi P, Bertrais S, Mennen L, et al. (2004) The SU.VI.MAX Study: a randomized, placebo-controlled trial of the health effects of antioxidant vitamins and minerals. Arch Intern Med Nov 22; 164(21): 2335–42. Erratum in: Arch Intern Med. 2005 Feb 14 165(3): 286. doi: 10.1001/archinte.164.21.2335
- 98. Hercberg S, Czernichow S, Galan P (2006) Antioxidant vitamins and minerals in prevention of cancers: lessons from the SU.VI.MAX study. Br J Nutr 96 Suppl 1S28–30. doi: 10.1079/bjn20061695
- 99. Hercberg S, Ezzedine K, Guinot C, Preziosi P, Galan P, et al. (2007) Antioxidant supplementation increases the risk of skin cancers in women but not in men. J Nutr 137(9): 2098–105.
- 100. Howard BV, Van Horn L, Hsia J, Manson JE, Stefanick ML, et al. (2006) Low-fat dietary pattern and risk of cardiovascular disease: The Women’s Health Initiative randomized controlled dietary modification trial. Journal of the American Medical Association 295(6): 655–66. doi: 10.1001/jama.295.6.655
- 101. Markopoulos C, Tzoracoleftherakis E, Polychronis A, Venizelos B, Dafni U, et al.. (2010) Management of anastrozole-induced bone loss in breast cancer patients with oral risedronate: results from the ARBI prospective clinical trial. Breast cancer research 12(2): R24. Epub 2010 Apr 16.
- 102. Schilsky RL, Allen J, Benner J, Sigal E, McClellan M (2010) Commentary: tackling the challenges of developing targeted therapies for cancer. Oncologist 15(5): 484–7. doi: 10.1634/theoncologist.2010-0079
- 103. Ellis GK, Bone HG, Chlebowski R, Paul D, Spadafora S, et al. (2008) Randomized trial of denosumab in patients receiving adjuvant aromatase inhibitors for nonmetastatic breast cancer. Journal of Clinical Oncology 26(30): 4875–4882. doi: 10.1200/jco.2008.16.3832
- 104. Femiano F, Gombos F, Scully C, Battista C, Belnome G, et al. (2001) Oral leukoplakia: open trial of topical therapy with calcipotriol compared with tretinoin. International Journal of Oral and Maxillofacial Surgery 30(5): 402–406. doi: 10.1054/ijom.2001.0107
- 105. Hines SL, Mincey B, Dentchev T, Sloan JA, Perez EA, et al. (2009) Immediate versus delayed zoledronic acid for prevention of bone loss in postmenopausal women with breast cancer starting letrozole after tamoxifen-N03CC. Breast Cancer Research and Treatment 117(3): 603–609. doi: 10.1007/s10549-009-0332-2
- 106. Hines SL, Mincey BA, Sloan JA, Thomas SP, Chottiner E, et al.. (2009) Phase III randomized, placebo-controlled, double-blind trial of risedronate for the prevention of bone loss in premenopausal women undergoing chemotherapy for primary breast cancer. J Clin Oncol 1; 27(7): 1047–53. Epub 2008 Dec 15.
- 107. Hines SL, Jorn HK, Thompson KM, Larson JM (2010) Breast cancer survivors and vitamin D: a review. Nutrition 26(3): 255–62. doi: 10.1016/j.nut.2009.08.020
- 108. Recker RR, Davies KM, Dowd RM, Heaney RP (1999) The effect of low-dose continuous estrogen and progesterone therapy with calcium and vitamin D on bone in elderly women. A randomized, controlled trial. Annals of Internal Medicine 130(11): 897–904. doi: 10.7326/0003-4819-130-11-199906010-00005
- 109. Beresford SA, Johnson KC, Ritenbaugh C, Lasser NL, Snetselaar LG, et al. (2006) Low-fat dietary pattern and risk of colorectal cancer: The Women’s Health Initiative randomized controlled dietary modification trial 295. (6): 643–654. doi: 10.1001/jama.295.6.643
- 110. Ding EL, Mehta S, Fawzi WW, Giovannucci EL (2008) Interaction of estrogen therapy with calcium and vitamin D supplementation on colorectal cancer risk: Reanalysis of Women’s Health Initiative randomized trial. International Journal of Cancer 122(8): 1690–1694. doi: 10.1002/ijc.23311
- 111. Heinonen OP, Albanes D, Virtamo J, Taylor PR, Huttunen JK, et al. (1998) Prostate cancer and supplementation with alpha-tocopherol and beta-carotene: incidence and mortality in a controlled trial. Journal of the National Cancer Institute 90(6): 440–6. doi: 10.1093/jnci/90.6.440
- 112. LaCroix AZ, Kotchen J, Anderson G, Brzyski R, Cauley JA, et al. (2009) Calcium plus vitamin D supplementation and mortality in postmenopausal women: the Women’s Health Initiative calcium-vitamin D randomized controlled trial. J Gerontol A Biol Sci Med Sci 64(5): 559–67. doi: 10.1093/gerona/glp006
- 113. Pritchard RS, Baron JA, Gerhardsson De Verdier M (1996) Dietary calcium, vitamin D, and the risk of colorectal cancer in Stockholm, Sweden. Cancer Epidemiology Biomarkers and Prevention 5(11): 897–900.
- 114. Sieg J, Sieg A, Dreyhaupt J, Schmidt-Gayk H (2006) Insufficient vitamin D supply as a possible co-factor in colorectal carcinogenesis. Anticancer Res 26(4A): 2729–33.
- 115. Skinner HG (2008) Vitamin D for the treatment and prevention of pancreatic cancer. Cancer Biol Ther 7(3): 437–9. Epub 2008 Apr 10.
- 116. Woo TCS, Choo R, Jamieson M, Chander S, Vieth R (2005) Pilot study: Potential role of vitamin D (cholecalciferol) in patients with PSA relapse after definitive therapy. Nutrition and Cancer 51(1): 32–6. doi: 10.1207/s15327914nc5101_5
- 117. Wood HM, Carducci MA (2000) Differentiation therapy for prostate cancer. Prostate Journal 2(1): 6–13. doi: 10.1046/j.1525-1411.2000.15002.x
- 118. Garssen J, Norval M, el-Ghorr A, Gibbs NK, Jones CD, et al. (1998) Estimation of the effects of increasing UVB exposure on the human immune system and related resistance to infectious diseases and tumours. J Photochem Photobiol B 42(3): 167–79. doi: 10.1016/s1011-1344(97)00122-x
- 119. Clinical Trial Website. Calcium and vitamin D malnutrition in elderly women.Available: www.clinicaltrials.gov. Accessed 2013 June 17.
- 120. The Lancet Website. Available: http://www.thelancet.com/protocol-reviews/02PRT-35. Accessed 2013 June 17.
- 121. Egger M, Smith GD, Altman DG (2001) Systematic Reviews in Health Care: Meta-Analysis in Context. London: BMJ Books.
- 122. Bischoff-Ferrari HA, Willett WC, Dietrich T, Dawson-Hughes B (2006) Estimation of optimal serum concentrations of 25-hydroxyvitamin D for multiple health outcomes. Am J Clin Nutr 84(1): 18–28.
- 123. Holick MF, Binkley NC, Bischoff-Ferrari HA, Gordon CM, Hanley DA, et al. (2011) Evaluation, treatment, and prevention of vitamin D deficiency: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab 96(7): 1911–30. Epub 2011 Jun 6. Erratum in: J Clin Endocrinol Metab. 2011 Dec 96(12): 3908. doi: 10.1210/jc.2011-0385
- 124. Forman MR (2006) LevinB (2006) Calcium plus vitamin D3 supplementation and colorectal cancer in women. N Engl J Med 16 354(7): 752–4. doi: 10.1056/nejme068006
- 125. Finkelstein JS (2006) Calcium plus vitamin D3 supplementation Calcium plus Vitamin D for Postmenopausal Women – Bone Appétit? N Engl J Med 354(7): 750–2. doi: 10.1056/nejme068007
- 126. Manson JE, Bassuk SS, Lee IM, Cook NR, Albert MA, et al. (2012) The VITamin D and OmegA-3 TriaL (VITAL): rationale and design of a large randomized controlled trial of vitamin D and marine omega-3 fatty acid supplements for the primary prevention of cancer and cardiovascular disease. Contemp Clin Trials 33(1): 159–71. doi: 10.1016/j.cct.2011.09.009
- 127. Current Controlled Trial website. Available: http://www.controlled-trials.com/ISRCTN46328341. Accessed 2013 June 17.