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Na SY, Kim KB, Lim YJ, Song HJ. Vitamin D and Colorectal Cancer: Current Perspectives and Future Directions. J Cancer Prev 2022; 27:147-156. [PMID: 36258716 PMCID: PMC9537583 DOI: 10.15430/jcp.2022.27.3.147] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2022] [Revised: 09/05/2022] [Accepted: 09/11/2022] [Indexed: 11/03/2022] Open
Abstract
Vitamin D is considered to be the main mediator of the beneficial effects of sun exposure. In humans, highest expression of Vitamin D receptors is found in the intestinal tract. In addition, 1α,25-dihydroxyvitamin D3 (or calcitriol), the most active Vitamin D metabolite, plays important homeostatic roles in the intestine, particularly calcium absorption. Vitamin D deficiency is defined as a serum 25-hydroxyvitamin D [25(OH)D] level of < 20 ng/mL. Previous studies show that higher circulating 25(OH)D levels are associated with reduced risk of colorectal cancer (CRC) and improved survival. Most research to date has been conducted in animals, specifically mice. Although human studies have a limited number of participants, one study recruiting a large cohort of patients with advanced or metastatic CRC revealed that higher plasma 25(OH)D levels are associated with improved overall and progression-free survival. However, the effects of Vitamin D supplementation on incidence and mortality of CRC remain inconclusive. Although Vitamin D may help to prevent cancer, there is a paucity of research demonstrating conclusively that Vitamin D alters prognosis after chemotherapy. Here, we review the mechanisms by which Vitamin D affects CRC, as well as the results of clinical, epidemiological, and human intervention studies. We also discuss current perspectives and future directions regarding Vitamin D and CRC.
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Affiliation(s)
- Soo-Young Na
- Department of Internal Medicine, Incheon St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Incheon, Korea
| | - Ki Bae Kim
- Department of Internal Medicine, Chungbuk National University Hospital, Cheongju, Korea
| | - Yun Jeong Lim
- Department of Internal Medicine, Dongguk University Ilsan Hospital, Dongguk University College of Medicine, Goyang, Korea,Correspondence to Yun Jeong Lim, E-mail: , https://orcid.org/0000-0002-3279-332X
| | - Hyun Joo Song
- Department of Internal Medicine, Jeju National University College of Medicine, Jeju, Korea,Hyun Joo Song, E-mail: , https://orcid.org/0000-0002-2561-555X
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Guo LL, Chen SS, Zhong LX, He KY, Li YT, Chen WW, Zeng QT, Tang SH. Vitamin D intake as well as circulating 25-hydroxyvitamin D level and risk for the incidence and recurrence of colorectal cancer precursors: A meta-analysis. Front Med (Lausanne) 2022; 9:877275. [PMID: 36091680 PMCID: PMC9452754 DOI: 10.3389/fmed.2022.877275] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2022] [Accepted: 08/02/2022] [Indexed: 11/27/2022] Open
Abstract
Objective Vitamin D consumption and circulating 25(OH)D level are associated with decreased risk of colorectal cancer (CRC) and colorectal adenoma (CRA), but few studies have assessed their relationship with the incidence and recurrence of CRC precursors. Therefore, we performed this meta-analysis to further evaluate the association. Methods We searched PubMed, Web of Science, Scopus and Embase databases in English until August 2021. Studies evaluating the association of vitamin D intake and circulating 25(OH)D level with risk of CRC precursors were included. A random-effects model was used to pool the risk estimates. Results A total of 48 studies were selected for inclusion. The CRC precursors incidence was negatively correlated with total vitamin D intake (RR = 0.84 95%CI: 0.80–0.88) and circulating 25(OH)D level (RR = 0.79 95%CI: 0.67–0.92). However, vitamin D intake and circulating 25(OH)D level did not show significant effects on the risk of CRC precursors recurrence. For dose-response analysis, evidence of a linear association was found between CRC precursors incidence and circulating 25(OH)D level, and the risk decreased by 14% per 10 ng/ml increment of circulating 25(OH)D level (RR = 0.86 95% CI: 0.75–0.99). Conclusion Vitamin D intake and circulating 25(OH)D level can play an effective role in reducing the risk of incidence of CRC precursors. However, they have not prevented the recurrence of CRC precursors.
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Liu D, Meng X, Tian Q, Cao W, Fan X, Wu L, Song M, Meng Q, Wang W, Wang Y. Vitamin D and Multiple Health Outcomes: An Umbrella Review of Observational Studies, Randomized Controlled Trials, and Mendelian Randomization Studies. Adv Nutr 2022; 13:1044-1062. [PMID: 34999745 PMCID: PMC9340982 DOI: 10.1093/advances/nmab142] [Citation(s) in RCA: 50] [Impact Index Per Article: 16.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2020] [Revised: 12/29/2020] [Accepted: 11/19/2021] [Indexed: 12/18/2022] Open
Abstract
Observational studies, randomized controlled trials (RCTs), and Mendelian randomization (MR) studies have yielded inconsistent results on the associations of vitamin D concentrations with multiple health outcomes. In the present umbrella review we aimed to evaluate the effects of low vitamin D concentrations and vitamin D supplementation on multiple health outcomes. We summarized current evidence obtained from meta-analyses of observational studies that examined associations between vitamin D concentrations and multiple health outcomes, meta-analyses of RCTs that investigated the effect of vitamin D supplementation on multiple health outcomes, and MR studies that explored the causal associations of vitamin D concentrations with various diseases (international prospective register of systematic reviews PROSPERO registration number CRD42018091434). A total of 296 meta-analyses of observational studies comprising 111 unique outcomes, 139 meta-analyses of RCTs comprising 46 unique outcomes, and 73 MR studies comprising 43 unique outcomes were included in the present umbrella review. Twenty-eight disease outcomes were identified by both meta-analyses of observational studies and MR studies. Seventeen of these reported disease outcomes had consistent results, demonstrating that lower concentrations of vitamin D were associated with a higher risk for all-cause mortality, Alzheimer's disease, hypertension, schizophrenia, and type 2 diabetes. The combinations of consistent evidence obtained by meta-analyses of observational studies and MR studies together with meta-analyses of RCTs showed that vitamin D supplementation was associated with a decreased risk for all-cause mortality but not associated with the risk for Alzheimer's disease, hypertension, schizophrenia, or type 2 diabetes. The results indicated that vitamin D supplementation is a promising strategy with long-term preventive effects on multiple chronic diseases and thus has the potential to decrease all-cause mortality. However, the current vitamin D supplementation strategy might not be an efficient intervention approach for these diseases, suggesting that new strategies are highly needed to improve the intervention outcomes.
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Affiliation(s)
- Di Liu
- Beijing Key Laboratory of Clinical Epidemiology, School of Public Health, Capital Medical University, Beijing, China
- Centre for Biomedical Information Technology, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, Guangdong, China
| | - Xiaoni Meng
- Beijing Key Laboratory of Clinical Epidemiology, School of Public Health, Capital Medical University, Beijing, China
| | - Qiuyue Tian
- Beijing Key Laboratory of Clinical Epidemiology, School of Public Health, Capital Medical University, Beijing, China
| | - Weijie Cao
- Beijing Key Laboratory of Clinical Epidemiology, School of Public Health, Capital Medical University, Beijing, China
| | - Xin Fan
- School of Basic Medical Sciences, Capital Medical University, Beijing, China
| | - Lijuan Wu
- Beijing Key Laboratory of Clinical Epidemiology, School of Public Health, Capital Medical University, Beijing, China
| | - Manshu Song
- Centre for Precision Health, School of Medical and Health Sciences, Edith Cowan University, Perth, WA, Australia
| | - Qun Meng
- Beijing Key Laboratory of Clinical Epidemiology, School of Public Health, Capital Medical University, Beijing, China
| | - Wei Wang
- Beijing Key Laboratory of Clinical Epidemiology, School of Public Health, Capital Medical University, Beijing, China
- Centre for Precision Health, School of Medical and Health Sciences, Edith Cowan University, Perth, WA, Australia
- School of Public Health, Shandong First Medical University and Shandong Academy of Medical Science, Tai'an, Shandong, China
| | - Youxin Wang
- Beijing Key Laboratory of Clinical Epidemiology, School of Public Health, Capital Medical University, Beijing, China
- Centre for Precision Health, School of Medical and Health Sciences, Edith Cowan University, Perth, WA, Australia
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Winandar T, Raharjo A, Wujoso H, Sidharta BRA, Bagus BI. Relationship between 25(OH)D and Colorectal Cancer Prevalence at Dr. Moewardi Hospital Surakarta-Indonesia: A Cross-Sectional Study. Open Access Maced J Med Sci 2021. [DOI: 10.3889/oamjms.2021.7396] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022] Open
Abstract
Background: Colorectal cancer is a malignancy of the colon and / or rectum. Vitamin D has a role as an inhibitor of tumor progression, namely through the process of influencing cellular differentiation and proliferation. (VDR) Vitamin D Receptor affects cell differentiation by upregulating brush boundary enzymes and improving morphological microvilli. This study seeks to determine the relationship between 25(OH)D levels and colorectal cancer in dr. Moewardi Hospital, Surakarta, Indonesia.
Methods: A cross-sectional design study with quantitative-analytical observation was conducted. All patients had symptoms of colorectal cancer, either undiagnosed or previously diagnosed. 25(OH)D samples were taken from a total of 50 patients at dr. Moewardi Surakarta and subsequent diagnostic measures from the results of histopathology were assessed. The parameters assessed were 25(OH)D level and a diagnosis of colorectal malignancy. Statistical analysis of 25(OH)D levels and colorectal diagnosis using the Chi Square test.
Results: The prevalence of colorectal cancer is higher in respondents with 25(OH)D deficiency and insufficiency compared to respondents with normal 25(OH)D concentrations who tend to have non-colorectal cancer. Based on the Chi-Square test result, the significance value was 0.004, marking a statistically significant association.
Conclusion: This study shows a significant relationship between deficiency and insufficiency of 25(OH)D concentrations with the occurrence of colorectal malignancy
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Chatterjee R, Fuss P, Vickery EM, LeBlanc ES, Sheehan PR, Lewis MR, Dolor RJ, Johnson KC, Kashyap SR, Nelson J, Pittas AG. Vitamin D Supplementation for Prevention of Cancer: The D2d Cancer Outcomes (D2dCA) Ancillary Study. J Clin Endocrinol Metab 2021; 106:2767-2778. [PMID: 33693713 PMCID: PMC8372641 DOI: 10.1210/clinem/dgab153] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/10/2020] [Indexed: 12/31/2022]
Abstract
CONTEXT Observational studies suggest that low vitamin D status may be a risk factor for cancer. OBJECTIVE In a population with prediabetes and overweight/obesity that is at higher risk of cancer than the general population, we sought to determine if vitamin D supplementation lowers the risk of cancer and precancers. METHODS The Vitamin D and type 2 diabetes (D2d) cancer outcomes study (D2dCA) is an ancillary study to the D2d study, which was conducted at 22 academic medical centers in the United States. Participants had prediabetes and overweight/obesity and were free of cancer for the previous 5 years. Participants were randomized to receive vitamin D3 4000 IU daily or placebo. At scheduled study visits (4 times/year), cancer and precancer events were identified by questionnaires. Clinical data were collected and adjudicated for all reported events. Cox proportional hazard models compared the hazard ratio (HR) of incident cancers and precancers between groups. RESULTS Over a median follow-up period of 2.9 years, among 2385 participants (mean age 60 years and 25-hydroxyvitamin D 28 ng/mL), there were 89 cases of cancer. The HR of incident cancer for vitamin D vs placebo was 1.07 (95% CI 0.70, 1.62). Of 241 participants with incident precancers, 239 had colorectal adenomatous polyps. The HR for colorectal polyps for vitamin D vs placebo was 0.83 (95% CI 0.64, 1.07). CONCLUSION In the D2d population of participants with prediabetes and overweight/obesity, not selected for vitamin D insufficiency, vitamin D supplementation did not have a significant effect on risk of incident cancer or colorectal polyps.
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Affiliation(s)
- Ranee Chatterjee
- Department of Medicine, Duke University, Durham, NC 27713, USA
- Correspondence: Ranee Chatterjee, MD, MPH, 800 Washington Street, Box 268, Boston, MA 02111, USA.
| | - Paul Fuss
- Division of Endocrinology, Diabetes and Metabolism, Tufts Medical Center, Boston, MA 02111, USA
| | - Ellen M Vickery
- Division of Endocrinology, Diabetes and Metabolism, Tufts Medical Center, Boston, MA 02111, USA
| | - Erin S LeBlanc
- Center for Health Research, Kaiser Permanente NW, Portland, OR 97227, USA
| | - Patricia R Sheehan
- Division of Endocrinology, Diabetes and Metabolism, Tufts Medical Center, Boston, MA 02111, USA
- Spaulding Rehabilitation Network, Boston, MA 02129, USA
- Tufts Medical Center, Boston, MA 02129, USA
| | - Michael R Lewis
- Department of Pathology and Laboratory Medicine, University of Vermont, Burlington, VT 05401, USA
| | - Rowena J Dolor
- Department of Medicine, Duke University, Durham, NC 27713, USA
| | - Karen C Johnson
- Department of Preventive Medicine, University of Tennessee Health Science Center, Memphis, TN 38105, USA
| | - Sangeeta R Kashyap
- Department of Endocrinology, Diabetes, and Metabolism, Cleveland Clinic, Cleveland, OH 44195, USA
| | - Jason Nelson
- Tufts CTSI, BERD Center, Tufts Medical Center, Boston, MA 02111, USA
| | - Anastassios G Pittas
- Division of Endocrinology, Diabetes and Metabolism, Tufts Medical Center, Boston, MA 02111, USA
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Sluyter JD, Manson JE, Scragg R. Vitamin D and Clinical Cancer Outcomes: A Review of Meta-Analyses. JBMR Plus 2020; 5:e10420. [PMID: 33553987 PMCID: PMC7839823 DOI: 10.1002/jbm4.10420] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/01/2020] [Revised: 08/26/2020] [Accepted: 09/29/2020] [Indexed: 12/13/2022] Open
Abstract
The relationship between vitamin D status or supplementation and cancer outcomes has been examined in several meta‐analyses. To address remaining knowledge gaps, we conducted a systematic overview and critical appraisal of pertinent meta‐analyses. For meta‐analyses of trials, we assessed their quality using AMSTAR‐2 (A Measurement Tool to Assess Systematic Reviews), strength of associations using umbrella review methodology and credibility of evidence using GRADE (Grading of Recommendations, Assessment, Development, and Evaluation) criteria. Meta‐analyses of observational studies reported inverse associations of 25OHD with risk of cancer incidence and cancer mortality and, particularly for colorectal cancer, fulfilled some of Bradford‐Hill's causation criteria. In meta‐analyses of trials, vitamin D supplementation did not affect cancer incidence. However, we found credible evidence that vitamin D supplementation reduced total cancer mortality risk, with five out of six meta‐analyses reporting a relative risk (RR) reduction of up to 16%: RR, 0.84 (95% CI, 0.74–0.95). The strength of the association, however, was classified as weak. This was true among meta‐analyses of high, moderate, and lower quality (AMSTAR‐2–rated). Trials did not include large numbers of vitamin D‐deficient participants; many tested relatively low doses and lacked sufficiently powered data on site‐specific cancers. In conclusion, meta‐analyses show that, although observational evidence indicates that low vitamin D status is associated with a higher risk of cancer outcomes, randomized trials show that vitamin D supplementation reduces total cancer mortality, but not cancer incidence. However, trials with larger proportions of vitamin D‐insufficient participants and longer durations of follow‐up, plus adequately powered data on site‐specific common cancers, would provide further insight into the evidence base. © 2020 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.
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Affiliation(s)
- John D Sluyter
- School of Population Health, University of Auckland Auckland New Zealand
| | - JoAnn E Manson
- Department of Medicine Brigham and Women's Hospital, and Harvard Medical School Boston MA USA.,Department of Epidemiology Harvard T.H. Chan School of Public Health Boston MA USA
| | - Robert Scragg
- School of Population Health, University of Auckland Auckland New Zealand
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Single Nucleotide Polymorphisms in 25-Hydroxyvitamin D3 1-Alpha-Hydroxylase ( CYP27B1) Gene: The Risk of Malignant Tumors and Other Chronic Diseases. Nutrients 2020; 12:nu12030801. [PMID: 32197412 PMCID: PMC7146376 DOI: 10.3390/nu12030801] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/29/2020] [Revised: 03/13/2020] [Accepted: 03/16/2020] [Indexed: 12/31/2022] Open
Abstract
: Vitamin D is widely known for its roles in the promotion of apoptosis and differentiation, with simultaneous inhibition of proliferation, inflammation, angiogenesis, invasion, and metastasis. Modern literature lacks complete information on polymorphisms in CYP27B1, the only enzyme capable of vitamin D activation. This review presents gathered data that relate to genetic variants in CYP27B1 gene in correlation to multiple diseases, mostly concerning colorectal, prostate, breast, lung, and pancreatic cancers, as well as on other pathologies, such as non-Hodgkin's lymphoma, oral lichen planus, or multiple sclerosis.
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Bouillon R, Marcocci C, Carmeliet G, Bikle D, White JH, Dawson-Hughes B, Lips P, Munns CF, Lazaretti-Castro M, Giustina A, Bilezikian J. Skeletal and Extraskeletal Actions of Vitamin D: Current Evidence and Outstanding Questions. Endocr Rev 2019; 40:1109-1151. [PMID: 30321335 PMCID: PMC6626501 DOI: 10.1210/er.2018-00126] [Citation(s) in RCA: 616] [Impact Index Per Article: 102.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/10/2018] [Accepted: 07/17/2018] [Indexed: 02/06/2023]
Abstract
The etiology of endemic rickets was discovered a century ago. Vitamin D is the precursor of 25-hydroxyvitamin D and other metabolites, including 1,25(OH)2D, the ligand for the vitamin D receptor (VDR). The effects of the vitamin D endocrine system on bone and its growth plate are primarily indirect and mediated by its effect on intestinal calcium transport and serum calcium and phosphate homeostasis. Rickets and osteomalacia can be prevented by daily supplements of 400 IU of vitamin D. Vitamin D deficiency (serum 25-hydroxyvitamin D <50 nmol/L) accelerates bone turnover, bone loss, and osteoporotic fractures. These risks can be reduced by 800 IU of vitamin D together with an appropriate calcium intake, given to institutionalized or vitamin D-deficient elderly subjects. VDR and vitamin D metabolic enzymes are widely expressed. Numerous genetic, molecular, cellular, and animal studies strongly suggest that vitamin D signaling has many extraskeletal effects. These include regulation of cell proliferation, immune and muscle function, skin differentiation, and reproduction, as well as vascular and metabolic properties. From observational studies in human subjects, poor vitamin D status is associated with nearly all diseases predicted by these extraskeletal actions. Results of randomized controlled trials and Mendelian randomization studies are supportive of vitamin D supplementation in reducing the incidence of some diseases, but, globally, conclusions are mixed. These findings point to a need for continued ongoing and future basic and clinical studies to better define whether vitamin D status can be optimized to improve many aspects of human health. Vitamin D deficiency enhances the risk of osteoporotic fractures and is associated with many diseases. We review what is established and what is plausible regarding the health effects of vitamin D.
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Affiliation(s)
- Roger Bouillon
- Laboratory of Clinical and Experimental Endocrinology, Department of Chronic Diseases, Metabolism and Ageing, KU Leuven, Belgium
| | - Claudio Marcocci
- Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | - Geert Carmeliet
- Laboratory of Clinical and Experimental Endocrinology, Department of Chronic Diseases, Metabolism and Ageing, KU Leuven, Belgium
| | - Daniel Bikle
- Veterans Affairs Medical Center and University of California San Francisco, San Francisco, California
| | - John H White
- Department of Physiology, McGill University, Montreal, Quebec, Canada
| | - Bess Dawson-Hughes
- Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University, Boston, Massachusetts
| | - Paul Lips
- Department of Internal Medicine, Endocrine Section, VU University Medical Center, HV Amsterdam, Netherlands
| | - Craig F Munns
- Children’s Hospital at Westmead, Sydney, New South Wales, Australia
- Sydney Medical School, University of Sydney, Sydney, New South Wales, Australia
| | - Marise Lazaretti-Castro
- Division of Endocrinology, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, Brazil
| | - Andrea Giustina
- Chair of Endocrinology, Vita-Salute San Raffaele University, Milan, Italy
| | - John Bilezikian
- Department of Endocrinology, Columbia University College of Physicians and Surgeons, New York, New York
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Extra-Skeletal Effects of Vitamin D. Nutrients 2019; 11:nu11071460. [PMID: 31252594 PMCID: PMC6683065 DOI: 10.3390/nu11071460] [Citation(s) in RCA: 77] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2019] [Revised: 06/23/2019] [Accepted: 06/25/2019] [Indexed: 02/06/2023] Open
Abstract
The vitamin D receptor is expressed in multiple cells of the body (other than osteoblasts), including beta cells and cells involved in immune modulation (such as mononuclear cells, and activated T and B lymphocytes), and most organs in the body including the brain, heart, skin, gonads, prostate, breast, and gut. Consequently, the extra-skeletal impact of vitamin D deficiency has been an active area of research. While epidemiological and case-control studies have often suggested a link between vitamin D deficiency and conditions such as type 1 and type 2 diabetes, connective tissue disorders, inflammatory bowel disorders, chronic hepatitis, food allergies, asthma and respiratory infections, and cancer, interventional studies for the most part have failed to confirm a causative link. This review examines available evidence to date for the extra-skeletal effects of vitamin D deficiency, with a focus on randomized controlled trials and meta-analyses.
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Chatterjee R, Erban JK, Fuss P, Dolor R, LeBlanc E, Staten M, Sheehan P, Pittas A. Vitamin D supplementation for prevention of cancer: The D2d cancer outcomes (D2dCA) study. Contemp Clin Trials 2019; 81:62-70. [PMID: 31048088 PMCID: PMC6570503 DOI: 10.1016/j.cct.2019.04.015] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2019] [Revised: 04/19/2019] [Accepted: 04/25/2019] [Indexed: 02/08/2023]
Abstract
Evidence on biological plausibility from mechanistic studies and data from observational studies suggest that vitamin D may be linked to risk of several types of cancer. However, evidence from clinical trials evaluating the effect of vitamin D supplementation on cancer risk is limited. The Vitamin D and Type 2 Diabetes (D2d) study is a multi-center, randomized, placebo-controlled clinical trial conducted to examine the causal relationship between oral vitamin D supplementation and development of diabetes among overweight adults with prediabetes. The D2d study provides a unique opportunity to assess the effect of vitamin D supplementation at a higher dose (4000 IU/day) than has been used in other clinical trials with cancer outcomes, in a population at higher than average risk for cancer. This paper provides: Krishnan and Feldman (2011) a) baseline characteristics of the D2d population included in the D2d cancer outcomes secondary study (D2dCA) and comparison to other large trials of vitamin D supplementation and cancer risk; Leyssens et al. (2013) b) description of data that are being collected during the trial and the planned statistical analyses to test whether vitamin D supplementation at a dose of 4000 IU/day has an effect on incident cancer overall, on incidence of certain types of cancer, and on incidence of precancerous lesions. Results of D2dCA will help guide future research and clinical recommendations related to vitamin D and cancer risk.
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Affiliation(s)
- Ranee Chatterjee
- Division of General Internal Medicine, 200 Morris Street, 3(rd) Floor, Box 104427, Durham, NC 27701, USA.
| | - John K Erban
- Cancer Center, Tufts Medical Center, 800 Washington St, Box 245, Boston, MA 02111, USA.
| | - Paul Fuss
- Division of Endocrinology, Tufts Medical Center, 800 Washington Street, Box 268, Boston, MA 02111, USA.
| | - Rowena Dolor
- Division of General Internal Medicine, 200 Morris Street, 3(rd) Floor, Box 104427, Durham, NC 27701, USA.
| | - Erin LeBlanc
- Kaiser Permanente Center for Health Research NW, 3800 N Interstate, Portland, OR 97229, USA.
| | - Myrlene Staten
- Kelly Government Services for the National Institute of Diabetes and Digestive and Kidney Diseases, 6701 Democracy Boulevard, Room 6107, Bethesda, MD 20817, USA.
| | - Patricia Sheehan
- Spaulding Rehabilitation Network, 300 1(st) Ave, Charlestown, MA 02129, USA.
| | - Anastassios Pittas
- Division of Endocrinology, Tufts Medical Center, 800 Washington Street, Box 268, Boston, MA 02111, USA.
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11
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Calderwood AH, Baron JA, Mott LA, Ahnen DJ, Bostick RM, Figueiredo JC, Passarelli MN, Rees JR, Robertson DJ, Barry EL. No Evidence for Posttreatment Effects of Vitamin D and Calcium Supplementation on Risk of Colorectal Adenomas in a Randomized Trial. Cancer Prev Res (Phila) 2019; 12:295-304. [PMID: 30833381 DOI: 10.1158/1940-6207.capr-19-0023] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2019] [Revised: 02/25/2019] [Accepted: 02/25/2019] [Indexed: 12/15/2022]
Abstract
Vitamin D and calcium supplementation are postulated to have chemopreventive effects against colorectal neoplasia, yet in our previously reported randomized trial, there was no overall efficacy of calcium and/or vitamin D3 against colorectal adenoma recurrence. It is possible vitamin D3 and calcium chemopreventive effects are not detectable until beyond the 3- to 5-year follow-up captured in that trial. Accordingly, we explored possible vitamin D and calcium effects on posttreatment (observational) adenoma occurrence. In this secondary analysis of the observational follow-up phase of the Vitamin D/Calcium Polyp Prevention Study, participants who completed the treatment phase were invited to be followed for one additional surveillance colonoscopy cycle. We evaluated adenoma occurrence risk at surveillance colonoscopy, with a mean of 55 ± 15 months after treatment follow-up, according to randomized treatment with vitamin D versus no vitamin D, calcium versus no calcium, and calcium plus vitamin D versus calcium alone. Secondary outcomes included advanced and multiple adenomas. Among the 1,121 participants with observational follow-up, the relative risk (95% confidence interval, CI) of any adenoma was 1.04 (0.93-1.17) for vitamin D versus no vitamin D; 0.95 (0.84-1.08) for calcium versus no calcium; 1.07 (0.91-1.25) for calcium plus vitamin D versus calcium; and 0.96 (0.81-1.15) for calcium plus vitamin D versus neither. Risks of advanced or multiple adenomas also did not differ by treatment. Our results do not support an association between supplemental calcium and/or vitamin D3 for 3 to 5 years and risk of recurrent colorectal adenoma at an average of 4.6 years after treatment.
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Affiliation(s)
- Audrey H Calderwood
- Section of Gastroenterology and Hepatology, Department of Medicine, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire.
| | - John A Baron
- Departments of Epidemiology and Medicine, Geisel School of Medicine at Dartmouth, Lebanon, New Hampshire; University of North Carolina School of Medicine, Chapel Hill, North Carolina
| | - Leila A Mott
- Department of Epidemiology, Geisel School of Medicine at Dartmouth, Lebanon, New Hampshire
| | - Dennis J Ahnen
- Division of Gastroenterology and Hepatology, University of Colorado School of Medicine, Denver, Colorado
| | - Roberd M Bostick
- Department of Epidemiology, Emory University; Winship Cancer Institute, Emory University, Atlanta, Georgia
| | - Jane C Figueiredo
- Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, California
| | - Michael N Passarelli
- Department of Epidemiology, Geisel School of Medicine at Dartmouth, Lebanon, New Hampshire
| | - Judy R Rees
- Department of Epidemiology, Geisel School of Medicine at Dartmouth, Lebanon, New Hampshire
| | - Douglas J Robertson
- VA Medical Center, White River Junction, Vermont; Section of Gastroenterology and Hepatology, Department of Medicine, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire
| | - Elizabeth L Barry
- Department of Epidemiology, Geisel School of Medicine at Dartmouth, Lebanon, New Hampshire
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Kwan AK, Um CY, Rutherford RE, Seabrook ME, Barry EL, Fedirko V, Baron JA, Bostick RM. Effects of vitamin D and calcium on expression of MSH2 and transforming growth factors in normal-appearing colorectal mucosa of sporadic colorectal adenoma patients: A randomized clinical trial. Mol Carcinog 2018; 58:511-523. [PMID: 30499618 DOI: 10.1002/mc.22945] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2018] [Revised: 09/24/2018] [Accepted: 11/22/2018] [Indexed: 12/14/2022]
Abstract
Abnormal expression of the DNA mismatch repair protein MSH2 and autocrine/paracrine transforming growth factors TGFα (growth promoter) and TGFβ1 (growth inhibitor) is common during colorectal carcinogenesis. To estimate vitamin D and calcium effects on these biomarkers in the normal-appearing colorectal mucosa of sporadic colorectal adenoma patients, we conducted a pilot, randomized, double-blinded, placebo-controlled, modified 2 × 2 factorial chemoprevention clinical trial (N = 104) of supplemental vitamin D3 (1000 IU daily) and calcium (1200 mg daily), alone and in combination, versus placebo over 1 year. The expression of the three biomarkers and Ki-67/mib-1 in colorectal crypts in biopsies of normal-appearing rectal mucosa were detected using automated immunohistochemistry and quantified using image analysis. In the vitamin D3 and vitamin D3 plus calcium groups, relative to their reference groups, in the upper 40% (differentiation zone) of crypts, it was estimated that, respectively, the MSH2/mib-1 ratio increased by 47% (P = 0.14) and 62% (P = 0.08), TGFβ1 expression increased by 41% (P = 0.25) and 78% (P = 0.14), and the TGFα/TGFβ1 ratio decreased by 25% (P = 0.31) and 44% (P = 0.13). Although not statistically significant, these results support further research into (i) whether supplemental vitamin D3 , alone or in combination with calcium, may increase DNA mismatch repair relative to proliferation, increase TGFβ1 expression, and decrease autocrine/paracrine growth promotion relative to growth inhibition in the colorectal epithelium, all hypothesized to reduce risk for colorectal carcinogenesis; and (ii) the expression of MSH2 relative to mib-1, TGFβ1 alone, and TGFα relative to TGFβ1 in the normal-appearing rectal mucosa as potential modifiable, pre-neoplastic markers of risk for colorectal neoplasms.
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Affiliation(s)
- Albert K Kwan
- Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, Georgia
| | - Caroline Y Um
- Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, Georgia
| | - Robin E Rutherford
- Division of Digestive Diseases, Department of Medicine, School of Medicine, Emory University, Atlanta, Georgia
| | | | - Elizabeth L Barry
- Department of Epidemiology, Geisel School of Medicine at Dartmouth, Lebanon, New Hampshire
| | - Veronika Fedirko
- Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, Georgia.,Winship Cancer Institute, Emory University, Atlanta, Georgia
| | - John A Baron
- Department of Epidemiology, Geisel School of Medicine at Dartmouth, Lebanon, New Hampshire.,Department of Medicine, Geisel School of Medicine at Dartmouth, Lebanon, New Hampshire.,University of North Carolina at Chapel Hill, Chapel Hill, North Carolina
| | - Roberd M Bostick
- Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, Georgia.,Winship Cancer Institute, Emory University, Atlanta, Georgia
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13
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Agten CA, Margaroli L, Bensler S, Fritz B, Rosskopf AB, Held U, Pfirrmann CWA. Prevalence of vitamin D insufficiency in radiologists: a cross-sectional study. Skeletal Radiol 2018; 47:981-988. [PMID: 29396695 DOI: 10.1007/s00256-018-2896-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/19/2017] [Revised: 01/15/2018] [Accepted: 01/18/2018] [Indexed: 02/02/2023]
Abstract
OBJECTIVE To compare the prevalence of vitamin D insufficiency between radiologists and a control group of non-radiologists. MATERIALS AND METHODS This prospective cross-sectional study was conducted at the Swiss Congress of Radiology in May of 2016. Attendees (radiologists and non-radiologists) were asked to give a venous blood sample to measure vitamin D (25-hydroxyvitamin D) blood serum level. Vitamin D insufficiency was defined as < 50 nmol/l (30 ng/ml). We collected information on profession, age, gender, vitamin D supplements, recent sunny vacation, and eating fish. We compared vitamin D between radiologists and non-radiologists. RESULTS A total of 137 radiologists (mean age, 38 ± 10 years) and 164 non-radiologists (mean age, 40 ± 12 years) participated in the study. Prevalence of vitamin D insufficiency in both groups was similar (58.4% (80/137) vs. 53.7% (88/164); p = 0.240). Forty-three participants were under vitamin D supplementation. In those without supplementation, we found no difference in vitamin D between groups (44.0 ± 16.2 nmol/l (17.6 ± 6.5 ng/ml) vs. 44.4 ± 16.9 nmol/l (17.8 ± 6.8 ng/ml); p = 0.757). Average vitamin D levels for radiologists were slightly lower (-0.98 nmol/l (0.39 ng/ml), 95% confidence interval - 5.96 to 4.00 (- 2.38 to 1.6 ng/ml); p = 0.699), when adjusting for the potential confounders, but not statistically significant. The odds ratio of vitamin D insufficiency for radiologists versus non-radiologists was 1.7 (95% CI = 0.94-3.06; p = 0.078) after adjusting for the other independent variables. CONCLUSIONS The prevalence of vitamin D insufficiency in radiologists was high (58.4%), but not substantially higher than in non-radiologists.
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Affiliation(s)
- Christoph Amadeus Agten
- Radiology, Balgrist University Hospital, Forchstrasse 340, 8008, Zurich, Switzerland. .,Faculty of Medicine, University of Zurich, Zurich, Switzerland.
| | - Lukas Margaroli
- Faculty of Medicine, University of Zurich, Zurich, Switzerland
| | - Susanne Bensler
- Radiology, Balgrist University Hospital, Forchstrasse 340, 8008, Zurich, Switzerland.,Faculty of Medicine, University of Zurich, Zurich, Switzerland
| | - Benjamin Fritz
- Radiology, Balgrist University Hospital, Forchstrasse 340, 8008, Zurich, Switzerland.,Faculty of Medicine, University of Zurich, Zurich, Switzerland
| | - Andrea B Rosskopf
- Radiology, Balgrist University Hospital, Forchstrasse 340, 8008, Zurich, Switzerland.,Faculty of Medicine, University of Zurich, Zurich, Switzerland
| | - Ulrike Held
- Horten Centre, University of Zurich, Zurich, Switzerland
| | - Christian W A Pfirrmann
- Radiology, Balgrist University Hospital, Forchstrasse 340, 8008, Zurich, Switzerland.,Faculty of Medicine, University of Zurich, Zurich, Switzerland
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14
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Marques da Costa P, Martins I, Neves J, Cortez-Pinto H, Velosa J. Serum vitamin D levels correlate with the presence and histological grading of colorectal adenomas in peri and postmenopausal women. Clin Nutr 2018; 38:1390-1397. [PMID: 29961649 DOI: 10.1016/j.clnu.2018.06.959] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2018] [Revised: 06/09/2018] [Accepted: 06/13/2018] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS Vitamin D is known to modulate immune function and proliferation. Higher vitamin D [25(OH)D3] serum levels have been reported to have protective effects on adenoma detection and colorectal cancer (CRC) development and survival. METHODS This retrospective cohort study included 315 peri and post-menopausal women submitted to opportunistic colorectal and osteoporosis screening at the gynaecology outpatient clinic of a tertiary medical centre between 2004 and 2015. Colonoscopy findings were correlated with 25(OH)D3 and PTH serum levels, and subsequently adjusted in a multivariate logistic regression model. Confounding factors included demographic and colorectal risk factors, pharmacological therapies and bone densitometry metrics. RESULTS A total of 77 lesions were identified in 66 patients. Vitamin D insufficiency (<30 ng/mL) and deficiency (<20 ng/mL) were identified in 79.4% and 35.2% of patients, respectively. In univariate analysis, lower levels of 25(OH)D3 were associated with polyp, adenoma and advanced adenoma detection. After adjusting for confounders, an association with polyps could not be observed, but a trend towards a negative correlation with adenoma detection was found (adjusted OR: 0.96; 95% CI 0.92-1.00; p = 0.083). Regarding advanced adenoma detection, 25(OH)D3 (adjusted OR: 0.86; 95% CI 0.77-0.97; p = 0.013) proved to be an independent predictive factor. No association was found between 25(OH)D3 levels and lesion detection site. CONCLUSION The association of 25(OH)D3 serum levels with colorectal lesions seems to be restricted to adenomatous lesions and is influenced by histological grading. Vitamin D may be a valuable biomarker for optimization of risk stratification in group-specific CRC screening protocols.
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Affiliation(s)
- Pedro Marques da Costa
- Serviço de Gastrenterologia e Hepatologia, Hospital de Santa Maria, Centro Hospitalar Lisboa Norte, Faculdade de Medicina da Universidade de Lisboa, Avenida Professor Egas Moniz, Lisboa 1649-035, Portugal.
| | - Inês Martins
- Departamento/Clínica Universitária de Obstetrícia, Ginecologia e Medicina da Reprodução, Hospital Santa Maria, Centro Hospitalar Lisboa Norte, Avenida Professor Egas Moniz, Lisboa 1649-035, Portugal.
| | - Joaquim Neves
- Departamento/Clínica Universitária de Obstetrícia, Ginecologia e Medicina da Reprodução, Hospital Santa Maria, Centro Hospitalar Lisboa Norte, Avenida Professor Egas Moniz, Lisboa 1649-035, Portugal.
| | - Helena Cortez-Pinto
- Serviço de Gastrenterologia e Hepatologia, Hospital de Santa Maria, Centro Hospitalar Lisboa Norte, Laboratório de Nutrição, Faculdade de Medicina da Universidade de Lisboa, Avenida Professor Egas Moniz, Lisboa 1649-035, Portugal.
| | - José Velosa
- Serviço de Gastrenterologia e Hepatologia, Hospital de Santa Maria, Centro Hospitalar Lisboa Norte, Faculdade de Medicina da Universidade de Lisboa, Avenida Professor Egas Moniz, Lisboa 1649-035, Portugal.
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15
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Stoffel EM. Updates on Translational Research on Prevention of Polyps and Colorectal Cancer. Clin Colon Rectal Surg 2018; 31:153-160. [PMID: 29720901 DOI: 10.1055/s-0037-1602235] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Morbidity and mortality from colorectal cancer (CRC) can be effectively reduced through early detection and prevention. To date, strategies for managing CRC risk have focused primarily on secondary prevention, through screening asymptomatic individuals for colorectal neoplasia. In the United States, implementation of screening among individuals age ≥50 has led to not only decreased CRC-related mortality but also reduced CRC incidence through colonoscopic removal of precancerous polyps. In contrast to screening's endpoint of early detection, the goal of primary prevention of CRC is to arrest and/or reverse colorectal carcinogenesis. Observational studies and randomized clinical trials continue to examine effects of specific pharmacologic agents (chemoprevention) and dietary interventions on development of advanced colorectal neoplasia. This review will present an overview of strategies for primary and secondary prevention of CRC, including endoscopic, pharmacologic, and dietary interventions.
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Affiliation(s)
- Elena M Stoffel
- Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan
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16
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Bryce C. Association of 25-OH Vitamin D Status with Findings on Screening Colonoscopy. Mil Med 2018; 183:547-551. [DOI: 10.1093/milmed/usx152] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2017] [Indexed: 12/31/2022] Open
Affiliation(s)
- Carl Bryce
- Nellis Family Medicine Residency, 4700 N Las Vegas Blvd, Nellis Air Force Base, NV 89191
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17
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Current therapies in alleviating liver disorders and cancers with a special focus on the potential of vitamin D. Nutr Metab (Lond) 2018; 15:13. [PMID: 29449867 PMCID: PMC5807831 DOI: 10.1186/s12986-018-0251-5] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2017] [Accepted: 01/30/2018] [Indexed: 02/06/2023] Open
Abstract
Background Liver dysfunction is a topic of global concern with many advancing therapies being researched. Though vitamin D takes a center place, other therapies especially nutritional are also gaining ground. Vitamin D has gone beyond its role in skeletal disorders by showcasing its associations in other metabolic dysfunctions too. Result Epidemiological evidences show a correlation between the status of vitamin D and different forms of cancer. Vitamin D receptors and alterations in gene expression appear decisive in the development of chronic liver disorders. Nutritional status therefore plays a significant role in avoiding the complications related to liver dysfunctions, making it mandatory in maintaining vitamin D sufficiency in the body. Therapies with omega-3 fatty acids, antioxidants, amino acids, steroids also render benefits which could be further explored. Recent research on the progression of certain forms of liver cancer using vitamin D analogs like Seocalcitol EB 1089 has shown good promise. Conclusion The anti-inflammatory and immuno- regulatory properties of vitamin D makes its analogs, suitable candidates of better choice for the prevention and treatment of liver disorders and cancer.
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18
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Bikle DD. Extraskeletal actions of vitamin D. Ann N Y Acad Sci 2017; 1376:29-52. [PMID: 27649525 DOI: 10.1111/nyas.13219] [Citation(s) in RCA: 100] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2016] [Revised: 07/26/2016] [Accepted: 08/03/2016] [Indexed: 12/16/2022]
Abstract
The vitamin D receptor (VDR) is found in nearly all, if not all, cells in the body. The enzyme that produces the active metabolite of vitamin D and ligand for VDR, namely CYP27B1, likewise is widely expressed in many cells of the body. These observations indicate that the role of vitamin D is not limited to regulation of bone and mineral homeostasis, as important as that is. Rather, the study of its extraskeletal actions has become the major driving force behind the significant increase in research articles on vitamin D published over the past several decades. A great deal of information has accumulated from cell culture studies, in vivo animal studies, and clinical association studies that confirms that extraskeletal effects of vitamin D are truly widespread and substantial. However, randomized, placebo-controlled clinical trials, when done, have by and large not produced the benefits anticipated by the in vitro cell culture and in vivo animal studies. In this review, I will examine the role of vitamin D signaling in a number of extraskeletal tissues and assess the success of translating these findings into treatments of human diseases affecting those extracellular tissues.
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Affiliation(s)
- Daniel D Bikle
- Departments of Medicine and Dermatology, Veterans Affairs Medical Center and University of California, San Francisco, San Francisco, California.
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19
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Moukayed M, Grant WB. The roles of UVB and vitamin D in reducing risk of cancer incidence and mortality: A review of the epidemiology, clinical trials, and mechanisms. Rev Endocr Metab Disord 2017; 18:167-182. [PMID: 28213657 DOI: 10.1007/s11154-017-9415-2] [Citation(s) in RCA: 61] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Global cancer incidence and mortality rates are high and increasing. Thus, it is imperative to find novel solutions to preventing cancer incidence and treating it at an affordable yet efficacious manner. The solar UVB-vitamin D-cancer hypothesis was first proposed in 1980 based on a geographical ecological study. Since then, numerous ecological and observational studies as well as studies of mechanisms have provided support for the hypothesis. However, observational studies have not provided consistent support, in part due to using a single blood draw from any season to use for serum 25-hydroxyvitamin D [25(OH)D] concentration in prospective studies with long follow-up times. Case-controls studies, in which blood is drawn near time of diagnosis, and prospective studies in which blood is drawn in the sunnier half of the year, are more likely to find significant inverse relations between 25(OH)D and cancer incidence. Three vitamin D plus calcium clinical trials have found significant reduction in all-cancer incidence. This paper reviews the evidence for vitamin D in reducing incidence of and increasing survival from breast, colorectal, lung, ovarian, pancreatic, and prostate cancer. The epidemiological evidence provides strong support for all of these types of cancer except for non-aggressive prostate cancer. Studies of the cellular mechanisms of vitamin D action in different cancer cell types, strongly indicate that vitamin D can exert protective and anti-tumorigenic activities that would retard cellular transformation, hyperplasia and cancer progression. Based on the scientific evidence reviewed in this paper, individuals and health providers can consider increasing 25(OH)D concentrations through sensible sun exposure and/or vitamin D supplementation to reduce risk of and, in conjunction with standard care, treat cancer. Public health acceptance of vitamin D for cancer prevention and treatment requires stronger support from vitamin D clinical trials.
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Affiliation(s)
- Meis Moukayed
- School of Arts and Sciences, American University in Dubai, P.O. Box 28282, Dubai, United Arab Emirates
| | - William B Grant
- Sunlight, Nutrition, and Health Research Center, P.O. Box 641603, San Francisco, CA, 94164-1603, USA.
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20
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Abstract
In many cells throughout the body, vitamin D is converted into its active form calcitriol and binds to the vitamin D receptor (VDR), which functions as a transcription factor to regulate various biological processes including cellular differentiation and immune response. Vitamin D-metabolising enzymes (including CYP24A1 and CYP27B1) and VDR play major roles in exerting and regulating the effects of vitamin D. Preclinical and epidemiological studies have provided evidence for anti-cancer effects of vitamin D (particularly against colorectal cancer), although clinical trials have yet to prove its benefit. In addition, molecular pathological epidemiology research can provide insights into the interaction of vitamin D with tumour molecular and immunity status. Other future research directions include genome-wide research on VDR transcriptional targets, gene-environment interaction analyses and clinical trials on vitamin D efficacy in colorectal cancer patients. In this study, we review the literature on vitamin D and colorectal cancer from both mechanistic and population studies and discuss the links and controversies within and between the two parts of evidence.
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21
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Marcinkowska E, Wallace GR, Brown G. The Use of 1α,25-Dihydroxyvitamin D₃ as an Anticancer Agent. Int J Mol Sci 2016; 17:E729. [PMID: 27187375 PMCID: PMC4881551 DOI: 10.3390/ijms17050729] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2016] [Revised: 04/22/2016] [Accepted: 05/10/2016] [Indexed: 12/12/2022] Open
Abstract
The notion that vitamin D can influence the incidence of cancer arose from epidemiological studies. The major source of vitamin D in the organism is skin production upon exposure to ultra violet-B. The very first observation of an inverse correlation between exposure of individuals to the sun and the likelihood of cancer was reported as early as 1941. In 1980, Garland and Garland hypothesised, from findings from epidemiological studies of patients in the US with colon cancer, that vitamin D produced in response to sun exposure is protective against cancer as opposed to sunlight per se. Later studies revealed inverse correlations between sun exposure and the occurrence of prostate and breast cancers. These observations prompted laboratory investigation of whether or not vitamin D had an effect on cancer cells. Vitamin D is not active against cancer cells, but the most active metabolite 1α,25-dihydroxyvitamin D₃ (1,25D) has profound biological effects. Here, we review the anticancer action of 1,25D, clinical trials of 1,25D to date and the prospects of the future therapeutic use of new and low calcaemic analogues.
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Affiliation(s)
- Ewa Marcinkowska
- Laboratory of Protein Biochemistry, Faculty of Biotechnology, University of Wroclaw, Joliot-Curie 14a, 50-383 Wroclaw, Poland.
| | - Graham R Wallace
- Institute of Inflammation and Aging, College of Medical and Dental Sciences, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK.
| | - Geoffrey Brown
- Institute of Clinical Sciences, College of Medical and Dental Sciences, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK.
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22
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Jacobs ET, Kohler LN, Kunihiro AG, Jurutka PW. Vitamin D and Colorectal, Breast, and Prostate Cancers: A Review of the Epidemiological Evidence. J Cancer 2016; 7:232-40. [PMID: 26918035 PMCID: PMC4747876 DOI: 10.7150/jca.13403] [Citation(s) in RCA: 80] [Impact Index Per Article: 8.9] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2015] [Accepted: 12/03/2015] [Indexed: 02/07/2023] Open
Abstract
Over the past two decades, the question of whether vitamin D has a role in cancer incidence, progression, and mortality has been studied in detail. Colorectal, breast, and prostate cancers have been a particular area of focus; together, these three malignancies account for approximately 35% of cancer cases and 20% of cancer deaths in the United States, and as such are a major public health concern. Herein, we review and synthesize the epidemiological research regarding vitamin D, as measured by the biomarker 25-hydroxycholecalciferol [25(OH)D], and the incidence, progression, and mortality of these cancers. Overall, the results of observational studies of the relationship between 25(OH)D and colorectal cancer have revealed a consistent inverse association for incidence and mortality; while for breast cancer, results have generally demonstrated a relationship between higher 25(OH)D and lower risk for progression and mortality. In contrast, randomized, double-blind clinical trials conducted to date have generally failed to support these findings. For prostate cancer, there is no convincing evidence of an association between 25(OH)D and incidence, and inconsistent data for progression and mortality, though results of one open label clinical trial suggest that supplementation with 4000 IU/d of vitamin D3 may inhibit progression of the disease. Nonetheless, until the results of additional ongoing randomized, double-blind clinical trials are reported, it will be difficult to ascertain if vitamin D itself is related to a reduction in risk for some cancer endpoints, or whether high concentrations of the vitamin D biomarker 25(OH)D may instead serve as a marker for an overall beneficial risk factor profile.
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Affiliation(s)
- Elizabeth T Jacobs
- University of Arizona Cancer Center, Tucson, Arizona (ETJ); Mel and Enid Zuckerman College of Public Health, University of Arizona, Tucson, Arizona (ETJ, LNK); Department of Nutritional Sciences, University of Arizona, Tucson, Arizona (ETJ, AGK); School of Mathematical and Natural Sciences, Arizona State University, Phoenix, Arizona (PWJ); Department of Basic Medical Sciences, The University of Arizona, College of Medicine, Phoenix, AZ (PWJ)
| | - Lindsay N Kohler
- University of Arizona Cancer Center, Tucson, Arizona (ETJ); Mel and Enid Zuckerman College of Public Health, University of Arizona, Tucson, Arizona (ETJ, LNK); Department of Nutritional Sciences, University of Arizona, Tucson, Arizona (ETJ, AGK); School of Mathematical and Natural Sciences, Arizona State University, Phoenix, Arizona (PWJ); Department of Basic Medical Sciences, The University of Arizona, College of Medicine, Phoenix, AZ (PWJ)
| | - Andrew G Kunihiro
- University of Arizona Cancer Center, Tucson, Arizona (ETJ); Mel and Enid Zuckerman College of Public Health, University of Arizona, Tucson, Arizona (ETJ, LNK); Department of Nutritional Sciences, University of Arizona, Tucson, Arizona (ETJ, AGK); School of Mathematical and Natural Sciences, Arizona State University, Phoenix, Arizona (PWJ); Department of Basic Medical Sciences, The University of Arizona, College of Medicine, Phoenix, AZ (PWJ)
| | - Peter W Jurutka
- University of Arizona Cancer Center, Tucson, Arizona (ETJ); Mel and Enid Zuckerman College of Public Health, University of Arizona, Tucson, Arizona (ETJ, LNK); Department of Nutritional Sciences, University of Arizona, Tucson, Arizona (ETJ, AGK); School of Mathematical and Natural Sciences, Arizona State University, Phoenix, Arizona (PWJ); Department of Basic Medical Sciences, The University of Arizona, College of Medicine, Phoenix, AZ (PWJ)
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Baron JA, Barry EL, Mott LA, Rees JR, Sandler RS, Snover DC, Bostick RM, Ivanova A, Cole BF, Ahnen DJ, Beck GJ, Bresalier RS, Burke CA, Church TR, Cruz-Correa M, Figueiredo JC, Goodman M, Kim AS, Robertson DJ, Rothstein R, Shaukat A, Seabrook ME, Summers RW. A Trial of Calcium and Vitamin D for the Prevention of Colorectal Adenomas. N Engl J Med 2015; 373:1519-30. [PMID: 26465985 PMCID: PMC4643064 DOI: 10.1056/nejmoa1500409] [Citation(s) in RCA: 226] [Impact Index Per Article: 22.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
BACKGROUND Epidemiologic and preclinical data suggest that higher intake and serum levels of vitamin D and higher intake of calcium reduce the risk of colorectal neoplasia. To further study the chemopreventive potential of these nutrients, we conducted a randomized, double-blind, placebo-controlled trial of supplementation with vitamin D, calcium, or both for the prevention of colorectal adenomas. METHODS We recruited patients with recently diagnosed adenomas and no known colorectal polyps remaining after complete colonoscopy. We randomly assigned 2259 participants to receive daily vitamin D3 (1000 IU), calcium as carbonate (1200 mg), both, or neither in a partial 2×2 factorial design. Women could elect to receive calcium plus random assignment to vitamin D or placebo. Follow-up colonoscopy was anticipated to be performed 3 or 5 years after the baseline examinations, according to the endoscopist's recommendation. The primary end point was adenomas diagnosed in the interval from randomization through the anticipated surveillance colonoscopy. RESULTS Participants who were randomly assigned to receive vitamin D had a mean net increase in serum 25-hydroxyvitamin D levels of 7.83 ng per milliliter, relative to participants given placebo. Overall, 43% of participants had one or more adenomas diagnosed during follow-up. The adjusted risk ratios for recurrent adenomas were 0.99 (95% confidence interval [CI], 0.89 to 1.09) with vitamin D versus no vitamin D, 0.95 (95% CI, 0.85 to 1.06) with calcium versus no calcium, and 0.93 (95% CI, 0.80 to 1.08) with both agents versus neither agent. The findings for advanced adenomas were similar. There were few serious adverse events. CONCLUSIONS Daily supplementation with vitamin D3 (1000 IU), calcium (1200 mg), or both after removal of colorectal adenomas did not significantly reduce the risk of recurrent colorectal adenomas over a period of 3 to 5 years. (Funded by the National Cancer Institute; ClinicalTrials.gov number, NCT00153816.).
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Affiliation(s)
- John A Baron
- From the Departments of Medicine (J.A.B., D.J.R., R.R.) and Epidemiology (J.A.B., E.L.B., L.A.M., J.R.R.), Geisel School of Medicine at Dartmouth, Hanover, and Department of Medicine, Dartmouth-Hitchcock Medical Center, Lebanon (D.J.R., R.R.) - both in New Hampshire; the Departments of Medicine (J.A.B., R.S.S.) and Biostatistics (A.I.), University of North Carolina at Chapel Hill, Chapel Hill; the Department of Pathology, Fairview Southdale Hospital, Edina (D.C.S.), and the Division of Environmental Health Sciences, University of Minnesota School of Public Health (T.R.C.), Minnesota Gastroenterology (A.S.K.), Department of Medicine, University of Minnesota (A.S.), and Minneapolis Veterans Affairs (VA) Medical Center (A.S.), Minneapolis - all in Minnesota; the Department of Epidemiology, Rollins School of Public Health, Emory University and Winship Cancer Institute, Emory University, Atlanta (R.M.B., M.G.); the Department of Mathematics and Statistics, University of Vermont, Burlington (B.F.C.), and VA Outcomes Group, White River Junction (D.J.R.) - both in Vermont; the Department of Medicine, University of Colorado School of Medicine, Denver (D.J.A.); the Departments of Quantitative Health Sciences (G.J.B.) and Gastroenterology and Hepatology (C.A.B.), Cleveland Clinic, Cleveland; the Department of Gastroenterology, Hepatology, and Nutrition, University of Texas M.D. Anderson Cancer Center, Houston (R.S.B.); Puerto Rico Cancer Center, Medical Sciences Campus, University of Puerto Rico, San Juan (M.C.-C.); the Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles (J.C.F.); Consultants in Gastroenterology, West Columbia, SC (M.E.S.); and the Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City (R.W.S.)
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Hibler EA, Klimentidis YC, Jurutka PW, Kohler LN, Lance P, Roe DJ, Thompson PA, Jacobs ET. CYP24A1 and CYP27B1 Polymorphisms, Concentrations of Vitamin D Metabolites, and Odds of Colorectal Adenoma Recurrence. Nutr Cancer 2015; 67:1131-41. [PMID: 26241700 DOI: 10.1080/01635581.2015.1068818] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
Development of colorectal adenoma and cancer are associated with low circulating 25-hydroxyvitamin D [25(OH)D] levels. However, less is known regarding colorectal neoplasia risk and variation in CYP27B1 or CYP24A1, genes encoding the enzymes responsible for the synthesis and catabolism of 1α,25-hydroxyvitamin D [1,25(OH)2D]. This study examined associations between CYP27B1 and CYP24A1 polymorphisms, circulating 25(OH)D and 1,25(OH)2D concentrations, and colorectal adenoma recurrence in a pooled sample from 2 clinical trials (n = 1,188). Nominal associations were observed between increasing copies of the T allele in CYP24A1 rs927650 and 25(OH)D concentrations (P = 0.02); as well as colorectal adenoma recurrence, with odds ratios (95% confidence intervals) of 1.30 (0.99-1.70) and 1.38 (1.01-1.89) for heterozygotes and minor allele homozygotes, respectively (P = 0.04). In addition, a statistically significant relationship between CYP24A1 rs35051736, a functional polymorphism, and odds for advanced colorectal adenoma recurrence was observed (P < 0.001). Further, nominally statistically significant interactions were observed between rs2296241 and 25(OH)D as well as rs2762939 and 1,25(OH)2D (P(interaction) = 0.10, respectively). Overall, CYP24A1 polymorphisms may influence the development of advanced lesions, and modify the effect of vitamin D metabolites on adenoma recurrence. Further study is necessary to characterize the differences between circulating vitamin D metabolite measurements compared to cellular level activity in relation to cancer risk.
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Affiliation(s)
- Elizabeth A Hibler
- a Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine , Nashville , Tennessee , USA
| | - Yann C Klimentidis
- b Mel and Enid Zuckerman College of Public Health, University of Arizona , Tucson , Arizona , USA
| | - Peter W Jurutka
- c School of Mathematical and Natural Sciences, Arizona State University , Phoenix , Arizona , USA
| | - Lindsay N Kohler
- b Mel and Enid Zuckerman College of Public Health, University of Arizona , Tucson , Arizona , USA
| | - Peter Lance
- d University of Arizona Cancer Center , Tucson , Arizona , USA
| | - Denise J Roe
- e Mel and Enid Zuckerman College of Public Health, University of Arizona , Tucson , Arizona , USA and University of Arizona Cancer Center , Tucson , Arizona , USA
| | | | - Elizabeth T Jacobs
- e Mel and Enid Zuckerman College of Public Health, University of Arizona , Tucson , Arizona , USA and University of Arizona Cancer Center , Tucson , Arizona , USA
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Masri OA, Chalhoub JM, Sharara AI. Role of vitamins in gastrointestinal diseases. World J Gastroenterol 2015; 21:5191-5209. [PMID: 25954093 PMCID: PMC4419060 DOI: 10.3748/wjg.v21.i17.5191] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/08/2015] [Revised: 02/23/2015] [Accepted: 03/31/2015] [Indexed: 02/06/2023] Open
Abstract
A tremendous amount of data from research was published over the past decades concerning the roles of different vitamins in various gastrointestinal diseases. For instance, most vitamins showed an inverse relationship with the risk of colorectal carcinoma as well as other malignancies like gastric and esophageal cancer in observational trials, however interventional trials failed to prove a clear beneficial preventive role. On the other hand, more solid evidence was obtained from high quality studies for a role of certain vitamins in specific entities. Examples for this include the therapeutic role of vitamin E in patients with non-alcoholic steatohepatitis, the additive role of vitamins B12 and D to the standard therapy of chronic hepatitis C virus, the role of vitamin C in reducing the risk of gallstones, the positive outcome with vitamin B12 in patients with aphthous stomatitis, and the beneficial effect of vitamin D and B1 in patients with inflammatory bowel disease. Other potential uses are yet to be elaborated, like those on celiac disease, pancreatic cancer, pancreatitis, cholestasis and other potential fields. Data from several ongoing interventional trials are expected to add to the current knowledge over the coming few years. Given that vitamin supplementation is psychologically accepted by patients as a natural compound with relative safety and low cost, their use should be encouraged in the fields where positive data are available.
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Janmaat VT, Van De Winkel A, Peppelenbosch MP, Spaander MCW, Uitterlinden AG, Pourfarzad F, Tilanus HW, Rygiel AM, Moons LMG, Arp PP, Krishnadath KK, Kuipers EJ, Van Der Laan LJW. Vitamin D Receptor Polymorphisms Are Associated with Reduced Esophageal Vitamin D Receptor Expression and Reduced Esophageal Adenocarcinoma Risk. Mol Med 2015; 21:346-54. [PMID: 25910066 DOI: 10.2119/molmed.2012.00336] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2012] [Accepted: 04/21/2015] [Indexed: 12/22/2022] Open
Abstract
Epidemiological studies indicate that vitamin D exerts a protective effect on the development of various solid cancers. However, concerns have been raised regarding the potential deleterious role of high vitamin D levels in the development of esophageal adenocarcinoma (EAC). This study investigated genetic variation in the vitamin D receptor (VDR) in relation to its expression and risk of Barrett esophagus (BE) and EAC. VDR gene regulation was investigated by immunohistochemistry, reverse transcriptase-polymerase chain reaction (RT-PCR) and gel shift assays. Fifteen haplotype tagging single-nucleotide polymorphisms (SNPs) of the VDR gene were analyzed in 858 patients with reflux esophagitis (RE), BE or EAC and 202 healthy controls. VDR mRNA expression was higher in BE compared with squamous epithelium. VDR protein was located in the nucleus in BE. An rs1989969T/rs2238135G haplotype was identified in the 5' regulatory region of the VDR gene. It was associated with an approximately two-fold reduced risk of RE, BE and EAC. Analysis of a replication cohort was done for BE that confirmed this. The rs1989969T allele causes a GATA-1 transcription factor binding site to appear. The signaling of GATA-1, which is regarded as a negative transcriptional regulator, could explain the findings for rs1989969. The rs2238135G allele was associated with a significantly reduced VDR expression in BE; for the rs1989969T allele, a trend in reduced VDR expression was observed. We identified a VDR haplotype associated with reduced esophageal VDR expression and a reduced incidence of RE, BE and EAC. This VDR haplotype could be useful in identifying individuals who benefit most from vitamin D chemoprevention.
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Affiliation(s)
- Vincent T Janmaat
- Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, Rotterdam, the Netherlands
| | - Anouk Van De Winkel
- Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, Rotterdam, the Netherlands
| | - Maikel P Peppelenbosch
- Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, Rotterdam, the Netherlands
| | - Manon C W Spaander
- Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, Rotterdam, the Netherlands
| | - André G Uitterlinden
- Department of Internal Medicine, Epidemiology and Clinical Chemistry, Erasmus MC-University Medical Center, Rotterdam, the Netherlands
| | - Farzin Pourfarzad
- Department of Cell Biology, Erasmus MC-University Medical Center, Rotterdam, the Netherlands
| | - Hugo W Tilanus
- Department of Surgery, Erasmus MC-University Medical Center, Rotterdam, the Netherlands
| | - Agnieszka M Rygiel
- Center for Experimental Molecular Medicine, Academic Medical Center, Amsterdam, the Netherlands
| | - Leon M G Moons
- Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, Rotterdam, the Netherlands
| | - Pascal P Arp
- Department of Internal Medicine, Epidemiology and Clinical Chemistry, Erasmus MC-University Medical Center, Rotterdam, the Netherlands
| | - Kausilia K Krishnadath
- Center for Experimental Molecular Medicine, Academic Medical Center, Amsterdam, the Netherlands
| | - Ernst J Kuipers
- Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, Rotterdam, the Netherlands.,Department of Internal Medicine, Epidemiology and Clinical Chemistry, Erasmus MC-University Medical Center, Rotterdam, the Netherlands
| | - Luc J W Van Der Laan
- Department of Surgery, Erasmus MC-University Medical Center, Rotterdam, the Netherlands
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Chandler PD, Buring JE, Manson JE, Giovannucci EL, Moorthy MV, Zhang S, Lee IM, Lin JH. Circulating Vitamin D Levels and Risk of Colorectal Cancer in Women. Cancer Prev Res (Phila) 2015; 8:675-82. [PMID: 25813525 DOI: 10.1158/1940-6207.capr-14-0470] [Citation(s) in RCA: 46] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2014] [Accepted: 03/23/2015] [Indexed: 12/31/2022]
Abstract
Observational data on the association between circulating 25(OH)D and colorectal cancer risk are limited in women. To determine whether prediagnostic levels of 25(OH)D were associated with risk of incident colorectal cancer in the Women's Health Study (WHS), we conducted a nested case-control study using 274 colorectal cases and 274 controls. Each case was matched to a control by age, ethnicity, fasting status at the time of blood collection, time of day when blood was drawn, and month of blood draw. Conditional logistic regression was used to estimate the OR and 95% confidence interval (CI) for colorectal cancer by 25(OH)D quartiles. Mean plasma 25(OH)D was lower in cases versus controls (21.9 vs. 23.9 ng/mL, P = 0.01). In multivariable-adjusted logistic regression models, plasma 25(OH)D was significantly and inversely associated with odds of colorectal cancer (quartile 4 [Q4] vs. quartile 1 [Q1]: OR, 0.45; 95% CI, 0.25-0.81; Ptrend 0.02). In addition, we observed a somewhat lower risk of colorectal cancer-related mortality after adjustment for matching variables, randomization treatment and other risk factors (Q4:Q1 OR, 0.40; 95% CI, 0.17-0.97; Ptrend 0.05). In this cohort of healthy women, we found a significant inverse association between prediagnostic 25(OH)D levels and risk of incident colorectal cancer, and a borderline significant inverse association between prediagnostic 25(OH)D levels and colorectal cancer-related mortality. These results support a possible association between plasma 25(OH)D and risk of colorectal cancer in women.
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Affiliation(s)
- Paulette D Chandler
- Division of Preventive Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
| | - Julie E Buring
- Division of Preventive Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts. Department of Nutrition, Harvard School of Public Health, Boston, Massachusetts. Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts
| | - JoAnn E Manson
- Division of Preventive Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts. Department of Nutrition, Harvard School of Public Health, Boston, Massachusetts. Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts
| | - Edward L Giovannucci
- Department of Nutrition, Harvard School of Public Health, Boston, Massachusetts. Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts
| | - M V Moorthy
- Division of Preventive Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts
| | - Shumin Zhang
- Takeda Pharmaceutical International, Inc., Deerfield, Illinois
| | - I-Min Lee
- Division of Preventive Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts
| | - Jennifer H Lin
- Takeda Pharmaceutical International, Inc., Deerfield, Illinois
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Schmutz EA, Zimmermann MB, Rohrmann S. The inverse association between serum 25-hydroxyvitamin D and mortality may be modified by vitamin A status and use of vitamin A supplements. Eur J Nutr 2015; 55:393-402. [PMID: 25701092 DOI: 10.1007/s00394-015-0860-y] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2014] [Accepted: 02/09/2015] [Indexed: 12/14/2022]
Abstract
BACKGROUND Low serum 25-hydroxyvitamin D [25(OH)D] levels have been associated with higher risk of many diseases that affect mortality, including cardiovascular disease (CVD) and cancer. The inverse association between serum 25(OH)D and mortality may be modified by excess circulating vitamin A, due to interactions of vitamin A at the level of the vitamin D nuclear receptor. In this prospective cohort study, we investigated whether the association of 25(OH)D with all-cause, cancer, and CVD mortality was modified by circulating vitamin A or preformed vitamin A intake from supplements. METHODS We analyzed 15,998 adults in the Third National Health and Nutrition Examination Survey (NHANES III), 1988-1994. Mortality data for all-cause (n = 3890), cancer (n = 844), and CVD mortality (n = 1715) were assessed through December 2006. Serum 25(OH)D was measured using a radioimmunoassay kit, vitamin A biomarkers were measured by HPLC, and information on supplement use was obtained by self-report. Multivariable hazard ratios (HRs) and corresponding 95% confidence intervals (CI) were estimated by proportional hazards regression. RESULTS Serum 25(OH)D was significantly inversely associated with all-cause mortality (HR 0.93, 95% CI 0.89, 0.97, per 10 ng/mL increase) and also with CVD mortality and mortality due to non-cancer/non-cardiovascular causes, but not with cancer mortality. The observed inverse associations remained statistically significant only among participants with serum retinyl esters <7.0 μg/dL. High intake (>5000 IU/day) of preformed vitamin A from supplements attenuated the inverse association of 25(OH)D with overall mortality. The observed interactions were not statistically significant. CONCLUSIONS 25(OH)D was inversely associated with overall mortality, CVD mortality, and mortality due to non-cancer/non-CVD causes, but not with cancer mortality. A possible interaction between vitamin A exposure and 25(OH)D concentration appears to be associated with an attenuation of the inverse association between risk of death and quartile of 25(OH)D concentration.
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Affiliation(s)
- Einat Avital Schmutz
- Laboratory of Human Nutrition, Institute of Food, Nutrition and Health, ETH Zurich, Zurich, Switzerland
| | - Michael Bruce Zimmermann
- Laboratory of Human Nutrition, Institute of Food, Nutrition and Health, ETH Zurich, Zurich, Switzerland
| | - Sabine Rohrmann
- Department of Chronic Disease Epidemiology, Epidemiology, Biostatistics and Prevention Institute (EBPI), University of Zurich, Zurich, Switzerland.
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Aigner E, Stadlmayr A, Huber-Schönauer U, Zwerina J, Husar-Memmer E, Niederseer D, Trauner M, Heuberger A, Hohla F, Schett G, Patsch W, Datz C. Gender- and site-specific differences of colorectal neoplasia relate to vitamin D. Aliment Pharmacol Ther 2014; 40:1341-8. [PMID: 25278035 DOI: 10.1111/apt.12981] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/28/2014] [Revised: 08/14/2014] [Accepted: 09/15/2014] [Indexed: 12/14/2022]
Abstract
BACKGROUND The effect of vitamin D on colorectal adenomas may vary with regard to gender, localisation and histological type of the lesion. AIM To define the role of vitamin D and gender in a Caucasian cohort of subjects undergoing screening colonoscopy after consideration of established risk factors. METHODS One thousand five hundred and thirty-two subjects (813 males, 58.8 ± 9.7 years; 719 females, 59.7 ± 10.7 years) were allocated to tertiles of 25-hydroxyvitamin D3 [25(OH)D3 ] serum concentrations. The number, localisation, size and histology of the detected colonic lesions were recorded. RESULTS Among men, no association was found between vitamin D and the total number, size and histological stage of adenomas at any site. In female subjects, less women with adenomas were found in the highest vitamin D tertile (N = 42/239; 17.2%) as compared to the low vitamin D group (N = 60/240; 25.0%; P = 0.035). In particular, the number of women with adenomas in the proximal colon was significantly lower in the highest tertile (N = 21/239, 8.8%) compared to the low vitamin D group (N = 41/240; 17.1%; P = 0.007). The rates at other sites were not different. The inverse association of vitamin D serum concentrations with the presence of adenomas in the proximal colon was maintained after adjustment for potential confounders. In 80 women on vitamin D supplementation, the rate of adenomas was lower compared to those not on supplementation (3/80; 3.8%; vs. 90/719; 12.5%; P = 0.016). CONCLUSIONS A potential preventive effect of vitamin D on colorectal adenomas was found in the proximal colon in women. This observation is supported by further decrease of lesions in the proximal colon of women on vitamin D supplementation.
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Affiliation(s)
- E Aigner
- Department of Internal Medicine, Oberndorf Hospital, Teaching Hospital of the Paracelsus Medical University Salzburg, Salzburg, Austria; First Department of Medicine, Paracelsus Medical University Salzburg, Salzburg, Austria; Obesity Research Unit, Paracelsus Medical University Salzburg, Salzburg, Austria
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Abstract
The negative association of the latitude where people live and the incidence of non cutaneous cancer in that population in North America have been demonstrated in many studies for many types of cancer. Since the intensity of UVB exposure decreases with increasing latitude, and UVB exposure provides the mechanism for vitamin D production in the skin, the hypothesis that increased vitamin D provides protection against the development of cancer has been proposed. This hypothesis has been tested in a substantial number of prospective and case control studies and in a few randomized clinical trials (RTC) assessing whether either vitamin D intake or serum levels of 25 hydroxyvitamin D (25OHD) correlate (inversely) with cancer development. Most of the studies have focused on colorectal, breast, and prostate cancer. The results have been mixed. The most compelling data for a beneficial relationship between vitamin D intake or serum 25OHD levels and cancer have been obtained for colorectal cancer. The bulk of the evidence also favors a beneficial relationship for breast cancer, but the benefit of vitamin D for prostate and skin cancer in clinical populations has been difficult to demonstrate. RTCs in general have been flawed in execution or too small to provide compelling evidence one way or the other. In contrast, animal studies have been quite consistent in their demonstration that vitamin D and/or its active metabolite 1,25 dihydroxyvitamin D (1,25(OH)2D) can prevent the development and/or treat a variety of cancers in a variety of animal models. Furthermore, 1,25(OH)2D has been shown to impact a number of cellular mechanisms that would be expected to underlie its anticancer effects. Thus, there is a dilemma-animal and cellular studies strongly support a role for vitamin D in the prevention and treatment of cancer, but the clinical studies for most cancers have not yet delivered compelling evidence that the promise from preclinical studies has been fulfilled in the clinic.
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Affiliation(s)
- Daniel D Bikle
- Endocrine Research Unit, Departments of Medicine and Dermatology, VA Medical Center and University of California San Francisco, 4150 Clement St (111N), San Francisco, CA, 94121, USA,
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Theodoratou E, Tzoulaki I, Zgaga L, Ioannidis JPA. Vitamin D and multiple health outcomes: umbrella review of systematic reviews and meta-analyses of observational studies and randomised trials. BMJ 2014; 348:g2035. [PMID: 24690624 PMCID: PMC3972415 DOI: 10.1136/bmj.g2035] [Citation(s) in RCA: 659] [Impact Index Per Article: 59.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 02/24/2014] [Indexed: 12/11/2022]
Abstract
OBJECTIVE To evaluate the breadth, validity, and presence of biases of the associations of vitamin D with diverse outcomes. DESIGN Umbrella review of the evidence across systematic reviews and meta-analyses of observational studies of plasma 25-hydroxyvitamin D or 1,25-dihydroxyvitamin D concentrations and randomised controlled trials of vitamin D supplementation. DATA SOURCES Medline, Embase, and screening of citations and references. ELIGIBILITY CRITERIA Three types of studies were eligible for the umbrella review: systematic reviews and meta-analyses that examined observational associations between circulating vitamin D concentrations and any clinical outcome; and meta-analyses of randomised controlled trials assessing supplementation with vitamin D or active compounds (both established and newer compounds of vitamin D). RESULTS 107 systematic literature reviews and 74 meta-analyses of observational studies of plasma vitamin D concentrations and 87 meta-analyses of randomised controlled trials of vitamin D supplementation were identified. The relation between vitamin D and 137 outcomes has been explored, covering a wide range of skeletal, malignant, cardiovascular, autoimmune, infectious, metabolic, and other diseases. Ten outcomes were examined by both meta-analyses of observational studies and meta-analyses of randomised controlled trials, but the direction of the effect and level of statistical significance was concordant only for birth weight (maternal vitamin D status or supplementation). On the basis of the available evidence, an association between vitamin D concentrations and birth weight, dental caries in children, maternal vitamin D concentrations at term, and parathyroid hormone concentrations in patients with chronic kidney disease requiring dialysis is probable, but further studies and better designed trials are needed to draw firmer conclusions. In contrast to previous reports, evidence does not support the argument that vitamin D only supplementation increases bone mineral density or reduces the risk of fractures or falls in older people. CONCLUSIONS Despite a few hundred systematic reviews and meta-analyses, highly convincing evidence of a clear role of vitamin D does not exist for any outcome, but associations with a selection of outcomes are probable.
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Affiliation(s)
- Evropi Theodoratou
- Centre for Population Health Sciences, University of Edinburgh, Edinburgh EH8 9AG, UK
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Pibiri F, Kittles RA, Sandler RS, Keku TO, Kupfer SS, Xicola RM, Llor X, Ellis NA. Genetic variation in vitamin D-related genes and risk of colorectal cancer in African Americans. Cancer Causes Control 2014; 25:561-70. [PMID: 24562971 PMCID: PMC3978221 DOI: 10.1007/s10552-014-0361-y] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2013] [Accepted: 02/12/2014] [Indexed: 12/21/2022]
Abstract
Purpose Disparities in both colorectal cancer (CRC) incidence and survival impact African Americans (AAs) more than other US ethnic groups. Because vitamin D is thought to protect against CRC and AAs have lower serum vitamin D levels, genetic variants that modulate the levels of active hormone in the tissues could explain some of the cancer health disparity. Consequently, we hypothesized that genetic variants in vitamin D-related genes are associated with CRC risk. Methods To test this hypothesis, we studied 39 potentially functional single-nucleotide polymorphisms (SNPs) in eight genes (CYP2R1, CYP3A4, CYP24A1, CYP27A1, CYP27B1, GC, DHCR7, and VDR) in 961 AA CRC cases and 838 healthy AA controls from Chicago and North Carolina. We tested whether SNPs are associated with CRC incidence using logistic regression models to calculate p values, odds ratios, and 95 % confidence intervals. In the logistic regression, we used a log-additive genetic model and used age, gender, and percent West African ancestry, which we estimated with the program STRUCTURE, as covariates in the models. Results A nominally significant association was detected between CRC and the SNP rs12794714 in the vitamin D 25-hydroxylase gene CYP2R1 (p = 0.019), a SNP that has previously been associated with serum vitamin D levels. Two SNPs, rs16847024 in the GC gene and rs6022990 in the CYP24A1 gene, were nominally associated with left-sided CRC (p = 0.015 and p = 0.018, respectively). Conclusions Our results strongly suggest that genetic variation in vitamin D-related genes could affect CRC susceptibility in AAs.
Electronic supplementary material The online version of this article (doi:10.1007/s10552-014-0361-y) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Fabio Pibiri
- Department of Pediatrics and the Institute of Human Genetics, University of Illinois at Chicago, 900 S. Ashland Ave. MC 767, Chicago, IL, 60607, USA
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Yin L, Ordóñez-Mena JM, Chen T, Schöttker B, Arndt V, Brenner H. Circulating 25-hydroxyvitamin D serum concentration and total cancer incidence and mortality: a systematic review and meta-analysis. Prev Med 2013; 57:753-64. [PMID: 24036014 DOI: 10.1016/j.ypmed.2013.08.026] [Citation(s) in RCA: 88] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/18/2013] [Revised: 08/28/2013] [Accepted: 08/31/2013] [Indexed: 12/31/2022]
Abstract
OBJECTIVE To conduct a systematic review and meta-analysis of longitudinal studies on the association of 25(OH)D with total cancer incidence and mortality. METHOD Relevant longitudinal observational studies were identified by systematically searching Ovid Medline, EMBASE, and ISI Web of Knowledge databases. Due to the heterogeneity across studies in categorizing 25(OH)D concentration, all results were recalculated for an increase of 25(OH)D by 50 nmol/L. RESULTS In meta-analyses with random effects models, the summary risk ratios and confidence intervals (RRs (95% CI)) for the association of an increase of 25(OH)D by 50 nmol/L with total cancer incidence (5 studies) and mortality (13 studies) were 0.89 (0.81, 0.97) and 0.83 (0.71, 0.96), respectively. In sex-specific analyses no significant association with total cancer incidence was observed among men or women. A clear inverse association with total cancer mortality was observed among women (0.76 (0.60, 0.98)) but not among men (0.92 (0.65, 1.32)). Large heterogeneity was observed for studies on total cancer mortality (P<0.01) but not for studies on cancer incidence (P=0.41). No publication bias was found. CONCLUSION The meta-analysis suggests a moderate inverse association of 25(OH)D concentration with total cancer incidence and mortality.
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Affiliation(s)
- Lu Yin
- Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany
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Jacobs ET, Hibler EA, Lance P, Sardo CL, Jurutka PW. Association between circulating concentrations of 25(OH)D and colorectal adenoma: a pooled analysis. Int J Cancer 2013; 133:2980-8. [PMID: 23754630 DOI: 10.1002/ijc.28316] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2013] [Revised: 05/14/2013] [Accepted: 05/17/2013] [Indexed: 12/16/2022]
Abstract
The relationship between the biomarker of vitamin D status, 25(OH)D, and the risk for colorectal neoplasia is suggestive but equivocal. Questions remain regarding whether there are differential associations between 25(OH)D and colorectal adenoma by gender, colorectal subsite or features of baseline and recurrent adenomas. We sought to investigate the relationship between 25(OH)D and both baseline and recurrent adenoma characteristics. Our study was conducted among 2,074 participants in a pooled population of two clinical intervention trials of colorectal adenoma recurrence. A cross-sectional analysis of 25(OH)D and baseline adenoma characteristics and a prospective study of recurrent adenomas and their characteristics were conducted. There was a statistically significant inverse association between the concentrations of 25(OH)D and the presence of three or more adenomas at baseline. Compared to participants with 25(OH)D levels of <20 ng/mL, the adjusted odds ratios (ORs) (95% condifdence intervals [CIs]) were 0.99 (0.70-1.41) for those with concentrations of ≥20 and <30 ng/mL, and 0.73 (0.50-1.06) among participants with levels of ≥30 ng/mL (p-trend = 0.05). Baseline villous histology was also significantly inversely related to 25(OH)D levels (p-trend = 0.04). Conversely, 25(OH)D concentrations were not associated with overall colorectal adenoma recurrence, with ORs (95% CIs) of 0.91 (0.71-1.17) and 0.95 (0.73-1.24; p-trend = 0.85). These findings support the concept that the relationship between vitamin D and colorectal neoplasia may vary by stage of adenoma development.
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Affiliation(s)
- Elizabeth T Jacobs
- University of Arizona Cancer Center, University of Arizona, Tucson, Arizona; Division of Epidemiology, Mel and Enid Zuckerman College of Public Health, University of Arizona, Tucson, Arizona
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Kitson MT, Roberts SK. D-livering the message: the importance of vitamin D status in chronic liver disease. J Hepatol 2012; 57:897-909. [PMID: 22634121 DOI: 10.1016/j.jhep.2012.04.033] [Citation(s) in RCA: 159] [Impact Index Per Article: 12.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/20/2012] [Revised: 03/29/2012] [Accepted: 04/01/2012] [Indexed: 02/06/2023]
Abstract
Vitamin D is synthesized predominantly in the liver and functions as an important secosteroid hormone with pleiotropic effects. While its key regulatory role in calcium and bone homeostasis is well established, recently there is increasing recognition that vitamin D also regulates cell proliferation and differentiation, and has immunomodulatory, anti-inflammatory and anti-fibrotic properties. These non-skeletal effects are relevant in the pathogenesis and treatment of many causes of chronic liver disease. Vitamin D deficiency is frequently present in chronic liver disease and may predict non-response to antiviral therapy in chronic hepatitis C. Small studies suggest that vitamin D supplementation improves sustained viral response rates, while 1α-hydroxylase polymorphisms and vitamin D-binding protein are also implicated in therapeutic outcomes. Vitamin D deficiency also closely relates to the severity of non-alcoholic fatty liver disease (NAFLD) and is implicated in the pathogenesis of insulin resistance, a key factor in the development of NAFLD. In preclinical studies, phototherapy and vitamin D supplementation ameliorate NAFLD histopathology, while vitamin D is a powerful anti-fibrotic against thioacetamide liver injury. In liver transplant recipients severe vitamin D deficiency predicts, and vitamin D supplementation prevents, acute cellular rejection. The role of vitamin D in the activation and regulation of both innate and adaptive immune systems may explain its importance in the above liver diseases. Further prospective studies are therefore warranted to investigate the therapeutic impact of vitamin D supplementation in chronic liver disease.
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Affiliation(s)
- Matthew T Kitson
- Department of Gastroenterology, The Alfred, Melbourne, Australia
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Treatment of vitamin D deficiency and the outcome in cardiac surgery*. Crit Care Med 2012; 40:2238-9. [PMID: 22710214 DOI: 10.1097/ccm.0b013e3182536d22] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
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Theodoratou E, Palmer T, Zgaga L, Farrington SM, McKeigue P, Din FVN, Tenesa A, Davey-Smith G, Dunlop MG, Campbell H. Instrumental variable estimation of the causal effect of plasma 25-hydroxy-vitamin D on colorectal cancer risk: a mendelian randomization analysis. PLoS One 2012; 7:e37662. [PMID: 22701574 PMCID: PMC3368918 DOI: 10.1371/journal.pone.0037662] [Citation(s) in RCA: 46] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2011] [Accepted: 04/23/2012] [Indexed: 12/31/2022] Open
Abstract
Vitamin D deficiency has been associated with several common diseases, including cancer and is being investigated as a possible risk factor for these conditions. We reported the striking prevalence of vitamin D deficiency in Scotland. Previous epidemiological studies have reported an association between low dietary vitamin D and colorectal cancer (CRC). Using a case-control study design, we tested the association between plasma 25-hydroxy-vitamin D (25-OHD) and CRC (2,001 cases, 2,237 controls). To determine whether plasma 25-OHD levels are causally linked to CRC risk, we applied the control function instrumental variable (IV) method of the mendelian randomization (MR) approach using four single nucleotide polymorphisms (rs2282679, rs12785878, rs10741657, rs6013897) previously shown to be associated with plasma 25-OHD. Low plasma 25-OHD levels were associated with CRC risk in the crude model (odds ratio (OR): 0.76, 95% Confidence Interval (CI): 0.71, 0.81, p: 1.4×10(-14)) and after adjusting for age, sex and other confounding factors. Using an allele score that combined all four SNPs as the IV, the estimated causal effect was OR 1.16 (95% CI 0.60, 2.23), whilst it was 0.94 (95% CI 0.46, 1.91) and 0.93 (0.53, 1.63) when using an upstream (rs12785878, rs10741657) and a downstream allele score (rs2282679, rs6013897), respectively. 25-OHD levels were inversely associated with CRC risk, in agreement with recent meta-analyses. The fact that this finding was not replicated when the MR approach was employed might be due to weak instruments, giving low power to demonstrate an effect (<0.35). The prevalence and degree of vitamin D deficiency amongst individuals living in northerly latitudes is of considerable importance because of its relationship to disease. To elucidate the effect of vitamin D on CRC cancer risk, additional large studies of vitamin D and CRC risk are required and/or the application of alternative methods that are less sensitive to weak instrument restrictions.
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Affiliation(s)
- Evropi Theodoratou
- Centre for Population Health Sciences, University of Edinburgh, Edinburgh, United Kingdom.
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Martínez ME, Jacobs ET, Baron JA, Marshall JR, Byers T. Dietary supplements and cancer prevention: balancing potential benefits against proven harms. J Natl Cancer Inst 2012; 104:732-9. [PMID: 22534785 PMCID: PMC3352833 DOI: 10.1093/jnci/djs195] [Citation(s) in RCA: 75] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2011] [Revised: 03/07/2012] [Accepted: 03/12/2012] [Indexed: 12/23/2022] Open
Abstract
Nutritional supplementation is now a multibillion-dollar industry, and about half of all US adults take supplements. Supplement use is fueled in part by the belief that nutritional supplements can ward off chronic disease, including cancer, although several expert committees and organizations have concluded that there is little to no scientific evidence that supplements reduce cancer risk. To the contrary, there is now evidence that high doses of some supplements increase cancer risk. Despite this evidence, marketing claims by the supplement industry continue to imply anticancer benefits. Insufficient government regulation of the marketing of dietary supplement products may continue to result in unsound advice to consumers. Both the scientific community and government regulators need to provide clear guidance to the public about the use of dietary supplements to lower cancer risk.
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