Vitamin D With or Without Calcium Supplementation for Prevention of Cancer and Fractures: An Updated Meta-analysis for the U.S. Preventive Services Task ForceFREE
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Abstract
Background:
Purpose:
Data Sources:
Study Selection:
Data Extraction:
Data Synthesis:
Limitations:
Conclusion:
Primary Funding Source:
Methods
Data Sources and Searches
Study Selection and Outcomes of Interest
Data Extraction and Quality Assessment
Data Synthesis
Role of the Funding Source
Results
Search Results
Effects of Vitamin D, With or Without Calcium, on Cancer and Fracture Outcomes
Cancer
Fracture
Associations Between Vitamin D Status and Cancer and Fracture Outcomes
Cancer
Fractures
Effects of Vitamin D With or Without Calcium on Changes in Vitamin D Status
Adverse Events Associated With Vitamin D With or Without Calcium
Discussion
Appendix
Supplemental Material
References
Information & Authors
Information
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Keywords
- Adults
- Age groups
- Blood
- Body fluids
- Breast cancer
- Cancers and neoplasms
- Cognitive psychology
- Colorectal cancer
- Endocrinology
- Hematology and oncology
- Nutrition
- Pathology and laboratory medicine
- Population statistics
- Prevention, policy, and public health
- Psychiatry and mental health
- Psychology
- Research and reporting methods
- Research design
- Vitamins
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Vitamin D With or Without Calcium Supplementation for Prevention of Cancer and Fractures: An Updated Meta-analysis for the U.S. Preventive Services Task Force. Ann Intern Med.2011;155:827-838. [Epub 20 December 2011]. doi:10.7326/0003-4819-155-12-201112200-00005
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Vitamin D Status vs. Cancer Survival/Prognosis
In the current (June 2012) summary of recommendations and evidence regarding Vitamin D and Calcium Supplementation to Prevent Cancer and Osteoporotic Fractures in Adults, the U.S. Preventive Services Task Force (USPSTF) indicates that “the current evidence is insufficient to assess the balance of the benefits and harms of vitamin D supplementation, with or without calcium, for the primary prevention of cancer in adults.” and that “There is inadequate evidence to determine the effect of vitamin D supplementation, with or without calcium, on overall cancer incidence and mortality in adults.”
Although vitamin D and calcium are often discussed as related supplements, it should be emphasized that an assessment of the effects of 400 IU of vitamin D3 combined with 1,000 mg of calcium carbonate supplementation on cancer incidence and/or mortality is not the same as, for example, 2,000 IU vitamin D3 supplementation without calcium carbonate vs. cancer mortality, survival rate and/or prognosis. Hence, vitamin D and calcium carbonate supplementations should be considered as two separate treatments requiring two separate evidence-based recommendations. A role of vitamin D in the immune system modulation should be recognized in light of the current evidence in the published literature [1-4]. Cancer patients should have their vitamin D status checked and those with an established vitamin D deficiency/insufficiency should be advised to take steps to improve their vitamin D status ether by supplementation or by spending more time outdoors exposed to sunlight.A statement by the USPSTF regarding renal stones that “There is adequate evidence that supplementation with ≤400 IU of vitamin D3 and 1,000 mg of calcium carbonate increases the incidence of renal stones.” is correct. However, it should be emphasized for the reader that the observed higher incidence of renal stone formation in the treatment when compared to the control group is associated with the calcium carbonate (not vitamin D) supplementation. A ≤400 IU of vitamin D3 supplementation is probably not sufficient to have a significant impact on the vitamin D status in the studied population. For example, a dose of 250 µg vitamin D/day (10,000 IU) for up to 5 months is not expected to elevate circulating 25(OH)D to the concentrations greater than 90 ng/mL (225 nmol/L), while doses < 25 µg vitamin D/day (<1,000 IU) are inadequate for maintaining physiologically normal circulating 25(OH)D concentrations of 15 to 80 ng/mL (37 to 200 nmol/L) [5].
Taking into consideration that “observational studies were heterogeneous and were limited by potential confounders”, Chung et al. [6] concluded that “evidence is not sufficiently robust to draw conclusions regarding the benefits or harms of vitamin D supplementation for the prevention of cancer”. However, with the exception of breast cancer in the combined vitamin D and calcium supplementation group, the summary of evidence on the basis of the Supplement 1 presented in Table 1 of this study shows that hazard ratios (HR) and risk ratios (RR) are consistently lower for the cancer mortality when compared to the cancer incidence rates. Apparently, vitamin D supplementation may have a beneficial effect for improving prognosis and reducing cancer mortality in the elderly population. This is one of the important findings of the study which should be highlighted in the overall conclusion.There is evidence in the published literature that incidence/mortality rates for some of the most common cancer types are negatively associated with regional insolation [7-10], suggesting that latitudinal variation in annual ultraviolet (UV-B) irradiation may play a role in the observed relationship through the production of vitamin D in the skin. In addition, a meta-analysis of vitamin D receptor (VDR) polymorphisms and cancer risk shows that two most studied VDR polymorphisms (Fok1 and Bsm1) could be involved in modulating the risks from breast, skin and prostate cancers [11], and the polymorphism on the loci for the genes encoding vitamin D activating enzyme 1-alpha hydroxylase (CYP27B1) is associated with the variation in colon cancer risk [12]. In their high-resolution map of VDR binding sites with influence on the immune and other functional pathways, Ramagopalan et al. [13] discuss the observed significant enrichment in regions near cancer-associated genes.
The presented meta-analysis by Chung et al. [6] depends inevitably on the accuracy of the observed vitamin D status which is measured in the studied elderly population(s) as a function of plasma 25-Hydroxyvitamin D3 (25[OH]D3 or calcidiol) concentration. However, the active form of vitamin D required for both the bone health and the functional immune system is 1,25-Dihydroxyvitamin D3 (1,25[OH]2D3 or calcitriol) [4,14,15], which could be low in individuals with insufficient or missing enzymes for the transformation of vitamin D precursors to the active 1,25[OH]2D3. In such individuals, one may observe “normal” or even higher than usual plasma levels of 25[OH]D3 which could prompt a potentially misleading conclusion that vitamin D has no effect on cancer prognosis/mortality or that higher levels in the circulation are associated with an elevated cancer risk [16]. For example, a recent study by Ramagopalan et al. [17] shows a causative role for CYP27B1 gene variants in multiple sclerosis (MS). Due to a lack of 1-alpha hydroxylase, even extremely high daily doses of vitamin D3 supplementation are not expected to improve the functional 1,25[OH]2D3 status in some MS patients and they may require a direct treatment with calcitriol [18].When compared to the control groups, one may expect to observe a higher prevalence of impaired vitamin D metabolism/transformation among the cases of cancer or other diseases associated with vitamin D deficiency which may introduce a significant bias into a comparative epidemiological study. Hence, the upcoming new studies on the role/value of vitamin D in the prevention/treatment of cancer or other diseases should focus on the functional/active form of vitamin D (i.e., 1,25[OH]2D3) rather than to rely on its metabolic precursors as perhaps cost-effective and/or convenient proxies. As it is the case in all epidemiological studies, the quality of the output and the conclusions should be expected to reflect the quality of input data.
References
1. Baeke F, Takiishi T, Korf H, Gysemans C, Mathieu C. Vitamin D: modulator of the immune system. Curr Opin Pharmacol. 2010;10(4):482-96.
2. Kamen DL, Tangpricha V. Vitamin D and molecular actions on the immune system: modulation of innate and autoimmunity. J Mol Med (Berl). 2010;88(5): 441–450.
3. Mead MN. Benefits of sunlight: A bright spot for human health. Environ Health Perspect. 2008;116(4):A160-A167.
4. Cutolo M. Vitamin D and autoimmune rheumatic diseases. Rheumatology 2009;48:210-212.
5. Hollis BW and Wagner CL. Assessment of dietary vitamin D requirements during pregnancy and lactation. Am J Clin Nutr. 2004;79(5):717-726.
6. Chung M, Lee J, Terasawa T, Lau J, Trikalinos TA. Vitamin D with or without calcium supplementation for prevention of cancer and fractures: an updated meta-analysis for the U.S. Preventive Services Task Force. Ann Intern Med. 2011;155:827-838.
7. Garland CF, Garland FC, Gorham ED, Lipkin M, Newmark H, Mohr SB et al. The role of vitamin D in cancer prevention. Am J Public Health. 2006;96:252–261.
8. Grant WB. An ecological study of cancer incidence and mortality rates in France with respect to latitude, an index for vitamin D production. Dermatoendocrinol. 2010;2(2):62-67.
9. Boscoe FP, Schymura MJ. Solar ultraviolet-B exposure and cancer incidence and mortality in the United States, 1993-2002. BMC Cancer. 2006;6:264.
10. Giovannucci E. The epidemiology of vitamin D and cancer incidence and mortality: a review (United States). Cancer Causes Control. 2005;16(2):83-95.
11. Raimondi S, Johansson H, Maisonneuve P, Gandini S. Review and meta-analysis on vitamin D receptor polymorphisms and cancer risk. Carcinogenesis. 2009;30(7):1170–1180.
12. Dong LM, Ulrich CM, Hsu L, Duggan DJ, Benitez DS et al. Vitamin D related genes, CYP24A1 and CYP27B1, and colon cancer risk. Cancer Epidemiol Biomarkers Prev. 2009;18(9):2540-8.
13. Ramagopalan SV, Heger A, Berlanga AJ, Maugeri NJ, Lincoln MR, Burrell A, et al. A ChIP-seq defined genome-wide map of vitamin D receptor binding: associations with disease and evolution. Genome Res. 2010;20(10):1352–1360.
14. Sutton ALM, MacDonald PN. Vitamin D: More than a “Bone-a-Fide” hormone. Molecular Endocrinology. 2003;17(5):777–791.
15. Bikle D. Nonclassic actions of vitamin D. J Clin Endocrinol Metab. 2009;94:26-34.
16. Krstić G. Re: “Circulating 25-hydroxyvitamin D and risk of pancreatic cancer”. Am J Epidemiol. 2011;173(4): 476.
17. Ramagopalan SV, Dyment DA, Cader MZ, Morrison KM, Disanto G, Morahan JM et al. Rare variants in the CYP27B1 gene are associated with multiple sclerosis. Ann Neurol. 2011;70(6):881-886.
18. Wingerchuk DM, Lesaux J, Rice GP, Kremenchutzky M, Ebers GC. A pilot study of oral calcitriol (1,25-dihydroxyvitamin D3) for relapsing-remitting multiple sclerosis. J Neurol Neurosurg Psychiatry. 2005;76(9):1294-6.
Vitamin D supplementation in cancer prevention; a solution?
Chung et al in his article titled 'Vitamin D with or without calcium supplementation for prevention of cancer and fractures: an updated meta- analysis for the U.S. Preventive Services Task Force'has discussed the role of vitamin D and calcium supplementation in reduction of fracture risk and prevention of cancer(1).The authors while taking into account various RCTs and observational studies, could not reach a concrete conclusion on whether vitamin D supplementation can reduce cancer risk. Vitamin D along with its proven role in maintaining bone health has also been implicated to have tumor suppressor properties as seen in preclinical models (2).Pakistan has a significant cancer burden, the Karachi Cancer Registry (KCR) data shows a high prevalence of lung cancer and breast cancer along with a rising incidence for oral cavity, prostrate,gynecological and colorectal malignancies(3).Malignancies responsible for 7% of total mortality in Pakistan as per the WHO health report released in 2011.
In a survey conducted in Karachi a city harboring 9% of the Pakistan's population,where we looked at serum 25-hydroxy vitamin D levels of asymptomatic individuals age 30 and above from the community(4), 58% had vitamin D deficiency(<20 ng/dL) while 26% had vitamin D insufficiency(20-29 ng/dL).Only 25% reported daily use of vitamin D supplements and mean 25(OH) vitamin D levels were significantly higher in those using vitamin D supplements (23 vs 19 ng/dL p=0.021). Our study results paint a grim picture , showing that more than 80% of our urban community dwelling asymptomatic adults have low levels of vitamin D(<30ng/dL) , and more than 75% of this subset do not follow the recommendations of the 2011 Institute of Medicine(IOM) report on vitamin D supplementation.
The gross national income per capita in Pakistan is US$2590 and total health expenditure is 2.6% of GDP with approximately eight physicians per 10,000 people. Keeping in view the prevailing lack of health care services and resources, a cost effective program is required to fully utilize the benefits which can be obtained from vitamin D. Government support in the form of policies of food fortification with vitamin D, education regarding adequate sun exposure and highlighting benefits of supplementation of vitamin D in improving serum levels, may all prove to be astute strategies to combat the common finding of low levels of vitamin D in our population.
REFERENCES
1. Chung M, Lee J, Terasawa T, Lau J, Trikalinos TA. Vitamin D with or without calcium supplementation for prevention of cancer and fractures: an updated meta-analysis for the U.S. Preventive Services Task Force. Ann Intern Med. 2011 Dec 20;155(12):827-38.
2. Krishnan AV, Trump DL, Johnson CS, Feldman D. The role of vitamin D in cancer prevention and treatment. Endocrinol Metab Clin North Am. 2010 Jun;39(2):401-18, table of contents.
3. Bhurgri Y, Bhurgri A, Nishter S, Ahmed A, Usman A, Pervez S, et al. Pakistan--country profile of cancer and cancer control 1995-2004. J Pak Med Assoc. 2006 Mar;56(3):124-30.
4. Sheikh A, Saeed Z, Jafri S A, Yazdani I, Hussain S. Vitamin D levels in asymptomatic adults-a population survey in Karachi,Pakistan. Under peer review. 2012.
Conflict of Interest:
None declared
Interpretation of the effects of calcium and vitamin D supplements
It is surprising that Chung and colleagues did not address the issue of the potential increased cardiovascular risk of calcium supplements when considering effects of co-administered calcium and vitamin D on fracture risk (1). Previously, we reported that co-administered calcium and vitamin D increased the risk of myocardial infarction by 21%, stroke by 20%, and that the cardiovascular risks of calcium supplements outweighed their benefits on fracture prevention (2).
Chung and colleagues concluded that 'combined vitamin D and calcium supplementation can reduce fracture risk, but the effects may be smaller among community-dwelling older adults than among institutionalized elderly persons.' However, the relative risk of fracture with co-administered calcium and vitamin D for community dwelling individuals was 0.89 (0.76- 1.04) which was not statistically significant (1). Similarly, in a recent meta-analysis in this journal, Wang and colleagues concluded that "... vitamin D supplements at moderate to high doses may reduce CVD risk, whereas calcium supplements seem to have minimal cardiovascular effects" (3). In those analyses, the relative risk of cardiovascular events with vitamin D supplements was 0.90 (0.77-1.05) and with calcium supplements was 1.14 (0.92-1.41). Thus, for 3 statistically non-significant results of the same magnitude (10-15% increase or decrease in risk), 3 different conclusions were reported: 'small reductions in risk', N'may reduce risk', and 'no effect'. Inconsistent interpretations of statistically non- significant results for the effects of vitamin D and calcium supplements continue to create confusion for researchers, clinicians, patients, and the media, and possibly reflect the preconceptions of the authors as much as the analyses themselves.
References
1. Chung M, Lee J, Terasawa T, Lau J, Trikalinos TA. Vitamin D With or Without Calcium Supplementation for Prevention of Cancer and Fractures: An Updated Meta-analysis for the U.S. Preventive Services Task Force. Ann Intern Med. 2011;155(12):827-38.
2. Bolland MJ, Grey A, Avenell A, Gamble GD, Reid IR. Calcium supplements with or without vitamin D and risk of cardiovascular events: reanalysis of the Women's Health Initiative limited access dataset and meta-analysis. BMJ. 2011;342:d2040.
3. Wang L, Manson JE, Song Y, Sesso HD. Systematic review: Vitamin D and calcium supplementation in prevention of cardiovascular events. Ann Intern Med. 2010;152(5):315-23.
Conflict of Interest:
None declared
Regulation of the Metabolic Steps Fairly Complex
In the December 20th issue of the Annals there were two articles regarding vitamin D. The actual information was about the 25 hydroxycalciferol (25 OHD) intermediate metabolite and there are some other important points to consider when reading and assessing these articles. Among them is to remember that the regulation of the metabolic steps in this pathway are fairly complex involving at least phosphorus, calcium, PTH as well as hepatic and renal functionality. These, and other limitations, must all be considered when assessing any discussion of the vitamin D pathways and intermediates. Since the total body load of any of the D metabolites has yet to be quantitatively assessed, there is no way of knowing if there is a deficiency state or not; what relationship, if any, exists between blood levels and the total body stores; or what the relationship between the active and inactive metabolites might be. These are key points. The other key point to at least be remembered is that no matter how strong a statistical correlation may be, it in no way infers causality.
The popular, and wrong, interpretation of low serum 25 hydroxycholecalciferol (25 OHD) is that this reflects a vitamin D deficiency state. No one has any idea what the actual total body stores of 25 OHD or 1,25 dihydroxycholecalciferol (1,25 OHD) are. Therefore one cannot say the stores of either metabolite are low or anything about the relationship of the 25 OHD to 1,25 OHD, which is the active metabolite. 25 OHD is inactive for all practical purposes and measurements of this metabolite are of questionable physiologic significance. The extrapolations of indirect data on which some of the basic assumptions have been made are, at best, supposition and cannot be considered proof on which clinical decisions should be made. 25 OHD is an intermediate which is the result of 25 hydroxylation of calciferol in the liver. It is no more an index of whole body D status, or even 25 OHD status, than a low serum Na reflects total body Na stores in edema or lowserum K reflects intracellular K stores until there is profound depletion. The total body stores of D can be high, as it is a fat soluble vitamin, and the serum level low if the 25 hydroxylase is relatively inactive. The stores can be low and the circulating 250HD high if the 25 hydroxylase has been stimulated. These are but one set of examples. There are, of course, several other scenarios in which there is a less than acceptable correlation.
While there may be some suggestive evidence of non calcium activity for 25 OHD, it must still be considered physiologically inactive for all practical purposes. There has been no evidence other than suggestive correlations for these, and even those studies are arguable.
These points suggest a critical, and even skeptical, approach to the studies presented before any clinical actions are taken based on these data. These, of course, represent my own views and not necessarily of any organization with which I am affiliated.
Plasma 25-Hydroxyvitamin D3 vs. 1,25-Dihydroxyvitamin D3
Taking into consideration that "observational studies were heterogeneous and were limited by potential confounders", Chung et al. [1] concluded that "evidence is not sufficiently robust to draw conclusions regarding the benefits or harms of vitamin D supplementation for the prevention of cancer". However, with the exception of breast cancer in the combined vitamin D and calcium supplementation group, the summary of evidence on the basis of the Supplement 1 presented in Table 1 of this study shows that mortality hazard ratios (HR) and relative risks (RR) are consistently lower for the cancer mortality when compared to the cancer incidence rates. Apparently, vitamin D supplementation may have a beneficial effect for improving prognosis and reducing cancer mortality in the elderly population. This is one of the important findings of the study which should be highlighted in the overall conclusion.
There is evidence in the published literature that incidence/mortality rates for some of the most common cancer types are negatively associated with regional insolation [2-5], suggesting that latitudinal variation in annual ultraviolet (UV-B) irradiation may play a role in the observed relationship through the production of vitamin D in the skin. In addition, a meta-analysis of vitamin D receptor (VDR) polymorphisms and cancer risk shows that two most studied VDR polymorphisms (Fok1 and Bsm1) could be involved in modulating the risks from breast, skin and prostate cancers [6], and the polymorphism on the loci for the genes encoding vitamin D activating enzyme 1-alpha hydroxylase (CYP27B1) is associated with the variation in colon cancer risk [7]. In their high-resolution map of VDR binding sites with influence on the immune and other functional pathways, Ramagopalan et al. [8] discuss the observed significant enrichment in regions near cancer- associated genes.
The presented meta-analysis by Chung et al. [1] depends inevitably on the accuracy of the observed vitamin D status which is measured in the studied elderly population(s) as a function of plasma 25-Hydroxyvitamin D3 (25[OH]D3 or calcidiol) concentration. However, the active form of vitamin D required for both the bone health and the functional immune system is 1,25-Dihydroxyvitamin D3 (1,25[OH]2D3 or calcitriol) [9-11], which could be low in individuals with insufficient or missing enzymes for the transformation of vitamin D precursors to the active 1,25[OH]2D3. In such individuals, one may observe "normal" or even higher than usual plasma levels of 25[OH]D3 which could prompt a potentially misleading conclusion that vitamin D has no effect on cancer prognosis/mortality or that higher levels in the circulation are associated with an elevated cancer risk [12]. For example, a recent study by Ramagopalan et al. [13] shows a causative role for CYP27B1 gene variants in multiple sclerosis (MS). Due to a lack of 1-alpha hydroxylase, even extremely high daily doses of vitamin D3 supplementation are not expected to improve the functional 1,25[OH]2D3 status in some MS patients and they may require a direct treatment with calcitriol [14].
When compared to the control groups, one may expect to observe a higher prevalence of impaired vitamin D metabolism/transformation among the cases of cancer or other diseases associated with vitamin D deficiency which may introduce a significant bias into a comparative epidemiological study. Hence, the upcoming new studies on the role/value of vitamin D in the prevention/treatment of cancer or other diseases should focus on the functional/active form of vitamin D (i.e., 1,25[OH]2D3) rather than to rely on its metabolic precursors as perhaps cost-effective and/or convenient proxies. As it is the case in all epidemiological studies, the quality of the output and the conclusions should be expected to reflect the quality of input data.
References
1. Chung M, Lee J, Terasawa T, Lau J, Trikalinos TA. Vitamin D with or without calcium supplementation for prevention of cancer and fractures: an updated meta-analysis for the U.S. Preventive Services Task Force. Ann Intern Med. 2011;155:827-838.
2. Garland CF, Garland FC, Gorham ED, Lipkin M, Newmark H, Mohr SB et al. The role of vitamin D in cancer prevention. Am J Public Health. 2006;96:252-261.
3. Grant WB. An ecological study of cancer incidence and mortality rates in France with respect to latitude, an index for vitamin D production. Dermatoendocrinol. 2010;2(2):62-67.
4. Boscoe FP, Schymura MJ. Solar ultraviolet-B exposure and cancer incidence and mortality in the United States, 1993-2002. BMC Cancer. 2006;6:264.
5. Giovannucci E. The epidemiology of vitamin D and cancer incidence and mortality: a review (United States). Cancer Causes Control. 2005;16(2):83-95.
6. Raimondi S, Johansson H, Maisonneuve P, Gandini S. Review and meta -analysis on vitamin D receptor polymorphisms and cancer risk. Carcinogenesis. 2009;30(7):1170-1180.
7. Dong LM, Ulrich CM, Hsu L, Duggan DJ, Benitez DS et al. Vitamin D related genes, CYP24A1 and CYP27B1, and colon cancer risk. Cancer Epidemiol Biomarkers Prev. 2009;18(9):2540-8.
8. Ramagopalan SV, Heger A, Berlanga AJ, Maugeri NJ, Lincoln MR, Burrell A, et al. A ChIP-seq defined genome-wide map of vitamin D receptor binding: associations with disease and evolution. Genome Res. 2010;20(10):1352-1360.
9. Sutton ALM, MacDonald PN. Vitamin D: More than a "Bone-a-Fide" hormone. Molecular Endocrinology. 2003;17(5):777-791.
10. Cutolo M. Vitamin D and autoimmune rheumatic diseases. 478 Rheumatology. 2009;48:210-212.
11. Bikle D. Nonclassic actions of vitamin D. J Clin Endocrinol Metab. 2009;94:26-34.
12. Krsti? G. Re: "Circulating 25-hydroxyvitamin D and risk of pancreatic cancer". Am J Epidemiol. 2011;173(4): 476.
13. Ramagopalan SV, Dyment DA, Cader MZ, Morrison KM, Disanto G, Morahan JM et al. Rare variants in the CYP27B1 gene are associated with multiple sclerosis. Ann Neurol. 2011;70(6):881-886.
14. Wingerchuk DM, Lesaux J, Rice GP, Kremenchutzky M, Ebers GC. A pilot study of oral calcitriol (1,25-dihydroxyvitamin D3) for relapsing- remitting multiple sclerosis. J Neurol Neurosurg Psychiatry. 2005;76(9):1294-6.
Conflict of Interest:
None declared
Follow-up period affects results of observational studies of cancer incidence
The paper by Chung et al. (1) found a 6% (95% CI, 3%-9%) reduction in risk of colorectal cancer for a 10-nmol/L increase in serum 25- hydroxyvitmin D [25(OH)D] concentration but no statistically significant reduction for breast or colorectal cancer. The findings for colorectal and prostate cancer agree with other recent meta-analyses (2,3) but the finding for breast cancer differs. The reason for the difference for breast cancer is that the other two meta-analyses included case-control studies while (1) did not. The reason this is an important difference is that the usefulness of a single serum 25(OH)D concentration value from the time of enrollment in a cohort study decreases with time. A study in Norway found that the correlation coefficient for serum draws 14 years apart was 0.42 (4). For breast cancer, the adjusted probability of incidence decreases fairly rapidly with increasing follow-up time. When four case-control study results and five nested case-control study results were plotted vs. follow-up period, it was found that all five studies with follow-up period less than three years found significantly reduced relative risks for a 50-nmol/L change in 25(OH)D concentration, but none of those with longer follow-up periods did (5). The data were fit with a linear function that increased from 0.62 at zero years to 0.95 for seven years of follow up.
For colorectal cancer, there were statistically significant inverse correlations of incidence with respect to serum 25(OH)D concentration out to follow-up periods of 14 years (5).
All four studies (1-3,5) agree that there is no significant correlation between prediagnostic serum 25(OH)D concentration and incidence of prostate cancer out to follow-up times of 28 years. In (5) the linear fit to the relative risk declined from 1.09 at 3 years to 0.93 at 28 years. Prostate cancer is a very slow growing cancer, and it could be that risk of prostate cancer related to vitamin D occurs early in life.
Thus, the differences in findings from observational studies could be due to differences in rate of cancer development, from rapid for breast cancer to slow for prostate cancer.
As discussed in (2) and (5), the observational results for breast and colorectal cancer with respect to serum 25(OH)D concentration are consistent with findings from ecological studies based on indices of solar ultraviolet-B doses and corrected for confounding factors. Ecological studies also find inverse correlations for about 15 other types of cancer incidence and/or mortality rate.
References
1. Chung M, Lee J, Terasawa T, Lau J, Trikalinos TA. Vitamin D With or Without Calcium Supplementation for Prevention of Cancer and Fractures: An Updated Meta-analysis for the U.S. Preventive Services Task Force. Ann Intern Med. 2011;155:827-38.
2. Grant WB. Relation between prediagnostic serum 25-hydroxyvitamin D level and incidence of breast, colorectal, and other cancers. J Photochem Photobiol B. 2010;101:130-6.
3. Gandini S, Boniol M, Haukka J, Byrnes G, Cox B, Sneyd MJ, et al. Meta- analysis of observational studies of serum 25-hydroxyvitamin D levels and colorectal, breast and prostate cancer and colorectal adenoma. Int J Cancer. 2011;128:1414-24.
4. Jorde R, Sneve M, Hutchinson M, Emaus N, Figenschau Y, Grimnes G. Tracking of serum 25-hydroxyvitamin D levels during 14 years in a population-based study and during 12 months in an intervention study. Am J Epidemiol. 2010;171:903-8.
5. Grant WB. Effect of interval between serum draw and follow-up period on relative risk of cancer incidence with respect to 25-hydroxyvitamin D level; implications for meta-analyses and setting vitamin D guidelines, Deramato-Endocrinology. 2011;3:3:199-204.
Conflict of Interest:
I receive funding from the UV Foundation (McLean, VA), Bio-Tech-Pharmacal (Fayetteville, AR), the Vitamin D Council (San Luis Obispo, CA), and the Vitamin D Society (Canada).