Evidence for beneficial effects of solar UV-B (UVB) irradiance and vitamin D in reducing the risk of adverse health outcomes comes from a variety of study types: ecological, cross-sectional, case–control, cohort, and intervention. Vitamin D researchers consider the evidence of beneficial effects to be strong.1-3 However, others have conducted systematic reviews that find the evidence lacking4,5—partly because at the time of the reviews, few well-conducted randomized controlled trials (RCTs) with vitamin D existed to analyze its nonskeletal effects.6 Also, findings from cohort studies7,8sometimes disagree with results from ecological studies.9
A recent paper argued that prospective studies with long follow-up times lead to errors because the single serum 25-hydroxyvitamin D [25(OH)D] concentration measurement taken at study enrollment loses prognostic value over time.10 For breast cancer, the linear regression line fit to the relative risk increased from 0.61 for case–control studies with no follow-up period to 0.95 for a 7-y follow-up, whereas for colorectal cancer, the regression line fit increased from 0.48 for case–control studies with no follow-up to 0.72 for a 14-y follow-up. For prostate cancer, no statistically significant correlation emerged with respect to 25(OH)D concentration for any follow-up time between 4 and 28 y. Further support for this assertion is that a prospective study of breast cancer incidence found a strong inverse correlation with high vitamin D intake in the first 5 y after baseline dietary assessment [relative risk = 0.66; 95% confidence interval (95% CI), 0.46–0.94 compared with lowest-intake group], with the association diminishing over time.11 Also, for a nested case-control study of lymphoma in Finland, the odds ratio for chronic lymphocytic leukemia or small lymphocytic lymphoma was 0.41 (95% CI, 0.15–1.09) for follow-up time shorter than 7 y but was 1.15 (95% CI, 0.44–3.01) for follow-up longer than 7 y.12
A recent meta-analysis of all-cause mortality rate with respect to prediagnostic serum 25(OH)D concentration mentioned that the cohort studies with shorter follow-up times had a stronger association than those with longer follow-up.13 My paper uses the data in that study to extend that analysis of follow-up time’s role in cohort studies of health outcomes with respect to prediagnostic serum 25(OH)D concentration.
The results in Figure 2 suggest that a 20-nmol/l increase in vitamin D serum level reduces the risk of all-cause mortality rate by 18–28%. The 18% is similar to the 7–17% reduction achieved by increasing serum 25(OH)D concentration from 54 to 110 nmol/l, as estimated in a recent study based on the serum 25(OH)D concentration–disease outcome relation for diseases contributing the most to all-cause mortality rate: cancer, cardiovascular disease, diabetes mellitus, respiratory diseases, respiratory infections, and tuberculosis.14 This reduction in mortality rate would increase life expectancy by an estimated 2 y.
However, because the 25(OH)D concentration–mortality rate relation is nonlinear, changing rapidly for low serum 25(OH)D concentrations and very little above 80 nmol/l, determining a more precise estimate would require a more careful analysis. On the basis of Figure 4 in Zittermann and colleagues,15 the 8% reduction in Schöttker et al.13 is consistent with an increase of serum 25(OH)D from 50 to 70 nmol/l.
These results further support the assertion that the apparent risk of adverse health outcomes decreases with longer follow-up time. However, in nested case–control studies, shorter follow-up times have fewer cases and thus wider 95% CIs. The rationale for conducting nested case–control studies instead of case–control studies with no follow-up interval includes concerns about bias in selecting controls and that the disease may affect the health outcome. For mortality rates, death often comes after long-term illness, which can affect serum 25(OH)D concentrations. For cancer incidence rates, this concern is not as well founded: people who have cancer often do not find out until diagnosis through screening (for breast and colorectal cancer) or until they notice persistent pain for a short time. For breast cancer, case–control studies found much greater inverse correlations between serum 25(OH)D concentration and incidence than did nested case–control studies.10
This study recommends that meta-analyses of cohort study findings incorporate follow-up time, as demonstrated here. It also suggests comparing case–control study results with those of cohort studies by plotting the results vs. follow-up interval; if the data from both types of studies can be modeled with a linear or second-order regression fit without large deviations, the case–control results should be afforded more credibility. This study also recommends that prospective cohort studies regularly measure serum 25(OH)D concentration, perhaps every 2–4 y. Doing so would add additional costs to the studies but would yield more accurate results.
Thus, in studies such as the Vitamin D Pooling Project of Rarer Cancers,7 the disagreement with ecological studies may be due partly to the long mean follow-up time of 6.63 y. Some of the disagreement can also be due to the few cases for each type of cancer. Also, the role of solar UVB and vitamin D appears to be stronger for mortality rates than for incidence rates in ecological studies.17,18Ecological studies of the seven types of cancers in the Vitamin D Pooling Project of Rarer Cancers (endometrial, esophageal, gastric, kidney, ovarian, pancreatic cancer, and non-Hodgkin’s lymphoma [NHL]) strongly support beneficial effects of solar UVB in reducing mortality rates.9 The evidence of beneficial effects for incidence rates for these types of cancer in ecological studies is weaker.17,18Results from prospective cohort studies also support a protective role of UVB irradiance for NHL19-21and 25(OH)D concentration for gastric22 and pancreatic23 cancer, with moderate support for a role of serum 25(OH)D concentration in ovarian cancer24,25but no support for endometrial cancer26 or NHL.17,27 However, long follow-up times could adversely affect some observational studies for endometrial and ovarian cancer and NHL.
There are some limitations of ecological studies. For one, there are risk-modifying factors that are not included in the analyses, such as physical activity, obesity rates, and immigration. For example, in the United States, there was considerable migration from the Northeast to the South and West in the second half of the twentieth century. The strength of the ecological approach is demonstrated in the fact that the results for many types of cancer are often repeated for different populations.9
This study offers additional support for the thesis that long follow-up times adversely affect nested case–control studies from prospective cohort studies regarding the role of prediagnostic serum 25(OH)D concentration in health outcomes such as all-cause mortality rate and many types of cancer. It is hoped that the research communities and health policy makers will take this thesis into account when analyzing epidemiological studies and making recommendations regarding vitamin D.
This study also indicates that observational studies can strongly support the UVB–vitamin D–disease reduction hypothesis if the existing studies in the journal literature are carefully assessed and systemic biases in the interpretation of the data are removed. Unfortunately, the Institute of Medicine Committee on Dietary Reference Intakes for Vitamin D and Calcium5 did not undertake that task. They opted instead to wait another 5–6 y for a “definitive” RCT of vitamin D supplementation.28 As Kristal29 and another paper in this issue30 pointed out, RCTs have several problems that, if not carefully addressed, can result in poor-quality studies. Ideally, results from all types of studies—clinical, cross-sectional, ecological, laboratory, and observational—would be considered together and reasons for differences resolved.
Souberbielle JC, Body JJ, Lappe JM, Plebani M, Shoenfeld Y, Wang TJ, et al.
Vitamin D and musculoskeletal health, cardiovascular disease, autoimmunity and cancer: Recommendations for clinical practice
Autoimmun Rev 2010;
9:709-15; PMID: 20601202
; DOI: 10.1016/j.autrev.2010.06.009
Holick MF, Binkley NC, Bischoff-Ferrari HA, Gordon CM, Hanley DA, Heaney RP, et al.
Evaluation, treatment, and prevention of vitamin D deficiency: an Endocrine Society clinical practice guideline
J Clin Endocrinol Metab 2011;
96:1911-30; PMID: 21646368
; DOI: 10.1210/jc.2011-0385
Short-term and long-term consequences and concerns regarding valid assessment of vitamin D deficiency: comparison of recent food supplementation and clinical guidance reports
Curr Opin Clin Nutr Metab Care 2011;
14:598-604; PMID: 21934610
; DOI: 10.1097/MCO.0b013e32834be798
IARC Working Group Report 5: Vitamin D and Cancer. IARC, Lyon, France. 2008.
Ross AC, Manson JE, Abrams SA, Aloia JF, Brannon PM, Clinton SK, et al.
The 2011 report on dietary reference intakes for calcium and vitamin D from the Institute of Medicine: what clinicians need to know
J Clin Endocrinol Metab 2011;
96:53-8; PMID: 21118827
; DOI: 10.1210/jc.2010-2704
Chung M, Balk EM, Brendel M, Ip S, Lau J, Lee J, et al. Vitamin D and calcium: a systematic review of health outcomes. Evid Rep Technol Assess (Full Rep)(183), 1-420. (Prepared by Tufts Evidence-based Practice Center under Contract No. 290-2007-10055-I). AHRQ Publication No. 09-E015, Rockville, MD: Agency for Healthcare Research and Quality. August 2009. (http://www.ahrq.gov/downloads/pub/evidence/pdf/vitadcal/vitadcal.pdf)
Overview of the Cohort Consortium Vitamin D Pooling Project of Rarer Cancers
Am J Epidemiol 2010;
172:4-9; PMID: 20562193
; DOI: 10.1093/aje/kwq119
Relation between prediagnostic serum 25-hydroxyvitamin D level and incidence of breast, colorectal, and other cancers
J Photochem Photobiol B 2010;
101:130-6; PMID: 20570169
; DOI: 10.1016/j.jphotobiol.2010.04.008
Ecological studies of the UVB-vitamin D-cancer hypothesis
Anticancer Res 2012;
32:223-36; PMID: 22213311
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
3:199-204; PMID: 22110780
Robien K, Cutler GJ, Lazovich D.
Vitamin D intake and breast cancer risk in postmenopausal women: the Iowa Women’s Health Study
Cancer Causes Control 2007;
18:775-82; PMID: 17549593
; DOI: 10.1007/s10552-007-9020-x
Lim U, Freedman DM, Hollis BW, Horst RL, Purdue MP, Chatterjee N, et al.
A prospective investigation of serum 25-hydroxyvitamin D and risk of lymphoid cancers
Int J Cancer 2009;
124:979-86; PMID: 19035445
; DOI: 10.1002/ijc.23984
Schöttker B, Ball D, Gellert C, Brenner H.
Serum 25-hydroxyvitamin D levels and overall mortality. A systematic review and meta-analysis of prospective cohort studies
Ageing Res Rev 2012;
; PMID: 22343489
; DOI: 10.1016/j.arr.2012.02.004
An estimate of the global reduction in mortality rates through doubling vitamin D levels
Eur J Clin Nutr 2011;
65:1016-26; PMID: 21731036
; DOI: 10.1038/ejcn.2011.68
Zittermann A, Iodice S, Pilz S, Grant WB, Bagnardi V, Gandini S.
Vitamin D deficiency and mortality risk in the general population: a meta-analysis of prospective cohort studies
Am J Clin Nutr 2012;
95:91-100; PMID: 22170374
; DOI: 10.3945/ajcn.111.014779
An ecological study of cancer mortality rates in the United States with respect to solar ultraviolet-B doses, smoking, alcohol consumption and urban/rural residence
2:68-76; PMID: 21547102
; DOI: 10.4161/derm.2.2.13812
Boscoe FP, Schymura MJ.
Solar ultraviolet-B exposure and cancer incidence and mortality in the United States, 1993-2002
BMC Cancer 2006;
6:264; PMID: 17096841
; DOI: 10.1186/1471-2407-6-264
Chen W, Clements M, Rahman B, Zhang S, Qiao Y, Armstrong BK.
Relationship between cancer mortality/incidence and ambient ultraviolet B irradiance in China
Cancer Causes Control 2010;
21:1701-9; PMID: 20552265
; DOI: 10.1007/s10552-010-9599-1
Hartge P, Lim U, Freedman DM, Colt JS, Cerhan JR, Cozen W, et al.
Ultraviolet radiation, dietary vitamin D, and risk of non-Hodgkin lymphoma (United States)
Cancer Causes Control 2006;
17:1045-52; PMID: 16933055
; DOI: 10.1007/s10552-006-0040-8
Kricker A, Armstrong BK, Hughes AM, Goumas C, Smedby KE, Zheng T, et al.
Personal sun exposure and risk of non Hodgkin lymphoma: a pooled analysis from the Interlymph Consortium
Int J Cancer 2008;
122:144-54; PMID: 17708556
; DOI: 10.1002/ijc.23003
Chang ET, Canchola AJ, Cockburn M, Lu Y, Wang SS, Bernstein L, et al.
Adulthood residential ultraviolet radiation, sun sensitivity, dietary vitamin D, and risk of lymphoid malignancies in the California Teachers Study
118:1591-9; PMID: 21622649
; DOI: 10.1182/blood-2011-02-336065
Ren C, Qiu MZ, Wang DS, Luo HY, Zhang DS, Wang ZQ, et al.
Prognostic effects of 25-hydroxyvitamin D levels in gastric cancer
J Transl Med 2012;
10:16; PMID: 22284859
; DOI: 10.1186/1479-5876-10-16
Wolpin BM, Ng K, Bao Y, Kraft P, Stampfer MJ, Michaud DS, et al.
Plasma 25-hydroxyvitamin D and risk of pancreatic cancer
Cancer Epidemiol Biomarkers Prev 2012;
21:82-91; PMID: 22086883
; DOI: 10.1158/1055-9965.EPI-11-0836
Toriola AT, Surcel HM, Calypse A, Grankvist K, Luostarinen T, Lukanova A, et al.
Independent and joint effects of serum 25-hydroxyvitamin D and calcium on ovarian cancer risk: a prospective nested case-control study
Eur J Cancer 2010;
46:2799-805; PMID: 20601305
; DOI: 10.1016/j.ejca.2010.05.019
Yin L, Grandi N, Raum E, Haug U, Arndt V, Brenner H.
Meta-analysis: Circulating vitamin D and ovarian cancer risk
Gynecol Oncol 2011;
121:369-75; PMID: 21324518
; DOI: 10.1016/j.ygyno.2011.01.023
McCullough ML, Bandera EV, Moore DF, Kushi LH.
Vitamin D and calcium intake in relation to risk of endometrial cancer: a systematic review of the literature
Prev Med 2008;
46:298-302; PMID: 18155758
; DOI: 10.1016/j.ypmed.2007.11.010
Manson JE, Bassuk SS, Lee IM, Cook NR, Albert MA, Gordon D, et al.
The VITamin D and OmegA-3 TriaL (VITAL): rationale and design of a large randomized controlled trial of vitamin D and marine omega-3 fatty acid supplements for the primary prevention of cancer and cardiovascular disease
Contemp Clin Trials 2012;
33:159-71; PMID: 21986389
; DOI: 10.1016/j.cct.2011.09.009
Are clinical trials the “gold standard” for cancer prevention research?
Cancer Epidemiol Biomarkers Prev 2008;
17:3289-91; PMID: 19064540
; DOI: 10.1158/1055-9965.EPI-08-1066
Lappe J, Heaney RP.
Why randomized controlled trials of calcium and vitamin D sometimes fail
Hofmann JN, Yu K, Horst RL, Hayes RB, Purdue MP.
Long-term variation in serum 25-hydroxyvitamin D concentration among participants in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial
Cancer Epidemiol Biomarkers Prev 2010;
19:927-31; PMID: 20332255
; DOI: 10.1158/1055-9965.EPI-09-1121
Rejnmark L, Lauridsen AL, Brot C, Vestergaard P, Heickendorff L, Nexo E, et al.
Vitamin D and its binding protein Gc: long-term variability in peri- and postmenopausal women with and without hormone replacement therapy
Scand J Clin Lab Invest 2006;
66:227-38; PMID: 16714251
; DOI: 10.1080/00365510600570623
Platz EA, Hankinson SE, Hollis BW, Colditz GA, Hunter DJ, Speizer FE, et al.
Plasma 1,25-dihydroxy- and 25-hydroxyvitamin D and adenomatous polyps of the distal colorectum
Cancer Epidemiol Biomarkers Prev 2000;
9:1059-65; PMID: 11045788
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; PMID: 20219763
; DOI: 10.1093/aje/kwq005
Visser M, Deeg DJH, Puts MTE, Seidell JC, Lips P.
Low serum concentrations of 25-hydroxyvitamin D in older persons and the risk of nursing home admission
Am J Clin Nutr 2006;
84:616-22, quiz 671-2; PMID: 16960177
Pilz S, Dobnig H, Nijpels G, Heine RJ, Stehouwer CD, Snijder MB, et al.
Vitamin D and mortality in older men and women
Clin Endocrinol (Oxf) 2009;
71:666-72; PMID: 19226272
; DOI: 10.1111/j.1365-2265.2009.03548.x
Semba RD, Houston DK, Bandinelli S, Sun K, Cherubini A, Cappola AR, et al.
Relationship of 25-hydroxyvitamin D with all-cause and cardiovascular disease mortality in older community-dwelling adults
Eur J Clin Nutr 2010;
64:203-9; PMID: 19953106
; DOI: 10.1038/ejcn.2009.140
Cawthon PM, Parimi N, Barrett-Connor E, Laughlin GA, Ensrud KE, Hoffman AR, et al.
Serum 25-hydroxyvitamin D, parathyroid hormone, and mortality in older men
J Clin Endocrinol Metab 2010;
95:4625-34; PMID: 20631024
; DOI: 10.1210/jc.2010-0638
Jia X, Aucott LS, McNeill G.
Nutritional status and subsequent all-cause mortality in men and women aged 75 years or over living in the community
Br J Nutr 2007;
98:593-9; PMID: 17442130
; DOI: 10.1017/S0007114507725163
Melamed ML, Michos ED, Post W, Astor B.
25-hydroxyvitamin D levels and the risk of mortality in the general population
Arch Intern Med 2008;
168:1629-37; PMID: 18695076
; DOI: 10.1001/archinte.168.15.1629
Virtanen JK, Nurmi T, Voutilainen S, Mursu J, Tuomainen TP.
Association of serum 25-hydroxyvitamin D with the risk of death in a general older population in Finland
Eur J Nutr 2011;
50:305-12; PMID: 20976461
; DOI: 10.1007/s00394-010-0138-3
Szulc P, Claustrat B, Delmas PD.
Serum concentrations of 17?-E2 and 25-hydroxycholecalciferol (25OHD) in relation to all-cause mortality in older men--the MINOS study
Clin Endocrinol (Oxf) 2009;
71:594-602; PMID: 19207314
; DOI: 10.1111/j.1365-2265.2009.03530.x
Hutchinson MS, Grimnes G, Joakimsen RM, Figenschau Y, Jorde R.
Low serum 25-hydroxyvitamin D levels are associated with increased all-cause mortality risk in a general population: the Tromsø study
Eur J Endocrinol 2010;
162:935-42; PMID: 20185562
; DOI: 10.1530/EJE-09-1041
Michaëlsson K, Baron JA, Snellman G, Gedeborg R, Byberg L, Sundström J, et al.
Plasma vitamin D and mortality in older men: a community-based prospective cohort study
Am J Clin Nutr 2010;
92:841-8; PMID: 20720256
; DOI: 10.3945/ajcn.2010.29749
Bates CJ, Hamer M, Mishra GD.
A study of relationships between bone-related vitamins and minerals, related risk markers, and subsequent mortality in older British people: the National Diet and Nutrition Survey of People Aged 65 Years and Over
Osteoporos Int 2012;
23:457-66; PMID: 21380638
; DOI: 10.1007/s00198-011-1543-z
Kestenbaum B, Katz R, de Boer I, Hoofnagle A, Sarnak MJ, Shlipak MG, et al.
Vitamin D, parathyroid hormone, and cardiovascular events among older adults
J Am Coll Cardiol 2011;
58:1433-41; PMID: 21939825
; DOI: 10.1016/j.jacc.2011.03.069