Vitamin D and risk of cause specific death: systematic review and meta-analysis of observational cohort and randomised intervention studies
BMJ 2014; 348 doi: https://doi.org/10.1136/bmj.g1903 (Published 01 April 2014) Cite this as: BMJ 2014;348:g1903
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Widely distribution of calcitriol receptors in the body has suggested extended roles for it beyond calcium homeostasis.Calcitriol affects maturation and differentiation of mononuclear cells and influences cytokine production (1). Calciteriol inhibits proliferation and differentiation of malignant cells (2, 3). Also calcitriol inhibits epidermal proliferation and promotes epidermal differentiation and therefore is a potential treatment for psoriasis vulgaris (4). It has been suggested that calcitriol also affects the function of skeletal muscle, brain and blood pressure (5-7).
Although the question is to what extent compensate of vitamin D deficiency in some diseases, including cancer can increase patient survival and suppress disease progression, or, how calcitriol administration in cardiovascular disease can be effective. Of course, as this article stated vitamin D deficiency can cause deterioration of the patient's condition. But cannot declare that correction of vitamin D deficiency cures the disease and increases patient survival, particularly in conditions such as cancer, because these diseases are associated with high mortality risk and cannot simply declare thatvitamin D deficiency is the only cause of death in these patients. The authors concluded that vitamin D3 can substantially reduce mortality rate in elderly people, but they stated that the exact dose and duration of vitamin D should be determined in future studies. Now the question is whether the effect of vitamin D has been determined in these patients so far. If not based on which data authors concluded that vitamin D can reduce mortality rate in elderly.
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2. Salomón DG1, Fermento ME, Gandini NA, Ferronato MJ, Arévalo J, Blasco J, Andrés NC, Zenklusen JC, Curino AC, Facchinetti MM. Vitamin D receptor expression is associated with improved overall survival in human glioblastoma multiforme. J Neurooncol. 2014 Mar 1. [Epub ahead of print]
3. Pilon C, Urbanet R, Williams TA, Maekawa T, Vettore S, Sirianni R, Pezzi V, Mulatero P, Fassina A, Sasano H, Fallo F. 1α,25-Dihydroxyvitamin D₃ inhibits the human H295R cell proliferation by cell cycle arrest: a model for a protective role of vitamin D receptor against adrenocortical cancer. J Steroid Biochem Mol Biol. 2014 Mar;140:26-33.
4. Kragballe K, Iversen L. Calcipotriol. A new topical antipsoriatic. Dermatol Clin, 1993, 11:137–141.[PMID: 8435908] [Full Text]
5. Girgis CM, Clifton-Bligh RJ, Mokbel N, Cheng K, Gunton JE. Vitamin D signaling regulates proliferation, differentiation, and myotube size in C2C12 skeletal muscle cells. Endocrinology. 2014 Feb;155(2):347-57.
6. Keeney JT, Förster S, Sultana R, Brewer LD, Latimer CS, Cai J, Klein JB, Porter NM, Allan Butterfield D. Dietary vitamin D deficiency in rats from middle to old age leads to elevated tyrosine nitration and proteomics changes in levels of key proteins in brain: implications for low vitamin D-dependent age-related cognitive decline. Free Radic Biol Med. 2013 Dec;65:324-34.
7. Min B. Effects of Vitamin D on Blood Pressure and Endothelial Function. Korean J Physiol Pharmacol. 2013 Oct;17(5):385-392.
Competing interests: No competing interests
Among other things, the paper by Chowdhury and colleagues reported the results of meta-analyses for cancer-specific incidence and mortality rates with respect to bottom versus top third of baseline 25-hydroxyvitamin D [25(OH)D] levels (Figure 1 and eFigure 2b) [1]. For healthy participants, the relative risk from 12 studies was 1.35 (95% confidence interval, 1.13 to 1.61), while for participants with preexisting cancer, the relative risk from five studies was 1.60 (1.32-1.94). A review of the studies included found that the follow-up time after blood draw ranged from 3.8 to 24 years for the healthy participants' studies and from six to 13 years for the participants with preexisting cancer studies. While there is concern that the longer the follow-up period, the weaker the observed effect of higher 25(OH)D level will be [2], follow-up period did not seem to be an important factor in the meta-analyses. Also, inspection of the studies used for the participants with pre-existing disease did not find an effect related to the tertile ranges.
Interestingly, in one of the studies included, the relative risk of non-vascular disease had two parallel regression lines, one for those with prior disease (range ~1.6 at 40 nmol/L to 1.06 at 80 nmol/L) and one for those with no prior disease (range ~0.99 at 40 nmol/L to 0.65 at 80 nmol/L) [3].
The implication of this finding is that vitamin D has a much stronger impact on survival after development of cancer than in reducing the risk of developing cancer. In fact, this point was made with respect to ecological study findings of cancer incidence and mortality rates in the United States with respect to calculated ultraviolet-B (UVD) doses:
"The relative risks for cancer incidence are similar to those for cancer mortality for most sites. For several sites (breast, colon, rectum, esophagus, other biliary, vulva), the relative risks of mortality are higher, possibly suggesting that the maintenance of adequate vitamin D levels is more critical for limiting tumor progression than for preventing tumor onset." [4].
A similar observation was made in an ecological study of cancer incidence and mortality rates in China with respect to calculated UVB doses:
"Mortality rates for all cancers and cancers of the esophagus, stomach, colon and rectum, liver, lung, breast, and bladder were inversely correlated with ambient UVB. This correlation was present in men and women and rural residents for all these cancers but not urban residents for cancers of the esophagus, colon and rectum and liver. ... Only incidence rates for cancers of the esophagus, stomach, colon and rectum and cervix were inversely correlated with ambient UVB." [5].
It is noted that findings of reduced risk of cancer from ecological studies are much stronger than those of observational studies, in part due to larger numbers of cases, and in part due to the stronger effect of vitamin D on cancer mortality rates than on cancer incidence rates [6, 7].
That vitamin D would exert a more important impact on cancer mortality than cancer incidence is reasonable since there are many risk factors for cancer incidence but only a few natural mechanisms in the body to reduce the progression and metastasis of cancer. Vitamin D can reduce both angiogenesis around tumors, which is important for tumor progression, as well as reduce metastasis [7].
The most important implication of this apparently general finding is that investigating whether higher 25(OH)D levels reduce the incidence of cancer is a much more difficult way to determine the importance of vitamin D in reducing risk of cancer death. Thus, more emphasis should be put on investigating the role of serum 25(OH)D level and vitamin D3 supplementation in increasing survival after diagnosis of cancer. For example, a one-year study of men with low-risk prostate cancer with vitamin D3 supplementation (4000 IU/d) found that "24 of 44 subjects (55%) showed a decrease in the number of positive cores or decrease in Gleason score; five subjects (11%) showed no change; 15 subjects (34%) showed an increase in the number of positive cores or Gleason score" [8].
More emphasis might also be placed on case-control studies of cancer incidence with respect to 25(OH)D levels. There is no evidence that having undiagnosed cancer such as breast or colorectal cancer affects 25(OH)D levels [2] and the 25(OH)D level-breast cancer incidence relation is quite robust based on comparison of findings from six studies from four countries [9].
The inverse association between 25(OH)D levels and poor cancer survival has been found for breast, colorectal, hematologic, lung, and prostate cancer [10]. It has also been suggested that the lower 25(OH)D levels of African Americans (~40 nmol/L) compared to white Americans (~65 nmol/L) explains the 0-50% (mean ~25%) lower survival rate of African Americans after consideration of socioeconomic status, stage at diagnosis, and treatment [11].
One additional thing that would help advance the research on vitamin D and cancer is for vitamin D randomized controlled trials to be designed properly and not on the model appropriate for pharmaceutical drugs. Those trials assume that the agent supplied in the trial is the only source and that there is a linear dose-response relation. Neither assumption is correct for vitamin D. See Heaney [12] for the appropriate guidelines.
After the emphasis changes to investigating the role of vitamin D in cancer survival for both observational studies and randomized controlled trials, hopefully this statement by Daniel Bikle will be retracted: "the clinical studies for most cancers have not yet delivered compelling evidence that the promise from preclinical studies has been fulfilled in the clinic." [13].
References
1. Chowdhury R, Kunutsor S, Vitezova A, Oliver-Williams C, Chowdhury S, Kiefte-de-Jong JC, et al. Vitamin D and risk of cause specific death: systematic review and meta-analysis of observational cohort and randomised intervention studies. BMJ. 2014;348:g1903.
2. Grant WB. Effect of follow-up time on the relation between prediagnostic serum 25-hydroxyitamin D and all-cause mortality rate. Dermatoendocrinol. 2012;4:198-202.
3. Tomson J, Emberson J, Hill M, Gordon A, Armitage J, Shipley M, et al. Eur Heart J. 2013;34:1365-74.
4. Boscoe FP, Schymura MJ. Solar ultraviolet-B exposure and cancer incidence and mortality in the United States, 1993-2000. BMC Cancer. 2006;6:264.
5. 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.
6. Grant WB. Ecological studies of the UVB–vitamin D–cancer hypothesis; review. Anticancer Res. 2012;32:223-36.
7. Moukayed M, Grant WB. Molecular link between vitamin D and cancer prevention. Nutrients. 2013;5:3993-4023.
8. Marshall DT, Savage SJ, Garrett-Mayer E, Keane TE, Hollis BW, Horst RL, et al. Vitamin D3 supplementation at 4000 international units per day for one year results in a decrease of positive cores at repeat biopsy in subjects with low-risk prostate cancer under active surveillance. J Clin Endocrinol Metab. 2012;97:2315-24.
9. Grant WB. A review of the evidence regarding the solar ultraviolet-B–vitamin D–cancer hypothesis. Standardy Medyczne/Pediatria. 2012;9:610-9.
10. Robsahm TE, Schwartz GG, Tretli S. The inverse relationship between 25-hydroxyvitamin D and cancer survival: Discussion of causation. Cancers 2013;5:1439-55.
11. Grant WB, Peiris AN. Differences in vitamin D status may account for unexplained disparities in cancer survival rates between African and White Americans. Dermatoendocrinol. 2012;4:85-94.
12. Heaney RP. Guidelines for optimizing design and analysis of clinical studies of nutrient effects. Nutr Rev. 2014;72:48-54.
13. Bikle DD. Vitamin D and cancer: the promise not yet fulfilled. Endocrine. 2014;46:29-38.
Competing interests: I receive funding from Bio-Tech Pharmacal (Fayetteville, AR), the Sunlight Research Forum (Veldhoven) and the UV Foundation (McLean, VA).
In their meta-analysis of 22 randomised controlled trials (RCTs), Chowdhury and colleagues report that, overall, vitamin D supplements had no effect on mortality, but a subgroup analysis suggested mortality was reduced in 14 RCTs of vitamin D3 and not in 8 RCTs of vitamin D2.1 However, 3 of the RCTs classified as vitamin D3 trials actually studied calcitriol (1,25-dihydroxyvitamin D3).2-4 Another trial compared the effects of an exercise programme plus vitamin D3 to a control group that did not receive an exercise programme.5 Results from the RCTs of either active metabolites of vitamin D or multifactorial interventions cannot be ascribed to vitamin D3. When these 4 RCTs are removed from the analyses by Chowdhury and colleagues, the pooled relative risk for all 18 trials is 0.98 (95%CI 0.92-1.06) and for the 10 vitamin D3 trials is 0.92 (95% CI 0.84-1.02). Therefore, these analyses do not provide evidence for an effect of vitamin D (or vitamin D3) on mortality.
In a recent trial sequential meta-analysis of vitamin D with or without calcium supplements on mortality,6 we included 7 other RCTs of vitamin D alone, and 7 RCTs of calcium and vitamin D compared with calcium, in addition to the RCTs in the analysis by Chowdhury and colleagues. The most recent Cochrane review included several other potentially relevant RCTs.7 There are numerous meta-analyses on vitamin D and health outcomes: we identified 45 meta-analyses on falls or fractures and 12 on mortality in a PubMed search. The differences between the results of these meta-analyses seem largely due to methodology adopted by the authors, such as their choice of studies that are included, how co-administration of calcium is addressed, and how the studies are divided in subgroup analyses.
References
1. Chowdhury R, Kunutsor S, Vitezova A, Oliver-Williams C, Chowdhury S, Kiefte-de-Jong JC, et al. Vitamin D and risk of cause specific death: systematic review and meta-analysis of observational cohort and randomised intervention studies. BMJ 2014;348:g1903.
2. Grady D, Halloran B, Cummings S, Leveille S, Wells L, Black D, et al. 1,25-Dihydroxyvitamin D3 and muscle strength in the elderly: a randomized controlled trial. J Clin Endocrinol Metab 1991;73:1111-7.
3. Gallagher JC. The effects of calcitriol on falls and fractures and physical performance tests. J Steroid Biochem Mol Biol 2004;89-90:497-501.
4. Beer TM, Ryan CW, Venner PM, Petrylak DP, Chatta GS, Ruether JD, et al. Double-blinded randomized study of high-dose calcitriol plus docetaxel compared with placebo plus docetaxel in androgen-independent prostate cancer: a report from the ASCENT Investigators. J Clin Oncol 2007;25:669-74.
5. Campbell AJ, Robertson MC, La Grow SJ, Kerse NM, Sanderson GF, Jacobs RJ, et al. Randomised controlled trial of prevention of falls in people aged > or =75 with severe visual impairment: the VIP trial. BMJ 2005;331:817.
6. Bolland MJ, Grey A, Gamble GD, Reid IR. The effect of vitamin D supplementation on skeletal, vascular, or cancer outcomes: a trial sequential meta-analysis. Lancet Diabetes Endocrinol 2014;2:307-20.
7. Bjelakovic G, Gluud LL, Nikolova D, Whitfield K, Wetterslev J, Simonetti RG, et al. Vitamin D supplementation for prevention of mortality in adults. Cochrane Database Syst Rev 2014;1:CD007470.
Competing interests: No competing interests
Re: Vitamin D and risk of cause specific death: systematic review and meta-analysis of observational cohort and randomised intervention studies
We cordially thank Dr Grant for his comments. We agree that while prior ecological studies are supportive of our current findings based on meta-analysis of observational studies; further work, especially those involving well-powered randomized intervention studies, is required. We would, however, like to add that the respective pooled risk ratios (RRs) that we reported by combining the primary and secondary prevention cohorts, are based on indirect comparison (ie, only a subset of studies provided mortality risk data on people with pre-existing disease).
We also thank Dr Bolland and colleagues for their observations and thoughts. The overall estimate from the vitamin D3 randomized controlled trials were indeed presented as a combination of both active and inactive vitamin D3 supplements, given a lack of power in each component in isolation. Additionally, we included the Campbell et al trial (1) as a study evaluating the effects of vitamin D3 alone without any concurrent administration of other pharmacological interventions (and was similarly kept as a vitamin D alone study in the earlier Cochrane report). Nonetheless, when this study and the other 3 calcitriol trials (2-4) were removed from the analyses, there was no significant effect of “any vitamin D supplementation” on mortality (which remains consistent with our original results). The pooled effect estimate for the 10 vitamin D3 trials became slightly attenuated (0.91 (95% CI 0.82-1.00) in our calculation), however, this apparent inverse effect differed significantly with the corresponding pooled estimate of vitamin D2 (P from meta-regression analysis=0.03, for a comparison between vitamin D3 and vitamin D2 trials). That said, we agree with Dr Bolland and colleagues that the selection criteria (eg, randomised vs. non-randomised, with vs. without calcium supplementation, etc.) and decisions on subgroup analyses vary across reviews on this topic, and may explain the differences of findings across these reports. However, as was discussed in our paper (and the accompanying editorial), all these reviews (including ours) are based on largely overlapping trials that principally included high risk, elderly populations (with an average age >75 years in all trials combined). Therefore, before any policy formulation, further large-scale and sufficiently prolonged trials involving sufficient samples derived from the general population will be required.
(1) Campbell AJ, Robertson MC, La Grow SJ, Kerse NM, Sanderson GF, Jacobs RJ, et al. Randomised controlled trial of prevention of falls in people aged > or =75 with severe visual impairment: the VIP trial. BMJ 2005;331:817.
(2) Grady D, Halloran B, Cummings S, Leveille S, Wells L, Black D, et al. 1,25-Dihydroxyvitamin D3 and muscle strength in the elderly: a randomized controlled trial. J Clin Endocrinol Metab 1991;73:1111-7.
(3) Gallagher JC. The effects of calcitriol on falls and fractures and physical performance tests. J Steroid Biochem Mol Biol 2004;89-90:497-501.
(4) Beer TM, Ryan CW, Venner PM, Petrylak DP, Chatta GS, Ruether JD, et al. Double-blinded randomized study of high-dose calcitriol plus docetaxel compared with placebo plus docetaxel in androgen-independent prostate cancer: a report from the ASCENT Investigators. J Clin Oncol 2007;25:669-74.
Rajiv Chowdhury[1]
cardiovascular epidemiologist
Oscar H Franco[2]
professor
On behalf of Setor Kunutsor, Anna Vitezova, Clare Oliver-Williams, Susmita Chowdhury, Jessica C Kiefte-de-Jong, Hassan Khan, Cristina P Baena, Dorairaj Prabhakaran, Moshe B Hoshen, Becca S Feldman, An Pan, Laura Johnson, Francesca Crowe, and Frank B Hu
[1] Department of Public Health and Primary Care, University of Cambridge, Strangeways Research Laboratory, Cambridge CB1 8RN, UK
[2] Department of Epidemiology, Erasmus MC, Rotterdam, The Netherlands
o.franco@erasmusmc.nl
Competing interests: No competing interests