Re: Cutaneous melanoma attributable to sunbed use: systematic review and meta-analysis
I thank the authors of Ref. 1 for responding to my rapid response and expanding the discussion of our different opinions [2]. In this response, I respond to specific points in their response, then discuss the more general questions regarding the evidence that UVB irradiance is more beneficial than harmful and that the evidence for beneficial effects of vitamin D without adverse effects is strong.
Regarding randomized controlled trials (RCTs), one was recently published reporting that a median intake of 800 IU/d vitamin D was associated with a 30% reduction in hip fracture rate [3]. Regarding a secondary analysis of the Women’s Health Initiative study based on the subset of participants who did not take personal calcium or vitamin D supplements prior to enrollment in the study [4], that approach has been proposed as a way of “correcting for errors in design or adjusting for problems in execution” of RCTs [5]. As noted in a recent paper, there are many problems inherent in designing and executing RCTs with vitamin D including knowing the serum 25-hydroxyvitamin D [25(OH)D] concentration-disease outcome relation, choosing participants who have 25(OH)D concentrations near the low end of the relation, giving sufficient vitamin D to increase 25(OH)D concentrations to the upper end of the relation, and measuring 25(OH)D concentrations after supplementation [6,7]. Unfortunately, the Women’s Health Initiative calcium and vitamin D supplementation study did not follow any of these criteria.
Regarding the recent finding in the Danish study of a J-shaped relation between serum 25(OH)D concentration and all-cause mortality rate observed during a mean three-year follow-up period [8], a possible explanation for the finding was that those with higher serum 25(OH)D concentrations (75-150 nmol/l) had started taking vitamin D supplements shortly before the blood draw because they were advised to do so by their physician, perhaps after diagnosis of osteoporosis. Vitamin D cannot overcome all of the adverse effects of low 25(OH)D concentrations for much of the lifetime. In support of this hypothesis are two recent studies of frailty index with respect to serum 25(OH)D concentrations in 4+ year follow-up studies: for men, higher 25(OH)D was associated with lower frailty index [9] but for women, there was a U-shaped relation [10].
The statement in [2]: “A key hypothesis to explain the discrepancy between observational and experimental studies would be the diversity of physiological functions of vitamin D in virtually all body organs. Low vitamin D status could be a reflection of metabolic disturbances found in patients with obesity, chronic inflammatory diseases, chronic heart failure, chronic kidney disease, particularly the bedridden, or those at the end of life.” is neither accurate [11] nor useful since many of the observational studies either not include such cases and the experimental studies to date have not been well conducted.
Regarding the Swedish Women’s Lifestyle and Health cohort study, regular use of a sunbed was associated with a reduced risk of breast cancer [12], not increased as claimed in [2]. It is noted that women in Nordic countries apparently have much less solar UVB irradiance than men since in a study of cancer related to occupation, outdoor occupations were associated with reduced risk of only three types of cancer for women but 14 types for men [13].
Regarding the carcinogenicity of UV radiation, as I stated in my original response [14], it is not the increased risk of melanoma per se that is important but, rather, whether the health benefits of artificial UV irradiance are outweigh the health risks. In my analysis, I found that it did by a wide margin. However, the estimate of benefit was overstated. An alternate calculation based on assuming that melanoma risks and cancer risk reduction associated with sunbed use are the same as those for above average solar UV irradiance. (Ref. 1 points out that sunbeds emit primarily UVA with <5% in the UVB range. This is the same as midday, midlatitude solar UV hitting the earth’s surface.) Using a value of a 15% reduction in overall cancer incidence rates for high vs. low serum 25(OH)D concentrations for Europe [4,6,13] using incidence data for the European Union [15] and assuming that all melanoma incidence is due to UV irradiance results in a ratio of 6.1 to 1 for males and 4.6 to one for females. Doing the same analysis for mortality rates yields a ratio of 13.3 for males and 12.7 for females. The discrepancy between incidence and mortality rates may be due to “excess” diagnosis of melanoma [16].
Of course vitamin D supplements could be used for the health benefits of UVB irradiance, but it is difficult to obtain high-dose vitamin D supplements in Europe. The same reasoning also applies to solar UVB irradiance. Solar UVB is the primary source of vitamin D for most people, e.g. [17], and human skin pigmentation has adapted to where people live for many generations to optimize vitamin D production while protecting against the adverse effects of UV [18]. In a review commissioned by the World Health Organization, it was stated that “UVR exposure is a minor contributor to the world's disease burden, causing an estimated annual loss of 1.6 million DALYs; i.e. 0.1% of the total global disease burden. A markedly larger annual disease burden, 3.3 billion DALYs, might result from reduction in global UVR exposure to very low levels.” [19] The accompanying commentary states: “But the importance of the exercise undertaken by Lucas et al. is to make clear that unless dietary/supplement intake in fact substitutes for some UV exposure, there are potentially substantial risks to markedly reducing UV exposure. What is clear is that the shaping of sun exposure policy should not ignore the major benefits of vitamin D, while at the same time acknowledging that UV is a known carcinogen and responsible for skin cancer and other ill effects.” [20]
Let’s turn now to evidence. Meta-analyses of observational studies are considered nearly as strong as RCTs. In fact, the analysis in [1] is just that. There are no RCTs of UV irradiance and risk of melanoma in humans as such studies would be both unethical and take many years. Since they are observational studies, they are subject to confounding, primarily from not considering skin type in the earlier studies and from solar UV irradiance, which is difficult to quantify. Meta-analyses have found significant inverse correlations between serum 25(OH)D concentrations and incidence of colorectal [21] and breast [22] cancer, diabetes and cardiovascular disease [23], and all-cause mortality rate [24,25]. The observational studies of breast and colorectal cancer are in excellent agreement with ecological studies [25]. Such ecological studies were recently supported in a large-scale prospective study that found solar UVB doses in the U.S. associated with a 22% (95% confidence interval 13%-32%) increased risk of melanoma but 9% to 43% reduced risk of bladder, colon, kidney, squamous cell lung, pleural, prostate and overall cancer and non-Hodgkin’s lymphoma [27].
References
1.Boniol M, Autier P, Boyle P, Gandini S. Cutaneous melanoma attributable to sunbed use: systematic review and meta-analysis. BMJ 2012;345:e4757.
2. Boniol M, Autier P, Boyle P, Gandini S. Re: Answer to the rapid response of WB Grant. BMJ 27 July 2012.
3. Bischoff-Ferrari HA, Willett WC, Orav EJ, Lips P, Meunier PJ, Lyons RA, et al. A pooled analysis of vitamin D dose requirements for fracture prevention. N Engl J Med 2012;367:40-9.
4. Bolland MJ, Grey A, Gamble GD, Reid IR. Calcium and vitamin D supplements and health outcomes: a reanalysis of the Women's Health Initiative (WHI) limited-access data set. Am J Clin Nutr 2011;94:1144-9.
5. Kristal AR. Are clinical trials the "gold standard" for cancer prevention research? Cancer Epidemiol Biomarkers Prev 2008;17:3289-91.
6. Lappe JM, Heaney RP. Why randomized controlled trials of calcium and vitamin D sometimes fail. Dermatoendocrin 2012;4(2) epub
7. Garland CF, French CB, Baggerly LL, Heaney RP. Vitamin D supplement doses and serum 25-hydroxyvitamin D in the range associated with cancer prevention. Anticancer Res 2011;31:617-22.
8. Durup D, Jørgensen HL, Christensen J, Schwarz P, Heegaard AM, Lind B. A reverse J-shaped association of all-cause mortality with serum 25-hydroxyvitamin D in general practice, the CopD Study. J Clin Endocrinol Metab 2012 May 9. [Epub ahead of print]
9. Ensrud KE, Blackwell TL, Cauley JA, Cummings SR, Barrett-Connor E, Dam TT, et al. Circulating 25-hydroxyvitamin D levels and frailty in older men: the osteoporotic fractures in men study. J Am Geriatr Soc 2011;59:101-6.
10. Ensrud KE, Ewing SK, Fredman L, Hochberg MC, Cauley JA, Hillier TA, et al. Circulating 25-hydroxyvitamin D levels and frailty status in older women. J Clin Endocrinol Metab 2010;95:5266-73.
11. Fung GJ, Steffen LM, Zhou X, Harnack L, Tang W, Lutsey PL, et al. Vitamin D intake is inversely related to risk of developing metabolic syndrome in African American and white men and women over 20 y: the Coronary Artery Risk Development in Young Adults study. Am J Clin Nutr 2012;96:24-9.
12. Yang L, Veierød MB, Löf M, Sandin S, Adami HO, Weiderpass E. Prospective Study of UV Exposure and Cancer Incidence among Swedish Women. Cancer Epidemiol Biomarkers Prev 2011;20:1358-67.
13. Grant WB. Role of solar UV irradiance and smoking in cancer as inferred from cancer incidence rates by occupation in Nordic countries. Dermatoendocrinol 2012;4(2) epub
14. Grant WB. Re: Cutaneous melanoma attributable to sunbed use: systematic review and meta-analysis. BMJ 25 July 2012.
15. Ferlay J, Shin HR, Bray F, Forman D, Mathers C, Parkin DM. Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. Int J Cancer. 2010;127:2893-917. http://globocan.iarc.fr/factsheet.asp
16. Weyers W. The 'epidemic' of melanoma between under- and overdiagnosis. J Cutan Pathol. 2012;39:9-16.
17. Hyppönen E, Power C. Hypovitaminosis D in British adults at age 45 y: nationwide cohort study of dietary and lifestyle predictors. Am J Clin Nutr 2007;85:860-8.
18. Jablonski NG. The evolution of human skin colouration and its relevance to health in the modern world. J R Coll Physicians Edinb 2012;42:58-63.
19. Lucas RM, McMichael AJ, Armstrong BK, Smith WT. Estimating the global disease burden due to ultraviolet radiation exposure. Int J Epidemiol 2008;37:654-67.
20. Freedman DM. Commentary: The complexities of minimizing risks due to UV exposures. Int J Epidemiol 2008;37:667-8.
21. Yin L, Grandi N, Raum E, Haug U, Arndt V, Brenner H. Meta-analysis: longitudinal studies of serum vitamin D and colorectal cancer risk. Aliment Pharmacol Ther 2009;30:113-25.
22. Yin L, Grandi N, Raum E, Haug U, Arndt V, Brenner H. Meta-analysis: Serum vitamin D and breast cancer risk. Eur J Cancer 2010;46:2196-205.
23. Parker J, Hashmi O, Dutton D, Mavrodaris A, Stranges S, Kandala NB, et al. Levels of vitamin D and cardiometabolic disorders: systematic review and meta-analysis. Maturitas 2010;65:225-36.
24. 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.
25. 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 Feb 16. [Epub ahead of print]
26. Grant WB. Ecological studies of the UVB–vitamin D–cancer hypothesis; review. Anticancer Res 2012;32:223-36.
27. Lin SW, Wheeler DC, Park Y, Cahoon EK, Hollenbeck AR, Freedman DM, et al. Prospective study of ultraviolet radiation exposure and risk of cancer in the U.S. Int J Cancer 2012;131:E1015-23.
Competing interests:
I receive funding from the UV Foundation (McLean, VA), Bio-Tech Pharmacal (Fayetteville, AR), the Vitamin D Council (San Luis Obispo, CA), the Vitamin D Society (Canada), and the Sunlight Research Forum (Veldhoven).
Rapid Response:
Re: Cutaneous melanoma attributable to sunbed use: systematic review and meta-analysis
I thank the authors of Ref. 1 for responding to my rapid response and expanding the discussion of our different opinions [2]. In this response, I respond to specific points in their response, then discuss the more general questions regarding the evidence that UVB irradiance is more beneficial than harmful and that the evidence for beneficial effects of vitamin D without adverse effects is strong.
Regarding randomized controlled trials (RCTs), one was recently published reporting that a median intake of 800 IU/d vitamin D was associated with a 30% reduction in hip fracture rate [3]. Regarding a secondary analysis of the Women’s Health Initiative study based on the subset of participants who did not take personal calcium or vitamin D supplements prior to enrollment in the study [4], that approach has been proposed as a way of “correcting for errors in design or adjusting for problems in execution” of RCTs [5]. As noted in a recent paper, there are many problems inherent in designing and executing RCTs with vitamin D including knowing the serum 25-hydroxyvitamin D [25(OH)D] concentration-disease outcome relation, choosing participants who have 25(OH)D concentrations near the low end of the relation, giving sufficient vitamin D to increase 25(OH)D concentrations to the upper end of the relation, and measuring 25(OH)D concentrations after supplementation [6,7]. Unfortunately, the Women’s Health Initiative calcium and vitamin D supplementation study did not follow any of these criteria.
Regarding the recent finding in the Danish study of a J-shaped relation between serum 25(OH)D concentration and all-cause mortality rate observed during a mean three-year follow-up period [8], a possible explanation for the finding was that those with higher serum 25(OH)D concentrations (75-150 nmol/l) had started taking vitamin D supplements shortly before the blood draw because they were advised to do so by their physician, perhaps after diagnosis of osteoporosis. Vitamin D cannot overcome all of the adverse effects of low 25(OH)D concentrations for much of the lifetime. In support of this hypothesis are two recent studies of frailty index with respect to serum 25(OH)D concentrations in 4+ year follow-up studies: for men, higher 25(OH)D was associated with lower frailty index [9] but for women, there was a U-shaped relation [10].
The statement in [2]: “A key hypothesis to explain the discrepancy between observational and experimental studies would be the diversity of physiological functions of vitamin D in virtually all body organs. Low vitamin D status could be a reflection of metabolic disturbances found in patients with obesity, chronic inflammatory diseases, chronic heart failure, chronic kidney disease, particularly the bedridden, or those at the end of life.” is neither accurate [11] nor useful since many of the observational studies either not include such cases and the experimental studies to date have not been well conducted.
Regarding the Swedish Women’s Lifestyle and Health cohort study, regular use of a sunbed was associated with a reduced risk of breast cancer [12], not increased as claimed in [2]. It is noted that women in Nordic countries apparently have much less solar UVB irradiance than men since in a study of cancer related to occupation, outdoor occupations were associated with reduced risk of only three types of cancer for women but 14 types for men [13].
Regarding the carcinogenicity of UV radiation, as I stated in my original response [14], it is not the increased risk of melanoma per se that is important but, rather, whether the health benefits of artificial UV irradiance are outweigh the health risks. In my analysis, I found that it did by a wide margin. However, the estimate of benefit was overstated. An alternate calculation based on assuming that melanoma risks and cancer risk reduction associated with sunbed use are the same as those for above average solar UV irradiance. (Ref. 1 points out that sunbeds emit primarily UVA with <5% in the UVB range. This is the same as midday, midlatitude solar UV hitting the earth’s surface.) Using a value of a 15% reduction in overall cancer incidence rates for high vs. low serum 25(OH)D concentrations for Europe [4,6,13] using incidence data for the European Union [15] and assuming that all melanoma incidence is due to UV irradiance results in a ratio of 6.1 to 1 for males and 4.6 to one for females. Doing the same analysis for mortality rates yields a ratio of 13.3 for males and 12.7 for females. The discrepancy between incidence and mortality rates may be due to “excess” diagnosis of melanoma [16].
Of course vitamin D supplements could be used for the health benefits of UVB irradiance, but it is difficult to obtain high-dose vitamin D supplements in Europe. The same reasoning also applies to solar UVB irradiance. Solar UVB is the primary source of vitamin D for most people, e.g. [17], and human skin pigmentation has adapted to where people live for many generations to optimize vitamin D production while protecting against the adverse effects of UV [18]. In a review commissioned by the World Health Organization, it was stated that “UVR exposure is a minor contributor to the world's disease burden, causing an estimated annual loss of 1.6 million DALYs; i.e. 0.1% of the total global disease burden. A markedly larger annual disease burden, 3.3 billion DALYs, might result from reduction in global UVR exposure to very low levels.” [19] The accompanying commentary states: “But the importance of the exercise undertaken by Lucas et al. is to make clear that unless dietary/supplement intake in fact substitutes for some UV exposure, there are potentially substantial risks to markedly reducing UV exposure. What is clear is that the shaping of sun exposure policy should not ignore the major benefits of vitamin D, while at the same time acknowledging that UV is a known carcinogen and responsible for skin cancer and other ill effects.” [20]
Let’s turn now to evidence. Meta-analyses of observational studies are considered nearly as strong as RCTs. In fact, the analysis in [1] is just that. There are no RCTs of UV irradiance and risk of melanoma in humans as such studies would be both unethical and take many years. Since they are observational studies, they are subject to confounding, primarily from not considering skin type in the earlier studies and from solar UV irradiance, which is difficult to quantify. Meta-analyses have found significant inverse correlations between serum 25(OH)D concentrations and incidence of colorectal [21] and breast [22] cancer, diabetes and cardiovascular disease [23], and all-cause mortality rate [24,25]. The observational studies of breast and colorectal cancer are in excellent agreement with ecological studies [25]. Such ecological studies were recently supported in a large-scale prospective study that found solar UVB doses in the U.S. associated with a 22% (95% confidence interval 13%-32%) increased risk of melanoma but 9% to 43% reduced risk of bladder, colon, kidney, squamous cell lung, pleural, prostate and overall cancer and non-Hodgkin’s lymphoma [27].
References
1.Boniol M, Autier P, Boyle P, Gandini S. Cutaneous melanoma attributable to sunbed use: systematic review and meta-analysis. BMJ 2012;345:e4757.
2. Boniol M, Autier P, Boyle P, Gandini S. Re: Answer to the rapid response of WB Grant. BMJ 27 July 2012.
3. Bischoff-Ferrari HA, Willett WC, Orav EJ, Lips P, Meunier PJ, Lyons RA, et al. A pooled analysis of vitamin D dose requirements for fracture prevention. N Engl J Med 2012;367:40-9.
4. Bolland MJ, Grey A, Gamble GD, Reid IR. Calcium and vitamin D supplements and health outcomes: a reanalysis of the Women's Health Initiative (WHI) limited-access data set. Am J Clin Nutr 2011;94:1144-9.
5. Kristal AR. Are clinical trials the "gold standard" for cancer prevention research? Cancer Epidemiol Biomarkers Prev 2008;17:3289-91.
6. Lappe JM, Heaney RP. Why randomized controlled trials of calcium and vitamin D sometimes fail. Dermatoendocrin 2012;4(2) epub
7. Garland CF, French CB, Baggerly LL, Heaney RP. Vitamin D supplement doses and serum 25-hydroxyvitamin D in the range associated with cancer prevention. Anticancer Res 2011;31:617-22.
8. Durup D, Jørgensen HL, Christensen J, Schwarz P, Heegaard AM, Lind B. A reverse J-shaped association of all-cause mortality with serum 25-hydroxyvitamin D in general practice, the CopD Study. J Clin Endocrinol Metab 2012 May 9. [Epub ahead of print]
9. Ensrud KE, Blackwell TL, Cauley JA, Cummings SR, Barrett-Connor E, Dam TT, et al. Circulating 25-hydroxyvitamin D levels and frailty in older men: the osteoporotic fractures in men study. J Am Geriatr Soc 2011;59:101-6.
10. Ensrud KE, Ewing SK, Fredman L, Hochberg MC, Cauley JA, Hillier TA, et al. Circulating 25-hydroxyvitamin D levels and frailty status in older women. J Clin Endocrinol Metab 2010;95:5266-73.
11. Fung GJ, Steffen LM, Zhou X, Harnack L, Tang W, Lutsey PL, et al. Vitamin D intake is inversely related to risk of developing metabolic syndrome in African American and white men and women over 20 y: the Coronary Artery Risk Development in Young Adults study. Am J Clin Nutr 2012;96:24-9.
12. Yang L, Veierød MB, Löf M, Sandin S, Adami HO, Weiderpass E. Prospective Study of UV Exposure and Cancer Incidence among Swedish Women. Cancer Epidemiol Biomarkers Prev 2011;20:1358-67.
13. Grant WB. Role of solar UV irradiance and smoking in cancer as inferred from cancer incidence rates by occupation in Nordic countries. Dermatoendocrinol 2012;4(2) epub
14. Grant WB. Re: Cutaneous melanoma attributable to sunbed use: systematic review and meta-analysis. BMJ 25 July 2012.
15. Ferlay J, Shin HR, Bray F, Forman D, Mathers C, Parkin DM. Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. Int J Cancer. 2010;127:2893-917. http://globocan.iarc.fr/factsheet.asp
16. Weyers W. The 'epidemic' of melanoma between under- and overdiagnosis. J Cutan Pathol. 2012;39:9-16.
17. Hyppönen E, Power C. Hypovitaminosis D in British adults at age 45 y: nationwide cohort study of dietary and lifestyle predictors. Am J Clin Nutr 2007;85:860-8.
18. Jablonski NG. The evolution of human skin colouration and its relevance to health in the modern world. J R Coll Physicians Edinb 2012;42:58-63.
19. Lucas RM, McMichael AJ, Armstrong BK, Smith WT. Estimating the global disease burden due to ultraviolet radiation exposure. Int J Epidemiol 2008;37:654-67.
20. Freedman DM. Commentary: The complexities of minimizing risks due to UV exposures. Int J Epidemiol 2008;37:667-8.
21. Yin L, Grandi N, Raum E, Haug U, Arndt V, Brenner H. Meta-analysis: longitudinal studies of serum vitamin D and colorectal cancer risk. Aliment Pharmacol Ther 2009;30:113-25.
22. Yin L, Grandi N, Raum E, Haug U, Arndt V, Brenner H. Meta-analysis: Serum vitamin D and breast cancer risk. Eur J Cancer 2010;46:2196-205.
23. Parker J, Hashmi O, Dutton D, Mavrodaris A, Stranges S, Kandala NB, et al. Levels of vitamin D and cardiometabolic disorders: systematic review and meta-analysis. Maturitas 2010;65:225-36.
24. 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.
25. 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 Feb 16. [Epub ahead of print]
26. Grant WB. Ecological studies of the UVB–vitamin D–cancer hypothesis; review. Anticancer Res 2012;32:223-36.
27. Lin SW, Wheeler DC, Park Y, Cahoon EK, Hollenbeck AR, Freedman DM, et al. Prospective study of ultraviolet radiation exposure and risk of cancer in the U.S. Int J Cancer 2012;131:E1015-23.
Competing interests: I receive funding from the UV Foundation (McLean, VA), Bio-Tech Pharmacal (Fayetteville, AR), the Vitamin D Council (San Luis Obispo, CA), the Vitamin D Society (Canada), and the Sunlight Research Forum (Veldhoven).