On 2014 Dec 31, William Grant commented:

The paper by Huss and colleagues studied the relation between 25-hydroxyvirtamin D [25(OH)D] concentrations and breast cancer mortality rates for women enrolled in the Malmö Diet and Cancer Study observed between 1991 and 2006 [1]. 17,035 women completed the baseline examination, and from these, 672 women were diagnosed with invasive unilateral breast cancer after baseline, of whom 101 died from breast cancer and 54 died from other causes. The mean time between enrollment and breast cancer was 6.0 to 8.3 years with standard deviations of 7.4 to 8.9 years. They found a U-shaped relation between 25(OH)D concentration at baseline and mortality rate for three tertiles with ranges <75 nmol/L 76-99 nmol/L, and >100 nmol/L. Each tertile had 216 to 221 invasive breast cancer cases and 21 to 30 breast cancer specific deaths. While no explanation was given why high 25(OH)D concentrations should be associated with increased risk. In this comment, I present three reasons why the increased mortality rate at the highest 25(OH)D tertile is probably not representative of natural 25(OH)D concentrations, i.e., derived from solar UVB or diet.

First, breast cancer develops very rapidly, so baseline 25(OH)D concentrations are not useful for long-term studies. For example, there is a global seasonality of breast cancer incidence rates, with peaks in spring and fall [2]. The authors of this paper suggested that UVB and vitamin D reduce incidence rates in summer while dark days and melatonin reduce incidence rates in winter. In addition, breast cancer screening using mammography is recommended annually, unlike colorectal cancer, for which decadal screening is generally used. There are large seasonal variations in 25(OH)D concentrations in Europe [3]. In addition, there are significant drifts in 25(OH)D concentrations over periods of years such that for periods longer than about three years, observational studies generally do not find significant inverse correlations between baseline 25(OH)D concentration and incidence of breast cancer, although they do for colorectal cancer [4]. Long follow-up times also adversely affect observational studies of all-cause mortality rate with respect to baseline 25(OH)D concentration [5].

Second, 25(OH)D concentrations above 100 nmol/L are most likely due to vitamin D supplementation. In addition, the supplementation may have begun late in life, perhaps after a physician noticed a vitamin D deficiency disease such as osteoporosis, or in order to prevent osteoporosis. Support for this hypothesis is found in a pair of observational studies on frailty as a function of 25(OH)D concentrations. In a cross-sectional study of elderly men in the United States, there was a monotonic decrease in frailty status with increasing 25(OH)D concentration [6]. However, in a similar study of elderly women, there was a U-shaped relation, with those having 25(OH)D concentration >75 nmol/L having significantly increased prevalence of frailty than those with 50 nmol/L <25(OH)D <75 nmol/L [7]. In the United States, postmenopausal women are often advised to take vitamin D supplements while men are not.

Third, there is no support for a U-shaped breast cancer mortality rate relation from geographical ecological studies with respect to solar UVB doses. In Ref. 8, there is a graph of breast cancer mortality rate with respect to July solar UVB doses in over 400 state economic areas of the United States. The regression line shows a monotonically decreasing mortality rate with respect so solar UVB doses from 3.5 kJ/m2 to 10 kJ/m2 with no evidence in the data of an upturn at higher UVB doses. Other ecological studies from mid- to high-latitude countries also do not show evidence of a U-shaped relation [9].

Thus, for these three reasons the finding of increased breast cancer specific mortality rate for 25(OH)D concentrations >100 nmol/L is most likely not due to long term natural 25(OH)D concentrations but, rather, vitamin D supplementation late in life. This does not imply that taking vitamin D supplements to raise 25(OH)D concentrations above 100 nmol/L is not recommended. However, it suggests that taking supplements should begin earlier in life since many chronic diseases including cancer can develop over periods of decades. That high concentrations are not adverse per se is demonstrated in a recent meta-analysis of 32 prospective observational studies of all-cause mortality rate with respect to baseline 25(OH)D concentration. There was a nearly linear decrease in the hazard ratio from 0-25 nmol/L to 50-73 nmol/L with a minimum reached at 90 nmol/L, after which there was no change [10].

References 1. Huss L, Butt S, Borgquist S, Almquist M, Malm J, Manjer J. Serum levels of vitamin D, parathyroid hormone and calcium in relation to survival following breast cancer. Cancer Causes Control. 2014;25:1131-1140. 2. Oh EY, Ansell C, Nawaz H, Yang CH, Wood PA, Hrushesky WJ. Global breast cancer seasonality. Breast Cancer Res Treat. 2010;123:233-243. 3. 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;85:860-868. 4. 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. Dermatoendocrinol. 2011;3:199-204. 5. 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. 6. Ensrud KE, Blackwell TL, Cauley JA, Cummings SR, Barrett-Connor E, Dam TT, Hoffman AR, Shikany JM, Lane NE, Stefanick ML, Orwoll ES, Cawthon PM; Osteoporotic Fractures in Men Study Group. Circulating 25-hydroxyvitamin D levels and frailty in older men: the osteoporotic fractures in men study. J Am Geriatr Soc. 2011;59:101-106. 7. Ensrud KE, Ewing SK, Fredman L, Hochberg MC, Cauley JA, Hillier TA, Cummings SR, Yaffe K, Cawthon PM; Study of Osteoporotic Fractures Research Group. Circulating 25-hydroxyvitamin D levels and frailty status in older women. J Clin Endocrinol Metab. 2010;95:5266-5273. 8. Grant WB. An estimate of premature cancer mortality in the U.S. due to inadequate doses of solar ultraviolet-B radiation. Cancer. 2002;94:1867-75. 9. Moukayed M, Grant WB. Molecular link between vitamin D and cancer prevention. Nutrients. 2013;5:3993-4023. 10. Garland CF, Kim JJ, Mohr SB, Gorham ED, Grant WB, Giovannucci EL, Baggerly L, Hofflich H, Ramsdell J, Zeng K, Heaney RP. Meta-analysis of all-cause mortality according to serum 25-hydroxyvitamin D. Am J Pub Health. 2014;104:e43-50.

Disclosure I receive funding from Bio-Tech Pharmacal (Fayetteville, AR) and Medi-Sun Engineering, LLC (Highland Park, IL).

On 2014 Dec 31, William Grant commented:

The paper by Huss and colleagues studied the relation between 25-hydroxyvirtamin D [25(OH)D] concentrations and breast cancer mortality rates for women enrolled in the Malmö Diet and Cancer Study observed between 1991 and 2006 [1]. 17,035 women completed the baseline examination, and from these, 672 women were diagnosed with invasive unilateral breast cancer after baseline, of whom 101 died from breast cancer and 54 died from other causes. The mean time between enrollment and breast cancer was 6.0 to 8.3 years with standard deviations of 7.4 to 8.9 years. They found a U-shaped relation between 25(OH)D concentration at baseline and mortality rate for three tertiles with ranges <75 nmol/L 76-99 nmol/L, and >100 nmol/L. Each tertile had 216 to 221 invasive breast cancer cases and 21 to 30 breast cancer specific deaths. While no explanation was given why high 25(OH)D concentrations should be associated with increased risk. In this comment, I present three reasons why the increased mortality rate at the highest 25(OH)D tertile is probably not representative of natural 25(OH)D concentrations, i.e., derived from solar UVB or diet.

First, breast cancer develops very rapidly, so baseline 25(OH)D concentrations are not useful for long-term studies. For example, there is a global seasonality of breast cancer incidence rates, with peaks in spring and fall [2]. The authors of this paper suggested that UVB and vitamin D reduce incidence rates in summer while dark days and melatonin reduce incidence rates in winter. In addition, breast cancer screening using mammography is recommended annually, unlike colorectal cancer, for which decadal screening is generally used. There are large seasonal variations in 25(OH)D concentrations in Europe [3]. In addition, there are significant drifts in 25(OH)D concentrations over periods of years such that for periods longer than about three years, observational studies generally do not find significant inverse correlations between baseline 25(OH)D concentration and incidence of breast cancer, although they do for colorectal cancer [4]. Long follow-up times also adversely affect observational studies of all-cause mortality rate with respect to baseline 25(OH)D concentration [5].

Second, 25(OH)D concentrations above 100 nmol/L are most likely due to vitamin D supplementation. In addition, the supplementation may have begun late in life, perhaps after a physician noticed a vitamin D deficiency disease such as osteoporosis, or in order to prevent osteoporosis. Support for this hypothesis is found in a pair of observational studies on frailty as a function of 25(OH)D concentrations. In a cross-sectional study of elderly men in the United States, there was a monotonic decrease in frailty status with increasing 25(OH)D concentration [6]. However, in a similar study of elderly women, there was a U-shaped relation, with those having 25(OH)D concentration >75 nmol/L having significantly increased prevalence of frailty than those with 50 nmol/L <25(OH)D <75 nmol/L [7]. In the United States, postmenopausal women are often advised to take vitamin D supplements while men are not.

Third, there is no support for a U-shaped breast cancer mortality rate relation from geographical ecological studies with respect to solar UVB doses. In Ref. 8, there is a graph of breast cancer mortality rate with respect to July solar UVB doses in over 400 state economic areas of the United States. The regression line shows a monotonically decreasing mortality rate with respect so solar UVB doses from 3.5 kJ/m2 to 10 kJ/m2 with no evidence in the data of an upturn at higher UVB doses. Other ecological studies from mid- to high-latitude countries also do not show evidence of a U-shaped relation [9].

Thus, for these three reasons the finding of increased breast cancer specific mortality rate for 25(OH)D concentrations >100 nmol/L is most likely not due to long term natural 25(OH)D concentrations but, rather, vitamin D supplementation late in life. This does not imply that taking vitamin D supplements to raise 25(OH)D concentrations above 100 nmol/L is not recommended. However, it suggests that taking supplements should begin earlier in life since many chronic diseases including cancer can develop over periods of decades. That high concentrations are not adverse per se is demonstrated in a recent meta-analysis of 32 prospective observational studies of all-cause mortality rate with respect to baseline 25(OH)D concentration. There was a nearly linear decrease in the hazard ratio from 0-25 nmol/L to 50-73 nmol/L with a minimum reached at 90 nmol/L, after which there was no change [10].

References 1. Huss L, Butt S, Borgquist S, Almquist M, Malm J, Manjer J. Serum levels of vitamin D, parathyroid hormone and calcium in relation to survival following breast cancer. Cancer Causes Control. 2014;25:1131-1140. 2. Oh EY, Ansell C, Nawaz H, Yang CH, Wood PA, Hrushesky WJ. Global breast cancer seasonality. Breast Cancer Res Treat. 2010;123:233-243. 3. 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;85:860-868. 4. 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. Dermatoendocrinol. 2011;3:199-204. 5. 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. 6. Ensrud KE, Blackwell TL, Cauley JA, Cummings SR, Barrett-Connor E, Dam TT, Hoffman AR, Shikany JM, Lane NE, Stefanick ML, Orwoll ES, Cawthon PM; Osteoporotic Fractures in Men Study Group. Circulating 25-hydroxyvitamin D levels and frailty in older men: the osteoporotic fractures in men study. J Am Geriatr Soc. 2011;59:101-106. 7. Ensrud KE, Ewing SK, Fredman L, Hochberg MC, Cauley JA, Hillier TA, Cummings SR, Yaffe K, Cawthon PM; Study of Osteoporotic Fractures Research Group. Circulating 25-hydroxyvitamin D levels and frailty status in older women. J Clin Endocrinol Metab. 2010;95:5266-5273. 8. Grant WB. An estimate of premature cancer mortality in the U.S. due to inadequate doses of solar ultraviolet-B radiation. Cancer. 2002;94:1867-75. 9. Moukayed M, Grant WB. Molecular link between vitamin D and cancer prevention. Nutrients. 2013;5:3993-4023. 10. Garland CF, Kim JJ, Mohr SB, Gorham ED, Grant WB, Giovannucci EL, Baggerly L, Hofflich H, Ramsdell J, Zeng K, Heaney RP. Meta-analysis of all-cause mortality according to serum 25-hydroxyvitamin D. Am J Pub Health. 2014;104:e43-50.

Disclosure I receive funding from Bio-Tech Pharmacal (Fayetteville, AR) and Medi-Sun Engineering, LLC (Highland Park, IL).