On 2015 Feb 23, William Grant commented:

Concerns over Vitamin D and clinical practice at a crossroads recommendations

In their viewpoint piece, Vitamin D and clinical practice at a crossroads, Manson and Bassuk state among other things that the Institute of Medicine (IOM) set the recommended dietary allowance for vitamin D at 600 IU/d for those living in the upper latitudes of North America aged to 70 years and 800 IU/d for those older in order to reach a 25-hydroxyvitamin D [25(OH)D] concentration of 20 ng/mL (50 nmol/L) [1]. However, it is not clear how the Dietary Reference Intakes for Calcium and Vitamin D committee arrived at that number. For example, on p. 3-20 of the vitamin D and calcium IOM report [2], Figure 3-4 from Cashman et al. [3] is given as Figure 3-4, although without the 95% confidence intervals as in the original paper. The results were based on a 22-week placebo, randomized controlled supplementation study involving men and women aged 20-40 years. Inspection of Figure 2 in Ref. 3 indicates that it would take 1155 IU/d vitamin D3 for 97.5% of the 20-40 year old population sampled to reach 50 nmol/L. In a subsequent paper based on a systematic review and meta-analysis of vitamin D intake and 25(OH)D concentrations, the same group determined that it would take 930 IU/d vitamin D3 for people living in northern Europe to reach 50 nmol/L [4]. Further complicating matters is the fact that not all of the contributions from diet are accounted for in most studies. It is becoming apparent that some food such as meat has vitamin D in the form of 25(OH)D. Thus, vegans in the UK have 25(OH)D concentrations 20 nmol/L lower than omnivores [5], so require higher vitamin D intake from non-dietary sources or solar UVB exposure.

Their comment that "while awaiting the results of the large trials now in progress, physicians would be well advised to follow current USPSTF and IOM recommendations and avoid overscreening and overprescribing supplemental vitamin D" is also not well grounded. The IOM restricted its assessment of the benefits of vitamin D to vitamin D randomized controlled trials [RCTs] with substantial benefits by 2010. A number of trials since then demonstrated health benefits, e.g., for biomarkers of inflammation, where it was found that RCTs with baseline 25(OH)D concentrations below 48 nmol/L had a 50% chance of findings benefits from vitamin D supplementation compared to 25% with baseline 25(OH)D concentrations above 50 nmol/L [6]. In addition, ecological, observational, clinical, and laboratory studies have found many health benefits of solar UVB exposure and/or vitamin D. Since the IOM report was published (29 November, 2010), 13,535 publications with vitamin D in the title or abstract have been published at PubMed.gov as of 23 February, 2015, compared with 27,775 published before that date. Many of these publications strengthen the case for vitamin D supplementation and UVB exposure.

In terms of confounding factors related to observational studies, one not mentioned in Ref. 1 is the possibility that solar UV exposure may have health benefits in addition to vitamin D production. As a result, 25(OH)D concentrations may be an index of UVB exposure. Beneficial effects of UV exposure in addition to vitamin D production have been reported for intestinal cancer [7], multiple sclerosis [8], and blood pressure [9].

As for concern about adverse effects of higher 25(OH)D concentrations based on observational studies, it should be noted that most such studies do not obtain any information from participants about vitamin D supplementation prior to having 25(OH)D concentrations measured. Thus, those with adverse health outcomes and high 25(OH)D concentrations may have started taking vitamin D supplements shortly before blood draw. For example, studies of frailty vs. 25(OH)D concentration found a U-shaded relation for elderly women [10] but a linear inverse relation for elderly men [11]. Elderly women in the U.S. are much more likely to be advised to take vitamin D supplements than men, and starting to take vitamin D late in life cannot erase the adverse effects of years of low 25(OH)D concentrations. In addition, meta-analyses of observational studies of health outcomes with respect to 25(OH)D concentrations do not show U-shaped relations for cardiovascular disease [12] or all-cause mortality rates [13].

As to their comment regarding how interest in vitamin D could jeopardize ongoing vitamin D RCTs, that should not be the case if trial participants are screened by measuring 25(OH)D concentration prior to acceptance and including only those with 25(OH)D concentrations below 50 nmol/L then dropping any who are subsequently prescribed supplements in excess of the IOM recommendations. Over 99% of the population is not enrolled in vitamin D RCTs and should not be held hostage to ongoing or planned trials since there appear to be many health benefits and very few risks of vitamin D supplementation below 4000 IU/d [14] even by the IOM's admission [2].

References 1. Manson JE, Bassuk SS. Vitamin D research and clinical practice: at a crossroads. JAMA. 2015 Feb 19. doi: 10.1001/jama.2015.1353. [Epub ahead of print] 2. Ross AC, Taylor CL, Yaktine AL, Del Valle HB, eds. ; Committee to Review Dietary Reference Intakes for Vitamin D and Calcium; Dietary Reference Intakes for Calcium and Vitamin D. Institute of Medicine. ISBN: 0-309-16395-1, 482 pages, (2010) Available from National Academies Press at: http://www.nap.edu/catalog/13050.html 3. Cashman KD, Hill TR, Lucey AJ, et al. Estimation of the dietary requirement for vitamin D in healthy adults. Am J Clin Nutr. 2008;88(6):1535-42. 4. Cashman KD, Fitzgerald AP, Kiely M, Seamans KM. A systematic review and meta-regression analysis of the vitamin D intake-serum 25-hydroxyvitamin D relationship to inform European recommendations. Br J Nutr. 2011;106(11):1638-48. 5. Crowe FL, Steur M, Allen NE, et al. Plasma concentrations of 25-hydroxyvitamin D in meat eaters, fish eaters, vegetarians and vegans: results from the EPIC-Oxford study. Public Health Nutr. 2011;14(2):340-6. 6. Cannell JJ, Grant WB, Holick MF. Vitamin D and inflammation. Dermato-Endocrinology. 2014;6(1):e983401-1-10.<br> 7. Rebel H, der Spek CD, Salvatori D, et al.UV exposure inhibits intestinal tumour growth and progression to malignancy in intestine-specific Apc mutant mice kept on low vitamin D diet. Int J Cancer. 2015;136(2):271-7. 8. Zivadinov R, Treu CN, Weinstock-Guttman B, et al. Interdependence and contributions of sun exposure and vitamin D to MRI measures in multiple sclerosis. J Neurol Neurosurg Psychiatry. 2013;84(10):1075-81. 9. Opländer C, Volkmar CM, Paunel-Görgülü A, et al. Whole body UVA irradiation lowers systemic blood pressure by release of nitric oxide from intracutaneous photolabile nitric oxide derivates. Circ Res. 2009;105(10):1031-40. 10. Ensrud KE, Ewing SK, Fredman L, et al. Circulating 25-hydroxyvitamin D levels and frailty status in older women. J Clin Endocrinol Metab. 2010;95(12):5266-73. 11. Ensrud KE, Blackwell TL, Cauley JA, et al. Circulating 25-hydroxyvitamin D levels and frailty in older men: the osteoporotic fractures in men study. J Am Geriatr Soc. 2011;59(1):101-6. 12. Wang L, Song Y, Manson JE, et al. Circulating 25-hydroxy-vitamin D and risk of cardiovascular disease: A meta-analysis of prospective studies. Circ Cardiovasc Qual Outcomes. 2012;5(6):819-29. 13. Garland CF, Kim JJ, Mohr SB, et al. Meta-analysis of all-cause mortality according to serum 25-hydroxyvitamin D. Am J Pub Health. 2014;104(8):e43-50. 14. Vieth R. Implications for 25-hydroxyvitamin D testing of public health policies about the benefits and risks of vitamin D fortification and supplementation. Scand J Clin Lab Invest Suppl. 2012;243:144-53.

Disclosure I receive funding from Bio-Tech Pharmacal, Inc. (Fayetteville, AR), MediSun Technology (Highland Park, IL), and the Vitamin D Council (San Luis Obispo, CA).

On 2015 Feb 23, William Grant commented:

Concerns over Vitamin D and clinical practice at a crossroads recommendations

In their viewpoint piece, Vitamin D and clinical practice at a crossroads, Manson and Bassuk state among other things that the Institute of Medicine (IOM) set the recommended dietary allowance for vitamin D at 600 IU/d for those living in the upper latitudes of North America aged to 70 years and 800 IU/d for those older in order to reach a 25-hydroxyvitamin D [25(OH)D] concentration of 20 ng/mL (50 nmol/L) [1]. However, it is not clear how the Dietary Reference Intakes for Calcium and Vitamin D committee arrived at that number. For example, on p. 3-20 of the vitamin D and calcium IOM report [2], Figure 3-4 from Cashman et al. [3] is given as Figure 3-4, although without the 95% confidence intervals as in the original paper. The results were based on a 22-week placebo, randomized controlled supplementation study involving men and women aged 20-40 years. Inspection of Figure 2 in Ref. 3 indicates that it would take 1155 IU/d vitamin D3 for 97.5% of the 20-40 year old population sampled to reach 50 nmol/L. In a subsequent paper based on a systematic review and meta-analysis of vitamin D intake and 25(OH)D concentrations, the same group determined that it would take 930 IU/d vitamin D3 for people living in northern Europe to reach 50 nmol/L [4]. Further complicating matters is the fact that not all of the contributions from diet are accounted for in most studies. It is becoming apparent that some food such as meat has vitamin D in the form of 25(OH)D. Thus, vegans in the UK have 25(OH)D concentrations 20 nmol/L lower than omnivores [5], so require higher vitamin D intake from non-dietary sources or solar UVB exposure.

Their comment that "while awaiting the results of the large trials now in progress, physicians would be well advised to follow current USPSTF and IOM recommendations and avoid overscreening and overprescribing supplemental vitamin D" is also not well grounded. The IOM restricted its assessment of the benefits of vitamin D to vitamin D randomized controlled trials [RCTs] with substantial benefits by 2010. A number of trials since then demonstrated health benefits, e.g., for biomarkers of inflammation, where it was found that RCTs with baseline 25(OH)D concentrations below 48 nmol/L had a 50% chance of findings benefits from vitamin D supplementation compared to 25% with baseline 25(OH)D concentrations above 50 nmol/L [6]. In addition, ecological, observational, clinical, and laboratory studies have found many health benefits of solar UVB exposure and/or vitamin D. Since the IOM report was published (29 November, 2010), 13,535 publications with vitamin D in the title or abstract have been published at PubMed.gov as of 23 February, 2015, compared with 27,775 published before that date. Many of these publications strengthen the case for vitamin D supplementation and UVB exposure.

In terms of confounding factors related to observational studies, one not mentioned in Ref. 1 is the possibility that solar UV exposure may have health benefits in addition to vitamin D production. As a result, 25(OH)D concentrations may be an index of UVB exposure. Beneficial effects of UV exposure in addition to vitamin D production have been reported for intestinal cancer [7], multiple sclerosis [8], and blood pressure [9].

As for concern about adverse effects of higher 25(OH)D concentrations based on observational studies, it should be noted that most such studies do not obtain any information from participants about vitamin D supplementation prior to having 25(OH)D concentrations measured. Thus, those with adverse health outcomes and high 25(OH)D concentrations may have started taking vitamin D supplements shortly before blood draw. For example, studies of frailty vs. 25(OH)D concentration found a U-shaded relation for elderly women [10] but a linear inverse relation for elderly men [11]. Elderly women in the U.S. are much more likely to be advised to take vitamin D supplements than men, and starting to take vitamin D late in life cannot erase the adverse effects of years of low 25(OH)D concentrations. In addition, meta-analyses of observational studies of health outcomes with respect to 25(OH)D concentrations do not show U-shaped relations for cardiovascular disease [12] or all-cause mortality rates [13].

As to their comment regarding how interest in vitamin D could jeopardize ongoing vitamin D RCTs, that should not be the case if trial participants are screened by measuring 25(OH)D concentration prior to acceptance and including only those with 25(OH)D concentrations below 50 nmol/L then dropping any who are subsequently prescribed supplements in excess of the IOM recommendations. Over 99% of the population is not enrolled in vitamin D RCTs and should not be held hostage to ongoing or planned trials since there appear to be many health benefits and very few risks of vitamin D supplementation below 4000 IU/d [14] even by the IOM's admission [2].

References 1. Manson JE, Bassuk SS. Vitamin D research and clinical practice: at a crossroads. JAMA. 2015 Feb 19. doi: 10.1001/jama.2015.1353. [Epub ahead of print] 2. Ross AC, Taylor CL, Yaktine AL, Del Valle HB, eds. ; Committee to Review Dietary Reference Intakes for Vitamin D and Calcium; Dietary Reference Intakes for Calcium and Vitamin D. Institute of Medicine. ISBN: 0-309-16395-1, 482 pages, (2010) Available from National Academies Press at: http://www.nap.edu/catalog/13050.html 3. Cashman KD, Hill TR, Lucey AJ, et al. Estimation of the dietary requirement for vitamin D in healthy adults. Am J Clin Nutr. 2008;88(6):1535-42. 4. Cashman KD, Fitzgerald AP, Kiely M, Seamans KM. A systematic review and meta-regression analysis of the vitamin D intake-serum 25-hydroxyvitamin D relationship to inform European recommendations. Br J Nutr. 2011;106(11):1638-48. 5. Crowe FL, Steur M, Allen NE, et al. Plasma concentrations of 25-hydroxyvitamin D in meat eaters, fish eaters, vegetarians and vegans: results from the EPIC-Oxford study. Public Health Nutr. 2011;14(2):340-6. 6. Cannell JJ, Grant WB, Holick MF. Vitamin D and inflammation. Dermato-Endocrinology. 2014;6(1):e983401-1-10.<br> 7. Rebel H, der Spek CD, Salvatori D, et al.UV exposure inhibits intestinal tumour growth and progression to malignancy in intestine-specific Apc mutant mice kept on low vitamin D diet. Int J Cancer. 2015;136(2):271-7. 8. Zivadinov R, Treu CN, Weinstock-Guttman B, et al. Interdependence and contributions of sun exposure and vitamin D to MRI measures in multiple sclerosis. J Neurol Neurosurg Psychiatry. 2013;84(10):1075-81. 9. Opländer C, Volkmar CM, Paunel-Görgülü A, et al. Whole body UVA irradiation lowers systemic blood pressure by release of nitric oxide from intracutaneous photolabile nitric oxide derivates. Circ Res. 2009;105(10):1031-40. 10. Ensrud KE, Ewing SK, Fredman L, et al. Circulating 25-hydroxyvitamin D levels and frailty status in older women. J Clin Endocrinol Metab. 2010;95(12):5266-73. 11. Ensrud KE, Blackwell TL, Cauley JA, et al. Circulating 25-hydroxyvitamin D levels and frailty in older men: the osteoporotic fractures in men study. J Am Geriatr Soc. 2011;59(1):101-6. 12. Wang L, Song Y, Manson JE, et al. Circulating 25-hydroxy-vitamin D and risk of cardiovascular disease: A meta-analysis of prospective studies. Circ Cardiovasc Qual Outcomes. 2012;5(6):819-29. 13. Garland CF, Kim JJ, Mohr SB, et al. Meta-analysis of all-cause mortality according to serum 25-hydroxyvitamin D. Am J Pub Health. 2014;104(8):e43-50. 14. Vieth R. Implications for 25-hydroxyvitamin D testing of public health policies about the benefits and risks of vitamin D fortification and supplementation. Scand J Clin Lab Invest Suppl. 2012;243:144-53.

Disclosure I receive funding from Bio-Tech Pharmacal, Inc. (Fayetteville, AR), MediSun Technology (Highland Park, IL), and the Vitamin D Council (San Luis Obispo, CA).