On 2015 Feb 01, William Grant commented:

The paper by Jorde and Grimes outlines the case for conducting more vitamin D randomized controlled trials (RCTs) [1]. They also point out that RCTs conducted on those with low baseline 25-hydroxyvitamin D [25(OH)D] concentration are more likely to find beneficial effects of vitamin D supplementation than those with higher baselines. In agreement with this point, we just published a review of vitamin D RCTs and biomarkers of inflammation. Among the 22 trials with baseline 25(OH)D concentration below 47 nmol/L, 49% found reduced biomarkers of inflammation while for the 12 trials with baseline 25(OH)D concentration above 48 nmol/L, only 27% did [2]. In addition, achieved 25(OH)D concentration was relatively unimportant.

Robert Heaney recently presented guidelines for designing nutrient RCTs. The key steps for vitamin D RCTs include starting with an understanding of the 25(OH)D concentration-health outcome relation, generally from observational studies, measure 25(OH)D concentrations of prospective participants, include only those with 25(OH)D concentrations near the low end of the relation, supplement with enough vitamin D3 to raise 25(OH)D concentrations to near the upper end of the relation, remeasure 25(OH)D concentrations, and optimize conutrient status [3]. Few vitamin D RCTs have been designed in accordance with these guidelines, including the major ones currently underway.

As to the concern about J- an U-shaped 25(OH)D concentration-health outcome relations, one of the reasons for such findings appears to be that those with the highest 25(OH)D concentrations started taking vitamin D supplements late in life, possibly after developing some vitamin D deficiency conditions such as osteoporosis. In support of this hypothesis, two similar observational studies of 25(OH)D concentration and frailty conducted in the United States found different results: for men, there was a nearly linear inverse relation between 25(OH)D and frailty [4] while for women, there was a U-shaped relation [5]. In the United States, postmenopausal women are often advised to take vitamin D but older men are not.

One of the emerging topics of research is whether the observational studies finding inverse correlations between health outcomes and 25(OH)D concentrations might be due to non-vitamin D effects of solar UV exposure. There is mounting evidence that this may be the case for at least three types of health outcomes.

For many types of cancer, geographical ecological studies find inverse correlations between solar UVB doses and cancer incidence and/or mortality rates [6]. A mouse model study recently found that UVB exposure was more effective in slowing the progression of intestinal tumors than was oral vitamin D intake when both raised 25(OH)D concentrations by similar amounts [7].

Several recent studies have found that there are non-vitamin D effects associated with solar UVB exposure for multiple sclerosis [8-11].

Long wave UV (UVA) has been found to lower blood pressure [12], a risk factor for cardiovascular disease.

The mechanisms whereby UVB reduces the risk of disease independent of vitamin D are not well known and determining what they are remains an active field of research.

Based on the knowledge to date, what seems to be a prudent policy is spending time in the sun daily when it is possible to make vitamin D, generally when the solar elevation angle is greater than 45 deg. [13] and taking vitamin D supplements when not.

References 1. Jorde R, Grimnes G. Vitamin D and health: The need for more randomized controlled trials. J Steroid Biochem Mol Biol. 2015 Jan 27. pii: S0960-0760(15)00033-3. doi: 10.1016/j.jsbmb.2015.01.021. [Epub ahead of print] Review. 2. Cannell JJ, Grant WB, Holick MF. Vitamin D and inflammation. Dermato-Endocrinology. 2015;6(1): e983401-1-10. DOI:10.4161/19381980.2014.983401 3. Heaney RP. Guidelines for optimizing design and analysis of clinical studies of nutrient effects. Nutr Rev. 2014;72(1):48-54. 4. 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(1):101-6. 5. 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(12):5266-73. 6. Moukayed M, Grant WB. Molecular link between vitamin D and cancer prevention. Nutrients. 2013;5(10):3993-4023. 7. Rebel H, der Spek CD, Salvatori D, van Leeuwen JP, Robanus-Maandag EC, de Gruijl FR.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. Lucas RM, Ponsonby AL, Dear K, Valery PC, Pender MP, Taylor BV, Kilpatrick TJ, Dwyer T, Coulthard A, Chapman C, van der Mei I, Williams D, McMichael AJ. Sun exposure and vitamin D are independent risk factors for CNS demyelination. Neurology. 2011;76(6):540-8. 9. Zivadinov R, Treu CN, Weinstock-Guttman B, Turner C, Bergsland N, O'Connor K, Dwyer MG, Carl E, Ramasamy DP, Qu J, Ramanathan M. Interdependence and contributions of sun exposure and vitamin D to MRI measures in multiple sclerosis. J Neurol Neurosurg Psychiatry. 2013;84(10):1075-81. 10. Bjørnevik K, Riise T, Casetta I, Drulovic J, Granieri E, Holmøy T, Kampman MT, Landtblom AM, Lauer K, Lossius A, Magalhaes S, Myhr KM, Pekmezovic T, Wesnes K, Wolfson C, Pugliatti M. Sun exposure and multiple sclerosis risk in Norway and Italy: The EnvIMS study. Mult Scler. 2014;20(8):1042-1049. 11. Knippenberg S, Damoiseaux J, Bol Y, Hupperts R, Taylor BV, Ponsonby AL, Dwyer T, Simpson S, van der Mei IA. Higher levels of reported sun exposure, and not vitamin D status, are associated with less depressive symptoms and fatigue in multiple sclerosis. Acta Neurol Scand. 2014;129(2):123-31. 12. Liu D, Fernandez BO, Hamilton A, Lang NN, Gallagher JM, Newby DE, Feelisch M, Weller RB. UVA irradiation of human skin vasodilates arterial vasculature and lowers blood pressure independently of nitric oxide synthase. J Invest Dermatol. 2014;134(7):1839-46. 13. Engelsen O. The relationship between ultraviolet radiation exposure and vitamin D status. Nutrients. 2010;2(5):482-95.

On 2015 Feb 01, William Grant commented:

The paper by Jorde and Grimes outlines the case for conducting more vitamin D randomized controlled trials (RCTs) [1]. They also point out that RCTs conducted on those with low baseline 25-hydroxyvitamin D [25(OH)D] concentration are more likely to find beneficial effects of vitamin D supplementation than those with higher baselines. In agreement with this point, we just published a review of vitamin D RCTs and biomarkers of inflammation. Among the 22 trials with baseline 25(OH)D concentration below 47 nmol/L, 49% found reduced biomarkers of inflammation while for the 12 trials with baseline 25(OH)D concentration above 48 nmol/L, only 27% did [2]. In addition, achieved 25(OH)D concentration was relatively unimportant.

Robert Heaney recently presented guidelines for designing nutrient RCTs. The key steps for vitamin D RCTs include starting with an understanding of the 25(OH)D concentration-health outcome relation, generally from observational studies, measure 25(OH)D concentrations of prospective participants, include only those with 25(OH)D concentrations near the low end of the relation, supplement with enough vitamin D3 to raise 25(OH)D concentrations to near the upper end of the relation, remeasure 25(OH)D concentrations, and optimize conutrient status [3]. Few vitamin D RCTs have been designed in accordance with these guidelines, including the major ones currently underway.

As to the concern about J- an U-shaped 25(OH)D concentration-health outcome relations, one of the reasons for such findings appears to be that those with the highest 25(OH)D concentrations started taking vitamin D supplements late in life, possibly after developing some vitamin D deficiency conditions such as osteoporosis. In support of this hypothesis, two similar observational studies of 25(OH)D concentration and frailty conducted in the United States found different results: for men, there was a nearly linear inverse relation between 25(OH)D and frailty [4] while for women, there was a U-shaped relation [5]. In the United States, postmenopausal women are often advised to take vitamin D but older men are not.

One of the emerging topics of research is whether the observational studies finding inverse correlations between health outcomes and 25(OH)D concentrations might be due to non-vitamin D effects of solar UV exposure. There is mounting evidence that this may be the case for at least three types of health outcomes.

For many types of cancer, geographical ecological studies find inverse correlations between solar UVB doses and cancer incidence and/or mortality rates [6]. A mouse model study recently found that UVB exposure was more effective in slowing the progression of intestinal tumors than was oral vitamin D intake when both raised 25(OH)D concentrations by similar amounts [7].

Several recent studies have found that there are non-vitamin D effects associated with solar UVB exposure for multiple sclerosis [8-11].

Long wave UV (UVA) has been found to lower blood pressure [12], a risk factor for cardiovascular disease.

The mechanisms whereby UVB reduces the risk of disease independent of vitamin D are not well known and determining what they are remains an active field of research.

Based on the knowledge to date, what seems to be a prudent policy is spending time in the sun daily when it is possible to make vitamin D, generally when the solar elevation angle is greater than 45 deg. [13] and taking vitamin D supplements when not.

References 1. Jorde R, Grimnes G. Vitamin D and health: The need for more randomized controlled trials. J Steroid Biochem Mol Biol. 2015 Jan 27. pii: S0960-0760(15)00033-3. doi: 10.1016/j.jsbmb.2015.01.021. [Epub ahead of print] Review. 2. Cannell JJ, Grant WB, Holick MF. Vitamin D and inflammation. Dermato-Endocrinology. 2015;6(1): e983401-1-10. DOI:10.4161/19381980.2014.983401 3. Heaney RP. Guidelines for optimizing design and analysis of clinical studies of nutrient effects. Nutr Rev. 2014;72(1):48-54. 4. 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(1):101-6. 5. 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(12):5266-73. 6. Moukayed M, Grant WB. Molecular link between vitamin D and cancer prevention. Nutrients. 2013;5(10):3993-4023. 7. Rebel H, der Spek CD, Salvatori D, van Leeuwen JP, Robanus-Maandag EC, de Gruijl FR.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. Lucas RM, Ponsonby AL, Dear K, Valery PC, Pender MP, Taylor BV, Kilpatrick TJ, Dwyer T, Coulthard A, Chapman C, van der Mei I, Williams D, McMichael AJ. Sun exposure and vitamin D are independent risk factors for CNS demyelination. Neurology. 2011;76(6):540-8. 9. Zivadinov R, Treu CN, Weinstock-Guttman B, Turner C, Bergsland N, O'Connor K, Dwyer MG, Carl E, Ramasamy DP, Qu J, Ramanathan M. Interdependence and contributions of sun exposure and vitamin D to MRI measures in multiple sclerosis. J Neurol Neurosurg Psychiatry. 2013;84(10):1075-81. 10. Bjørnevik K, Riise T, Casetta I, Drulovic J, Granieri E, Holmøy T, Kampman MT, Landtblom AM, Lauer K, Lossius A, Magalhaes S, Myhr KM, Pekmezovic T, Wesnes K, Wolfson C, Pugliatti M. Sun exposure and multiple sclerosis risk in Norway and Italy: The EnvIMS study. Mult Scler. 2014;20(8):1042-1049. 11. Knippenberg S, Damoiseaux J, Bol Y, Hupperts R, Taylor BV, Ponsonby AL, Dwyer T, Simpson S, van der Mei IA. Higher levels of reported sun exposure, and not vitamin D status, are associated with less depressive symptoms and fatigue in multiple sclerosis. Acta Neurol Scand. 2014;129(2):123-31. 12. Liu D, Fernandez BO, Hamilton A, Lang NN, Gallagher JM, Newby DE, Feelisch M, Weller RB. UVA irradiation of human skin vasodilates arterial vasculature and lowers blood pressure independently of nitric oxide synthase. J Invest Dermatol. 2014;134(7):1839-46. 13. Engelsen O. The relationship between ultraviolet radiation exposure and vitamin D status. Nutrients. 2010;2(5):482-95.