From my review of the journal literature, 30 ng/ml is the minimum 25(OH)D concentration associated with optimal health. This value has been reported for pregnancy outcomes, breast cancer in case-control studies, colorectal cancer in case-control and cohort studies, cardiovascular disease, all-cause mortality rate, and agreed to in several reviews.1, 2, 3, 4, 5, 6, 7
The Institute of Medicine recommended 20 ng/ml in part since they accepted only randomized controlled trials (RCTs), and then, only for fractures.8 They were using the tenets of “evidence based medicine,” which puts meta-analyses of RCTs as the strongest evidence. That approach may or may not be appropriate for pharmaceutical drugs9, but is not appropriate for vitamin D, which is not a drug, but a molecule largely derived from the interaction of solar ultraviolet-B (UVB) irradiance on 7-dehydrocholesterol in the skin. Thus, observational and ecological studies can provide much of the evidence.
One of the problems with nested case-control studies with long follow-up times is that serum 25(OH)D concentration changes with time, so the longer the follow-up time, the lower the beneficial effect found for 25(OH)D as I’ve demonstrated in two recent papers.10, 11
A problem with cross-sectional studies is that the disease state may influence the serum 25(OH)D concentration, for example, by making the person more likely to stay indoors.
The papers listed below provide some of the evidence, based primarily on observational studies with some cross-sectional studies and RCTs, for the minimum optimal serum 25(OH)D concentration is 30 ng/ml:
- Breast cancer from case-control studies12, 13, 14, 15, 16, 17, 18
- Cognitive decline19
- Colorectal cancer from case-control and cohort studies20
- Cardiovascular disease21, 22, 23, 24, 25
- Diabetes mellitus26, 27
- Metabolic syndrome28
- Mortality rate, all-cause29
- Osteoarthritis of the hip30
- Physical performance31
- Pregnancy32, 33, 34, 35
- Respiratory infections36
There is also evidence for beneficial effects near or above 40 ng/ml from RCTs and an observational study:
- Pregnancy38, 39
- Respiratory infections, acute40
There are few data for health outcomes above 50 ng/ml. The U-shaped 25(OH)D concentration-health outcomes showing generally do not report statistically significant findings. Other such findings are not supported by other studies for the same outcome, such as pancreatic and prostate cancer. There is one recent study from Denmark showing a J-shaped serum 25(OH)D concentration-all-cause mortality rate relation.41 In my opinion, that finding was due to older people being informed that they had a vitamin D deficiency, perhaps due to a diagnosis of osteoporosis, and being advised to take vitamin D supplements.
In support of this hypothesis, I note that two studies of frailty among elderly Americans determined four years after serum 25(OH)D concentration measurement found a linear inverse relation between frailty status and serum 25(OH)D concentration for men42 but a U-shaped relation for women.43 In the United States, women are much more likely to be diagnosed with osteoporosis and then be told to take vitamin D supplements than are men. As mentioned by Dr. Hypponen, there does not appear to be a mechanism to explain why serum 25(OH)D concentrations between, say, 50 ng/ml and 100 ng/ml, should be associated with increased risk of disease.
1. Bischoff-Ferrari HA, Giovannucci E, Willett WC, Dietrich T, Dawson-Hughes B. Estimation of optimal serum concentrations of 25-hydroxyvitamin D for multiple health outcomes. Am J Clin Nutr. 2006 Jul;84(1):18-28. Review. Erratum in: Am J Clin Nutr. 2006 Nov;84(5):1253.
2. Bischoff-Ferrari HA. Optimal serum 25-hydroxyvitamin D levels for multiple health outcomes. Adv Exp Med Biol. 2008;624:55-71.
3. Holick MF, Binkley NC, Bischoff-Ferrari HA, Gordon CM, Hanley DA, Heaney RP, Murad MH, Weaver CM. Evaluation, treatment, and prevention of vitamin D deficiency: an Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab, 2011 Jul;96(7):1911-30.
4. Miller PD. Vitamin D, calcium, and cardiovascular mortality: a perspective from a plenary lecture given at the annual meeting of the American Association of Clinical Endocrinologists. Endocr Pract. 2011 Sep-Oct;17(5):798-806.
5. Pérez-López FR, Brincat M, Erel CT, Tremollieres F, Gambacciani M, Lambrinoudaki I, Moen MH, Schenck-Gustafsson K, Vujovic S, Rozenberg S, Rees M. EMAS position statement: Vitamin D and postmenopausal health. Maturitas. 2012 Jan;71(1):83-8.
6. Souberbielle JC, Body JJ, Lappe JM, Plebani M, Shoenfeld Y, Wang TJ, Bischoff-Ferrari HA, Cavalier E, Ebeling PR, Fardellone P, Gandini S, Gruson D, Guérin AP, Heickendorff L, Hollis BW, Ish-Shalom S, Jean G, von Landenberg P, Largura A, Olsson T, Pierrot-Deseilligny C, Pilz S, Tincani A, Valcour A, Zittermann A. Vitamin D and musculoskeletal health, cardiovascular disease, autoimmunity and cancer: Recommendations for clinical practice. Autoimmun Rev. 2010 Sep;9(11):709-15.
7. Vieth R. Why the minimum desirable serum 25-hydroxyvitamin D level should be 75 nmol/L (30 ng/ml). Best Pract Res Clin Endocrinol Metab. 2011 Aug;25(4):681-91.
8. Ross AC, Manson JE, Abrams SA, Aloia JF, Brannon PM, Clinton SK, Durazo-Arvizu RA, Gallagher JC, Gallo RL, Jones G, Kovacs CS, Mayne ST, Rosen CJ, Shapses SA. The 2011 report on dietary reference intakes for calcium and vitamin D from the Institute of Medicine: what clinicians need to know. J Clin Endocrinol Metab. 2011 Jan;96(1):53-8.
9. Hickey S, Roberts H. Tarnished Gold, the Sickness of Evidence Based Medicine. 2011
10. 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(3):199-204.
11. Grant WB. Effect of follow-up time on the relation between prediagnostic serum 25-hydroxyitamin D and all-cause mortality rate. Dermatoendocrinol. 2012;4(2):198-202.
12. Abbas S, Linseisen J, Slanger T, Kropp S, Mutschelknauss E, Flesch-Janys D, Chang-Claude J. Serum 25-hydroxyvitamin D and risk of postmenopausal breast cancer – results of a large case-control study. Carcinogenesis. 2008 Jan;29(1):93-9.
13. Abbas S, Chang-Claude J, Linseisen J. Plasma 25-hydroxyvitamin D and premenopausal breast cancer risk in a German case-control study. Int J Cancer. 2009 Jan 1;124(1):250-5.
14. Crew KD, Gammon MD, Steck SE, Hershman DL, Cremers S, Dworakowski E, Shane E, Terry MB, Desai M, Teitelbaum SL, Neugut AI, Santella RM. Association between plasma 25-hydroxyvitamin D and breast cancer risk. Cancer Prev Res (Phila Pa). 2009 Jun;2(6):598-604.
15. Fedirko V, Torres-Mejía G, Ortega-Olvera C, Biessy C, Angeles-Llerenas A, Lazcano-Ponce E, Saldaña-Quiroz VA, Romieu I. Serum 25-hydroxyvitamin D and risk of breast cancer: results of a large population-based case-control study in Mexican women. Cancer Causes Control. 2012;23(7): 1149-1162.
16. Grant WB. Relation between prediagnostic serum 25-hydroxyvitamin D level and incidence of breast, colorectal, and other cancers. J Photochem Photobiol B, 2010;101(2):130–6.
17. Grant WB. A review of the evidence regarding the solar ultraviolet-B–vitamin D–cancer hypothesis. Standardy Medyczne/Pediatria. 2012;9:610-9.
18. Lowe LC, Guy M, Mansi JL, Peckitt C, Bliss J, Wilson RG, Colston KW. Plasma 25-hydroxy vitamin D concentrations, vitamin D receptor genotype and breast cancer risk in a UK Caucasian population. Eur J Cancer. 2005 May;41(8):1164-9.
19. Slinin Y, Paudel M, Taylor BC, Ishani A, Rossom R, Yaffe K, Blackwell T, Lui LY, Hochberg M, Ensrud KE; Study of Osteoporotic Fractures Research Group. Association between serum 25(OH) vitamin D and the risk of cognitive decline in older women. J Gerontol A Biol Sci Med Sci. 2012 Oct;67(10):1092-8.
20. Grant WB. An estimate of the global reduction in mortality rates through doubling vitamin D levels. Eur J Clin Nutr. 2011 September;65(9):1016-26.
21. Anderson JL, May HT, Horne BD, Bair TL, Hall NL, Carlquist JF, Lappé DL, Muhlestein JB; Intermountain Heart Collaborative (IHC) Study Group. Relation of vitamin D deficiency to cardiovascular risk factors, disease status, and incident events in a general healthcare population. Am J Cardiol. 2010 Oct 1;106(7):963-8.
22. Kim DH, Sabour S, Sagar UN, Adams S, Whellan DJ. Prevalence of hypovitaminosis D in cardiovascular diseases (from the National Health and Nutrition Examination Survey 2001 to 2004). Am J Cardiol. 2008 Dec 1;102(11):1540-4.
23. Liu L, Chen M, Hankins SR, Nùñez AE, Watson RA, Weinstock PJ, Newschaffer CJ, Eisen HJ; Drexel Cardiovascular Health Collaborative Education, Research, and Evaluation Group. Serum 25-hydroxyvitamin D concentration and mortality from heart failure and cardiovascular disease, and premature mortality from all-cause in United States adults. Am J Cardiol. 2012 Sep 15;110(6):834-9.
24. Riek AE, Sprague JE, Timpson A, de las Fuentes L, Bernal-Mizrachi L, Schechtman KB, Bernal-Mizrachi C. Vitamin D suppression of endoplasmic reticulum stress promotes an anti-atherogenic monocyte/macrophage phenotype in type 2 diabetic patients. Journal of Biological Chemistry vol. 2011;287 (46):38482-38494.
25. Wang L, Song Y, Manson JE, Pilz S, März W, Michaëlsson K, Lundqvist A, Jassal SK, Barrett-Connor E, Zhang C, Eaton CB, May HT, Anderson JL, Sesso HD. Circulating 25-Hydroxy-Vitamin D and Risk of Cardiovascular Disease: A Meta-Analysis of Prospective Studies. Circ Cardiovasc Qual Outcomes. 2012 Nov 13. [Epub ahead of print]
26. González-Molero I, Rojo-Martínez G, Morcillo S, Gutiérrez-Repiso C, Rubio-Martín E, Almaraz MC, Olveira G, Soriguer F. Vitamin D and incidence of diabetes: a prospective cohort study. Clin Nutr. 2012 Aug;31(4):571-3.
27. Pittas AG, Nelson J, Mitri J, Hillmann W, Garganta C, Nathan DM, Hu FB, Dawson-Hughes B; Diabetes Prevention Program Research Group. Plasma 25-hydroxyvitamin D and progression to diabetes in patients at risk for diabetes: an ancillary analysis in the Diabetes Prevention Program. Diabetes Care. 2012 Mar;35(3):565-73.
28. Pacifico L, Anania C, Osborn JF, Ferraro F, Bonci E, Olivero E, Chiesa C. Low 25(OH)D3 levels are associated with total adiposity, metabolic syndrome, and hypertension in Caucasian children and adolescents. Eur J Endocrinol. 2011 Oct;165(4):603-11.
29. 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(1):91-100.
30. Chaganti RK, Parimi N, Cawthon P, Dam TL, Nevitt MC, Lane NE. Association of 25-hydroxyvitamin D with prevalent osteoarthritis of the hip in elderly men: the osteoporotic fractures in men study. Arthritis Rheum. 2010 Feb;62(2):511-4.
31. Wicherts IS, van Schoor NM, Boeke AJ, Visser M, Deeg DJ, Smit J, Knol DL, Lips P. Vitamin D status predicts physical performance and its decline in older persons. J Clin Endocrinol Metab. 2007 Jun;92(6):2058-65.
32. Bodnar LM, Catov JM, Simhan HN, Holick MF, Powers RW, Roberts JM. Maternal vitamin D deficiency increases the risk of preeclampsia. J Clin Endocrinol Metab. 2007;92:3517–3522.
33. Bodnar LM, Krohn MA, Simhan HN. Maternal vitamin D deficiency is associated with bacterial vaginosis in the first trimester of pregnancy. J Nutr. 2009;139:1157–1161.
34. Bodnar LM, Catov JM, Zmuda JM, Cooper ME, Parrott MS, Roberts JM, et al. Maternal serum 25-hydroxyvitamin D concentrations are associated with small-for-gestational age births in white women. J Nutr. 2010;140:999–1006.
35. Merewood A, Mehta SD, Chen TC, Bauchner H, Holick MF. Association between vitamin D deficiency and primary cesarean section. J Clin Endocrinol Metab. 2009;94:940–945.
36. Ginde AA, Mansbach JM, Camargo CA Jr. Association between serum 25-hydroxyvitamin D level and upper respiratory tract infection in the Third National Health and Nutrition Examination Survey. Arch Intern Med. 2009 Feb 23;169(4):384-90.
37. Lappe JM, Travers-Gustafson D, Davies KM, Recker RR, Heaney RP. Vitamin D and calcium supplementation reduces cancer risk: results of a randomized trial. Am J Clin Nutr. 2007 Jun;85(6):1586-91.
38. Hollis BW, Johnson D, Hulsey TC, Ebeling M, Wagner CL. Vitamin D supplementation during pregnancy: double-blind, randomized clinical trial of safety and effectiveness. J Bone Miner Res. 2011 Oct;26(10):2341-57.
39. Morales E, Guxens M, Llop S, Rodríguez-Bernal CL, Tardón A, Riaño I, Ibarluzea J, Lertxundi N, Espada M, Rodriguez A, Sunyer J; on behalf of the INMA Project. Circulating 25-Hydroxyvitamin D3 in Pregnancy and Infant Neuropsychological Development. Pediatrics. 2012 Oct;130(4):e913-e920.
40. Sabetta JR, DePetrillo P, Cipriani RJ, Smardin J, Burns LA, Landry ML. Serum 25-hydroxyvitamin D and the incidence of acute viral respiratory tract infections in healthy adults. PLoS One. 2010 Jun 14;5(6):e11088.
41. 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 Aug;97(8):2644-52.
42. 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 Jan;59(1):101-6.
43. 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 Dec;95(12):5266-73.