November 16, 2012; Revised April 3, 2013; August 16, 2013
Is 50 ng of vitamin D too high, just right, or not enough
30 to 50 ng of vitamin D is optimal – Central Europe consensus Sept 2013
Chart of Vitamin D levels vs disease - Grassroots Health June 2013
Defining normal level of vitamin D (need 4000-5000 IU) - Heaney Spring 2013
Elite outdoor athletes had 52 ng of vitamin D – March 2013
Many sleep disorders cured with vitamin D levels of 60 to 80 nanograms – May 2012
More than 30 ng of vitamin D probably needed for long-latency diseases – Aug 2012
Need 40 to 80 ng of vitamin D to lose weight – Colgan Sept 2013
Need at least 80 ng of vitamin D if have chronic kidney disease – May 2012
Noticed bones heal faster when more than 60 ng of vitamin D
Polish conference recommended vitamin D levels from 30 to 60 ng – Oct 2012
Populations with more than 50 ng of vitamin D
Traditionally living Africans have 46 ng vitamin D levels – Jan 2012
Update on Treating Multiple Sclerosis with high dose vitamin D - Sept 2013
Vitamin D Insufficiency is less than 32 or 40 ng – Heaney 2012
Vitamin D of 32 to 60 ng is needed before, during, and after pregnancy – Dec 2012
Vitamin D provides many benefits and is cost-effective (need 32-40 ng) – Summer 2013
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 [Bischoff-Ferrari, 2006, 2008; Holick, 2011; Miller, 2011; Pérez-López, 2012; Souberbielle, 2010; Vieth, 2011].
The Institute of Medicine recommended 20 ng/ml in part since they accepted only randomized controlled trials (RCTs), and then, only for fractures [Ross, 2011]. 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 drugs [Biesalski et al., 2011; Hickey and Roberts, 2011], 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 [Grant, 2011a, 2012a].
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:
- Arterial calcification [Naves-Diaz, 2013]
- Asthma severity [Majak, 2012]
- Athletic performance [Larson-Meyer, 2010, 2013; Udowenko, 2010]
- Blood pressure [Larsen, 2012]
- Bones, fractures [Bonnot, 2011; Carmel, 2012; Dawson-Hughes, 2012; Rizzoli, 2013; von Domarus, 2011]
- Breast cancer from case-control studies [Abbas, 2008, 2008; Bilinski and Boyages, 2012; Crew, 2009; Fedirko, 2012; Grant, 2010, 2012b; Lowe, 2005]
- Breast cancer survival [Bauer, 2013; Hatse, 2012; Tretli, 2012]
- Cardiovascular disease [Anderson, 2010; Brøndum-Jacobsen, 2012; Kim, 2008; Liu, 2012; Riek, 2012; Vacek, 2012; Wang, 2012]
- Cognitive decline [Slinin, 2012; Soni, 2012]
- Colorectal cancer from case-control and cohort studies [Grant, 2010]
- Cystic fibrosis [Tangpricha, 2012]
- Dental caries [Grant, 2012; Schroth, 2012]
- Diabetes mellitus [González-Molero, 2012; Pittas, 2012]
- Function [Sohl, 2013]
- Immune status [Dixon, 2012]
- Insulin resistance [Heaney, 2013; Kelly, 2011; von Hurst, 2010]
- Metabolic syndrome [Pacifico, 2011]
- Mobility limitation, disability [Houston, 2012]
- Mortality rate, all-cause [Schöttker, 2013; Signorello, 2012; Zittermann, 2012; ]
- Multiple sclerosis [Holmøy, 2012]
- Osteoarthritis of the hip [Chaganti, 2010]
- Physical performance [Wicherts, 2007]
- Pregnancy outcomes [Bodnar, 2007, 2009, 2010, 2013; Merewood, 2007; Principi, 2012; Whitehouse, 2012]
- Quality of life [Ecemis, 2013]
- Respiratory infections [Ginde, 2009; Science, 2013]
- Review [Battault, 2012; Bischoff-Ferrari, 2010; Holick, 2011; Hossein-Nezhad, 2013; Pludowski, 2013; Souberbielle, 2010]
- Tuberculosis [Nnoaham, 2008]
- Athletic performance [Larson-Meyer, 2013]
- Bones [Binkley, 2012; Prieto-Alhambra, 2012]
- Cancer [Lappe, 2007]
- Chronic kidney disease [Kramer, 2012]
- Crohn’s disease [Yang, 2013]
- Depression [Jaddou, 2012]
- Infections, hospital [Quraishi, 2013]
- Multiple sclerosis [Pierrot-Deseilligny, 2012]
- PTH [Lu, 2012; Valcour, 2012]
- Pregnancy [Hollis, 2011; Hollis and Wagner, 2011; Morales, 2012]
- Respiratory infections, acute [Sabetta, 2010]
- Review [Grant, 2011b]
- Systemic lupus erythematosus [Petri, 2013]
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 [Durup, 2012]. 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 men [Ensrud, 2011] but a U-shaped relation for women [Ensrud, 2010]. 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.
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- 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.
- 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.
- Battault S, Whiting SJ, Peltier SL, Sadrin S, Gerber G, Maixent JM. Vitamin D metabolism, functions and needs: from science to health claims. Eur J Nutr. 2013 Mar;52(2):429-41
- Bauer SR, Hankinson SE, Bertone-Johnson ER, Ding EL. Plasma Vitamin D Levels, Menopause, and Risk of Breast Cancer: Dose-Response Meta-Analysis of Prospective Studies. Medicine (Baltimore). 2013 May;92(3):123-31.
- Biesalski HK, Aggett PJ, Anton R, Bernstein PS, Blumberg J, Heaney RP, Henry J, Nolan JM, Richardson DP, van Ommen B, Witkamp RF, Rijkers GT, Zöllner I. 26th Hohenheim Consensus Conference, September 11, 2010 Scientific substantiation of health claims: evidence-based nutrition. Nutrition. 2011 Oct;27(10 Suppl):S1-20.
- Bilinski K, Boyages J. Association between 25-hydroxyvitamin D concentration and breast cancer risk in an Australian population: an observational case-control study. Breast Cancer Res Treat. 2013;137(2):599-607.
- Binkley N, Lewiecki EM. Vitamin D and common sense. J Clin Densitom. 2011 Apr-Jun;14(2):95-9.
- 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.
- Bischoff-Ferrari HA, Shao A, Dawson-Hughes B, Hathcock J, Giovannucci E, Willett WC. Benefit-risk assessment of vitamin D supplementation. Osteoporos Int. 2010 Jul;21(7):1121-32.
- Bischoff-Ferrari HA. Optimal serum 25-hydroxyvitamin D levels for multiple health outcomes. Adv Exp Med Biol. 2008;624:55-71.
- 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.
- 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.
- 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.
- Bodnar LM, Rouse DJ, Momirova V, Peaceman AM, Sciscione A, Spong CY, Varner MW, Malone FD, Iams JD, Mercer BM, Thorp JM Jr, Sorokin Y, Carpenter MW, Lo J, Ramin SM, Harper M; for the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) Maternal-Fetal Medicine Units (MFMU) Network. Maternal 25-Hydroxyvitamin D and Preterm Birth in Twin Gestations. Obstet Gynecol. 2013 Jun 5. [Epub ahead of print]
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- Brøndum-Jacobsen P, Nordestgaard BG, Schnohr P, Benn M. 25-Hydroxyvitamin D and symptomatic ischemic stroke: An original study and meta-analysis. Ann Neurol. 2013 Jan;73(1):38-47.
- Carmel AS, Shieh A, Bang H, Bockman RS. The 25(OH)D level needed to maintain a favorable bisphosphonate response is ≥33 ng/ml. Osteoporos Int. 2012 Oct;23(10):2479-87.
- 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.
- 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.
- Dawson-Hughes B. What is the optimal dietary intake of vitamin D for reducing fracture risk? Calcif Tissue Int. 2013 Feb;92(2):184-90.
- Dixon BM, Barker T, McKinnon T, Cuomo J, Frei B, Borregaard N, Gombart AF. Positive correlation between circulating cathelicidin antimicrobial peptide (hCAP18/LL-37) and 25-hydroxyvitamin D levels in healthy adults. BMC Res Notes. 2012 Oct 24;5:575.
- 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.
- Ecemis GC, Atmaca A. Quality of life is impaired not only in vitamin D deficient but also in vitamin D insufficient premenopausal women. J Endocrinol Invest. 2013 Mar 19. [Epub ahead of print]
- 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.
- 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.
- 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.
- 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.
- 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.
- Grant WB. (2010) 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.
- Grant WB. (2011a) 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.
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- Grant WB. (2012a) 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.
- Grant WB. (2012b) A review of the evidence regarding the solar ultraviolet-B–vitamin D–cancer hypothesis. Standardy Medyczne/Pediatria. 2012;9:610-9.
- Grant WB. A review of the role of solar ultraviolet-B irradiance and vitamin D in reducing risk of dental caries. Dermatoendocrinol. 2011 Jul;3(3):193-8.
- Hatse S, Lambrechts D, Verstuyf A, Smeets A, Brouwers B, Vandorpe T, Brouckaert O, Peuteman G, Laenen A, Verlinden L, Kriebitzsch C, Dieudonné AS, Paridaens R, Neven P, Christiaens MR, Bouillon R, Wildiers H. Vitamin D status at breast cancer diagnosis: correlation with tumor characteristics, disease outcome and genetic determinants of vitamin D insufficiency. Carcinogenesis. 2012 Jul;33(7):1319-26.
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- 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.
- Hollis BW, Wagner CL. Vitamin D requirements and supplementation during pregnancy. Curr Opin Endocrinol Diabetes Obes. 2011 Dec;18(6):371-5.
- Holmøy T, Kampman MT, Smolders J. Vitamin D in multiple sclerosis: implications for assessment and treatment. Expert Rev Neurother. 2012 Sep;12(9):1101-12.
- Hong Z, Tian C, Zhang X. Dietary calcium intake, vitamin D levels, and breast cancer risk: a dose-response analysis of observational studies. Breast Cancer Res Treat. 2012 Nov;136(1):309-12.
- Hossein-Nezhad A, Holick MF. Vitamin D for Health: A Global Perspective. Mayo Clin Proc. 2013;88(7):720-55.
- Houston DK, Neiberg RH, Tooze JA, Hausman DB, Johnson MA, Cauley JA, Bauer DC, Shea MK, Schwartz GG, Williamson JD, Harris TB, Kritchevsky SB; for the Health ABC Study. Low 25-hydroxyvitamin D predicts the onset of mobility limitation and disability in community-dwelling older adults: The Health ABC Study. J Gerontol A Biol Sci Med Sci. 2013 Feb;68(2):181-187
- Jaddou HY, Batieha AM, Khader YS, Kanaan SH, El-Khateeb MS, Ajlouni KM. Depression is associated with low levels of 25-hydroxyvitamin D among Jordanian adults: results from a national population survey. Eur Arch Psychiatry Clin Neurosci. 2012 Jun;262(4):321-7.
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