Clinical Education Center
Vitamin D and Its Benefits Beyond Bone Health
The role of vitamin D in relation to bone health has been well established. There is also increasing evidence suggesting an association between vitamin D and a wide range of other health conditions, including cardiovascular disease, cancer and infectious disease.
Dr. Harvey Kaufman, Senior Medical Director, Quest Diagnostics, discusses our growing understanding of vitamin D and the rationale for vitamin D supplementation for the majority of Americans.
Vitamin D Measurement and Vitamin D Deficiency
When testing vitamin D levels the form typically measured is 25-hydroxyvitamin D [25-(OH)D], explains Dr. Kaufman. “The active form of vitamin D is 1,25 dihydroxyvitamin D [1,25(OH)2 D], but its concentration is around 1% of the 25-hydroxyvitamin D, so for practical reasons of measurement, and because it has a longer half-life than the 1,25-(OH)D, we measure 25-(OH)D.”
Vitamin D deficiency is generally defined as a level below 20 ng/mL.1 Another category, referred to as sub-optimal vitamin D or vitamin D insufficiency, applies to values between 20 ng/mL and 29 ng/mL.1
“One issue with these definitions is that they do not take into account seasonal variation,” notes Dr. Kaufman. “We have much higher vitamin D levels at the end of the summer and lower values at the end of the winter because more people go outside in the summertime and get exposed to the sun than in the winter. The difference between the peak and the low point is about 7 ng/mL, so that needs to be considered when interpreting a vitamin D test result.”
The Role of Vitamin D – Bone Health and Beyond
Historically, researchers and physicians have focused on bone disease, primarily osteoporosis, and in severe cases rickets, as the consequences of vitamin D deficiency.
“This is based on extensive scientific evidence,” says Dr. Kaufman, “but there are vitamin D receptors on virtually every cell in our body, which indicates that vitamin D plays a role well beyond that of bone health. In fact, there’s growing evidence to suggest vitamin D is essential to many functions in the body. Associations have been shown between sub-optimal and deficient levels of vitamin D and heart disease2-18, many cancers19-24, multiple sclerosis25-26, diabetes27-32, tuberculosis33, and even seasonal flu34-35.”
Vitamin D and Cardiovascular Disease
“Vitamin D deficiency has long been associated with incident cardiovascular disease in numerous retrospective studies,” notes Dr. Kaufman.2 “Several published reports suggest an association between low vitamin D levels and increased risk for acute myocardial infarction, stroke, heart failure, and overall cardiovascular disease.3,4,5
“Firstly, there are observations linking the degree of sun exposure to cardiovascular disease. People living closest to the Equator have lower rates of cardiovascular disease than people living further from the Equator, where there is a greater amount of ultraviolet-B light filtering.6 Even in similar areas, people living for extended periods of time at high altitudes, where solar ultraviolet-B exposure is higher, have lower rates of cardiovascular disease than people living for extended periods at lower altitudes.7 Also, cardiovascular disease is lowest in the summer than in the winter, when there is less ultraviolet-B light exposure. These different observations support an association among sun exposure, vitamin D levels, and incidence of cardiovascular disease,” concludes Dr. Kaufman.8,9
A Framingham Heart Study prospective study published in 2008 suggested that vitamin D deficiency is associated with increased cardiovascular disease risk above established risk factors.10 “This observation was most striking among study participants with hypertension,” says Dr. Kaufman. “Individuals with vitamin D levels <15 ng/mL had an associated two-fold increased risk of cardiovascular events. In two studies, vitamin D was measured at time of admission for myocardial infarction. Given the half-life of vitamin D of several weeks, the vitamin D level measured upon admission reflects pre-existing vitamin D levels.3,5 Low vitamin D levels correlated with myocardial infarctions. Another prospective study found higher cardiovascular mortality in patients on hemodialysis who had low vitamin D levels.11 A study of more than 10,000 Danes involved measuring vitamin D status in 1981-1983 and following participants for nearly 30 years.12 Participants with low levels of vitamin D, compared to participants in the top half of the distribution of vitamin D levels, had 40% higher risk of ischemic heart disease, 57% higher risk of early death, and 81% higher risk of death from heart disease.”
Dr. Kaufman explains how vitamin D affects the cardiovascular system:
“Vitamin D receptors are found in a wide spectrum of tissues, including vascular smooth muscle,13,14 endothelium,15 and cardiomyocytes.16 Vitamin D may promote cell differentiation and exhibit anti-inflammatory, propototic, and antiangiogenic effects. Further low levels of vitamin D have been associated with plasma renin levels,17 blood pressure, and coronary artery calcification.18,19 Maybe our focus on the vitamin D-calcium-parathyroid hormone axis has distracted us from other critical roles of vitamin D in our health, such as our cardiovascular system. It should be noted, however, that we have not yet established that correction of vitamin D deficiency reduces cardiovascular disease risk.20 Ongoing randomized studies may provide new light on this issue.”
There is, however, some evidence that correction of vitamin D deficiency is beneficial to cardiovascular disease health. A 2010 study from Intermountain Medical Center Heart Institute in Utah examined 9,400 patients with low levels of vitamin D.21 Approximately half of these patients raised their vitamin D concentration to >30 ng/mL. Those patients who raised their vitamin D concentration were 33% less likely to have a myocardial infarction and 20% less likely to have heart failure in the subsequent year than the patients who did not achieve optimal vitamin D levels, >30 ng/mL. Patients who raised their vitamin D levels to >43 ng/dL had the lowest incidence of heart disease and stroke. There was no benefit observed for the patients who raised their vitamin D levels to >60 ng/mL.
Limited prospective studies have even found the benefit of correcting vitamin D deficiency as related to lowering cardiovascular disease events.10 More studies are needed to gain a better understanding of the role of vitamin D in cardiovascular disease and the optimal level for vitamin D as it pertains to cardiovascular health.
Vitamin D and Cancer
There have also been studies indicating a possible relationship between vitamin D levels and cancer22-27.
“Over two decades ago data were presented showing a relationship between colon cancer and geography: those living in the northern United States had much higher rates of colon or rectal cancer than those living further south,”22 says Dr. Kaufman. “Since then, there have been dozens of studies showing relationships and associations between various types of common cancers—prostate cancer, breast cancer, bladder cancer—and vitamin D levels.22,23,24,25 There is no study that predicts that if you have a low level of vitamin D you're going to develop cancer, but there are many studies that have shown the associations. There are even studies showing that patients with optimal levels of vitamin D are more likely to recover from cancer than those who have deficient levels of vitamin D, which may relate to how our immune system functions.”26, 27
Associations With Other Diseases
A summary of some of the associations between vitamin D and other conditions is as follows:·
Multiple Sclerosis (MS)
The further one lives away from the Equator, the rate of MS incidence increases. It has also been shown that the intake of vitamin D from supplements is inversely associated with risk of MS and that there may be a protective effect of vitamin D intake on risk of developing MS.28,29
A child in Finland is around 400 times more likely to develop diabetes than a child living near the Equator.30,31 A study that looked at vitamin D levels in the first year of life and followed these children into adulthood found that those who were deficient early in life were much more likely to develop type 1 diabetes than those who had optimal levels of vitamin D.32,33 Other studies have provided evidence that an increase in circulating concentrations of 25(OH)D shows a delayed temporal association with leveling off of type 1 diabetes.34,35
Low vitamin D levels have been associated with a 5-fold increased risk for progression to tuberculosis.36
Work by researchers studying seasonal flu has suggested that levels of vitamin D may influence how the body's immune system responds when exposed to the influenza virus.37,38
Causes of Vitamin D Deficiency
There are multiple causes of vitamin D deficiency. These need to be identified and addressed before proceeding with therapy.
“One cause is malabsorption, which one needs to resolve before supplementing with vitamin D,” notes Dr. Kaufman. “If the cause is chronic kidney disease, one needs to make that diagnosis and potentially get a vitamin D analog because the final step in converting inactive to active vitamin D is facilitated through an enzyme made in the kidneys. If one has diminished kidney function, one can't manufacture enough of that enzyme to convert the inactive to the active form, so giving supplements isn't going to fix the problem. One needs either to treat the kidneys or give an analog to bypass that step.
“But for the vast majority of us, vitamin D deficiency is a result of our bodies not producing enough vitamin D. One way to make more vitamin D is to get sunshine, but for those who live in the northern part of the country it's hard to get sufficient sunlight with the right ultraviolet B frequencies in the fall and winter. Even those in southern states may not get sufficient sun exposure if they don’t go outside much or of if their skin is covered by clothing or sunscreen,” explains Dr. Kaufman.
Vitamin D Supplementation
Due to lack of sun exposure, almost everybody needs to take a daily vitamin D supplement, says Dr. Kaufman.
“You can't get enough in your diet. Even though milk and other products are fortified with vitamin D, they do not contain enough to achieve the recommended vitamin D level. In November 2010 the Institute of Medicine revised their guidance for the daily intake of vitamin D.39 For adults the recommended dietary allowance is 600 international units per day (IU/day), which is significantly above the amount in traditional supplements. In fact, those who are severely deficient may need to receive prescription-strength vitamin D to bring them up to a more suitable level quicker.”
While guidelines do not address monitoring vitamin D levels for those treated for vitamin D deficiency, Dr. Kaufman suggests it may be appropriate to monitor periodically, such as once per year.
“Using data from the Quest Diagnostics Blueprint for Wellness® program, which is a wellness program that we offer to hundreds of employers, one of the questions we asked is, ‘Are you taking vitamin D supplements?’, and of those who said yes, 10% still had a deficient level of vitamin D. Suggesting that even though they're taking supplements, they may not be taking enough or may not have been taking it long enough.”
There is a very low risk to vitamin D supplementation, as it is very hard to reach a level that is toxic. The Institute of Medicine indicates that only once intake goes above 4,000 IU/day does the risk of harm begin to increase.
“In fact,” concludes Dr. Kaufman, “there is no reason the majority of us in the United States should not be taking a vitamin D supplement, given the potentially significant health benefits it may provide.”
- Evaluation, Treatment, and Prevention of Vitamin D Deficiency: An Endocrine Society Clinical Practice Guideline. J Clin Endocr Metab. July 2011, 96(7): 1911–1930. http://www.endocrine.org/~/media/endosociety/Files/Publications/Clinical%20Practice%20Guidelines/FINAL-Standalone-Vitamin-D-Guideline.pdf. Accessed January 5, 2016.
- Zittermann A, Schleithoff SS, Koerfer R. Putting cardiovascular disease and vitamin D insufficiency into perspective. Br J Nutr. 2005;94:483-92.
- Scragg R, Jackson R, Holdaway IM, Lim T, et al. Myocardial infarction is inversely associated with plasma 25-hydroxyvitamin D3 levels: a community-based study. Int J Epidemiol. 1990;19:559-63.
- Zittermann A, Schleithoff SS, Tenderich G, Berthold HK, Korfer R, Stehle P. Low vitamin D status: a contributing factor in the pathogenesis of congestive heart failure? J Am Coll Cardiol. 2003;41:105-12.
- Poole KE, Loveridge N, Barker PJ, Halsall DJ, Rose C, et al. Reduced vitamin D in acute status. Stroke. 2006;37:243-45.
- Fleck A. Latitude and ischemic heart disease. Lancet. 1989;1:613.
- Voors AW, Johnson WD. Altitude and arterosclerotic heart disease mortality in white residents of 99 of the 100 largest cities in the United States. J Chronic Dis. 1979;32:157-62.
- Grimes DS, Hindle E, Dyer T. Sunlight, cholesterol and coronary heart disease. QJM. 1996;89:579-89.
- Rostand SG. Ultraviolet light may contribute to geographic and racial blood pressure differences. Hypertension. 1997;30:150-56.
- Wang TJ, Pencina MJ, Booth SL, Jacques PF, et al. Vitamin D deficiency and risk of cardiovascular disease. Circulation. 2008;117:503-11.
- Wolf M, Shah A, Guitierrez O, Ankers E, Monroy M, et al. Vitamin D levels and early mortality among incident hemodialysis patients. Kidney Int. 2007;72:1004-13.
- Brondum-Jacobsen P, Benn M, Jensen GB, Nordesgaard BG. 25-hydroxyvitamin D levsls and risk of ischemic heart disease, myocardial infarction, and early death: population-based study and meta-analysis of 18 and 17 studies. Arterioscl Thrombosis Vasc Biology. 2012;DOI:10.1161/ATVBAHA.112.248039.
- Merke J, Hoffman W, Goldschmidt D, Ritz E. Demonstration of 1,25(OH)2 vitamin D3 receptors and actions vascular smooth muscle cell in vitro. Calcif Tissue Int. 1987;42:112-14.
- Somjen D, Weisman Y, Kohen F, Gayer B, Limor R, Sharon O, Jaccard N, Knoll E, Stern N. 25-Hydroxyvitamin D3-1-alpha-hydroxylase is expressed in human vascular smooth muscle cells and is upregulated by parathyroid hormone and estrogenic compounds. Circulation. 2005;111:1666-71.
- Merke J, Milde P, Lewicka S, et al. Identification and regulation of 1,25-dihydroxyvitamin D3 receptor activity and biosynthesis of 1,25-dihydroxyvitamin D3: studies in cultured bovine aortic endothelial cells and human dermal capillaries. J Clin Invest. 1989;83:1903-15.
- O’Connell TD, Berry JE, Jarvis AK. Somerman MJ, Simpson RU. 1,25-Dihydroxyvitamin D3 regulation of cardiac myocyte proliferation and hypertrophy. Am J Physiol. 1997;272:H1751-58.
- Li YC, Kong J, Wei M, Chen ZF, et al. Dihydroxyvitamin D(#) is a negative endocrine regulator of the renin-angiotensin system. J Clin Invest. 2002;110:229-38.
- Watson KE, Abrolat ML, Malone LL, Hoeg JM, et al. Active serum vitamin D levels are inversely correlated with coronary calcification. Circulation. 1997;96:1755-60.
- Doherty TM, Tang W, Dascalos S, Watson KE, et al. Ethnic origin and serum levels of 1-alpha-25-dihydroxyvitamin D3 are independent predictors of coronary calcium mass measured by electron-beam computed tomography. Circulation. 1997;96:1477-81.
- Ponda MP, Huang X, Odeh MA, Breslow JL, Kaufman HW. Vitamin D may not improve lipid levels: a serial clinical laboratory data study. Circulation. 2012;126:3 270-277.
- Muhlestein JB, Lundberg G, Lichtenstein A. American College of Cardiology’s 59th Annual Scientific Session, Atlanta, GA. March 14-16, 2010.
- Lipkin M, Newmark HL, Kelloff G. Calcium, Vitamin D and Prevention of Colon Cancer. Proceedings of a workshop sponsored by the Chemoprevention Branch of the National Cancer Institute. 1991 CRC Press. https://books.google.ch/books?id=-XIWzAYXqKoC&pg=PA82&lpg=PA82&dq=association+of+colon+cancer+and+geography&source=bl&ots=O2zpUW0JLH&sig=qgoRGEv_EDnrIRaCDVE1mqkK8xo&hl=en&sa=X&ved=0ahUKEwi_n627iJDKAhUE8XIKHbguBnIQ6AEIWjAJ#v=onepage&q=association%20of%20colon%20cancer%20and%20geography&f=false. Accessed on January 5, 2016.
- Ma Y, Zhang P, Wang F, et al. Association between vitamin D and risk of colorectal cancer: a systematic review of prospective studies. Journal of Clinical Oncology. 2011;29(28):3775-3782.
- Gandini S, Boniol M, Haukka J, et al. Meta-analysis of observational studies of serum 25-hydroxyvitamin D levels and colorectal, breast and prostate cancer and colorectal adenoma. International Journal of Cancer.2011;128(6):1414-1424
- Vitamin D and Cancer Prevention. National Cancer Institute.http://www.cancer.gov/about-cancer/causes-prevention/risk/diet/vitamin-d-fact-sheet#q2.Accessed on January 5, 2016.
- Tretli S, Schwartz GG, Torjesen PA, Robsahm TE. Serum levels of 25-hydroxyvitamin D and survival in Norwegian patients with cancer of breast, colon, lung, and lymphoma: a population-based study.Cancer Causes Control. 2012 Feb;23(2):363-70. doi: 10.1007/s10552-011-9885-6. Epub 2011 Dec 23.
- Mian Li, Peizhan Chen, Jingquan Li, Ruiai Chu, Dong Xie, and Hui Wang Review: The Impacts of Circulating 25-Hydroxyvitamin D Levels on Cancer Patient Outcomes: A Systematic Review and Meta-Analysis. J Clin Endocrinol Metab.2014;99(7):2327–2336http://press.endocrine.org/doi/pdf/10.1210/jc.2013-4320.Accessed January 5, 2016.
- Munger KL, Zhang SM, O'Reilly E et al.Vitamin D intake and incidence of multiple sclerosis.Neurology. 2004 Jan 13;62(1):60-5.
- Summerday NM, Brown SJ, Allington DR, Rivey MP. Vitamin D and multiple sclerosis: review of a possible association.J Pharm Pract. 2012 Feb;25(1):75-84. doi: 10.1177/0897190011421839.
- Rostand SG. Ultraviolet light may contribute to geographic and racial blood pressure differences.Hypertension. 1997;30:150–6.
- Karvonen M, Viik-Kajander M, Moltchanova E, Libman I, LaPorte R, Tuomilehto J. Incidence of childhood type 1 diabetes worldwide. Diabetes Mondiale (DiaMond) Project Group.Diabetes Care. 2000 Oct;23(10):1516-26.
- Hyppönen E, Läärä E, Reunanen A, Järvelin MR, Virtanen SM. Intake of vitamin D and risk of type 1 diabetes: a birth-cohort study. Lancet. 2001;358:1500–3.
- Vitamin D and diabetes C. Mathieu, C. Gysemans Av Diabetol. 2006; 22(3): 187-193.
- Dong J-Y, Zhang W, Chen JJ, Zhang Z, Han S, and Qin L.Vitamin D Intake and Risk of Type 1 Diabetes: A Meta-Analysis of Observational Studies.Nutrients. 2013 Sep; 5(9): 3551–3562.Published online 2013 Sep 12. doi: 10.3390/nu5093551.
- Mäkinen M, Simell V, Mykkänen J, Ilonen J et al.An increase in serum 25-hydroxyvitamin D concentrations preceded a plateau in type 1 diabetes incidence in Finnish children.J Clin Endocrinol Metab. 2014 ;99(11):E2353-6. doi:10.1210/jc.2014-1455. Epub 2014 Jul 25.
- Talat N, Perry S, Parsonnet J, Dawood G, and Hussain R. Vitamin D Deficiency and Tuberculosis Progression. Emerg Infect Dis.2010; 16(5): 853–855.
- Urashima M, Segawa T, Okazaki M, Kurihara M, Wada Y and Ida H. Randomized trial of vitamin D supplementation to prevent seasonal influenza A in schoolchildren. Am J Clin Nutr. 2010;91(5):1255-60. doi: 10.3945/ajcn.2009.29094. Epub 2010 Mar 10.
- Aranow C.Vitamin D and the Immune System.J Investig Med.2011; 59(6): 881–886.
- Dietary Reference Intakes for Calcium and Vitamin D. Institute of Medicine of the National Academies.http://iom.nationalacademies.org/Reports/2010/Dietary-Reference-Intakes-for-Calcium-and-Vitamin-D.aspx. Accessed January 5, 2016.