Health Care Professional Information

Scientific Name
Calciferol, ergocalciferol (D2), calcitriol, cholecalciferol (D3)
Clinical Summary

Vitamin D refers to several forms of fat-soluble vitamins found naturally in plants, fish, and dairy products. The two forms utilized in humans are ergocalciferol (D2) and the more potent cholecalciferol (D3). Sunlight can promote the synthesis of D3 in the skin. Vitamin D maintains serum calcium and phosphorus levels by regulating their absorption and excretion. It is also important for bone formation; deficiency can cause rickets and other bone disorders. Other biologic functions include its role as a potent antiproliferative agent and as a pro-differentiation hormone (1) (2).

Vitamin D was shown to have a beneficial effect on bone mineral density and the prevention of bone fractures in the elderly (3) (4) and in postmenopausal women (38). However, conflicting data from the Women's Health Initiative studies found no such effects (5).
According to the latest statement from the U.S. Preventive Services Task Force (USPSTF), current evidence is insufficient to assess the balance of the benefits and harms of combined vitamin D and calcium supplementation for the primary prevention of fractures in premenopausal women or in men. Evidence is also lacking to determine the balance of the benefits and harms of daily supplementation with greater than 400 IU of vitamin D3 and greater than 1000 mg of calcium for the primary prevention of fractures in noninstitutionalized postmenopausal women. The USPSTF recommends against daily supplementation with 400 IU or less of vitamin D3 and 1000 mg or less of calcium for the primary prevention of fractures in noninstitutionalized postmenopausal women (55).

Recent data show that calcium and vitamin D supplementation reduce may reduce weight gain (6), but does not affect cardiovascular events (7), or reduce risk of invasive breast cancer (37) in postmenopausal women. However, low levels of vitamin D were associated with upregulated circulating renin-angiotensin system which suggests that vitamin D may play a role in cardiovascular health (42).
In type 2 diabetic patients, a single, large dose of vitamin D2 improved endothelial function (8); however, vitamin D supplementation did not reduce infections or antibiotic use in an elderly population (9). Another large study found no association between low vitamin D levels and cognitive function (39). Vitamin D is effective in treating psoriasis (10), but data are inconsistent regarding its role in seasonal affective disorder (SAD) (11) (12). Low levels of Vitamin D have been associated with greater risk of mortality (18). Vitamin D supplementation reduced the risk of relapse in patients with Crohn's disease (40).
Contrary to observational data, vitamin D did not decrease the incidence or severity of upper respiratory tract infections (UTRIs) in healthy adults (54).

Vitamin D has been examined for its benefits as a preventative agent and as a treatment for many types of cancer. Vitamin D from sunlight exposure and from dietary intake may have protective effect against breast cancer (13) (14). This correlates with observations in many breast cancer survivors who were vitamin D deficient (15).

In prostate cancer patients, higher serum levels of vitamin D were correlated with greater risk of aggressive cancer (16). Vitamin D improved pain and muscle strength in patients with advanced hormone-refractory prostate cancer (17), and slowed the rate of rise of prostate specific antigen (18). There are studies on using vitamin D and its analogs singly or with chemotherapy in prostate cancer patients (19) (20).
In postmenopausal women, vitamin D and calcium supplementation may reduce the incidence of colorectal cancer, but only in women who did not use estrogen therapy concurrently (28) (29).
Preliminary results suggest vitamin D did not increase toxicity of docetaxel (21) (22) and may offer other treatment benefits (23).

Although reduced risk of cancer has been associated with increased vitamin D intake (24) (25) (26), data from a large, prospective study showed that with the exception of colorectal cancer (52), vitamin D may not protect against other cancers (27) (41). Similarly, data from the Cohort Consortium Vitamin D Pooling Project of Rarer Cancers (VDPP) epidemiological studies do not support the association between low levels of circulating vitamin D and reduced risk of non-Hodgkin lymphoma (45), ovarian (46), kidney (47), endometrial (48), or esophageal and gastric (49) cancers; however, a significant increase in the risk of pancreatic cancer was observed with high levels of circulating vitamin D (50).

According to The National Health and Nutrition Examination Survey, chronic steroid use is associated with vitamin D deficiency (53).
And the Institute of Medicine, in a report on vitamin D and calcium supplementation, recommends a higher Dietary Allowance of vitamin D at 600 IU/day with the Upper level Intake at 4,000 IU/day for bone health (51).
Patients should consult with their physicians if more vitamin D is needed for health maintenance.

Food Sources

Fortified milk, margarine, and cereals, fatty fish, fish liver oils, egg yolks (4)

Purported Uses
  • Cancer prevention
  • Osteoporosis
  • Psoriasis
  • Scleroderma
  • Seasonal affective disorder (SAD)
Mechanism of Action

Vitamin D's primary function in humans is to maintain serum calcium and phosphorus concentrations within normal limits by enhancing the efficiency of the small intestine to absorb these minerals from the diet. 1, 25-dihydroxyvitamin D enhances the efficiency of calcium and phosphorus absorption along the entire small intestine, but primarily in the duodenum and jejunum (4). When the intake of calcium from the diet is insufficient, 1, 25(OH)²D and parathyroid hormone (PTH) mobilize monocytic stem cells in the bone marrow to become mature osteoclasts. These osteoclasts mobilize calcium from the bones, thereby maintaining blood calcium levels (31). Vitamin D is thought to have physiological effects in other parts of the body as receptors are also found in the cells of other organs, like the intestine, kidney, stomach, brain, prostate, breast, and white blood cells (32) (2). The anticancer effect of vitamin D is thought to be due to the induction of cell differentiation (1) (33) and antiproliferation (34). Oral supplementation has been shown to be the safest way of increasing vitamin D levels (44).

Pharmacokinetics

Absorption: Dietary vitamin D is well absorbed from the small intestine. Absorption occurs principally in the duodenum and jejunum, and bile salts are required for peak efficiency (4). Vitamin D is fat soluble and, once ingested, incorporated into the chylomicron fraction and absorbed via the lymph system. It has been estimated that approximately 80 percent of dietary vitamin D enters the body by this pathway.
Distribution: Vitamin D enters the circulation from the skin or from the lymph system via the thoracic duct. It accumulates in the liver where it undergoes hydroxylation at the 25-carbon position and thereafter reappears in the circulation as 25-hydroxyvitamin D (25(OH)D). Its half-life in the circulation is approximately 10 days to 3 weeks. To become biologically active at physiological concentrations, 25(OH)D must be hydroxylated in the kidneys on the 1-carbon position to form 1,25-dihydroxyvitamin D (1,25(OH)D²), which has been described as a biologically active hormone and the form of vitamin D responsible for most, if not all, of its biological functions. 1,25(OH)²D has a relatively short serum half-life of approximately 4-6 hours. Due to the kidney's tight regulation of its production, and its short half-life, it is not a useful marker of vitamin D deficiency, adequacy, or excess.
Metabolism/Excretion: Vitamin D is excreted primarily in the bile, but a small amount is reabsorbed in the small intestine (31).

Adverse Reactions
  • High dose of vitamin D can cause hypercalcemia (30).
  • Rare: Dry mouth, metallic taste, nausea/vomiting, constipation, diarrhea. Toxicity associated with long-term and high-dose use includes polydipsia, depression, headache, drowsiness, weakness, calcium and bone loss, hypercalcemia, and metastatic calcification of soft tissues in kidney, heart, blood vessels, and lung (35).
  • Case Report: Two women developed life-threatening hypercalcemia resulting from intake of over-the-counter vitamin-D concentrated supplements that were 100 — 1,000 times higher than stated on the label (43).
Herb-Drug Interactions

Thiazide diuretics: May increase risk of hypercalcemia.
Atorvastatin: Vitamin D reduces the blood level of atorvastatin but it also helps lowering cholesterol concentrations (56).

Literature Summary and Critique

Pittas AG, Harris SS, Stark PC, et al. The effects of calcium and vitamin D supplementation on blood glucose and markers of inflammation in nondiabetic adults. Diabetes Care 2007 Apr;30(4):980-6. Epub 2007 Feb 2.
Because studies have shown an inverse association between type 2 diabetes and high calcium and vitamin D intake, a double-blind, randomized, placebo-controlled trial was initiated to determine the effects of calcium (500 mg daily) and vitamin D (700 IU daily) supplementation in nondiabetic adults (65 years). After 3 years, fasting blood glucose, insulin sensitivity (as assessed by HOMA-IR), C-reactive protein, and IL-6 levels were determined in 314 participants. In adults with impaired fasting blood glucose, calcium and vitamin D reduced increases in plasma glucose and insulin resistance whereas no differences were detected in adults with normal fasting blood glucose levels. Further studies are required to determine if these effects are due to either supplement alone or the combination.

Caan B, Neuhoser M, Aragaki A, et al. Calcium plus vitamin D supplementation and the risk of postmenopausal weight gain. Arch Int Med 2007 May 14;167(9):893-902.
In order to determine if calcium and vitamin D supplementation affected weight gain in postmenopausal women, the Women's Health Initiative recruited 36,282 women for this randomized, double-blind, placebo-controlled trial. Participants received calcium (1000 mg/day) and vitamin D (400 IU/day) or placebo and were followed for an average of 7 years. A modest reduction in weight gain was reported in participants receiving calcium and vitamin D supplementation, especially in those women who reported low initial calcium intake. Further studies are required to determine if these effects are due to calcium alone or its combination with vitamin D.

Jackson, RD, et al. Calcium plus Vitamin D supplementation and the risk of fractures. N Engl J Med 2006; 354(7): 669-83.
Data obtained from the Women's Health Initiative study was analyzed to determine the efficacy of calcium and vitamin D supplementation for reducing hip fractures. The study involved 36,282 postmenopausal women who were randomized to receive 1000mg of calcium as calcium carbonate with 400 IU vitamin D3 daily or placebo for seven years. There was no significant reduction in hip fractures. But there was a small but significant improvement in hip bone density and an increased risk of kidney stones.

Wactawski-Wende J, et al. Calcium plus Vitamin D supplementation and the risk of colorectal cancer. N Engl J Med 2006; 354(7):684-96.
Data obtained from the Women's Health Initiative study were analyzed to determine the association of calcium and vitamin D supplementation with reduced risk of colorectal cancer. The study involved 36,282 postmenopausal women who were randomly assigned to receive 500 mg calcium as calcium carbonate with 200 IU of vitamin D3 twice daily or a matching placebo for seven years. Results showed no effect of supplementation on the incidence of colorectal cancer.

These data conflict those of several earlier studies that associate increased calcium and vitamin D supplementation with reduced risk of cancer. Researchers point to the drawbacks of earlier studies since most were observational in nature and prone to bias. They also indicate the limitations of the present study that may have contributed to these findings. These include the timing of supplementation and the short follow-up period as colorectal cancer can be latent for 10-20 years. In addition, participants in the study were taking calcium and vitamin D supplements prior to enrollment. So the higher intake of supplements during the study period may have also affected the rates of colorectal cancer.

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References
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  17. Van Veldhuizen PJ, et al. Treatment of Vitamin D Deficiency in Patients with Metastatic Prostate Cancer May Improve Bone Pain and Muscle Strength J Urol 2000;163:187-90.
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  19. Vijayakumar S, Boerner PS, Mehta RR, et al. Clinical trials using chemopreventive vitamin D analogs in breast cancer. Cancer J. 2006 Nov-Dec;12(6):445-50.
  20. Beer TM. ASCENT: the androgen-independent prostate cancer study of calcitriol enhancing taxotere. BJU Int. 2005 Sep;96(4):508-13.
  21. Beer TM, Ryan CW, Venner PM, et al. Double-blinded randomized study of high-dose calcitriol plus docetaxel compared with placebo plus docetaxel in androgen-independent prostate cancer: a report from the ASCENT Investigators. J Clin Oncol. 2007 Feb 20;25(6):669-74.
  22. Attia S, Eickhoff J, Wilding G, et al. Randomized, double-blinded phase II evaluation of docetaxel with or without doxercalciferol in patients with metastatic, androgen-independent prostate cancer. Clin Cancer Res. 2008 Apr 15;14(8):2437-43.
  23. Beer TM, Ryan CW, Venner PM, et al. Intermittent chemotherapy in patients with metastatic androgen-independent prostate cancer: results from ASCENT, a double-blinded, randomized comparison of high-dose calcitriol plus docetaxel with placebo plus docetaxel. Cancer. 2008 Jan 15;112(2):326-30.
  24. Garland CF, et al. Dietary vitamin D and calcium and risk of colorectal cancer: a 19-year prospective study in men. Lancet 1985;1:307-9.
  25. Garland CF, et al. The role of vitamin D in cancer prevention. Am J Public Health 2006; 96(2):9-18.
  26. Lappe JM, Travers-Gustafson D, Davies KM, et al. Vitamin D and calcium supplementation reduces cancer risk: results of a randomized trial. Am J Clin Nutr 2007;85: 1586-91.
  27. Freedman MD, Looker AC, Chang SC, Graubard BI. Prospective study of serum vitamin D and cancer mortality in the United States. JNCI 2007;99(21):1594-1602.
  28. Ding EL, Mehta S, Fawzi WW, et al. Interaction of estrogen therapy with calcium and vitamin D supplementation on colorectal cancer risk: reanalysis of Women's Health Initiative randomized trial. Int J Cancer. 2008 Apr 15;122(8):1690-4.
  29. Wactawski-Wendi J, et al. Calcium plus vitamin D supplementation and the risk of colorectal cancer. N Engl J Med 2006; 354(7):684-96.
  30. Koeffler HP, Hirji K, Itri L. 1,25-Dihydroxyvitamin D3: in vivo and in vitro effects on human preleukemic and leukemic cells. Cancer Treat Rep 1985 Dec;69(12):1399-407.
  31. Dietary Reference Intakes for Calcium, Phosphorus, Magnesium, Vitamin D, and Fluoride. National Academy Press, Washington D.C. 2000.
  32. Stumpf WE, Sar M, Reid FA, et al. Target cells for 1,25-dihydroxyvitamin D3 in intestinal tract, stomach, kidney, skin, pituitary, and parathyroid. Science 1979 Dec 7;206(4423):1188-90.
  33. Jamshidi F, Zhang J, Harrison JS, et al. Induction of differentiation of human leukemia cells by combinations of COX inhibitors and 1,25-dihydroxyvitamin D3 involves Raf1 but not Erk 1/2 signaling. Cell Cycle 2008 Apr 1;7(7):917-24. Epub 2008 Jan 14.
  34. Popadic S, Ramic Z, Medenica L, et al. Antiproliferative effect of vitamin A and D analogues on adult human keratinocytes in vitro. Skin Pharmacol Physiol. 2008;21(4):227-34. Epub 2008 May 29.
  35. Pronsky ZM. Power's and Moore's Food-Medication Interactions, 11th ed. Pottstown (PA): Food Medication Interactions; 2000.
  36. Pittas AG, Harris SS, Stark PC, et al. The effects of calcium and vitamin D supplementation on blood glucose and markers of inflammation in nondiabetic adults. Diabetes Care 2007 Apr;30(4):980-6. Epub 2007 Feb 2.
  37. Chlebowski RT, Johnson KC, Kooperberg C, et al. Calcium Plus Vitamin D Supplementation and the Risk of Breast Cancer. JNCI 2008 Nov 11.
  38. DIPART (Vitamin D Individual Patient Analysis of Randomized Trials) Group. Patient level pooled analysis of 68 500 patients from seven major vitamin D fracture trials in US and Europe. BMJ. 2010 Jan 12;340:b5463. doi: 10.1136/bmj.b5463.
  39. Slinin Y, Paudel ML, Taylor BC, et al. 25-Hydroxyvitamin D levels and cognitive performance and decline in elderly men. Neurology. 2010 Jan 5;74(1):33-41.
  40. Jørgensen SP, Agnholt J, Glerup H, et al. Clinical trial: vitamin D3 treatment in Crohn's disease - a randomised double-blind placebo-controlled study. Aliment Pharmacol Ther. 2010 May 11. [Epub ahead of print]
  41. Gandini S, Boniol M, Haukka J, Byrnes G, et al. Meta-analysis of observational studies of serum 25-hydroxyvitamin D levels and colorectal, breast and prostate cancer and colorectal adenoma. Int J Cancer. 2010 May 6. [Epub ahead of print]
  42. Tomaschitz A, Pilz S, Ritz E, Grammer T, et al. Independent association between 1,25-dihydroxyvitamin D, 25-hydroxyvitamin D and the renin-angiotensin system The Ludwigshafen Risk and Cardiovascular Health (LURIC) Study. Clin Chim Acta. 2010 May 29. [Epub ahead of print]
  43. Kaptein S, Risselada AJ, Boerma EC, Egbers PH, Nieboer P. Life-threatening complications of vitamin D intoxication due to over-the-counter supplements. Clin Toxicol (Phila). 2010 Jun 1. [Epub ahead of print]
  44. Terushkin V, Bender A, Psaty EL, et al. Estimated equivalency of vitamin D production from natural sun exposure versus oral vitamin D supplementation across seasons at two US latitudes. J Am Acad Dermatol. 2010 Jun;62(6):929.e1-9.
  45. Purdue MP, Freedman DM, Gapstur SM, et al. Circulating 25-hydroxyvitamin D and risk of non-hodgkin lymphoma: Cohort Consortium Vitamin D Pooling Project of Rarer Cancers. Am J Epidemiol. 2010 Jul 1;172(1):58-69.
  46. Zheng W, Danforth KN, Tworoger SS, et al. Circulating 25-hydroxyvitamin D and risk of epithelial ovarian cancer: Cohort Consortium Vitamin D Pooling Project of Rarer Cancers. Am J Epidemiol. 2010 Jul 1;172(1):70-80.
  47. Gallicchio L, Moore LE, Stevens VL, et al. Circulating 25-hydroxyvitamin D and risk of kidney cancer: Cohort Consortium Vitamin D Pooling Project of Rarer Cancers. Am J Epidemiol. 2010 Jul 1;172(1):47-57.
  48. Zeleniuch-Jacquotte A, Gallicchio L, Hartmuller V, et al. Circulating 25-hydroxyvitamin D and risk of endometrial cancer: Cohort Consortium Vitamin D Pooling Project of Rarer Cancers. Am J Epidemiol. 2010 Jul 1;172(1):36-46.
  49. Abnet CC, Chen Y, Chow WH, et al. Circulating 25-hydroxyvitamin D and risk of esophageal and gastric cancer: Cohort Consortium Vitamin D Pooling Project of Rarer Cancers. Am J Epidemiol. 2010 Jul 1;172(1):94-106.
  50. Stolzenberg-Solomon RZ, Jacobs EJ, Arslan AA, et al. Circulating 25-hydroxyvitamin D and risk of pancreatic cancer: Cohort Consortium Vitamin D Pooling Project of Rarer Cancers. Am J Epidemiol. 2010 Jul 1;172(1):81-93.
  51. Institute of Medicine of the National Academies. Dietary Reference Intakes for Calcium and Vitamin D. Consensus Report, Nov 30, 2010.
  52. Ma Y, Zhang P, Wang F,Association between vitamin d and risk of colorectal cancer: a systematic review of prospective studies. J Clin Oncol. 2011 Oct 1;29(28):3775-82.
  53. Skversky AL, Kumar J, Abramowitz MK, Kaskel FJ, Melamed ML. Association of Glucocorticoid Use and Low 25-Hydroxyvitamin D Levels: Results from the National Health and Nutrition Examination Survey (NHANES): 2001-2006. J Clin Endocrinol Metab. 2011 Dec;96(12):3838-45.
  54. Murdoch DR, Slow S, Chambers ST, et al. Effect of Vitamin D3 Supplementation on Upper Respiratory Tract Infections in Healthy Adults. JAMA. 2012;308(13):1333-1339.
  55. Virginia A. Moyer. Vitamin D and Calcium Supplementation to Prevent Fractures in Adults: U.S. Preventive Services Task Force Recommendation Statement. Annals of Internal Medicine. 2013 Feb 26. doi: 10.7326/0003-4819-158-9-201305070-00603.. [Epub ahead of print]
  56. Schwartz JB. Effects of vitamin D supplementation in atorvastatin-treated patients: a new drug interaction with an unexpected consequence. Clin Pharmacol Ther. 2009 Feb;85(2):198-203. doi: 10.1038/clpt.2008.165. Epub 2008 Aug 27.

Consumer Information

How It Works

Bottom Line: Adequate vitamin D intake is needed for prevention of osteoporosis. It has not been shown to treat cancer.

Vitamin D is an essential vitamin that is found in foods such as fortified milk, cereals, egg yolks, and fish. It is also produced in the skin when the skin is exposed to sunlight. Its primary function in humans is to maintain adequate blood calcium and phosphorus levels by increasing the absorption of these minerals from the diet through the small intestine. When the intake of calcium from the diet is too low, vitamin D helps move calcium stores from the bones into the blood. Although scientists know that it is helpful to take vitamin D supplements when patients are deficient in this vitamin, it is not clear that taking extra vitamin D will provide any extra benefit. Because vitamin D facilitates the absorption of calcium from the intestine, women taking calcium supplements to prevent osteoporosis should get enough vitamin D in their diet.

In a recent report on vitamin D and calcium supplementation, the Institute of Medicine recommends a higher Dietary Allowance of vitamin D at 600 IU/day with the Upper level Intake at 4,000 IU/day for bone health. Patients should consult with their physicians if more vitamin D is needed for health maintenance.

Purported Uses
  • To prevent cancer
    Very few clinical trials have tested this use. One population-based cohort study found that people with a lower vitamin D intake had a higher risk of colorectal cancer, while one pilot study found that vitamin D could slow the rising of PSA levels in men with recurrent prostate cancer. No other clinical trials have tested this use.
  • To prevent osteoporosis and bone fractures
    Several clinical trials and population studies show that adequate levels of vitamin D intake are needed to prevent osteoporosis and bone fractures.
  • To treat psoriasis
    This use is supported by clinical trials.
  • To treat scleroderma
    No scientific evidence supports this use.
  • To treat seasonal affective disorder (SAD)
    Clinical trial results are inconsistent regarding this use.
Research Evidence

Prevention of osteoporosis and hip fractures:
The ability of vitamin D intake in the diet to prevent hip fractures was studied in a population-cased cohort study. For 18 years, 72,337 postmenopausal women were asked about their diets and supplement use and they were followed to monitor falling and hip fractures. It was found that women who had a high vitamin D intake (>12.5 micrograms per day) were 37% less likely to have a hip fracture than women with low vitamin D intake (<3.5 micrograms per day). This is a very large study and its results are most likely valid.

Bone pain and muscle strength in prostate cancer:
Vitamin D deficiency develops in a large percent of patients with advanced prostate cancer that has not responded to hormone therapy. A small clinical trial tested whether vitamin D supplements could reduce bone pain from metastases and increase muscle strength in 16 men with advanced prostate cancer. After three months, four men reported less pain (although they didn't reduce their usage of pain medications) and six men had improved muscle strength. These results are not very strong, although it may be that vitamin D supplements may only be helpful in prostate cancer patients who have a vitamin D deficiency.

Prostate cancer:
In the body, vitamin D is processed to its active form, 1,25-dihydroxy vitamin D, also known as calcitriol. A small pilot study examined the ability of calcitriol to prevent progression of recurrent prostate cancer. Seven men were studied for 6 to 15 months, in which time they were given anywhere from 0.5 to 2.5 micrograms of calcitriol daily. (Maximum dose was limited by high levels of calcium in the blood and urine.) After treatment with calcitriol, six of the men had significantly reduced rate of rise of prostate specific antigen (PSA), which is an indicator of prostate cancer growth. These results are promising, but because this is only a pilot study, they need to be confirmed with a randomized controlled trial.

Side Effects
  • Dry mouth
  • Metallic taste
  • Nausea/vomiting
  • Constipation
  • Diarrhea
  • Toxicity associated with long-term and high-dose use of vitamin D includes: excessive thirst, depression, headache, drowsiness, weakness, calcium and bone loss, hypercalcemia (abnormally high blood calcium levels) and calcification of the soft tissues in the kidney, heart, blood vessels, and lung.
  • Case Report: Two women developed life-threatening hypercalcemia resulting from intake of over-the-counter vitamin-D concentrated supplements that were 100 — 1,000 times higher than stated on the label.
E-mail your questions and comments to aboutherbs@mskcc.org.