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 in fortified milk and cereals, egg yolks, and fish. The two forms utilized in humans are ergocalciferol (D2) and 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, and is important for bone formation. Other biologic functions include its role as an antiproliferative agent (1), and as a pro-differentiation hormone (2) with anti-inflammatory and immunoregulatory effects (3).

Vitamin D was shown to improve bone mineral density and fracture prevention in the elderly (4) (5) and in postmenopausal women (6). However, there are conflicting data for primary fracture prevention in men or women when combined with calcium supplements (7) (8) (9).

Data show that calcium and vitamin D supplementation may reduce weight gain in postmenopausal women (10). In type 2 diabetic patients, a single large dose of vitamin D2 improved endothelial function (11). Vitamin D3 supplementation reduced relapse risk in patients with Crohn's disease (12). Low vitamin D levels are associated with a greater risk of mortality (13) and may affect cardiovascular health (14). Another large study found no association between low vitamin D levels and cognitive function (15). Vitamin D supplementation did not decrease incidence or severity of upper respiratory tract infections (URTIs) in healthy adults (16) or reduce infections or antibiotic use in an elderly population (17). It also does not appear to improve seasonal affective disorder (SAD) (18) (19).

Vitamin D has been examined for its benefits as a preventative agent and as a treatment for many types of cancer. In animal models, dietary vitamin D3 demonstrates chemopreventive effects against breast cancer equivalent to those elicited by calcitriol without causing hypercalcemia (20).

In humans, vitamin D from sunlight exposure and dietary intake may have protective effects against breast cancer (21) (22), and correlates with observations in many breast cancer survivors who were vitamin D-deficient (23). In postmenopausal women who do not use estrogen therapy, vitamin D and calcium supplementation may reduce the incidence of colorectal cancer (24) (25). In men, vitamin D improved pain and muscle strength in patients with advanced hormone-refractory prostate cancer (26), and slowed the rate of rise of prostate specific antigen (13). In older patients with diffuse large B-cell lymphoma, vitamin D supplementation normalized deficient levels and enhanced rituximab efficacy (27). Active vitamin D compounds may also decrease the incidence of post-transplant malignancy among kidney transplant recipients (28).

Despite associations between increased vitamin D intake and reduced cancer risk (29) (30) (31), data from a large prospective study showed that with the exception of colorectal cancer (32), vitamin D may not protect against other cancers (33) (34). Similarly, data from the Cohort Consortium Vitamin D Pooling Project of Rarer Cancers (VDPP) epidemiological studies do not support associations between high circulating vitamin D levels and reduced risk of non-Hodgkin lymphoma (35), ovarian (36), kidney (37), endometrial (38), or esophageal and gastric (39) cancers, but were associated with a significant increase in pancreatic cancer risk (40). Other data reveal no associations between vitamin D levels and skin cancer incidence (41) or survival for advanced pancreatic cancer patients (42). Another study found higher D levels correlated with greater risk of aggressive prostate cancer (43).

The most recent meta-analyses evaluating vitamin D supplementation for cancer prevention in adults indicates that although it decreased cancer mortality and all-cause mortality, these findings are at risk of error due to the small numbers of participants across studies and attrition bias (44). More studies are needed to evaluate its effects in different populations, such as patients with low vitamin D status, men, and younger adults, using longer treatment durations and higher dosages.

Vitamin D deficiency can cause rickets or other bone disorders, and may also be a risk factor for extraskeletal diseases (45). Deficiencies can also be prevalent in certain demographics including time of year or living in northern climates (9), non-Caucasian race (46), or obese individuals (47); with chronic use of steroids or anticonvulsants; or with diseases such as autoimmune disorders (3), cystic fibrosis (48), kidney disease, and cancer (46) (48) (49).

The Institute of Medicine generally recommends a Daily Dietary Allowance of vitamin D at 600 IU/day with the Upper Level Intake at 4,000 IU/day for bone health (50), but food sources are limited. Oral supplementation has been shown to be the safest way to increase vitamin D levels (51), although considerable debate continues on how this may translate in optimizing vitamin D status (45). Therefore, patients should consult with their physicians if a deficiency is suspected to assess whether more vitamin D is needed for health maintenance and to avoid side effects such as kidney stones or high levels of calcium in blood or urine.

Food Sources

Fatty fish, fish liver oils, egg yolks, fortified milk and cereals (5)

Purported Uses
  • Cancer prevention
  • Immune regulation
  • Osteoporosis
  • Seasonal affective disorder (SAD)
Mechanism of Action

The most biologically active metabolite of vitamin D is calcitriol, which regulates calcium and phosphate homeostasis (52).

In humans, the primary function of vitamin D is to maintain normal levels of serum calcium and phosphorus concentrations by enhancing small intestine dietary absorption efficiency of these minerals. 25-hydroxyvitamin D [25(OH)D] enhances the efficiency of calcium and phosphorus absorption along the entire small intestine, but primarily in the duodenum and jejunum (5). When dietary calcium intake is insufficient, 25(OH)D 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 (50). Vitamin D is thought to have physiological effects in other parts of the body as vitamin D receptors (VDRs) are also found in the cells of other organs, like the intestine, kidney, stomach, brain, prostate, breast, and white blood cells (2) (53).

The anticancer effect of vitamin D is thought to be due to induction of cell differentiation (1) (54) and antiproliferation (55). In lymphoma cells, interventional 25(OH)D3 to normalize levels (>30 ng/mL) resulted in significantly stronger antibody-dependent cell-mediated cytotoxicity, suggesting benefit in D-deficient individuals receiving chemotherapies such as rituximab that utilize this mechanism (27). In xenograft models of breast cancer, dietary D3 elevated circulating D levels and increased CYP27B1 expression in both tumor and intestines, suggesting it stimulates local calcitriol synthesis in the tumor microenvironment and promotes ensuing paracrine/autocrine actions that contribute to its anticancer activity (20). The upregulation of CYP27B1 expression by tumors was unique to D3 versus calcitriol in the same tissue (20). In other animal models, a positive feedback signaling loop between the serine-protein kinase ATM (ataxia telangiectasia mutated) and the VDR was identified as critical for cancer chemoprevention by vitamin D (56).

Calcitriol, the hormonally active form of vitamin D3, targets the vitamin D degrading enzyme CYP24A1, which is most abundant in the kidney, but also expressed in several other tissues (57). CYP24A1 overexpression in colon, ovary, breast, lung, and esophageal malignancies, likely leads to degradation of the locally available D3, impairing its antitumorigenic action in the tumor tissue (57).

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 (5). 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(OH)D. Circulation half-life 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 (50).

Metabolism/Excretion: Vitamin D is excreted primarily in the bile, but a small amount is reabsorbed in the small intestine (50).

Contraindications

Individuals with kidney stones, kidney disease, high blood calcium levels, gastrointestinal disease, heart disease, liver disease or other diseases associated with disorders of calcium metabolism should seek medical advice before taking supplemental vitamin D (9).

Adverse Reactions

Rare: Gastrointestinal symptoms, renal disease, nephrolithiasis, hypercalcemia, hypercalciuria (9) (44).

Case Reports
Life-threatening hypercalcemia: In two women resulting from intake of over-the-counter vitamin-D concentrated supplements that were 100 — 1,000 times higher than stated on the label (58).
Hypercalcemic crisis: A 5-day history of worsening abdominal pain, nausea, and vomiting in a 30-year old woman who had been taking large quantities of vitamin D for an unknown period of time (59).
Acute renal failure and hypervitaminosis A: In a 51-year old woman after consuming an over-the-counter vitamin D supplement, which also caused Vitamin A toxicity possibly caused by renal failure related to the hypercalcemia induced by vitamin D toxicity (60).

Herb-Drug Interactions

Aluminum hydroxide: May increase the absorption and blood level of aluminum (61).
Atorvastatin: Vitamin D reduces blood levels of atorvastatin but it also helps to lower cholesterol concentrations (62) .
Thiazide diuretics: May increase serum calcium level (63).

Literature Summary and Critique

Bittenbring JT, et al. Vitamin D deficiency impairs rituximab-mediated cellular cytotoxicity and outcome of patients with diffuse large b-cell lymphoma treated with but not without rituximab. J Clin Oncol. 2014.
Vitamin D deficiency (VDD, ≤8 ng/mL) is a risk factor for elderly patients with DLBCL treated with the rituximab-containing regimen known as R-CHOP. In this study, event-free and overall survival (EFS and OS) were evaluated in these patients to identify impact and mechanisms. A total of 359 samples from patients pre-D3-treatment from the RICOVER-60 study (6 vs 8 cycles; biweekly CHOP-14 ± rituximab) and 63 samples as an independent validation set from the RICOVER-noRTh study (amended RICOVER-60 regimen: 6 cycles of cyclophosphamide, doxorubicin, vincristine, and prednisone at 2-wk intervals + 2 cycles of rituximab [R-CHOP-14] but without radiation) were used to assess rituximab-mediated cellular cytotoxicity (RMCC).

RICOVER-60 patients with VDD (≤8 ng/mL) vs levels >8 ng/mL who were treated with rituximab had a 3y-EFS of 59% vs 79% and a 3y-OS of 70% and 82%, respectively. Differences were significant in multivariate analysis that adjusted for International Prognostic Index risk factors, with hazard ratios of 2.1 (P=.008) and 1.9 (P=.040) for EFS and OS, respectively. There was no significant difference in EFS between ≤ 8 or >8 ng/mL groups for those treated without rituximab, as confirmed by the RICOVER-noRTh validation set. For those with VDD who received supplementation to achieve normalized vitamin D levels (n=7), RMCC increased significantly (P<.001). This small subsample suggests that vitamin D substitution can enhance rituximab efficacy, but such findings should be confirmed in appropriately designed clinical trials that address both VDD and vitamin D substitution in malignancies treated with monoclonal antibodies that use this mechanism (trastuzumab, cetuximab, or rituximab).

Van Loon K, et al. 25-Hydroxyvitamin D levels and survival in advanced pancreatic cancer: findings from CALGB 80303 (Alliance). J Natl Cancer Inst. 2014;106.
In this correlative study (CALGB 151006) of advanced pancreatic cancer patients who had no difference in overall survival (OS) in CALGB 80303 when treated with gemcitabine plus either bevacizumab or placebo, baseline serum 25[OH]D were measured. Associations between these levels and progression-free survival (PFS) and OS were evaluated using two-sided statistical tests. Median 25(OH)D level was 21.7 ng/mL (range, 4–77) among 256 samples. Of these patients, 44.5% were vitamin D deficient (<20 ng/mL) and 32.4% were insufficient (20–<30 ng/mL). Although low vitamin D levels were highly prevalent among the newly diagnosed and significantly lower in black than white or other/undisclosed race patients (10.7 vs 22.4 vs 20.9 ng/mL; P<.001), baseline levels were not found to be associated with PFS or OS.

Jackson RD, et al. Calcium plus Vitamin D supplementation and the risk of fractures. N Engl J Med. 2006; 354: 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 1000 mg of calcium as calcium carbonate with 400 IU vitamin D3 daily or placebo for 7 years. Although there was no significant reduction in hip fractures, there was a small, significant improvement in hip bone density, but also 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; 354:684-96.
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 that limitations in the present study including timing of supplementation and the short follow-up period may have contributed to these findings, as colorectal cancer can be latent for 10–20 years. In addition, since participants were taking calcium and vitamin D supplements prior to enrollment, any further effects of study supplementation on the rates of colorectal cancer may have been limited.

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Consumer Information

How It Works

Bottom Line: Adequate vitamin D intake is needed for bone health and other important biologic functions. There are links between increased vitamin D intake and reduced risk of breast and colorectal cancers, but protection against other cancers remains unclear.

Vitamin D is an essential vitamin that is found in certain foods such as fortified milk and cereals, egg yolks, and fish. It is also produced in skin that is exposed to sunlight. Its primary function is to maintain adequate blood calcium and phosphorus levels by increasing absorption of these minerals from the diet through the small intestine. When dietary calcium intake is too low, vitamin D helps move calcium stores from the bones into the blood.

Vitamin D is also involved in many other biologic functions such as immune and hormone regulation, and has anti-cancer properties. Intake of vitamin D through diet may protect against breast or colorectal cancers or improve markers of prostate cancer. However, effects against other cancers remain unclear.

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. Scientists know that it is helpful to take vitamin D supplements when patients are deficient in this vitamin, and certain populations including cancer patients can be especially prone to this deficiency. However, there is some debate about what level of supplementation is appropriate. Patients should consult with their physicians if more vitamin D is needed for health maintenance or to treat deficiency.

Purported Uses
  • To prevent or treat cancer
    Intake of vitamin D through diet may protect against breast or colorectal cancers or affect markers for prostate cancer. However, vitamin D by itself does not prevent or treat cancer. Other large studies show that high vitamin D levels do not reduce the risk of many other cancers, and may increase risk for pancreatic or aggressive prostate cancer. More studies are needed to evaluate vitamin D in different populations.
  • For immune regulation
    Vitamin D contributes to hormone regulation and other processes involving immune function. In addition, a deficiency in this vitamin can be prevalent in certain populations, including those with cancer or autoimmune disorders. However, studies on effects of vitamin D supplementation on immune regulation are lacking.
  • To prevent osteoporosis
    Several clinical trials and population studies show that adequate levels of vitamin D intake are needed to prevent osteoporosis and bone fractures. In postmenopausal women and elderly populations, vitamin D supplementation may improve bone mineral density and help to prevent fractures.
  • To treat seasonal affective disorder (SAD)
    Vitamin D supplementation does not appear to improve SAD.
Research Evidence

Vitamin D deficiency in cancer patients
In 256 patients with advanced pancreatic cancer, vitamin D levels were evaluated to see whether there was a relationship between these levels and both progression-free and overall survival. A majority were found to be either vitamin D-deficient or -insufficient. Low vitamin D levels were determined to be common among newly diagnosed and particularly black patients. However, baseline vitamin D levels were not found to be associated with survival.

Vitamin D supplementation to reduce cancer risk
Data from one of the largest national health prevention studies known as the Women's Health Initiative were analyzed to see whether calcium and vitamin D supplementation could reduce colorectal cancer risk in 36,282 postmenopausal women. Women were randomly assigned to receive calcium carbonate 500 mg and vitamin D3 200 IU twice daily or a matching placebo for 7 years. Results showed no effect of supplementation on the incidence of colorectal cancer.

Many other studies on whether vitamin D intake reduces cancer risk are mixed. Therefore, there is no agreement on whether this is true and what level of supplementation would be needed. There is also some indication that too much vitamin D might increase the risk of some aggressive cancers.

Prevention of hip fractures in postmenopausal women
Data from the Women's Health Initiative, a long-term national health study, was analyzed to see if calcium and vitamin D supplementation reduced hip fractures. A total of 36,282 postmenopausal women were randomly assigned to receive either calcium carbonate 1000 mg plus vitamin D3 400 IU daily or placebo for 7 years. Although there was no significant reduction in hip fractures, there was a small, significant improvement in hip bone density, but also an increased risk of kidney stones.

Do Not Take If
  • You take aluminum hydroxide: Vitamin D supplementation may increase the absorption and blood level of aluminum.
  • You take atorvastatin: Vitamin D reduces blood levels of atorvastatin, but it also helps to lower cholesterol concentrations.
  • You take thiazide diuretics: Vitamin D supplementation may increase serum calcium levels.
Side Effects

Rare: Gastrointestinal symptoms, kidney disease, kidney stones, excess calcium in blood or urine

Case reports of high blood calcium levels and kidney disease from ingesting high levels of vitamin D have occurred.

Special Point
  • Although rare, too much vitamin D can cause abnormally high levels of calcium in the blood or urine, or kidney stones.
  • Patients with kidney stones, kidney disease, high blood calcium levels, gastrointestinal disease, heart disease, liver disease or other diseases associated with disorders of calcium metabolism should seek medical advice before taking supplemental vitamin D.
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