Vitamin D

• How It Works

  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. Intake of vitamin D through diet may protect against breast or colorectal cancers or improve markers of prostate cancer. However, other factors may contribute to these benefits, such as better diet and lifestyle habits. In addition, high blood levels of vitamin D may increase risks of pancreatic or aggressive prostate cancer in some cases. 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. Certain populations including cancer patients can be especially prone to this deficiency. However, there is some debate about the right amount needed. There is also a possible connection between taking vitamin D plus calcium and an increased risk for kidney stones, so patients should check with their doctors if they feel they aren’t getting enough.

• 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 common 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 prevent multiple sclerosis (MS)
    A recent study involving a large number of women suggests that correcting vitamin D deficiency may reduce future risk of MS.
  • To treat seasonal affective disorder (SAD)
    Vitamin D supplementation does not appear to improve SAD.
• 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.
• 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 properties ⁽³⁾. Low levels of vitamin D are associated with a greater risk of mortality ⁽¹³⁾, may affect cardiovascular health ⁽¹⁴⁾, and increase the risk for development of multiple sclerosis in women ⁽⁷⁴⁾, but a large study found no association between lower levels and cognitive function ⁽¹⁵⁾. However, deficiency during pregnancy may affect the neuro-cognitive development of newborns ⁽⁷⁵⁾. Deficiency can also cause rickets or other bone disorders, and may be a risk factor for extra-skeletal diseases ⁽⁴⁵⁾. Lower D levels may occur due to time of year or living in northern climates ⁽⁹⁾; in 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)}.

  Clinical data show that vitamin D improves bone mineral density and fracture prevention in the elderly ^(4) (5) and in postmenopausal women ⁽⁶⁾, but data are conflicting for primary fracture prevention in men or women following vitamin D and calcium supplementation ^{(7) (8) (9)}. Recent US Preventive Services Task Force reports found no associations between vitamin D supplementation and reduced falls or fracture incidence for community-dwelling older adults ^(79) (80); another study also failed to find such association with chronic pain ⁽⁸⁸⁾. High-dose vitamin D had no benefit on lower extremity function and was associated with an increased risk of falls ⁽⁶⁴⁾.

  Findings on whether vitamin D protects against cardiovascular (CV) risk factors have varied across populations and regimens. In a Women’s Health Initiative sub-study, calcium plus vitamin D and hormone therapy had a greater effect than either intervention alone or placebo ⁽⁶⁷⁾; but vitamin D did not improve CV risk factors or physical function in a large long-term trial of older adults ⁽⁶⁸⁾, and a meta-analysis also found no effect on vascular function markers ⁽⁸¹⁾. Yet, in another placebo-controlled trial, vitamin D supplementation benefited diabetic patients with coronary artery disease who were vitamin D-deficient ⁽⁶⁹⁾. In addition, a single large dose of vitamin D2 improved endothelial function in type-2 diabetic patients ⁽¹¹⁾. In non-dialysis patients with chronic kidney disease, D3 was more effective than D2 in raising serum D levels ⁽⁷⁰⁾. Dietary vitamin D intake was shown to be inversely associated with mortality from stroke ⁽⁷⁶⁾.

  In other trials, vitamin D did not significantly reduce upper respiratory tract infections (URTIs) in healthy adults ⁽¹⁶⁾, or infections/antibiotic use in the elderly ⁽¹⁷⁾, or prevent viral URTIs in children ⁽⁷¹⁾. However, it may protect against influenza ⁽⁷⁸⁾ and reduce wheezing in some infants ⁽⁸²⁾. Vitamin D was not helpful for mild psoriasis ⁽⁸³⁾ or seasonal affective disorder ^(18) (19). Supplementation may reduce relapse risk in Crohn’s disease ⁽¹²⁾, and D3 plus calcium may have a small effect on postmenopausal weight gain ⁽¹⁰⁾. A single oral high-dose of D3 significantly improved fatigue in healthy persons who were vitamin D-deficient ⁽⁷²⁾. Supplementation can also improve sexual function in women with sexual dysfunction and vitamin D deficiency ⁽⁸⁹⁾.

  Vitamin D has also been examined for prevention of and effects on cancer. In animal models, dietary vitamin D3 demonstrated 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 insufficiency among breast cancer patients is high ⁽²³⁾. In postmenopausal women not on estrogen therapy, vitamin D and calcium supplementation may reduce colorectal cancer incidence ^(24) (25); in women with grade 1 cervical intraepithelial neoplasia, long-term supplementation resulted in regression and improved metabolic status ⁽⁶⁶⁾. However, in a large trial of healthy postmenopausal women with mean vitamin D levels above those of the US population, taking vitamin D3 plus calcium did not lower cancer risk after 4 years of supplementation ⁽⁷³⁾. In addition, even though pooled analyses found associations between higher serum D levels and lower risks of breast and colon cancers ^(85) (86), other analyses have not found preventive effects against cancer with high-dose supplementation ⁽⁸⁷⁾. Other factors contributing to higher D levels and benefit may be at play, such as better diet and lifestyle habits.

  In patients with advanced hormone-refractory prostate cancer, vitamin D improved pain and muscle strength ⁽²⁶⁾, and slowed the rate of rise of prostate specific antigen ⁽¹³⁾. In older patients with diffuse large B-cell lymphoma, supplementation normalized vitamin D levels and enhanced efficacy of rituximab ⁽²⁷⁾. Active vitamin D compounds may also decrease incidence of post-transplant malignancy among kidney transplant recipients ⁽²⁸⁾.

  Other data reveal that vitamin D deficiency is highly prevalent in advanced pancreatic cancer ⁽⁴²⁾ and colorectal cancer patients ⁽⁴³⁾, and that CRC patients with higher blood 25(OH)D concentrations have better survival ⁽⁸⁴⁾; in patients with metastatic CRC, addition of high-dose vitamin D3 to chemotherapy resulted in statistically insignificant progression-free survival but improved the supportive hazard ratio ⁽⁹⁰⁾. Increased vitamin D intake reduced colorectal cancer risk ^{(29) (31) (32) (33)}, but had no effect on colorectal adenomas ⁽⁶⁵⁾. Vitamin D does not have a protective effect against non-Hodgkin lymphoma ⁽³⁴⁾, ovarian ⁽³⁵⁾, kidney ⁽³⁶⁾, endometrial ⁽³⁷⁾, skin ⁽³⁸⁾, esophageal and gastric ⁽³⁹⁾ cancers, or improve relapse-free survival in patients with digestive tract cancers ⁽⁹¹⁾, and may significantly increase risk of pancreatic ⁽⁴⁰⁾ or aggressive prostate cancer ⁽⁴¹⁾. In addition, data from meta-analyses are conflicting on whether vitamin D supplementation can reduce cancer incidence or mortality ^(44) (77).

  The Institute of Medicine 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⁾. Oral supplementation has been shown to be the safest way to increase vitamin D levels ⁽⁵¹⁾, although debate continues on how this may translate to optimizing vitamin D status ⁽⁴⁵⁾. Combined vitamin D and calcium supplementation has been associated with increased kidney stone incidence ^(7) (80). Therefore, patients should consult with their physicians if a deficiency is suspected to assess the amount of vitamin D needed for health maintenance and to avoid side effects.

• Food Sources

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

• Purported Uses
  • Cancer prevention
  • Immune regulation
  • Osteoporosis
  • Multiple sclerosis
  • 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 well because vitamin D receptors (VDRs) are found in the cells of other organs that include intestines, 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 rituximab ⁽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 the 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⁾.

• 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: In a 30-year-old woman after 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 due to 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 lower cholesterol concentrations ⁽⁶²⁾ .
  • Thiazide diuretics: May increase serum calcium level ⁽⁶³⁾.
• References

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