- Vitamin D
- Sunshine vitamin
- D2; D3
For Patients & Caregivers
Tell your healthcare providers about any dietary supplements you’re taking, such as herbs, vitamins, minerals, and natural or home remedies. This will help them manage your care and keep you safe.
What is it?
Vitamin D is a vitamin your body needs to keep your bones healthy. Your bones need calcium to stay strong and your body needs vitamin D to absorb calcium. This is why it’s important to get vitamin D. You can get vitamin D from some foods like fortified milk and cereals, egg yolks, and fish. Your body can also make some vitamin D when you’re exposed to sunlight.
If you don’t get enough vitamin D, your healthcare provider may recommend you take vitamin D supplements, or take a multivitamin that has vitamin D.
What are the potential uses and benefits?
Vitamin D is used to:
- Prevent osteoporosis (a condition in which bones become weak and brittle)
- Prevent certain cancers
- Treat a type of depression called seasonal affective disorder. This is related to the changes in season. It is seen mostly in people who live in climates where there is less sunlight during fall and winter.
Vitamin D also has other uses that haven’t been studied by doctors to see if they work.
It’s safe to eat foods with vitamin D. However, talk with your healthcare providers before taking supplements or higher amounts of vitamin D.
Supplements can interact with some medications and affect how they work. For more information, read the “What else do I need to know?” section below.
What are the side effects?
Vitamin D is generally safe. But it can sometimes cause side effects such as:
- Vomiting (throwing up)
- Abdominal (stomach) pain
- High levels of calcium in the blood
- High levels of calcium in urine (pee)
- Kidney stones
What else do I need to know?
- Talk to your healthcare provider if you have kidney stones, kidney disease, high blood calcium levels, heart disease, or liver disease. Vitamin D supplements may make these conditions worse.
- Talk to your healthcare provider if you’re taking diuretics or water pills (medications that make you urinate more often) such as indapamide (Lozol), hydrochlorothiazide (Microzide®), or chlorthalidone (Thalitone®). Vitamin D may increase the calcium level in your blood. This can weaken your bones and create kidney stones.
For Healthcare Professionals
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 neurocognitive development in newborns (75). Deficiency can also cause rickets or other bone disorders, and may be a risk factor for extraskeletal 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).
Although some studies suggest vitamin D improves bone mineral density and prevents fractures in the elderly (4) (5) and in postmenopausal women (6), it did not lower risk of fractures in midlife and older adults (108) or improve lower extremity function and was associated with an increased fall risk in older adults (64). Safety concerns also arose with doses of 1000 IU/d or higher in older persons who had elevated fall risk and low serum D levels (99) but conflicting findings do not support such concerns (113). Data are also conflicting for primary fracture prevention in other populations (7) (8) (9), and a meta-analysis did not find benefit for preventing fractures or falls, or for bone mineral density (100).
In healthy adults, D3 also does not appear to decrease fall risk (101) and high-dose supplementation did not benefit bone health (92), with 4000 or 10,000 IU compared with 400 IU resulting in greater bone mineral density loss in healthy vitamin D-sufficient women, but not men (93). Supplementation did not affect the rate of frailty change or incidence over time in healthy community-dwelling older adults (109), and US Preventive Services Task Force reports also found no associations between supplementation and reduced falls or fracture incidence in this subset (79) (80). Another study failed to find associations between vitamin D status and chronic pain (88).
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 large long-term trials of older adults (68) (110) or reduce all-cause mortality in older adults who are vitamin D-replete (111). Meta-analyses also found no effect on vascular function markers (81) nor reduction in CV disease endpoints (94). Yet in another placebo-controlled trial, 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), but supplementation was not associated with reduced all-cause mortality in critically ill patients (102), and did not reduce risk of atrial fibrillation (103).
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). 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 may also improve sexual function in women with sexual dysfunction and vitamin D deficiency (89), but a large study did not find any benefits of long-term supplementation for preventing depression in healthy adults (96). In a small study, higher serum levels of vitamin D were associated with increased beneficial gut bacteria and decreased pathogenic bacteria (95).
Vitamin D has also been examined for its anticancer potential. In animal models, dietary vitamin D3 exerted 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), and vitamin D supplementation did not prevent aromatase-induced arthralgia (97) or affect cognition when combined with calcium, protein and a multicomponent exercise training in men treated with ADT for prostate cancer (112). 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), and contributing factors such as better diet and lifestyle habits may also be at play.
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 (CRC) patients (43), and that CRC patients with higher blood 25(OH)D concentrations have better survival (84). A meta-analysis of vitamin D supplementation on CRC survival outcomes also suggests clinically meaningful benefit (104). In patients with metastatic CRC, addition of high-dose vitamin D3 to chemotherapy resulted in statistically insignificant progression-free survival but improved supportive hazard ratio (90). Increased vitamin D intake reduced CRC risk (29) (31) (32) (33), but had no effect on colorectal adenomas (65). Data on benefits to reduce skin cancer risk (38) (105) and advanced cancers (106) are mixed. Vitamin D did not have a protective effect against non-Hodgkin lymphoma (34), ovarian (35), kidney (36), endometrial (37), esophageal or gastric (39) cancers, may significantly increase risk of pancreatic (40) or aggressive prostate cancer (41), and did not improve relapse-free survival in patients with digestive tract cancers (91) although conflicting findings in p53 immunoreactive subset suggest otherwise (116). Data from meta-analyses, however, are conflicting on whether vitamin D supplementation can reduce cancer incidence or mortality (44) (77) (94).
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). 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), although safety concerns have been noted with higher doses in some populations (99). Also, 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.
Purported Uses and Benefits
- Cancer prevention
- Seasonal affective disorder
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).
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).
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).
Severe hypercalcemia: In a 37-year-old man with previously undiagnosed sarcoidosis who was prescribed 50,000 units of weekly vitamin D 25 (OH) therapy for 4 weeks and presented after 2 weeks therapy with abdominal pain, nausea, and vomiting for 2 days (107).
Hypercalcemic crisis: In three cases after taking large quantities of vitamin D for an extended period of time (59) (118).
Post-prandial food vomiting and severe abdominal pain: In a 64-year-old woman after taking various vitamin complexes, including cholecalciferol, once daily for about 6 months (98).
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).
Acute pancreatitis: In a 61-year-old man following vitamin D toxicity due to intake of large doses (119).
Hypercalcemia and acute kidney injury: In a patient who was given high-dose vitamin D along with immunosuppressive therapy following autologous stem cell transplant for multiple sclerosis (120).