Vitamin D // Calciferol

Disease risk reduction

Osteoporosis

Without sufficient vitamin D from sun exposure or dietary intake, calcium absorption in the digestive tract cannot be maximized. Low calcium levels in blood result in increased calcium resorption from bone, which may lead to osteoporotic fracture (15). Although osteoporosis is a multifactorial disease, vitamin D insufficiency can be an important contributing factor.

A multinational survey of more than 2,600 postmenopausal women with osteoporosis revealed that 64% of subjects had 25(OH)D levels lower than 75 nanomoles/liter (30 nanograms/milliliter) (16). A prospective cohort study that followed more than 72,000 postmenopausal women in the U.S. for 18 years found that those who consumed at least 600 IU/day of vitamin D from dietary sources and supplements had a 37% lower risk of osteoporotic hip fracture than women who consumed less than 140 IU/day of vitamin D (17).

The results of most clinical trials suggest that vitamin D supplementation can slow bone density losses or decrease the risk of osteoporotic fracture in men and women who are unlikely to be getting enough vitamin D. However, more recent analyses indicate that there is a threshold of vitamin D intake that is necessary to observe reductions in fracture risk.

For instance, a meta-analysis of randomized controlled trials in older adults found that supplementation with 700 to 800 IU vitamin D daily had a 26% and 23% lower risk of hip fracture and non-vertebral fracture, respectively. In contrast, supplementation with 400 IU of vitamin D daily did not decrease risk of either hip or non-vertebral fracture (18). Additionally, results from the Women's Health Initiative trial in 36,282 postmenopausal women showed that daily supplementation with 400 IU of vitamin D3, in combination with 1,000 mg calcium, did not significantly reduce risk of hip fracture compared to a placebo (19).

Some scientists suggest that daily intakes of greater than 700 IU of vitamin D may be necessary to optimize serum concentrations of 25(OH)D and thus reduce fracture risk (20). Support for such a threshold effect of vitamin D on bone health comes from several studies in the U.S., France, and U.K. (21, 22, 23, 24, 25). All of these studies indicate that at least 700 IU of vitamin D3 daily may be required to observe a beneficial effect on fracture incidence.

However, the Randomised Evaluation of Calcium Or vitamin D (RECORD) trial reported that oral supplemental vitamin D3 (800 IU/day) alone, or in combination with calcium (1,000 mg/day), did not prevent the occurrence of osteoporotic fractures in elderly adults who had already experienced a low-trauma, osteoporotic fracture (26). A lack of an effect could be possibly due to a low compliance in this study (after one year of supplementation less than 50% of the subjects were still participating in the trial) or the fact that vitamin D supplementation did not raise serum 25(OH)D levels to a extent that would protect against fractures (20).

Overall, the current evidence suggests that the dose vitamin D3 is very important to be effective and that an optimal plasma 25(OH)D level of at least 75 nmol/L (30 ng/mL) should be achieved. Vitamin D3 supplements of at least 800–1,000 IU/day may be helpful in reducing bone loss and fracture rates in the elderly.

Based on double-blind randomized controlled trials for fall and fracture prevention there was a significant dose-response relationship between higher dose and higher achieved 25(OH)D plasma level. Optimal benefits were observed at the highest vitamin D dose per day of 700–1,000 IU (17.5–25 mcg) as published to date, or achieved mean 25(OH)D plasma level between 75–110 nmol/L (30–44 ng/mL).

In order for vitamin D supplementation to be effective in preserving bone health, adequate dietary calcium should also be consumed.

Clinical trials have generally found that vitamin D2 (ergocalciferol) is less effective than vitamin D3 (27).

Cancer

Two characteristics of cancer cells are lack of specialization (‘differentiation’) and rapid growth (‘proliferation’). Many progressively worsening (‘malignant‘) tumors have been found to contain vitamin D receptors (VDR), including breast, lung, skin (‘melanoma’), colon, and bone. Vitamin D has been found to induce cell differentiation and/or inhibit proliferation of a number of cell types maintained in vitro (‘cell culture’) (28).

Results of some, but not all, human studies suggest that vitamin D may protect against various cancers. However, it is important to note that epidemiological studies cannot prove such associations.

Colorectal cancer 
Prospective cohort studies have not generally found total vitamin D intake to be associated with significant reductions in risk of colorectal cancer when other risk factors are taken into account (29, 30, 3132).

However, some more recent studies have reported that higher vitamin D intakes and blood 25(OH)D levels are associated with reductions in colorectal cancer risk. One five-year study of more than 120,000 people found that men with the highest vitamin D intakes had a risk of colorectal cancer that was 29% lower than men with the lowest vitamin D intakes (33). Vitamin D intake in this study was not significantly associated with colorectal cancer risk in women. More recently, a case-control analysis from the Nurses' Health Study group reported that higher blood 25(OH)D levels were associated with lower colorectal cancer risk (34).

randomized, double-blind, placebo-controlled trial in 36,282 postmenopausal women participating in the Women's Health Initiative study found that a combination of supplemental vitamin D (400 IU/day) and calcium (1,000 mg/day) did not lower incidence of colorectal cancer (35). However, it has been suggested that the daily vitamin D dose, 400 IU, was too low to detect any effect on cancer incidence (36).

In fact, a dose-response analysis estimated that 1,000 IU of oral vitamin D daily would lower one's risk of colorectal cancer by 50% (37).

Breast cancer

Direct evidence of an association between vitamin D nutritional status and breast cancer risk is limited. A prospective study of women who participated in the first National Health and Nutrition Examination Survey (NHANES I) found that several measures of sunlight exposure and dietary vitamin D intake were associated with a reduced risk of breast cancer 20 years later (38). More recently, a 16-year study of more than 88,000 women found that higher intakes of vitamin D were associated with significantly lower breast cancer risk in premenopausal women but not postmenopausal women (39).

Scientists, conducting a pooled, dose-response analysis of two case-control studies reported that women with a 25(OH)D level of 52 nanograms/milliliter (130 nanomoles/liter) experienced a 50% lower risk of developing breast cancer compared to women with 25(OH)D levels lower than 13 ng/mL (32.5 nmol/L) (40–42). The authors state that to obtain a 25(OH)D level of 52 ng/mL, around 4,000 IU of vitamin D3 would need to be consumed daily, or 2,000 IU of vitamin D3 daily plus very moderate sun exposure.

Prostate cancer

Epidemiological studies have shown correlations between risk factors for prostate cancer (e.g. increased age and dark-colored skin, decreased availability of sunlight) and conditions that can result in decreased vitamin D levels (28).

In contrast, prospective studies have not generally found significant relationships between serum 25(OH)D levels and subsequent risk of developing prostate cancer (43, 44, 45, 46).

Although a prospective study of Finnish men found that low serum 25(OH)D levels were associated with earlier and more aggressive prostate cancer development (47), another prospective study of men from Finland, Norway and Sweden found blood 25(OH)D concentrations of 19 nmol/L or lower and 80 nmol/L or higher were associated with higher prostate cancer risk (48).

Further research is needed to determine the nature of the relationship between vitamin D nutritional status and prostate cancer risk.

Autoimmune diseases

Autoimmune diseases, such as type 1 diabetes mellitus (T1DM), multiple sclerosis (MS), and rheumatoid arthritis (RA), occur when the body mounts an immune response against its own tissue, rather than a foreign pathogen (49). Vitamin D3 has been found to modulate the autoimmune responses mediating immune cells (‘T cells’), such that the autoimmune responses are diminished.

The results of several prospective cohort studies suggest that adequate vitamin D intake may decrease the risk of autoimmune diseases.

A prospective cohort study of children born in Finland during the year 1966, which followed them for 30 years, found that those who received supplemental vitamin D during the first year of life had a significantly lower risk of developing type 1 diabetes mellitus (T1DM), while children suspected of developing severe vitamin D deficiency (‘rickets’) during the first year of life had a significantly higher risk of developing IDDM(50).

Vitamin D deficiency has also been implicated in multiple sclerosis (MS). A north south gradient shows increased MS risk in the north compared with the south, as also shown for cancer. A case-control study among U.S. military personnel, including 257 cases of diagnosed MS, found that white subjects with the highest blood 25(OH)D levels (greater than 99.1 nmol/L) had a 62% lower risk of developing MS (51). A relationship between this indicator of vitamin D status and MS was not observed in blacks or Hispanics, but the power to detect such an association was limited by small sample sizes and overall low serum 25(OH)D concentrations (51). In two large groups of U.S. women followed for at least ten years, vitamin D supplement use was associated with a significant reduction in the risk of developing MS (52).

Similarly, postmenopausal women with the highest total vitamin D intakes were at significantly lower risk of developing rheumatoid arthritis (RA) after 11 years of follow-up than those with the lowest intakes (53).

Thus, evidence from human epidemiological studies suggests that maintaining sufficient vitamin D levels may help decrease the risk of several autoimmune diseases.

High blood pressure

The results of epidemiological and clinical studies suggest a relationship between higher blood 25(OH)D levels and lower blood pressure, which may be explained by findings that 25(OH)D decreases the synthesis of the enzyme ‘renin’, playing a key role in the regulation of blood pressure (see Biological Functions).

A controlled clinical trial in 18 hypertensive men and women with high blood pressure (‘hypertension’) living in the Netherlands found that exposure to UVB radiation three times weekly for six weeks during the winter increased blood 25(OH)D levels and significantly decreased blood pressure by an average of 6 mm Hg (54). In randomized controlled trials of vitamin D supplementation, a combination of 1,600 IU/day of vitamin D and 800 mg/day of calcium for eight weeks significantly decreased systolic blood pressure in elderly women by 9% compared to calcium alone (55), but supplementation with 400 IU of vitamin D daily or a single dose of 100,000 IU of vitamin D did not significantly lower blood pressure in elderly men and women over a two-month period (56, 57).

At present, data from controlled clinical trials determining the efficacy of vitamin D supplementation in lowering blood pressure or preventing hypertension are limited.

Tuberculosis

Low levels of vitamin D may make a person more likely to get tuberculosis. Preliminary reports suggest that vitamin D may be a worthwhile addition to the usual treatment for this infection (58).

Authored by Dr Peter Engel in 2010, reviewed and updated by Dr Igor Bendik-Falconnier on 18.06.2017