VITAMIN D-3

BACKGROUND

Ingredient Type: Vitamin

Also Known As: Cholecalciferol, Cholecalciferol-D3, Ergocalciferol-D2 alfacalcidol

Vitamin D3 is a fat-soluble vitamin that is one of the two major forms of vitamin D.  The other major form is vitamin D2, which is commonly found in plants, whereas vitamin D3 is typically found in animal tissues.  Vitamin D3 is classified as a prohormone, meaning it is inactive by itself, but will lead to powerful metabolites that become active in the body.  Vitamin D3’s main function within the body is to absorb and metabolize calcium and phosphorus (1).  As a result, vitamin D3 is necessary for strong and healthy bones.  Vitamin D is produced by the body when exposed to sunlight but can also be obtained through one’s diet (2).  Unfortunately, fatty fish are the only food that is naturally high in vitamin D.  To help avoid vitamin D deficiency, some food items such as milk, orange juice, and cereals can be fortified with vitamin D.

The discovery of vitamin D3 ultimately began with the first classification of rickets, which commonly causes the softening and distortions of bones in the seventeenth century in England.  Due to a large number of outbreaks occurring in this area at the time, investigations into the development of the disease began (3).  No major advancements were made during the seventeenth century, although in 1824, it was proposed that cod liver oil was an effective treatment for rickets (4).  Edward Mellanby conducted research on dogs between 1919 and 1924 in which he discovered that rickets was caused by a deficiency in a fat-soluble vitamin, although this was not specifically linked to vitamin D at the time (5).  Vitamin D was isolated and officially discovered by Elmer McCollum in 1922 (6).  A few years later in 1925, Hess and Weinstock discovered that sunlight exposure to the skin caused the production of vitamin D3 (5).  Further research into the chemical structure of vitamin D discovered a difference between vitamin D3 and vitamin D2.  This led to the realization that the active form of vitamin D in cod liver oil is vitamin D3 and does, in fact, influence bone health (4).

By 1964, the nutritional importance of vitamin D3 was well known, and further studies clarified that vitamin D acts more like a steroid hormone than a vitamin within the body.  This characteristic is what causes vitamin D3 to promote calcium absorption in the body.  The first clinical uses of vitamin D3 started in 1971 and revolved mostly around treating renal osteodystrophy, a bone disease which is caused by damage to the kidneys (4).  Since then, research has expanded on the various uses of vitamin D3 as a supplement to help treat many different conditions.

TRADITIONAL USES

Vitamin D3, in the form of cod liver oil, has traditionally been used to treat bone disorders that are the result of soft and brittle bones from low bone mineral density such as rickets, osteoporosis, and osteomalacia (6).

WHAT DOES SCIENCE TELL US?

Vitamin D3 Might Help Support Healthy Bones:

Bone mineral density (BMD) is an important indicator of bone health and strength in humans.  When it is too low, bones begin to soften.  Research suggests that vitamin D supplementation is highly effective when coupled with calcium supplements.

A meta-analysis looked at the effects of vitamin D supplementation on bone mineral density among children between the ages of one month and twenty years.  The study found that supplementation with vitamin D did not significantly improve BMD in the hip or forearm, although lumbar spine BMD was slightly affected in comparison to placebo groups (p=0.07).  The analysis also found that there was a greater increase in total body BMD in participants who had low serum vitamin D levels rather than high serum levels (p=0.09).  The study ultimately concluded that vitamin D supplementation is not particularly useful in children who are not deficient in the vitamin but could provide clinical benefits for children with low vitamin D levels (7).  Another meta-analysis determined that vitamin D supplementation alone did not produce significant improvements in BMDs at multiple body sites, except for the femoral neck which showed a small benefit (p<0.00027) (8).

A randomized, placebo-controlled study evaluated the effects of 20,000 IU of vitamin D3 a week versus placebo for five years in adult men with prediabetes.  Results showed that men who received the D3 supplementation showed significantly less reduction in femoral neck BMD than the controls (p=0.008) (9).  Another clinical trial gave 52 vitamin D deficient, obese adults 7,000 IU of vitamin D daily for 26 weeks and observed the changes in BMD and bone turnover.  Results showed that BMD of the forearm significantly increased in those receiving vitamin D in comparison to a placebo (p=0.03) and decreased bone turnover in this study group (10).  Another randomized study was conducted among 32 preterm infants residing in the NICU, who either received 400 IU or 800 IU of vitamin D3 daily for a duration of 4 weeks.  It was found that the group receiving 800 IU of vitamin D3 had significant improvements in serum vitamin D levels (p=0.048) as well as bone density (11).

Although evidence of vitamin D alone improving BMD is inconclusive, positive effects on BMD have consistently been seen with supplementation of vitamin D and calcium together.  243 men and women going through army basic training were enrolled in a randomized, double-blind, placebo-controlled study that looked at the effects of vitamin D and calcium supplementation on bone density.  In comparison to those that received the placebo, participants who consumed the vitamin D and calcium supplement daily (1,000 IU vitamin D and 2,000 mg Ca) saw a significant improvement in BMD throughout the nine-week trial period (p=0.024) (12).  This indicates that vitamin D in combination with calcium may help increase BMD in young adults during times of high bone turnover, such as military basic training.  Another double-blind trial gave 240 healthy, postmenopausal women a combined vitamin D and calcium supplement for two years.  BMD of the lumbar spine was found to increase by 1.6% in the treatment group compared to the placebo group (p<0.05).  Changes in BMD of the hip and forearm, however, were not significant (13).  Among individuals over the age of 65, vitamin D and calcium supplementation were found to significantly reduce bone loss at the femoral neck (p=0.02), spine (p=0.04), and total body (p<0.001).  These results were seen with supplementation of 700 IU of vitamin D3 in combination with 500 mg of calcium daily for three years (14).  This trend suggests that vitamin D supplementation is more beneficial to bone mineral density when coupled with calcium supplements.

A lowered incidence of falls was reported in a randomized clinical trial observing the effects of vitamin D supplementation on elderly adults living in nursing homes.  Specifically, participants who orally took 800 IU of vitamin D daily for five consecutive months had a 72% lower rate ratio of falls than participants who received the placebo (15).  A meta-analysis found that hip fractures and non-vertebral hip fractures among elderly women over the age of 50 decreased with vitamin D3 and calcium supplementation when compared to placebo (16).  Another meta-analysis reported that supplementation of vitamin D in high doses (700-1000 IU/day) reduces the risk of falling in the elderly population by 19%.  Low dose supplementation (<700 IU/day) did not significantly decrease the risk of falls (17), suggesting that vitamin D may need to be taken in higher doses to experience its positive effects.  In contrast, a randomized double-blinded clinical trial concluded that low levels of vitamin D supplementation, in combination with calcium, may decrease the risk of falling (p=0.537).  This study did, however, also report a higher proportion of adverse effects among the group taking the supplement than the placebo group (p=0.019), and ultimately concluded that vitamin D supplementation is not an effective approach to reducing falls in the elderly (18).

Vitamin D3 Possibly Supports Cardiovascular Health:

Evidence for the use of vitamin D supplementation to improve cardiovascular health is limited and inconclusive.  Most of the randomized clinical trials investigating this relationship are in combination with calcium supplementation, which makes establishing a causal relationship difficult.

Multiple studies have shown that low vitamin D serum levels within the body are associated with an increased risk of cardiovascular diseases.  One cross-sectional study determined that those with low vitamin D serum levels (<30 ng/ml) had a significantly higher risk of cardiovascular disease such as atherosclerosis, in comparison to those with higher vitamin D serum levels (≥30 ng/ml) (19).  Another cross-sectional study found that individuals with vitamin D levels less than 17.8 ng/ml had an increased rate of all-cause mortality, including cardiovascular disease, of 26% (20).  Furthermore, a prospective cohort study of 3,258 men and women scheduled for a coronary angiography found that those with lower vitamin D levels (7.6-13.3 ng/ml) had a higher multivariate-adjusted hazard ratio (2.22; 95% CI, 1.57-3.13) for deaths from cardiovascular disease than those with higher vitamin D levels (28.4 ng/ml).  The research concluded that low levels of vitamin D are independently related to cardiovascular mortality (21).  Arterial stiffness may be improved with vitamin D3 supplementation, as was tested in a randomized, placebo-controlled clinical trial.  70 African Americans between the ages of 13 and 45 who were overweight were given either 18,000 IU, 60,000 IU, or 120,000 IU of vitamin D3 once a month for 16 weeks.  The research revealed a dose-dependent, significant trend for improving arterial stiffness with vitamin D3 supplementation (p<0.01) (22).

Of the randomized clinical trials examining the effects of vitamin D supplementation on cardiovascular health, results have been inconclusive.  One such study gave 2,686 older men and women either 100,000 IU of vitamin D3 or a placebo every four months for five consecutive years.  The study was mainly looking at the rate of fractures, but they did not find a significant reduction in the number of deaths from cardiovascular disease (RR=0.84) (23).  A similar study gave 36,282 post-menopausal women either a combined supplement of vitamin D3 (400 IU) and calcium (1,000 mg) or a placebo every day for seven years.  After the seven years, there was no significant decrease in any of the cardiovascular outcomes, including myocardial infarction, coronary heart disease death, or stroke (24).  These conclusions suggest that vitamin D3 may not provide any significant benefits for improving cardiovascular health.

On the other hand, a group of 108 patients with diabetes received 7,143 IU of vitamin D3 and 1,000 mg of calcium daily for eight weeks and had a significantly lowered systolic blood pressure compared to those who received placebos (p=0.001).  There was not a significant change in diastolic blood pressure in this group (25).

Vitamin D3 Possibly Supports a Healthy Immune System:

One randomized, double-blind study gave eight healthy adults either 400 IU or 2000 IU of vitamin D3 daily for two months.  The difference in gene expression was observed and there was an increase in expression of 291 genes, some of which are important for immune health and repairing DNA.  The changes in gene expression from vitamin D3 supplementation may positively affect biological pathways associated with autoimmune disorders, as well as cancer and heart health (26).  Markers of regulatory immunity may increase with vitamin D3 supplementation among pregnant women.  A randomized, double-blind study administered 400 IU or 2,000 IU of vitamin D3 a day to 57 pregnant women due to deliver within 20 weeks.  It was found that the women who regularly took 2,000 IU of vitamin D3 daily had 36% more regulatory CD4+ T cells than the 400 IU group (p<0.007) (27).  This boost in the immune system may indicate that vitamin D3 supplementation is beneficial for pregnant women.  Furthermore, a double-blind, randomized, placebo-controlled study enrolled 40 elderly women with a diagnosed vitamin D deficiency.  These women received either 200,000 IU of vitamin D3 or a placebo.  After four weeks, blood samples were analyzed for inflammatory markers and antioxidant capacity.  The results showed that vitamin D3 was responsible for a significant decrease of inflammatory markers (p=0.007) and an increase in antioxidant capacity (p=0.03), in comparison to the women who received the placebo (28).

Vitamin D supplementation has also been found to decrease respiratory infections in adults who have experienced frequent respiratory tract infections.  In one randomized, placebo-controlled, double-blind study, 124 patients were given 4,000 IE of vitamin D a day for one year.  Supplementation with vitamin D resulted in a higher likelihood of having less respiratory tract infections during the study year (p=0.05), as well as a longer time to first respiratory tract infection (p=0.0376) (29).

These results are not consistent across studies, however.  Another study administered vitamin D3 for 5 months to 475 critically ill patients with a deficiency in vitamin D.  The research aimed to determine if supplementation had an effect on length of stay in the hospital and mortality.  It was concluded that high dose supplementation of vitamin D3 resulted in no significant differences for the length of stay in the hospital (p=0.98) or mortality rates (p=0.18) (30).

Vitamin D3 Possibly Supports Healthy Parathyroid Hormone Levels:

One double-blind, placebo-controlled trial gave 32 four to eight-year-old children 1,000 IU of vitamin D3 and 32 children a placebo daily for eight weeks.  A significant decrease in parathyroid hormone was observed in the group receiving the vitamin D3 supplement in comparison to the placebo group (p=0.001) (31).  Another study of 60 hemodialysis adult patients were all given 2 mcg of paricalcitol and cholecalciferol, a manmade vitamin D supplements often used to treat hyperparathyroidism.  Half of these patients were allocated to a placebo group, while the other half received cholecalciferol for sixteen weeks.  Parathyroid hormone levels were tested among these groups and those in the cholecalciferol group saw a significant decrease in parathyroid hormone levels (p<0.05).  After the sixteen-week study period, a significant number of patients in the cholecalciferol group reached the target level of parathyroid hormone in comparison to the placebo group (p=0.00032) (32).  Research among 46 primary hyperparathyroidism patients who received either 2,800 IU of vitamin D3 or a placebo daily for 52 weeks found that vitamin D3 significantly reduced parathyroid hormone by 17% (p=0.01) (33).

Similar findings were seen in a double-blind, randomized clinical trial conducted among 150 men and women with primary hyperparathyroidism.  Participants were either given 1,000 mg calcium carbonate or 1,000 mg calcium carbonate and 1,600 IU cholecalciferol daily for one year.  Results indicated that patients receiving the calcium and vitamin D supplement had lower parathyroid hormone levels and higher circulating levels of vitamin D in the body (p<0.05).  These results indicate that vitamin D may be useful for lowering parathyroid hormone levels, although it cannot be established that vitamin D alone will produce such effects (34).

In contrast, vitamin D supplementation was found to have no effect on parathyroid hormones in patients undergoing long-term dialysis treatments.  A total of 105 patients were given 50,000 IU of vitamin D weekly, monthly, or a placebo for twelve weeks.  While the supplementation was proven safe and effective for treating vitamin D deficiency within these patients, parathyroid hormone levels were not different between the three groups (35).

Vitamin D3 Possibly Helps Support Balanced Blood Sugar Levels:

Review of the literature suggests that vitamin D is not useful for treating diabetes, although it has been shown to slow the progression from prediabetes to diabetes.  In contrast, some research points to the effectiveness of vitamin D to treat gestational diabetes, although it did not appear to help prevent gestational diabetes.  Overall, the available data for vitamin D on diabetes is inconclusive.

A randomized, placebo-controlled trial examined the effect of vitamin D3 and calcium carbonate supplementation on insulin sensitivity, insulin secretion, and β-cell function.  95 adult patients who were at risk for diabetes ingested 2,000-6,000 IU of vitamin D3 and 1,200 mg of calcium carbonate, or a placebo daily for six months.  The authors found no significant changes in any category for those at risk of diabetes.  However, they did conclude that insulin sensitivity may be improved with vitamin D3 and calcium supplements in those that already have prediabetes (36).  Similar to these results, another study found that among adults with a vitamin D deficiency and prediabetes, vitamin D supplementation significantly slowed the progression to diabetes (p=0.04) and helped normalize blood glucose levels (p=0.02) (37).

The effects of vitamin D supplementation on long-term glycemic control was evaluated in patients with Type II diabetes in a prospective, randomized controlled trial.  After 129 patients received either 1,000 IU of vitamin D3 and 100 mg of calcium or a placebo daily for 24 weeks, there were no significant changes in glycemic control between the two groups (0=0.415) (38).  A similar study was conducted in 275 adults with type II diabetes who were not receiving insulin treatment. Patients were given either 50,000 IU of vitamin D3 or a placebo once a month, for six months.  At the end of the study period, there were no significant changes in measures of glycemic control, which included blood glucose levels, insulin resistance, and fasting insulin (p=0.42) (39).

Research conducted among pregnant women found that daily high dose (5,000 IU) vitamin D supplementation for about half the pregnancy did not improve glucose levels during pregnancy (40).  This suggests that vitamin D may not be useful for preventing gestational diabetes.  However, another randomized, double-blind, placebo-controlled trial gave pregnant women already diagnosed with gestational diabetes mellitus vitamin D3 supplements.  This research concluded that consuming two tablets containing 50,000 IU of vitamin D3 over six weeks led to a lowered fasting plasma glucose (p<0.001) and serum insulin (p<0.01) compared with a placebo (41).  This research may be indicative that vitamin D3 supplementation can help treat gestational diabetes.

SAFETY

Vitamin D3 is likely safe for most people who are deficient in the vitamin.  The supplement was found to be safe for patients with type II diabetes and insufficient levels of vitamin D in the blood (38), pregnant women of all races (42), and the elderly population (43).

Interactions:

Moderate

• Vitamin D can increase the amount of toxic elements that the body absorbs.  These elements include aluminum, lead, arsenic, strontium, and cobalt.  Taking vitamin D if you are exposed to these elements can be problematic.  Furthermore, taking medications that contain these toxins, such as antacids that contain aluminum, can become dangerous for some people with certain health conditions (44).
• Vitamin D assists the body in calcium uptake, which can affect the heart.  Taking vitamin D supplements in combination with heart medications such as digoxin, diltiazem, and verapamil can alter the effectiveness of these heart medications (45).
• Due to vitamin D increasing calcium absorption in the body, it may be harmful to take vitamin D in conjunction with thiazide diuretics, or water pills as these can increase the amount of calcium in the body as well (46).

Side-Effects:

• Majority of people do not experience side effects with vitamin D supplementation.  However, if too much vitamin D is in the body, symptoms such as nausea, vomiting, headache, fatigue, acute kidney damage, weight loss, constipation, pancreatitis, and confusion can occur (47).

REFERENCES

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43. Delomas C, Hertzog M, Vogel T, Lang P-O. Vitamin D supplementation in nursing home residents: Randomized single cholecalciferol loading protocol vs. individualized loading dose regimen. J Nutr Health Aging. 2017;21(4):421-428. doi:10.1007/s12603-016-0788-9
44. Moon J. The role of vitamin D in toxic metal absorption: a review. J Am Coll Nutr. 1994;13(6):559-564. doi:10.1080/07315724.1994.10718447
45. Schwalfenberg GK, Genuis SJ. Vitamin D, Essential Minerals, and Toxic Elements: Exploring Interactions between Nutrients and Toxicants in Clinical Medicine. Sci World J. 2015;2015:1-8. doi:10.1155/2015/318595
46. Parfitt AM. The interactions of thiazide diuretics with parathyroid hormone and vitamin D. J Clin Invest. 1972;51(7):1879-1888. doi:10.1172/JCI106990
47. Kaur P, Mishra SK, Mithal A. Vitamin D toxicity resulting from overzealous correction of vitamin D deficiency. Clin Endocrinol (Oxf). 2015;83(3):327-331. doi:10.1111/cen.12836

See the MedlinePlus entry for vitamin D, this American Academy of Family Physicians article on vitamin D, the National Institutes of Health Office of Dietary Supplements entry for vitamin D, the Mayo Clinic entry for vitamin D, the Examine.com entry for vitamin D, or the Drugs.com entry for vitamin D3 for more information.