▎ WuXi AppTec content team editor
We know that consuming 400 IU of vitamin D per day prevents rickets in infants and young children. However, whether vitamin D deficiency has an effect on bones in adults and the elderly (> 65 years old), and the potential effects of vitamin D on other health, has been controversial.
Vitamin D supplementation has not been shown to prevent the development of cancer, cardiovascular events, and type 2 diabetes. Other studies have found that vitamin D supplementation can help improve immunity and prevent bone loss. So what are the health effects of vitamin D supplementation?
A recent review, published in Nature Reviews Endocrinology, summarized data from randomized controlled trials (RCTs) and Mendelian randomized studies from 2017 to 2020, both of which focused on exploring causal associations, and discussed in depth the role and effects of vitamin D in common diseases.
Screenshot source: Nature Reviews Endocrinology
What are the effects of vitamin D supplementation?
The researchers note that the vitamin D mentioned in the article refers to vitamin D3 unless otherwise noted.
The vitamin D endocrine system includes the active form of vitamin D, precursor forms and metabolites of vitamin D, and vitamin D receptors (VDRs). As shown in the figure below, the vitamin D endocrine system has potential effects on both bone and skeletal target tissue.
Human observational data are largely consistent with preclinical data. However, Mendelian randomization studies and randomized controlled trials have not confirmed that vitamin D also has such a wide range of action characteristics in adults with adequate vitamin D. Given that the results of vitamin D studies vary from type to type of study, the health effects of vitamin D deficiency may remain controversial.
▲Target tissue and role of the vitamin D endocrine system. For example, to promote the balance of calcium and bone, balance the immune system, help the secretion of hormones, etc., the thickness of the arrow indicates the relationship between the vitamin D endocrine system and health effects. (Image source: References[1])
01
Type 2 Diabetes (T2DM)
Many studies have shown a link between low vitamin D status and T2DM. Meta-analyses have shown that vitamin D supplementation can reduce the risk of developing T2DM by about 10% compared to people who do not have vitamin D deficiency but prediabetes, or in people who take more than 1,000 IU of vitamin D per day and are not obese.
Although the conclusions of these meta-analyses are largely consistent, importantly, large RCTs only show a non-significant trend in slowing prediabete progression to T2DM. More or deeper analysis of existing studies is needed to validate these findings. In addition, all Mendelian randomized studies yielded contradictory results, none of which found a significant relationship between 25-hydroxyvitamin D and T2DM risk.
Overall, mendel randomization studies and the evidence for RCTs are consistent and do not yet support taking vitamin D supplements to prevent T2DM.
02
cancer
Strong preclinical data suggest that the relationship between vitamin D and cancer may be related to the cell cycle. There are many studies that point to a poor status of vitamin D that may be associated with an increased risk of cancer or a poor prognosis.
But there are also large RCTs and Mendelian randomized studies that have shown that vitamin D supplementation to adults who have an adequate intake of vitamin D does not seem to change the risk of various cancers. Meanwhile, vital trial data suggest that vitamin D supplementation is associated with a decline in cancer mortality over time. The researchers concluded that while a link between vitamin D status and cancer incidence or mortality could not be ruled out, it was difficult to verify.
03
Cardiovascular events
Whether vitamin D supplementation is beneficial for cardiovascular health remains controversial. Lower serum vitamin D concentrations have been associated with a 43% increased risk of cardiovascular disease, hypertension, and cardiovascular events (including ischemic heart disease, cardiomyopathy, congestive heart failure, stroke, etc.) compared with people with better vitamin D status (RR=1.43).
But there are plenty of studies that point to vitamin D supplementation that doesn't reduce the risk of cardiovascular disease. Even though vitamin D supplementation may be beneficial for blood pressure, the studies were smaller, and the association may be influenced by a variety of factors, such as other diets and lifestyles.
04
Bone health and muscle strength
Previous guidelines have agreed that serum 25-hydroxyvitamin D concentrations below 30 nmol/l are risk factors for rickets or osteomalacia. Therefore, it is recommended that daily supplementation of 400 IU of vitamin D prevents rickets and osteomalacia and makes serum concentrations of 25 hydroxyvitamin D well above 30 nmol/l.
However, the effects of vitamin D supplementation on fractures and muscle strength are controversial in adults and older adults, and the conclusions of various analyses vary. There is a large body of literature supporting that poor vitamin D condition is associated with an increased risk of falls; however, high doses of vitamin D (increasing serum 25-hydroxyvitamin D concentrations above 112 nmol/l) may increase the risk of falls in older adults.
The paper notes that for people with adequate vitamin D intake, vitamin D supplementation alone is unlikely to reduce fracture risk or improve bone mass. However, if calcium and vitamin D supplementation are combined, the incidence of hip and other bone (other than vertebrae) fractures can be reduced by about 20% in the elderly, especially those with poor vitamin D status and insufficient calcium intake.
The researchers recommend that all high-risk populations or older adults with vitamin D deficiency supplement with about 800 IU of vitamin D per day and consume more than 1,000 mg of calcium per day. It is important to note that it is recommended that the daily intake of vitamin D should not exceed 4000 IU in the elderly who are vitamin D deficient, as high doses of vitamin D may reduce bone density.
Image credit: 123RF
05
Autoimmune diseases
The paper notes that the adaptive immune system may be down-regulated by 1,25(OH)2D, so vitamin D deficiency can lead to autoimmune diseases, and the vitamin D endocrine system may affect all cells and most cytokines of the immune system.
Researchers have pointed out that poor vitamin D status is associated with an increased risk of infection or autoimmune diseases, such as multiple sclerosis (MS), inflammatory bowel disease, or type 1 diabetes. Strong evidence supports that hereditary low serum 25-hydroxyvitamin D levels are associated with an increased risk of MS; but the evidence is insufficient to support the association of vitamin D with systemic lupus erythematosus or rheumatoid arthritis.
In addition, at the same time that the review was published, another supplemental analysis study from the Harvard team based on the VITAL trial found that vitamin D supplementation alone was associated with a 32% reduction in the risk of autoimmune disease (HR= 0.68) for people who could not sunbathe all day and eat fish. The researchers also observed that the longer the supplementation, the more pronounced the effect appeared to be, and that in participants with low BMI, vitamin D supplementation had a stronger preventive effect on autoimmune diseases (P=0.02).
06
Diseases of the respiratory system
A growing body of research suggests that the lungs are an important target tissue for vitamin D, and that poor vitamin D status is associated with several inflammatory lung diseases or lung function. Some studies have pointed out that vitamin D supplementation to patients with severe vitamin D deficiency can reduce acute upper respiratory tract infections and moderately improve expiratory lung function, which is beneficial for participants in lung diseases such as chronic obstructive pulmonary disease and asthma.
However, analyses have shown that intermittent vitamin D supplementation (monthly or less frequent) does not have a protective effect on the respiratory system, but daily or weekly vitamin D supplementation may be effective in preventing acute respiratory infections. This may be related to the fact that 1,25(OH)2D stimulates the innate immune system.
07
pregnant
Studies have shown that vitamin D supplementation significantly reduces maternal morbidity and improves baby health compared to people who do not have vitamin D supplementation. Specifically, the maternal risk of developing preeclampsia and gestational diabetes was reduced by 52% (RR= 0.48) and 49% (RR = 0.51), respectively, and the risk of low birth weight (RR = 0.55) was reduced by 45%.
However, at present, there is insufficient evidence for causality, and the effect of vitamin D supplementation during pregnancy, or poor vitamin D status, on maternal and infant pregnancy outcomes remains undetermined.
08
Patients in intensive care
Although researchers have pointed out that serum 25 hydroxyvitamin D concentrations are generally low in patients with severe acute illness requiring intensive care, this poor vitamin D status is associated with increased morbidity and mortality. But studies of patients admitted to intensive care units (ICUs) to date have inconsistent results.
09
mortality
In all studies of vitamin D supplementation, participants with poor vitamin D status were found to have increased mortality, but whether vitamin D supplementation reduced mortality was controversial. Studies have shown that participants who received vitamin D supplements for a long time had an overall mortality rate reduction of about 11 percent; however, other studies have shown that vitamin D supplementation does not change mortality compared to those who do not.
Image credit: 123RF
Is vitamin D supplementation safe?
The researchers concluded that participants who intermittently injected high doses (4,000 IU to 10,000 IU) of vitamin D may have an increased risk of fractures and falls. However, a daily intake of 2,000 IU to 4,000 IU of vitamin D is safe in adults. In addition, there is some controversy about whether vitamin D supplementation increases the risk of kidney stones and whether it has an effect on serum calcium or urinary calcium.
summary
About 7% of people worldwide currently suffer from severe vitamin D deficiency or do not have access to normal doses of vitamin D, especially in many countries in the Middle East, North Africa and Asia. About one-third of people do not have optimal serum 25-hydroxyvitamin D concentrations (less than 20 ng/ml). The researchers point out that correcting severe vitamin D deficiencies is essential.
The Scientific Research Report on Dietary Guidelines for Chinese Residents (2021) points out the nutritional status of vitamin D in Chinese:
Children and adolescents aged 6-17 years: The serum vitamin D deficiency rate of children aged 6-17 years from 2016 to 2017 was 18.6%, of which 15.0% were boys and 22.7% were girls, 18.7% in urban areas and 18.5% in rural areas.
Adults: The vitamin D deficiency rate in adults aged 18 years and older was 21.4% in 2015, of which 16.1% were men and 26.8% were women; 24.7% in urban areas and 17.8% in rural areas.
Pregnant women: The median serum vitamin D concentration in pregnant women was 13.0 ng/mL in 2015, the median urban median was 12.9 ng/mL, and the median rural median was 13.2 ng/mL; the rate of vitamin D deficiency in pregnant women (43.0% in urban areas and 40.4% in rural areas).
Vitamin D is a general term for a class of hormones, most commonly vitamin D2 and vitamin D3. Vitamin D2 is mainly derived from plants or yeasts, and vitamin D3 is mainly transformed by subcutaneous cholesterol derivatives (7-dehydrocholesterol) under ultraviolet light exposure.
When daily sunshine is insufficient, vitamin D must be supplied by diet, such as animal liver, marine fish, egg yolks, lean meats, dairy products, etc. The Recommended Dietary Guidelines for Chinese Residents (2013) states that the recommended intake of vitamin D for people aged 1 to 60 years is 10 micrograms per day (equivalent to 400 IU). 400 to 450 IU of vitamin D per day is about the equivalent of eating 100 g of salmon, 300 g of sardines, and 750 g of yogurt.
Image credit: 123RF
However, large trials conducted between 2017 and 2020 in most adults with adequate vitamin D showed that vitamin D supplementation increased serum 25 hydroxyvitamin D concentrations to within normal high values and did not have overall benefits for global health, major diseases or medical events such as cancer, cardiovascular events, T2DM, falls or fractures. Therefore, there is currently no reason to recommend vitamin D supplementation for individuals who are no longer deficient in vitamin D. It is important to note that the above data do not contradict the dangers of severe vitamin D deficiency and the need to correct severe vitamin D deficiency in people of any age.