essay on vitamin d

Vitamin D is both a nutrient we eat and a hormone our bodies make. It is a fat-soluble vitamin that has long been known to help the body absorb and retain calcium and phosphorus ; both are critical for building bone. Also, laboratory studies show that vitamin D can reduce cancer cell growth, help control infections and reduce inflammation. Many of the body’s organs and tissues have receptors for vitamin D, which suggest important roles beyond bone health, and scientists are actively investigating other possible functions.

Few foods naturally contain vitamin D, though some foods are fortified with the vitamin. For most people, the best way to get enough vitamin D is taking a supplement because it is hard to eat enough through food. Vitamin D supplements are available in two forms: vitamin D2 (“ergocalciferol” or pre-vitamin D) and vitamin D3 (“cholecalciferol”). Both are also naturally occurring forms that are  produced in the presence of the sun’s ultraviolet-B (UVB) rays, hence its nickname, “the sunshine vitamin,” but D2 is produced in plants and fungi and D3 in animals, including humans. Vitamin D production in the skin is the primary natural source of vitamin D, but many people have insufficient levels because they live in places where sunlight is limited in winter, or because they have limited sun exposure due to being inside much of the time. Also, people with darker skin tend to have lower blood levels of vitamin D because the pigment (melanin) acts like a shade, reducing production of vitamin D (and also reducing damaging effects of sunlight on skin, including skin cancer).

Recommended Amounts

The Recommended Dietary Allowance for vitamin D provides the daily amount needed to maintain healthy bones and normal calcium metabolism in healthy people. It assumes minimal sun exposure.

RDA: The Recommended Dietary Allowance for adults 19 years and older is 600 IU (15 mcg) daily for men and women, and for adults >70 years it is 800 IU (20 mcg) daily.

UL: The Tolerable Upper Intake Level is the maximum daily intake unlikely to cause harmful effects on health. The UL for vitamin D for adults and children ages 9+ is 4,000 IU (100 mcg).

Many people may not be meeting the minimum requirement for the vitamin. NHANES data found that the median intake of vitamin D from food and supplements in women ages 51 to 71 years was 308 IU daily, but only 140 IU from food alone (including fortified products). [1] Worldwide, an estimated 1 billion people have inadequate levels of vitamin D in their blood, and deficiencies can be found in all ethnicities and age groups. [2-4] In the U.S., about 20% of White adults and 75% of Black adults have blood levels of vitamin D below 50 nmol/L. [83] In industrialized countries, doctors are seeing the resurgence of rickets, the bone-weakening disease that had been largely eradicated through vitamin D fortification. [5-7] There is scientific debate about how much vitamin D people need each day and what the optimal serum levels should be to prevent disease. The Institute of Medicine (IOM) released in November 2010 recommendations increasing the daily vitamin D intake for children and adults in the U.S. and Canada, to 600 IU per day. [1] The report also increased the upper limit from 2,000 to 4,000 IU per day. Although some groups such as The Endocrine Society recommend 1,500 to 2,000 IU daily to reach adequate serum levels of vitamin D, the IOM felt there was not enough evidence to establish a cause and effect link with vitamin D and health benefits other than for bone health.  Since that time, new evidence has supported other benefits of consuming an adequate amount of vitamin D, although there is still not consensus on the amount considered to be adequate.

Vitamin D and Health

The role of vitamin D in disease prevention is a popular area of research, but clear answers about the benefit of taking amounts beyond the RDA are not conclusive. Although observational studies see a strong connection with lower rates of certain diseases in populations that live in sunnier climates or have higher serum levels of vitamin D, clinical trials that give people vitamin D supplements to affect a particular disease are still inconclusive. This may be due to different study designs, differences in the absorption rates of vitamin D in different populations, and different dosages given to participants. Learn more about the research on vitamin D and specific health conditions and diseases:  

Several studies link low vitamin D blood levels with an increased risk of fractures in older adults. Some studies suggest that vitamin D supplementation in certain amounts may prevent such fractures, while others do not. [8-11]

• A meta-analysis of 12 randomized controlled trials that included more than 42,000 people 65+ years of age, most of them women, looked at vitamin D supplementation with or without calcium, and with calcium or a placebo. Researchers found that higher intakes of vitamin D supplements—about 500-800 IU per day—reduced hip and non-spine fractures by about 20%, while lower intakes (400 IU or less) failed to offer any fracture prevention benefit. [12]
• A systematic review looked at the effect of vitamin D supplements taken with or without calcium on the prevention of hip fractures (primary outcome) and fractures of any type (secondary outcome) in older men and postmenopausal women 65+ years of age. It included 53 clinical trials with 91,791 participants who lived independently or in a nursing home or hospital. It did not find a strong association between vitamin D supplements alone and prevention of fractures of any type. However, it did find a small protective effect from all types of fractures when vitamin D was taken with calcium. All of the trials used vitamin D supplements containing 800 IU or less. [13]
• The VITamin D and OmegA-3 TriaL (VITAL) double-blind placebo-controlled randomized trial of 25,871 women and men, 55+ years and 50+ years of age, respectively, did not find a protective effect from vitamin D supplements on bone fractures. [81] The participants were healthy at the start of the study—representative of the general population and not selected based on low bone mass, osteoporosis, or vitamin D deficiency—and were given either 2,000 IU of vitamin D or a placebo taken daily for about five years. Vitamin D did not lower the incidence of total bone fractures or fractures of the hip or spine.

Vitamin D may help increase muscle strength by preserving muscle fibers, which in turn helps to prevent falls, a common problem that leads to substantial disability and death in older people. [14–16] A combined analysis of multiple studies found that taking 700 to 1,000 IU of vitamin D per day lowered the risk of falls by 19%, but taking 200 to 600 IU per day did not offer any such protection. [17] However, the VITAL trial following healthy middle-aged men and women did not find that taking 2,000 IU of vitamin D daily compared with a placebo pill reduced the risk of falls. [82]

Though taking up to 800 IU of vitamin D daily may benefit bone health in some older adults, it is important to be cautious of very high dosage supplements. A clinical trial that gave women 70+ years of age a once-yearly dosage of vitamin D at 500,000 IU for five years caused a 15% increased risk of falls and a 26% higher fracture risk than women who received a placebo. [18] It was speculated that super-saturating the body with a very high dose given infrequently may have actually promoted lower blood levels of the active form of vitamin D that might not have occurred with smaller, more frequent doses. [13]

JoAnn Manson, MD, DrPH , leader of the main VITAL trial and coauthor of the report on fracture, commented:

“We conclude that, in the generally healthy U.S. population of midlife and older adults, vitamin D supplementation doesn’t reduce the risk of fractures or falls. This suggests that only small-to-moderate amounts of vitamin D are needed for bone health and fall prevention, achieved by most community-dwelling adults. Of course, vitamin D deficiency should always be treated and some high-risk patients with malabsorption syndromes, osteoporosis, or taking medications that interfere with vitamin D metabolism will benefit from supplementation.”

Nearly 30 years ago, researchers noticed an intriguing relationship between colon cancer deaths and geographic location: People who lived at higher latitudes, such as in the northern U.S., had higher rates of death from colon cancer than people who lived closer to the equator. [19] Many scientific hypotheses about vitamin D and disease stem from studies that have compared solar radiation and disease rates in different countries. These studies can be a good starting point for other research but don’t provide the most definitive information. The sun’s UVB rays are weaker at higher latitudes, and in turn, people’s vitamin D blood levels in these locales tend to be lower. This led to the hypothesis that low vitamin D levels might somehow increase colon cancer risk. [3]

Animal and laboratory studies have found that vitamin D can inhibit the development of tumors and slow the growth of existing tumors including those from the breast, ovary, colon, prostate, and brain. In humans, epidemiological studies show that higher serum levels of vitamin D are associated with substantially lower rates of colon, pancreatic, prostate, and other cancers , with the evidence strongest for colorectal cancer. [20-32]

However, clinical trials have not found a consistent association:

The Women’s Health Initiative trial, which followed roughly 36,000 women for an average of seven years, failed to find any reduction in colon or breast cancer risk in women who received daily supplements of 400 IU of vitamin D and 1,000 mg of calcium, compared with those who received a placebo. [33,34] Limitations of the study were suggested: 1) the relatively low dose of vitamin D given, 2) some people in the placebo group decided on their own to take extra calcium and vitamin D supplements, minimizing the differences between the placebo group and the supplement group, and 3) about one-third of the women assigned to vitamin D did not take their supplements. 4) seven years may be too short to expect a reduction in cancer risk. [35,36]

A large clinical trial called the VITamin D and OmegA-3 TriaL (VITAL) followed 25,871 men and women 50+ years of age free of any cancers at the start of the study who took either a 2,000 IU vitamin D supplement or placebo daily for a median of five years. [37] The findings did not show significantly different rates of breast, prostate, and colorectal cancer between the vitamin D and placebo groups. The authors noted that a longer follow-up period would be necessary to better assess potential effects of supplementation, as many cancers take at least 5-10 years to develop.

Although vitamin D does not seem to be a major factor in reducing cancer incidence, evidence including that from randomized trials suggests that having higher vitamin D status may improve survival if one develops cancer.  In the VITAL trial, a lower death rate from cancer was observed in those assigned to take vitamin D, and this benefit seemed to increase over time since starting on vitamin D. A meta-analysis of randomized trials of vitamin D, which included the VITAL study, found a 13% statistically significant lower risk of cancer mortality in those assigned to vitamin D compared to placebo. [38] These findings are consistent with observational data, which suggest that vitamin D may have a stronger effect on cancer progression than for incidence.  

The heart is basically a large muscle, and like skeletal muscle, it has receptors for vitamin D. [39] Immune and inflammatory cells that play a role in cardiovascular disease conditions like atherosclerosis are regulated by vitamin D. [40] The vitamin also helps to keep arteries flexible and relaxed, which in turn helps to control high blood pressure. [41]

In the Health Professionals Follow-up Study nearly 50,000 healthy men were followed for 10 years. [42] Those who had the lowest levels of vitamin D were twice as likely to have a heart attack as men who had the highest levels. Meta-analyses of epidemiological studies have found that people with the lowest serum levels of vitamin D had a significantly increased risk of strokes and any heart disease event compared with those with the highest levels. [40;43-46]

However, taking vitamin D supplements has not been found to reduce cardiovascular risk. A meta-analysis of 51 clinical trials did not demonstrate that vitamin D supplementation lowered the risk of heart attack, stroke, or deaths from cardiovascular disease. [47] The VITamin D and OmegA-3 TriaL (VITAL) came to the same conclusion; it followed 25,871 men and women free of cardiovascular disease who took either a 2,000 IU vitamin D supplement or placebo daily for a median of five years. No association was found between taking the supplements and a lower risk of major cardiovascular events (heart attack, stroke, or death from cardiovascular causes) compared with the placebo. [37]  

Vitamin D deficiency may negatively affect the biochemical pathways that lead to the development of Type 2 diabetes (T2DM), including impairment of beta cell function in the pancreas, insulin resistance, and inflammation. Prospective observational studies have shown that higher vitamin D blood levels are associated with lower rates of T2DM. [48]

More than 83,000 women without diabetes at baseline were followed in the Nurses’ Health Study for the development of T2DM. Vitamin D and calcium intakes from diet and supplements were assessed throughout the 20-year study. [49] The authors found that when comparing the women with the highest intakes of vitamin D from supplements with women with the lowest intakes, there was a 13% lower risk of developing T2DM. The effect was even stronger when vitamin D was combined with calcium: there was a 33% lower risk of T2DM in women when comparing the highest intakes of calcium and vitamin D from supplements (>1,200 mg, >800 IU daily) with the lowest intakes (<600 mg, 400 IU).

A randomized clinical trial gave 2,423 adults who had prediabetes either 4000 IU of vitamin D or a placebo daily for two years. The majority of participants did not have vitamin D deficiency at the start of the study. At two years, vitamin D blood levels in the supplement versus placebo group was 54.3 ng/mL versus 28.2 ng/mL, respectively, but no significant differences were observed in rates of T2DM at the 2.5 year follow-up. [50] The authors noted that a lack of effect of vitamin D may have been due to the majority of participants having vitamin D blood levels in a normal range of greater than 20 ng/mL, which is considered an acceptable level to reduce health risks.  Notably, among the participants who had the lowest blood levels of vitamin D at the beginning of the study, vitamin D supplementation did reduce risk of diabetes. This is consistent with the important concept that taking additional vitamin D may not benefit those who already have adequate blood levels, but those with initially low blood levels may benefit.

Vitamin D’s role in regulating the immune system has led scientists to explore two parallel research paths: Does vitamin D deficiency contribute to the development of multiple sclerosis, type 1 diabetes, and other so-called “autoimmune” diseases, where the body’s immune system attacks its own organs and tissues? And could vitamin D supplements help boost our body’s defenses to fight infectious disease, such as tuberculosis and seasonal flu?

Multiple Sclerosis The rate of multiple sclerosis (MS) is increasing in both developed and developing countries, with an unclear cause. However, a person’s genetic background plus environmental factors including inadequate vitamin D and UVB exposure have been identified to increase risk. [51] Vitamin D was first proposed over 40 years ago as having a role in MS given observations at the time including that rates of MS were much higher far north (or far south) of the equator than in sunnier climates, and that geographic regions with diets high in fish had lower rates of MS. [52] A prospective study of dietary intake of vitamin D found women with daily intake above 400 IU had a 40% lower risk of MS. [53] In a study among healthy young adults in the US, White men and women with the highest vitamin D serum levels had a 62% lower risk of developing MS than those with the lowest vitamin D levels. [54] The study didn’t find this effect among Black men and women, possibly because there were fewer Black study participants and most of them had low vitamin D levels, making it harder to find any link between vitamin D and MS if one exists. Another prospective study in young adults from Sweden also found a 61% lower risk of MS with higher serum vitamin D levels; [55] and a prospective study among young Finnish women found that low serum vitamin D levels were associated with a 43% increased risk of MS. [56] In prospective studies of persons with MS, higher vitamin D levels have been associated with reduced disease activity and progression. [57,58] While several clinical trials are underway to examine vitamin D as a treatment in persons with MS, there are no clinical trials aimed at prevention of MS, likely because MS is a rare disease and the trial would need to be large and of long duration. Collectively, the current evidence suggests that low vitamin D may have a causal role in MS and if so, approximately 40% of cases may be prevented by correcting vitamin D insufficiency. [59] This conclusion has been strengthened substantially by recent evidence that genetically determined low levels of vitamin D predict higher risk of multiple sclerosis.

Type 1 Diabetes Type 1 diabetes (T1D) is another disease that varies with geography—a child in Finland is about 400 times more likely to develop T1D than a child in Venezuela. [60] While this may largely be due to genetic differences, some studies suggest that T1D rates are lower in sunnier areas. Early evidence suggesting that vitamin D may play a role in T1D comes from a 30-year study that followed more than 10,000 Finnish children from birth: Children who regularly received vitamin D supplements during infancy had a nearly 90% lower risk of developing type 1 diabetes than those who did not receive supplements. [61] However, multiple studies examining the association between dietary vitamin D or trials supplementing children at high risk for T1D with vitamin D have produced mixed and inconclusive results [62] Approximately 40% of T1D cases begin in adulthood. A prospective study among healthy young adults in the US found that White individuals with the highest levels of serum vitamin D had a 44% lower risk of developing T1D in adulthood than those with the lowest levels. [63] No randomized controlled trials on vitamin D and adult onset T1D have been conducted, and it is not clear that they would be possible to conduct. More research is needed in this area.

Flu and the Common Cold The flu virus wreaks the most havoc in the winter, abating in the summer months. This seasonality led a British doctor to hypothesize that a sunlight-related “seasonal stimulus” triggered influenza outbreaks. [64] More than 20 years after this initial hypothesis, several scientists published a paper suggesting that vitamin D may be the seasonal stimulus. [65] Among the evidence they cite:

• Vitamin D levels are lowest in the winter months. [65]
• The active form of vitamin D tempers the damaging inflammatory response of some white blood cells, while it also boosts immune cells’ production of microbe-fighting proteins. [65]
• Children who have vitamin D-deficiency rickets are more likely to get respiratory infections, while children exposed to sunlight seem to have fewer respiratory infections. [65]
• Adults who have low vitamin D levels are more likely to report having had a recent cough, cold, or upper respiratory tract infection. [66]

A randomized controlled trial in Japanese school children tested whether taking daily vitamin D supplements would prevent seasonal flu. [67] The trial followed nearly 340 children for four months during the height of the winter flu season. Half of the study participants received pills that contained 1,200 IU of vitamin D; the other half received placebo pills. Researchers found that type A influenza rates in the vitamin D group were about 40% lower than in the placebo group; there was no significant difference in type B influenza rates.

Although randomized controlled trials exploring the potential of vitamin D to prevent other acute respiratory infections have yielded mixed results, a large meta-analysis of individual participant data indicated that daily or weekly vitamin D supplementation lowers risk of acute respiratory infections. [68] This effect was particularly prominent for very deficient individuals.

The findings from this large meta-analysis have raised the possibility that low vitamin D levels may also increase risk of or severity of novel coronavirus 2019 (COVID-19) infection. Although there is no direct evidence on this issue because this such a new disease, avoiding low levels of vitamin D makes sense for this and other reasons. Thus, if there is reason to believe that levels might be low, such as having darker skin or limited sun exposure, taking a supplement of 1000 or 2000 IU per day is reasonable. This amount is now part of many standard multiple vitamin supplements and inexpensive.

More research is needed before we can definitively say that vitamin D protects against the flu and other acute respiratory infections. Even if vitamin D has some benefit, don’t skip your flu shot. And when it comes to limiting risk of COVID-19, it is important to practice careful social distancing and hand washing.

Tuberculosis Before the advent of antibiotics, sunlight and sun lamps were part of the standard treatment for tuberculosis (TB). [69] More recent research suggests that the “sunshine vitamin” may be linked to TB risk. Several case-control studies, when analyzed together, suggest that people diagnosed with tuberculosis have lower vitamin D levels than healthy people of similar age and other characteristics. [70] Such studies do not follow individuals over time, so they cannot tell us whether vitamin D deficiency led to the increased TB risk or whether taking vitamin D supplements would prevent TB. There are also genetic differences in the receptor that binds vitamin D, and these differences may influence TB risk. [71] Again, more research is needed.

Other A utoimmune Conditions The Vitamin D and Omega 3 trial (VITAL), a randomized double-blind placebo-controlled trial following more than 25,000 men and women ages 50 and older, found that taking vitamin D supplements (2,000 IU/day) for five years, or vitamin D supplements with marine omega-3 fatty acids (1,000 mg/day), reduced the incidence of autoimmune diseases by about 22%, compared with a placebo. Autoimmune conditions observed included rheumatoid arthritis, psoriasis, polymyalgia rheumatica, and autoimmune thyroid diseases (Hashimoto’s thyroiditis, Graves’ disease). [80]   The doses in these supplements are widely available and generally well-tolerated. The authors recommended additional trials to test the effectiveness of these supplements in younger populations and those at high risk of developing autoimmune diseases.

• A promising report in the Archives of Internal Medicine suggests that taking vitamin D supplements may reduce overall mortality rates: A combined analysis of multiple studies found that taking modest levels of vitamin D supplements was associated with a statistically significant 7% reduction in mortality from any cause. [72] The analysis looked at the findings from 18 randomized controlled trials that enrolled a total of nearly 60,000 study participants; most of the study participants took between 400 and 800 IU of vitamin D per day for an average of five years. Keep in mind that this analysis has several limitations, chief among them the fact that the studies it included were not designed to explore mortality in general, or explore specific causes of death.  A recent meta-analysis suggests that this reduction in mortality is driven mostly by a reduction in cancer mortality. [38] More research is needed before any broad claims can be made about vitamin D and mortality. [73]
• A large cohort study of more than 307,000 White European participants found a 25% increased risk of premature deaths from any cause in those who had vitamin D blood levels of 25 nmol/L (10 ng/ml), compared with those who had 50 nmol/L (20 ng/ml) (the National Academy of Medicine cites a vitamin D blood level of 50 nmol/L as adequate for most people). [74] Similar increases in risks were seen for deaths due to cardiovascular disease, cancer, and respiratory disease, and risks increased sharply among those with even lower levels of vitamin D. Although the numbers of non-White participants were small, the findings were similar in this group. The study used Mendelian randomization, which measured genetic variations to confirm these findings. This confirmation is important because it documents that the adverse health outcomes among people with low levels of vitamin D represent a causal relationship between vitamin D deficiency and premature death. Specifically, this method removed potential confounding by factors such as obesity, smoking, and alcohol intake.

In an analysis of more than 427,000 White European participants using Mendelian randomization, a 54% higher risk of dementia was seen among participants with low vitamin D blood levels of <25 nmol/L compared with those having adequate levels of 50 nmol/L. [75]

Food Sources

Few foods are naturally rich in vitamin D3. The best sources are the flesh of fatty fish and fish liver oils. Smaller amounts are found in egg yolks, cheese, and beef liver. Certain mushrooms contain some vitamin D2; in addition some commercially sold mushrooms contain higher amounts of D2 due to intentionally being exposed to high amounts of ultraviolet light. Many foods and supplements are fortified with vitamin D like dairy products and cereals.

• Cod liver oil
• Orange juice fortified with vitamin D
• Dairy and plant milks fortified with vitamin D
• Fortified cereals

Is There a Difference Between Vitamin D3 and Vitamin D2 Supplements?

Ultraviolet light.

Vitamin D3 can be formed when a chemical reaction occurs in human skin, when a steroid called 7-dehydrocholesterol is broken down by the sun’s UVB light or so-called “tanning” rays. The amount of the vitamin absorbed can vary widely. The following are conditions that decrease exposure to UVB light and therefore lessen vitamin D absorption:

• Use of sunscreen; correctly applied sunscreen can reduce vitamin D absorption by more than 90%. [78]
• Wearing full clothing that covers the skin.
• Spending limited time outdoors.
• Darker skin tones due to having higher amounts of the pigment melanin, which acts as a type of natural sunscreen. [79]
• Older ages when there is a decrease in 7-dehydrocholesterol levels and changes in skin, and a population that is likely to spend more time indoors.
• Certain seasons and living in northern latitudes above the equator where UVB light is weaker. [78] In the northern hemisphere, people who live in Boston (U.S.), Edmonton (Canada), and Bergen (Norway) can’t make enough vitamin D from the sun for 4, 5, and 6 months out of the year, respectively. [78] In the southern hemisphere, residents of Buenos Aires (Argentina) and Cape Town (South Africa) make far less vitamin D from the sun during their winter months (June through August) than they can during their spring and summer months. [78] The body stores vitamin D from summer sun exposure, but it must last for many months. By late winter, many people in these higher-latitude locales are deficient. [79]

Note that because ultraviolet rays can cause skin cancer, it is important to avoid excessive sun exposure and in general, tanning beds should not be used.

Signs of Deficiency and Toxicity

Vitamin D deficiency may occur from a lack in the diet, poor absorption, or having a metabolic need for higher amounts. If one is not eating enough vitamin D and does not receive enough ultraviolet sun exposure over an extended period (see section above), a deficiency may arise. People who cannot tolerate or do not eat milk, eggs, and fish, such as those with a lactose intolerance or who follow a vegan diet, are at higher risk for a deficiency. Other people at high risk of vitamin D deficiency include:

• People with inflammatory bowel disease (ulcerative colitis, Crohn’s disease) or other conditions that disrupt the normal digestion of fat. Vitamin D is a fat-soluble vitamin that depends on the gut’s ability to absorb dietary fat.
• People who are obese tend to have lower blood vitamin D levels. Vitamin D accumulates in excess fat tissues but is not easily available for use by the body when needed. Higher doses of vitamin D supplementation may be needed to achieve a desirable blood level. Conversely, blood levels of vitamin D rise when obese people lose weight.
• People who have undergone gastric bypass surgery, which typically removes the upper part of the small intestine where vitamin D is absorbed.

Conditions resulting from prolonged vitamin D deficiency:

• Rickets: A condition in infants and children of soft bones and skeletal deformities caused by failure of bone tissue to harden.
• Osteomalacia: A condition in adults of weak and softened bones that can be reversed with supplementation. This is different than osteoporosis, in which the bones are porous and brittle and the condition is irreversible.

Vitamin D toxicity most often occurs from taking supplements. The low amounts of the vitamin found in food are unlikely to reach a toxic level, and a high amount of sun exposure does not lead to toxicity because excess heat on the skin prevents D3 from forming. It is advised to not take daily vitamin D supplements containing more than 4,000 IU unless monitored under the supervision of your doctor.

Symptoms of toxicity:

• Weight loss
• Irregular heart beat
• Hardening of blood vessels and tissues due to increased blood levels of calcium, potentially leading to damage of the heart and kidneys

Did You Know?

Catching the sun’s rays in a sunny office or driving in a car unfortunately won’t help to obtain vitamin D as window glass completely blocks UVB ultraviolet light.

Vitamins and Minerals

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• Mitri J, Pittas AG. Vitamin D and diabetes. Endocrinol Metab Clin North Am . 2014 Mar;43(1):205-32.
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• Ascherio A, Munger KL, White R, Köchert K, Simon KC, Polman CH, Freedman MS, Hartung HP, Miller DH, Montalbán X, Edan G. Vitamin D as an early predictor of multiple sclerosis activity and progression. JAMA neurology . 2014 Mar 1;71(3):306-14.
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• Munger KL, Levin LI, Massa J, Horst R, Orban T, Ascherio A. Preclinical serum 25-hydroxyvitamin D levels and risk of type 1 diabetes in a cohort of US military personnel. American journal of epidemiology . 2013 Mar 1;177(5):411-9.
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• Ginde AA, Mansbach JM, Camargo CA. Association between serum 25-hydroxyvitamin D level and upper respiratory tract infection in the Third National Health and Nutrition Examination Survey. Archives of internal medicine . 2009 Feb 23;169(4):384-90.
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• LeBoff MS, Murata EM, Cook NR, Cawthon P, Chou SH, Kotler G, Bubes V, Buring JE, Manson JE. VITamin D and OmegA-3 TriaL (VITAL): effects of vitamin D supplements on risk of falls in the US population. The Journal of Clinical Endocrinology & Metabolism . 2020 Sep;105(9):2929-38.
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Last reviewed March 2023

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The Benefits vs. Side Effects of Vitamin D

• Effect on the Body
• How to Get Vitamin D
• Signs You Need More
• Side Effects of High Levels

Dosing Vitamin D

Frequently asked questions.

Vitamin D , also known as calciferol, is a fat-soluble vitamin essential for physical and mental health. The two primary forms of vitamin D are vitamin D2 ( ergocalciferol ), found in plants, and vitamin D3 ( cholecalciferol ), found in animal tissues.

Vitamin D is essential for immune system function and bone health. It may also influence mood regulation and reduce the risk of several chronic health conditions.

This article looks at vitamin D's benefits and side effects, deficiency symptoms, and how much you should consume each day.

Grace Cary / Getty Images

Effect of Vitamin D on the Body

Vitamin D helps the body retain and absorb calcium and phosphorus, which are important for building and maintaining healthy bones and teeth. Your nerves need vitamin D to carry messages between your brain and body, your immune system needs it to fight off bacteria and viruses, and your muscles need it to move.

Studies have shown that vitamin D may affect our mental health by reducing negative emotions. Researchers noted that individuals with major depressive disorder and vitamin D deficiency are most likely to benefit from supplementation.

Vitamin D deficiency can lead to decreased bone density, which can eventually cause osteoporosis and broken bones. In adults, a severe deficiency can also result in osteomalacia , which causes muscle and bone pain and weakness.

While more research is needed, several studies link vitamin D deficiency to several health conditions, including:

• High blood pressure ( hypertension )
• Autoimmune diseases like multiple sclerosis

Vitamin D and Children

Vitamin D is important for children because it helps build strong bones and protects against rickets . This rare condition affects bone development, primarily in the first two years of life. The vitamin also protects against broken bones in children and teens.

Different Ways to Get Vitamin D

Your body makes vitamin D when it’s exposed directly to sunlight. However, prolonged sun exposure is advised against because it can increase your risk of other ailments, such as premature aging and skin cancer . Additionally, most people get less vitamin D during the winter months because of insufficient exposure to sunlight.

This makes it necessary to get vitamin D from other sources. Because vitamin D is not naturally present in many foods, fortified foods provide most of the vitamin D in the American diet.

Dietary sources of vitamin D include:

• Fatty fish, such as tuna, salmon, and mackerel
• Fortified dairy products
• Fortified breakfast cereals and orange juice

What Are Signs You Need Vitamin D?

Vitamin D deficiencies are relatively common throughout the United States. Many people with vitamin D deficiency have no symptoms. However, a deficiency may cause the following symptoms:

• Muscle pain
• Muscle weakness
• Dental problems
• Cognitive impairment

Risk Factors

You may have a greater risk of developing vitamin D deficiency if you take medications that interfere with vitamin D metabolism or if you have the following conditions:

• A history of gastric bypass surgery (a type of weight-loss surgery)
• Celiac disease (immune reaction to the protein gluten found in wheat, barley, and rye)
• Osteoporosis (reduced bone mineral density causing weak and brittle bones)
• Chronic kidney disease or liver disease
• Crohn's disease (an inflammatory bowel disease causing chronic inflammation of the digestive tract)
• Sarcoidosis (autoimmune disease causing collections of inflammatory tissue in parts of your body)
• Histoplasmosis (infection caused by breathing in fungal spores)
• Tuberculosis (infectious lung disease mainly caused by a bacterium)
• Hyperparathyroidism (parathyroid glands release too much hormone, raising calcium levels)

Your healthcare provider can order a blood test to measure the level of vitamin D in your blood. If your levels are low, your provider will likely recommend taking a vitamin D supplement to correct the deficiency.

Side Effects of High Vitamin D Levels

Vitamin D toxicity is unlikely to occur from diet or excess sun exposure since your body can control the amount of vitamin D it makes from the sun. In most cases, toxicity occurs due to the overuse of vitamin D supplements .

The main side effect of vitamin D toxicity is a condition called hypercalcemia , in which too much calcium builds up in the blood, causing symptoms like:

• Nausea, vomiting
• Decreased appetite
• Generalized pain
• Excessive thirst and urination
• Dehydration
• Kidney stones

Extremely high vitamin D levels can cause more serious side effects, including irregular heartbeat , kidney failure, and death.

Vitamin D intake is measured in international units (IU) and micrograms (mcg). The amount of vitamin D you need daily depends on your age and other health factors.

The daily vitamin D requirements are:

When to Take Vitamin D: Morning or Night?

Though some anecdotal reports claim that taking vitamin D before bed suppresses melatonin production and negatively impacts sleep quality, there is no solid evidence to support this theory. You can take vitamin D supplements any time of the day.

However, because vitamin D is a fat-soluble vitamin , it is best taken with meals or snacks containing fat, which helps your body better absorb the vitamin.

Vitamin D is involved in many bodily functions and plays a vital role in immune health and maintaining healthy bones and teeth. It may also help improve mood and protect against certain diseases. Vitamin D is found in some food products, such as fatty fish and fortified dairy foods.

The potential benefits of vitamin D supplementation are more significant in people with a confirmed vitamin D deficiency. Boost your vitamin D intake by making simple dietary changes, spending a safe amount of time in the sun, eating a balanced diet, and taking supplements.

Vitamin D deficiency can cause fatigue. Studies have shown that vitamin D supplementation may improve fatigue in otherwise healthy individuals with vitamin D deficiency.

It usually takes a few months to raise vitamin D levels with consistent supplementation.

Symptoms of low vitamin D levels can include fatigue, muscle pain or weakness, bone pain, depression, and cognitive impairment.

Mohammad S, Mishra A, Ashraf MZ. Emerging role of vitamin d and its associated molecules in pathways related to pathogenesis of thrombosis .  Biomolecules . 2019;9(11):649. doi:10.3390/biom9110649

National Institutes of Health. Vitamin D : Consumer fact sheet .

Cheng Y, Huang Y, Huang W. The effect of vitamin D supplement on negative emotions: A systematic review and meta‐analysis .  Depress Anxiety . 2020;37(6):549-564. doi:10.1002/da.23025

MedlinePlus. Vitamin D deficiency .

American Academy of Pediatrics. Vitamin D for babies, children & adolescents .

National Institutes of Health. Vitamin D: Health professional .

Nowak A, Boesch L, Andres E, et al. Effect of vitamin D3 on self-perceived fatigue: A double-blind randomized placebo-controlled trial .  Medicine . 2016;95(52):e5353. doi:10.1097/MD.0000000000005353

Nowak A, Boesch L, Andres E, et al. Effect of vitamin D3 on self-perceived fatigue .  Medicine (Baltimore) . 2016;95(52):e5353. doi: 10.1097/MD.0000000000005353

By Lindsey DeSoto, RD, LD Desoto is a registered dietitian specializing in nutrition and health and wellness content.

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Vitamin D for the Prevention of Disease Guideline Resources

June 3, 2024

Vitamin D for the Prevention of Disease: An Endocrine Society Clinical Practice Guideline JCEM  | August 2024 (online June 2024)

Marie B. Demay (Chair), Anastassios G. Pittas (Co-Chair), Daniel D. Bikle, Dima L. Diab, Mairead E. Kiely, Marise Lazaretti-Castro, Paul Lips, Deborah M. Mitchell, M. Hassan Murad, Shelley Powers, Sudhaker D. Rao, Robert Scragg, John A. Tayek, Amy M. Valent, Judith M. E. Walsh, Christopher R. McCartney

The 2024 guideline on vitamin D for the prevention of disease:

• Updates and replaces the 2011 Evaluation, Treatment, and Prevention of Vitamin D Deficiency guideline and focuses on the use of vitamin D to lower the risk of disease in individuals without established indications for vitamin D treatment or 25(OH)D testing.

A Systematic Review Supporting the Endocrine Society Clinical Practice Guidelines on Vitamin D

Navigating Complexities: Vitamin D, Skin Pigmentation, and Race: An Endocrine Society Guideline Communication 

Vitamin D Insufficiency and Epistemic Humility: An Endocrine Society Guideline Communication

• Clinician Education Presentation (Free CME) | Endocrine Society
• Patient Resource | Patient Engagement (LINK COMING SOON)
• Guidelines Pocket Card | Guideline Central
• Guideline Feature Article | Endocrine News

Essential Points

• Numerous studies demonstrate an association between serum concentrations of 25-hydroxyvitamin D (25[OH]D) and a variety of common disorders including musculoskeletal, metabolic, cardiovascular, malignant, autoimmune, and infectious diseases. This has led to widespread supplementation with vitamin D supplementation and increased laboratory testing for 25(OH)D in the general population.
• The benefit-risk ratio of this increase in vitamin D supplementation is not clear, and the optimal vitamin D intake and serum 25(OH)D concentrations for disease prevention remain uncertain.
• This guideline offers clinical guidelines for the use of vitamin D to lower the risk of disease in individuals without established indications for vitamin D treatment or 25(OH)D testing.

List of Recommendations

Question 1. Should empiric vitamin D supplementation vs no empiric vitamin D supplementation be used for children and adolescents (ages 1-18 years)?

Recommendation 1

In children and adolescents ages 1-18 years, we suggest empiric vitamin D supplementation to prevent nutritional rickets and potentially lower the risk of respiratory tract infections. (2 | ⊕⊕ OO )

Technical remarks:

• Empiric vitamin D may include daily intake of fortified foods, vitamin formulations that contain vitamin D and/or daily intake of a vitamin D supplement (pill or drops).
• In the clinical trials included in the SR, with respect to respiratory tract infections in children, vitamin D doses ranged from 300 to 2000 IU (7.5 to 50 μg ) daily equivalent. The estimated weighted average was approximately 1200 IU (30 μg ) per day.

Question 2. Should empiric vitamin D supplementation vs no empiric vitamin D supplementation be used for nonpregnant adults <50 years of age?

Question 3. Should vitamin D supplementation vs no vitamin D supplementation be used for nonpregnant adults <50 years of age only when 25(OH)D levels are below a threshold?

Recommendation 2

In the general adult population younger than age 50 years, we suggest against empiric vitamin D supplementation. (2 | ⊕ OOO )

Technical remark:

• This recommendation relates to empiric vitamin D supplementation that exceeds the DRIs established by the IOM. Adults in this age group should follow the Recommended Daily Allowance established by the IOM (600 IU [15 μg] daily).

Recommendation 3

In the general adult population younger than age 50 years, we suggest against routine 25(OH)D testing. (2 | ⊕ OOO )

• In this population, 25(OH)D levels that provide outcome-specific benefits have not been established in clinical trials.
• The panel suggests against (a) routine screening for a 25(OH)D level to guide decision-making (i.e., vitamin D vs no vitamin D) and (b) routine follow-up testing for 25(OH)D level to guide vitamin D dosing.
• This recommendation relates to generally healthy adults who do not otherwise have established indications for 25(OH)D testing (e.g., hypocalcemia).

Question 4. Should empiric vitamin D supplementation vs no empiric vitamin D supplementation be used for adults aged 50-74 years?

Question 5. Should vitamin D supplementation vs no vitamin D supplementation be used for adults aged 50-74 years only when 25(OH)D levels are below a threshold?

Recommendation 4

In the general population ages 50 to 74 years, we suggest against routine vitamin D supplementation. (2 | ⊕⊕⊕ O )

• This recommendation relates to empiric vitamin D supplementation that exceeds the DRIs established by the IOM. Adults in this age group should follow the Recommended Daily Allowance established by the IOM (600 IU [15 μg] daily for those aged 50 to 70 years; 800 IU [20 μg] daily for those older than 70 years).

Recommendation 5

In the general population ages 50 to 74 years, we suggest against routine 25(OH)D testing . (2 | ⊕ OOO )

Question 6. Should empiric vitamin D supplementation vs no empiric vitamin D supplementation be used by adults ages > 75 years?

Question 7. Should vitamin D supplementation vs no vitamin D supplementation be used by adults ages > 75 years only when 25(OH)D levels are below a threshold?

Recommendation 6

In the general population ages 75 years and older, we suggest empiric vitamin D supplementation because of the potential to lower the risk of mortality. (2 | ⊕⊕⊕ O )

• Empiric vitamin D may include daily intake of fortified foods, vitamin formulations that contain vitamin D and/or daily intake of a vitamin D supplement.
• For empiric supplementation, daily, lower-dose vitamin D is preferred over non-daily, higher doses. 
• In the clinical trials included in the SR that reported on the mortality outcome , vitamin D dose ranged from 400 to 3333 IU [10 to 83 μg ] daily equivalent. The estimated weighted average was average was approximately 900 IU (23 μg) daily. Participants in many trials were allowed to remain on their routine supplements, including up to 800 IU (20 μg) of vitamin D daily.

Recommendation 7

In the general population ages 75 years and older, we suggest against routine testing for 25(OH)D levels. (2 | ⊕ OOO )

• In this population, 25(OH)D thresholds that provide outcome-specific benefits have not been established in clinical trials.

Question 8. Should empiric vitamin D supplementation vs no empiric vitamin D supplementation be used during pregnancy? 

Question 9. Should vitamin D supplementation vs no vitamin D supplementation be used during pregnancy only when 25(OH)D levels are below a threshold? 

Recommendation 8

We suggest empiric vitamin D supplementation during pregnancy, given its potential to lower risk of preeclampsia, intra-uterine mortality, preterm birth, small for gestational age birth, and neonatal mortality. (2 | ⊕⊕ OO )

• This recommendation is based on evidence from trials conducted in healthy individuals during pregnancy. 
• Empiric vitamin D may include daily intake of fortified foods, prenatal vitamin formulations that contain vitamin D, and/or a vitamin D supplement (pills or drops).
• In the clinical trials included in the SR, the vitamin D doses ranged from 600 to 5000 IU (15 -125 μg) daily equivalent, usually provided daily or weekly. The estimated weighted average was approximately 2500 IU (63 μg ) per day.

Recommendation 9

During pregnancy, we suggest against routine 25(OH)D testing. (2 | ⊕ OOO )

• In this population, 25(OH)D levels that provide pregnancy outcome-specific benefits have not been established in clinical trials.
• The panel suggests against (a) routine screening for a 25(OH)D level to guide decision-making (ie, vitamin D vs no vitamin D) and (b) routine follow-up testing for 25(OH)D level to guide vitamin D dosing.
• This recommendation relates to generally healthy pregnant individuals who do not otherwise have established indications for 25(OH)D testing (e.g., hypocalcemia). 

Question 10. Should empiric vitamin D supplementation vs no empiric vitamin D supplementation be used for adults with prediabetes (by glycemic criteria)?

Recommendation 10

For adults with high-risk prediabetes, in addition to lifestyle modification, we suggest empiric vitamin D supplementation to reduce the risk of progression to diabetes. (2 | ⊕⊕⊕ O )

• Lifestyle modification must be a routine management component for adults with prediabetes.
• The clinical trials informing this recommendation primarily related to adults with high-risk prediabetes, identified as meeting two or three American Diabetes Association glycemia criteria (fasting glucose, HbA1c, 2-hour glucose after a 75-gram oral glucose challenge) for prediabetes and those with impaired glucose tolerance.
• In the clinical trials included in the SR, the vitamin D doses ranged from 842 to 7543 IU (21 to 189 μg ) daily equivalent. The estimated weighted average was approximately 3500 IU (88 μg ) per day. Participants in some trials were allowed to remain on their routine supplements, including up to 1000 IU (25 μg) of vitamin D daily.

Question 11. Should a daily, lower-dose vitamin D vs. non-daily (i.e., intermittent), higher-dose vitamin D be used for nonpregnant people for whom vitamin D treatment is indicated?

Recommendation 11

In adults ages 50 years and older who have indications for vitamin D supplementation or treatment, we suggest daily, lower-dose vitamin D instead of non-daily, higher-dose vitamin D. (2 | ⊕⊕ OO )

• The panel did not identify evidence related to individuals younger than age 50 years.

Question 12. Should screening with a 25(OH)D test (with vitamin D supplementation/treatment only if below a threshold) vs no screening with a 25(OH)D test be used for healthy adults?

Recommendation 12

In healthy adults, we suggest against routine screening for 25(OH)D levels. (2 | ⊕ OOO )

• In healthy adults, 25(OH)D levels that provide outcome-specific benefits have not been established in clinical trials.
• This recommendation relates to adults who do not otherwise have established indications for testing with 25(OH)D levels (e.g., hypocalcemia).

Question 13. Should screening with a 25(OH)D test ( with vitamin D supplementation/treatment only if below a threshold ) vs no screening with a 25(OH)D test be used for adults with dark complexion?

Recommendation 13

In adults with dark complexion, we suggest against routine screening for 25(OH)D levels. (2 | ⊕ OOO )

• This recommendation relates to generally healthy adults with dark complexion who do not otherwise have established indications for 25(OH)D testing (e.g., hypocalcemia).
• The panel did not identify any clinical trials that related clinical outcomes to skin complexion per se. A secondary analysis did not clearly suggest net benefit with vitamin D in those who self-identify as Black. The panel recognized that self-identified race is an inaccurate and otherwise problematic proxy for dark complexion.

Question 14. Should screening with a 25(OH)D test (with vitamin D supplementation/treatment only if below a threshold) vs no screening with a 25(OH)D test be used for adults with obesity?

Recommendation 14

In adults with obesity, we suggest against routine screening for 25(OH)D levels. (2 | ⊕ OOO )

• In adults with obesity, 25(OH)D thresholds that provide outcome-specific benefits have not been established in clinical trials.
• This recommendation relates to generally healthy adults with obesity who do not otherwise have established indications for 25(OH)D testing (e.g., hypocalcemia).

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Vitamin D: An Evidence-Based Review

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• Errata - January 01, 2010

Vitamin D is a fat-soluble vitamin that plays an important role in bone metabolism and seems to have some anti-inflammatory and immune-modulating properties. In addition, recent epidemiologic studies have observed relationships between low vitamin D levels and multiple disease states. Low vitamin D levels are associated with increased overall and cardiovascular mortality, cancer incidence and mortality, and autoimmune diseases such as multiple sclerosis. Although it is well known that the combination of vitamin D and calcium is necessary to maintain bone density as people age, vitamin D may also be an independent risk factor for falls among the elderly. New recommendations from the American Academy of Pediatrics address the need for supplementation in breastfed newborns and many questions are raised regarding the role of maternal supplementation during lactation. Unfortunately, little evidence guides clinicians on when to screen for vitamin D deficiency or effective treatment options.

• Background and Physiology

Vitamin D is a hormone precursor that is present in 2 forms. Ergocalciferol, or vitamin D 2 , is present in plants and some fish. Cholecalciferol, or vitamin D 3 , is synthesized in the skin by sunlight. Humans can fulfill their vitamin D requirements by either ingesting vitamin D or being exposed to the sun for enough time to produce adequate amounts. Vitamin D controls calcium absorption in the small intestine and works with parathyroid hormone to mediate skeletal mineralization and maintain calcium homeostasis in the blood stream. In addition, recent epidemiologic studies have observed relationships between low vitamin D levels and multiple disease states, probably caused by its anti-inflammatory and immune-modulating properties and possible affects on cytokine levels.

Vitamin D 3 can be manufactured in the skin by way of ultraviolet (UV) B rays. UVB rays are present only during midday at higher latitudes and do not penetrate clouds. The time needed to produce adequate vitamin D from the skin depends on the strength of the UVB rays (ie, place of residence), the length of time spent in the sun, and the amount of pigment in the skin. Tanning beds provide variable levels of UVA and UVB rays and are therefore not a reliable source of vitamin D.

Vitamin D 3 is synthesized from 7-dehydrocholesterol in the skin. The vitamin D binding protein transports the vitamin D 3 to the liver where it undergoes hydroxylation to 25(OH)D (the inactive form of vitamin D) and then to the kidneys where it is hydroxylated by the enzyme 1 αhydroxylase to 1,25(OH)D, its active form. 1 This enzyme is also present in a variety of extrarenal sites, including osteoclasts, skin, colon, brain, and macrophages, which may be the cause of it's broad-ranging effects. 1 The half-life of vitamin D in the liver is approximately 3 weeks, which underscores the need for frequent replenishment of the body's supply.

Vitamin D and Mortality

Vitamin D may be a determinant of mortality because of its anti-inflammatory and immune-modulating effects. It has been used to treat secondary hyperparathyroidism in people on dialysis. Retrospective trials show that vitamin D supplementation is associated with decreased mortality in people on dialysis. 2 Low serum vitamin D levels are also related to increased mortality in most patients with chronic kidney disease before dialysis. 3 However, there have been no randomized prospective trials examining this relationship. 4

In patients not on dialysis, low vitamin D levels are associated with increased levels of inflammation and oxidative load. A prospective study of more than 3000 male and female patients scheduled for coronary angiography found a positive association between low vitamin D levels and cardiovascular as well as all-cause mortality. 5 Data analysis from the National Health and Nutrition Examination Survey III (more than 13,000 adults) showed that people with vitamin D levels in the lowest quartile had a mortality rate ratio of 1.26 (95% CI, 1.08–1.46). 6 A recent meta-analysis demonstrated that intake of a vitamin D supplement at normal doses also was associated with decreased all-cause mortality rates. 7 These data suggest that vitamin D may play a part in multiple causes of death, although causality has not been determined.

Vitamin D and Cardiovascular Disease

Vitamin D receptors are present in vascular smooth muscle, endothelium, and cardiomyocytes and may have an impact on cardiovascular disease. Observational studies have shown a relationship between low vitamin D levels and blood pressure, coronary artery calcification, and existing cardiovascular disease. A large cohort study that included more than 1700 participants from the Framingham offspring study looked at vitamin D levels and incident cardiovascular events. 8 During a period of 5 years, participants who had 25-OH D levels of <15 were more likely to experience cardiovascular events (hazard ratio, 1.62; 95% CI, 1.11–2.36). The relationship remained significant among people with hypertension but not among those without hypertension. 8

Vitamin D and Diabetes

Recent studies in animal models and humans have suggested that vitamin D may also play a role in the homeostasis of glucose metabolism and the development of type 1 and type 2 diabetes mellitus (DM). Epidemiologic data has long suggested a link between exposure to vitamin D early in life and the development of type 1 DM. 9 ,10 Vitamin D 3 receptors have strong immune-modulating effects. In some populations the development of type 1 DM is associated with polymorphisms in the vitamin D receptor gene. 11 ,12 There is also some evidence that increased vitamin D intake by infants may reduce the risk of the development of type 1 DM. 13

Vitamin D has recently been associated with several of the contributing factors known to be linked to the development of type 2 DM, including defects in pancreatic βcell function, insulin sensitivity, and systemic inflammation. Several physiologic mechanisms have been proposed, including the effect of vitamin D on insulin secretion, the direct effect of calcium and vitamin D on insulin action, and the role of this hormone in cytokine regulation. 9 ,12 ,13 Although most studies indicating this relationship are observational, one meta-analysis showed a relatively consistent association between low vitamin D status, calcium or dairy intake, and prevalence of type 2 DM or metabolic syndrome. The study concluded that the highest type 2 DM prevalence, 0.36 (95% CI, 0.16–0.80), among participants who were not black was associated with the lowest blood levels of 25-hydroxyvitamin D. In addition, metabolic syndrome prevalence of 0.71 (95% CI, 0.57–0.89) was highest among those with the lowest dairy intake. There was also an inverse relationship between type 2 DM and metabolic syndrome incidences and vitamin D and calcium intake. 14

Vitamin D and Osteoporosis

Osteoporosis is the most common metabolic bone disease in the world. A low vitamin D level is an established risk factor for osteoporosis. Inadequate serum vitamin D levels will decrease the active transcellular absorption of calcium.

Although combination calcium and vitamin D supplementation is associated with higher bone mineral density and decreased incidence of hip fractures, 15 the evidence for vitamin D supplementation alone is less clear. A recent evidence summary found that vitamin D supplementation at doses of more than 700 IU daily (plus calcium) prevented bone loss compared with placebo. 16 However, vitamin D supplementation (300 to 400 IU daily) without calcium did not affect fractures. 16 A Cochrane review found unclear evidence that vitamin D alone affected hip, vertebral, or other fracture rates but supported the use of vitamin D with calcium in frail, elderly nursing home residents. 17 A subsequent meta-analysis of trials looking at vitamin D and fracture rates concurred that calcium was also necessary to affect a significant difference. 18

The most recent meta-analysis of 12 randomized, controlled trials that included more than 42,000 people found that vitamin D supplementation of more than 400 IU daily slightly reduced incidence of nonvertebral fractures (rate ratio, 0.86; 95% CI, 0.77–0.96). 19 The effect was dose dependent and was not significant if doses were ≤400 IU daily.

Vitamin D and Falls among the Elderly

Vitamin D status is increasingly recognized as an important factor in fall status among elderly patients. Several trials have demonstrated that vitamin D supplementation decreases the risk of falling. One proposed mechanism is that higher vitamin D levels are associated with improved muscle function.

A randomized, controlled trial from Australia evaluated women with at least one fall in the preceding 12 months and with a plasma 25-hyroxyvitamin D level <24.0 ng/mL. 20 All women were given calcium 1000 mg per day and were randomized to receive either ergocalciferol 1000 IU per day or placebo. Women in the study group had fewer falls after 12 months, but this was not a significant difference (53% versus 62.9%; odds ratio, 0.66; 95% CI, 0.41–1.06). After correction for height difference in the 2 groups, the ergocalciferol group had a significantly lower risk of falling (odds ratio, 0.61; 95% CI, 0.37–0.99).

A dose of 800 IU daily significantly reduced the risk of falling compared with a placebo in a dose-stratified analysis of the effect of 5 months of vitamin D supplementation on fall risk (72% lower incidence rate ratio; rate ratio, 0.28; 95% CI, 0.10–0.75). Lower doses of vitamin D, however, did not significantly change the rate of fall incidence compared with placebo. 21

A review of 12 randomized, controlled trials studying the effect of vitamin D supplementation on fall risk among both nursing home residents and community dwellers found a small benefit of supplementation on fall risk (odds ratio, 0.89; 95% CI, 0.80–0.99), 9 an effect that was also shown in a review of randomized, controlled trials with strict inclusion criteria, which included 1237 men and women with a mean age of 70 years and supplementation for 2 months to 3 years. The pooled results showed a significant 22% decrease in fall risk among those treated with vitamin D versus placebo or calcium only. The number needed to treat from the pooled results was 15 to prevent 1 person from falling 22 Assessing vitamin D levels in a population at high risk for falling and supplementing with 800 to 1000 IU daily of vitamin D should be a part of any fall prevention program.

Vitamin D and Cancer

Both observational studies in humans and animal models support that vitamin D has a beneficial role in cancer prevention and survival. The mechanism of action is probably related to its role in the regulation of cell growth and differentiation. 23 In the Health Professionals Follow-Up study (a cohort study of 1095 men), each increment in 25(OH)D level of 25mmol/L was associated with a 17% reduction of total cancer cases. 24 However, the National Health and Nutrition Examination Survey of 16,818 men and women did not find a relationship between total cancer mortality and vitamin D level. There was an inverse relationship between vitamin D level and colorectal cancer, however. In this study, serum 25(OH)D levels of ≥80 nmol/L conferred a 72% reduction in risk of colorectal cancer compared with a level lower than 50 nmol/L. 25

A recent meta-analysis of 63 observational studies looked at the relationship between vitamin D levels and cancer incidence and mortality. 26 Twenty of the 30 studies looking at vitamin D and colon cancer showed that people with higher vitamin D levels had either a lower incidence of colon cancer or decreased mortality. Similarly, 9 of the 13 studies about breast cancer and 13 of the 26 studies about prostate cancer showed beneficial effects of vitamin D levels on cancer incidence or mortality (some of the studies included more than one type of cancer). 26

A population-based randomized, control trial found that postmenopausal women who were supplemented with calcium and vitamin D had a reduced risk of cancer after the first year of treatment (rate ratio, 0.232; 95% CI, 0.09–0.60). 27 There was not a group that was supplemented with vitamin D alone.

Vitamin D and Multiple Sclerosis

Multiple sclerosis (MS) is a neurodegenerative, T lymphocyte-mediated, autoimmune disease of uncertain etiology. Although genetic susceptibility may be involved, epidemiologic studies suggest environmental influence because the development of MS correlates most strongly with rising latitude in both the northern and southern hemispheres. 28 Migration studies show that risk can be modified at an early age from both low to high and high to low prevalence rates. 28 Exposure to sun in early childhood is associated with reduced risk of developing MS 29 and population-based studies about MS in Canada have also shown that birth timing is a risk factor for MS because there are statistically significantly fewer patients with MS born in November and more born in May compared with controls. 30 A birth-timing association suggests that seasonality and sunlight exposure may also have an effect on the developing fetus in utero. 30 ,31

Several studies have shown that vitamin D affects the growth and differentiation of immune-modulator cells such as macrophages, dendritic cells, T cells, and B cells. 32–34 This immune-modulatory effect has implications for a variety of autoimmune diseases including rheumatoid arthritis, systemic lupus erythematosous, type I DM, inflammatory bowel disease, and MS. 33

Despite the wealth of epidemiologic studies supporting a relationship between vitamin D and MS in humans, data showing a link between serum vitamin D levels and MS are only beginning to emerge. One prospective, nested, case-control study examined the serum samples of 7 million military veterans and compared serum samples of 257 MS patients before diagnosis with those of matched controls. 35 An inverse relationship between vitamin D levels and MS risk was found, particularly for vitamin D levels measured in patients younger than 20. Another case-control study compared the serum vitamin D levels of 103 MS patients with 110 controls and found that for every 10-nmol/L increase of serum 25(OH)D level the odds of MS was reduced by 19% in women, suggesting a “protective” effect of higher vitamin D levels. 36 In addition, a negative correlation was found between Expanded Disability Status Scale scores among female MS patients and 25(OH)D levels. Several other studies have supported the finding that lower levels of vitamin D in MS patients are associated with more severe disability. 37 Lower levels during relapses have also been reported in patients with relapse-remitting MS. 38–40

The potential effects of oral vitamin D intake have been observed in several different ways. A Norwegian case-control study found that fish and cod liver oil have a protective effect against the development of MS. 29 A large observational study in the United States that followed 2 large cohorts of women—the Nurses’ Health Study (92,253 women followed from 1980 to 2000) and the Nurses’ Health Study II (95,310 women followed from 1991 to 2001)—found that vitamin D supplementation in the form of a multivitamin seemed to lower their MS risk by 40%. 41 However, several methodological weaknesses in study design made the results inconclusive. 42

Despite the overwhelming amount of data describing the association between vitamin D and MS, there is a paucity of research describing the benefit of vitamin D supplementation to these patients. One small safety study of 12 patients taking 1000 μg per day (40,000 IU) of vitamin D for 28 weeks showed a decline in the number of gadolinium-enhancing lesions on magnetic resonance imaging per patient; this led to a 25(OH)D serum concentration of 386 nmol/L (158 ng/mL) without causing hypercalcemia, hypercalciuria, or other complication. 43

Vitamin D and Cognition

Observational studies have shown that people with Alzheimer dementia have lower vitamin D levels than do matched controls without dementia. 44 The biological plausibility of this relationship includes vitamin D's antioxidative effects and the presence of vitamin D receptors in the hippocampus, which has been seen in rats and humans. 44 A cross-sectional study of 225 outpatients diagnosed with Alzheimer disease found a correlation between vitamin D levels (but not other vitamin levels) and their score on a Mini Mental Status Examination. 45

Vitamin D and Chronic Pain

Because of the important role vitamin D plays in bone homeostasis, some have questioned whether vitamin D deficiency may also correlate with chronic pain syndromes, including chronic low back pain. Several case series and observational studies have suggested that vitamin D inadequacy may represent a source of nociception and impaired neuromuscular functioning among patients with chronic pain.

The data to support this conclusion are mixed. A recent review of 22 relevant studies found no convincing link between prevalence and latitude and no association between serum levels of 25-OH vitamin D in chronic pain patients and controls. Interestingly, though, there was a contrast in treatment effects between randomized, double-blind trials that minimized bias and those with studies known to be subject to bias. In those that blinded the vitamin D therapy, only 10% of patients were in trials showing a benefit of vitamin D treatment, whereas among those who did not blind the treatment 93% were in trials showing a benefit of vitamin D supplementation. 46

A second review examined the role of vitamin deficiency in patients from outpatient and inpatient rehab units. Fifty-one articles were reviewed and a direct correlation was noted between vitamin D deficiency and musculoskeletal pain. Treatment of vitamin D deficiency produced an increase in muscle strength and a marked decrease in back and lower-limb pain within 6 months. 47 Although these data were suggestive of a link between vitamin D and pain, the available evidence does not imply causality. The verdict on this topic will remain undecided until this is evaluated by double-blind, randomized, controlled trials stratified by baseline vitamin D level with defined treatments and comparison placebo groups.

• Vitamin D Supplementation for Infants and Breastfeeding Mothers

Breast milk is an ideal form of nourishment for a newborn. Because of most nursing mother's own vitamin D deficiency, however, and despite the mother taking a prenatal vitamin, breast milk alone is not sufficient to maintain newborn vitamin D levels within a normal range. 48 Many nursing mothers or their infants require vitamin D supplementation for optimal health. 49

In 2003, the American Academy of Pediatrics recommended that 200 IU of vitamin D be used as supplementation for all infants beginning during the first 2 months after birth. 50 More recently, in 2008 the recommendation has been increased to a minimum of 400 IU daily during the first days of life to prevent vitamin D deficiency that may lead to rickets. 48

A 2004 systematic review looked at 166 cases of nutritional rickets diagnosed between 1986 and 2004 in 17 states from the mid-Atlantic region to Texas and Georgia. A disproportionate number of rickets cases were found in African-American, breastfed infants. 51 In addition to rickets and the risk of developing type I DM, other pediatric and adult health conditions may be impacted by insufficient vitamin D levels in infants and their mothers. 52 Both bone mineral accrual in early childhood 53 and the risk of recurrent wheezing episodes in children at age 3 54 were linked to insufficient vitamin D intake by women during pregnancy. If a fetus or breastfeeding infant receives an inadequate amount of vitamin D from its mother it can have a direct impact on the baby's health as an adult. Because of these findings, in 2007 the Canadian Pediatric Society recommended 2000 IU of vitamin D 3 for pregnant and lactating mothers with periodic blood tests to check levels of 25 (OH)D and calcium. 52 The American Academy of Pediatrics recommendations focus on supplementing the infant and make no specific recommendations about universally supplementing breastfeeding mothers. 48

Supplementing the Newborn: 2008 Recommendations from the American Academy of Pediatrics

The American Academy of Pediatrics recommends supplementing all children who are exclusively breastfed with 400 IU of vitamin D from the first few days of life. Children who are fed by breast and formula or who are exclusively formula fed should also be supplemented until they are consistently ingesting 1 L of formula a day (approximately 1 quart). The supplementation should continue until 1 year of age, when children begin ingesting vitamin D-fortified milk. 48 All formulas sold in the United States contain at least 400 IU/L of vitamin D 3 ; therefore, 1 L per day would meet the vitamin D recommendations set by the American Academy of Pediatrics. 55

Preparations for Supplementation

There are many available preparations for newborns ( Table 1 ). Some companies make a single-drop preparation that contains 400 IU, but caution should be used when prescribing this product because of the ease of dispensing too much vitamin D to a newborn with just a few drops. 48

• View inline

Vitamin D Preparations for Newborns

Checking Serum Levels in Infants

Clinicians should obtain a serum vitamin D level (25-OH-D not 1,25-OH 2 -D) among infants with malabsorption disorders or who take anticonvulsants because they may need additional supplementation above 400 IU daily. Actual values of 25-OH-D that determine vitamin D insufficiency in children have not been defined. The ≥20 ng/mL of 25-OH-D that determines a sufficient vitamin D level for adults has been used for children. 48

Supplementing Breastfeeding Mothers

Mothers who were supplemented with 400 IU of vitamin D daily produced milk with vitamin D levels that ranged from <25 to 78 IU per liter. 48 Supplementing the mother alone with 400 IU—equivalent to a prenatal vitamin—produced inadequate vitamin D levels in the breastfed infants. 55 A randomized, controlled trial evaluated 19 breastfeeding mothers who were supplemented with 6000 IU of vitamin D 3 and a prenatal vitamin with 400 IU of vitamin D. The vitamin D levels found in their breast milk and in the exclusively breastfed infants themselves were found to be equivalent to the infants who received oral supplementation (300 IU per day). This level of maternal supplementation showed no toxic effects and provided adequate vitamin D to nursing infants without needing to supplement the infant. 56 Safety and efficacy of this dosing during pregnancy and lactation has not been confirmed. In the meantime, screening high-risk women is appropriate and supplementing breastfeeding women who are vitamin D 3 deficient is warranted. 57

• Testing for Vitamin D Deficiency

There are many causes of vitamin D deficiency, as listed in ( Table 2 ), 59 and despite growing attention to this deficiency, there are no established guidelines to help clinicians decide which patients warrant screening laboratory testing. The US Preventive Services Task Force does not comment for or against routine screening for vitamin D deficiency. One approach is to consider serum testing in patients at high risk for vitamin D deficiency but treating without testing those at lower risk.

Causes of Vitamin D Deficiency 58

An Australian working group issued a position statement itemizing groups of people at risk for vitamin D deficiency. The risk groups include: (1) older people in low- and high-level residential care; (2) older people admitted to hospital; (3) patients with hip fracture; (4) dark-skinned women (particularly if veiled); and (5) mothers of infants with rickets (particularly if dark-skinned or veiled). 58

If electing to test vitamin D status, serum 25-hydroxyvitamin D is the accepted biomarker. 60 Although 1,25-OH-D is the active circulating form of vitamin D, measuring this level is not helpful because it is quickly and tightly regulated by the kidney. True deficiency would be evident only by measuring 25-OH-D. Of note, questions have been raised regarding the need for standardization of assays. 61 A large laboratory (Quest Diagnostics) recently reported the possibility of thousands of incorrect vitamin D level results. 62 Sunlight exposure questionnaires are imprecise and are not currently recommended. 63

Controversy exists regarding the optimum level of serum 25-hydroxyvitamin D in a healthy population. Most experts agree that serum vitamin D levels <20 ng/mL represent deficiency. However, some experts recommend aiming for a higher minimum target level of 30 ng/mL of 25-hydroxyvitamin D 49 in a healthy population. Vitamin D intoxication can occur when serum levels are greater than 150 ng/mL. Symptoms of hypervitaminosis D include fatigue, nausea, vomiting, and weakness probably caused by the resultant hypercalcemia. Of note, sun exposure alone cannot lead to vitamin D intoxication as excess vitamin D 3 is destroyed by sunlight.

Given concern about skin cancer, many patients and clinicians are cautious regarding sun exposure recommendations. However, exposure of arms and legs for 5 to 30 minutes between the hours of 10 am and 3 pm twice a week can be adequate to prevent vitamin D deficiency. 59

Natural dietary sources of vitamin D include salmon, sardines, mackerel, tuna, cod liver oil, shiitake mushrooms, and egg yolk. 58 Fortified foods include milk, orange juice, infant formulas, yogurts, butter, margarine, cheeses, and breakfast cereals. 59

Over-the-counter multivitamin supplements frequently contain 400 IU of vitamins D 1 , D 2 , or D 3 . Alternatively, over-the-counter vitamin D 3 supplements can be found in 400, 800, 1000, and 2000 IU strengths. Prescription-strength supplementation choices include vitamin D 2 (ergocalciferol), which provides 50,000 IU per capsule, and vitamin D 2 liquid (drisdol) at 8000 IU/mL. 59

To prevent vitamin D deficiency in healthy patients, the 1997 Institute of Medicine recommendations suggested a daily vitamin D intake of 200 IU for children and adults up to 50 years of age; 400 IU for adults 51 to 70 years of age; and 600 IU for adults 71 years or older. 64 The upper limit recommended was 2000 IU daily. However, some experts consider this to be too low and recommend that children and adults without adequate sun exposure consume 800 to 1000 IU daily to achieve adequate serum vitamin D levels. 59

Treatment recommendations vary depending on the cause of the deficiency. For example, patients with chronic kidney disease are recommended to have 1000 IU of vitamin D 3 daily. 59 The expected blood level response to a given vitamin D dose varies, probably because of differences in the cause of the deficit as well as the starting point for correction. A recent editorial reported that supplemental intakes of 400 IU per day of vitamin D increase 25(OH)D concentrations by only 2.8 to 4.8 ng/mL (7–12 nmol/L) and that daily intakes of approximately 1700 IU are needed to raise these concentrations from 20 to 32 ng/mL (50–80 nmol/L). 65 Responses to vitamin D supplementation or sun exposure may vary by patient, so clinicians may need to continue to monitor abnormal levels.

This article was externally peer reviewed.

Funding: none.

Conflict of interest: none declared.

• Received for publication February 27, 2009.
• Revision received July 10, 2009.
• Accepted for publication July 13, 2009.
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Article Contents

Introduction, limitations, list of recommendations, methods of development of evidence-based clinical practice guidelines, evidence-to-decision considerations common to multiple clinical questions, vitamin d use for children aged 1 to 18 years, vitamin d use in nonpregnant adults aged < 50 years, vitamin d use in adults aged 50 to 74 years, vitamin d use in adults aged ≥ 75 years, vitamin d supplementation during pregnancy, vitamin d for adults with prediabetes, vitamin d dosing, vitamin d screening with a 25(oh)d test for healthy adults, vitamin d screening with a 25(oh)d test for adults with dark complexion, vitamin d screening with a 25(oh)d test for adults with obesity, acknowledgments, disclosures, appendix a. guideline development panel (gdp) makeup, roles, and management plans, vitamin d for the prevention of disease: an endocrine society clinical practice guideline.

Co-Sponsoring Organizations: American Association of Clinical Endocrinology (AACE), European Society of Endocrinology (ESE), Pediatric Endocrine Society (PES), American Society for Bone and Mineral Research (ASBMR), Vitamin D Workshop, American Society for Nutrition (ASN), Brazilian Society of Endocrinology and Metabolism (SBEM), Society of General Internal Medicine (SGIM), Endocrine Society of India (ESI)

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Marie B Demay, Anastassios G Pittas, Daniel D Bikle, Dima L Diab, Mairead E Kiely, Marise Lazaretti-Castro, Paul Lips, Deborah M Mitchell, M Hassan Murad, Shelley Powers, Sudhaker D Rao, Robert Scragg, John A Tayek, Amy M Valent, Judith M  E Walsh, Christopher R McCartney, Vitamin D for the Prevention of Disease: An Endocrine Society Clinical Practice Guideline, The Journal of Clinical Endocrinology & Metabolism , 2024;, dgae290, https://doi.org/10.1210/clinem/dgae290

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Numerous studies demonstrate associations between serum concentrations of 25-hydroxyvitamin D (25[OH]D) and a variety of common disorders, including musculoskeletal, metabolic, cardiovascular, malignant, autoimmune, and infectious diseases. Although a causal link between serum 25(OH)D concentrations and many disorders has not been clearly established, these associations have led to widespread supplementation with vitamin D and increased laboratory testing for 25(OH)D in the general population. The benefit-risk ratio of this increase in vitamin D use is not clear, and the optimal vitamin D intake and the role of testing for 25(OH)D for disease prevention remain uncertain.

To develop clinical guidelines for the use of vitamin D (cholecalciferol [vitamin D3] or ergocalciferol [vitamin D2]) to lower the risk of disease in individuals without established indications for vitamin D treatment or 25(OH)D testing.

A multidisciplinary panel of clinical experts, along with experts in guideline methodology and systematic literature review, identified and prioritized 14 clinically relevant questions related to the use of vitamin D and 25(OH)D testing to lower the risk of disease. The panel prioritized randomized placebo-controlled trials in general populations (without an established indication for vitamin D treatment or 25[OH]D testing), evaluating the effects of empiric vitamin D administration throughout the lifespan, as well as in select conditions (pregnancy and prediabetes). The panel defined “empiric supplementation” as vitamin D intake that (a) exceeds the Dietary Reference Intakes (DRI) and (b) is implemented without testing for 25(OH)D. Systematic reviews queried electronic databases for publications related to these 14 clinical questions. The Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) methodology was used to assess the certainty of evidence and guide recommendations. The approach incorporated perspectives from a patient representative and considered patient values, costs and resources required, acceptability and feasibility, and impact on health equity of the proposed recommendations. The process to develop this clinical guideline did not use a risk assessment framework and was not designed to replace current DRI for vitamin D.

The panel suggests empiric vitamin D supplementation for children and adolescents aged 1 to 18 years to prevent nutritional rickets and because of its potential to lower the risk of respiratory tract infections; for those aged 75 years and older because of its potential to lower the risk of mortality; for those who are pregnant because of its potential to lower the risk of preeclampsia, intra-uterine mortality, preterm birth, small-for-gestational-age birth, and neonatal mortality; and for those with high-risk prediabetes because of its potential to reduce progression to diabetes. Because the vitamin D doses in the included clinical trials varied considerably and many trial participants were allowed to continue their own vitamin D–containing supplements, the optimal doses for empiric vitamin D supplementation remain unclear for the populations considered. For nonpregnant people older than 50 years for whom vitamin D is indicated, the panel suggests supplementation via daily administration of vitamin D, rather than intermittent use of high doses. The panel suggests against empiric vitamin D supplementation above the current DRI to lower the risk of disease in healthy adults younger than 75 years. No clinical trial evidence was found to support routine screening for 25(OH)D in the general population, nor in those with obesity or dark complexion, and there was no clear evidence defining the optimal target level of 25(OH)D required for disease prevention in the populations considered; thus, the panel suggests against routine 25(OH)D testing in all populations considered. The panel judged that, in most situations, empiric vitamin D supplementation is inexpensive, feasible, acceptable to both healthy individuals and health care professionals, and has no negative effect on health equity.

The panel suggests empiric vitamin D for those aged 1 to 18 years and adults over 75 years of age, those who are pregnant, and those with high-risk prediabetes. Due to the scarcity of natural food sources rich in vitamin D, empiric supplementation can be achieved through a combination of fortified foods and supplements that contain vitamin D. Based on the absence of supportive clinical trial evidence, the panel suggests against routine 25(OH)D testing in the absence of established indications. These recommendations are not meant to replace the current DRIs for vitamin D, nor do they apply to people with established indications for vitamin D treatment or 25(OH)D testing. Further research is needed to determine optimal 25(OH)D levels for specific health benefits.

The role of vitamin D in the regulation of skeletal and mineral ion homeostasis is well established. Epidemiologic evidence has shown consistent associations of low vitamin D status with increased risk of a variety of common disorders, including musculoskeletal, metabolic, cardiovascular, malignant, autoimmune, and infectious diseases ( 1-3 ,). However, observational studies are prone to confounding and various forms of bias, and a causal link between low vitamin D status, as assessed by serum 25-hydroxyvitamin D (25[OH]D) levels, and many disorders has not been clearly established. Nonetheless, these associations have led to widespread supplementation and increased laboratory testing for 25(OH)D levels in the general population. In the United States, the prevalence of supplemental vitamin D use of 1000 IU (25 μg) or more per day increased from 0.3% in the 1999-2000 National Health and Nutrition Examination Survey (NHANES) to 18.2% in the 2013-2014 NHANES ( 4 ). The use of 25(OH)D testing in clinical practice has also been increasing; however, the cost-effectiveness of widespread testing has been questioned, especially given the uncertainty surrounding the optimal level of 25(OH)D required to prevent disease.

Vitamin D is not a true vitamin (defined as a nutrient that cannot be endogenously synthesized), as intake is not required in those who have adequate sun exposure. However, seasonal variation in UV-B availability and decreased sun exposure associated with clothing and limited time outdoors has resulted in the general population being increasingly reliant on oral intake of vitamin D in a few natural sources, foods fortified with vitamin D, and supplements containing vitamin D. Whether ingested or synthesized in the skin, vitamin D is converted to 25(OH)D in the liver ( 5 ). This process is not tightly regulated; therefore, the 25(OH)D concentration most accurately reflects vitamin D status. A second hydroxylation step (1-alpha) leads to the formation of the active metabolite, 1,25-dihydroxyvitamin D in many tissues. Circulating 1,25-dihydroxyvitamin D is thought to derive primarily from renal 1-alpha hydroxylation in the absence of pathologic conditions ( 6 ). Although loss of function mutations in vitamin D hydroxylases are rare, genetic variants and several pharmacologic agents may affect their activity ( 7-10 ). Vitamin D metabolites are secreted with bile acids and reabsorbed in the terminal ileum; therefore, terminal ileal disease, as well as general malabsorption and having a short gut (including from Roux-en-Y gastric bypass), can lead to low levels of serum 25(OH)D. There are other conditions that place individuals at risk for low 25(OH)D levels. For example, vitamin D metabolites bound to vitamin D–binding protein and albumin are lost in the urine of those with nephrotic syndrome. In addition, vitamin D metabolites are inactivated primarily by the 24-hydroxylase, which is induced by high levels of 1,25-dihydroxyvitamin D as well as by fibroblast growth factor-23, as seen in chronic kidney disease ( 11 ). Importantly, these guidelines do not apply to individuals with such underlying conditions that substantially alter vitamin D physiology.

The actions of vitamin D metabolites are mediated by the vitamin D receptor (VDR), which is expressed in most tissues. The VDR has been shown to regulate cellular differentiation and target gene expression in many cell types, including those of the immune system. The best-established physiologic role of the VDR is promoting intestinal calcium absorption, which is critical for maintaining skeletal and mineral ion homeostasis ( 12 , 13 ). The skeletal effects of vitamin D are dependent on adequate calcium intake. The effects of vitamin D on the immune system are due to local activation of 25(OH)D to 1,25-dihydroxyvitamin D and induction of VDR expression ( 14 ). Thus, the optimal level of 25(OH)D to prevent disease likely depends on the clinical outcomes being evaluated. Similarly, the required duration of exposure to vitamin D for specific outcomes is expected to vary, depending on the underlying pathophysiology (eg, acute [infections] vs chronic [cancer]).

In contrast to previous guidelines that broadly addressed the evaluation, treatment, and prevention of vitamin D deficiency, with an emphasis on the care of patients who are at risk for deficiency ( 15 ), the goal of this Guideline Development Panel was to establish clinical guidelines for the use of vitamin D to lower the risk of disease in individuals without established indications for vitamin D treatment or 25(OH)D testing. The panel recognized that there are numerous important clinical questions regarding the use of vitamin D and 25(OH)D testing in the general population; however, due to limited resources, 14 of these clinical questions were prioritized and 4 to 6 outcomes were addressed for each question. Because patient-important clinical outcomes are expected to differ according to the target population, the panel proposed specific outcomes for the pediatric population (ages 1 to 18 years), and for ages 19 to 49 years, 50 to 74 years, and 75 years and older. Established guidelines recommend empiric vitamin D in the first year of life, specifically to prevent nutritional rickets ( 16-18 ); thus, this demographic was not addressed. Other populations examined were pregnant individuals and those with prediabetes, dark complexion, and obesity. The panel also addressed whether daily supplementation with vitamin D should be recommended rather than intermittent (nondaily), higher-dose vitamin D, and whether supplementation should be limited to those with circulating 25(OH)D levels below a threshold.

Evidence from randomized controlled trials (RCTs) was prioritized for the systematic reviews. Large (> 1000 participants) longitudinal observational cohort studies were considered if they included appropriate comparators (supplementation vs no supplementation) and outcomes, but only when an insufficient number of RCTs was available. Trials where the intervention was a vitamin D analog or metabolite other than vitamin D2 or vitamin D3 were excluded because these compounds are not globally available. Mendelian randomization studies were excluded because they do not evaluate response to supplementation. The Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) methodology was used to assess the certainty of evidence and inform recommendations. The panel sought evidence relevant to all elements of the Evidence-to-Decision (EtD) framework, which included stakeholder values and preferences (including input from clinical experts and a patient representative), costs and other resources required, cost-effectiveness, acceptability, feasibility, and impact on health equity. The panel did not identify robust evidence pertinent to these EtD factors for most clinical questions.

In formulating this Guideline, several challenges were encountered that influenced the formulation of the final recommendations.

Because those with lower baseline levels of 25(OH)D are expected to benefit more from vitamin D supplementation than those with higher levels ( 19 ), a major limitation in formulating recommendations was the paucity of RCTs addressing the efficacy and safety of vitamin D supplementation in populations with low baseline 25(OH)D levels. Average baseline levels of 25(OH)D in many large trials were in a range that most would consider adequate (eg, 31 ng/mL [78 nmol/L] in the VITAL trial) ( 20 ). In such trials, a lack of effect of vitamin D does not necessarily indicate that vitamin D does not influence the relevant outcome, but rather that the study populations had baseline levels of 25(OH)D that were adequate for the desired outcome.

Unlike typical trials for pharmacologic agents, in which control participants are not exposed to the intervention, all participants in vitamin D trials were routinely exposed to vitamin D through sun exposure and dietary sources. In addition, many trials allowed participants to remain on their current supplements that contained vitamin D which often reflected the DRI (eg, 600-800 IU [15-20 μg] daily for adults). Such circumstances may have biased trial results toward the null hypothesis.

Most vitamin D trials did not include a specific 25(OH)D level as an eligibility criterion, and no trials were designed or powered to address the effect of vitamin D in subgroups stratified by either baseline or achieved 25(OH)D levels. This prevented the panel from proposing thresholds for 25(OH)D adequacy or providing target 25(OH)D levels for disease prevention, especially since 25(OH)D thresholds are likely to vary by population and outcome. Although many systematic reviews include subgroup analyses according to the study average baseline 25(OH)D levels, such analyses are subject to ecological fallacy in which inferences about individuals are based on aggregate group data. Therefore, the commissioned systematic review informing this guideline does not include study subgroup analyses according to average baseline 25(OH)D levels.

Many trials were considered to be of insufficient duration to adequately assess the effect of the vitamin D intervention on some outcomes, due to the long latency for the development of chronic diseases such as cancer, diabetes, cardiovascular disease (CVD) and osteoporosis.

Because the included trials used various doses and administration schedules of vitamin D, specific dose recommendations for vitamin D could not be proposed for specific populations. Instead, in the technical remarks, vitamin D doses used in the included trials are summarized.

The trials that the panel considered were performed in overall healthy populations at average risk for the outcomes of interest; therefore, the recommendations are limited to generally healthy individuals without established indications for vitamin D treatment or 25(OH)D testing.

In most trials, study participants were largely of European ancestry or identified as non-Hispanic White, with very few trials including large numbers of participants from other races or ethnicities.

The panel developed clinical questions for different age groups of adults (<50 years, 50 to 74 years, and 75 years and older) to represent different stages of life. However, the panel recognizes the somewhat arbitrary nature of these categories and acknowledges that many trials included populations that spanned these age categories. As a result, it was challenging to directly apply study results to narrowly defined age groups.

Many trials in those aged older than 50 years combined vitamin D with calcium, making it difficult to isolate the effect of vitamin D from that of calcium. This is especially relevant to outcomes related to skeletal health, for which both vitamin D and calcium are considered essential.

Due to resource limitations, not all potential outcomes of interest were addressed in all populations of interest. The panel prioritized outcomes that they felt were most relevant to the specific populations under consideration.

Thus, these clinical guidelines relate to the use of vitamin D to lower the risk of disease in individuals without established indications for vitamin D treatment or 25(OH)D testing. The Guideline Development Panel assumed that the Institute of Medicine's (IOM, now known as the National Academy of Medicine) DRIs for vitamin D ( 21 ) represent a baseline standard for all individuals. Importantly, the panel's recommendations should not be extrapolated to those with underlying medical conditions that are known to negatively impact vitamin D physiology. For those living in countries where food fortification with vitamin D is not standard or where dietary supplements are not routinely used, interventions may be required to insure a baseline intake consistent with the IOM DRIs.

Question 1. Should empiric vitamin D supplementation vs no empiric vitamin D supplementation be used for children and adolescents (ages 1 to 18 years)?

In children and adolescents aged 1 to 18 years, we suggest empiric vitamin D supplementation to prevent nutritional rickets and potentially lower the risk of respiratory tract infections. (2 | ⊕⊕◯◯)

Empiric vitamin D may include daily intake of fortified foods, vitamin formulations that contain vitamin D, and/or daily intake of a vitamin D supplement (pill or drops).

In the clinical trials included in the systematic review, with respect to respiratory tract infections in children, vitamin D dosages ranged from 300 to 2000 IU (7.5 to 50 μg) daily equivalent. The estimated weighted average was approximately 1200 IU (30 μg) per day.

Question 2. Should empiric vitamin D supplementation vs no empiric vitamin D supplementation be used for nonpregnant adults < 50 years of age?

Question 3. Should vitamin D supplementation vs no vitamin D supplementation be used for nonpregnant adults < 50 years of age only when 25(OH)D levels are below a threshold?

In the general adult population younger than age 50 years, we suggest against empiric vitamin D supplementation. (2 | ⊕◯◯◯)

This recommendation relates to empiric vitamin D supplementation that exceeds the DRIs established by the IOM. Adults in this age group should follow the Recommended Daily Allowance established by the IOM (600 IU [15 µg] daily).

In the general adult population younger than age 50 years, we suggest against routine 25(OH)D testing. (2 | ⊕◯◯◯)

In this population, 25(OH)D levels that provide outcome-specific benefits have not been established in clinical trials.

The panel suggests against (a) routine screening for a 25(OH)D level to guide decision-making (ie, vitamin D vs no vitamin D) and (b) routine follow-up testing for 25(OH)D level to guide vitamin D dosing.

This recommendation relates to generally healthy adults who do not otherwise have established indications for 25(OH)D testing (eg, hypocalcemia).

Question 4. Should empiric vitamin D supplementation vs no empiric vitamin D supplementation be used for adults aged 50 to 74 years?

Question 5. Should vitamin D supplementation vs no vitamin D supplementation be used for adults aged 50 to 74 years only when 25(OH)D levels are below a threshold?

In the general population aged 50 to 74 years, we suggest against routine vitamin D supplementation. (2 | ⊕⊕⊕◯)

This recommendation relates to empiric vitamin D supplementation that exceeds the DRIs established by the IOM. Adults in this age group should follow the Recommended Daily Allowance established by the IOM (600 IU [15 µg] daily for those aged 50 to 70 years; 800 IU [20 µg] daily for those older than 70 years).

In the general population aged 50 to 74 years, we suggest against routine 25(OH)D testing. (2 | ⊕◯◯◯)

Question 6. Should empiric vitamin D supplementation vs no empiric vitamin D supplementation be used by adults aged ≥ 75 years?

Question 7. Should vitamin D supplementation vs no vitamin D supplementation be used by adults aged ≥ 75 years only when 25(OH)D levels are below a threshold?

In the general population aged 75 years and older, we suggest empiric vitamin D supplementation because of the potential to lower the risk of mortality. (2 | ⊕⊕⊕◯)

Empiric vitamin D may include daily intake of fortified foods, vitamin formulations that contain vitamin D and/or daily intake of a vitamin D supplement.

For empiric supplementation, daily, lower-dose vitamin D is preferred over nondaily, higher doses.

In the clinical trials included in the systematic review that reported on the mortality outcome, vitamin D dosage ranged from 400 to 3333 IU (10 to 83 μg) daily equivalent. The estimated weighted average was approximately 900 IU (23 μg) daily. Participants in many trials were allowed to remain on their routine supplements, including up to 800 IU (20 µg) of vitamin D daily.

In the general population aged 75 years and older, we suggest against routine testing for 25(OH)D levels. (2 | ⊕◯◯◯)

In this population, 25(OH)D thresholds that provide outcome-specific benefits have not been established in clinical trials.

Question 8. Should empiric vitamin D supplementation vs no empiric vitamin D supplementation be used during pregnancy?

Question 9. Should vitamin D supplementation vs no vitamin D supplementation be used during pregnancy only when 25(OH)D levels are below a threshold?

We suggest empiric vitamin D supplementation during pregnancy, given its potential to lower risk of preeclampsia, intra-uterine mortality, preterm birth, small-for-gestational-age (SGA) birth, and neonatal mortality. (2 | ⊕⊕◯◯)

This recommendation is based on evidence from trials conducted in healthy individuals during pregnancy.

Empiric vitamin D may include daily intake of fortified foods, prenatal vitamin formulations that contain vitamin D, and/or a vitamin D supplement (pills or drops).

In the clinical trials included in the systematic review, the vitamin D dosages ranged from 600 IU to 5000 IU (15 to 125 μg) daily equivalent, usually provided daily or weekly. The estimated weighted average was approximately 2500 IU (63 μg) per day.

During pregnancy, we suggest against routine 25(OH)D testing. (2 | ⊕◯◯◯)

In this population, 25(OH)D levels that provide pregnancy outcome-specific benefits have not been established in clinical trials.

This recommendation relates to generally healthy pregnant individuals who do not otherwise have established indications for 25(OH)D testing (eg, hypocalcemia).

Question 10. Should empiric vitamin D supplementation vs no empiric vitamin D supplementation be used for adults with prediabetes (by glycemic criteria)?

For adults with high-risk prediabetes, in addition to lifestyle modification, we suggest empiric vitamin D supplementation to reduce the risk of progression to diabetes. (2 | ⊕⊕⊕◯)

Lifestyle modification must be a routine management component for adults with prediabetes.

The clinical trials informing this recommendation primarily related to adults with high-risk prediabetes, identified as meeting 2 or 3 American Diabetes Association glycemia criteria (fasting glucose, glycated hemoglobin [HbA1c], 2-hour glucose after a 75-gram oral glucose challenge) for prediabetes and those with impaired glucose tolerance.

In the clinical trials included in the systematic review, the vitamin D dosages ranged from 842 to 7543 IU (21 to 189 μg) daily equivalent. The estimated weighted average was approximately 3500 IU (88 μg) per day. Participants in some trials were allowed to remain on their routine supplements, including up to 1000 IU (25 µg) of vitamin D daily.

Question 11. Should a daily, lower-dose vitamin D vs nondaily (ie, intermittent), higher-dose vitamin D be used for nonpregnant people for whom vitamin D treatment is indicated?

In adults aged 50 years and older who have indications for vitamin D supplementation or treatment, we suggest daily, lower-dose vitamin D instead of nondaily, higher-dose vitamin D. (2 | ⊕⊕◯◯)

The panel did not identify evidence related to individuals younger than age 50 years.

Question 12. Should screening with a 25(OH)D test (with vitamin D supplementation/treatment only if below a threshold) vs no screening with a 25(OH)D test be used for healthy adults?

In healthy adults, we suggest against routine screening for 25(OH)D levels. (2 | ⊕◯◯◯)

In healthy adults, 25(OH)D levels that provide outcome-specific benefits have not been established in clinical trials.

This recommendation relates to adults who do not otherwise have established indications for testing with 25(OH)D levels (eg, hypocalcemia).

Question 13. Should screening with a 25(OH)D test (with vitamin D supplementation/treatment only if below a threshold) vs no screening with a 25(OH)D test be used for adults with dark complexion?

In adults with dark complexion, we suggest against routine screening for 25(OH)D levels. (2 | ⊕◯◯◯)

This recommendation relates to generally healthy adults with dark complexion who do not otherwise have established indications for 25(OH)D testing (eg, hypocalcemia).

The panel did not identify any clinical trials that related clinical outcomes to skin complexion per se. A secondary analysis did not clearly suggest net benefit with vitamin D in those who self-identify as Black. The panel recognized that self-identified race is an inaccurate and otherwise problematic proxy for dark complexion.

Question 14. Should screening with a 25(OH)D test (with vitamin D supplementation/treatment only if below a threshold) vs no screening with a 25(OH)D test be used for adults with obesity?

In adults with obesity, we suggest against routine screening for 25(OH)D levels. (2 | ⊕◯◯◯)

In adults with obesity, 25(OH)D thresholds that provide outcome-specific benefits have not been established in clinical trials.

This recommendation relates to generally healthy adults with obesity who do not otherwise have established indications for 25(OH)D testing (eg, hypocalcemia).

The Guideline Development Panel did not find clinical trial evidence that would support establishing distinct 25(OH)D thresholds tied to outcome-specific benefits in the populations examined. Hence, the Endocrine Society no longer endorses the target 25(OH)D level of 30 ng/mL (75 nmol/L) suggested in the previous guideline ( 15 ). Similarly, the Endocrine Society no longer endorses specific 25(OH)D levels to define vitamin D sufficiency, insufficiency, and deficiency.

The current guideline suggests against routine 25(OH)D screening (in the absence of well-established indications), including in adults and children with obesity, in adults and children with dark complexion, and during pregnancy. This also represents a change from the 2011 guideline ( 15 ).

Vitamin D for the prevention of disease.

This guideline was developed using the process detailed on the Endocrine Society website ( https://www.endocrine.org/clinical-practice-guidelines/methodology ) and summarized here. The Endocrine Society follows the GRADE (Grading of Recommendations Assessment, Development and Evaluation) methodology ( 22 ) ( Tables 1 and 2 ). This methodology includes the use of evidence-to-decision (EtD) frameworks to ensure all important criteria are considered when making recommendations ( 23 , 24 ). The process was facilitated by the GRADEpro Guideline Development Tool (GRADEpro GDT) ( 25 ). This Guideline Development Panel (GDP) consisted of content experts representing the following specialties: adult endocrinology, general internal medicine, obstetrics and gynecology, pediatric endocrinology, nutrition, and epidemiology. A patient representative was also included on the panel. Members were identified by the Endocrine Society Board of Directors and the Clinical Guidelines Committee (CGC) and were vetted according to the conflict-of-interest policy ( 26 ), which was adhered to throughout the guideline process to manage and mitigate conflicts of interest. Detailed disclosures of panel members and the management strategies implemented during the development process can be found in   Appendix A . In addition, the group included a clinical practice guideline methodologist from the Mayo Evidence-Based Practice Center, who led the team that conducted the systematic reviews and meta-analyses, and a methodologist from the Endocrine Society, who advised on methodology and moderated the application of the EtD framework and development of the recommendations.

GRADE certainty of evidence classifications

Source: Reprinted with permission from Schünemann HJ, Brożek J, Guyatt GH, Oxman AD. GRADE Handbook. Handbook for grading the quality of evidence and the strength of recommendations using the GRADE approach. Updated October 2013 ( 27 ).

GRADE strength of recommendation classifications and interpretation

Source: Reprinted from Schünemann HJ et al. Blood Adv, 2018;2(22):3198-3225. © The American Society of Hematology, published by Elsevier ( 28 ).

From the Guideline Development Panel, 2 to 3 members were assigned to lead each guideline question. The clinical questions addressed in this guideline were prioritized from an extensive list of potential questions through a survey of the panel members and discussion; 14 questions were identified as most important. The Mayo Evidence-Based Practice Center conducted a systematic review for each question and produced GRADE evidence profiles that summarized the body of evidence for each question and the certainty of the evidence ( 29 ). The systematic searches for evidence were conducted in February 2022 and updated in December 2023. In parallel to the development of the evidence summaries, the Guideline Development Panel members searched for and summarized research evidence for other EtD criteria, such as patients’ values and preferences, feasibility, acceptability, costs/resource use, cost-effectiveness, and health equity. Research evidence summaries noted in the EtD frameworks were compiled using standardized terminology templates for clarity and consistency ( 30 ). During an in-person panel meeting and a series of video conferences, the Guideline Development Panel judged the balance of benefits and harms, in addition to the other EtD criteria, to determine the direction and strength of each recommendation ( 30 , 31 ); see Tables 1 and 2 .

The draft recommendations were posted publicly for external peer review and internally for Endocrine Society members, and the draft guideline manuscript was reviewed by the Society's Clinical Guidelines Committee, representatives of co-sponsoring organizations, a representative of the Society's Board of Directors, and an Expert Reviewer. Revisions to the guideline were made based on submitted comments and approved by the Clinical Guidelines Committee, the Expert Reviewer, and the Board of Directors. Finally, the guideline manuscript was reviewed before publication by the Journal of Clinical Endocrinology and Metabolism's publisher's reviewers.

This guideline will be reviewed annually to assess the state of the evidence and determine if there are any developments that would warrant an update to the guideline.

Many of the EtD considerations were common to the clinical questions addressing empiric vitamin D supplementation. Most multivitamins contain 800 to 1000 IU (20-25 μg) of vitamin D. Vitamin D is inexpensive and available without a prescription, at costs varying from the equivalent of US $10 to $50 per year in North America, South America, New Zealand, Europe, and India. Because empiric vitamin D supplementation intervention would be limited to a daily supplement that is readily available, the panel judged that the intervention would be acceptable and feasible. Most vitamin D3 on the market is from animal sources (lanolin), but vegan vitamin D3 from lichen is also available. Vitamin D2, which is plant-based, is widely available, and the costs are similar. Evaluations of costs, acceptability, and feasibility refer to routine vitamin D use in the general population, and special considerations that pertain to children and specific demographics are discussed elsewhere.

When beneficial effects of empiric vitamin D were identified, the panel judged that empiric vitamin D will not likely have a negative impact on health equity and may have a favorable impact on improving health equity because low vitamin D status is more prevalent in disadvantaged populations, including those with lower socioeconomic status. In addition, disadvantaged persons tend to be at higher baseline risk for many of the outcomes assessed (eg, poor maternal-fetal outcomes, nutritional rickets, diabetes); thus, whenever benefit is expected for such outcomes, disadvantaged populations would be expected to derive greater absolute benefit.

When the intervention involved testing for 25(OH)D prior to treatment with vitamin D, the costs were felt to be moderate and the intervention less acceptable. The cost of a 25(OH)D assay varies from the equivalent of US $25 to $100 in North America, South America, New Zealand, and Europe. However, this does not include the cost of health care visits for ordering the test, interpreting the test result, and the potential need for additional testing and health care visits. Thus, while conditioning vitamin D supplementation on 25(OH)D test results would be acceptable to many, the panel judged that such an approach may be unacceptable to some. In addition, access to accurate 25(OH)D testing is variable across the globe, and an approach requiring such testing may not be feasible in some settings.

Even if there were beneficial effects to screening with 25(OH)D and treating based on the results, the panel was uncertain about the impact of such an approach on health equity. While the panel acknowledged the increased prevalence of low vitamin D status in disadvantaged populations, those with low socioeconomic status, and those with dark complexion, the costs and time commitment required to implement the intervention may limit its acceptability and feasibility in these populations and those across the globe with poor access to health care.

For each clinical question, additional details regarding all EtD considerations are included in the supplemental materials available online.

The prevalence of low vitamin D status in childhood is high, with marked variability across the globe. In the United States, the population-based NHANES 2011-2014 survey found 25(OH)D levels lower than 20 ng/mL (50 nmol/L) in 7% of 1- to 5-year-olds, 12% of 6- to 11-year-olds, and 23% of 12- to 19-year-olds ( 32 ). Much higher prevalence of low vitamin D status is found in Northern Europe ( 33 ) and in low- and middle-income countries, where the majority of children have 25(OH)D concentrations lower than 10 ng/mL (25 nmol/L) ( 34 ). Particularly high-risk pediatric groups include children with limited exposure to sunlight, children with dietary restrictions, and children with high skin melanin content.

Several well-established guidelines recommend empiric vitamin D in the first year of life, specifically to prevent nutritional rickets ( 16-18 ); thus, in this guideline and the associated systematic review, the panel did not address children aged 0-1 years. However, nutritional rickets is not limited to infancy. While rickets is often considered a historical disease, its incidence is rising in high-income countries. Recent surveys indicate an incidence of up to 24 per 100 000 patient-years in North America, Australia, and Europe ( 35 ). In Western countries, rickets mainly affects children from racial and ethnic minority groups and non-Western immigrants and refugees ( 36 , 37 ). In low- and middle-income countries in the Middle East, South Asia, and Africa, the burden of nutritional rickets is substantially higher, with reported prevalence of 1% to 24% ( 35 , 38 ). In Turkey, a survey of 946 children with rickets showed peak incidences at ages 0 to 2 years and 12 to 15 years ( 39 ), indicating risk throughout childhood and adolescence. Nutritional rickets leads to pain, deformity, delayed milestone acquisition, and poor growth, and can be complicated by seizure and dilated cardiomyopathy ( 40 ).

Vitamin D has been implicated in the prevention of respiratory infections, which are very common in children, with pneumonia being the most common infectious cause of death in the first 5 years of life ( 41-45 ). In addition, low vitamin D status is associated with tuberculosis infection ( 46 ), another major cause of childhood mortality, with an estimated 230 000 deaths annually ( 47 ). A potential role for vitamin D in additional health outcomes affecting childhood, including autoimmune disease, atopy, and diabetes, has also been proposed. For example, several Mendelian randomization studies have suggested an association between genetically determined 25(OH)D levels and multiple sclerosis ( 48-51 ). In addition, vitamin D is thought to play a role in immunity, and childhood offers a unique window of opportunity to train the immune system ( 52 ). Bone health is also important during childhood, since peak bone mass accrual occurs during this period, extending into early adulthood. Thus, inadequate vitamin D status in childhood may affect disease vulnerability throughout the lifespan. The guideline panel therefore addressed the question of whether empiric vitamin D supplementation should be continued throughout childhood and adolescence.

Question 1. Should empiric vitamin D supplementation vs no empiric vitamin D supplementation be used for children and adolescents (aged 1 to 18 years)?

Summary of Evidence

The evidence summaries, meta-analysis results, and a detailed summary of the evidence and EtD tables can be found online at https://guidelines.gradepro.org/profile/gNMKfIPr5u4 .

Benefits and Harms

The systematic review found no RCTs on the efficacy of vitamin D in children and adolescents to prevent symptomatic nutritional rickets. This was because vitamin D supplementation was studied and implemented widely for prevention of rickets long before clinical trial methodology was standardized ( 53 ), and a placebo-controlled trial for nutritional rickets would currently be considered unethical. Several lines of evidence, however, indicate that vitamin D supplementation prevents the development of nutritional rickets in children. In 1917, Hess and Unger treated 49 infants and toddlers aged 1 month to 17 months, who were at high risk of rickets, with cod liver oil, the active ingredient of which is vitamin D, and then compared them with 16 infants and children in the same community. Eight of 49 infants in the treatment group and 15 of 16 in the control group developed rickets (odds ratio 0.18, P = .002) ( 54 ). Chick and colleagues in Vienna compared institutionalized infants fed either a standard diet or one enriched with cod liver oil from 1920 to 1922 and observed that 58% of the control group developed rickets compared to none in the cod liver oil group ( 55 ). The institution of a free vitamin D distribution program (400 IU/d [10 μg/d]) in Turkey was associated with a reduction in the prevalence of nutritional rickets from 6% in 1998 to 0.1% in 2008 ( 56 ). These and other data were summarized in an earlier systematic review ( 18 ). While these interventions were primarily in infants, the panel judged that these observations can be reasonably generalized to all children with open growth plates at risk for nutritional rickets.

The systematic review informing this guideline identified 12 RCTs ( 57-68 ) (12 951 participants) reporting on the effect of vitamin D on the incidence of respiratory infection, with individuals experiencing any respiratory infection representing the unit of analysis. Five of these trials were conducted in South Asia (India and Bangladesh), 5 trials in East Asia (Taiwan, Vietnam, Mongolia, and Japan), and 1 each in Afghanistan and Israel. Vitamin D regimens varied greatly, ranging from daily dosing of 300 to 2000 IU (7.5 to 50 μg), weekly dosing of 10 000 and 14 000 IU (250 and 350 μg), and a single dose of 100 000 (2500 μg) to 120 000 IU (3000 μg). The relative risk (RR) for developing any respiratory tract infection was 0.94 (95% CI, 0.87-1.02), with an estimated absolute effect size of 43 fewer respiratory infections per 1000 (93 fewer to 14 more). Studies that had some concern for bias showed a lower risk (RR 0.75 [95% CI, 0.61-0.94]) while studies with low risk of bias showed no difference in risk (RR 0.99 [95% CI, 0.92-1.07]) ( P for heterogeneity 0.022). Study subgroup analyses did not implicate vitamin D dosage or study participant age (younger vs older than 5 years) as significant predictors of outcomes. Among 6 trials ( 58 , 60 , 63 , 64 , 66 , 68 ) that reported lower respiratory tract infection specifically (10 356 participants), the RR for infection was 0.93 (95% CI, 0.83-1.04), with an absolute effect size of 33 fewer lower respiratory infections per 1000 (81 fewer to 19 more). Study subgroup analysis suggested the possibility that higher vitamin D dosages led to greater reductions in lower respiratory tract infection risk (RR 0.82 [95% CI, 0.68-1.00]) compared to standard dosages (RR 0.98 [95% CI, 0.94-1.03]), although this was not a statistically significant interaction ( P = .087). The RR of developing tuberculosis (2 trials, 10 533 participants) ( 68 , 69 ) was 0.67 (95% CI, 0.14-3.11) in those supplemented with vitamin D (10 000 and 14 000 IU [250-350 μg] weekly) with an absolute effect size of 1 fewer per 1000 (from 2 fewer to 6 more). Three trials ( 58 , 62 , 70 ) reported data on the total number of respiratory infections as the unit of analysis. After combining data from these trials, the incidence rate ratio (IRR) favored vitamin D (0.64 [95% CI, 0.51-0.82]). Supporting this finding was the trial in which all patients had at least one acute respiratory infection in the 6 months following the intervention, but the proportion who had at least 3 infections was lower in the intervention group (7.7% vs 32.4%) ( 67 ). Study subgroup analyses did not strongly implicate study risk of bias or vitamin D dosage as significant predictors of these outcomes.

The panel found limited RCT data on the impact of vitamin D on the incidence of autoimmune disease, allergic disease, and asthma, with too few events to analyze. The panel found no RCT data on the effect of treating this population with vitamin D to lower the risk of prediabetes and type 2 diabetes, or fractures (in adulthood).

The systematic review did not find clear evidence that vitamin D increases adverse events in children. Available trials documented one case of symptomatic hypercalcemia in an individual assigned to vitamin D and one case of kidney failure in an individual assigned to the control group; there were no reported kidney stones.

Based on the panel's best estimates of treatment effects, the panel judged that the anticipated desirable effects of empiric vitamin D supplementation are likely to be beneficial for many, and that the anticipated undesirable effects are likely to be trivial for all.

Other Evidence-to-Decision Criteria and Considerations

The cost of vitamin D supplementation is low, although variable in different countries. Cost-effectiveness of universal vitamin D supplementation for the prevention of rickets has been addressed in economic modeling studies in the United Kingdom. Two studies suggested that targeted vitamin D administration to those with moderate-to-dark complexion (defined in the study as having Afro-Caribbean ancestry) and those with Asian ancestry would be either cost-saving or cost-effective ( 71 , 72 ). An additional study suggested that universal vitamin D supplementation via flour fortification would be cost-saving, while targeted supplementation of children would be cost-effective ( 73 ). Given that the risk of nutritional rickets is likely substantially increased among children with darker complexion and among immigrants to high-income countries ( 35 , 40 , 74-77 )—populations that may experience lower health equity as a group—the panel concluded that vitamin D supplementation in children could potentially improve health equity.

There is limited evidence regarding the acceptability of vitamin D supplementation in children and among their caregivers. In one trial in which children aged 9 to 12 years were offered various forms of vitamin D and calcium, 44% agreed to continue fortified milk, 66% agreed to fortified orange juice, and 95% agreed to supplements, suggesting that supplement use may be the most accepted formulation ( 78 ). In one small survey study in the United Kingdom, approximately 25% of caregivers aware of governmental recommendations about vitamin D supplementation were not adherent to the recommendations. Reasons for nonadherence included the child's dislike of drops, low priority, and belief that other strategies such as breastfeeding, outdoor play, and a varied diet were sufficient ( 79 ).

Justification for the Recommendation

Given the high stakes of very low vitamin D status during skeletal growth—the risk of nutritional rickets in particular—the panel judged that empiric vitamin D supplementation may be prudent in growing children/adolescents, especially for those who are not otherwise expected to have adequate vitamin D stores via sun exposure (for example, from adequate levels of sun-safe outdoor physical activity) and ingestion of vitamin D–containing or vitamin D–fortified foods, and those for whom confidence is low that IOM DRIs are being achieved reliably. The panel agreed that low- to moderate-certainty evidence suggests that vitamin D supplementation in children may be beneficial for respiratory infections, which are a leading cause of mortality. The panel also concluded that supplementation costs are generally low, that supplementation is likely to be feasible and acceptable, and that empiric supplementation may improve health equity. Given the low overall certainty of evidence, and since net benefits may vary according to individual circumstances, a conditional recommendation was issued.

Additional Considerations

The optimal dosage for prevention of respiratory tract infections in children remains uncertain. In the trials included in this systematic review, the vitamin D dosages ranged from 300 to 2000 IU (7.5 to 50 μg) daily equivalent. The estimated median vitamin D dosage used in these studies was 811 IU (20 μg) daily, and estimated weighted average dosages were 1203 IU (30 μg) per day for the any respiratory infection outcome and 1473 IU (37 μg) per day for the lower respiratory tract infection outcome. (Here and elsewhere in this document, the estimated weighted average dosage for an outcome represents each relevant study's vitamin D dosage weighted according to the study's weight in the meta-analysis for that outcome.)

Research Considerations

Proposed areas for research include:

Adequately powered trials among children with appropriate controls to detect rare outcomes and long-term follow-up should be conducted in specific populations (eg, children with a history of asthma, risk of type 1 diabetes, new-onset type 1 diabetes) with outcomes specific to these populations (eg, asthma exacerbations, incident type 1 diabetes, progression of type 1 diabetes).

Since the majority of trials in children were conducted in Asia, it is important to undertake studies examining the effects of vitamin D on outcomes in other populations that may differ in terms of diet, sun exposure, and complexion.

While adults younger than age 50 years have lower health care usage compared to older individuals ( 80 ), this is a critical time during which many chronic diseases linked to environmental and nutritional factors develop. A significant percentage of adults in this age group have low vitamin D status. Levels of 25(OH)D lower than 12 ng/mL (30 nmol/L) were seen in 14% of Europeans and lower than 20 ng/mL (50 nmol/L) in 40% ( 81 ). In the United States, 24% and 6% of adults have 25(OH)D levels lower than 20 ng/mL (50 nmol/L) and 10 ng/mL (25 nmol/L), respectively ( 82 ). Numerous studies have found associations between low 25(OH)D levels, low BMD, and fractures. Low 25(OH)D levels have also been associated with fatigue and higher risks for respiratory infections, including COVID-19 ( 83 ).

The age span of 18 to 50 years is when peak bone mass occurs, and the National Osteoporosis Foundation's systematic review and implementation recommendations suggest that vitamin D plays an important role in peak bone mass accrual ( 84 ), which has implications for risk of osteoporotic fractures later in life. Most pregnancies occur between ages 19 and 50 years, and, while pregnancy-specific recommendations are addressed elsewhere, those who are pregnant most often do not present for care before the end of the first trimester, and having adequate vitamin D status preconception may be important. Fatigue is also common in this age group and, like respiratory infections, contributes to loss of productivity and increased medical care.

The evidence summaries, meta-analysis results, and a detailed summary of the evidence and EtD tables can be found online at https://guidelines.gradepro.org/profile/5NvU2k7Tig0 and https://guidelines.gradepro.org/profile/PdgmJZLRZTs .

The systematic review identified 2 RCTs ( 85 , 86 ) (17 074 participants in New Zealand and Norway) reporting on the development of a respiratory infection, with participants as the unit of analysis. There was no significant difference between the vitamin D and placebo groups (RR 1.02 [95% CI, 0.96-1.08]), with an estimated absolute effect size of 5 more per 1000 (11 fewer to 22 more). In the New Zealand study ( 85 ), the baseline mean 25(OH)D level was 29 ng/mL (73 nmol/L), and vitamin D was given as 200 000 IU (5000 μg) monthly for 2 months, followed by 100 000 IU (2500 μg) monthly for 18 months. In the Norwegian study ( 86 ), the baseline mean 25(OH)D level was not reported and vitamin D was given as 400 IU (10 μg) of cod liver oil daily.

The systematic review identified 4 studies ( 85 , 87-89 ) (1120 participants, New Zealand, Finland, Canada, Australia) addressing the total number of respiratory infections as the unit of analysis; the IRR was 0.95 (95% CI, 0.83-1.07). The baseline mean 25(OH)D levels in these trials were 24 to 30 ng/mL (60 to 75 nmol/L) (one trial did not report baseline 25[OH]D). The intervention in 2 trials was daily vitamin D (400 IU [10 μg] and 5000 IU [125 μg]), whereas nondaily doses were administered in 2 other trials (10 000 IU [250 μg] per week and 20 000 IU [500 μg] per week).

The systematic review did not identify any trials examining the effects of vitamin D on new-onset fatigue. One small RCT (120 participants, Switzerland) ( 90 ) examined improvement in fatigue among participants with fatigue and baseline 25(OH)D levels lower than 20 ng/mL (50 nmol/L) with a mean level of 13 ng/mL (33 nmol/L). Participants were randomized to receive a single dose of 100 000 IU (2500 μg) of vitamin D or placebo. Four weeks later, those who received vitamin D were more likely to report amelioration of fatigue (72% vs 50%; RR 1.49 [95% CI, 1.08-1.94]), suggesting an improvement in 245 per 1000 (40 fewer to 470 more). The improvement in fatigue was modest (change in the Fatigue Assessment Scale [maximum score = 50] from 24.9 ± 5.4 to 21.6 ± 5.8 in the intervention group vs 23.3 ± 5.4 to 22.5 ± 5.9 in the placebo group).

Studies examining the effects of vitamin D on BMD tested different dosage regimens. Four studies ( 91-94 ) examined lumbar spine BMD, 2 examined total hip BMD ( 93 , 94 ), 2 examined femoral neck BMD ( 92 , 94 ) and 2 ( 95 , 96 ) reported on volumetric tibial bone density by high-resolution peripheral quantitative computed tomography (HR-pQCT) (Denmark, Norway, Bangladesh, Austria, USA). Vitamin D was administered either daily (400 IU [10 μg], 800 IU [20 μg], 1000 IU [25 μg], 4000 IU [100 μg], or 7000 IU [175 μg]) or nondaily (40 000 IU [1000 μg] per week, or 50 000 IU [1250 μg] twice monthly). Estimated mean differences in BMD were 0.003 g/cm 2 lower at the lumbar spine (0.042 lower to 0.036 higher), 0.049 g/cm 2 lower at the total hip (0.060 lower to 0.038 higher), and 0.033 g/cm 2 higher at the femoral neck (0.023 lower to 0.090 higher); volumetric bone density by HR-pQCT was 6.862 mg/cm 3 higher at the tibia (8.082 lower to 21.805 higher). Some trials were felt to be of insufficient duration (< 1 year) to robustly evaluate the effects of vitamin D on bone density.

The systematic review found no evidence of increased adverse events (symptomatic hypercalcemia, nephrolithiasis, and kidney disease/kidney failure) in trial participants assigned to vitamin D.

Based on the panel's best estimates of treatment effects (the point estimates derived from meta-analyses), the panel judged that the anticipated desirable effects of vitamin D are likely to be small at best, and that the anticipated undesirable effects are likely to be trivial.

Considerations related to required resources, costs, acceptability, and feasibility have been previously addressed. A comprehensive review of studies addressing female patients’ views of osteoporosis therapy revealed that calcium and vitamin D were viewed as safe and natural ( 97 ). Panel members judged that empiric vitamin D would likely be acceptable to individuals in this age group, especially females with risk factors for developing osteoporosis.

While vitamin D supplementation appears to be safe, inexpensive, and readily available, the trials identified in the systematic review did not clearly show a substantive benefit of vitamin D supplementation. For this reason, the panel issued a conditional recommendation against routine vitamin D supplementation above what would be required to meet dietary reference guidelines.

The panel was unable to recommend a 25(OH)D threshold below which vitamin D administration provides outcome-specific benefits, primarily due to the absence of large RCTs designed to assess the effects of the intervention in those with low baseline 25(OH)D levels. In addition, the financial costs associated with both 25(OH)D testing and medical visits, as well acceptability of testing in this age group, where routine phlebotomy is not typically indicated for healthy individuals, factored into the panel's judgment. The panel also acknowledged that feasibility of 25(OH)D testing is variable across the globe; and in the absence of evidence for benefit, a recommendation for 25(OH)D testing could decrease health equity. For all these reasons, the panel suggested against routine 25(OH)D testing in generally healthy adults who do not otherwise have established indications for 25(OH)D testing (eg, hypocalcemia).

The panel judged that healthy adults in this age group could rationally choose to take vitamin D supplements if they are not expected to have adequate vitamin D status via sun exposure and do not reliably meet DRI of vitamin D from vitamin D–containing or fortified foods.

Testing to identify those with low 25(OH)D level, or to monitor response to therapy, may be required in special populations who are expected to require more than the DRI of vitamin D to prevent/reverse low vitamin D status, including those with malabsorption (eg, from short gut syndrome, gastric bypass, inflammatory bowel disease), those with increased vitamin D catabolism (eg, due to certain medications), and those with increased renal losses of vitamin D (eg, nephrotic syndrome).

Large clinical trials in populations with low baseline 25(OH)D levels will be required to determine if vitamin D prevents disease and what dosages are required for the desired outcomes. Although placebo-controlled trials in those known to have low 25(OH)D levels may be viewed as unethical, inclusion of various daily dosages and targeting several levels of 25(OH)D would inform the dosages and target levels required for disease prevention.

Clinical trials must be designed to be of sufficient duration to address the outcomes being examined, considering the natural history and pathophysiology of the diseases of interest (eg, acute infectious diseases vs fractures or cancer).

Vitamin D status may decrease with age due to impaired biosynthesis (reduced biosynthesis capacity, lower sun exposure), low dairy and fish consumption, and increased weight, although the decrease is most marked above age 75 years. Population-based data from the United States (NHANES) in 3377 adults aged 40 to 59 years and 3602 adults aged 60 years and older indicate that 24% and 22%, respectively, had 25(OH)D concentrations lower than 20 ng/mL (50 nmol/L), and 5.9% and 5.7%, respectively, had 25(OH)D concentrations lower than 10 ng/mL (25 nmol/L), with similar values for women and men ( 82 ). Population-based data from Europe (ODIN) in children and adults (all ages) show a higher prevalence of low vitamin D status, with 40% having values lower than 20 ng/mL (50 nmol/L) and 13% having values lower than 12 ng/mL (30 nmol/L), with similar values for women and men ( 81 ). The prevalence of low 25(OH)D levels is most marked in housebound and institutionalized individuals ( 98 ).

The period between 50 and 74 years of age corresponds to a time of bone loss related to menopause and normal aging, decreasing muscle function, and increasing fall risk, all predisposing to increased risk of fractures. Importantly, some studies suggest that these risks can be attenuated by vitamin D and calcium ( 99 ). Vitamin D has also been hypothesized to have a role in modifying the risk of CVD, diabetes, cancer, acute respiratory infections, and mortality, all of which are important outcomes relevant to this age group ( 100-102 ).

Many of the RCTs designed to address these questions involved groups with mean baseline 25(OH)D levels that would be considered adequate (approximately 25 ng/mL [63 nmol/L]). This has contributed to uncertainty regarding whether empiric vitamin D supplementation in those aged 50 to 74 years can reduce risk of chronic conditions common to this population. Additionally, it is unclear whether this age group should undergo screening to identify those with low levels of 25(OH)D who might be more likely to benefit from vitamin D supplementation. For example, a meta-analysis of RCTs suggests that vitamin D combined with calcium appears to decrease the incidence of fractures in the older and institutionalized population ( 103 ). However, several recent clinical trials ( 104 , 105 ) did not reveal similar findings, perhaps because many participants in these trials did not have low baseline 25(OH)D levels. This suggests—but does not prove—that the individuals most likely to benefit from vitamin D supplementation are those at risk for low baseline 25(OH)D levels, a group that is overrepresented in housebound and institutionalized populations ( 106 , 107 ). However, 25(OH)D thresholds required to prevent disease may differ according to the outcome, as suggested by epidemiological studies ( 108 ). Trials specifically targeting people with low vitamin D status and/or “treat-to-target” trials documenting the benefit of achieving and maintaining specific 25(OH)D levels with vitamin D have not been done.

The evidence summaries, meta-analysis results, and a detailed summary of the evidence and EtD tables can be found online at https://guidelines.gradepro.org/profile/9FN6GJZdDJ4 and https://guidelines.gradepro.org/profile/-NxdICB9sYc .

The systematic review identified 13 RCTs ( 104 , 105 , 109-119 ) (86 311 community-dwelling participants) comparing vitamin D vs placebo with any fracture as the outcome. The vitamin D dosages varied between 300 and 3500 IU/daily equivalent (7.5 and 88 μg) with a median dosage of 1500 IU (37.5 μg) daily. In many trials, the participants were allowed to take a daily supplement that contained no more than 400 to 800 IU of vitamin D. The median of the average baseline 25(OH)D concentrations in these studies was 24 ng/mL (ranging from 13 to 32 ng/mL) (60 nmol/L [32 to 80 nmol/L]). The RR for any fracture with vitamin D was 0.97 (95% CI, 0.91-1.03), with an estimated absolute risk reduction of 2 fewer per 1000 (7 fewer to 2 more). Study subgroup analyses suggested that the effect of vitamin D on fracture risk was not modified by risk of bias, sex, dosage of vitamin D, or calcium co-administration.

All-cause mortality was reported as an outcome in 13 RCTs ( 20 , 109 , 111 , 116 , 119-127 ) (81 695 participants). The estimated daily vitamin D dosage varied between 400 IU (10 μg) and 4800 IU (120 μg), with a median of 2000 IU (50 μg). Most trials allowed participants to take a supplement with vitamin D between 400 to 800 IU/d. The median of the average baseline 25(OH)D concentrations in these studies was 24 ng/mL (ranging from 18 to 31 ng/mL) (60 nmol/L [45-78 nmol/L]). The RR for mortality was 1.07 (95% CI, 0.95-1.20), translating to 2 more per 1000 (2 fewer to 6 more). The risk of mortality in studies involving calcium co-administration (RR 0.90 [95% CI, 0.79-1.01]) appeared to be lower than those involving vitamin D alone (RR 1.12 [95% CI, 1.01-1.24]) ( P for heterogeneity = .021). In addition, the risk of mortality appeared to be higher with vitamin D in the studies involving high dosages of vitamin D (RR 1.22 [95% CI, 1.06-1.39]) relative to those involving standard dosages (RR 0.95 [95% CI, 0.86-1.04]) ( P for heterogeneity = .003). Study subgroup analyses suggested that the effect of vitamin D on mortality risk was not modified by risk of bias or sex.

Cancer was reported as an outcome in 15 RCTs ( 20 , 109 , 111 , 119 , 123 , 125 , 126 , 128-135 ) (91 223 participants), using dosages of 300 to 4800 IU/daily equivalent, with a median dosage of 2000 IU/d (50 μg/d). In many trials, the participants were allowed to take a daily supplement that contained no more than 400 to 800 IU of vitamin D. Mean baseline 25(OH)D ranged from 13 to 33 ng/mL (median 26 ng/mL) (33 to 83 nmol/L [median 65 nmol/L]). The relative risk for cancer with vitamin D was 1.00 (95% CI, 0.97-1.03) translating to 0 fewer patients with cancer per 1000 (4 fewer to 4 more). Study subgroup analyses suggested that the effect of vitamin D on cancer outcomes was not modified by risk of bias, sex, dosage of vitamin D or calcium co-administration.

Fourteen RCTs ( 20 , 109 , 111 , 116 , 118 , 119 , 122 , 125-127 , 131 , 134 , 136 , 137 ) involving 80 547 participants reported on CVD events using dosages of 300 to 4800 IU/daily equivalent, with a median dosage of 2000 IU/d (50 μg/d). In addition, most trials allowed a vitamin D–containing supplement from 400 to 800 IU/d. Mean baseline 25(OH)D ranged from 13 to 31 ng/mL (mean 24 ng/mL) (33 to 78 nmol/L; mean 60 nmol/L]). The relative risk for CVD with vitamin D was 1.00 (95% CI, 0.93-1.08), translating to 0 fewer patients with CVD per 1000 (2 fewer to 3 more). Seven RCTs ( 20 , 109 , 111 , 119 , 122 , 125 , 136 ) reported stroke with a summary RR of 0.95 (95% CI, 0.83-1.09), translating to 1 fewer patient with stroke per 1000 (2 fewer to 1 more). Myocardial infarction (MI) was an outcome in 7 RCTs ( 20 , 109 , 111 , 119 , 122 , 125 , 131 ), with a summary RR of 1.00 (95% CI, 0.83-1.20), translating to 0 fewer patients with MI per 1000 (2 fewer to 2 more). Study subgroup analyses suggested that the effects of vitamin D on cardiovascular events, stroke, and MI were not modified by risk of bias, sex, dosage of vitamin D or calcium co-administration.

Kidney stones were reported in 10 RCTs ( 20 , 109-111 , 118 , 125 , 129 , 135 , 138 , 139 ) with a summary RR of 1.10 (95% CI, 1.00-1.19), translating to 2 more patients with kidney stones per 1000 (0 fewer to 4 more). Kidney disease was reported in 4 RCTs ( 20 , 119 , 127 , 134 ) with a summary RR of 1.04 (95% CI, 0.76-1.42), translating to 0 fewer patients with kidney disease per 1000 (1 fewer to 2 more). Study subgroup analyses suggested that the effects of vitamin D on kidney stones and kidney disease were not modified by risk of bias, sex, dosage of vitamin D, or calcium co-administration.

The systematic review identified 3 RCTs that reported outcomes specifically in participants with baseline serum 25(OH)D below 20 ng/mL (50 nmol/L) (or the lowest quartile, ie, < 24 ng/mL [60 nmol/L]) receiving vitamin D vs placebo ( 29 ). Meta-analysis of such data from 2 of these RCTs ( 20 , 124 ) suggested an RR of 1.11 (95% CI, 0.85-1.46) for the mortality outcome. Cancer was reported in 2 RCTs ( 20 , 130 ), and vitamin D was associated with a RR of 0.91 (95% CI, 0.70-1.19) compared to placebo. Cardiovascular disease events were reported in 3 RCTs ( 20 , 122 , 137 ) with a RR of 1.02 (95% CI, 0.87-1.19) compared to placebo. Subgroup analyses in single trials suggested no clear impact on fractures (RR 1.01 [95% CI, 0.81-1.24]), stroke (RR 1.04 [95% CI, 0.39-2.75]), MI (RR 0.93 [95% CI, 0.38-2.29]), and adverse events (RR 1.26 [95% CI, 0.77-2.12]).

Based on the panel's best estimates of treatment effects, the panel judged that the anticipated desirable effects of vitamin D, in addition to the anticipated undesirable effects, are likely to be trivial.

Considerations related to required resources (costs), acceptability, and feasibility of vitamin D have already been addressed. Prevention of hip fractures in older people at risk is highly valued, as demonstrated by time-trade-off studies ( 140 ). The effect of coronary artery disease on quality of life may be small except for recurrent angina ( 141 ).

A cost-benefit analysis concluded that the costs of vitamin D and calcium would be much lower than the costs of fractures resulting from no supplementation. This result was mainly driven by the age group older than 65 years ( 142 ). Although a French study concluded that treatment based on 25(OH)D concentrations was more cost-effective than treating everybody ( 143 ), a systematic review of economic evaluations concluded that there was insufficient economic evidence to draw conclusions about the cost-effectiveness of population strategies ( 144 ). The panel found these cost-effectiveness studies difficult to contextualize given that the commissioned systematic review of clinical trials did not disclose a substantive benefit of vitamin D on fractures in those aged 50 to 74 years.

A comprehensive review of studies addressing women's views of osteoporosis therapy revealed that vitamin D and calcium were viewed as safe and natural and preferred to hormones and other treatments ( 97 ). As such, vitamin D is likely to be considered acceptable. The panel judged that empiric vitamin D supplementation is feasible to implement, although conditioning vitamin D supplementation on 25(OH)D levels could represent an important barrier for some.

Justification for the Recommendations

Vitamin D supplementation appears to be safe when taken as outlined in the IOM DRIs. Vitamin D is also inexpensive, readily available, acceptable to patients, and relatively easy to implement. Adherence may be a challenge, because supplementation typically involves lifelong use of vitamin D. Based on the meta-analyses of the available trials, which yielded high certainty of evidence for fractures, CVD events, cancer and mortality, the panel judged that vitamin D supplementation appears to have little or no beneficial impact on the outcomes analyzed in healthy populations aged 50 to 74 years. There was therefore no compelling rationale to recommend empiric vitamin D in this age group, especially since supplementation would involve costs (admittedly minor) and inconvenience.

Importantly, most of the recent trials were completed in populations that were meeting their DRI and did not have low vitamin D status at baseline. Given the well-established harmful consequences of very low vitamin D status on skeletal health and calcium homeostasis, the panel judges that some subgroups in this age group could rationally choose to take vitamin D supplementation, especially if they are not expected to have adequate vitamin D status via sun exposure (dark complexion, housebound, clothing style) or reliable IOM-recommended intake via diet, supplements or ingestion of vitamin D–fortified foods.

Subgroup analyses did not provide evidence for benefit with vitamin D in subgroups with 25(OH)D below 20 to 24 ng/mL (50-60 nmol/L). In addition, there are monetary costs associated with both 25(OH)D testing and medical visits, the panel judged that a recommendation for 25(OH)D testing could decrease feasibility and health equity (especially when compared to empiric vitamin D supplementation). For all these reasons, the panel suggested against routine 25(OH)D testing (eg, screening) in generally healthy adults aged 50 to 74 years.

These recommendations should not be extrapolated to individuals with conditions known to substantially impact vitamin D physiology, including malabsorption (eg, from gastric bypass), increased vitamin D catabolism, renal loss of vitamin D metabolites, and decreased vitamin D activation.

With regard to 25(OH)D screening, the panel noted that 2 risk scoring systems can predict serum 25(OH)D concentrations lower than 20 ng/mL and 12 ng/mL (< 50 and < 30 nmol/L), respectively, with reasonable accuracy, and thus may be useful in clinical practice to identify persons aged 55 to 85 years at high risk for low vitamin D without the need for 25(OH)D testing ( 145 ). Risk factors in these scoring systems include female sex, alcohol use, smoking, season, medication use, no vitamin use, and limited outdoor activities such as gardening and bicycling.

The age group 65 to 74 years requires more attention, since the risks of chronic diseases and the outcomes being examined are higher than in those aged 50 to 64 years. The age group of 50 to 74 years is a heterogenous population in which some may be in excellent health, whereas others may have chronic conditions and may be housebound. Thus, trials addressing the effect of vitamin D on individuals with different health status are required.

RCTs specifically in those with low baseline 25(OH)D levels are required to clarify the risks and benefits of vitamin D and/or calcium supplementation.

Studies with longer follow-up may be needed, as some outcomes may become apparent only after 5 years ( 117 ).

In secondary, exploratory analyses, vitamin D in this age group has been implicated in the prevention of autoimmune disease such as rheumatoid arthritis, polymyalgia rheumatica, and autoimmune thyroid disease ( 146 ). These data need confirmation by additional RCTs.

Studies of the effect of vitamin D fortification on vitamin D status in different populations at risk of low vitamin D status are needed.

Low 25(OH)D levels are common among older people in the United States. Recent results from NHANES surveys during 2001-2018 showed that the prevalence of low vitamin D status (25[OH]D ≤ 20 ng/dL [50 nmol/L]) in the US population older than 80 years was 19.6% in females and 18.9% in males ( 147 ). Many observational studies have reported inverse associations between 25(OH)D levels and adverse health outcomes such as falls, fractures, and respiratory disease ( 148-152 ). These conditions contribute significantly to morbidity and mortality in older people. For example, falls occur commonly in older people, with more than 14 million US adults 65 years and older falling one or more times each year ( 153 ), resulting in an estimated 9 million fall injuries annually ( 154 ). Falls are the leading cause of injury-related death in this age group, which is an increasing subset of the population ( 155 ). The annual health care costs from fall injuries are about $50 billion ( 156 ). More than 95% of hip fractures are caused by falling ( 157 ), with more than 300 000 people 65 years and older hospitalized for a hip fracture each year in the United States ( 158-160 ). Hip fractures are also associated with increased mortality ( 161 ). Despite the importance of these conditions associated with low vitamin D status in observational studies, it remains unclear whether vitamin D supplementation lowers the risks of such conditions: the data from randomized, placebo-controlled trials of vitamin D supplementation are inconsistent, and systematic reviews and meta-analyses of RCTs have reported heterogeneous results for these outcomes ( 162-165 ).

In the clinical trials included in the systematic review that reported on the mortality outcome, vitamin D dosage ranged from 400 to 3333 IU [10 to 83 μg] daily equivalent. The estimated weighted average was approximately 900 IU (23 g) daily. Participants in many trials were allowed to remain on their routine supplements, including up to 800 IU (20 µg) of vitamin D daily.

The evidence summaries, meta-analysis results, and a detailed summary of the evidence and EtD tables can be found online at https://guidelines.gradepro.org/profile/3knvwnbvIkQ and https://guidelines.gradepro.org/profile/ySx1d8ko_C4 .

The systematic review included 25 trials ( 20 , 104 , 121 , 124 , 166-186 ) (49 879 participants) that reported on the effect of vitamin D on all-cause mortality. These trials involved participants from community settings (n = 17), nursing homes (n = 6), and hospital clinics (n = 2). Most trials assessed the impact of vitamin D3 (cholecalciferol), commonly given as a daily dose (13 trials), either alone or combined with calcium. Follow-up durations ranged from 12 weeks to 7 years, with a median of 2 years. Meta-analysis suggested that vitamin D lowers mortality compared to placebo (RR 0.96 [95% CI, 0.93-1.00]), with an estimated absolute effect size of 6 fewer deaths per 1000 people (from 11 fewer to 0 more). Study subgroup analyses revealed no differences according to risk of bias, gender, calcium co-administration, vitamin D dosage (high vs standard), or setting (community, hospitalized, institutionalized). When restricting analysis to community-based studies, vitamin D appeared to be associated with a similar reduction in mortality risk (RR 0.95 [95% CI, 0.90-0.99]). Among study participants with low vitamin D status (< 20 ng/mL [50 nmol/L]), the results were consistent with those observed in the broader population (RR of mortality 0.88 [95% CI, 0.46-1.67]).

The systematic review identified 14 trials ( 104 , 117 , 170 , 171 , 173 , 177 , 178 , 180 , 181 , 183 , 184 , 187-190 ) that reported the number of participants with a fracture as the unit of measure (43 585 participants), and the RR for vitamin D was 1.01 (95% CI, 0.94-1.08), with an estimated absolute effect size of 1 fewer per 1000 people (from 5 fewer to 6 more). Fourteen trials ( 168 , 172 , 175 , 191 ) [male and female, separately] ( 174 , 180 , 184 , 185 , 188 , 189 , 192-195 ) reported the total number of fractures as the unit of measure, and the IRR was 0.95 (95% CI, 0.82-1.10). Study subgroup analysis suggested that estimated IRR may vary according to study risk of bias, with IRR estimates appearing to be lower in studies with some concerns compared to those with either low or high risk of bias. The IRR for number of fractures was lower in studies involving calcium co-administration (0.78 [95% CI, 0.68-0.90]) vs no calcium co-administration (1.05 [95% CI, 0.88-1.28]) ( P for heterogeneity .005), but a similar interaction was not observed when participants with fractures served as the unit of analysis. Study subgroup analyses did not implicate sex, vitamin D dosage, or setting (community vs institutional) as significant predictors of fracture outcomes. Data addressing fracture outcomes specifically in those with 25(OH)D levels < 20 ng/mL (50 nmol/L) were unavailable.

The systematic review identified 16 trials ( 104 , 166 , 170 , 171 , 173 , 174 , 176 , 184 , 188 , 189 , 193 , 194 , 196-199 ) that reported the number of participants with any fall as the unit of measure (12 342 participants) and the RR for vitamin D was 0.97 (95% CI, 0.91-1.03), with an absolute effects size of 16 fewer people with falls per 1000 (from 48 fewer to 16 more). Fifteen trials ( 166 , 173 , 175 , 184 , 185 , 187-190 , 194 , 195 , 197-200 ) reported the number of falls as the unit of measure, and the IRR was 0.91 (95% CI, 0.81-0.99). The reduction in IRR for falls was confined mainly to studies with high risk of bias, and no effect was seen in studies with low risk of bias (IRR 1.03 [95% CI, 0.92, 1.11]). Study subgroup analyses suggested that vitamin D reduced fall risk more so in studies involving standard vitamin D dosages (RR 0.93 [95% CI, 0.85-1.01]; IRR 0.88 [95% CI, 0.76-1.00]) compared to studies involving high vitamin D dosages (RR 1.06 [95% CI, 1.01-1.11]; IRR 1.02 [95% CI, 0.86-1.10]) ( P for interaction = .007 for RR and 0.033 for IRR). The risk for falls appeared to be reduced by vitamin D to a greater degree in studies involving calcium co-administration (RR 0.85 [95% CI, 0.74-0.97]; IRR 0.73 [95% CI, 0.53-0.92]) vs studies without calcium co-administration (RR 1.04 [95% CI, 1.01-1.08]; IRR 0.99 [95% CI, 0.91-1.07]) ( P for interaction = .004 for RR and 0.007 for IRR). In addition, study subgroup analysis suggested that vitamin D reduced total number of falls more so in institutional-based studies (IRR 0.82 [95% CI, 0.69-0.94]) compared to community-based studies (IRR 0.96 [95% CI, 0.83-1.05]) ( P for interaction = .024), but a similar interaction was not observed when persons with falls served as the unit of analysis. Analysis of 2 studies reporting falls among participants with low vitamin D status (< 20 ng/mL [50 nmol/L]) ( 194 , 199 ), the RR for fall with vitamin D was 0.65 (95% CI, 0.40-1.05).

The systematic review identified only 2 trials ( 168 , 201 ) that reported on the effect of vitamin D on respiratory infections in adults older than age 75 years. Both trials reported subgroup analyses for both upper and lower respiratory tract infections combined. The ViDA study compared monthly vitamin D3 with placebo, with number of participants experiencing respiratory tract infection as the unit of measure, and the adjusted hazard ratio (HR) was 1.11 (95% CI, 0.94-1.30) ( 201 ). In the DO-HEALTH trial, which evaluated the total number of infections as the unit of measure, the adjusted IRR was 1.15 (95% CI, 0.94-1.41) for daily 2000 IU (50 μg) vitamin D3 ( 168 ). No trials reported subgroup analyses related to the impact of vitamin D on respiratory infections specifically for those with low 25(OH)D levels in this age group.

Four trials reported possible undesirable outcomes in adults aged 75 years and older ( 29 ). With the number of participants as the unit of measure, the RR for nephrolithiasis among 6306 participants in 3 trials ( 20 , 138 , 168 ) was 0.94 (95% CI, 0.54-1.65) for vitamin D vs placebo, with an estimated absolute effect size of 1 fewer per 1000 [7 fewer to 10 more]), and the RR for kidney disease among 5634 participants in 3 trials ( 20 , 166 , 168 ) was 0.76 (95% CI, 0.44-1.32) with an estimated absolute effect size of 3 fewer per 1000 [6 fewer to 3 more]).

Based on the panel's best estimates of treatment effects (ie, stipulating the veracity of point estimates), the panel judged that the anticipated desirable effects of vitamin D are likely small, and that the anticipated undesirable effects are likely trivial. Among study participants with low vitamin D status, the results were consistent with those observed in the broader population.

The panel concluded that the costs of empiric vitamin D supplementation were negligible because vitamin D is inexpensive. Although the panel identified some cost-effectiveness analyses related to falls and fractures, these were difficult to apply because the systematic review suggested little to no benefit for the fall and fracture outcomes. Regardless, given minimal costs of vitamin D supplementation, the panel reasoned that vitamin D is likely to be cost-effective with regard to its (likely) mortality benefit. Given that low vitamin D status tends to be more prevalent among those with lower health equity, assuming that vitamin D supplementation is most likely to benefit those with low vitamin D status, and recognizing that vitamin D supplementation is inexpensive, the panel reasoned that vitamin D probably improves equity, based on its (likely) mortality benefit. The panel judged that empiric vitamin D supplementation would be feasible and acceptable to stakeholders.

The systematic review did not find evidence suggesting that benefit with vitamin D is restricted to those with baseline 25(OH)D levels below a threshold. In addition, the panel concluded that conditioning vitamin D supplementation/treatment on 25(OH)D screening may create barriers for some (eg, in places where access to laboratory testing is difficult). Moreover, the addition of a 25(OH)D testing requirement would increase costs, possibly decreasing acceptability for some.

Based on the systematic review, vitamin D probably results in a slight decrease in all-cause mortality in this age group (high certainty of evidence), and probably results in little to no difference in fractures (high certainty of evidence), or adverse events (moderate certainty of evidence), including falls. The panel had concerns that clinical trials using high dosages of vitamin D may have masked improvement in fall risk, and study subgroup analysis suggested that fall risk was likely reduced in trials employing standard vitamin D dosages.

While specific data related to respiratory infections were inadequate (low certainty of evidence), indirect data from general populations suggest that vitamin D is unlikely to be harmful in this regard, and the panel prioritized the mortality outcome. Given that the best available evidence suggests a small but important benefit in terms of mortality risk and minimal to no harms, the panel judged that the balance between desirable and undesirable effects probably favors empiric vitamin D supplementation. In addition, the panel judged that empiric vitamin D supplementation is typically inexpensive, may be cost-effective, may increase health equity, and is probably both acceptable to key stakeholders and feasible to implement. For these reasons, the panel suggests empiric vitamin D supplementation. In the absence of high overall certainty of evidence, the panel issued a conditional recommendation in this regard.

The systematic review did not find evidence suggesting that net benefit is restricted to those with 25(OH)D below a threshold, and the few available clinical trials that reported subgroup results by 25(OH)D level did not clearly implicate baseline 25(OH)D level as a significant predictor of treatment effect; however, data were judged to be sparse in this regard. In addition, 25(OH)D testing and medical visits involve monetary costs, and the panel judged that a recommendation for 25(OH)D testing could decrease feasibility and health equity (especially when compared to empiric vitamin D supplementation). For these reasons, the panel suggests against routine 25(OH)D testing (eg, screening) in adults aged 75 years and older.

When considering all 25 clinical trials reporting mortality data, the median (interquartile range) vitamin D dosage approximated 833 (800-1370) IU/day (21 μg/day [20-34 μg/day]), and the estimated weighted average vitamin D dosage (ie, each study's vitamin D dosage weighted according to the study's weight in the meta-analysis for the mortality outcome) was approximately 909 IU/day (23 μg/day). In many trials, participants were permitted to remain on vitamin D supplements up to 800 IU (20 μg)/day.

Vitamin D with calcium may be superior to vitamin D alone at decreasing the risk of falls and fractures. Subgroup analysis revealed that vitamin D significantly lowers fracture risk with calcium co-administration when number of fractures was the outcome; however, when the number of participants with fracture was the unit of measure, the interaction was not statistically significant. The median dosage of calcium used in the included trials was 1000 mg per day (500-1500 mg/day). Calcium supplementation does not appear to increase the risk of CVD overall ( 202 ) nor mortality risk in the current meta-analysis ( 29 ).

Based on the known effects of vitamin D on the musculoskeletal system, it may be unethical to keep a group of people with low 25(OH)D levels on placebo for long periods to evaluate the effectiveness of vitamin D supplementation on falls or fractures, both long-term outcomes. However, studies using several different daily dosages of vitamin D and targeting several achieved 25(OH)D levels are feasible and would define the achieved levels that prevent adverse outcomes.

The great variability of protocols used in clinical trials may have interfered in the evaluation of supplementation on musculoskeletal health in this group of older individuals. Future studies will require specific protocols, avoiding bolus doses, and selecting individuals at risk for fractures and falls to evaluate the effect of the intervention.

Nutritional status during pregnancy plays a critical role in perinatal health, fetal growth, and infant development. The fetus is dependent on maternal circulating 25(OH)D for placental metabolism and transfer of vitamin D metabolites ( 203 , 204 ). In pregnancy, very low vitamin D status (25[OH]D < 10-12 ng/mL [< 25-30 nmol/L]) is associated with increased risk of neonatal hypocalcemic seizures, cardiomyopathy, and neonatal rickets, with life-limiting and potentially fatal outcomes ( 18 , 205 ). Very low vitamin D status during pregnancy is prevalent in both low- and high-income settings ( 206 , 207 ).

Many studies, for example ( 208 ), have described associations between 25[OH]D levels < 20 ng/mL (<50 nmol/L) and increased risk of hypertensive disorders of pregnancy (gestational hypertension, preeclampsia, eclampsia, and HELLP syndrome [Hemolysis, Elevated Liver enzymes and Low Platelets]). Hypertensive disorders of pregnancy increase risks for fetal growth restriction, small-for-gestational-age (SGA) infants, and induced preterm delivery, with potentially serious and lifelong consequences for infant bone and brain development, as well as maternal and offspring long-term cardiometabolic health ( 209 ). Economic costs of preeclampsia have been estimated at twice those of healthy pregnancies for maternal postnatal care ( 210 ). Hao et al ( 211 ) estimated a 3-fold higher cost for pregnancies complicated by hypertensive disorders relative to uncomplicated care when both maternal and infant costs were included.

Whether nutritional requirements for vitamin D change during pregnancy is not known, and evidence for the role of vitamin D in improving perinatal outcomes is conflicting ( 212 ). Accordingly, preconception or pregnancy-specific recommendations for vitamin D are not universal, nor is there a consensus on the dosage of vitamin D or 25(OH)D level required to support a healthy pregnancy. While harmonized global estimates do not yet exist, reported prevalence rates for low and very low vitamin D status (25[OH]D < 20 and < 12 ng/mL [< 50 and < 30 nmol/L], respectively) are high among women of reproductive age and during pregnancy, particularly among individuals with decreased skin synthesis due to low exposure to UV-B light, low vitamin D intakes, low nutrient-dense diets, and dark complexion ( 34 , 213-216 ). This, along with the fetal dependence on maternal vitamin D and the inverse associations of low vitamin D status with undesirable outcomes in the perinatal period, make it important to evaluate the role of vitamin D supplementation during pregnancy. Additional high-priority clinical questions relate to the potential utility of 25(OH)D testing during pregnancy and optimal maternal 25(OH)D concentrations during pregnancy.

We suggest empiric vitamin D supplementation during pregnancy, given its potential to lower risk of preeclampsia, intra-uterine mortality, preterm birth, SGA birth, and neonatal mortality. (2 | ⊕⊕◯◯)

In the clinical trials included in the systematic review, the vitamin D dosages ranged from 600 to 5000 IU (15 to 125 μg) daily equivalent, usually provided daily or weekly. The estimated weighted average was approximately 2500 IU (63 μg) per day.

The evidence summaries, meta-analysis results, and a detailed summary of the evidence and EtD tables can be found online at https://guidelines.gradepro.org/profile/kZ8sir4uV7M and https://guidelines.gradepro.org/profile/QSOmqUUCVGE .

The systematic review identified 10 RCTs that met the inclusion criteria ( 29 ). Due to the panel's a priori decision to include only trials involving placebo-treated controls (rather than allowing the control group to remain on routine supplements or receive low-dose vitamin D), many RCTs were excluded, including many from the United States, where 400 IU (10 μg) was often given to the control group. Three included studies were conducted in Europe; 2 in Bangladesh; 2 in India; 2 in Iran and 1 in Pakistan. Of the 2979 participants, almost half (n = 1298) came from the trial by Roth et al ( 217 ) in Bangladesh. The included trials varied greatly in terms of dose frequency (one-time vs daily vs intermittent dosing) and dose ranges (600 to 200 000 IU [15 to 5000 μg]). The median gestational age at which the intervention (vitamin D vs placebo) was initiated was about 20 weeks. Of the 7 trials that reported baseline 25(OH)D concentrations, mean values were below 12 ng/mL (30 nmol/L) in 4 ( 217-220 ).

When combined, data from 8 studies ( 217 , 219 , 221-226 ) (2674 participants) suggest that vitamin D may reduce the risk of preeclampsia (RR 0.73; 95% CI, 0.46-1.15]) with an estimated absolute effect size of 23 fewer per 1000 (46 fewer to 13 more).

Data from 4 trials ( 217-219 , 223 ) (1738 participants) suggest that vitamin D may reduce the risk of intra-uterine mortality slightly (RR 0.70 [95% CI, 0.34-1.46]) with an estimated absolute effect size of 6 fewer per 1000 (13 fewer to 9 more). Similarly, data from 3 trials ( 217 , 218 , 223 ) (1576 participants) indicate that vitamin D may reduce the risk of neonatal mortality slightly (RR 0.57 [95% CI, 0.22-1.49]), with an estimated absolute effect size of 8 fewer per 1000 (14 fewer to 9 more).

Data from 6 trials ( 217 , 219 , 222-225 ) (2085 participants) suggest that vitamin D may reduce the risk of preterm birth (RR 0.73 [95% CI, 0.39-1.36]) with an estimated absolute effect size of 28 fewer per 1000 (62 fewer to 37 more). Data from 5 trials ( 217 , 219 , 220 , 224 , 225 ) (2355 participants) suggest that vitamin D may reduce the risk of SGA birth (RR 0.78 [95% CI, 0.50-1.20]) with an estimated absolute effect size of 41 fewer per 1000 (94 fewer to 38 more). SGA status was variably defined in the different trials.

Adverse events of interest (nephrolithiasis, symptomatic hypercalcemia, kidney disease) were rare (one case of proteinuria related to nephrotic syndrome in the vitamin D arm), but most trials did not prespecify adverse events except for the trials by Roth et al ( 217 , 223 ), which reported no cases of symptomatic hypercalcemia.

Study subgroup analyses did not implicate either risk of bias or vitamin D dosage as a significant predictor of study outcomes. Data were insufficient to address whether baseline 25(OH)D level was a significant predictor of treatment effects.

Based on the panel's best estimates of treatment effects (ie, stipulating the veracity of point estimates), the panel judged that the anticipated desirable effects of vitamin D during pregnancy for the outcomes specified are likely to be moderate. Although the panel recognized that the 95% CIs included the possibility for harm for each outcome, the panel noted that all point estimates favored benefit and judged that the anticipated undesirable effects are likely to be trivial.

The panel also considered a 2019 systematic review performed by Palacios et al ( 227 ). According to this meta-analysis, vitamin D supplementation during pregnancy reduced risks of preeclampsia (RR 0.48 [95% CI, 0.30-0.79]), low birthweight (RR 0.55 [95% CI, 0.35-0.87]), and gestational diabetes (RR 0.51 [95% CI, 0.27-0.97]), with a nonsignificant reduction in preterm birth (RR 0.66 [95% CI, 0.34-1.30]).

Although the panel identified no direct evidence, the panel judged that vitamin D supplementation would be acceptable and feasible to implement during pregnancy, when health care supervision is frequently available. The panel judged that preventing low vitamin D status during pregnancy, particularly among individuals most at risk for low vitamin D status ( 206 , 213 ), may improve health equity. Floreskul ( 71 ) reported that free-of-charge provision of vitamin D supplements to pregnant individuals and children younger than age 4 years for rickets prevention in the United Kingdom would be clinically effective and cost-saving in participants with “dark and medium skin tone,” especially in regions with high incidence of rickets.

The systematic review suggested anticipated benefit with empiric vitamin D for all selected outcomes: preeclampsia (2.3% anticipated absolute reduction with low certainty of evidence), intra-uterine mortality (0.6% anticipated absolute reduction with moderate certainty of evidence), preterm birth (2.8% anticipated absolute reduction with low certainty of evidence), SGA birth (4.1% anticipated absolute reduction with low certainty of evidence) and neonatal mortality (0.8% anticipated absolute reduction with moderate certainty of evidence). The meta-analysis by Palacios et al ( 227 ) showed benefits in the same direction (lower risk of preeclampsia, low birthweight, gestational diabetes, and preterm birth). When taken together, and if stipulating the veracity of these point estimates, the panel judged that these desirable anticipated effects were moderately substantial. However, for all the described outcomes, the 95% CIs included the potential for harm, and available evidence for maternal mortality and maternal adverse events was not very robust. Nonetheless, given that the best available evidence (point estimates) suggested moderate benefit and minimal harm, the panel judged that the balance between desirable and undesirable effects probably favors empiric vitamin D supplementation. In addition, the panel judged that empiric vitamin D is typically inexpensive, may be cost-effective, may increase health equity, and is probably acceptable to key stakeholders and feasible to implement. Thus, the panel suggests empiric vitamin D supplementation during pregnancy. Given the low overall certainty of evidence, the panel issued a conditional recommendation.

Available evidence did not permit a well-supported judgment about the net benefit of 25(OH)D testing during pregnancy followed by vitamin D supplementation only in those with low 25(OH)D levels. In addition, compared to empiric vitamin D supplementation, adding the need for 25(OH)D testing would add costs, and the panel judged that testing could also decrease feasibility and health equity. For all these reasons, the panel suggests that vitamin D supplementation should generally proceed without testing for baseline 25(OH)D levels and without the need for subsequent monitoring of 25(OH)D levels to assess response to supplementation, provided that vitamin D dosages are within the tolerable upper intake level as established by the IOM.

Additional Comments

This guideline is different from the World Health Organization (WHO) guideline on vitamin D supplementation in pregnancy, which was published in 2016 ( 228 ) and updated in 2020 ( 229 ). Largely based on the systematic reviews by De-Regil ( 230 ), which found a possible beneficial effect of vitamin D on reducing preeclampsia, low birthweight, and preterm birth but a potential adverse effect of calcium plus vitamin D supplementation on preterm birth, the guideline group did not recommend vitamin D for pregnancy to improve maternal and infant health outcomes ( 228 ). The updated WHO 2020 guideline ( 229 ), which also did not recommend vitamin D, was largely based on the systematic review by Palacios et al ( 227 ), which reported outcomes similar to those of the present guideline for pre-eclampsia, preterm birth, low birth weight, and adverse effects. There were some differences in the studies selected for data synthesis, as Palacios et al ( 227 ), included a larger number of studies, including trials that administered, or allowed control participants to take, a low dosage of vitamin D and trials that co-administered vitamin D and calcium. The current guideline had access to more recent RCTs, including Roth et al ( 217 ). Overall, the current panel found very little evidence for harm with vitamin D supplementation, along with some evidence for benefit.

The optimal dosage of vitamin D for the prevention of maternal and fetal complications remains unclear. In the studies included in the commissioned systematic review, the estimated median vitamin D dosage for preeclampsia evaluation was 3161 IU (79 μg) daily, and the estimated weighted average dosage was 2639 IU (66 μg) per day. The estimated median vitamin D dosages in the studies assessing intra-uterine and neonatal mortality were 3375 IU (84 μg) and 2750 IU (69 μg) daily, respectively, and corresponding estimated weighted average dosages were 2908 IU (73 μg) and 3052 IU (76 μg) per day. For preterm birth and SGA birth studies, the estimated median dosages were 3375 IU (84 μg) and 2750 IU (69 μg) daily, respectively, while estimated weighted average dosages were 2735 IU (68 μg) and 2642 IU (66 μg) per day.

Adequately powered clinical trials with prespecified outcomes to address whether and to what degree vitamin D impacts patient-important perinatal outcomes, in both healthy individuals and those with high-risk pregnancies. Particular attention should be paid to individuals at high risks for adverse pregnancy and perinatal outcomes, with medium and dark complexion, those with low UV-B exposure, and those living with obesity. In future trials, it will be critically important to assess baseline vitamin D status and to gain a complete understanding of the roles of vitamin D dosing strategies and calcium co-supplementation.

Future trials should include umbilical cord blood 25(OH)D analysis and a plan to follow the offspring throughout early childhood.

Diabetes mellitus poses a significant challenge to global health care. Prediabetes increases the risk of developing diabetes and CVD. In the United States, more than one in three adults 18 years and older have prediabetes, and only about 20% of these individuals have been informed of their prediabetes status by a health care professional. Worldwide, diabetes affects more than 537 million people, and this number is predicted to rise to 643 million by 2030 and 783 million by 2045 ( 231 ). In clinical trials, intensive lifestyle changes focused on weight loss and increased physical activity reduced the risk of developing diabetes among adults with prediabetes who have impaired glucose tolerance. However, these lifestyle modifications are challenging to maintain over the long term. Even with successful implementation, a residual risk remains, and most individuals with prediabetes eventually progress to diabetes. While certain medications approved for treating type 2 diabetes have been shown to reduce diabetes risk among people with prediabetes ( 232 ), the use of pharmacotherapy for diabetes prevention is not widely practiced or generally recommended due to the associated burden and cost. The search for weight-independent, easy-to-implement, and low-cost interventions continues to be a priority to lower diabetes risk. Over the last decade, several studies have reported on the role of vitamin D in attenuating the progression to type 2 diabetes in adults with prediabetes.

The clinical trials informing this recommendation primarily related to adults with high-risk prediabetes, identified as meeting 2 or 3 American Diabetes Association glycemia criteria (fasting glucose, HbA1c, 2-hour glucose after a 75-gram oral glucose challenge) for prediabetes and those with impaired glucose tolerance.

The evidence summaries, meta-analysis results, and a detailed summary of the evidence and EtD tables can be found online at https://guidelines.gradepro.org/profile/zE0nxO7MCXw .

The commissioned systematic review included 11 RCTs ( 233-243 ) that reported on the effect of vitamin D on new-onset diabetes in adults with prediabetes (total of 5316 participants). The trials were conducted in India (n = 4), Iran (n = 1), Greece (n = 1), Norway (n = 1), Japan (n = 1), and the United States (n = 3). The panel also considered a recently published individual participant data meta-analysis (IPD-MA) ( 101 ) of the 3 vitamin D trials ( 233 , 234 , 243 ) that were specifically designed for diabetes prevention. In contrast to aggregate data meta-analysis, an IPD-MA increases the statistical power to detect benefits and risks; avoids ecological fallacy in examining sources of between-study heterogeneity; and, through data harmonization, improves the precision of results and allows for additional analyses.

Nine trials ( 233-239 , 241 , 242 ) used cholecalciferol (vitamin D3), one trial ( 240 ) used both cholecalciferol and ergocalciferol (D2), and one trial ( 243 ) used eldecalcitol, an active vitamin D analog. While the panel did not specifically address vitamin D analogs in its other questions, the panel recognized the importance of including the second largest trial for diabetes prevention (DPVD) ( 243 ), which tested eldecalcitol, when addressing the question about vitamin D and diabetes prevention; consequently, the findings from the DPVD trial were incorporated in the evidence synthesis. This approach aligns the commissioned systematic review with 3 other recent meta-analyses in this topic ( 101 , 244 , 245 ), ensuring consistency of the evidence synthesis. The results of the commissioned systematic review were similar with or without the DPVD trial; however, to be consistent with the rest of the guideline, we first present the meta-analysis results without the DPVD trial, thereafter, presenting results with the DPVD trial.

Participants in the included trials were at high risk for diabetes, based on having impaired glucose tolerance or meeting 2 or 3 glycemic criteria (fasting glucose, HbA1c, 2-hour glucose after a 75-gram oral glucose challenge) for prediabetes. The baseline mean 25(OH)D level in the 11 trials was 12 to 28 ng/mL (30-70 nmol/L). Among the 8 trials that did not include low baseline 25[OH]D as an eligibility criterion, the baseline mean level of 25[OH]D was 18 to 28 ng/mL (45-70 nmol/L). When combining data from the 10 trials ( 233-242 ) that used either cholecalciferol or ergocalciferol, vitamin D reduced the risk of developing diabetes (RR 0.90 [95% CI, 0.81-1.00]). The estimated absolute effect size was 24 fewer per 1000 progressing to type 2 diabetes (46 fewer to 0 fewer). When the DPVD trial ( 243 ) was included, the results were similar (RR 0.90 [95% CI, 0.81-0.99]). The IPD-MA of the 3 trials ( 233 , 234 , 243 ) that were specifically designed for diabetes prevention (total of 4190 participants) showed a 15% reduction in new-onset diabetes in adults with prediabetes randomized to vitamin D compared to placebo (HR 0.85 [95% CI, 0.75-0.96]) ( 101 ). In these trials, the impact of vitamin D on new-onset diabetes was in addition to participants receiving lifestyle interventions for diabetes prevention.

In the commissioned systematic review, the beneficial effect of vitamin D on diabetes risk was consistent across subgroups by risk of bias or vitamin D dosage. In the IPD-MA, the effect of vitamin D appeared to be more pronounced in the following subgroups: age older than 62 years (HR 0.81 [95% CI, 0.68-0.98]), baseline 25(OH)D level lower than 12 ng/mL (30 nmol/L) (HR 0.58 [95% CI, 0.35-0.97]), and body mass index (BMI) less than 30 kg/m 2 (HR 0.79 [95% CI, 0.66-0.95]) ( 101 ). However, the P values for these interactions were not statistically significant.

The commissioned systematic review included 15 RCTs ( 234-240 , 242 , 246-252 ) that reported the effect of cholecalciferol or ergocalciferol on HbA1c in adults with prediabetes, 12 RCTs ( 234-238 , 241 , 242 , 246-248 , 251 , 253 ) that reported on fasting blood glucose, and 13 RCTs ( 234-238 , 241 , 242 , 246 , 248-251 , 254 ) that reported on blood glucose 2 hours after a 75-gram oral glucose load. Compared to placebo, vitamin D lowered fasting blood glucose (mean difference −5.3 mg/dL [95% CI, −7.9 to −2.7]) and 2-hour blood glucose after a 75-gram oral glucose tolerance test (mean difference −7.6 mg/dL [95% CI, −12.6 to −2.7]). There was a trend for vitamin D to lower HbA1c (mean difference −0.05% [95% CI, −0.10 to 0.01]). When the DPVD trial ( 243 ) was included, the results were similar (mean difference in fasting blood glucose −4.9 mg/dL [95% CI, −7.3 to −2.4; 2-hour blood glucose −6.6 mg/dL [95% CI, −11.2 to −2.1]; HbA1c −0.04% [95% CI, −0.90 to 0.00).

The commissioned systematic review also examined other outcomes aside from the risk of diabetes in this population. The Tromsø study ( 234 ) found no differences in upper respiratory infections between those who took 20 000 IU (500 μg) of vitamin D per week and those who took a placebo. In the same study, men who received vitamin D had less reduction in BMD at the femoral neck compared to those who took a placebo (0.000 vs −0.010 g/cm 2 ; P = .008). There were no differences in BMD at the femoral neck in women and no differences in BMD at the hip in either gender. The study found no difference in fractures between the vitamin D and placebo groups; however, the data on fractures was sparse.

Meta-analyses of the 2 trials ( 234 , 255 ) that used cholecalciferol suggested no clear differences in all-cause mortality with vitamin D (RR 0.75 [95% CI, 0.26-2.18]; estimated absolute effect size of 1 fewer per 1000 [4 fewer to 6 more]) or CVD events ( 234 , 256 ) with vitamin D (RR 1.08 [95% CI, 0.33-3.57]; estimated absolute effect size of 1 more per 1000 [8 fewer to 31 more]). After including the DPVD trial, results did not change.

The commissioned systematic review found no clear difference in nephrolithiasis ( 234 , 255 ) with vitamin D (RR 1.20 [95% CI, 0.71-2.03]; estimated absolute effect size of 3 more per 1000 [5 fewer to 17 more]). There were no cases of symptomatic hypercalcemia reported in any trial. In the D2d study, there was 1 case of new-onset kidney disease in the vitamin D group and 2 cases in the placebo group (RR 0.50 [95% CI, 0.05-5.51]) ( 255 ). In the IPD-MA, the frequency of the prespecified adverse events of interest (nephrolithiasis, hypercalcemia, and hypercalciuria) was low, and there were no differences between vitamin D and placebo ( 101 ). In the D2d study, adverse events were overall less frequent in the vitamin D group (4000 IU/day [100 μg/day] of cholecalciferol) compared to placebo (IRR 0.94 [95% CI, 0.90-0.98]) ( 255 ).

Based on the point estimates derived from meta-analyses of available clinical trials, the panel judged that the anticipated desirable effects of vitamin D for diabetes prevention are likely moderate, while the anticipated undesirable effects are likely trivial.

Vitamin D is generally available over the counter, and it is inexpensive. There are no cost-effectiveness studies of vitamin D for preventing diabetes, fractures, all-cause mortality, cardiovascular events, or respiratory infections in adults with prediabetes. However, there is ample evidence of substantial economic value in preventing the development of type 2 diabetes with non–vitamin D interventions (eg, lifestyle, metformin) that are more expensive and burdensome to implement than vitamin D ( 257 ). Therefore, the panel reasoned that there are likely cost savings with using vitamin D for diabetes prevention.

The panel judged vitamin D use would be acceptable to adults with prediabetes and to other stakeholders, such as clinicians. Given ease of administration and low cost, the panel judged empiric vitamin D to lower diabetes risk as a feasible intervention for adults with prediabetes.

The risk of developing diabetes, the prevalence of diabetes, and the burdens related to having diabetes are higher among racial and ethnic minority groups (primarily Hispanic and non-Hispanic Asian populations) in the United States. In clinical trials, intensive lifestyle changes have been found to lower the risk of diabetes, regardless of race or ethnicity. However, accessing the necessary resources, such as nutritionists and exercise facilities, can be difficult, and there are disparities in access to these resources. Racial and ethnic minority groups (in the United States) are also at higher risk for having low vitamin D status, and consumption of vitamin D supplements in these groups is about half of that compared to non-Hispanic White groups, suggesting differences in vitamin D use. Although vitamin D should not be viewed as a replacement for lifestyle approaches to diabetes prevention, the panel judged that using vitamin D in adults with prediabetes would likely have a favorable impact on health equity, especially in low-resource environments.

The panel justified a recommendation favoring empiric vitamin D in adults with prediabetes based on moderate certainty of evidence that vitamin D likely decreases progression to type 2 diabetes, likely without harm. In the commissioned systematic review, there was low certainty of evidence for the cardiovascular and mortality outcomes with wide 95% CIs; however, none of the included trials were designed or powered for cardiovascular events or mortality, and only 3 trials (including the DPVD trial) reported on these outcomes. Specific data related to fractures and respiratory infections were inadequate.

The benefits of vitamin D supplementation may preferentially accrue to those at highest risk for vitamin D deficiency. Although not addressed in the commissioned systematic review, the IPD-MA suggested that the benefit may be greatest for those with baseline 25(OH)D level lower than 12 ng/mL (20 nmol/L) (HR 0.58 [95% CI, 0.35-0.97]) ( 101 ). However, overall evidence did not support the net benefit of 25(OH)D testing in adults with prediabetes followed by vitamin D supplementation in those with low 25(OH)D levels. Vitamin D supplementation that leads to higher 25(OH)D levels may further lower the risk of diabetes ( 101 , 258 ), but it could potentially increase the risk of adverse effects (hypercalcemia, hypercalciuria, kidney stones), although there was no evidence of this in in the IPD-MA ( 101 ). In addition, compared to empiric vitamin D supplementation alone, adding 25(OH)D testing would increase costs, thus decreasing feasibility and health equity. Given these uncertainties, the panel did not recommend screening or routine monitoring with 25(OH)D in individuals with prediabetes to guide vitamin D supplementation.

Ten trials (including the DPVD trial) reported on the effect of vitamin D and regression to normal glucose regulation, defined as having glycemic measures in the normal range, in people with prediabetes. The commissioned systematic review did not combine data on the effect of vitamin D on regression to normal glucose regulation; however, other meta-analyses have synthesized data on this outcome. Zhang et al combined aggregate data from 5 trials totaling 1080 participants with prediabetes and found a significant vitamin D benefit for regression to normal glucose regulation by 48% compared to placebo (RR 1.48 [95% CI, 1.14-1.92]) ( 244 ). In the IPD-MA, vitamin D increased the likelihood of regression to normal glucose regulation by 30% (RR 1.30 [95% CI, 1.16-1.46]) ( 101 ).

The clinical trials informing this recommendation primarily related to adults with high risk for diabetes, identified by meeting 2 or 3 American Diabetes Association glycemia criteria (fasting glucose, HbA1c, 2-hour glucose after a 75-gram oral glucose challenge) for prediabetes or by having impaired glucose tolerance. The panel's use of the term “high-risk prediabetes” aligns with the clinical trial evidence and aims to focus the recommendation on adults at the highest risk for diabetes, not to mandate specific testing methods.

The included trials used varying dosages of cholecalciferol or ergocalciferol. The median (interquartile range) dosage employed was approximately 2663 (1410-3893) IU/day (67 [35-97] μg/day), and the estimated weighted average was 3520 IU (88 μg) per day. Due to this variability, the panel could not recommend a specific dosage of vitamin D. In general, trial participants in both active and placebo groups were allowed to take vitamin D supplements on their own, up to a certain dosage specific for their age.

While the absolute reduction in the risk of developing new-onset diabetes may be relatively small, the panel considered that such interventions with modest benefits could significantly impact prevalent conditions like prediabetes. For example, the absolute 3-year risk reduction in diabetes risk with vitamin D (24 fewer per 1000 participants based on the systematic review or 33 fewer per 1000 based on the IPD-MA) compares favorably with metformin in the Diabetes Prevention Program in the United States (70 fewer per 1000), especially when considering that in the clinical trials, the vitamin D intervention was applied in addition to recommended lifestyle changes.

Randomized controlled trials to evaluate a treat-to-target strategy to define the 25(OH)D level that optimally reduces the risk of new-onset diabetes and increases time spent in normoglycemia.

Randomized controlled trials designed to identify subpopulations with prediabetes who are more likely to benefit from vitamin D, focusing not only on biological variables, including body composition, but on environmental, lifestyle, and dietary factors.

Cost-effectiveness analyses.

Implementation studies to assess the practicality and effectiveness of vitamin D in real-world settings.

Studies on the effect of vitamin D in people at risk for or with new-onset type 1 (autoimmune) diabetes.

There is uncertainty regarding the best approach to vitamin D supplementation. Options range from daily intake to less frequent regimens, such as weekly or monthly. While infrequent dosing may improve adherence, large doses of vitamin D have been associated with higher levels of inactive 24,25(OH)2 vitamin D ( 259 ), raising concerns about the benefit-risk ratio of intermittent, high doses of vitamin D. Important questions include the effect of nondaily dosing on clinical outcomes and potential impact on the risk of adverse events.

The evidence summaries, meta-analysis results, and a detailed summary of the evidence and EtD tables can be found online at https://guidelines.gradepro.org/profile/rzh7ywOCsRY .

Two trials ( 260 , 261 ) with a total of 537 patients met the original inclusion criteria, which specified a direct comparison between intermittent high-dose vs daily lower-dose vitamin D supplementation. After expanding eligibility criteria to include trials that compared high-dose intermittent doses vs placebo, the systematic review included 19 manuscripts derived from 15 studies ( 29 ) involving 53 527 participants. In the included trials, daily vitamin D doses ranged from 400 to 800 IU (10-20 μg). Doses given at nondaily intervals included 50 000 IU (1250 μg) every 2 weeks, 60 000-100 000 IU (1500-2500 μg) monthly, 96 000-150 000 IU (2400-3750 μg) every 2 to 4 months, and 300 000 IU-500,000 IU (7500-12 500 μg) annually.

The systematic review identified 5 studies ( 104 , 119 , 180 , 184 , 190 ) that evaluated fractures with participants as the unit of analysis. There was a trend for intermittent high-dose vitamin D to increase fracture risk (RR 1.08 [95% CI, 0.98-1.19]), with an estimated absolute effect size of 5 more participants with a fracture per 1000 (1 fewer to 11 more). In subgroup analyses, studies involving doses higher than 100 000 IU (2500 μg) may have had higher risk of fracture (RR 1.14 [95% CI, 1.02-1.27]) than those involving lower doses (RR 0.94 [95% CI, 0.79-1.12]) ( P = .07 for interaction). When examining the 7 studies ( 118 , 174 , 180 , 184 , 185 , 260 , 261 ) reporting the total number of fractures as the unit of analysis, the IRR for fractures was 0.96 (95% CI, 0.75-1.21) for intermittent high-dose vitamin D. Studies involving doses higher than 100 000 IU (2500 μg) had an IRR of 1.23 (95% CI, 0.81-1.61) compared to an IRR of 0.86 (95% CI, 0.71-1.02) for studies involving doses 50 000-100 000 IU (1250-2500 μg) ( P = .026 for interaction). In study subgroup analyses, dosing interval (every 1-12 weeks vs > 12 weeks for intermittent high-dose vitamin D) was not a significant predictor of fracture risk.

In the meta-analysis of 6 studies ( 104 , 118 , 119 , 174 , 176 , 184 ) reporting on falls with participants as the unit of analysis, the RR for intermittent high-dose vitamin D was 1.01 (95% CI, 0.93-1.10). Study subgroup analyses suggested the possibility that doses greater than 100 000 IU (2500 μg) may have higher fall risk (RR 1.04 [95% CI, 0.96-1.12]) compared to lower doses (RR 0.79 [95% CI, 0.61-1.03]) ( P = .056 for interaction). Studies employing a dosing interval greater than every 12 weeks showed higher fracture risk with vitamin D (RR 1.08 [95% CI, 1.03-1.14]) compared to dosing intervals of 1 to 12 weeks (RR 0.98 [0.92-1.04]) ( P = .01 for interaction). Analysis of 6 studies ( 118 , 184 , 185 , 190 , 200 , 260 ) that reported on the number of falls as the unit of analysis revealed an IRR of 1.05 (95% CI, 0.96-1.13) for intermittent, high-dose vitamin D; subgroup analyses for falls as a unit of analysis did not disclose significant study subgroup effects according to dose or dosing interval.

For the 5 studies ( 85 , 119 , 123 , 201 , 260 ) reporting participants with respiratory infections as the unit of analysis, there were no differences between high-dose nondaily vitamin D vs placebo (OR 1.00 [95% CI, 0.98-1.03]). Similarly, analysis of 4 studies ( 85 , 123 , 139 , 260 ) that reported on the number of respiratory infections as the unit of analysis revealed an IRR of 0.98 (95% CI, 0.88-1.03) for intermittent, high-dose vitamin D. Study subgroup analyses did not implicate vitamin D dose as a predictor of these study outcomes.

The 3 studies ( 118 , 124 , 138 ) that reported on nephrolithiasis administered 50 000 to 100 000 IU (1250-2500 μg) vitamin D every 2 to 4 weeks. The RR for nephrolithiasis was 1.00 (95% CI, 0.84-1.19) for intermittent, high-dose vitamin D. Two studies ( 119 , 166 ) did not disclose a clear difference in kidney disease (RR 0.64 [95% CI, 0.28-1.47]), with an estimated absolute effect size of 2 fewer per 1000 (3 fewer to 2 more). No trials reported cases of symptomatic hypercalcemia.

Based on the panel's best estimates of treatment effects in adults aged 50 years and older, the panel judged that any desirable effects of intermittent, high-dose vitamin D (compared to lower-dose, daily vitamin D) are likely trivial, while the anticipated undesirable effects are likely to be small.

Vitamin D is relatively inexpensive and available over the counter; however, higher dosages may require prescriptions, which increase cost and burden. The panel did not identify any cost-effectiveness studies addressing daily lower-dose vitamin D vs intermittent, higher-dose vitamin D. The panel did not identify any studies that addressed the potential impact of intermittent high-dose vitamin D vs daily lower-dose vitamin D on health equity, although any additional costs and requirements for health care visits could decrease health equity. The panel identified no studies that addressed the possibility of differential acceptability or feasibility of intermittent high-dose vitamin D vs daily lower-dose vitamin D. Nonetheless, the panel assumed that less frequent dosing (weekly, monthly, or yearly) may be more acceptable to some individuals and may possibly be associated with better adherence, based on experience with medications like bisphosphonates, for which nondaily administration improves adherence ( 262 ).

The available evidence (which is specifically pertinent to persons age > 50 years) suggests that, compared to daily lower-dose vitamin D or placebo, intermittent high-dose vitamin D offers no desirable effects, and may be associated with undesirable anticipated effects (namely, moderate certainty of evidence suggests an estimated 0.5% absolute increase in fracture risk). The panel judged that the potential convenience advantage of intermittent high-dose vitamin D may be outweighed by the potential for undesirable anticipated effects. The panel identified no evidence to suggest material differences in cost, equity, or feasibility, although cost likely favors daily, lower-dose vitamin D, since the higher dosages commonly require a prescription and thus involve the costs of health care visits. Since overall certainty of evidence was very low, and since individuals may value anticipated advantages and disadvantages differently, the panel issued a conditional recommendation.

Screening for Low Vitamin D Status With 25(OH)D Testing

Vitamin D deficiency is traditionally defined clinically as having symptoms and signs of rickets or osteomalacia. Although these conditions are not uncommon, vitamin D “deficiency” is more frequently defined based on circulating 25(OH)D levels. However, the 25(OH)D level for defining deficiency has been controversial, thus the prevalence of vitamin D deficiency varies depending on the 25(OH)D threshold used. For example, if vitamin D deficiency is defined as a 25(OH)D concentration less than 20 ng/mL (50 nmol/L), 24% of US adults meet that criterion, whereas if defined as a 25(OH)D concentration less than 10 ng/mL (25 nmol/L), 6% of US adults would be considered vitamin D–deficient ( 82 ).

Low vitamin D status has been associated with increased risks for several common chronic conditions, such as osteoporosis (risk of fractures), CVD, and diabetes. However, whether vitamin D supplementation lowers risk for developing such outcomes in generally healthy populations has remained unclear. Nonetheless, rates of screening for low 25(OH)D levels have increased in recent years. For example, in one study, testing with 25(OH)D rose from 0.29 per 1000 person-years at risk (95% CI, 0.27-0.31) in 2005 to 16.1 per 1000 person-years at risk (95% CI, 15.9-16.2) in 2015 ( 263 ).

The panel prioritized 3 clinical questions related to screening for 25(OH)D levels and whether vitamin D should be given only to individuals who have 25(OH)D levels below a threshold, recognizing that appropriate thresholds likely vary based on the outcome of interest. In particular, the panel chose to address 25(OH)D screening in adults with dark complexion, in adults with obesity, and in the general adult population who do not have otherwise an established indication for screening (eg, hypocalcemia). These screening questions relate to whether vitamin D administration may be primarily—or perhaps even exclusively—beneficial for adults with 25(OH)D levels below a population- and condition-specific (and thus far undetermined) threshold. If the net benefit of vitamin D supplementation specifically accrues to those with low 25(OH)D levels, then it could be important to perform 25(OH)D testing to identify those individuals. In contrast, if the net benefit of vitamin D supplementation does not specifically accrue to those with 25(OH)D levels below a threshold (ie, if net benefit is also realized in those with 25[OH]D levels above that threshold), or if no net benefit of vitamin D administration is apparent, then 25(OH)D screening in these populations would presumably be unnecessary.

Importantly, for all 3 screening questions, no studies were identified that compared a screening approach (testing for 25[OH]D levels followed by vitamin D treatment as indicated) to a nonscreening approach. Therefore, the panel's approach to the 3 screening questions followed a framework proposed by Murad and colleagues ( 264 ). These criteria can be broadly grouped into considerations related to the medical condition in question, the test's characteristics, and the overall impact on patient care. According to this framework, screening would be justified when the following conditions are met:

Importance: The condition is an important health problem in terms of prevalence and/or consequences.

The panel noted that low vitamin D status has been linked to a number of important health problems.

Natural history: The condition for which screening is being performed has a well-understood natural history that includes a latent (preclinical) phase.

The panel agreed that the adverse effects of low vitamin D status may manifest only after a long latency period, and early detection could plausibly lead to better long-term outcomes.

Difference in management and treatment availability: Persons with positive screening test results would be managed differently from those with negative screening test results.

The panel agreed that vitamin D supplementation is widely available, inexpensive, and highly effective at raising 25(OH)D levels.

Test accuracy and safety: High- or moderate-certainty evidence supports acceptable accuracy of the screening test (eg, acceptable false-positive and false-negative rates).

There have been considerable efforts over the last decade to standardize the 25(OH)D assays, and the assays are significantly more reproducible than in the past, as most large laboratories follow a standardization protocol based on the work of the Vitamin D Standardization Protocol ( https://www.cdc.gov/labstandards/csp/pdf/hs/vitamin_d_protocol-508.pdf ). However, there is still considerable variability of 25(OH)D assays. The systematic review did not identify any studies showing that 25(OH)D testing is harmful.

Available treatment: Effective management is available that improves patient-important outcomes when implemented in the latent (preclinical) phase.

Vitamin D supplementation is highly effective at raising 25(OH)D levels. Questions regarding whether vitamin D supplementation lowers the risks of patient-important outcomes—including in those with low 25(OH)D concentrations specifically—were the primary objective of the commissioned systematic reviews described throughout this document.

Difference in outcomes: The benefits of management according to screening results outweigh the harms of screening (eg, overdiagnosis, unnecessary treatment for false positives, anxiety, stigma, etc.).

The panel did not identify any harms related to screening other than the financial costs associated with tests, health care visits, and (potentially) unnecessary treatment.

Other considerations: The screening strategy should be cost-effective, acceptable to relevant stakeholders, and feasible to implement.

Vitamin D supplementation and 25(OH)D testing are judged to be acceptable and feasible. Data on implementation costs and cost-effectiveness considerations are scant.

This section addresses whether to screen with a 25(OH)D test in generally healthy populations. The panel did not specifically address whether and how those who present with documented low levels of 25(OH)D should be evaluated and/or treated.

Recent trends have shown a rise in screening rates for vitamin D status using serum 25(OH)D in the general population. Specifically, 25(OH)D testing frequency rose from 0.29 per 1000 person-years at risk in 2005 to 16.1 per 1000 person-years at risk by 2015, highlighting a growing interest by patients and physicians in assessing vitamin D status ( 263 , 265 ). Advocating for the routine screening of 25(OH)D levels in healthy adults is contingent upon demonstrating that such screenings can effectively identify individuals with low 25(OH)D who might not be detected through traditional risk factor assessments, and that vitamin D supplementation, following the identification of a low 25(OH)D level, leads to improvements in clinical outcomes (eg, prevention of osteoporosis, CVD, diabetes, respiratory infections, overall mortality).

Screening for low 25(OH)D in generally healthy adults (ie, those who are not at increased risk for vitamin D deficiency) would involve testing large numbers of people, with important implications for health care systems.

The US Preventive Services Task Force (USPSTF) recently concluded that there was insufficient evidence to inform a decision regarding the balance of benefits and harms of screening for vitamin D status with 25(OH)D in asymptomatic adults ( 266 ). A recommendation against population screening for vitamin D deficiency with 25(OH)D is included in the “Choosing Wisely” campaign, an initiative by the American Board of Internal Medicine to spark conversations between clinicians and patients about the value of common tests ( choosingwisely.org ).

The evidence summaries, meta-analysis results, and a detailed summary of the evidence and EtD tables can be found online at https://guidelines.gradepro.org/profile/7Pf6NRYV8TE .

The benefits and harms of vitamin D supplementation in nonpregnant adults with a 25(OH)D concentration below a threshold are addressed in clinical questions 3, 5, and 7. The available clinical trial data were insufficient to satisfactorily assess whether net benefit varied according to baseline 25(OH)D level. When available, trial subgroup analyses did not clearly indicate that net benefit of vitamin D specifically accrues to those with low baseline 25(OH)D level. However, conclusions drawn from subgroup analyses in each individual trial are limited as subgroups lacked adequate statistical power. Meta-analyses that combine aggregate study data and perform subgroup analyses according to average 25(OH)D in each study are subject to ecological fallacy, and thus were not included in the systematic reviews commissioned for this guideline.

The panel judged that screening for 25(OH)D would be acceptable to relevant stakeholders, assuming net benefit is expected. While the panel judged that screening would be feasible for many individuals, there are costs that accompany screening, including the direct and indirect costs of a visit for the test, the cost of the 25(OH)D test itself, the time and cost for a health care provider visit to review results, and potentially follow-up visits for consultation and more testing. Variable access to 25(OH)D testing could be an important barrier for some. In addition, screening entire adult populations would involve substantial costs and effort, thus feasibility from a societal perspective is unclear. The panel did not identify studies that adequately addressed the cost-effectiveness of 25(OH)D screening in all adults. One study estimated that among White adults aged 65 to 80 years, screening would be slightly more effective than universal supplementation for reducing falls and mortality ( 267 ). However, this modeling study relied on trials published more than 15 years ago, so its current relevance is unclear.

The effect of screening on health equity is unclear. Screening with 25(OH)D may worsen health equity because screening requires resources that may not be universally available or accessible, but it could improve health equity if screening led to the identification and effective treatment of prevalent and important health conditions in disadvantaged populations.

The panel's conditional recommendation against routine screening for 25(OH)D levels in generally healthy adults primarily related to the lack of clinical trial–based evidence regarding what 25(OH)D levels would inform a treatment decision and the resultant effect of treatment with vitamin D, compared with no screening. The panel also considered the lack of clinical trial evidence that clearly supports the hypothesis that net benefit specifically accrues to those with a 25(OH)D level below a threshold. The panel was uncertain that any putative benefits of screening would outweigh the increased burden and cost, and whether implementation of universal 25(OH)D screening would be feasible from a societal perspective. Importantly, the panel recognized that it is possible that there is no single threshold 25(OH)D level appropriate for the entire general population.

“Dark complexion” is defined by a phenotype that involves the color of eyes, hair, and skin. In relation to vitamin D, the panel was especially interested in skin pigmentation, determined by the amount of melanin that can interfere with the production of vitamin D in response to exposure to UV-B rays. People at higher risk of low vitamin D status include individuals with dark skin, generally those whose ancestors originated from sunnier regions of the planet, including those with African heritage and descendants of indigenous peoples of the Americas, Oceania, and Asia. In addition, some ( 268 , 269 ) but not all ( 270 ) studies suggest that the increase in 25(OH)D levels in response to vitamin D supplementation is not as robust in those with dark complexion compared to those with lighter complexion. Importantly, many such studies assessed groups according to race/ethnicity rather than skin complexion, introducing uncertainty regarding the degree to which dark complexion per se impacts circulating 25(OH)D concentrations. Nonetheless, since lower 25(OH)D levels have been consistently observed in populations who tend to have darker complexion ( 147 ), the panel judged that it would be important to determine whether screening for 25(OH)D levels is beneficial in persons with dark complexion.

The evidence summaries, meta-analysis results, and a detailed summary of the evidence and EtD tables can be found online at https://guidelines.gradepro.org/profile/pHw68lfsrzU .

Benefits and Harms in Persons With Dark Complexion

The systematic review did not identify any trials that examined whether screening with 25(OH)D (and vitamin D treatment when 25[OH]D is found to be low) improves the outcomes of interest in people with dark complexion per se. The systematic review also did not identify any vitamin D trials that assessed whether outcomes of interest vary according to skin complexion per se. This absence of high-quality supportive data was the primary reason why the panel suggested against routine 25(OH)D screening in adults with dark skin complexion.

Benefits and Harms in Persons Who Self-Identify as Black

The panel specifically aimed to address screening for 25(OH)D in persons with dark complexion given that melanin can interfere with endogenous vitamin D production in response to sun (UV-B) exposure. The panel also recognized that clinical questions about the utility of 25(OH)D screening are frequently posed for racial groups in which dark complexion is common (although variable). The panel judged that such clinical questions are not without merit, especially given differences in 25(OH)D levels in people of different races and ethnicities. In a recent analysis of the NHANES in the United States, 25(OH)D levels lower than 10 ng/mL (< 25 nmol/L) were present in 1% of those who self-identified as White and in 11% of those who self-identified as Black, with levels of 12 to 20 ng/mL (25-50 nmol/L) in 14% and 49% of those self-identifying as White and Black, respectively ( 147 ). However, the panel recognized that racial categories represent social rather than biological constructs, and self-identified race is an inaccurate proxy for skin complexion ( 271 ). Although as a group, persons who self-identify as Black have darker skin complexion, they have highly variable skin pigmentation. Accordingly, using race as a proxy for skin complexion is subject to ecological fallacy and will misclassify many individuals. In addition, other factors (eg, social determinants of health) may be associated with both self-identified race and risk of low 25(OH)D levels, and outcomes of interest (eg, risk of diabetes), yielding uncertainty regarding the degree to which skin pigmentation per se predicts vitamin D-related outcomes in clinical studies ( 271 ). Nonetheless, given that clinicians frequently pose similar clinical questions for subgroups defined by race, the systematic review included a secondary analysis that addressed the potential benefits and harms of 25(OH)D screening in persons who self-identified as Black or African American.

The systematic review did not identify any trials that examined whether outcomes are improved by screening with 25(OH)D (with vitamin D treatment when 25[OH]D is found to be low) in people who self-identify as Black. Hence, the panel gathered evidence from clinical trials that reported results for the prespecified outcomes of interest in subgroup analyses by self-identified race.

The systematic review identified 2 RCTs that reported subgroup analyses on fracture risk in individuals who self-identified as Black. The VITAL trial ( 105 ) reported no difference in the incidence of total, nonvertebral, and hip fractures among 5106 Black participants who received 2000 IU (50 μg /day) of vitamin D daily vs placebo (HR 0.89 [95% CI, 0.62-1.30]). The baseline 25(OH)D level among Black participants was 25 ng/mL (62.5 nmol/L), and the cohort was at low baseline risk for fractures. The Women’s Health Initiative (WHI) study ( 110 ) showed no statistically significant benefit of low-dose vitamin D (400 IU/day; 10 μg/day) (co-administered with calcium) over placebo (HR 0.73 [95% CI, 0.16-3.32]) on hip fractures in the subgroup of 3317 postmenopausal women who self-identified as Black.

One study ( 272 ) reported subset analyses on all-cause mortality in women who self-identified as Black, showing no difference between vitamin D (co-administered with calcium) and placebo (HR 0.97 [0.84-1.11]).

Three RCTs ( 20 , 126 , 272 , 273 ) reported on the impact of vitamin D on cardiovascular adverse events in Black persons. In the VITAL trial ( 20 ), the risk of major adverse cardiovascular adverse events in those randomized to vitamin D vs placebo was similar in those who self-identified as Black (HR 0.91 [95% CI, 0.65-1.26], 5106 participants) and those who self-identified as White (HR 0.93 [95% CI, 0.79-1.10]). No differences in CVD between vitamin D vs placebo groups were observed in the PODA trial (Physical Performance, Osteoporosis and Vitamin D in African American Women trial) (HR 2.23 [95% CI, 0.85-6.23]; 260 African American female participants) ( 126 ) and the WHI study (vitamin D co-administered with calcium, HR 0.99 [95% CI, 0.87-1.13]; 3325 Black female participants) ( 272 ). Among Black women in the WHI ( 272 , 273 ), there was no significant difference between vitamin D (co-administered with calcium) vs placebo on the risk of MI (HR 0.89 [95% CI, 0.66-1.20]), heart failure (HR 0.95 [95% CI, 0.73-1.23]), stroke (HR 0.87 [95% CI, 0.68-1.12]), transient ischemic attack (HR 0.99 [95% CI, 0.71-1.38]), or undergoing coronary artery bypass grafting or percutaneous transluminal coronary angioplasty (HR 1.05 [95% CI, 0.80-1.38]).

The systematic review identified 2 RCTs ( 20 , 272 ) and 1 observational study ( 274 ) that reported on the risk of developing cancer in Black participants. The VITAL trial ( 20 ) reported a HR of 0.77 (95% CI, 0.59-1.01; 5106 participants), and the WHI ( 272 ) reported a HR of 0.99 (95% CI, 0.84-1.16) Among Black participants in the WHI trial, vitamin D co-administered with calcium was not statistically different than placebo for gastrointestinal cancer (HR 0.83 [95% CI, 0.60-1.15]), hematologic cancer (HR 0.72 [95% CI, 0.52-1.23]), lung cancer (HR 0.98 [95% CI, 0.63-1.51]), or breast cancer (HR 0.95 [95% CI, 0.74-1.23]) ( 272 ). In a 10-year observational cohort study ( 274 ) of women with sisters who had breast cancer, no association was found between use of use of vitamin D supplements and breast cancer among Black women (HR 0.89 [95% CI, 0.68-1.2]).

The systematic review did not identify trials addressing the role of vitamin D in preventing respiratory infections in adults who self-identify as Black.

No significant differences in kidney stones, symptomatic hypercalcemia, kidney disease, or renal failure were observed in the RCTs that performed subgroup analyses of adults who self-identified as Black.

In summary, based on an assessment of the small number of clinical trials that reported results according to self-identified race, vitamin D did not clearly have a beneficial effect on fractures, mortality, cardiovascular events, or cancer among participants who self-identified as Black or African American. Available studies only addressed US individuals who self-identified as Black or African American, limiting generalizability. Data were insufficient for other populations in which dark complexion is common (eg, descendants of certain indigenous populations of Asia, the Americas, or Oceania).

The panel judged that testing for 25(OH)D levels (with vitamin D supplementation/treatment as indicated) would be acceptable to many, although access to testing is variable across the globe, which may limit feasibility for some. Conditioning vitamin D supplementation on 25(OH)D test results would be expected to increase costs and burden, and the panel did not identify any studies that adequately addressed the cost-effectiveness of such an approach.

The panel did not identify any studies that adequately addressed the potential equity impact of 25(OH)D screening for people with dark complexion, although the panel had concerns that such a testing approach could negatively impact health equity, especially given the absence of evidence for a net benefit with vitamin D supplementation in those with both dark complexion and low 25(OH)D. The panel also considered the potential equity impact of a 25(OH)D screening strategy vs empiric vitamin D supplementation in those with dark complexion. Similar to the general population, from an equity standpoint, the panel judged that empiric vitamin D supplementation could possibly be preferred to a screening strategy—assuming that net benefit is expected from vitamin D supplementation—since it does not require healthcare access, overall anticipated costs would be lower, and since vitamin D supplementation is judged to be safe when kept within tolerable upper intake levels as recommended by the IOM.

The panel's conditional recommendation against routine 25(OH)D screening for those with dark complexion primarily related to the lack of clinical trial evidence that would support the benefit of 25(OH)D screening in addition to the lack of clinical trial evidence that would support net benefit related to vitamin D supplementation in those with dark complexion. The panel was also uncertain that any putative benefits of screening would outweigh potential downsides, including the costs of 25(OH)D tests, and whether implementation of 25(OH)D screening for those with dark complexion would be feasible from a societal perspective.

Clinical trials should address whether the benefits and harms of vitamin D screening (and treatment) vary according to skin complexion per se (a biological characteristic relevant to vitamin D), rather than using self-identified race (a social construct) as a proxy for skin complexion. At the same time, research is needed to assess whether the benefits and harms of vitamin D screening and/or treatment vary according to race/ethnicity, as well as to define how social determinants of health vs biological factors (eg, skin pigmentation) impact clinical outcomes. Research should also address whether advisable vitamin D intake (ie, DRIs) varies according to skin complexion, race/ethnicity, or both.

It will be important to undertake studies to determine the concentrations of 25(OH)D that are considered optimal for disease prevention in individuals with dark complexion, and what dosages of vitamin D are required to achieve these levels.

People with dark complexion are overrepresented in immigrants to northern latitudes and in resource-poor settings. The consequences of low vitamin D levels in this population are not well studied.

Low serum 25(OH)D levels are common among people with obesity. This is likely multifactorial, including insufficient dietary intake of vitamin D; reduced sun exposure; diminished 25-hydroxylase activity ( 275 ); and changes in the gut microbiome, which have been shown to affect vitamin D absorption ( 276 , 277 ). Notably, the absolute increase in 25(OH)D levels observed after 2 years of vitamin D supplementation (2000 IU [50 μg] per day) was attenuated in participants with obesity, relative to those with a BMI < 25 kg/m 2 (10.5 vs 13.5 ng/mL [26 vs 34 nmol/L]) ( 278 ). After adjustment for other potential predictors, adults with obesity in the United States were found to have a 3-fold higher prevalence of 25(OH)D less than 20 ng/mL (50 nmol/L) and 2-times higher prevalence of 25(OH)D between 20 and 30 ng/mL (50-75 nmol/L) than adults without obesity ( 279 ).

While obesity is associated with higher bone density, this does not necessarily translate into a reduced risk of fractures. In fact, postmenopausal females with obesity were shown to have a 50% higher risk of ankle and 70% higher risk of upper leg fractures ( 280 ). Obesity has also been associated with an increased risk of diabetes, all-cause mortality, CVD, cancer, and lower tract respiratory infections. Notably, levels of 25(OH)D lower than 20 ng/mL (50 nmol/L) are associated with an increased risk of cardiometabolic mortality. Data from NHANES suggest an additive effect of obesity and low vitamin D status (25[OH]D less than 12 or 20 ng/mL [30 or 50 nmol/L]) on CVD, cancer mortality, and all-cause mortality ( 281 ).

Thus, if optimizing 25(OH)D levels lowers risk of these conditions, high value could be realized at both individual and health care system levels.

The evidence summaries, meta-analysis results, and a detailed summary of the evidence and EtD tables can be found online at https://guidelines.gradepro.org/profile/iNI2fGcamG8 .

The systematic review did not identify any trials that examined whether screening for 25(OH)D levels (with vitamin D treatment when 25[OH]D is found to be low) in people with obesity improves the prespecified outcomes of interest. Thus, clinical trials in which subgroup analyses were performed by baseline BMI were examined.

Vitamin D supplementation in adults with a BMI higher than 30 kg/m 2 was not shown to have a significant effect on fractures in 2 RCTs reporting on fractures in participants with obesity. The VITAL RCT performed in the United States ( 105 ) showed no reduction in fracture risk in adults with a BMI higher than 30 kg/m 2 randomized to 2000 IU (50 μg) vitamin D daily vs placebo (HR 1.17 [95% CI, 0.95-1.44]). However, the average baseline 25(OH)D level in those with a BMI higher than 30 kg/m 2 was 28 ng/mL (72 nmol/L), the cohort was at low risk for fractures, and outcomes based on baseline 25(OH)D in individuals with obesity were not presented. The WHI, which was also performed in the United States ( 110 ) showed a HR of 0.73 (95% CI, 0.49-1.09) for femoral fractures in female individuals with a BMI higher than 30 kg/m 2 who were randomized to 1000 mg calcium and 400 IU (10 μg) vitamin D supplementation daily vs placebos. Baseline 25(OH)D levels were not available in this subgroup. In the entire study cohort, the risk of fracture decreased among those who were adherent to calcium and vitamin D treatment, but there are no available data among those with a BMI higher than 30 kg/m 2 who were adherent to study medications.

The WHI also examined the effects of vitamin D (400 IU [μg] with 1000 mg calcium daily) on all-cause mortality in individuals with obesity and did not show a statistically significant effect (HR 0.93 [95% CI, 0.80-1.09]), including among participants adherent to study medications (HR 0.87 [95% CI, 0.73-1.04] ( 121 ).

Two RCTs ( 20 , 125 ) examining the incidence of major cardiovascular events in individuals with obesity found no overall benefit in those who were randomized to vitamin D. In the VITAL study, participants with obesity who received 2000 IU (50 μg) of vitamin D daily and those who received placebo had a comparable risk of cardiac events (HR 0.98 [95% CI, 0.76-1.26] ( 20 ). Of interest, the FIND trial, performed in Finland ( 125 ), suggested a reduction in the risk of developing a major cardiovascular event in those with a BMI higher than 30 kg/m 2 receiving higher dosages of vitamin D (3200 IU/day [80 μg /day]), which increased 25(OH)D levels from 30 ng/mL (75 nmol/L) at baseline to 48 ng/mL (120 nmol/L) (HR 0.19 [95% CI, 0.04-0.82]).

Three RCTs and one observational study examined the effect of vitamin D on the development of cancer in adults with obesity ( 29 ). None of these trials demonstrated a significant effect of vitamin D on developing cancer. An HR of 1.13 (95% CI, 0.9-1.37); 2000 IU [50 μg] vitamin D/day) was reported in the VITAL trial ( 20 ). In the FIND trial ( 125 ) neither the high (3200 IU/d, 80 μg/d) nor the lower dosage (1600 IU/d; 40 μg/d) decreased cancer risk (HR 0.91 [95% CI; 0.36-2.32] and HR 1.61 [95% CI; 0.72-3.59 respectively). In the WHI, vitamin D plus calcium supplementation did not alter the risk of colorectal cancer ( 282 ) (HR 1.07 [95% CI, 0.76-1.52]); invasive breast cancer ( 283 ) (HR 0.93 [95% CI, 0.77-1.12]), or in situ ductal breast cancer ( 284 ) (HR 0.81 [95% CI, 0.62-1.06]). In the Sister observational study ( 274 ) use of vitamin D supplements did not decrease the risk of breast cancer in obese women whose sisters had breast cancer (HR 0.94 [95% CI, 0.82-1.10). Baseline 25(OH)D levels for individuals with obesity were not available for all these trials, but in the VITAL trial, the average baseline level in those with a BMI higher than 30 kg/m 2 was 28 ng/mL (72 nmol/L).

The ViDA trial, performed in New Zealand, reported no beneficial effect of vitamin D on the risk of developing respiratory infections in adults with obesity. The baseline 25(OH)D levels of participants with obesity were not presented.

The systematic review did not identify studies that reported the risk of developing hypercalcemia in patients with obesity receiving vitamin D. The risk of nephrolithiasis and a decline in kidney function were examined in 1 RCT each, and no statistically significant effect of vitamin D supplementation was observed ( 120 , 126 ).

Considerations related to required resources (costs), acceptability, and feasibility have been discussed. The panel did not identify any studies that adequately addressed the cost-effectiveness, or the potential equity impact of 25(OH)D screening, for people with obesity. However, since obesity has been associated with reduced health equity, if optimizing 25(OH)D levels were to preferentially improve outcomes in persons with obesity and low 25(OH)D, then 25(OH)D screening in those with obesity could possibly improve health equity. The panel judged that screening would be acceptable to most, assuming that a net benefit is expected. Although there is variability in the cost and availability of testing for 25(OH)D levels across the globe, the panel judged that this is feasible in many settings, as is the resultant intervention of taking a daily nonprescription supplement. Given the very high prevalence of obesity in many countries (eg, the prevalence of obesity in the United States is estimated to be 41.9% ( 285 ), a 25(OH)D screening strategy for all individuals with obesity would require significant effort and resources, which may not be feasible from a societal perspective.

The panel's conditional recommendation against routine 25(OH)D screening for those with obesity is related primarily to the lack of clinical trials examining the benefit of 25(OH)D screening in those with obesity and treating only those with a 25(OH)D level below a threshold. Moreover, subgroup analyses from available clinical trials did not clearly demonstrate a net benefit of vitamin D in individuals with obesity as a group. The panel was also uncertain that any putative benefits of screening would justify the additional burden and costs of 25(OH)D testing, including health care visits (cost-effectiveness); and whether implementation of universal 25(OH)D screening for those with obesity would be feasible from a societal perspective. In addition, the panel was uncertain about what 25(OH)D level would necessitate subsequent vitamin D administration.

Large RCTs in participants with obesity will be required to determine if vitamin D lowers the risk of disease, whether benefit is limited to those with low baseline levels (and defining what these levels are), what target levels are required for optimal disease prevention, and what dosages are required to achieve these target levels/desired outcomes. Although placebo-controlled vitamin D trials may be viewed as unethical for participants known to have low 25(OH)D levels, inclusion of several daily dosages and targeting several levels of 25(OH)D would inform the dosages and target levels required for disease prevention.

Clinical trials must be designed to be of sufficient duration to address the outcomes being examined, considering the natural history and pathophysiology of the diseases of interest (eg, acute infectious diseases vs cancer).

The Endocrine Society and the Guideline Development Panel thank Marie McDonnell, MD, who served as Clinical Guidelines Committee chair during the development of this clinical practice guideline (CPG), for the contributions she made through her leadership and expertise. The panel thanks Maureen Corrigan, MA, Director for Clinical Practice Guidelines for the Endocrine Society, and Elizabeth York, MPH, Manager of Clinical Practice Guidelines for the Endocrine Society, for their expert guidance and assistance with all aspects of guideline development. We thank the numerous contributors from the Mayo Evidence-Based Practice Center, especially Vishal Shah, MD, MPH, for their contribution in conducting the evidence reviews for the guideline. We also thank John Sluyter for his contribution in extracting the data for the ViDA participants younger than and older than 75 years of age. We also thank the American College of Physicians for their identification of John Tayek as a primary care representative for this guideline.

The Endocrine Society's clinical practice guidelines are developed to be of assistance to endocrinologists by providing guidance and recommendations for particular areas of practice. The guidelines should not be considered as an all-encompassing approach to patient care and not inclusive of all proper approaches or methods, or exclusive of others. The guidelines cannot guarantee any specific outcome, nor do they establish a standard of care. The guidelines are not intended to dictate the treatment of a particular patient. Treatment decisions must be made based on the independent judgment of healthcare providers and each patient's individual circumstances. The Endocrine Society makes every effort to present accurate and reliable information. This publication is provided “as is” and the Society makes no warranty, express or implied, regarding the accuracy and reliability of these guidelines and specifically excludes any warranties of merchantability and fitness for a particular use or purpose, title, or noninfringement of third-party rights. The Society, its officers, directors, members, employees, and agents shall not be liable for direct, indirect, special, incidental, or consequential damages, including the interruption of business, loss of profits, or other monetary damages, regardless of whether such damages could have been foreseen or prevented, related to this publication or the use of or reliance on the information contained herein.

Funding for the development of this guideline was provided by The Endocrine Society. No other entity provided financial support.

Total number of Guideline Development Panel members = 14

Percentage of total Guideline Development Panel members with relevant (or potentially relevant) conflicts of interest = 7%

Data availability

The data underlying this article are available in the article, in its online supplementary material, and in the accompanying systematic review publication.

Individual Disclosures, Conflicts, and Management Strategies

Chair: Marie Demay, MD

Massachusetts General Hospital

Expertise: Adult endocrinology

Disclosures (2020-2024):

National Institutes of Health: Investigator on vitamin D action, growth plate

Endocrine Society: Annual Meeting Steering Committee Member

Open Payments Database: N/A

Assessment and Management:

No conflict of interest (COI) relevant to this CPG.

No management required.

Co-Chair: Anastassios G. Pittas, MD, MS

Tufts Medical Center

National Institutes of Health: Investigator on vitamin D

National Institutes of Health: Data Safety Monitoring Board for melatonin, lifestyle intervention

National Institutes of Health: Data Safety Monitoring Board for the DISCOVERY study, diabetes risk in children

Expert testimony for various hospitals on cases that involved diabetes

No COI relevant to this CPG.

Daniel Bikle, MD, PhD

University of California San Francisco

Radius: Investigator on abaloparatide

Elsevier: Journal Associate Editor

Amgen: own stocks/shares

International Vitamin D Workshop

Endocrine Society

American Society for Bone and Mineral Research

Author on “Consensus Statement on Vitamin D Status Assessment and Supplementation: Whys, Whens, and Hows” (Giustina A, Bilezikian JP, Adler RA, et al. Consensus Statement on Vitamin D Status Assessment and Supplementation: Whys, Whens, and Hows. Endocr Rev. Published online April 27, 2024. doi: 10.1210/endrev/bnae009 )

Open Payments Database: https://openpaymentsdata.cms.gov/physician/74931

Dr. Bikle’s authorship on this consensus statement was made known after the completion of this guideline. Although participation in multiple consensus statements or guidelines could generate intellectual dualities of interest, an evaluation indicated no potential conflict with the present guideline.

Dima Diab, MD

University of Cincinnati

Disclosures (2021-2024):

American Association of Clinical Endocrinology: Vice Chair for the Bone Network

Mairead Kiely, PhD

University College Cork

Expertise: Human Nutrition

Research funding: Irish Government Department of Agriculture Food and the Marine

Research funding: Science Foundation Ireland

Research funding: European Commission

Research funding: Enterprise Ireland Meat Technology Institute

Research funding: Wellcome Leap 1KD

Member: UK Scientific Advisory Committee for Nutrition (SACN)

Member: Vitamin D Workshop Executive Committee; Co-chair 2024 Workshop

Marise Lazaretti-Castro, MD, PhD

The Federal University of São Paulo

Mantecorp-Farmasa: Primary Investigator on pharmaceutical product

Mantecorp-Farmasa: Consultant on pharmaceutical product

Alexion: Speaking engagement for pharmaceutical product

Amgen: Advisory Board for pharmaceutical product

Associacao Brasileira de Avaliaçcao Ossea e Osteometabolismo

It was determined that Dr. Lazaretti-Castro would refrain from future consultation for products related to vitamin D.

Paul Lips, MD, PhD

Vrije Universiteit Amsterdam

Abiogen: Speaking Engagement on controversies in vitamin D

Vitamin D Workshop: Scientific Programme Advisory Board

Deborah Mitchell, MD

Expertise: Pediatric endocrinology

Amolyt: Consultant for hypoparathyroidism

American Society for Bone and Mineral Research: Education Committee Member, Chair of the Pediatric Working Group

Shelley Powers

Patient Representative

American Bone Health: Board of Directors, Committee Chair

International Society for Clinical Densitometry: Patient Advocate

Sudhaker Rao, MD

Henry Ford Hospital and Michigan State University

Department of Defense: Investigator on bone quality using digital tomosynthesis

Open Payments Database: https://openpaymentsdata.cms.gov/physician/390118

Robert Scragg, MBBS, PhD

University of Auckland

Expertise: Epidemiology

Health Research Council of New Zealand: Investigator on arterial function and cardiovascular disease

John Tayek, MD, MS

Harbor-University of California Los Angeles Medical Center

Expertise: General internal medicine and adult endocrinology

Ajinomoto USA: Investigator for amino acid supplements in end-stage renal disease (ESRD)

Open Payments Database: https://openpaymentsdata.cms.gov/physician/165331

Amy Valent, DO

Oregon Health and Sciences University

Expertise: Obstetrics and gynecology

Disclosures (2022-2024):

Dexcom: Investigator for device

Dexcom: Consultant

Open Payments Database: https://openpaymentsdata.cms.gov/physician/1355801

Judith Walsh, MD, MPH

Expertise: Internal medicine

National Institutes of Health: Investigator on cancer screening, primary care, smoking cessation

Up to Date: Consultant on colon cancer screening

Kaiser Permanente Medical Center: Speaking engagement on cancer screening, women's health

Christopher McCartney, MD

University of Virginia and West Virginia University

Expertise: Clinical practice guideline methodology

National Institutes of Health: Investigator on reproductive endocrinology/polycystic ovary syndrome

Endocrine Society: Editor or member of an editorial board, Vice Chair Ethics and Professionalism Committee, Chair of COI Advisory Group, Clinical Science Chair Annual Meeting Steering Committee

M. Hassan Murad, MD, MPH

Mayo Clinic

Society for Vascular Surgery: Methodology Consultant

American Society of Hematology: Methodology Consultant

CHEST: Methodology Consultant

World Health Organization: Methodology Consultant

Evidence Foundation: Board Member

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Singh Ospina   N , Diaz-Thomas   A , McDonnell   ME  et al.    Navigating complexities: vitamin D, skin pigmentation, and race . JCEM . 2024 .

Kato   I , Sun   J , Hastert   TA , et al.    Association of calcium and vitamin D supplementation with cancer incidence and cause-specific mortality in black women: extended follow-up of the Women's health initiative calcium-vitamin D trial . Int J Cancer . 2023 ; 153 ( 5 ): 1035 ‐ 1042 .

Blondon   M , Rodabough   RJ , Budrys   N , et al.    The effect of calcium plus vitamin D supplementation on the risk of venous thromboembolism. From the Women's health Initiative Randomized Controlled Trial . Thromb Haemost . 2015 ; 113 ( 5 ): 999 ‐ 1009 .

O'Brien   KM , Keil   AP , Harmon   QE , et al.    Vitamin D supplement use and risk of breast cancer by race-ethnicity . Epidemiology . 2022 ; 33 ( 1 ): 37 ‐ 47 .

Roizen   JD , Long   C , Casella   A , et al.    Obesity decreases hepatic 25-hydroxylase activity causing low serum 25-hydroxyvitamin D . J Bone Miner Res . 2019 ; 34 ( 6 ): 1068 ‐ 1073 .

Yang   X , Zhu   Q , Zhang   L , et al.    Causal relationship between gut microbiota and serum vitamin D: evidence from genetic correlation and Mendelian randomization study . Eur J Clin Nutr . 2022 ; 76 ( 7 ): 1017 ‐ 1023 .

Jones   ML , Martoni   CJ , Prakash   S . Oral supplementation with probiotic L. reuteri NCIMB 30242 increases mean circulating 25-hydroxyvitamin D: a post hoc analysis of a randomized controlled trial . J Clin Endocrinol Metab . 2013 ; 98 ( 7 ): 2944 ‐ 2951 .

Tobias   DK , Luttmann-Gibson   H , Mora   S , et al.    Association of body weight with response to vitamin D supplementation and metabolism . JAMA Netw Open . 2023 ; 6 ( 1 ): e2250681 .

Liu   X , Baylin   A , Levy   PD . Vitamin D deficiency and insufficiency among US adults: prevalence, predictors and clinical implications . Br J Nutr . 2018 ; 119 ( 8 ): 928 ‐ 936 .

Compston   JE , Watts   NB , Chapurlat   R , et al.    Obesity is not protective against fracture in postmenopausal women: GLOW . Am J Med . 2011 ; 124 ( 11 ): 1043 ‐ 1050 .

Al-Khalidi   B , Kimball   SM , Kuk   JL , Ardern   CI . Metabolically healthy obesity, vitamin D, and all-cause and cardiometabolic mortality risk in NHANES III . Clin Nutr . 2019 ; 38 ( 2 ): 820 ‐ 828 .

Wactawski-Wende   J , Kotchen   JM , Anderson   GL , et al.    Calcium plus vitamin D supplementation and the risk of colorectal cancer . N Engl J Med . 2006 ; 354 ( 7 ): 684 ‐ 696 .

Chlebowski   RT , Johnson   KC , Kooperberg   C , et al.    Calcium plus vitamin D supplementation and the risk of breast cancer . J Natl Cancer Inst . 2008 ; 100 ( 22 ): 1581 ‐ 1591 .

Peila   R , Xue   X , Cauley   JA , et al.    A randomized trial of calcium plus vitamin D supplementation and risk of ductal carcinoma in situ of the breast . JNCI Cancer Spectr . 2021 ; 5 ( 4 ): pkab072 .

Stierman   B , Afful   J , Carroll   MD , et al.    National Health and Nutrition Examination Survey 2017–March 2020 Prepandemic Data Files Development of Files and Prevalence Estimates for Selected Health Outcomes. National Health Statistics Reports; 2021; NHSR No. 158 .

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Companion articles.

• Navigating Complexities: Vitamin D, Skin Pigmentation, and Race
• Vitamin D Insufficiency and Epistemic Humility: An Endocrine Society Guideline Communication
• A Systematic Review Supporting the Endocrine Society Clinical Practice Guidelines on Vitamin D

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Vitamin D for Human Body

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Vitamin D: an evidence-based review

Affiliation.

• 1 Department of Family Medicine, University of Wisconsin, Madison, WI 53715, USA.
• PMID: 19897699
• DOI: 10.3122/jabfm.2009.06.090037
• J Am Board Fam Med. 2010 Jan-Feb;23(1):138

Vitamin D is a fat-soluble vitamin that plays an important role in bone metabolism and seems to have some anti-inflammatory and immune-modulating properties. In addition, recent epidemiologic studies have observed relationships between low vitamin D levels and multiple disease states. Low vitamin D levels are associated with increased overall and cardiovascular mortality, cancer incidence and mortality, and autoimmune diseases such as multiple sclerosis. Although it is well known that the combination of vitamin D and calcium is necessary to maintain bone density as people age, vitamin D may also be an independent risk factor for falls among the elderly. New recommendations from the American Academy of Pediatrics [corrected] address the need for supplementation in breastfed newborns and many questions are raised regarding the role of maternal supplementation during lactation. Unfortunately, little evidence guides clinicians on when to screen for vitamin D deficiency or effective treatment options.

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This is a general overview. For more in-depth information, see our health professional fact sheet .

For information on vitamin D and COVID-19, see Dietary Supplements in the Time of COVID-19 .

What is vitamin D and what does it do?

Vitamin D is a nutrient you need for good health. It helps your body absorb calcium , one of the main building blocks for strong bones. Together with calcium, vitamin D helps protect you from developing osteoporosis , a disease that thins and weakens the bones and makes them more likely to break. Your body needs vitamin D for other functions too. Your muscles need it to move, and your nerves need it to carry messages between your brain and your body. Your immune system needs vitamin D to fight off invading bacteria and viruses .

How much vitamin D do I need?

The amount of vitamin D you need each day depends on your age. Average daily recommended amounts are listed below in micrograms (mcg) and International Units ( IU ).

What foods provide vitamin D?

Very few foods naturally contain vitamin D. Fortified foods provide most of the vitamin D in the diets of people in the United States. Check the Nutrition Facts label for the amount of vitamin D in a food or beverage.

• Almost all of the U.S. milk supply is fortified with about 3 mcg (120 IU) vitamin D per cup. Many plant-based alternatives such as soy milk, almond milk, and oat milk are similarly fortified, but foods made from milk, like cheese and ice cream, are usually not fortified.
• Vitamin D is added to many breakfast cereals and to some brands of orange juice, yogurt, margarine, and other food products.
• Fatty fish (like trout, salmon, tuna, and mackerel) and fish liver oils are among the best natural sources of vitamin D.
• Beef liver, egg yolks, and cheese have small amounts of vitamin D.
• Mushrooms provide a little vitamin D. Some mushrooms have been exposed to ultraviolet light to increase their vitamin D content.

Can I get vitamin D from the sun?

Your body makes vitamin D when your bare skin is exposed to the sun. Most people get at least some vitamin D this way. However, clouds, smog, old age, and having dark-colored skin reduce the amount of vitamin D your skin makes. Also, your skin does not make vitamin D from sunlight through a window.

Ultraviolet radiation from sunshine can cause skin cancer , so it’s important to limit how much time you spend in the sun. Although sunscreen limits vitamin D production, health experts recommend using sunscreen with a sun protection factor ( SPF ) of 15 or more when you’re out in the sun for more than a few minutes.

What kinds of vitamin D dietary supplements are available?

Vitamin D is found in multivitamin/mineral supplements. It is also available in dietary supplements containing only vitamin D or vitamin D combined with a few other nutrients. The two forms of vitamin D in supplements are D2 (ergocalciferol) and D3 (cholecalciferol). Both forms increase vitamin D in your blood, but D3 might raise it higher and for longer than D2. Because vitamin D is fat soluble, it is best absorbed when taken with a meal or snack that includes some fat.

Am I getting enough vitamin D?

• Levels of 50 nmol/L (20 ng/mL) or above are adequate for most people for bone and overall health.
• Levels below 30 nmol/L (12 ng/mL) are too low and might weaken your bones and affect your health.
• Levels above 125 nmol/L (50 ng/mL) are too high and might cause health problems.

In the United States, most people have adequate blood levels of vitamin D. However, almost one out of four people have vitamin D blood levels that are too low or inadequate for bone and overall health.

Some people are more likely than others to have trouble getting enough vitamin D:

• Breastfed infants . Breast milk alone does not provide infants with an adequate amount of vitamin D. Breastfed infants should be given a supplement of 10 mcg (400 IU) of vitamin D each day.
• Older adults. As you age, your skin's ability to make vitamin D when exposed to sunlight declines.
• People who seldom expose their skin to sunshine because they do not go outside or because they keep their body and head covered. Sunscreen also limits the amount of vitamin D your skin produces.
• People with dark skin. The darker your skin, the less vitamin D you make from sunlight exposure.
• People with conditions that limit fat absorption , such as Crohn’s disease , celiac disease , or ulcerative colitis . This is because the vitamin D you consume is absorbed in the gut along with fat, so if your body has trouble absorbing fat, it will also have trouble absorbing vitamin D.
• People with obesity or who have undergone gastric bypass surgery. They may need more vitamin D than other people.

What happens if I don’t get enough vitamin D?

In children, vitamin D deficiency causes rickets , a disease in which the bones become soft, weak, deformed, and painful. In teens and adults, vitamin D deficiency causes osteomalacia , a disorder that causes bone pain and muscle weakness.

What are some effects of vitamin D on health?

Scientists are studying vitamin D to better understand how it affects health. Here are several examples of what this research has shown.

Bone health and osteoporosis

Long-term shortages of vitamin D and calcium cause your bones to become fragile and break more easily. This condition is called osteoporosis. Millions of older women and men have osteoporosis or are at risk of developing this condition. Muscles are also important for healthy bones because they help maintain balance and prevent falls. A shortage of vitamin D may lead to weak, painful muscles.

Getting recommended amounts of vitamin D and calcium from foods (and supplements, if needed) will help maintain healthy bones and prevent osteoporosis. Taking vitamin D and calcium supplements slightly increases bone strength in older adults, but it’s not clear whether they reduce the risk of falling or breaking a bone.

Vitamin D does not seem to reduce the risk of developing cancer of the breast, colon , rectum, or lung . It is not clear whether vitamin D affects the risk of prostate cancer or chance of surviving this cancer. Very high blood levels of vitamin D may even increase the risk of pancreatic cancer .

Clinical trials suggest that while vitamin D supplements (with or without calcium) may not affect your risk of getting cancer, they might slightly reduce your risk of dying from this disease. More research is needed to better understand the role that vitamin D plays in cancer prevention and cancer-related death.

Heart disease

Vitamin D is important for a healthy heart and blood vessels and for normal blood pressure. Some studies show that vitamin D supplements might help reduce blood cholesterol levels and high blood pressure —two of the main risk factors for heart disease. Other studies show no benefits. If you are overweight or have obesity, taking vitamin D at doses above 20 mcg (800 IU) per day plus calcium might actually raise your blood pressure. Overall, clinical trials find that vitamin D supplements do not reduce the risk of developing heart disease or dying from it, even if you have low blood levels of the vitamin.

Vitamin D is needed for your brain to function properly. Some studies have found links between low blood levels of vitamin D and an increased risk of depression. However, clinical trials show that taking vitamin D supplements does not prevent or ease symptoms of depression.

Multiple sclerosis

People who live near the equator have more sun exposure and higher vitamin D levels. They also rarely develop multiple sclerosis (MS), a disease that affects the nerves that carry messages from the brain to the rest of the body. Many studies find a link between low blood vitamin D levels and the risk of developing MS. However, scientists have not actually studied whether vitamin D supplements can prevent MS. In people who have MS, clinical trials show that taking vitamin D supplements does not keep symptoms from getting worse or coming back.

Type 2 diabetes

Vitamin D helps your body regulate blood sugar levels. However, clinical trials in people with and without diabetes show that supplemental vitamin D does not improve blood sugar levels, insulin resistance , or hemoglobin A1c levels (the average level of blood sugar over the past 3 months). Other studies show that vitamin D supplements don’t stop most people with prediabetes from developing diabetes.

Weight loss

Taking vitamin D supplements or eating foods that are rich in vitamin D does not help you lose weight.

Can vitamin D be harmful?

Yes, getting too much vitamin D can be harmful. Very high levels of vitamin D in your blood (greater than 375 nmol/L or 150 ng/mL) can cause nausea , vomiting, muscle weakness, confusion, pain, loss of appetite, dehydration, excessive urination and thirst, and kidney stones . Extremely high levels of vitamin D can cause kidney failure , irregular heartbeat, and even death. High levels of vitamin D are almost always caused by consuming excessive amounts of vitamin D from dietary supplements. You cannot get too much vitamin D from sunshine because your skin limits the amount of vitamin D it makes.

The daily upper limits for vitamin D include intakes from all sources—food, beverages, and supplements—and are listed below in micrograms (mcg) and IU. However, your health care provider might recommend doses above these upper limits for a period of time to treat a vitamin D deficiency.

Does vitamin D interact with medications or other dietary supplements?

Yes, vitamin D supplements may interact with some medicines. Here are several examples:

• Orlistat (Xenical and alli) is a weight-loss drug . It can reduce the amount of vitamin D your body absorbs from food and supplements.
• Cholesterol-lowering statins might not work as well if you take high-dose vitamin D supplements. This includes atorvastatin (Lipitor), lovastatin (Altoprev and Mevacor), and simvastatin (FloLipid and Zocor)
• Steroids such as prednisone (Deltasone, Rayos, and Sterapred) can lower your blood levels of vitamin D.
• Thiazide diuretics (such as Hygroton, Lozol, and Microzide) could raise your blood calcium level too high if you take vitamin D supplements.

Tell your doctor, pharmacist , and other health care providers about any dietary supplements and prescription or over-the-counter medicines you take. They can tell you if the dietary supplements might interact with your medicines. They can also explain whether the medicines you take might interfere with how your body absorbs or uses other nutrients.

Vitamin D and healthful eating

Where can I find out more about vitamin D?

• Office of Dietary Supplements (ODS)  Health Professional Fact Sheet on Vitamin D
• ODS  Health Professional Fact Sheet on Vitamin D
• Nutrient List for vitamin D (listed by food or by vitamin D content ), USDA
• ODS  Frequently Asked Questions: Which brand(s) of dietary supplements should I purchase?

This fact sheet by the National Institutes of Health (NIH) Office of Dietary Supplements (ODS) provides information that should not take the place of medical advice. We encourage you to talk to your health care providers (doctor, registered dietitian, pharmacist, etc.) about your interest in, questions about, or use of dietary supplements and what may be best for your overall health. Any mention in this publication of a specific product or service, or recommendation from an organization or professional society, does not represent an endorsement by ODS of that product, service, or expert advice.

Updated: November 8, 2022 History of changes to this fact sheet

• DOI: 10.15406/joentr.2017.06.00174
• Corpus ID: 196481665

Vitamin D Deficiency to Ill Health Essay

• Nawal B Dubey
• Published 7 April 2017
• Journal of Otolaryngology-ENT Research

32 References

Vitamin d deficiency: a worldwide problem with health consequences., vitamin d deficiency in general medical inpatients in summer and winter, sunlight and vitamin d for bone health and prevention of autoimmune diseases, cancers, and cardiovascular disease., vitamin d and cardiovascular disease: a novel agent for reducing cardiovascular risk, vitamin d: a growing perspective., optimize dietary intake of vitamin d: an epigenetic perspective, vitamin d-directed rheostatic regulation of monocyte antibacterial responses1, cell defenses and the sunshine vitamin., vitamin d therapy of osteoporosis: plain vitamin d therapy versus active vitamin d analog (d-hormone) therapy, vitamin d deficiency in children living in jeddah, saudi arabia, related papers.

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Essay on Vitamin D: Top 6 Essays | Nutrition | Living Organisms | Biology

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Essay on Vitamin D

Essay Contents:

• Essay on the Deficiency of Vitamin D

Essay # 1. Historical Review of Vitamin D:

In 1782 it was found out that cod-liver oil cured rickets. In 1918 Mellanby produced experimental rickets in animals and confirmed the conception which was so far prevalent that rickets was due to deficiency of vitamin D.

Since then further advancement has been made and it is now established that synthesis of vitamin D occurs in the body under the influence of the ultra-violet rays of the sunlight. The amount of vitamin D thus formed is greatest during summer months and low amount in the winter.

There is a group of vitamin D of which D 2 and D 3 are chief for nutritional purposes. Calciferol is applied to a number of chemically related thermostable compounds, all of which, have physiological property of curing or/and prevent­ing rickets.

Essay # 2. Chemical Structure of Vitamin D:

All the members are sterol compounds. D 2 or activated ergosterol or ergocalciferol or viosterol is an isomer of ergosterol. This vitamin is very thermostable. The structure of vitamin D 3 or cholecalciferol (also known activated 7-dehydrocholesterol) is the same as that of D 2 , except that the side chain on position 17 is that of cholesterol. The structures of vitamin D 2 and D 3 are given below.

v. It influences the handling of phosphate by the kidney. In the parathyroidectomised animals, vitamin D increases the clearance of phosphate and promotes lowering of serum phosphate. It may act in connection with alkaline phosphatase, liberating inorganic phosphate which influences the deposition of calcium phosphate in ossification process.

vi. It is necessary for proper bone growth perhaps by promoting endochondral growth of long bones.

vii. Probably, vitamin D controls the retention of calcium and parathyroid regulates the level of blood calcium by controlling mobilization of calcium from the bones. Thus vitamin D and parthyroid help each other in Ca metabolism and bone formation.

viii. It lowers the pH in the colon, caecum, ileum, etc., and increases the urinary pH simultaneously. This may be a secondary effect due to absorption of Ca.

ix. In physiological dose, it increases the citrate content of bone, blood and other tissues as well as urinary excretion.

x. It counteracts the inhibitory effect of calcium ions on the hydrolysis of phytate (inositol hexaphosphate). The mode of action is mainly by promoting the transport of calcium and secondarily phosphate in the blood stream. On the whole the function of vitamin D is to cause increased absorption, longer retention and better utilisation of calcium and phosphorus in the body.

Essay # 6. Deficiency of Vitamin D:

The fundamental change in this vitamin deficiency is an increased loss of calcium and phosphate in the faeces. This leads to a fall in their blood level, and hence not available for bone formation. Due to this reason, the children suffer from rickets (wrickken = to twist), and adults from osteomalacia.

i. Rickets:

In rickets the bones remain soft due to less deposition of cal­cium salts. So the long bones remain cartilagenous and easily bend under the weight of the body (Fig. 11.4). There is defec­tive ossification at the epiphyseal line. The epiphyseal line re­mains wide and irregular and there is irregular proliferation of the cartilage cells. Due to defective ossification there is mal­formation of the chest and pelvis, and changes in the spinal curvature (scoliosis), softness in parietal bones (craniotabes), etc. Rickets occur in children between 6 and 18 months of life during the period of skeletal growth.

ii. Osteomalacia:

It is form of adult ricket. It is due to deficiency of vitamin D and calcium salts in the diet. It occurs in women during pregnancy and lactation when a large amount of calcium is depleted from the pregnant woman (mother).

International Unit:

Equivalent to activity of 0.025 micro-gram of calciferol.

Daily Requirement:

Exogenous vitamin D is required throughout the period of skeletal growth, i.e., to adult life. The recommen­dations for infants under 1 year are 400-800 i.u. daily, and for children and adolescents up to 20 years 400 i.u. This should be simultaneously supplemented with adequate intake of calcium and phosphorus. In the latter half of pregnancy and throughout lactating period, the dose should be 400-800 i.u.

Poisoning Action (Hypervitaminosis D):

Poisoning action has been noted after large doses of vitamin D. It causes loss of weight, reduced excretion of calcium and phosphorus, increased blood calcium, and various other toxic symptoms like nausea, vomiting, headache and drowsiness. Extensive deposit of calcium is found in the soft regions which are not normally calcified, such as kidney, heart, artery, etc. The signs of renal failure may appear.

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• Review Article
• Published: 20 January 2020

Vitamin D deficiency 2.0: an update on the current status worldwide

• Karin Amrein   ORCID: orcid.org/0000-0003-0915-085X 1 , 2 ,
• Mario Scherkl 1 ,
• Magdalena Hoffmann   ORCID: orcid.org/0000-0003-1668-4294 1 , 3 , 4 ,
• Stefan Neuwersch-Sommeregger 5 , 6 ,
• Markus Köstenberger 5 , 6 ,
• Adelina Tmava Berisha 7 ,
• Gennaro Martucci   ORCID: orcid.org/0000-0001-8443-2414 8 ,
• Stefan Pilz 1 &
• Oliver Malle 1  

European Journal of Clinical Nutrition volume  74 ,  pages 1498–1513 ( 2020 ) Cite this article

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• Endocrine system and metabolic diseases
• Risk factors

Vitamin D testing and the use of vitamin D supplements have increased substantially in recent years. Currently, the role of vitamin D supplementation, and the optimal vitamin D dose and status, is a subject of debate, because large interventional studies have been unable to show a clear benefit (in mostly vitamin D replete populations). This may be attributed to limitations in trial design, as most studies did not meet the basic requirements of a nutrient intervention study, including vitamin D-replete populations, too small sample sizes, and inconsistent intervention methods regarding dose and metabolites. Vitamin D deficiency (serum 25-hydroxyvitamin D [25(OH)D] < 50 nmol/L or 20 ng/ml) is associated with unfavorable skeletal outcomes, including fractures and bone loss. A 25(OH)D level of >50 nmol/L or 20 ng/ml is, therefore, the primary treatment goal, although some data suggest a benefit for a higher threshold. Severe vitamin D deficiency with a 25(OH)D concentration below <30 nmol/L (or 12 ng/ml) dramatically increases the risk of excess mortality, infections, and many other diseases, and should be avoided whenever possible. The data on a benefit for mortality and prevention of infections, at least in severely deficient individuals, appear convincing. Vitamin D is clearly not a panacea, and is most likely efficient only in deficiency. Given its rare side effects and its relatively wide safety margin, it may be an important, inexpensive, and safe adjuvant therapy for many diseases, but future large and well-designed studies should evaluate this further. A worldwide public health intervention that includes vitamin D supplementation in certain risk groups, and systematic vitamin D food fortification to avoid severe vitamin D deficiency, would appear to be important. In this narrative review, the current international literature on vitamin D deficiency, its relevance, and therapeutic options is discussed.

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Official recommendations for vitamin d through the life stages in developed countries.

The health effects of vitamin D supplementation: evidence from human studies

Introduction.

Vitamin D testing has exponentially increased in recent years [ 1 ]. The definition and relevance of vitamin D deficiency are still under debate. Recent large observational data have suggested that ~40% of Europeans are vitamin D deficient, and 13% are severely deficient [ 2 ]. The relevance of this widespread deficiency and necessity for supplementation has been questioned [ 3 ]. Certainly, vitamin D is not a panacea. Because more often than not, trials have included non-deficient individuals, it is not surprising that interventional trials have usually not been able to find a benefit of vitamin D supplementation on clinical outcomes. This was also reflected in meta-analyses on the topic that were carried out with poor methodological standards [ 4 ]. Consequently, many authors have dismissed a role of vitamin D on important clinical outcomes, and suggested that vitamin D may be more an associative than a causal factor in acute and chronic disease.

On the other hand, a low vitamin D status is emerging as a very common condition worldwide, and several studies from basic science to clinical applications have highlighted a strong association with chronic diseases, as well as acute conditions. Moreover, the large amount of observational data currently available are also accompanied by pathophysiological associations of vitamin D with energy homeostasis, and regulation of the immune and endocrine systems [ 5 ].

Recent negative interventional trials may be biased by substantial methodological and study design errors, making it impossible to show the potential contributing role of vitamin D supplementation in a deficient population. Typically, most studies have missed important prerequisites for a nutrient intervention trial: the absence of the problem to be solved—vitamin D deficiency, often ridiculously small sample sizes, and varying interventional regimes regarding dose and metabolite. Even the recent very large trials did not exclusively include deficient populations [ 6 , 7 , 8 ]. Moreover, interventional regimes have used a one-size-fits-all approach without taking into account individual differences in BMI and vitamin D metabolism.

Articles were individually retrieved up to October 2019 by search in PubMed (MEDLINE). Studies were excluded if they were not in English. Across the last few decades, vitamin D-related research/publications have dramatically increased. Therefore, we decided to focus on the largest, most relevant, and most recent studies that are now in this version of the review.

All authors supplied a first draft paper on a specific topic. All papers were then exchanged and discussed among authors by e-mail.

Definition of vitamin D deficiency

Serum 25(OH)D is considered to be the best marker for assessing vitamin D status, and reliably reflects the free fractions of the vitamin D metabolites, despite the fact that, in theory, the bioavailable fractions may be more clinically informative [ 9 , 10 ]. A range of below 75 nmol/L (or 30 ng/ml) of serum/plasma 25(OH)D concentration is considered vitamin D deficiency by most authors [ 11 , 12 ]. A cutoff of <25 or <30 nmol/L (or 10/12 ng/ml) increases the risk of osteomalacia and nutritional rickets dramatically, and therefore is considered to determine severe vitamin D deficiency [ 13 , 14 , 15 , 16 ]. The clinical practice guidelines of the Endocrine Society Task Force on Vitamin D [ 12 ] have defined a cutoff level of 50 nmol/L as vitamin D deficient. Furthermore, different societies and expert bodies have defined 50 nmol/L as “vitamin D requirement of nearly all normal healthy persons,” by using bone health as the main basis. For example, a cutoff level of 50 nmol/L is recommended by the Institute of Medicine (IOM, USA) in their “Dietary Reference Intakes”. Vitamin D levels of <30 nmol/L (or 12 ng/ml) should likely be prevented with a public health approach [ 17 ]. There are many large and relevant risk groups for vitamin D deficiency (Table 1 ).

Prevalence of vitamin D deficiency worldwide

Prevalence rates of severe vitamin D deficiency, defined as 25(OH)D <30 nmol/L (or 12 ng/ml), of 5.9% (US) [ 18 ], 7.4% (Canada) [ 19 ], and 13% (Europe) [ 2 ] have been reported. Estimates of the prevalence of 25(OH)D levels <50 nmol/L (or 20 ng/ml) have been reported as 24% (US), 37% (Canada), and 40% (Europe) [ 2 , 17 , 18 , 19 ]. This may vary by age, with lower levels in childhood and the elderly [ 17 ], and also ethnicity in different regions, for example, European Caucasians show lower rates of vitamin D deficiency compared with nonwhite individuals [ 2 , 17 ]. Worldwide, many countries report very high prevalences of low vitamin D status. 25(OH)D levels <30 nmol/L (or 12 ng/ml) in >20% of the population are common in India, Tunisia, Pakistan, and Afghanistan. For example, it has been estimated that 490 million individuals are vitamin D deficient in India [ 2 , 17 ].

Specific categories of patients have a very high prevalence of vitamin D deficiency. Often, they are characterized by an insufficiency or failure of organs involved in vitamin D metabolism. Patients with chronic renal failure and on hemodialysis, renal transplant recipients affected with liver disease or after liver transplantation may have a prevalence of vitamin D deficiency ranging from 85 to 99% [ 20 , 21 , 22 ].

Vitamin D deficiency in critical illness

Similarly, critically ill patients have a very high prevalence of vitamin D deficiency, and low vitamin D levels are clearly associated with greater illness severity, morbidity, and mortality in both adult and pediatric intensive care unit (ICU) patients, as well as medical and surgical ICUs [ 23 ]. However, as in most other populations, the most important question remains unanswered: whether low vitamin D is an innocent bystander, simply reflecting greater disease severity, or represents an independent and modifiable risk factor amenable to rapid normalization through loading dose supplementation [ 24 , 25 ].

The question is meaningful, since in this subgroup of patients, many factors contribute to low levels: hemodilution, reduced production and conversion by the liver, reduced synthesis of vitamin D-binding protein, higher consumption during the acute phase of disease and systemic inflammation, and increased tissue demand and enhanced catabolism of metabolites. More data are emerging from basic science about the immediate and late effects of vitamin D supplementation on endocrine, autocrine, and paracrine and genomic targets.

Vitamin D replacement

Metabolites.

It cannot be emphasized enough that various vitamin D metabolites with a very different efficacy, half-life, and risk of toxicity exist. This is discussed in detail in “Vitamin D supplementation: cholecalciferol, calcifediol and calcitriol” by Reinold Vieth et al. in this special issue.

Interval, target level, and dose

For some time, bolus dosing was en vogue because it was thought to be interesting for practical reasons. With the exception of critical care, bolus doses with long dosing intervals are not used. They are no longer recommended because of the higher risk of adverse effects (falls and fractures) associated with them [ 26 ]. Moreover, the 2017 individual patient data meta-analysis by Martineau et al. showed a clear benefit for vitamin D on acute respiratory infection when daily or weekly dosing was used, but not with longer dosing intervals [ 16 ]. In the intensive care, however, a typical daily dose is inefficient, and an upfront loading dose (followed by a daily dose) is necessary to improve vitamin D levels rapidly [ 27 ].

It is also important to note that different dosing regimes may have different effects on clinical outcomes. Because a daily dose leads to stable availability of various vitamin D metabolites, this could be an important explanation for many of the negative vitamin D intervention trials [ 28 ].

To maintain optimal vitamin D status, use of vitamin D supplementation is often required, as sunlight exposure and dietary intake alone is usually insufficient in most individuals [ 29 , 30 , 31 ]. Currently, there is no international consensus on the optimal level for vitamin D supplementation. Recommendations differ in many countries, and range from 400 to 2000 IU daily [ 11 ]. A safe and commonly available dose of 25 μg of vitamin D3 (1000 IU) raises 25-hydroxyvitamin D [25(OH)D] serum level by 15–25 nmol/L on average (over weeks/months) [ 32 , 33 ]; it should be noted that there is a nonlinear response of serum 25(OH)D, with a steeper rise with <1 IU/day of vitamin D, and a more flattened response with >1 IU/day. This is evidenced by several studies in all age groups [ 11 , 34 ].

By using the above-mentioned recommended vitamin D supplementation levels, there is no need to monitor serum or urinary calcium or renal function [ 35 , 36 ]. There is no international consensus on the safe upper level for vitamin D supplementation. While the upper daily limit given by the Endocrine Society is 10,000 IU [ 12 ], the IOM and The European Food and Safety Authority recommend staying below 4000 IU/day (100 µg) [ 37 , 38 ]. Most countries have prudently set the safe upper level at 50 μg daily (2000 IU) for adults [ 35 ]. However, this level was set despite the availability of adequate studies of dose–response relationships or toxicity. There is no convincing evidence that daily intakes of up to 125 μg (5000 IU) elicit severe adverse effects [ 39 ]. It has been reported that an intake of 1250 µg (50,000 IU) once every 2 weeks for several years, equivalent to 89.3 µg (3571 IU) daily, did not cause hypercalcemia or other evidence of hypervitaminosis D [ 40 ]. Small studies showed that even a daily consumption of up to 250 μg (10,000 IU) of vitamin D over long periods did not cause adverse effects in healthy adults [ 32 , 33 ], though some studies revealed a negative impact on bone mineral density by using high-dose vitamin D supplementation of 10,000 IU/day [ 11 ]. Nevertheless, supplementation of >10,000 IU of vitamin D is rarely necessary in clinical practice.

As there is no evidence that increasing the recommended daily dose of vitamin D supplementation up to 50 μg (2000 IU) would cause severe side effects in the general population, and considering that 20 μg (800 IU) is the lowest dose consistently associated with a bone benefit, it seems reasonable to recommend a daily dose of 20–50 μg (800–2000 IU) (levels 2–4 evidence, grades B–D recommendation) [ 39 ]. In general, a daily vitamin D of 800 IU appears to be sufficient to achieve a target 25(OH)D level of at least 50 nmol/L (or 20 ng/mL) in most healthy individuals, whereas 2000 IU is sufficient to achieve a level of at least 75 nmol/L (or 30 ng/mL).

Some data suggest that a higher 25(OH)D level than 50 nmol/L (or 20 ng/mL) may be required for optimal risk reduction for various endpoints [ 41 , 42 , 43 , 44 ].

The use of vitamin D supplementation has increased substantially. Growing awareness of vitamin D in the general population, and over-the-counter vitamin D with partially very high doses, include the risk for uncontrolled use and exogenous hypervitaminosis D, resulting in high concentrations of serum 25(OH)D or free 1,25-dihydroxyvitamin D [1,25(OH) 2 D], leading to hypercalciuria and finally hypercalcemia [ 45 ]. Reports of vitamin D overdose are rare in the literature. Serum 25(OH)D usually exceeds 375 nmol/l (or 150 ng/ml), and factors such as high-calcium intake contribute to the risk of hypercalcemia [ 46 ]. However, there are also endogenous causes of hypervitaminosis D, such as increased production of 1,25(OH) 2 D as part of granulomatous disorders or lymphomas [ 47 ]. Having a long half-life in the tissues, vitamin D accumulation due to excessive intake lasts up to 18 months [ 48 ], and may cause chronic toxic effects such as nephrocalcinosis following hypercalcemia and hypercalciuria [ 47 ].

Since the 1930s, public health officials in the United States and the United Kingdom have recommended routine fortification of foods like milk to prevent vitamin D deficiency and low vitamin D status, which was expected to be an effective public health strategy [ 46 ]. However, there was an increased incidence of hypercalcemia due to massive intakes of vitamin D from various food fortifications. In some cases, hypercalcemia was associated with drinking vitamin D-fortified milk, revealing a fortification of up to 232,565 IU instead of standard 400 IU/quart, and consequently, prohibition of milk fortification [ 49 ]. However, current evidence suggests that vitamin D fortification prevents deficiency safely and effectively [ 50 , 51 ]. Feeding animals might represent an additional source of vitamin D without compromising product quality. For example, consumption of vitamin D-enriched eggs from hens fed with additional vitamin D3 resulted in a zero prevalence <25 nmol/L, while the control group showed an usual seasonal decline in winter with 22% being <25 nmol/L [ 52 ]. The rationale and guidance for systematic vitamin D food fortification, including a call for action, has recently been published by an expert group of vitamin D scientists.

Selected RCTs in recent years

Several very large randomized controlled trials have been or are being performed in recent years. They are summarized in Table 2 [ 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 , 62 , 63 ].

Effect size and basic statistical principles

Though it appears attractive to dismiss any relevant effect of vitamin D on all the conditions that have been studied in those partly very large trials in recent years, it must be considered that often the basic principles for optimal design of a nutrient intervention study were not fulfilled [ 64 ], e.g., measurement of vitamin D at baseline and choosing vitamin D deficiency as an inclusion criterion, using a meaningful intervention able to change vitamin D status, and verification of vitamin D status improvement by repeat measurement.

Moreover, even in the largest trials including thousands of individuals, the sample size was still too small when mostly individuals without vitamin D deficiency and a low baseline risk were included. By modeling future intervention trials, Brenner et al. reported that several hundreds of thousands of participants would be necessary to be able to show an effect on mortality [ 65 ].

On the other hand, even a very small effect may be useful for a substance with such an excellent safety profile and low cost, especially when considering a public health approach. However, to show a small, but meaningful benefit on important outcomes like mortality or infections, very large population samples are needed, but such trials are very costly and will likely be scant.

Important systematic reviews and meta-analyses

The association of vitamin D supplementation on a number of endpoints including mortality has been explored in more detail in the last few years. Selected relevant systematic reviews and meta-analyses are summarized in Table 3 [ 16 , 66 , 67 ].

Selected target organs, conditions, and endpoints

Vitamin D deficiency has been strongly associated with various health outcomes, including all-cause mortality [ 68 ]. A 2014 Cochrane meta-analysis showed a relevant and significant lower all-cause mortality of ~7% and cancer mortality of ~13% in patients who received vitamin D3 [ 69 ]. The results of a meta-analysis by using individual participant data conducted by Gaksch et al., analyzing almost 17,000 individuals, showed a strong association between low 25(OH)D and increased risk of all-cause mortality [ 70 ]. Using a Mendelian randomization with genetic variants in the vitamin D synthesis pathway, the analysis of Aspelund et al. supports a causal relationship between vitamin D deficiency and increased all-cause mortality. However, despite a cohort of >10,000 participants, it was still too underpowered to confirm a causal relationship [ 71 ].

The effect of vitamin D on the lungs has a strong rationale, demonstrated by basic science, due to its immunomodulant, anti-inflammatory, and anti-infective role that has been highlighted in patients with community-acquired infections, acute respiratory failure, as well as in lung transplantation recipients (this is a very specific model for severe infective and inflammatory lung disease) [ 21 ].

Vitamin D supplementation reveals direct anti-inflammatory properties in the lungs. This is due to local inhibition of nuclear factor-κB and mitogen-activated protein kinase activity, reducing the secretion of inflammatory cytokines and chemokines involved in the lung inflammatory process and extravascular leaking, such as interleukin (IL)-1β, IL-6, and IL-8. This, in turn, also influences the number of inflammatory cells infiltrating the interstitial space [ 72 ]. Moreover, 1,25(OH) 2 D is also implicated in the reduction of oxidative stress by inhibiting anti-protease activity, and acting on the nuclear factor erythroid-related factor 2, a transcriptional regulator of most antioxidant genes. Moreover, vitamin D acts with well-known anti-infectious properties by increasing proliferation of monocytes to macrophages (acting as a fine-tuner of the innate and adaptive immunity), and determining a transcriptional upregulation of cathelicidin also in the airway epithelial cells. Finally, 1,25(OH) 2 D inhibits the expression of several metalloproteinases in airway smooth-muscle cells and alveolar macrophages, thus being involved in the tissue remodeling pathway by regulating the process of bronchial airway muscle activation and extracellular matrix deposition by fibroblasts. All these complex pathways, partially modified by vitamin D, warrant supplementation in patients with respiratory disease. Significant benefits have already been shown in adults and children with asthma, and for the prevention of respiratory tract infections, particularly in severe vitamin D deficiency.

Sepsis, a complication of severe infection, is characterized by signs of systemic inflammation expressed with failure of organs often remote from the site of the initial infection. Septic patients have high mortality and lower circulating levels of vitamin D. The interest in vitamin D for infection has risen after the recognition of the expression of the vitamin D receptor, ubiquitous in cells of the innate and adaptive immune system. Vitamin D is an important link between Toll-like receptor activation and antibacterial responses. The in vivo supplementation of a high dose of cholecalciferol (400.000 IU as a single bolus) in the early stage of sepsis and septic shock has been shown able to safely and rapidly increase the level of vitamin D, as well as the circulating level of cathelicidin, a vitamin D-dependent endogenous anti-microbial and endotoxin-binding peptide largely found in human neutrophils [ 73 ]. These findings were corroborated by the significant reduction of IL-1β and IL-6, which play important roles in the early inflammatory response.

Organ transplantation recipients

Several studies have highlighted that lower 25(OH)D levels are associated with prolonged hospitalization and mortality, also in the postsurgical setting. Given its wide immunobiological effects, vitamin D has been frequently considered a potential modulating factor after solid organ (and stem cell) transplantation (mainly liver, kidney, and lung). The transplantation recipient population is particularly prone to infections, mainly in the early stage after transplantation, due to immunomodulation/chronic immunosuppressive therapy and to long-term bone dysfunction. The recipients of solid organ transplantation are, by definition, vitamin D insufficient for manifold reasons, including limited sunlight exposure, limited physical activity, reduced dietary intake of vitamin D in food, as well as liver and kidney dysfunction according to their main disease. As an example, in liver transplantation recipients (a group of patients with very low vitamin D levels), osteoporosis has a high prevalence, with a large decline in bone mineral density in the first year after transplantation. Moreover, a negative association between low vitamin D levels and graft function, as well as a role of vitamin D in reducing the recurrence of hepatitis C virus infection, has been demonstrated. Several interventional trials on vitamin D supplementation in lung and kidney recipients are ongoing under the hypothesis that vitamin D supplementation may contribute to reducing the occurrence of rejection by it immunomodulating action.

In 2019, two Cochrane analyses on vitamin D and pregnancy were published. They suggested that vitamin D supplementation may reduce gestational diabetes, low birthweight, and preeclampsia, but a higher than currently recommended dose appeared to have no additional benefit except for possible further reduction of gestational diabetes [ 74 , 75 ]. However, several studies in recent years have highlighted that women are at high risk for vitamin D deficiency, and this is associated with adverse pregnancy outcomes, including preeclampsia and gestational diabetes [ 76 , 77 , 78 , 79 , 80 ]. It has been demonstrated that vitamin D supplementation is able to reduce adverse pregnancy outcomes when a higher level is achieved, with an increasing efficacy when the target level is raised from 20 to 40 ng/mL or 50 ng/mL. Interestingly, the maximum change is achieved 6–8 weeks after initiating the treatment, likely exerting the genomic actions of vitamin D [ 81 , 82 , 83 ]. Three major adverse pregnancy outcomes appear to improve with vitamin D supplementation: a 60% reduction in preeclampsia, a 50% reduction in gestational diabetes, and a 40% reduction in preterm delivery [ 84 ]. These data are consistent with previous work on the topic [ 82 ]. Moreover, following the genomic and epigenetic effects of vitamin D supplementation, vitamin D deficiency during pregnancy also seems able to induce specific genomic pathways relevant to autoimmune disease in childhood and later in life [ 85 , 86 ]. The placenta can convert 25(OH)D to the active form 1,25(OH) 2 D, similarly to the kidneys; therefore, more basic research should shed light in the future on the specific vitamin D metabolism during pregnancy [ 85 ]. The FDA has recently approved the statement “Pregnant women who have higher serum vitamin D levels have a decreased risk of preterm birth.”

Taking into account the recent literature, vitamin D deficiency is associated with worse outcomes during pregnancy, and at least 400–600 IU of daily vitamin D supplementation is reasonable for women with a vitamin D level <40 ng/mL, with higher required doses in more severe deficiency.

Vitamin D supplementation as a strategy for preventing cancer was considered, as results from several observational studies suggested an association between vitamin D deficiency and risk for several types of cancer [ 87 ]. It was already assumed in 1980 that calcitriol could inhibit the growth of malignant melanoma cells [ 88 ]. Ecologic studies revealed a decreased cancer mortality in areas with greater sun exposure [ 11 ]. Over the decades, vitamin D and its anticancer action was investigated for various malignancies resulting in mixed findings [ 89 ]. Hence, the cancer-protective effect of vitamin D remained unclear. In 2014, two meta-analyses revealed no significant decrease in the incidence of cancer in association with vitamin D supplementation, but a significant reduction in the rate of death from cancer [ 90 , 91 ]. However, as most of the data derive from observational studies, correlation does not imply causation. Investigating cancer incidence following vitamin D plus calcium supplementation, Lappe et al. revealed a non-, but nearly significant (hazard ratio 0.70; 95% CI 0.47–1.02) 30% risk reduction compared with placebo [ 92 ]. A recent large RCT using a daily dose of 2000 IU vitamin D3 conducted by Manson et al. [ 7 ], analyzing the incidence of cancer following vitamin D supplementation in over 25,000 participants, did not reveal a significant reduction neither of invasive cancer of any type nor in the rate of death from any cause. However, subgroup analyses revealed a significant lower cancer incidence in normal-weight individuals. Considering that the study was not adjusted for this comparison, this finding should be considered hypothesis-generating. An ongoing long-term RCT [ 93 ], investigating vitamin D supplementation and the incidence of cancer and precancerous lesions in a high-risk population (overweight adults with prediabetes), will provide further and important data on the causality.

Several studies demonstrated a link between 25(OH)D levels and diabetes, and revealed a higher frequency of vitamin D deficiency in patients with type 1 diabetes mellitus (T1DM) compared with healthy individuals [ 94 , 95 , 96 , 97 ]. Investigating prenatal vitamin D exposure of the fetus, a lower gestational 25(OH)D level [ 98 ] or avoiding vitamin D-fortified food [ 99 ] was significantly associated with higher risk of developing T1DM. In infancy, vitamin D supplementation [ 100 ] or vitamin D-fortified margarine [ 99 ] was shown to reduce the risk of developing type 1 diabetes mellitus. The effect of vitamin D supplementation on T1DM onset seems to be dependent on life stage. Supplementation between 7 and 12 months of age resulted in an almost twofold lower risk of developing T1DM compared with earlier supplementation [ 101 ]. In adolescents, many studies revealed no association between 25(OH)D level and onset of T1DM [ 102 , 103 , 104 ]. However, there is a clear effect of vitamin D in young adults, as low 25(OH)D levels were significantly associated with developing T1DM [ 105 ]. However, according to the available literature, the cause-and-effect relationship is inconclusive. On the other hand, diabetes per se results in physiological changes too, such as increased renal elimination of vitamin D-binding protein compared with healthy individuals [ 106 ]. Therefore, the value of hypovitaminosis D as a trigger for developing T1DM remains unclear. Vitamin D deficiency was also shown to have a negative impact on insulin resistance [ 107 ]. Hence, a higher risk of developing type 2 diabetes mellitus (T2DM) in individuals with low 25(OH)D levels was assumed. However, vitamin D supplementation did overall not result in a lower risk of developing T2DM [ 6 , 108 ]. In the recent D2D study by Pittas et al., vitamin D did not significantly reduce new onset of diabetes, but vitamin D deficiency was no inclusion criterion, and only a minority of included patients had a 25(OH)D level <50 nmol//L (or 20 ng/mL). Moreover, the hypothesized treatment effect used for the sample size calculation was relatively large (hazard ratio 0.75 for the vitamin D group). The actual hazard ratio for vitamin D as compared with placebo was 0.88 (95% confidence interval, 0.75–1.04; P  = 0.12). Interestingly, the effect appeared to be stronger in patients with a BMI <30. However, a post hoc subgroup analysis of individuals with a 25(OH)D level below 12 ng/ml (30 nmol/l) revealed a significantly reduced risk of developing T2DM (hazard ratio 0.38; 95% CI, 0.18–0.80).

Musculoskeletal effects of vitamin D

The detrimental effects of vitamin D deficiency on the musculoskeletal system were the first visible mode of action that was attributed to vitamin D (i.e., rickets in children).

The necessity of an adequate vitamin D status for muscle and bone health is undebated, and therefore not discussed in detail in this review.

Vitamin D intoxication and hypersensitivity

Vitamin D intoxication is rare and usually only occurs at very high supplementation doses [ 109 ]. However, various mutations in vitamin D metabolizing enzymes that may lead to increased sensitivity to standard vitamin D supplementation or even endogenous vitamin D intoxication with hypercalcemia, hypercalciuria, and nephrocalcinosis/chronic renal insufficiency have been described [ 110 ]. Typically, these mutations affect CYP24A1, the enzyme that catabolizes 1,25OHD2 to the inactive metabolite 24,25OHD2. Therefore, a diagnosis can be made by using the ratio of 24,25:25 D and does not necessarily require genetic testing.

This condition has been termed idiopathic infantile hypercalcemia, but due to the greatly varying clinical phenotypes, patients may well become symptomatic only in adulthood. Currently, no causal treatment is available, but avoidance of a high-calcium diet, UV-B exposure, and vitamin D or calcium supplements is advised.

Vitamin D deficiency is highly prevalent, but the literature to support vitamin D supplementation is unsatisfactory to date. Unless major funding sources are used for vitamin D research, it appears sensible to focus on vitamin D-deficient populations with a high event rate. Vitamin D is clearly not a panacea, but may be an important, inexpensive, and safe adjuvant therapy for many diseases and stages of life, including pregnancy, childhood, and old age. Public health efforts to prevent severe vitamin D deficiency should therefore be further promoted.

In the critically ill setting, one large vitamin D supplementation trial has recently been published (VIOLET [ 111 ]) and one is still ongoing (NCT03096314 and NCT03188796). VIOLET randomized patients with 25(OH)D levels below 50 nmol/L (or 20 ng/ml) “at risk for ARDS” to one single high dose of vitamin D3 (540,000 IU), and evaluated its effect on the primary outcome: 90-day mortality. It was prematurely stopped in mid-2018 after inclusion of ca. One-third of the patients originally planned, and no differences in mortality and secondary endpoints have been reported, with no differences in subgroup analyses and safety endpoints [ 111 ].

VITDALIZE is a European multicenter RCT, including severely vitamin D-deficient ICU patients with a 25 OH D level <30 nmol/L (or 12 ng/ml), and randomizes patients to a loading dose of oral/enteral vitamin D3 (540,000 IU) followed by 4000 IU daily for 90 days, with the primary outcome being 28-day mortality. Recruitment is ongoing in Austria and Belgium, should be expanded to other European countries in 2020, and will likely continue for a few more years.

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Department of Internal Medicine, Division of Endocrinology and Diabetology, Medical University of Graz, Graz, Austria

Karin Amrein, Mario Scherkl, Magdalena Hoffmann, Stefan Pilz & Oliver Malle

Thyroid Endocrinology Osteoporosis Institute Dobnig, Graz, Austria

Karin Amrein

Executive Department for Quality and Risk Management, University Hospital Graz, Graz, Austria

Magdalena Hoffmann

Research Unit for Safety in Health, Division of Plastic, Aesthetic and Reconstructive Surgery, Department of Surgery, Medical University of Graz, Graz, Austria

Department of Anaesthesiology and Intensive Care Medicine, Klinikum Klagenfurt am Wörthersee, Klagenfurt am Wörthersee, Austria

Stefan Neuwersch-Sommeregger & Markus Köstenberger

Immunology and Pathophysiology, Otto Loewi Research Center, Medical University of Graz, Heinrichstrasse 31a, A-8010, Graz, Austria

Department of Psychiatry and Psychotherapeutic Medicine, Medical University of Graz, Graz, Austria

Adelina Tmava Berisha

Department of Anesthesia and Intensive Care, IRCCS-ISMETT (Istituto Mediterraneo per i Trapianti e Terapie ad Alta Specializzazione), Palermo, Italy

Gennaro Martucci

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Amrein, K., Scherkl, M., Hoffmann, M. et al. Vitamin D deficiency 2.0: an update on the current status worldwide. Eur J Clin Nutr 74 , 1498–1513 (2020). https://doi.org/10.1038/s41430-020-0558-y

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Received : 06 October 2019

Revised : 17 December 2019

Accepted : 06 January 2020

Published : 20 January 2020

Issue Date : November 2020

DOI : https://doi.org/10.1038/s41430-020-0558-y

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Preventive vitamin d supplementation and risk for covid-19 infection: a systematic review and meta-analysis.

1. Introduction

2. materials and methods, 2.1. data sources and search strategy, 2.2. selection of studies, 2.3. data extraction and risk of bias assessment, 2.4. statistical analysis, 3.1. evidence from rcts on covid-19 infection risk, 3.2. evidence from analytic studies on covid-19 infection risk, 3.3. evidence from rcts and analytical studies on sars-cov-2-related mortality, 3.4. evidence from analytical studies on icu admissions, 4. discussion, 5. conclusions, author contributions, institutional review board statement, informed consent statement, data availability statement, conflicts of interest, abbreviations.

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Share and Cite

Sartini, M.; Del Puente, F.; Oliva, M.; Carbone, A.; Bobbio, N.; Schinca, E.; Giribone, L.; Cristina, M.L. Preventive Vitamin D Supplementation and Risk for COVID-19 Infection: A Systematic Review and Meta-Analysis. Nutrients 2024 , 16 , 679. https://doi.org/10.3390/nu16050679

Sartini M, Del Puente F, Oliva M, Carbone A, Bobbio N, Schinca E, Giribone L, Cristina ML. Preventive Vitamin D Supplementation and Risk for COVID-19 Infection: A Systematic Review and Meta-Analysis. Nutrients . 2024; 16(5):679. https://doi.org/10.3390/nu16050679

Sartini, Marina, Filippo Del Puente, Martino Oliva, Alessio Carbone, Nicoletta Bobbio, Elisa Schinca, Luana Giribone, and Maria Luisa Cristina. 2024. "Preventive Vitamin D Supplementation and Risk for COVID-19 Infection: A Systematic Review and Meta-Analysis" Nutrients 16, no. 5: 679. https://doi.org/10.3390/nu16050679

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Vitamin D and Calcium Supplementation Essay

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Vitamin D and Calcium

Literature review, methodology.

The associated with vitamin D and calcium publications are primarily based on their respective supplements’ health effects. They have clarified an interesting scenario regarding the consumption of these elements. The landscape of vitamin D and Ca can be observed across different populations. To test the prevalence of vitamin D and Ca deficiency, similarities, and differences, alongside their health benefits, a cross-sectional study was deliberated in Sharjah, United Arab Emirates. The research established that these elements are synergistic and integral for immunological functions, including the formation of healthy teeth. However, they displayed characteristic physiological differences. Sources and resources used in the study were obtained from internet sources. Sites like Google Books, Google Scholar, and EBSCOhost were used to acquire possible research information. Intending to seek facts and evidence surrounding the health benefits of Ca and vitamin D, the research established research gaps like the high prevalence of vitamin D and Ca deficiencies among the study group regardless of the increasing literacy and education levels.

Introduction

There have been numerous publications associated with the various aspects of vitamin D and calcium. The studies primarily focus on the physiological and therapeutic aspects of the micronutrient. The florid scientific literature does not eliminate the uncertainty on numerous issues. For example, there is no consensus on the importance of vitamin D and calcium in people’s health and well-being. Endless debates have been highlighted, including the standard means of measuring the 25-hydroxyvitamin D (25(OH) D), precursors, and metabolites. Excessive calcium absorption could lead to nephrolithiasis and nephrocalcinosis 1 . The other debate is associated with hypovitaminosis in the general population concerning a specific clinical condition such as pregnancy and health condition. The research will focus on vitamin D and calcium issues concerning the modalities used to ensure sufficiency and health benefits. The target group will be the United Arab Emirates population that has faced significant health issues associated with the nutrients.

Roles of Vitamin D in the Body

Vitamin D is essential for physiology and anatomy. First, vitamin D is preventing rickets’ development. The formation of healthy bones is dependent on this element’s presence, but it is also influenced by calcium. Vitamin D enhances dietary calcium intake, a mineral integral to the formation of such bust bones. Secondly, it promotes the physiology of parathyroid glands. Because they balance calcium levels via the kidney, vitamin D is directly involved in homeostasis maintenance 2 . Calcium and/or vitamin D insufficiency condition parathyroid glands to break down bones to obtain calcium or vitamin D.

Functions of Ca

While 99% of it is located in teeth, bones, calcium is also found in body fluids, blood, tissues, and nerve cells. The intake of calcium helps with the coagulation, healthy forming of bones, sending and reception of nerve signals, squeezing and relaxing muscle cells, releasing hormones and other chemicals essential for body functioning, and maintaining a regular heartbeat. After a human being stops growing, calcium is vital to maintaining the bone structure. The mineral is also crucial in ensuring that the bone density growth is minimal. Noteworthy, diminishing bone density is a natural part experienced in the aging process. The mineral is also essential in the cardiovascular system because it is one of the agents supporting blood clotting. Some studies have correlated much calcium intake with a low prevalence of high blood pressure 3 . The rationale behind the indication is that calcium is responsible for relaxing the muscles surrounding blood vessels.

Effects of Vitamin D and Ca Deficiency in the Body

Poor immunity, allergic responses, and enhanced weight loss.

Their physiological functions inform the effects of Vitamin D-Calcium deficiencies. First, Vitamin D promotes immunity and is expressed on immunologic cells such as B and T cells and antigen. Secondly, Vitamin D can help prevent various infectious diseases; therefore, it can improve current global public health associated with the COVID-19 pandemic 4 . Calcium is required for activating the immune system when it enters immune cells, especially those involved in allergic responses. In lymphocytes, calcium ions act as intermediaries that trigger lymphocytes’ actions. Vitamin D and calcium combination enhances calcium absorption, hence a necessity among obese individuals because of enhanced weight loss. Current evidence on vitamin D and calcium combination also cite helping with the weight loss. The latter indirectly reduces comorbidities like hypertension or diabetes. Therefore, vitamin D and calcium deficiency leads to low immune and allergic responses. The rationale of this argument regards the pivotal roles they play in enhancing immunity and allergic reactions.

Diseases like Osteoporosis and Poor Related Physiological Functions

Vitamin D and calcium are equally integral to the formation of healthy bones and teeth, and this vitamin insufficiency leads to poor Ca absorption. Because both of these elements are similarly essential, in case of deficiency, bones will be degraded, as well as physiological functions like the formation of bone marrow and immune cells.

Gaps in Existing Literature

The following are some of the gaps in the literature;

• High rates of supplement ignorance across the sample population
• Even though the global community is becoming more literate, vitamin D and calcium deficiencies are equally increasing. The scene is quite surprising because increasing literacy across the global population should inform the appreciation of vitamin D and calcium supplements.
• Medical professionals’ response and roles in addressing or stressing the importance and benefits of supplements across the study group of the global population.
• Vitamin D and calcium interplay and their concomitant/synergistic roles in facilitating human health and well-being.
• The increasing vitamin D and calcium deficiency despite increasing literacy across the global population.

Aims of the Paper

The primary aim of this paper is to clear the debate surrounding vitamin D and calcium supplements. The discussion covers the prevalence of vitamin D and calcium deficiency in the UAE. The discussion is based on a practical approach via a cross-sectional study in Sharjah to display vitamin D and calcium prevalence, alongside the specimen’s health effects.

Research Design

A cross-sectional research design was used to study the specimen, n=480, in Sharjah. They were randomly selected from Sharjah’s population. The study grouped aged between 5 to 79 years. The actual research was conducted at the American University of Sharjah, UAE 5 . Ethical values and competence are crucial elements in such studies. A mixed methodology was used in the survey to acquire qualitative and quantitative data about the topic. Qualitative and quantitative data is necessary to account for a given phenomenon according to the figures captured among the participants 6 . An open-ended questionnaire was administered to the patients to obtain data on their condition. They elaborated on their health based on vitamin D deficiency. A survey was also conducted across Sharjah’s medical facilities to establish the trends and patterns of consumption of drugs concerning vitamin D deficiency and calcium-related complications. The survey stretched to the business sector to obtain statistical data and qualitative comments from supplement dealers. The study majorly discovered demographic information on the prevalence of vitamin D deficiency, their dietary practices, exposure to the sun, immunity, and comorbidities related to low immunity. The data captured the specific figure of Sharjah’s vitamin D deficient individuals. The latter was also tied to calcium-related health issues like osteoporosis, low immunity, and weak teeth.

A demonstration of the research and search phrases are highlighted in Fig. 1. The process involved searching through databases to identify critical literature. Some of these databases and research browse include ‘EBSCOhost,’ ‘Google Books,’ ‘Science Direct,’ and ‘Google Scholar.’ However, the search was run using essential words and phrases relevant to the research topic. These are ‘vitamin D,’ ‘calcium mineral,’ ‘Hypovitaminosis D,’ ‘Osteomalacia,’ ‘Osteoporosis,’ ‘Calcium,’ and ‘Vitamin.’ Age and relevance filters were further used to qualify or discredit material found using this technique. For instance, papers were only considered if published after 2015 to increase data relevance and accuracy. Twelve articles were eventually considered after critical evaluation for relevance to the study.

Research Agents Used and the Wording Employed to Acquire the Sources

The following flow chart shows research agents and wording used to acquire data in the research;

The Prevalence of Vitamin D and Calcium Deficiency in UAE

UAE’s vitamin D deficiency victims rangers between 50% to 90% of the total population who suffer from osteoporosis 7 8 .The study found that at least 90% of the participants were suffering from vitamin D deficiency. The conclusion that 90% of the population experienced vitamin D deficiency was drawn from the results’ multidimensional elements. The most prevalent aspect of vitamin D deficiency across the specimen were fatigue, painful bones, and muscle weaknesses. Both young and elderly participants complained about the complications mentioned above. They were registered to have consumed painkillers and medicines addressing bone-related disorders. The medical practitioners and clinicians in the medical facilities commented on the same by asserting the vitamin D deficiency resulted in those conditions due to low calcium absorption. Data collected from medical facilities and supplement dealers indicated low supplement consumption. While 92% of supplement dealers cited caution among Sharjah’s residents on safety issues surrounding the supplements, medical facilities stressed that UAE residents would never consume supplements whatsoever. The study group indicated an attitude and negative perception of the supplements based on perceived adverse effects and health implications conferred by supplements. Participants also stated that they were not exposed to the sun.

Nutritional entries often fail to emphasize the importance of calcium as a singular mineral in the human body. Most studies are quick to divert from this topic after highlighting the essential role of vitamin D and calcium deficiency instances. Nimri notes that “Vitamin D deficiency is most often associated with inadequate calcium intakes and causes bone degeneration or osteoporosis” 9 .Therefore, Ca deficiency cases are overshadowed by vitamin D deficiency issues, making it difficult to locate information for this statistic alone. However, Nimri explains the decrease in Ca intake among youth by the popularity of carbonated drinks over healthier choices like milk. Therefore, cases of vitamin D are a manifestation of Ca deficiencies that contributes to weak bones.

The Prevalence of the Usage of Vitamin D and Calcium Supplements

While 70% of the study group were unaware of the importance of sun exposure in acquiring vitamin D, 30% were unconcerned with exposure to the sun. 60% of the study group indicated that they never consume foods rich in vitamin D like fish liver oils and fatty fish like tuna, salmon, mackerel, and trout. Laboratory tests on calcium deficiency were tied to vitamin D deficiency. Individuals composing 90% of participants found with vitamin D deficiency were found with calcium deficiency. The figure indicated a direct relationship between vitamin D deficiency and calcium deficiency. 20% of the affected population was subjected to treatment to test the parathyroid organs’ effectiveness and roles.

The Medical Effects of the Supplements

Medical effects of ca supplements.

• Constipation
• Prevention against osteoporosis by inhibiting osteopenia
• Formation of strong teeth and bones
• Weight loss
• Regulation of phosphorus, magnesium, and potassium in the blood

Medical Effects of Vitamin D Supplements

• High calcium absorption
• Regulates phosphorus and calcium absorption
• Boosting immunity and preventing depression
• Promoting weight loss

Similarities Between Vitamin D and Calcium

• Maintaining homeostasis of the skeletal system.
• Formation of strong bones and teeth
• A healthy skeletal system produces vibrant blood cells.
• White blood cells are integral to fighting diseases.
• Hypertension
• Musculoskeletal diseases 10
• The two elements need and/or rely on each other to deliberate their functions
• They can be supplied by diet and supplements.

Differences Between Vitamin D and Calcium

Vitamin D and calcium differences regard physiological elements and sources. While vitamin D is freely and naturally available from the sun and enhances Ca absorption, the final is integral for forming healthy teeth and bones. Unlike vitamin D, Ca not be obtained freely from the sun. It can be obtained from diet and supplements.

Al Kattub (2017) argues that vitamin D deficiency predisposes individuals to heart disease, kidney disease, hypertension, liver disease, and disease 11 . The argument encapsulates a multidimensional element on the subject because of Vitamin D and Calcium interaction and immunity development roles. Further, organ failure is another contributing factor to the conditions mentioned above. Vitamin D is needed to facilitate calcium absorption from dietary foodstuffs, and calcium is required in order to form a robust immune system. Therefore, individuals suffering from vitamin D deficiency will undoubtedly suffer from calcium deficiency and equally low immunity. Sharjah’s studied population is a classic reflection and illustration of the perspective issued above. The community stressed that they hardly consume vitamin D rich foods mentioned earlier and are do not bask in the sun. The sun is a free source of vitamin D. Therefore, they are not immune to the health complications and developmental problems associated with vitamin D and calcium deficiency.

Vitamin D and calcium is found to be an element among the study population. With the laboratory tests revealing abnormally minimal metabolites and precursors of 25-hydroxyvitamin D and the participants’ confession of minimal and/or no consumption of vitamin D rich foods, the conclusion that the debate surrounds negligence and negative perception of supplements is inevitable. 90% of the specimen would have been saved via supplement consumption. However, the negative perception of supplements prevented their consumption and informed unsatisfactory purchases from dealers. Medical and health issues found among the participants are an image of caution and safety issues posited regardless of whether they are relevant. Arguably, the safety issues and concerns are somewhat blown out of proportion because the supplements pass quality tests and safety measures and guidelines established to guide their manufacturing and production.

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Ferretti, M., Cavani, F., Roli, L., Checchi, M., Magarò, M. S., Bertacchini, J., & Palumbo, C. (2019). Interaction among Calcium Diet Content, PTH (1-34) Treatment and Balance of Bone Homeostasis in Rat Model: The Trabecular Bone as Keystone. International Journal of Molecular Sciences, 20 (3). Web.

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Palacios, C., & Gonzalez, L. (2014). Is vitamin D deficiency a major global public health problem?. The Journal of steroid biochemistry and molecular biology , 144 , 138-145.

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Shakoor, H., Feehan, J., Al Dhaheri, A. S., Ali, H. I., Platat, C., Ismail, L. C.,… & Stojanovska, L. (2020). Immune-boosting role of vitamins D, C, E, zinc, selenium and omega-3 fatty acids: could they help against COVID-19?. Maturitas .

• Liu, M., Yao, X., & Zhu, Z. (2019). Associations between serum calcium, 25(OH)D level, and bone mineral density in older adults. Journal of Orthopaedic Surgery and Research, 14 , 1-7. Web.
• Ferretti, M., Cavani, F., Roli, L., Checchi, M., Magarò, M. S., Bertacchini, J., & Palumbo, C. (2019). Interaction among Calcium Diet Content, PTH (1-34) Treatment and Balance of Bone Homeostasis in Rat Model: The Trabecular Bone as Keystone. International Journal of Molecular Sciences, 20 (3) Web.
• Shakoor, H., Feehan, J., Al Dhaheri, A. S., Ali, H. I., Platat, C., Ismail, L. C.,… & Stojanovska, L. (2020). Immune-boosting role of vitamins D, C, E, zinc, selenium, and omega-3 fatty acids: could they help against COVID-19. Maturitas .
• Palacios, C., & Gonzalez, L. (2014). Is vitamin D deficiency a significant global public health problem? The Journal of steroid biochemistry and molecular biology , 144 , 138-145.
• Nimri, L. F. (2018). Vitamin D status of female UAE college students and associated risk factors, e284.
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IvyPanda. (2022, February 25). Vitamin D and Calcium Supplementation. https://ivypanda.com/essays/vitamin-d-and-calcium-supplementation/

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IvyPanda . 2022. "Vitamin D and Calcium Supplementation." February 25, 2022. https://ivypanda.com/essays/vitamin-d-and-calcium-supplementation/.

1. IvyPanda . "Vitamin D and Calcium Supplementation." February 25, 2022. https://ivypanda.com/essays/vitamin-d-and-calcium-supplementation/.

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