Vitamin D: Status, Testing and Clinical Relevance

Few nutrients have ridden such a wave of enthusiasm as vitamin D. Over 2 decades, observational studies linked low vitamin D levels to almost every chronic disease, testing rates rose steeply in many countries, and supplementation became routine for millions of people. Then the large randomised trials reported, and the picture became considerably more complicated. Practitioners now need to hold 2 truths at once: vitamin D deficiency is real and important, and vitamin D supplementation is not the broad preventive tool it was once hoped to be.

How vitamin D works

Vitamin D is unusual among vitamins because the body can make it. Ultraviolet B radiation in sunlight converts a precursor in the skin into vitamin D3. Smaller amounts come from food, including oily fish, egg yolk, fortified foods and, as vitamin D2, some mushrooms. Vitamin D is converted in the liver to 25 hydroxyvitamin D, the main circulating form and the one measured in blood tests, and then in the kidney and other tissues to 1,25 dihydroxyvitamin D, the active hormone.

The active form increases intestinal absorption of calcium and phosphate, works with parathyroid hormone to regulate blood calcium, and supports bone mineralisation. Vitamin D receptors are present in many tissues, including immune cells, muscle and the pancreas, which is part of why its role beyond bone attracted so much research.

Who is at risk of deficiency

• People with little sun exposure: those who are housebound, live in care homes, work indoors or cover most of their skin
• People with darker skin living at higher latitudes, since melanin reduces vitamin D production
• People living far from the equator during winter months, when UVB is insufficient for synthesis
• Older adults, whose skin produces less vitamin D
• People with obesity, in whom vitamin D is sequestered in fat tissue
• People with malabsorption, including coeliac disease, inflammatory bowel disease and after bariatric surgery
• People with chronic kidney or liver disease
• People taking some medicines, including certain antiepileptics and glucocorticoids
• Exclusively breastfed infants without supplementation

The threshold debate

There is no universal agreement on what level of 25 hydroxyvitamin D represents sufficiency, and practitioners will encounter conflicting numbers.

To convert between units, 1 ng/mL equals about 2.5 nmol/L. Laboratories and countries differ in which units they report, which is a common source of confusion.

In 2024, the Endocrine Society published a guideline on vitamin D for disease prevention that moved away from defining target levels for the general population. It recommended against routine testing of 25 hydroxyvitamin D in healthy people and suggested empiric supplementation for specific groups, including children and adolescents, adults over 75, pregnant people and adults with high risk prediabetes.

What the large trials found

Cancer and cardiovascular disease. The VITAL trial gave 2000 IU of vitamin D3 daily or placebo to more than 25,000 adults in the United States for about 5 years and found no reduction in the incidence of cancer or major cardiovascular events. Secondary analyses suggested a possible reduction in cancer deaths, which has been seen in some meta analyses and remains under investigation. The D Health trial in Australia, using monthly doses in older adults, found no reduction in mortality.

Fractures and falls. In people not selected for deficiency, vitamin D alone has generally not reduced fractures. Combined vitamin D and calcium may reduce fractures in some high risk groups, such as older people in institutional care. Notably, a trial giving a very high annual dose of vitamin D to older women increased the risk of falls and fractures, a reminder that large intermittent doses can be harmful.

Autoimmune disease. An ancillary analysis of VITAL reported fewer confirmed autoimmune disease diagnoses in the vitamin D group over the study period, an intriguing finding that requires confirmation.

Respiratory infections. Meta analyses have suggested a small protective effect of daily or weekly vitamin D against acute respiratory infections, particularly in people with low baseline levels; findings have varied between analyses.

The overall lesson is that the strong associations between low vitamin D and disease seen in observational studies are only partly causal. Low vitamin D is, in part, a marker of poor health, indoor lifestyles, obesity and chronic illness, rather than always their cause.

When to test

Testing is most useful when a result will change management:

• suspected osteomalacia or rickets, such as bone pain, proximal muscle weakness or raised alkaline phosphatase;
• osteoporosis or fragility fractures;
• malabsorption, bariatric surgery, chronic kidney or liver disease;
• medicines that affect vitamin D metabolism;
• abnormal calcium, phosphate or parathyroid hormone levels.

For people at risk who are likely to be low, simply recommending a standard supplement is often more practical than testing.

Supplementing sensibly

• Daily or weekly dosing is preferred to large intermittent boluses.
• Maintenance doses recommended for adults in many countries are in the range of 400 to 800 IU a day, with higher doses sometimes used for older adults or people at risk. Treatment doses for confirmed deficiency are higher and time limited, followed by maintenance.
• Vitamin D3 generally raises levels more effectively than D2.
• Calcium intake should be adequate, preferably from food, particularly where bone health is the concern.
• Toxicity is uncommon but occurs with very high doses taken over time, causing hypercalcaemia, kidney stones and kidney injury. Patients taking several products may unknowingly exceed safe intakes.
• Caution is needed in conditions that increase sensitivity to vitamin D, such as sarcoidosis and some other granulomatous diseases, and in people with a history of kidney stones or hypercalcaemia.

An illustrative case

A 46 year old woman with fatigue brings a 25 hydroxyvitamin D result of 48 nmol/L from an online test, labelled “insufficient”, and asks whether low vitamin D explains her tiredness. She has also started taking 10,000 IU a day on the advice of a website.

The practitioner explains that her level is close to what many bodies consider sufficient for bone health, and that trials have not shown vitamin D supplementation relieves fatigue in people who are not clearly deficient. The high dose is reduced to a standard maintenance dose given her limited sun exposure. Her fatigue is investigated in its own right: her ferritin is low and her sleep is poor. Treating the iron deficiency and improving her sleep address the actual causes. Vitamin D was a reasonable thing to consider, but not the explanation.

A balanced view

Vitamin D matters. Deficiency causes real disease, and people at risk should be identified and supplemented. But it is not a remedy for every chronic condition, higher is not always better, and routine testing of healthy people often creates more uncertainty than it resolves. The evidence now supports a targeted, measured approach.