Vitamin D: Hype vs. Reality — What the Science Really Tells Us

Vitamin D production can begin in the skin.

The skin naturally contains 7-dehydrocholesterol, a cholesterol-derived molecule.

When ultraviolet B (UVB) radiation from sunlight reaches the skin, it converts 7-dehydrocholesterol into previtamin D3.

Previtamin D3 then undergoes a temperature-dependent rearrangement to become:
Vitamin D3, also called cholecalciferol. (same form D3 oral supplementation)

This is an important distinction.

Vitamin D3 is not the active vitamin D hormone.

It is a precursor that must undergo additional processing before becoming biologically active.

Therefore, two people spending similar amounts of time outdoors may not necessarily produce identical amounts of vitamin D3.

Vitamin D3 can also enter the body through food or supplementation.

Most commonly used vitamin D supplements contain cholecalciferol—the same vitamin D3 molecule produced following UVB exposure to the skin.

Another supplemental form, vitamin D2 or ergocalciferol, can also increase vitamin D status, although vitamin D3 generally produces a more sustained increase in circulating 25-hydroxyvitamin D.

Once absorbed through the gastrointestinal tract, supplemental vitamin D3 enters essentially the same metabolic pathway as vitamin D3 produced in the skin.

But swallowing vitamin D3 does not mean that the body has immediately received the active vitamin D hormone.

It has received the precursor.

That precursor still needs to be processed.

Vitamin D3 travels through the circulation to the liver, largely transported by vitamin D-binding protein.

In the liver, vitamin D3 undergoes hydroxylation, primarily involving the enzyme CYP2R1.

This produces:
25-hydroxyvitamin D [25(OH)D], also called calcidiol.

This is the major circulating form of vitamin D.

It is also the form generally measured when your physician orders a “vitamin D level.”

This distinction becomes very important when interpreting vitamin D research.

A supplement provides vitamin D3.

A conventional vitamin D blood test measures 25(OH)D.

Those are different molecules at different stages of the pathway.

Yes.

Because the liver participates in converting vitamin D3 into 25(OH)D, significant liver dysfunction can interfere with normal vitamin D metabolism.

However, mild liver abnormalities do not necessarily prevent vitamin D activation. Clinically meaningful impairment of this conversion is more commonly associated with substantial liver disease.

Vitamin D status may also be affected by conditions that impair gastrointestinal absorption before vitamin D ever reaches the liver.

These can include certain disorders affecting intestinal or pancreatic function and other causes of fat malabsorption.

This is another important distinction.

Taking more vitamin D3 provides the body with additional precursor.

It does not necessarily guarantee a proportional increase in active calcitriol.

This means the relationship between vitamin D3 intake, serum 25(OH)D, and active 1,25(OH)₂D is not simply linear.

Kidney disease provides a particularly important example.

As chronic kidney disease progresses, the kidneys may become less capable of converting 25(OH)D into calcitriol.

Changes in phosphate metabolism and increasing FGF23 can further suppress renal calcitriol production.

Therefore, a patient may have available 25(OH)D while still having impaired production of circulating active vitamin D hormone.

Likewise, significant liver dysfunction can interfere with the conversion of vitamin D3 into 25(OH)D before the vitamin D ever reaches the kidney activation step.

The kidneys are the principal source of circulating calcitriol, but they are not the only tissues capable of activating vitamin D.

Several other cell types express CYP27B1 and can convert 25(OH)D into calcitriol locally.

This local activation is particularly interesting because it may allow individual tissues to regulate vitamin D signaling for their own cellular functions.

This raises an obvious question.

If calcitriol is the active hormone, why don’t we simply measure it instead of 25-hydroxyvitamin D?

Because circulating calcitriol is tightly regulated and does not reliably reflect the body’s vitamin D reserves or nutritional vitamin D status.

In fact, during vitamin D deficiency, calcitriol can remain normal or even become elevated.

As calcium absorption decreases, parathyroid hormone may increase.

PTH then stimulates renal 1-alpha-hydroxylase, increasing conversion of available 25(OH)D into calcitriol.

Therefore, someone can have significant vitamin D deficiency while maintaining a seemingly normal active vitamin D concentration.

For this reason, 25-hydroxyvitamin D is generally the preferred laboratory measurement for evaluating vitamin D status.

Measurement of 1,25-dihydroxyvitamin D is usually reserved for specific clinical situations involving abnormal calcium metabolism, kidney disease, granulomatous disorders, or abnormalities of vitamin D activation.

Suppose a clinical trial finds that 10,000 IU daily is associated with an adverse outcome.

It would be inappropriate to automatically conclude that a serum concentration of 60 ng/mL causes that outcome unless the achieved concentrations and their relationship with the outcome were specifically analyzed.

The reverse is also true.

If 2,000 IU daily reduces autoimmune disease incidence, that does not prove that 2,000 IU is the universally optimal dose.

Different participants may achieve very different serum concentrations from the same intervention.

However, achieved-concentration studies have limitations too.

Participants who naturally achieve higher vitamin D concentrations may differ in body composition, health status, outdoor activity, diet, genetics, or other factors that independently influence disease risk.

One of the most important investigations into vitamin D and mortality was published in Annals of Internal Medicine in 2022.

Researchers analyzed approximately 307,600 UK Biobank participants, including roughly 18,700 deaths during follow-up.

The researchers used nonlinear Mendelian randomization, using genetic variants associated with vitamin D concentrations to investigate whether low vitamin D may contribute causally to mortality rather than simply being associated with poorer health.

The relationship was nonlinear.

Mortality risk increased substantially at lower vitamin D concentrations.

The association was particularly pronounced below approximately:
50 nmol/L—or 20 ng/mL.

These findings provide evidence supporting the importance of avoiding significant vitamin D deficiency.

But they do not demonstrate that mortality continues declining as concentrations increase from 30 to 50 to 70 to 100 ng/mL.

This distinction is critical.

Evidence that low vitamin D is harmful is not automatically evidence that progressively higher vitamin D is progressively better.

Some of the research supporting higher vitamin D concentrations comes from cancer epidemiology.

A particularly interesting 2018 analysis evaluated more than 5,000 women aged 55 and older.

Women with serum 25-hydroxyvitamin D concentrations of at least:
60 ng/mL
had approximately 80% lower observed breast cancer risk compared with women whose concentrations were below 20 ng/mL.

The adjusted hazard ratio was approximately 0.20.

That is a striking association and deserves attention.

Importantly, researchers examined measured vitamin D concentrations rather than simply supplement doses.

However, there were only 77 breast cancer cases, and participants were not randomized to maintain particular vitamin D concentrations.

Therefore, the study cannot establish that increasing someone’s vitamin D from 35 to 65 ng/mL will reduce her breast cancer risk by 80%.

Large randomized supplementation trials have also failed to demonstrate major reductions in overall cancer incidence.

The VITAL trial, involving more than 25,000 adults, did not demonstrate a statistically significant reduction in invasive cancer incidence with 2,000 IU vitamin D3 daily. Again, a study based on dose and not actual blood values.

Some secondary analyses and meta-analyses have suggested possible reductions in cancer mortality, but this remains an area of continuing investigation.

Hashimoto’s thyroiditis is an autoimmune condition in which the immune system targets thyroid tissue.

A 2023 systematic review and meta-analysis of randomized trials involving more than 800 participants found that vitamin D supplementation was associated with reductions in:

• Thyroid peroxidase antibodies
• Thyroglobulin antibodies

Some thyroid function measurements also improved.

However, reduced antibody concentrations do not necessarily establish improvements in symptoms, long-term thyroid function, or medication requirements.

Vitamin D may influence autoimmune thyroid activity, but the clinical significance remains incompletely defined.

A randomized substudy of VITAL evaluated vitamin D supplementation and leukocyte telomere length.

Participants received 2,000 IU vitamin D3 daily or placebo.

Telomere length was measured at baseline, two years, and four years.

Vitamin D supplementation was associated with approximately:
140 base pairs less telomere shortening over four years.

This is particularly interesting because it suggests vitamin D may influence a biological process associated with cellular aging.

However, the study does not establish that vitamin D slows whole-body aging, improves healthspan, or extends lifespan.

It also does not tell us whether achieving 60 ng/mL provides greater telomere protection than achieving 30 or 40 ng/mL.

Vitamin D has one of its strongest epidemiological relationships with multiple sclerosis.

Higher vitamin D concentrations have repeatedly been associated with lower MS risk.

Some research suggests that concentrations above approximately 40 ng/mL are associated with substantially lower disease risk.

Vitamin D’s immunoregulatory activity provides biological plausibility for this relationship.

However, observational association does not establish that increasing vitamin D prevents MS.

Trials investigating vitamin D supplementation in patients with established multiple sclerosis have produced mixed results.

The evidence supports continued investigation but does not establish 60–100 ng/mL as a proven therapeutic target.

Vitamin D does not function in isolation.

Magnesium participates in numerous enzymatic processes involved in vitamin D metabolism.

A randomized trial published in the American Journal of Clinical Nutrition demonstrated that magnesium supplementation influenced vitamin D metabolism differently depending on participants’ baseline vitamin D status.

Interestingly, magnesium did not simply raise vitamin D concentrations in everyone.

Its effects depended partly on the individual’s starting physiology.

This reinforces a broader theme:
Nutrient physiology is rarely as simple as adding more of a single nutrient.

Correcting magnesium deficiency may be important when present.

However, this does not mean everyone taking vitamin D requires magnesium supplementation.

Vitamin K2 is also sometimes claimed to improve the absorption or increase the blood concentration of vitamin D3.

At present, there is not strong clinical evidence demonstrating that K2 directly increases gastrointestinal absorption of vitamin D3 or reliably raises serum 25-hydroxyvitamin D concentrations.

Clinically, however, I have observed some patients achieve higher 25-hydroxyvitamin D concentrations after changing from vitamin D3 alone to a D3/K2 combination despite otherwise similar supplementation.

That observation is interesting, but it should be recognized for what it is: a clinical observation rather than established evidence of improved vitamin D absorption.

There could also be other explanations, including differences in supplement formulation, absorption, adherence, dietary intake, seasonal sun exposure, or normal biological variability.

For now, the stronger scientific rationale for combining vitamin D3 and K2 involves their complementary roles in calcium and bone metabolism, rather than evidence that K2 directly improves vitamin D3 absorption.

As with vitamin D itself, this is an area where biological plausibility and clinical experience continue to generate questions that have not yet been fully answered by clinical trials.

Vitamin D receptors are present in tissues involved in glucose metabolism.

Researchers have investigated possible relationships involving:

• Insulin secretion
• Insulin sensitivity
• Inflammation
• Type 2 diabetes

Observational studies frequently identify lower vitamin D concentrations in people with obesity, insulin resistance, and diabetes.

However, obesity itself influences vitamin D distribution and circulating concentrations.

Therefore, low vitamin D does not necessarily cause obesity or insulin resistance.

The D2d randomized trial evaluated 4,000 IU vitamin D daily in adults with prediabetes.

The primary analysis did not demonstrate a statistically significant reduction in progression to diabetes.

Subsequent pooled analyses suggest vitamin D may modestly reduce diabetes progression in selected individuals with prediabetes.

Vitamin D may therefore play a supporting role in metabolic health, but it is not a substitute for exercise, nutrition, appropriate weight management, and other established interventions.

Vitamin D’s hormone-like activity has generated considerable interest in testosterone optimization.

Some observational studies have found associations between lower vitamin D and lower testosterone concentrations.

Vitamin D receptors and vitamin D-metabolizing enzymes are also present within reproductive tissues.

However, randomized clinical trials have not consistently demonstrated meaningful increases in testosterone following vitamin D supplementation.

Correcting significant vitamin D deficiency may support normal physiology.

But vitamin D should not be considered an established treatment for testosterone deficiency.

Observational research has repeatedly associated lower vitamin D concentrations with greater cardiovascular risk.

Potential mechanisms involve:

• Inflammation
• Vascular function
• Blood pressure regulation
• Renin-angiotensin signaling

However, randomized supplementation trials have not consistently demonstrated reductions in cardiovascular events.

The VITAL trial did not show a significant reduction in major cardiovascular events with 2,000 IU vitamin D3 daily.

Again, this demonstrates why supplementation dose and vitamin D concentration should not automatically be treated as equivalent.

The study tells us what happened with that supplementation strategy in that population.

It does not establish that every serum vitamin D concentration has the same cardiovascular effect.

But there is also insufficient evidence that maintaining 60–100 ng/mL prevents cardiovascular disease.

Possibly.

Vitamin D toxicity is usually associated with excessive supplementation leading to hypercalcemia.

Severe toxicity generally occurs at substantially elevated serum 25-hydroxyvitamin D concentrations, often above approximately 150 ng/mL.

But toxicity and optimal physiology are not the same thing.

A concentration can be below the classical toxicity threshold without necessarily being beneficial.

Vitamin D is far more than simply a vitamin for bone health.

It participates in calcium metabolism, immune regulation, gene expression, cellular signaling, and numerous other biological processes.

Emerging research involving autoimmune disease, cancer, metabolic health, mortality, and telomere biology suggests that vitamin D deserves continued investigation beyond traditional skeletal health.

But vitamin D physiology is also more complicated than simply taking a supplement.

The pathway begins with vitamin D3 produced in the skin or obtained through supplementation.

That vitamin D3 must be absorbed and transported.

The liver converts it into 25-hydroxyvitamin D.

The kidneys and certain other tissues can then convert 25(OH)D into active calcitriol.

Calcitriol must subsequently interact with the vitamin D receptor to influence cellular activity.

The evidence strongly supports avoiding significant vitamin D deficiency.

There are also legitimate scientific reasons to investigate whether concentrations above traditional adequacy thresholds provide additional benefits for selected individuals or health conditions.

But the evidence becomes progressively less certain when universal targets of 60–100 ng/mL are recommended.

The goal should therefore not simply be to take more vitamin D or achieve the highest laboratory number possible.

At R2 Medical Clinic in Denver, Colorado, we believe preventive, integrative, and longevity medicine should combine an understanding of human physiology with careful interpretation of scientific research.

Vitamin D illustrates why this approach matters.

A supplementation dose does not necessarily predict an individual’s blood concentration, and a blood concentration does not necessarily tell us the entire story about vitamin D activation or cellular response.

Our approach emphasizes individualized evaluation, appropriate laboratory testing, hormone and metabolic health, nutritional considerations, and evidence-informed treatment strategies.

Rather than relying solely on universal supplementation doses or arbitrary laboratory targets, we focus on understanding each patient’s physiology and determining whether an intervention is likely to improve meaningful health outcomes.