Vitamin D and Cancer: Why Keep 25(OH)D Above 40 ng/mL

A large systematic review has been published in Nutrients, which collects dozens of epidemiological and clinical studies on the relationship between vitamin D and cancer outcomes. The author makes a sharp but well-reasoned conclusion: for cancer prevention, it is not the “fact of supplementation” that is important, but the achieved level of 25(OH)D in the blood, and the “threshold of effectiveness” is above 40 ng/ml (100 nmol/l). According to the review, it is precisely these and higher levels that are associated with a lower incidence of a number of tumors and, especially, with a decrease in cancer mortality; on the contrary, many “negative” mega-RCTs simply did not increase the level of 25(OH)D high enough or recruited participants who were already “fed” in the vitamin, and therefore did not find an effect on the primary endpoints.

Background

Vitamin D has long been considered not only as a “bone” nutrient: the active form (calcitriol) via the VDR receptor affects proliferation, apoptosis, DNA repair and inflammation - processes directly related to carcinogenesis and cancer survival. The key clinical marker of status is 25(OH)D in the blood. Low levels are common throughout the world: according to a meta-assessment for 2000-2022, the proportion of people with 25(OH)D <30 nmol/L (12 ng/mL) reaches ~16% globally, and with <50 nmol/L (20 ng/mL) - up to 24-40% in North America and Europe.

Normative “threshold” values have traditionally been set based on bone health considerations: the IOM/NAM report (2011) linked target intakes of 600-800 IU/day with achieving ≥20 ng/mL (50 nmol/L) 25(OH)D in most of the population; the tolerable upper intake level (UL) was set at 4000 IU/day in adolescents and adults. The European regulator EFSA confirms the UL at 100 μg/day (≈4000 IU) for adolescents and adults. In 2024, the Endocrine Society updated its recommendations for the prophylactic use of vitamin D: for healthy adults up to 75 years old - adhere to the recommended daily allowances, routine screening of 25(OH)D is not indicated, and the emphasis has shifted to risk groups.

Epidemiologically, higher 25(OH)D levels have been repeatedly associated with lower risks of a number of tumors and especially with a decrease in cancer mortality, which is biologically plausible against the background of anti-inflammatory and antiproliferative effects of D-signaling. However, the largest randomized trials with a "fixed dose" often gave a null result for primary prevention: in VITAL (2000 IU/day) there was no decrease in the overall incidence of cancer; the Australian D-Health with boluses of 60,000 IU/month also did not show cancer prevention (and mortality - in the main analysis). At the same time, meta-analyses indicate that daily intake (as opposed to rare boluses) is associated with a ~12% decrease in cancer mortality - that is, the regimen and the achieved level may be more critical than the "nominal dose" itself.

Against this background, the arguments of the new systematic review in Nutrients appear: the author argues that the “bottleneck” of many negative RCTs was precisely the failure to achieve sufficient levels of 25(OH)D (or the inclusion of participants who were already “fed” with the vitamin), while protective associations become stable at ≥40 ng/ml and above; the emphasis is proposed to shift from “how many IU were prescribed” to “what level of 25(OH)D was actually achieved and maintained.” This coincides with the general trend in the literature - moving away from dose-centric logic towards biomarker targeting, taking into account the duration and regimen of administration.

In practice, this sets the framework for further studies: if we are testing the effect of vitamin D on cancer incidence and especially mortality, the design should ensure that participants are within the specified 25(OH)D corridor (at least ≥40 ng/mL), safety is monitored within the established UL, daily regimens are preferred, and the observation period is sufficient. Otherwise, we again risk measuring not the effect of the nutrient, but the effect of an “underdosed” intervention.

What exactly does the review claim?

The author systematically went through PRISMA/PICOS and collected studies that compared 25(OH)D levels, D₃/calcifediol intake, sun exposure, and cancer outcomes (incidence, metastasis, mortality). As a result, he formulates several “hard” theses:

• The relationship "the higher the 25(OH)D, the lower the risk" is observed for a whole list of tumors: colorectal, stomach, mammary and endometrium, urinary bladder, esophagus, gallbladder, ovaries, pancreas, kidney, vulva, as well as lymphomas (Hodgkin's and non-Hodgkin's). This is especially stable for mortality (a clear end point), slightly weaker - for incidence.
• Threshold: levels around 20 ng/ml are sufficient for bones, but for cancer prevention ≥40 ng/ml is required, and often 50-80 ng/ml. Below the threshold, the effect is simply “not visible”.
• Why “mega-RCTs” are often negative: they often recruit participants without D deficiency at the start, give low doses and/or infrequently, do not follow-up for long periods, and do not monitor whether the participant has reached the therapeutic zone of 25(OH)D. This design “guarantees” that there will be no difference at the end.

Now to the practical details that concern both the clinician and the reader. The review contains enough specifics to "calculate" the path to the desired levels, but the caveats about safety and individualization are important.

Numbers and benchmarks from the work

• Target levels: minimum ≥40 ng/ml, optimum 50-80 ng/ml to reduce cancer risk and mortality.
• Maintenance doses (if there is little sun): for most non-obese people - ≈5000-6000 IU D₃/day, the "safe upper limit" for long-term use is 10,000-15,000 IU/day (according to the author of the review). In obesity, the requirements may be 3-4 times higher due to the distribution of the vitamin in adipose tissue. Monitoring of 25(OH)D and calcium is mandatory.
• Solar contribution: With sufficient UVB exposure, desired levels are easier to maintain; in some places the author even discusses the economic effect of increasing population 25(OH)D (reduced burden of chronic diseases).
• Calcium + D: data are mixed; in some cohorts focusing on achieved 25(OH)D in women, breast cancer risk was lower at ≥60 ng/mL, whereas dose-centered RCTs "saw no effect."
• Toxicity: rare; mostly associated with multiple overdose (tens of thousands of IU/day for long periods) or errors; the author emphasizes the safety of the indicated ranges under laboratory control.

Where biology works

• Vitamin D acts not only through genomic mechanisms (VDR/calcitriol), but also through membrane, autocrine, paracrine pathways, modulating inflammation, immune response, DNA repair - everything that is directly related to carcinogenesis, progression and metastasis.
• In epidemiology, the most consistent signal is mortality (a hard metric), while morbidity is sensitive to screening and access to medical care, which blurs the picture.

Why the Review's Conclusions Sound Harsh - and Where to Strike the Balance

The author directly criticizes the transfer of pharma logic to nutrients: "there is no such thing as a true placebo" (no one has cancelled sunlight and OTC supplements), and the correct unit of measurement is not mg D₃ on the label, but the achieved 25(OH)D. Hence the proposal: either RCT, but with bringing participants to target levels, or large ecological/population studies, where the 25(OH)D levels themselves are analyzed, and not the "prescribed dose".

It is important to remember that this is a systematic review by one author, without its own meta-analytic pool of effects, and its position is stricter than most clinical recommendations, where target levels are usually 30-50 ng/ml and more moderate doses. For practice, this means personalization and control, and not “10,000 IU for everyone urgently.”

What does this all mean for the reader (and the doctor)

• The point is in the measurements: if you are discussing vitamin D for long-term cancer prevention, focus on the 25(OH)D blood test and trend, not the “universal dose.” The goal is at least ≥40 ng/mL, but the path to that goal is different for everyone.
• Sun + diet + supplements: safe UVB exposure, vitamin D₃ and, where appropriate, fortified foods are a compatible strategy. High doses only with monitoring (calcium, creatinine, 25(OH)D).
• Not "instead of", but "together": vitamin D is not an anti-cancer pill, but one of the factors of multifactorial prevention (screening, weight, activity, sleep, quitting tobacco/excessive alcohol, etc.). The review simply argues that the level of D matters and should not be underestimated.

Limitations and Controversies

• Observational data are subject to confounding: low 25(OH)D often coexists with sedentary lifestyle, obesity, and a “low-quality” diet – all of which in themselves increase cancer risk.
• Mega-RCTs like VITAL have indeed shown no benefit in primary cancer prevention, albeit with the design flaws described; these results cannot be ignored. The balance of evidence shifts in favor of mortality and secondary outcomes.
• Doses “higher than usual” and target levels of 50-80 ng/ml are the position of the review, more aggressive than those of a number of societies; using it without control is risky.

Summary

The review loudly returns the debate to 25(OH)D levels as a therapeutic target. If its claims are confirmed in properly designed studies (reaching ≥40 ng/mL and of sufficient duration), vitamin D may gain a more significant place in cancer prevention and cancer mortality reduction – as a cheap and scalable public health tool. Until then, the rational formula is measure, personalize, monitor.

Source: Wimalawansa SJ Vitamin D's Impact on Cancer Incidence and Mortality: A Systematic Review. Nutrients 17(14):2333, 16 July 2025. Open access. https://doi.org/10.3390/nu17142333