Vitamin D treatment could have positive effects on cancer related fatigue

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Fatigue, or severe tiredness and exhaustion, is a distressing condition for many patients with advanced cancer. Unfortunately, good pharmacological treatment options are limited, and the ones available come with a risk of side effects and/or habituation.

In a recently conducted study in palliative home care in Stockholm, Palliative-D, we were able to show that correction of vitamin D deficiency reduced both pain and fatigue in patients with advanced and metastatic cancer.

The effects were moderate, but the treatment was surprisingly well tolerated without any severe side effects.

In a recently published study in Cancers, researchers performed a so-called post-hoc analysis of the material from the Palliative-D study, where sex differences regarding the effects of vitamin D were examined. The study showed that correction of vitamin D deficiency caused significantly reduced fatigue in men, but not in women.

Even after adjusting the results for factors that could affect the outcome (confounding factors), i.e., differences in pain medication, type of cancer, ongoing oncological treatment, colectomy and vitamin D levels prior to the start of the study, the effects of vitamin D treatment in men remained.

After only four or eight weeks of treatment, no significant effect of vitamin D were noticed, and the effect was evident first after 12 weeks of treatment.

The Palliative-D study is the first study to show that vitamin D treatment could have positive effects on cancer related fatigue, and that there are sex differences in the effects of vitamin D.

The strength of this study is that it is based on data from a randomized, placebo-controlled double-blind study; thus, the risk is small that the findings are due to chance or confounding factors. However, the weakness of the study is a high drop-out rate in the original study – of 244 patients included, only 150 completed all 12 weeks.

The major cause of drop-out was that the patients died of their cancer before finishing the study. Another weakness is that the Palliative-D study was not originally designed to examine sex differences.

Fatigue was also a secondary outcome measure in the original study; primary focus was pain. Drawing reliable conclusions will require a new study designed specifically to study fatigue and sex differences of vitamin D treatment.

To summarize, this study shows that correction of vitamin D deficiency in cancer patients in palliative care seems to reduce fatigue in men, but not in women. Although the effects are moderate, vitamin D is a gentle treatment, and even a moderate effect may make an important difference in the combined symptom burden of a single patient.

However, in patients with an expected surivival time less than 12 weeks, treatment would probably not be relevant.


Vitamin D is a fat-soluble vitamin that exists in two forms: vitamin D2 (ergocalciferol) and vitamin D3 (cholecalciferol) (1,2). Dietary consumption of UVB-exposed plants and fungi is the primary source of vitamin D2 in humans (3,4). Vitamin D3 can also be obtained through diet, mostly from oily fish. However, over 90% of the body’s daily vitamin D requirements are produced in the skin upon exposure to sunlight (5).

After consumption or synthesis of vitamin D, both forms must be hydroxylated to become biologically active. The first hydroxylation occurs in the liver to create the compound 25-hydroxyvitamin D. This molecule is the major circulating form of vitamin D in the human body, and therefore is used as a diagnostic marker of deficiency (2).

Subsequently, it is hydroxylated again in the kidney to form 1,25-dihydroxyvitamin D, the metabolically-active form of vitamin D. 1,25-dihydroxyvitamin D plays a crucial role in a number of processes, most notably calcium and phosphorus homeostasis (2).

The US Preventive Services Task Force (USPSTF) has not made specific recommendations with regards to screening for vitamin D deficiency in asymptomatic patients (6), yet literature has demonstrated that there are wide disparities in average serum vitamin D levels in different populations across the world – with individuals from Africa and the Middle East being of particular risk for deficiency (7).

The association between vitamin D deficiency and carcinogenesis has been studied thoroughly over the last two decades (5), but the potential role of vitamin D supplementation in cancer care is not yet clear. The vitamin D receptor (VDR) is a member of the steroid nuclear receptor family. Its activation results in receptor dimerization and downstream recruitment of vitamin D response elements (VDREs) that form a regulatory complex modulating gene expression (8).

Cancer cell lines expressing VDR exhibit inhibited cellular proliferation when exposed to 1,25-dihydroxyvitamin D in cultures of prostate, colon, breast, lung, and skin (5). Recent reviews summarizing the mechanistic relationship between vitamin D and cancer have focused heavily on older studies (9-13).

In outlining new areas for future research, we believe there is utility in summarizing these novel molecular mechanisms and assessing how they fit into the context of existing models relating vitamin D to cancer.

Thus, in this review, we evaluate literature published over the last five years to explore the underlying molecular biology linking vitamin D to carcinogenesis, focusing on the most commonly reported cancer subtypes: breast cancer, colon cancer, and melanoma.


More information: Caritha Klasson et al, Sex Differences in the Effect of Vitamin D on Fatigue in Palliative Cancer Care—A Post Hoc Analysis of the Randomized, Controlled Trial ‘Palliative-D’, Cancers (2022). DOI: 10.3390/cancers14030746

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