Prostate Cancer

Vitamin D Deficiency And Prostate Cancer: Is There A Link?

Prostate cancer is the fifth cause of death due to cancer in men around the world (1).

However, after ongoing research, we don’t know the exact causes of prostate cancer. Instead, we have a few risk factors.

While some risk factors such as genetics and race cannot be modified, others such as diet and physical activity can. (2) Research has also shown that certain vitamins may help to reduce the risk of developing prostate cancer.

Vitamin D is one such vitamin that has received increasing attention, with studies indicating that vitamin d deficiency may be linked to prostate cancer.

Vitamin D is one of the most important vitamins. Among the functions of vitamin D in the body, we have bone mineralization and regulation of phosphate and calcium metabolism. (3).

Is there a connection between vitamin D and prostate cancer? Is it possible to prevent prostate cancer by using vitamin D supplements?

Is there a connection?

Before diving into the connection between vitamin D and prostate cancer, we should differentiate the concept of incidence and progression. Incidence refers to new cases of prostate cancer. Progression refers to diagnosed patients and how their prostate cancer behaves over time.

Vitamin D connection can be evaluated in healthy patients who want to prevent prostate cancer. Similarly, the connection can be assessed in patients with prostate cancer. In this case, we would evaluate how vitamin D influences prostate cancer progression.

The receptor of vitamin D is active in many different tissues. The most significant role of vitamin D is associated with bone mineralization. However, other structures of the body have an active receptor as well. One of them is the human prostate tissue (4).

Prostate cancer incidence and vitamin D

Interestingly, prostate cancer prevalence is reduced in countries with higher sun exposure. This is apparently due to an increase in vitamin D synthesis (5). However, the connection between prostate cancer and vitamin D appears to be inconclusive.

The World Cancer Research Fund Continuous Update Project evaluates the link between cancer and diet. They report divergent results in the scientific literature. Thus, they say it is still soon to raise any conclusion about prostate cancer and vitamin D (6).

For example, some studies show that vitamin D deficiency increases the risk. In contrast, others suggest that high concentrations have the exact same result.

These inconsistencies may be explained because the studies have small sample sizes. However, it appears that there’s a genetic variation that mediates susceptibility (7). Thus, more research is required to evaluate the connection between prostate cancer incidence and vitamin D.

What about prostate cancer progression?

In patients with a prostate cancer diagnosis, it appears that vitamin D is more useful. Randomized trials in humans show that vitamin D supplements may have a positive effect. This effect is modest and more likely in patients with vitamin D deficiency (8).

There’s also a recent systematic review and meta-analysis that evaluated cancer progression and vitamin D. This study reviewed circulating levels of vitamin D and survival rates. The authors reported that higher levels of vitamin D were associated with improved survival and progression-free survival.

In other words, patients with cancer survive for longer when they have higher vitamin D levels. They may even survive prostate cancer longer without experiencing any progression at all (9).

What the research says

If we consider the investigation so far, we can raise a few educated conclusions.

For instance, let us review the research on prostate cancer incidence, and vitamin D. A U-shaped association may explain what appears to be diverging results. In other words, both deficient levels and very high levels of vitamin D may be associated with a higher incidence.

What we need to reach is that point in the U-shaped curve where we get appropriate levels. Not low levels, and not very high levels, either. Some authors have reached this conclusion because (10):

  • Among people with vitamin D deficiency, the incidence is higher in those with the lowest level.

  • Among people with high vitamin D levels, the incidence is higher in those with the highest level.

So, a U-shaped association is a hypothesis currently on debate. It takes into consideration the studies so far, and it is an interesting proposal. Thus, according to research, the most recommended levels of vitamin D to prevent prostate cancer are under the range of 20 to 30 ng/ml. This is actually the level currently accepted by the Institute of Medicine (11).

However, we should still consider that higher levels of vitamin D may be useful for other types of cancer. That’s especially the case of colorectal cancer. Therefore, there is not a single preventative recommendation for all patients. Instead, urology specialists should evaluate the risk and provide recommendations accordingly.

On the other hand, vitamin D appears to be very useful in controlling prostate cancer patients. In their case, vitamin D has been found to increase apoptosis. That is, cancer cells undergo programmed death when there are appropriate levels.

Vitamin D is also useful for cell differentiation. This process prevents the conversion of new healthy cells. However, the exact mechanisms in patients with prostate cancer are still elusive. Some authors suggest that vitamin D influences testosterone levels, and that’s how it modulates prostate cancer. Still, more research is needed to understand the metabolic pathway (12).

Vitamin D supplements and prostate cancer progression

Using vitamin D supplements in patients with cancer may slow down cancer progression.

For example, an open-label trial evaluated the effect of 4,000 UI of vitamin D in prostate cancer. These prostate cancer patients took the supplement every day for one year.

The PSA levels remained the same, but there were other changes. 55% of the patients reduced the number of positive cancer cores in biopsies in some cases. In other cases, the Gleason score was significantly reduced in localized prostate cancer (13).

Other recent studies have used vitamin D receptor agonists instead of vitamin D supplements. By stimulating vitamin D receptors, researchers found a 30% decline in PSA levels.

It only took 3 months to register this change in 85% of the studied patients. The reduction of PSA was higher than 50% in 76% of these patients. These are encouraging news. They show a potential therapeutic option in vitamin D supplements (14).

In a nutshell, the recommended vitamin D level for prostate cancer patients is 30 ng/ml or more. Reaching 30 ng/ml appears to reduce mortality rates and cancer recurrence.

To achieve these levels, it will be appropriate to use vitamin D3 supplements. As we do, we should also monitor blood levels. In the future, it might be possible to use vitamin D receptor agonists, too. However, they still need more extensive clinical trials to evaluate the safety of these drugs (10).

Is there an explanation?

How can we explain the association between vitamin D and prostate cancer? The exact mechanism is unknown. However, there are many hypotheses we can consider. One of the most accepted mechanisms is through the anti-inflammatory potential of vitamin D.

Vitamin D inhibits the production of inflammatory cytokines. It acts in the macrophages and monocytes, but also in prostate cells. In these cells, it inhibits the expression of IL-6, IL-8, and TNF. They mediate inflammatory reactions.

Moreover, TNF and IL-6 upregulate the expression of calcium-sensing receptors (CaSR). High levels of CaSR increases the risk of lethal prostate cancer. Thus, by reducing levels of IL-6, vitamin D is thought to reduce CaSR. As a consequence, it reduces the risk of aggressive prostate cancer. This mechanism can be confirmed.

In the presence of calcitriol (metabolized from vitamin D), CaSR levels are reduced. Thus, the anti-inflammatory potential of vitamin D has a protective role in the progression of prostate cancer (10).

Other risk factors for prostate cancer

Vitamin D is apparently an important risk factor for prostate cancer. But it is not the only one. As mentioned above, there are many other modifiable and non-modifiable risk factors. According to the American Cancer Society, we can divide the risk factors into two types (2):

  • Endogenous risk factors: These risk factors are naturally found in your body, and the majority of them cannot be changed.
  • Exogenous risk factors: These risk factors come from the outside, and the majority of them are modifiable.

Thus, let us briefly review each one of them and how they affect prostate cancer incidence and progression.

Endogenous risk factors

The most important risk factors associated with your organism are as follows (2):

  • Family history: If you have family members with prostate cancer, your risk will be higher. That’s especially the case when it is a first-degree family member, including brothers and your father. The greater the number of relatives affected by prostate cancer, the higher risk you have to be diagnosed with the same disease.

  • Hormones: Prostate cancer cells depend on hormones to continue replicating. In this regard, it is similar to breast cancer. That’s why manipulating hormones is a form of therapy. In practice, low androgen bioactivity can be associated with a higher risk. But very high levels of testosterone for a long time can also increase the risk. The association between prostate cancer and testosterone is quite complex. Thus, there is not a single recommendation that works for all patients in this regard.

  • Race: Prostate cancer is more common in African Americans than Whites. Hispanic men are usually diagnosed earlier than white men. This difference is probably due to a difference in androgen levels and some genetic polymorphisms.

  • Age: As we age, a few changes take place in the body. DNA adducts accumulate over time, and oxidative stress increases. Free radicals are continuously changing body structures, and DNA becomes progressively damaged. Additionally, inflammation adds to the problem along with chronic disease. All of this causes an increase in the incidence of prostate cancer.

Exogenous risk factors

The most important risk factors associated with the environment are as follows (2):

  • Diet and nutrition: Many aspects of the diet influence prostate cancer risk. For example, high-fat food increases the risk of prostate cancer when it is predominantly saturated fat. But consuming unsaturated fats as in olive oil reduces the incidence. Studies have also suggested that low levels of vitamin A and carotenoids may increase the risk.

  • Minerals: Similarly, vitamin C and vitamin E protect the body with their antioxidant role. Minerals are also important to prevent prostate cancer. For example, zinc, selenium, and calcium are associated with prostate cancer risk. That’s why they are used in dietary supplements for these patients.
  • Alcohol intake: Some studies suggest that higher consumption of alcohol increases the risk. However, other studies are showing diverging results.

  • Smoking: Smoking increases the circulating levels of androgen and exposes the body to cadmium. The association between cigarette and prostate cancer is significant in many studies. However, there are still conflicting results in the reviews so far.

  • Endocrine disruptors: Exposure to synthetic estrogens, detergents, plastics, and agricultural chemicals increases the risk of prostate cancer. In many cases, dangerous chemicals have been taken out of the market for this cause.

  • Cadmium exposure: Some studies suggest that exposure to cadmium increases the risk of prostate cancer. There’s a modest increase in risk, and it is not reported in all studies.

Conclusion

Prostate cancer and its associations with supplements and hormones are complex. However, we can still reach many conclusions in light of the evidence. Let us break down the finding in two, and consider prostate cancer prevention and progression as different entities.

Despite the apparent contradictions in the evidence, we can use vitamin D to prevent prostate cancer. Vitamin D is recommended to optimize bone health.

Following the same recommendation may also reduce the risk of prostate cancer. However, keep in mind that the ideal blood levels should be 20-30 ng/ml. A higher or lower concentration is associated with an increased risk of prostate cancer. Supplementation may be beneficial, especially in countries with low sun exposure. Vitamin D may also be found in fortified foods and other sources.

In men with prostate cancer, vitamin D recommendations are not the same. All of the available data points out at vitamin D as a useful tool to prevent advanced prostate cancer. It reduces the mortality and progression of prostate cancer. It counteracts the effect of high-calcium diets in prostate tumors.

Thus, it can be useful in patients with prostate cancer and bone mineralization problems. In these men, the ideal level of vitamin D is 30-50 ng/ml, especially if they are at risk of osteoporosis.

The best way to use vitamin D for prostate health is by taking into consideration the recommendations above and measuring serum levels until reaching the appropriate dose of vitamin D supplements.

Sources

  1. Zhou, C. K., Check, D. P., Lortet‐Tieulent, J., Laversanne, M., Jemal, A., Ferlay, J., … & Devesa, S. S. (2016). Prostate cancer incidence in 43 populations worldwide: an analysis of time trends overall and by age group. International journal of cancer, 138(6), 1388-1400.
  2. Bostwick, D. G., Burke, H. B., Djakiew, D., Euling, S., Ho, S. M., Landolph, J., … & Timms, B. (2004). Human prostate cancer risk factors. Cancer: Interdisciplinary International Journal of the American Cancer Society, 101(S10), 2371-2490.
  3. Feldman, D., Krishnan, A. V., Swami, S., Giovannucci, E., & Feldman, B. J. (2014). The role of vitamin D in reducing cancer risk and progression. Nature reviews cancer, 14(5), 342-357.
  4. Holick, M. F. (2007). Vitamin D deficiency. New England Journal of Medicine, 357(3), 266-281.
  5. Loke, T. W., Sevfi, D., & Khadra, M. (2011). Prostate cancer incidence in Australia correlates inversely with solar radiation. BJU international, 108, 66-70.
  6. World Cancer Research Fund International. (2014). Continuous update project report: diet, nutrition, physical activity, and prostate cancer.
  7. Mondul, A. M., Shui, I. M., Yu, K., Travis, R. C., Stevens, V. L., Campa, D., … & Crawford, E. D. (2013). Genetic variation in the vitamin D pathway in relation to risk of prostate cancer—results from the breast and prostate cancer cohort consortium. Cancer Epidemiology and Prevention Biomarkers, 22(4), 688-696.
  8. Vaughan-Shaw, P. G., O’sullivan, F., Farrington, S., Theodoratou, E., Campbell, H., Dunlop, M. G., & Zgaga, L. (2017). The impact of vitamin D pathway genetic variation and circulating 25-hydroxyvitamin D on cancer outcome: systematic review and meta-analysis. British journal of cancer, 116(8), 1092-1110.
  9. Vaughan-Shaw, P. G., O’sullivan, F., Farrington, S., Theodoratou, E., Campbell, H., Dunlop, M. G., & Zgaga, L. (2017). The impact of vitamin D pathway genetic variation and circulating 25-hydroxyvitamin D on cancer outcome: systematic review and meta-analysis. British journal of cancer, 116(8), 1092-1110.
  10. Capiod, T., Delongchamps, N. B., Pigat, N., Souberbielle, J. C., & Goffin, V. (2018). Do dietary calcium and vitamin D matter in men with prostate cancer?. Nature Reviews Urology, 15(7), 453-461.
  11. Ross, A. C., Manson, J. E., Abrams, S. A., Aloia, J. F., Brannon, P. M., Clinton, S. K., … & Kovacs, C. S. (2011). The 2011 report on dietary reference intakes for calcium and vitamin D from the Institute of Medicine: what clinicians need to know. The Journal of Clinical Endocrinology & Metabolism, 96(1), 53-58.
  12. Robles, L. A., Dawe, K., Martin, R. M., Higgins, J. P., & Lewis, S. J. (2019). Does testosterone mediate the relationship between vitamin D and prostate cancer? A systematic review and meta-analysis protocol. Systematic reviews, 8(1), 52.
  13. Marshall, D. T., Savage, S. J., Garrett-Mayer, E., Keane, T. E., Hollis, B. W., Horst, R. L., … & Gattoni-Celli, S. (2012). Vitamin D3 supplementation at 4000 international units per day for one year results in a decrease of positive cores at repeat biopsy in subjects with low-risk prostate cancer under active surveillance. The Journal of Clinical Endocrinology & Metabolism, 97(7), 2315-2324.
  14. 14. Medioni, J., Deplanque, G., Ferrero, J. M., Maurina, T., Rodier, J. M. P., Raymond, E., … & Renaux, S. (2014). Phase I safety and pharmacodynamic of inecalcitol, a novel VDR agonist with docetaxel in metastatic castration-resistant prostate cancer patients. Clinical Cancer Research, 20(17), 4471

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