Dear Osa friends,

There isn’t a single one of us who isn’t affected by cancer in some way–either you know or knew someone who has or has had cancer, or you have received a cancer diagnosis yourself. We know that the development of cancer is heavily influenced by environmental factors, including toxin exposures and nutrition; however, I think we can often feel both confused and powerless amid the rising incidence of cancer coupled with the glut of conflicting information about what we might do to prevent it or to increase our survival odds. Below I’m going to discuss two nutrients of interest in colon cancer: vitamin D and calcium. This conversation will also touch briefly on cardiovascular disease, which is indeed the leading cause of death for adult men and women in the United States, although cancer is a very close second.

Calcium and vitamin D in colon cancer

A number of research studies have illustrated an inverse relationship between vitamin D level (measured as serum 25-hydroxyvitamin D and written as 25(OH)D ) and colon cancer¹, and dietary calcium has also been found to have an inverse relationship with colon cancer, particularly of the distal colon and when taken at least 10 years before diagnosis².  

When considering the efficacy of nutrients for disease prevention, the question that always comes to my mind is, “How does it work?”  I want to know the mechanism or mechanisms by which the nutrient exerts its effect.  These biological mechanisms are a type of evidence which we consider alongside epidemiological data and randomized controlled trials to determine the safety and efficacy of nutrients, especially when we’re using them for a specific purpose, such as disease treatment or prevention.

Recently I was interested to come across a 2005 prospective study³ investigating the relationship between calcium and vitamin D and cellular apoptosis (normal cell death) as it relates to colon cancer.  Apoptosis is an important factor to look at because individuals with adenomas (aka polyps) have lower levels of apoptosis in their colorectal tissue⁴.  In this 2005 study, several hundred adults undergoing colonoscopies completed food frequency questionnaires, had their serum 25(OH)D level measured, and agreed to two rectal biopsies for the apoptosis analysis.  In individuals who had adenomas found in their colonoscopy, those in the highest tertile of dietary calcium intake (>739 mg/day) had 3 times higher odds of an apoptotic score above the median, compared to those in the lowest tertile of calcium intake (<419 mg/day), whereas there was no association in patients without adenomas.  This finding suggests that adequate dietary calcium may be protective against the development of colon cancer in those with risk factors such as the presence of adenomas.  As for vitamin D, a serum level in the highest tertile (>35 ng/mL) increased the odds of having an apoptosis score above the mean, but this association was found only in patients without pre-existing adenomas.  This finding is consistent with cell studies which have found that vitamin D metabolites induce apoptosis, and suggests a preventive benefit of vitamin D.

Summary: Dietary calcium intake > 739 mg/day and vitamin D > 35 ng/mL are related to beneficial apoptosis in the colon, and this effect may help to to prevent or slow cancer development.

Could vitamin D be a “double-edged sword?”: Women’s Health Initiative post-hoc analysis

Just recently, a new post hoc analysis of data from the Women’s Health Initiative “CaD” trial, a 7-year randomized intervention of 1,000 mg/day calcium carbonate and 400 IU vitamin D3 or placebo, was published⁵.  The original study began 30 years ago, and this new analysis took into account cancer and cardiovascular disease incidence and mortality data for the participants in the 20+ years since the randomization period concluded. For women who received the calcium and vitamin D, a 7% reduction in cancer mortality and a 6% increase in cardiovascular disease mortality were observed after a follow-up period of 22 years.  There was no effect found on other measures which also included all-cause mortality and hip fracture.  Last month I received an opinionated review of this study entitled entitled “Vitamin D: a double-edged sword?” from Medscape, an online news source for healthcare professionals. The author of this review sought to portray vitamin D as something which may modestly reduce colorectal cancer death while simultaneously increasing cardiovascular disease death–hence the “double-edged sword” idiom. 

I found this interpretation to be flawed and problematic for several reasons:

1. It is incorrect to draw conclusions about the individual effects of one part of a multi-part intervention in a randomized controlled trial.  In this case, vitamin D and calcium were given together, so we cannot separate their effects.  His analysis would seem to imply that calcium is a neutral player, but it is incorrect to make this assumption.  While calcium supplementation generally has not been found to impact the development of cardiovascular disease, there is some contrary data to this regard, including a recent observational analysis which found that habitual calcium supplementation was associated with a significant increased risk of cardiovascular disease and mortality in diabetic individuals⁶.
2. When interpreting results from randomized trials, biological plausibility must also be considered.  Are there known mechanisms by which vitamin D may lower cancer incidence or progression? Yes. Vitamin D is well recognized for its immunomodulatory, anti-inflammatory, and beneficial cell differentiation effects⁷^,⁸. Are there known mechanisms by which vitamin D may increase cardiovascular disease risk? Possibly, but there is no published data to support this. Because vitamin D does increase calcium absorption from the gut, it can result in more calcium in the blood and could, hypothetically, increase the risk of  calcification of atherosclerotic lesions.  However, hypercalcemia due to vitamin D would not be a concern until levels of vitamin D reach 100 ng/mL or higher, which in most individuals requires supplementation at substantially higher doses, such as over 10,000 IU daily for an extended period of time.  (As a side note, I would not recommend a calcium supplement without also recommending a vitamin K supplement, because vitamin K essentially tells calcium where to go in the body, and we want the vast majority of that calcium to go to our bones! Magnesium intake should also be considered when supplementing with calcium because calcium and magnesium compete for absorption and have somewhat opposing roles in the body).
3. Speaking of vitamin D dosage, 400 IU is a very small dose and would be expected to have no more than a small effect on circulating 25(OH)D in adults.
4. Extrapolating results from a trial of 7 years time to 20+ years after completion of the trial does not tell us anything about continued supplementation of vitamin D and calcium over the long term–it can only tell us what impact 7 years of calcium and very modest vitamin D supplementation might have further down the road, Conclusions about long-term vitamin D and calcium supplementation, or any doses different than those used in the study, simply cannot be drawn from this analysis.

In summary, to say that vitamin D is a “double-edged sword” in light of these results is poor interpretation of the data, shows little understanding of the complex biological mechanisms of vitamin D, and disregards effects of calcium supplementation. I think this is potentially harmful to patients whose doctors may read this analysis and take such an interpretation to heart. 

It is so important to individualize recommendations.  If you are someone with a family history of cancer, you would do well to note the reduced cancer mortality risk with vitamin D supplementation (and take into account the above discussion on dietary calcium as well).  Individuals will require different levels of supplementation to get to a protective level of vitamin D, and this level is also a matter of debate. Most functional practitioners recognize that over 40 ng/mL is desirable for most people, owing to epidemiological data demonstrating increased incidence of autoimmune conditions, allergies, high blood pressure, and depression, among other conditions, at levels lower than this. The Institute for Functional Medicine recommends 50-80 ng/mL as an optimal range, due to evidence of reduced solid cancers. Currently, the Institute of Medicine has set 4,000 IU/day as the upper level of daily intake for safety, although the RDA remains at 600 IU for adults**. Whenever you choose to supplement, you should monitor your 25(OH)D level. As for calcium, supplementation with this nutrient should also be individualized, and proper balance with other minerals needs to be addressed.  In terms of cancer risk, remember that dietary but not supplemental calcium has been associated with reduced risk of colorectal cancer.

If any of this information pertains to you, I hope you will take it to your healthcare provider at your next medical appointment to help inform the best choices for your individual situation.

Be well,

**This does not constitute medical advice. Always consult a healthcare provider before making any changes or additions to your supplements.

References

1. Gorham, E. D., Garland, C. F., Garland, F. C., Grant, W. B., Mohr, S. B., Lipkin, M., Newmark, H. L., Giovannucci, E., Wei, M., & Holick, M. F. (2007). Optimal vitamin D status for colorectal cancer prevention: a quantitative meta analysis. American journal of preventive medicine, 32(3), 210–216. https://doi.org/10.1016/j.amepre.2006.11.004 https://pubmed.ncbi.nlm.nih.gov/17296473/
2. Zhang, X., Keum, N., Wu, K., Smith-Warner, S. A., Ogino, S., Chan, A. T., Fuchs, C. S., & Giovannucci, E. L. (2016). Calcium intake and colorectal cancer risk: Results from the nurses’ health study and health professionals follow-up study. International journal of cancer, 139(10), 2232–2242. https://doi.org/10.1002/ijc.30293 https://pubmed.ncbi.nlm.nih.gov/27466215/
3. Miller, E. A., Keku, T. O., Satia, J. A., Martin, C. F., Galanko, J. A., & Sandler, R. S. (2005). Calcium, vitamin D, and apoptosis in the rectal epithelium. Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology, 14(2), 525–528. https://doi.org/10.1158/1055-9965.EPI-04-0466 https://pubmed.ncbi.nlm.nih.gov/15734982/
4. Martin, C., Connelly, A., Keku, T. O., Mountcastle, S. B., Galanko, J., Woosley, J. T., Schliebe, B., Lund, P. K., & Sandler, R. S. (2002). Nonsteroidal anti-inflammatory drugs, apoptosis, and colorectal adenomas. Gastroenterology, 123(6), 1770–1777. https://doi.org/10.1053/gast.2002.37053 https://pubmed.ncbi.nlm.nih.gov/12454832/
5. Thomson, C. A., Aragaki, A. K., Prentice, R. L., Stefanick, M. L., Manson, J. E., Wactawski-Wende, J., Watts, N. B., Van Horn, L., Shikany, J. M., Rohan, T. E., Lane, D. S., Wild, R. A., Robles-Morales, R., Shadyab, A. H., Saquib, N., & Cauley, J. (2024). Long-Term Effect of Randomization to Calcium and Vitamin D Supplementation on Health in Older Women : Postintervention Follow-up of a Randomized Clinical Trial. Annals of internal medicine, 177(4), 428–438. https://doi.org/10.7326/M23-2598 https://pubmed.ncbi.nlm.nih.gov/38467003/
6. Qiu, Z., Lu, Q., Wan, Z., Geng, T., Li, R., Zhu, K., Li, L., Chen, X., Pan, A., Manson, J. E., & Liu, G. (2024). Associations of Habitual Calcium Supplementation With Risk of Cardiovascular Disease and Mortality in Individuals With and Without Diabetes. Diabetes care, 47(2), 199–207. https://doi.org/10.2337/dc23-0109 https://pubmed.ncbi.nlm.nih.gov/37506393/
7. Moreno, J., Krishnan, A. V., Swami, S., Nonn, L., Peehl, D. M., & Feldman, D. (2005). Regulation of prostaglandin metabolism by calcitriol attenuates growth stimulation in prostate cancer cells. Cancer research, 65(17), 7917–7925. https://doi.org/10.1158/0008-5472.CAN-05-1435 https://pubmed.ncbi.nlm.nih.gov/16140963/
8. Pálmer, H. G., González-Sancho, J. M., Espada, J., Berciano, M. T., Puig, I., Baulida, J., Quintanilla, M., Cano, A., de Herreros, A. G., Lafarga, M., & Muñoz, A. (2001). Vitamin D(3) promotes the differentiation of colon carcinoma cells by the induction of E-cadherin and the inhibition of beta-catenin signaling. The Journal of cell biology, 154(2), 369–387. https://doi.org/10.1083/jcb.200102028 https://pubmed.ncbi.nlm.nih.gov/11470825/