Impact of Vitamin D Supplements on Mortality Risk

In a new study published in Nutrients, researchers analyzed the results of 80 randomized clinical trials and assessed the impact of vitamin D supplementation on mortality [1].

According to the CDC, 6.7% to 36.9% of Americans take vitamin D supplements, depending on age group. This makes it the second most popular supplement in the USA.

Vitamin D has a wide spectrum of activity. It is essential in calcium absorption in the gut, regulates calcium, phosphorus, and glucose metabolism, and supports bone growth, remodeling, and mineralization. Other roles of vitamin D include the reduction of inflammation, modulation of cell growth, and neuromuscular and immune function. Sufficient vitamin D levels protect adults from osteoporosis and prevent rickets in children.

There are many genes that are controlled by vitamin D, and the vitamin D receptor is present in many bodily tissues [2]. It is not surprising, then, that low levels of vitamin D have been reported to be associated with multiple disorders, including cardiovascular problems, diabetes, cancer, and inflammatory disorders.

Due to Vitamin D’s essential role, much research has been done on its impact on mortality risk. However, the reported results are inconsistent. This inconsistency, the limitations of previous research, and the emergence of new studies prompted these researchers to analyze existing and new research for an in-depth look at vitamin D supplementation.

Researchers looked at the results of randomized controlled trials that were published between 1983 and 2022. They wanted to know if taking vitamin D supplements affected overall mortality and wanted to know if it was linked to deaths from cardiovascular diseases. Therefore, studies included in the analysis differentiated between all-cause mortality, cardiovascular mortality, non-cardiovascular mortality, and cardiovascular morbidities: cardiovascular issues that do not necessarily lead to death themselves.

Studies included in the analysis investigated vitamin D supplementation with or without calcium. They needed to include at least one year of follow up.

The total number of participants in all analyzed studies combined was more than 160,000, with a mean age of 66. However, it didn’t include pregnant or lactating women, frail elderly, or patients with serious conditions, such as stroke, COVID-19, and HIV.

The studies in this analysis varied in their design and quality. Therefore, these researchers divided the studies into low, fair, and good quality by assessing their risk of bias, with high-quality studies having a low risk of bias.

Out of the 80 studies chosen, 11 were found to have a high risk of bias. Additionally, 34 studies were identified as having a fair risk of bias, and 35 studies were labeled good quality with a low risk of bias.

The good-quality studies included over 120,000 participants, and the lowest-quality studies represented only over a thousand participants.

Based on the analysis of all 80 studies, these researchers concluded that vitamin D supplementation reduced the risk of all-cause mortality. When they analyzed good- and fair-quality studies together, they saw the same effect. However, when good- or fair-quality studies were analyzed separately, the effect of vitamin D supplementation on all-cause mortality was close to being statistically significant but didn’t reach the mark. The association was not observed when only poor-quality studies were analyzed.

The researchers analyzed 38 randomized controlled trials that examined cardiovascular mortality. No link was found between taking vitamin D and a lower risk of cardiovascular mortality, whether studies were analyzed together or separately.

The association between vitamin D supplementation and non-cardiovascular mortality risk was close to statistical significance but didn’t reach significance. Similarly, statistical significance was not achieved when analyzing subgroups of low-, fair-, or good-quality studies separately.

The authors also analyzed the effect of vitamin D supplementation on specific conditions, such as heart attack, stroke, heart failure, and other adverse cardiovascular events. There was no association between vitamin D supplementation and a lower risk of cardiovascular morbidities.

This study used data obtained from 80 different studies that varied on many levels. For example, participants in those studies took different doses of vitamin D. Additionally, participants in each of those studies could differ in age, gender, basal levels of vitamin D before the study, etc. These studies may also have been done at different seasons of the year, which affects natural vitamin D exposure.

Even though all these factors could influence the overall results, they were not accounted for in the analysis, limiting the conclusions that can be drawn.

These authors believe there is a need for well-planned and executed studies to address the question of vitamin D supplementation and mortality risk, which would need to be done before any strong recommendation could be given. They also brought up the important issue of study quality. They note that, in some cases, adding substandard results to the analysis changes its overall results and thus could affect recommendations.

Their opinion is echoed by the participants of a conference focused on vitamin D controversies. There, attendees stated the need for definitive randomized controlled trials that can conclusively assess which disorders vitamin D can help [3].

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[1] Ruiz-García, A., Pallarés-Carratalá, V., Turégano-Yedro, M., Torres, F., Sapena, V., Martin-Gorgojo, A., & Martin-Moreno, J. M. (2023). Vitamin D Supplementation and Its Impact on Mortality and Cardiovascular Outcomes: Systematic Review and Meta-Analysis of 80 Randomized Clinical Trials. Nutrients, 15(8), 1810.

[2] Bouillon, R., Marcocci, C., Carmeliet, G., Bikle, D., White, J. H., Dawson-Hughes, B., Lips, P., Munns, C. F., Lazaretti-Castro, M., Giustina, A., & Bilezikian, J. (2019). Skeletal and Extraskeletal Actions of Vitamin D: Current Evidence and Outstanding Questions. Endocrine reviews, 40(4), 1109–1151.

[3] Giustina, A., Adler, R. A., Binkley, N., Bouillon, R., Ebeling, P. R., Lazaretti-Castro, M., Marcocci, C., Rizzoli, R., Sempos, C. T., & Bilezikian, J. P. (2019). Controversies in Vitamin D: Summary Statement From an International Conference. The Journal of clinical endocrinology and metabolism, 104(2), 234–240.

 Tags: Cardiovascular Disease, Vitamin D