▎ WuXi AppTec content team editor
Vitamin D prevents rickets and hypochondriasis. Vitamin D has also been shown to regulate the renin-angiotensin pathway and affect cancer and cardiovascular disease.
Is vitamin D supplementation related to lower mortality? Previous studies have found that high-dose vitamin D supplementation is not associated with reduced all-cause mortality, and other studies have suggested that vitamin D supplementation may be associated with a significant reduction in cancer mortality. But most of the studies were not followed up for long periods of time, and there were few large population-based trials.
Screenshot source: Lancet Diabetes & Endocrinology
Recently, a study published in Lancet Diabetes & Endocrinology (called the "D-Health Trial") explored the relationship between vitamin D supplementation and all-cause mortality. The findings suggest that high-dose vitamin D supplementation had no effect on all-cause mortality in the population without screening, and population-wide vitamin D supplementation was not necessary. According to the researchers in the paper, "this trial is the largest to date and patient compliance is high."
What did the new study find?
In this randomized, double-blind controlled trial, the investigators included 21,315 participants over the age of 60. All participants were randomly assigned to the vitamin group and the placebo group: participants in the vitamin group took vitamin D3 supplements (at 60,000 IU) once a month; participants in the placebo group took a placebo once a month, all of whom took it for 5 years. The primary endpoint of the study was all-cause mortality after 5 years for all participants; the secondary endpoint was the association between vitamin D3 supplementation and death from cancer, cardiovascular disease and other causes.
During the follow-up period, the researchers randomly took blood samples from 3943 participants and found that the supplement did raise vitamin D levels in the body:
Participants in the placebo group had an average serum concentration of 25-hydroxyvitamin D (25-hydroxy-vitamin D, [25(OH)D]) of 77 nmol/L;
Participants in the vitamin group had an average serum concentration of 25(OH)D of 115 nmol/L.
Serum 25 (OH)D is an intermediate product of vitamin D metabolism and a precursor to the synthetic activity of 1,25 dihydroxyvitamin D [1-25(OH)2D3], with the highest concentration in the blood, the most stable level, the longest half-life, and is the best indicator of the nutritional status of vitamin D in the body.
The optimal serum 25(OH)D concentrations needed to maintain bone health are controversial. The American Institute of Medicine (IOM) agrees that serum 25(OH)D concentrations in adults should be maintained at 20-40 ng/mL (50-100 nmol/L); vitamin D deficiency is characterized by serum 25(OH)D<50 nmol/L. For overall health, it is recommended to maintain the concentration of serum 25(OH)D in the normal range.
After a median follow-up of 5.7 years, a total of 1100 deaths were found, including 538 (5.1%) deaths in the placebo group and 562 (5.3%) deaths in the vitamin D group, and further analysis found that taking vitamin D3 was associated with all-cause mortality (HR 1.04, P=0.47), cardiovascular mortality (HR 0.96, P=0.77), cancer mortality (HR 1.15, P=0.13) and other mortality rates (HR 0.83, P=). The association of 0.15) is not significant.
Following per-protocol analyses, the investigators found that all participants who actually took vitamin D3 and completed the entire study showed an increase in all-cause mortality by 18% but not significantly (OR 1.18 [95% CI 1.00-1.40]; P=0.06）。
In a further exploratory analysis, after excluding data from the first 2 years of follow-up (because the mortality rate in the vitamin D supplementation group was significantly higher than in the placebo group in the first 2 years, which may affect the outcome), the researchers found that participants randomly assigned to receive vitamin D3 had a higher risk of cancer death than the placebo group by 24% (HR 1.24, P=0.05).
The researchers concluded that giving vitamin D3 to unfiltered older adults on a monthly basis did not reduce their all-cause mortality. This regimen may not be suitable for disease prevention in people with adequate vitamin D intake and further studies are expected to validate it.
Image credit: 123RF
Should I supplement with vitamin D?
The accompanying review article in the journal notes that studies have shown that vitamin D has a wide range of roles in physiological systems and biological responses, including maintaining calcium and phosphorus homeostasis, bone health, immune function, cell cycle, and differentiation. A number of observational studies have found that low vitamin D status may be associated with an increased risk of chronic and acute adverse health outcomes. However, health outcomes appear to be less consistent in interventional trials, and the health benefits of increasing vitamin D intake are generally not supported in studies.
Some of the reasons for the inconsistencies in the findings may be:
It has to do with the complexity of vitamin D metabolism, and may also be related to the source of vitamin D supply, such as vitamin D obtained through sun exposure and eating food, which is different from dietary supplements.
Moreover, the impact of vitamin D status on health may also be related to related factors such as the participant's overall health status, lifestyle, body composition, and so on. Therefore, the potential confounding factors present in the study make it difficult to distinguish the causal relationship of the results of the study.
In addition, the findings may be related to the vitamin D concentrations in the participants at baseline and the overall state after vitamin D supplementation. In particular, for high-risk populations where 25(OH)D levels may be low, the benefits may be more pronounced than in the general population.
The intervention dose in the study was 60,000 IU per month, which equates to 2,000 IU per day. The dose of this intervention is higher than the recommended intake in Australia and most other countries, which may affect the findings.
The American Institute of Medicine notes that long-term concentrations of vitamin D in plasma are higher than 125 nmol/L, and there may be potential adverse reactions. Although the incidence of adverse events was similar in the vitamin and placebo groups, the potential adverse effects that may occur in the study also need to be considered, such as whether long-term vitamin D supplementation will lead to plasma concentrations of 25 (OH)D in more than 125 nmol/L in more people.
Taken together, the study showed that vitamin D supplementation did not affect all-cause mortality in people with adequate vitamin D intake. However, participants who had their own 25(OH)D concentrations below 50 nmol/L were most likely to benefit from supplementation. In addition, longer follow-up may be required to adequately study the effects of vitamin D supplementation on disease development over decades, such as mortality over the next 10 years.