Clinical Context

There are few areas in healthcare that are more controversial than vitamin D. Vitamin D receptors abound in multiple tissues in the body, and vitamin D has pleiotropic effects on metabolism. Yet between 5% and 50% of the adult population has vitamin D deficiency, and this rate is highly dependent on geographic location, as well as the demographic and disease characteristics of the population sample.

Still, randomized trials of vitamin D supplementation have generally been disappointing in regard to the prevention of major outcomes such as cardiovascular events and mortality. In a systematic review and meta-analysis of 50randomized trials of vitamin D vs no treatment or placebo by Yu Zhang and colleagues, supplementation made no difference in the risk for all-cause or cardiovascular mortality.^[1] Nonetheless, their research, which was published in the August 12, 2019, issue of British Medical Journal, found an association between vitamin D supplements and a lower risk for cancer-related mortality.

The authors of the current study argue that clinical trials of vitamin D supplementation are limited because they cannot ethically randomize an individual with severe vitamin D deficiency to a placebo or no treatment. To include more adults with vitamin D deficiency while also accounting for multiple variables that promote both vitamin D deficiency and worse overall health/early mortality, they employ a Mendelian randomization approach that uses genetic signals to help determine causation--in this case between vitamin D deficiency and mortality.

Study Synopsis and Perspective

Vitamin D deficiency increases mortality risk, and raising levels even slightly could decrease the risk, researchers examining data from the UK Biobank have found.

They used a Mendelian randomization approach, which uses genetic variants as "proxy indicators" for external factors that affect vitamin D levels, such as sun exposure or dietary intake. It allows for analysis of the relationship between deficiency and outcomes including mortality, which cannot be done in randomized clinical trials for ethical reasons.

Using this method, nutritionist Joshua P. Sutherland, PhD, from the Australian Centre for Precision Health, Adelaide, and colleagues found an association between genetically predicted vitamin D levels [25-(OH)D] and mortality from several major causes, with evidence of causality among people with measured concentrations below, but not above, 50 nmol/L. The findings were published online October 24 in the Annals of Internal Medicine.^[2]

"Unlike other types of observational studies, we have overcome some of the methodological obstacles. What is special about this new study is we were able to look at people with very low vitamin D concentrations and what would happen if their concentrations were a little bit higher. Most randomized controlled trials don't show much of an effect. That's because most people have sufficient concentrations. Ethically you can't do a trial of people with very low levels without treating them," senior author Elina Hyppӧnen, PhD, told Medscape Medical News.

The data support the 50 nmol/L cutoff endorsed by the National Academy of Medicine and align with previous data suggesting that the benefit of vitamin D supplementation is largely seen in people with deficiency.

"Everybody with vitamin D levels less than 50 nmol/L is recommended to increase their levels. Our results suggest there's no need to go very high. The positive message is that if we are able to raise levels to just the current US recommendations, that's fine. There's no need to use large supplement doses," Dr Hyppӧnen explained.

Thus, she advised, "Supplementation will clearly help, especially during wintertime or if a person isn't getting enough vitamin D from the sun or in places where food isn't fortified with vitamin D."

But the data do not support the approach of using large intermittent doses, she added.

"Sometimes doctors want to fix the deficiency quickly with a large 'bolus' dose, then continue with a maintenance dose. Increasing evidence suggests that's not beneficial and might disturb the body's metabolism so that it can't get the amount it needs. It's safe overall, but might not work the way we want it to work."^[3]

Rather, Dr Hyppӧnen said, "My sense is that daily modest vitamin D dose supplementation when it's needed is the best way forward."

The investigators analyzed data from 307,601 individuals in the UK Biobank, a prospective cohort of people recruited from England, Scotland, and Wales during March 2006 and July 2010. Most were of White European ancestry and were aged between 37 and 73 years at baseline.

Genetically predicted vitamin D levels were estimated using 35 confirmed 25-(OH)D variants. Participants were followed for outcomes up to June 2020.

The average baseline measured 25-(OH)D concentration was 45.2 nmol/L, and 11.71% (n=36,009) of participants had levels between 10.0 and 24.9 nmol/L. Higher levels were seen in people living in southern areas and nonsmokers, as well as those with a higher level of physical activity, less socioeconomic deprivation, and lower body mass index.

During follow-up, 6.08% of participants died (n=18,700). After adjustment for variables, odds ratios for all causes of mortality were highest among people with 25-(OH)D levels below 25 nmol/L and appeared to plateau between 50 and 75 nmol/L, with no further reduction in mortality at values of 75 to 125 nmol/L.

The risk for mortality was a significant 36% higher for participants with 25-(OH)D 25 nmol/L compared with 50 nmol/L.

With the Mendelian randomization, there was an L-shaped association between genetically predicted 25-(OH)D level and all-cause mortality (P for nonlinearity<.001) and for mortality attributable to cancer and cardiovascular disease (P for nonlinearity≤.033).

Again, the strongest association with those outcomes and genetically predicted 25-(OH)D was found at levels below 25 nmol/L and a plateau seen by 50 nmol/L.

Compared with a measured 25-(OH)D concentration of 50 nmol/L, investigators estimated that the genetically predicted odds of all-cause mortality would increase 6-fold (odds ratio [OR], 6.00) for participants at 10 nmol/L and by 25% (OR, 1.25) for those at 25 nmol/L.

In addition, compared with a measured 25-(OH)D concentration of 50 nmol/L, those with 10 nmol/L had genetically predicted odds ratios of 5.98 for cardiovascular mortality, 3.37 for cancer mortality, and 12.44 for respiratory mortality.

Comparing measured 25-(OH)D concentrations of 25 nmol/L versus 50 nmol/L, odds ratios for those outcomes were 1.25, 1.16, and 1.96, respectively. All were statistically significant.

Consistent results supportive of a causal effect of genetically predicted 25-(OH)D on all-cause mortality in those with low measured vitamin D concentrations were also found in a sensitivity analysis of 20,837 people of non-White ethnic origin.

The study was funded by the Australian National Health and Medical Research Council. Dr Sutherland's studentship is funded by an Australian Research Training Program Scholarship.

Ann Intern Med. Published online October 24, 2022. 

Clinical Implications

• A previous meta-analysis of randomized trials found that vitamin D supplementation made no difference in the risk for all-cause or cardiovascular mortality, but there was an association between vitamin D supplements and a lower risk for cancer-related mortality.
• In the current study, using a unique analysis based on genetic polymorphisms, vitamin D deficiency appears to be causal in promoting overall mortality, as well as cardiovascular, cancer, and respiratory mortality.
• Implications for the healthcare team: The health care team should treat vitamin D insufficiency and follow-up to ensure that levels reach the target goal.

Earn Credit