March 17, 2021
Vitamin D supplementation for older healthy adults has been much debated. Recent attention has been focused on its potential for reducing the risk for and severity of COVID-19, but there is an older argument, boosted by recent evidence, for taking vitamin D to reduce deaths from cancer.
The recent data come from three meta-analyses published in 2019 that show a consistent and significant 13% reduction in cancer mortality with vitamin D.
Impressed with these data, a group of German researchers has proposed that all patients older than 50 years receive vitamin D supplements.
If all persons older than 50 in Germany were given a daily dose of 1000 IU of vitamin D, almost 30,000 cancer deaths a year could be prevented, and Germany’s annual costs for cancer care would be slashed by more than €250 ($300) million, says the team.
Their article was published in Molecular Oncology on February 4.
«I was surprised by the magnitude of the effect that could be achieved with something as cheap as vitamin D, which costs almost nothing,» lead author Tobias Niedermaier, PhD, an epidemiologist at the University of Heidelberg, Heidelberg, Germany, told Medscape Medical News.
Most of the financial savings would come from a reduction in costs for end-of-life cancer care, he noted.
«From a cost perspective, it makes a big difference if people die from cancer or later from some other disease,» explained Neidermaier. «End-of-life care for a cancer patient in [their] last month of life is about four times higher than the medical care costs for people who die from other diseases like heart attack [or] cardiovascular diseases.»
This is also the case in the United States. As an example, in a recent analysis, end-of-life care for a patient younger than 65 with stage IV breast cancer was $6099 per month, compared to $2988 for a patient who died from a cause other than cancer.
Germany provides healthcare insurance for 100% of its citizens through a mix of public and private contributions. In their study, Niedermaier and colleagues calculated that distributing vitamin D 1000 IU/d to every person older than 50 in Germany would cost around €900 ($1072) million but would result in savings of €1.16 ($1.9) billion.
This represents a net saving of €254 ($302) million annually, or approximately 0.4% of Germany’s total drug expenditure in 2018. Moreover, 321,671 years of life would be saved.
In the United States, distributing a 5-cent vitamin D tablet to persons older than 50 would cost about $2.2 billion per year but would prevent 78,000 cancer deaths, save $3.7 billion, and endow older Americans with an additional 870,000 years of life.
An American expert who led one of the meta-analyses that acted as a springboard for the Niedermaier study agrees that the evidence that vitamin D reduces cancer mortality is indeed impressive.
«All of the trials showed a signal for risk reduction quite similar in magnitude,» commented JoAnn Manson, MD, chief of the Division of Preventive Medicine at Brigham and Women’s Hospital and professor of medicine at Harvard Medical School, Boston, Massachusetts. «There was a 13% reduction that was quite strongly significant for cancer deaths,» she said.
Despite the impressive results regarding cancer mortality, vitamin D did not appear to have any effect on cancer incidence in any of the studies. Manson said this finding is important: «There was really no reduction in cancer incidence, suggesting that vitamin D supplementation may affect tumor biology, rather than the initiation of cancer,» she said. «It may be affecting the invasiveness of the cancer, its aggressiveness, how likely it is to metastasize.»
Manson supports supplementation with vitamin D at a dose of 1000 IU. «I think [for] anyone with any concern about the amount of vitamin D they’re getting, it would be really reasonable for them to take at least 1000 IU a day, especially if they’re over the age of 50,» she said.
However, when it comes to population-based approaches, Manson prefers to focus on the food supply: «Food fortification is going to go a long way,» she said. «Lots of countries don’t have it. They should seriously consider policies of food fortification as the first line of defense.» (In the United States, vitamin D fortification is mandatory only for infant formula.)
A drug-repurposing expert expressed a note of caution about the proposal. «There’s evidence to suggest that increasing our intake of vitamin D would be a good thing to do,» commented Pan Pantziarka, PhD, «but it’s a very hard thing to prove a population-level [benefit]. The only way to do this is to look at prospective data in randomized control trial.»
Pantziarka is head of the Repurposing Drugs in Oncology (ReDO) project, an international collaboration between US-based GlobalCures and Belgium’s Anticancer Fund that seeks new indications for existing medications. ReDO provides grants for researching drugs that lack commercial backing. The organization has just signed up to support a randomized controlled trial called VidMe in Belgium and Hungary that is testing the use of vitamin D for patients with cutaneous malignant melanoma.
There have already been numerous studies of vitamin D and oncology outcomes, beginning with a trial led by veteran vitamin-D researcher Cedric Garland, MD, that appeared in The Lancet in 1985.
Pantziarka pointed out that there is «so much conflicting data…. When you look down into the detail, you find that even the recommended daily dose is subject to huge controversies, and the effects of vitamin D are modified quite strongly by things like body mass index [BMI].»
The relationship between body weight and benefit from vitamin D was highlighted in results of the VITAL trial, conducted in Brigham and Womens Hospital in Boston by Manson.
With 27,416 participants, this is the largest vitamin D study by far. It is comparing daily doses of 2000 IU of vitamin D (cholecalciferol) and 1 g of marine n-3 fatty acids, separately and in combination, against placebo. Women make up 50.6% of the participants, and 20.2% are Blacks.
Initial 5-year data from VITAL were published in the New England Journal of Medicine in 2019. The article, which detailed oncology outcomes, shows that deaths from cancer were 17% lower in the vitamin-D arm. A post hoc analysis in which the first 2 years of data were excluded to account for a latency period found that the effect was even greater (a 25% reduction).
Manson explained the reasoning behind this post hoc analysis: «You’re not really expecting that in the first few days ― or even the first year ― of taking vitamin D supplements, that’s going to lower your risk of dying from cancer; you suspect that there’s a latency involved. In cancer, even cancer death, the tumor takes a while to cause mortality.
«The 25% risk reduction [in the post hoc analysis] was statistically significant, so the bottom line is, I do think there’s biological plausibility here,» Manson said.
VITAL will continue to accrue data for at least 2 years because there are still some unanswered questions, according to Manson.
Benefit Only in Normal Weight, Not in Obese?
One of the questions that need to be clarified regards the differential effect that vitamin D has with respect to BMI or body weight. When the VITAL data were reanalyzed for people with a normal BMI (<25), the cancer-mortality risk reduction was 40%, said Manson, but there was no benefit for individuals whose BMI was in the overweight or obese range.
Other studies confirm these findings. It’s possible that vitamin D has greater bioactivity for people with healthy weight, said Manson.
A study by a Harvard team that included Manson and that was published last year found that obesity does indeed modify vitamin D efficacy. Healthy adults were treated for 3 months with either placebo or vitamin D3 at doses of 1000, 2000, or 4000 IU/d. More than half the group (56%, n = 141) were obese, and all were Blacks.
The team used suppression of parathyroid hormone (PTH) as a surrogate for vitamin D activity, said lead author Edward Giovannucci, MD, ScD, professor of nutrition and epidemiology at the Harvard School of Public Health. In the persons of normal weight, there was a clear dose response between vitamin D and suppression of PTH. By contrast, in the individuals with obesity, 1000 IU of vitamin D dramatically reduced PTH, but there was no further reduction with the higher vitamin D doses.
«While it is not surprising that overweight people have higher PTH due to generally lower vitamin D, we cannot completely overcome the effect of higher body weight by giving more and more vitamin D,» Giovannucci told Medscape Medical News,
Translating the Proposal to the United States
How might the estimates for Germany translate to the United States? A quick calculation suggests it could save $1.5 billion.
Assuming that all the persons older than 50 are provided with the cheapest brand of vitamin D 1000 IU, at 5 cents per tablet, a strategy similar to that advocated by Niedermaier and colleagues would cost $18.25 per year per person, or $2.2 billion per year across the United States.
On the basis of US costs for end-of-life cancer care provided in the German article, this would result in savings of $3.7 billion for families, government, and insurers in the United States and a net benefit (after paying for the vitamin D) of $1.5 billion.
Americans would gain an additional 870,000 years of life per year. In a very conservative scenario in which end-of-life costs are disregarded, the cost-effectiveness ratio is $2529 per life-year saved.
Niedermaier and colleagues found that vitamin D 400 IU/d and 1000 IU/d were «cost saving,» that is, there was no extra cost per life-year saved because of the healthcare savings. The highest dose ― 2000 IU/d ― cost €692 ($830) per extra life-year saved.
The researchers found that in a worst-case scenario, there was a 4% reduction in cancer mortality, rather than a 13% reduction. In this scenario, the cost per life-year saved for vitamin D 1000 IU/d was €5506 ($6600).
By contrast, the authors indicate that letrozole costs $71,084 per life-year saved, and atezolimumab costs $94,965 for each extra year of life. In Germany, FOLFIRI plus cetuximab for RAS wild-type metastatic colon cancer confers an extra year of life at a cost of €36,360 ($44,000).
The authors conclude, «Our results suggest that daily vitamin D supplementation in the German population aged 50 years and older for reducing cancer mortality would be overall cost saving, or at least highly cost-effective.»
The study was funded by the German Cancer Aid. Neidermaier, Manson, Pantziarka, and Giovannucci have disclosed no relevant financial relationships.
Mole Oncol. Published online February 4, 2021. Full text