 In 2019, a study found an association between high intakes of vitamins B6 and B12 from food and supplements with the risk of hip fracture among post-menopausal women in the Harvard Nurses' Health study. But note it was only the combined high intake of vitamins B6 and B12. We know that treatment with high doses of vitamin B6 may alone increase hip fracture risk after a decade or so. Those who had been taking high-dose B6 supplements had about 40% higher hip fracture risk, but not in those taking B12. And that's what the Harvard study found, too. High intake of vitamin B12 alone was not associated with increased risk. In fact, some observational studies suggest slightly lower fracture risk at high B12 blood levels, but what we care about most are interventional studies where people are randomized to B12 so we can see what happens. And when you do that, no increased fracture risk among those given B12. In conclusion, based on randomized controlled trials, high doses of vitamin B12 have not been shown to be associated with the risk of fractures. Okay, but what about this? In 2017, a study found that men taking vitamin B12 supplements appeared to have an increase in lung cancer risk. Now they didn't find any such association in women. It was mostly among smoking men. I mean, could it be that B12 was like feeding some budding tumors? I mean, it's hard to imagine a vitamin being carcinogenic on its own, and especially somehow only men, not women. The bottom line is that replication of these findings with additional studies is necessary. And indeed, when you put all the observational studies together, there was no significant correlation between the levels of B12 in the blood and lung cancer, whether you smoked or not. I mean, if anything, most studies seem to be trending towards higher B12 levels being protected. But then in 2018, a new study found an association between overall lung cancer risk and higher circulating levels of B12, again appearing to be more of a smoker thing. Now this was another observational study. Those with higher B12 levels were just observed to have higher cancer levels. And so those of you who've been following my work know the drill. There are two potential issues that arise in observational studies that prevent you from ascribing cause and effect, confounding factors, also known as lurker variables, and reverse causation. What might be a lurker variable in this case? A third factor associated with both higher B12 levels in cancer, and that may be the true cause? Well, who has higher levels of B12 circulating in their blood? Those who eat lots of meat and dairy. In fact, probably the most important contributors. And those who eat more meat do tend to have more lung cancer, about 35% more risk for every about daily quarter-pound burger, and 20% increased risk for each like breakfast sausage leg. So no wonder. Those with higher B12 levels in their blood could have more lung cancer. The B12 could just be a marker for meat intake. And if you remember, reverse causation is when instead of X leading to Y, maybe Y is instead leading to X. So instead of high B12 blood levels leading to cancer, I mean maybe cancer leads to high blood levels, and indeed nearly three-quarters of cancer patients exhibit elevated B12 levels. So elevated B12 levels may just be a marker for cancer. There's all sorts of things beyond just taking extra B12 that can raise your levels of liver problems, kidney problems, bone marrow problems, and cancer. So high levels may just be a marker of a brewing not yet diagnosed cancer. Yeah, but what about observational states specifically linking supplement use to lung cancer? That too could be reverse causation, where being at risk for cancer, in other words being a smoker, makes you more likely to take vitamins to try to decrease your risk. And basically any behavior tied to smoking could be indirectly tied to lung cancer, but it's the smoking itself, of course. It's the real lung cancer risk. So we're left with this chicken-of-the-egg causality dilemma, which is why ideally we need to randomize controlled trials to see if there's any cause and effect. This became even more urgent, with genetic evidence suggesting that those just born with higher life-long levels may be at increased risk. Thankfully we do have randomized controlled trials over a dozen randomized controlled trials randomizing thousands of people. Up to 2,000 micrograms of B12 every single day for years. And vitamin B supplementation does not have any effect on getting cancer, dying from cancer, or dying overall. And this includes specifically looking at lung cancer. And in fact, if anything, vitamin B supplements may actually lower the risk of the most dangerous form of skin cancer.