Get In Mah Belly 2: Fun Size Food Facts



What originally started as a "fun size food facts" blog has quickly turned into "all you can eat buffet world eating champ facts" blog. I've combined calcium and vitamin D as you really can't talk about one without talking about the other and quickly found out that I bit off more than I could chew. A lot like real life eating for me actually. Much of this might be review for you (especially SFH residents) but it's always good to have a refresher. And since calcium-vitamin D is a pretty dry topic, I have decided to post random pictures of cheese for your viewing pleasure.

If there was a single vitamin or mineral that my mom used to back her opinions on food, it'd be calcium. Every healthy thing in our fridge or pantry was a "good source of calcium", especially foods I hated (looking at you, beans). I kind of think she stole it from the boxes of cereal that would advertise that same statement. In actuality, it's not that hard to get a decent amount of calcium on a traditional American diet. Cheeseburger here. Milkshake there. Metformin for dessert and you're done. But what about more calcium or vitamin D for either the general public or those at higher risk for osteoporosis? 

The now well known landmark study that helped propel the calcium-vitamin D discussion was the Women's Health Initiative (WHI) [1]. In short, the massive study looking at women aged 50-79 years old found a small benefit in terms of bone mineralization but no significant benefit in fracture rate in those taking 1,000mg calcium and 400IU vitamin D supplementation when compared to placebo. [2] The study did have some limitations as it was looking at a general population and not specifically at higher risk patients (decrease calcium-vitamin D in diet, known low bone mineralization) in addition to being a relatively low dose of both. But overall it gave some evidence to the thought that maybe the ol' calcium-vitamin D combo wasn't as potent as once thought.

There was also another study that also came out in 2006 but this one pointed to some benefit. It was a double-blind five-year RCT that looked specifically at elderly females (>70yo). They were randomized to take calcium carbonate (600mg BID) versus placebo and found that there was indeed a significant decrease in fracture incidence (10.2% vs 15.4%; HR, 0.66; CI 0.45-0.97). But the kicker? It was only seen in those were took their supplements greater than 80% of the time. [3] Surprise - you have to take your medications for them to actually work.

That was 2006. But what did 2007 bring? More evidence for the calcium-vitamin D tag team.

A meta-analysis of 29 RCTs looking at all adults greater than age 50 found a significant decrease in both all fractures (RR 0.88, CI 0.83-0.95; p=0.0004) as well as bone-mineral density. They also note again that compliance was a big component as there was a greater fracture incidence reduction (24%) in those with high compliance (>80% of the time taken). Dose was also a big variable as those taking less than 1200mg had less of a benefit than those taking more than that dose (0.80 vs. 0.94; p=0.006). So what do we take away from this? Again, dose and compliance seem to be major players in preventing fractures in older adults. [4]

So it looks like there's some growing evidence for calcium supplementation in older, compliant adults.

Now what about vitamin D?

Again, looking back at the WHI study. We saw that the combination of calcium and vitamin D yielded no benefit in terms of fracture incidence. One thing to remember is that they studied a relatively low dose of 400IU daily. Looking back at the 2007 meta-analysis above, they found a small but significant incidence reduction in fractures when patients supplemented with 800IU or more versus those with less than that amount (RR reduction 3%, p=0.03). So it might just be a dose dependent thing?

Unfortunately, the years 2007-2010 say no.

From 2007-2010, several studies came out that showed no evidence for fracture incidence reduction in those taking only vitamin D. [5,6,7] These studies mainly looked at all adults greater than age 50 and most studies included in these pooled analysis looked at vitamin D dosages greater than or equal to 800IU. The largest and most recent of these [7], had a mean age of 69.9 years and looked at over 68,000 patients. It found no evidence for either 10 or 20 microg doses of vitamin D (aka 400 or 800IU). Bummer.

But wait! The years 2011-2012 say.... maybe?

A meta-analysis was done for the USPSTF in 2011 that looked at the potential benefits and harms of vitamin D with and without calcium supplementation [8]. This study ended up showing a significant reduction in fracture incidence for institutionalized patients (RR=0.71, CI 0.57-0.89]) but not in community-dwelling patients when supplementing with calcium-vitamin D. They also found no significant reduction in incidence for any dose of vitamin D. This was the start to the 2013 recommendation by USPSTF, which we'll see in a little bit. On the flip side, an equally large meta-analysis in 2012 showed there was actually a benefit to fracture incidence reduction in higher vitamin D dose supplementation (>800IU) in those 65 years or older. [9]

Ok, let's regroup.

All this back and forth is great and stuff but there isn't a really reliable trend in all of this data, especially for vitamin D - leads us to February 2013, when the USPSTF came out and gave no recommendation for vitamin D and calcium supplementation (Meta-analysis). Specifically, they gave an "I" recommendation for insufficient evidence to adequately weigh the harms and benefits of calcium and vitamin D supplementation. So why the sudden change from previous recommendations?

A very long story short(er) is that there just wasn't enough robust data to trump the sporadic data showing potential harms. Specifically, those harms involve kidney stones and cardiovascular disease (CVD). Initially in the WHI, they proposed that they would actually see a benefit in terms of CVD outcomes. However, they ended up finding no benefits at all and some subsequent studies in 2010 and 2011 actually showed a potential increase in CVD outcomes in those with calcium and vitamin D supplementation. [10,11] One of these two studies actually reanalyzed the WHI data set to specifically look for those women who began supplementation after the start of the trial. They found a RR of 1.24 (p=0.004) for risk of MI's. Their rationale for why the WHI showed no change in CVD outcomes was that a vast number of participants were actually taking supplements prior to the trial, thus negating and difference seen in the control and study groups.

Even more recently, there have been studies in the past 2 years looking at calcium supplementation that showed potential excess CVD risk in adults aged 35-64 as well as men aged 50-71 but not women. [12,13] Combine this with the WHI also finding a small but significant increased risk of kidney stones (HR, 1.17; CI 1.02-1.34) and you have yourself a nice smear campaign going. But of course in the midst of all these negative studies there was also a meta-analysis that found no increase CVD risk with calcium supplements and even a small benefit (RR=0.90) for fracture incidence for vitamin D. [14] It's important to remember though that there has not been a single study yet (as far as I know) that has shown an increase in all-cause mortality. The only adverse studies have been with regards to CVD events.

You can now start to see that the once clear waters of calcium appear to be quite milky murky.

With regards to adverse effects of vitamin D, there aren't many unless you're taking outrageous doses (500,000IU single dose increasing fracture risk) or for some other reason have elevated levels in your body. One study looking at several different nutrients and vitamin levels (B12, folate, iron, vitamin D) in adults aged greater than 75 found that both low (<20ng/mL) and high (>30-50 ng/mL) vitamin D levels were correlated to mortality.  [15] That really doesn't mean much to me except don't take exorbitant amount of vitamin D.

So what did I take from all of this? To me, calcium is much like fish oil in that you'll never find a negative study on it as long as it's dietary. All of the main positive fish oil studies were dietary and all of the negative calcium studies have been supplements. So overall, I'd probably take a cup of milk or a slice of Gruyere over a calcium pill. If I had a patient with increased fracture risk and no cardiovascular history, I'd probably advise them to take 1200mg calcium and 800IU of vitamin D. If the opposite were true, I'd probably advise them not to take any calcium-vitamin D supplements. I'm less convinced either way with Vitamin D alone as there isn't really a concerning side effect profile but there's also not a ton of great evidence for it with regards to fracture risk. I'd probably tell my patients I'm fine with 800IU vitamin D either way, especially if they have a history or risk of falls.

In the end, the best medicine is probably not a supplement but to tell your patient to smile and say "cheese".