  resisting  of ʻʻqvai ʻtana ʻtanga Thank you Frank. ʻthe ʻjianni wrafārwā ora gaija bangat aicok, ʻi qxatak o bet venir o bet hohven ʻtaia. ʻĀtata ʻu ʻalsu rai wia uʻtina kai ʻeʻtā u rai kai skirts ʻpā ʻaetama bai qoya ʻaту. ʻkezi ʻi ʻadenduri ʻaerikair anget ʻo ʻi rai ʻaerikair ngen gai. ʻu ʻlenia ʻmila guarantees but unfortunately he didn't get a skull x-ray done before he died, so that remains a speculation. But what I'm going to take you through now is a sort of a 7 minute whilst through 20 years of work, and about 20 years ago we started thinking it was time someone did a definitive study of calcium supplements, we all prescribed them, lots of people took them, self-prescribed, and we all knew they worked. It's just that there wasn't any hard evidence that they worked. We all knew they were safe, though that had never been documented either. And there were hypotheses that they might do other things apart from making your bones stronger and preventing fractures, that might be good for your heart. And so we decided we'd do a study with the support of the Health Research Council that would address those questions. And we called it the Auckland calcium study, and our principal hypothesis was that calcium would prevent fractures, but we did have the secondary hypothesis that calcium would reduce the incidence of heart disease. And there's some evidence that people who come from hard water areas and hard water is caused amongst other things by having lots of calcium in it, have less heart disease. And there's some evidence that if you dose people up with calcium, you make their lipid profiles better. So that wasn't just something we plucked out of the thin air. And so we recruited 41471 willing volunteers from around the Auckland region. They were randomised to calcium each day, or to placebo, and they took that for five years. So that was one of the primary end points, as I pointed out, were fractures and bone density and then indices of heart health. The funding issue if we want to get into the politics of it is quite important. This was funded by the Health Research Council, and that actually proved to be critically important when we got answers that we didn't want or expect, because it meant we weren't held hostage to various commercial entities, though the calcium was supplied by an American company, and it's interesting when we got to the critical break point and we thought they were going to give us a really hard time about what our findings were. We discovered that they had divested themselves with that portfolio, which raises a number of different and rather interesting issues that we won't need to talk about today. So just to quickly leap forward seven or eight years from the planning stage to the results stage, this was the bone density data. And so we can see the changes in bone density and percent of baseline over the five years of the study. This is the placebo group, which as we expect in normal postmenopausal women lost bone density, and the people who were randomized to calcium actually lost bone density as well, but at a slightly slower rate. But the difference all occurred in the first half of the study. We don't know how early because we only measured bone density. The first follow-up bone density was at two and a half years, and the difference is really quite small on absolute terms. It's about 1%, which doesn't sound like a lot and probably isn't. And in the second half of the study, the two groups really just paralleled one another. Fractures, of course, is what matters a lot more. And this is where it starts to get complicated. So these are the percent of people in the calcium group shown in blue and the placebo group shown in black over the five years who have had a fracture. And if you look at total fractures, there is no significant difference between the groups. The blue line and the black line are all wrapped up between one another. If you're a true calcium believer, then you focus on the forearm data where it seemed that using calcium had reduced the risk of fracture by perhaps one half. And if you're a calcium skeptic, you focus on the hip fracture data where the effect actually went the other way and was rather larger in magnitude and remains quite a significant source of concern because other studies since then have actually found a somewhat similar finding. So on the basis of the bone data, we concluded that perhaps the fracture data was inconclusive, but there were positive effects there with bone density. And so it can't be doing any harm, so people might as well take it. And then we moved on and started looking at the heart endpoints. And this is the data for myocardial infarction. So this is the same sort of format as the fracture data. So the percent of individuals who've had a heart attack over the five years of the study and over the first couple of years not really very much happened in the line started to separate and did actually separate in a statistically significant manner. The only problem was it was the wrong way round. And so we found, depending on how you do the analysis, a 30% to 40% increase in the risk of having a heart attack if you were randomized to calcium. So the British Medical Journal had the courage to publish that. It caused something of a storm. I myself thought if this was really true, someone would have found it before then, but of course, no, we didn't ever looked before. And of course, if you don't look, you may not see. And we decided the only way forward. I mean, the definitive way when you get a surprising or inconclusive result in a clinical trial is to do a much bigger clinical trial. But of course, you can't recruit a whole lot of normal volunteers and say, by the way, our hypothesis is that this tablet might give you a heart attack. And so we wrote to everyone who had ever done a decent sized study of calcium supplements and said, did you collect other medical data on the subjects in your study? And many of them had and all of them were happy to share that with us. And so Mark Boland and our group put together a series of meta-analyses and this is really the last of these meta-analyses where we had almost 30,000 people involved in this group of studies. And the way this data is presented, the vertical solid line is the line of no effect. The size of the square indicates the size of the study and the horizontal line represents the confidence intervals. And so you can see all the major studies actually suggested there was an increase in the risk of heart attacks, though none of them, or perhaps with the exception of this, well, Women's Health Initiative study, were actually statistically significant. But when you lump them all together, there was a 24% increase in the risk of heart attacks, which was statistically significant. And actually that effect appeared really quite early on. So really from perhaps after the first year or so of being on calcium there appeared to be an increase in the risk of having heart attacks. More recently then we've gone on to try and find what the mechanisms for this might be. The simplest explanation, of course, is that we know that sick arteries have calcium in their walls and if you just feed lots of calcium to people, some of it will deposit it in the arterial walls. And we've actually got a PhD student working on that hypothesis at the moment and there is evidence from other researchers that that does indeed happen. But that doesn't rule out other possibilities. And so Sarah Bristow, who was my PhD student and over the last couple of years started looking at what happens biochemically when you take a calcium supplement. And so this is the change in blood calcium levels in the eight hours after normal women take a simple one gram calcium supplement, two different sorts of supplements here. But your blood calcium level goes up quite a long way, often above the upper end of the normal range, whereas people who take a placebo meal don't have any significant change in their calcium over that time. Does that matter? Well, it just might. And so one of the other parameters Sarah looked at was blood pressure. And so we see the placebo group here whose blood pressure actually fell during the day. It went up and down a bit according to whether they'd had meals or whatever. But actually it fell rather less than the people who were given a calcium supplement at time zero. And for much of this period of this day after they'd taken their calcium supplement, the difference in blood pressure is about 10 millimetres of mercury, which is quite a big difference in blood pressure. And that's the sort of decrease in blood pressure that your doctor might hope to get when he or she starts you on a blood pressure medication. So we have now reproduced that in the second study. And those sorts of changes in blood pressure certainly could account for changes in heart attack risk. Sarah also looked at the coagulability of blood because one of the key functions of calcium is to facilitate the coagulation of blood. And she calculated a complicated index called the coagulation index, which actually goes up significantly in patients and individuals, normal individuals who take a calcium supplement. So your blood is more clotting after you've taken a calcium supplement. And again, that can contribute to you having a heart attack. Has this had effect? Well, this is what's happened to calcium supplement used in New Zealand steadily building throughout the first decade of this millennium. This is our first BMJ paper we're at leveled off. And then this is our subsequent meta-analyses in the BMJ and calcium use in this country has been in freefall. Since that time, the effects overseas have been slightly less dramatic because they're more skeptical overseas. But we've taken $1 billion a year off the world consumption of calcium supplements. And so that's quite a significant environmental impact, we think. More importantly, it's led to a re-evaluation of the role of calcium intake, which has probably been hugely over-emphasised in the past. And it's led to international consensus that we should be looking to our diets to get calcium, as well as probably most of the other nutrients we use or we need rather than taking supplements. And if we really want to prevent fractures, then we should be looking for other means which, fortunately, are available. Thank you for your time. APPLAUSE