Ian Reid, M.D., featuring Natalie Sims, Ph.D.

In this JBMR at 40 anniversary episode, Natalie Sims, PhD speaks with Professor Ian Reid (University of Auckland), a leading figure whose work has helped define modern osteoporosis research and care.

Reid reflects on landmark contributions — from early bisphosphonate trials that reshaped treatment pathways to influential, and at times controversial, findings on calcium supplementation and cardiovascular risk. He also shares insights on the evolution of the field, the enduring impact of JBMR and ASBMR, and the importance of rigorous, evidence-based science.

With candor and perspective, Reid offers valuable guidance for the next generation: ask meaningful questions, design studies carefully, and have the courage to trust the data.

A thoughtful and celebratory look at four decades of progress through the lens of one of the field’s most impactful voices.

Transcript

SPEAKER_00 0:39

Particularly, but not exclusively, in clinical trials, including identifying the effects of calcium supplementation on cardiovascular risk and looking at the use of different mistosphanates in over his career, but particularly most recently looking at solidronic acid in osteopenia and changing the way that that's prescribed. Ian, it's really nice to be talking to you.

SPEAKER_01 1:04

Thank you for doing me the honour.

SPEAKER_00 1:07

Ian, we'll start with some sort of questions about your history. And I'd like to start with hearing about your first paper in JBMR and perhaps what influence that paper or something else you published in JBMR had on your career.

SPEAKER_01 1:23

Well, my first paper in JBMR, I had to go and look this up, but my recollection was correct. And so it was a study of giving permitronate to people who were receiving uh steroid treatment, and the end point being bone density. And actually, that key paper, which really was a very pivotal paper for me, but I think also for the field, because it was the first successful trial of the bisphosphonate in any form of osteoporosis. And we published that in the Lancet in 28, uh 1988. Um, but it we didn't put any of the biochemistry in it because that all got cut out. So we published that in this JBMR paper, uh, which came out, I suppose, two years later. And I I I one of the referees I think had a problem with it. I can't quite remember what it was, but I remember Larry Royce played a very key role as the editor and smoothing all of that over. So just do the system as in it'll all be fine, which I did. And uh and that led to uh me doing lots and lots of uh uh reviews over the years for JBMR. So sort of Larry adopted me as one of his reviewers at that very early stage of my career, which was also um a great honour. And and I think subsequently I did a quick count for my CV. I think I've had almost 50 publications in JBMR. A lot of those were letters because some things we wrote were controversial and led to a significant amount of to and fro. But I think JBMR has been really critical. And at times I've gone off into other journals because I've sort of found other journals have significantly higher impact factors. But actually, I keep coming back to JBMR because if you actually want your the bone colleagues wherever they are in the world to read a paper, put it in JBMR. If you put it in higher impact general medical journals in Europe, then you find no one's actually seen it. And um, and you sort of have to sort of almost republish it through presenting it at meetings and things. So I think JBMR has absolutely been the go-to place for all of us working in the bone field basic or clinical, um, because everyone who works in that field scans JBMR, and I think very much JBMR Plus now as well. And so I think the PRFM are a very powerful way of communicating the things that you think matter to your colleagues, and also it doesn't publish any rubbish. So that's why that we all look at it, we don't all necessarily look at every other journal in the area because what's in JBMR is generally uh quite significant.

SPEAKER_00 3:50

Um you talked a little bit about about Larry Royce's influence on you in in coming in and and doing some reviews for JBMR. Um what who were some other people who were were strong influences on your career?

SPEAKER_01 4:04

Yeah, I sort of thought about that, and it's very difficult because there are so many people who have, if you like, nurtured me, supported me, uh argued with me. Um, you know, ego seaman is someone who stands out as someone who always argues, and and it's brilliant because um I've often said to people can't say that at a meeting, you know, ego would leap up and you know wave assists. So, you know, I think having people like that in the field that keep you honest because they test everything, sometimes more than they perhaps should, but I think that's a very important influence in the whole field. I think the the people who influenced me most were perhaps a variety of um non-bone people who were my senior colleague who and I was a first, second, third year doctor. Um, and in a totally non-threatening way on Woodrunch, we would say, so what's the evidence for that? Whatever it was. And I just got used to the idea before anyone talked about evidence-based medicine, as being aware of what we did because it was customary practice and there was no evidence in that space, or what we did because there was a good trial that showed that this worked better than that worked. And so I when I moved into the bone field a few years later, I brought that background with me, which I think has stood me in good stead. There are other people who were important influences early in my career and have are still there. Uh you know, Jack Martin, uh Graham Russell are two um very distinguished people who've always sort of been there providing advice, refereeing my grants over a period of 40 years almost. Um, Steve Cummings, who really taught me how to do RCTs and I think rigorous RCTs and rigorous interpretation of the data rather than trying to squeeze things out of trials that fit your own particular prejudices. Um, and then more recently, Mark Boland, who um is a junior, was a junior colleague of mine now, uh a colleague of mine in Auckland, but he really introduced me to meta-analyses uh in various forms. Um, and that really was what led us into um the the morass of calcium and vitamin D, and you know, there's one positive study and there's four negative studies, and everyone just wants to talk about the one positive study and forget the other four. And I think that more uh holistic view of the whole literature uh that meta-analyses bring when they are done properly, and of course, meta-analyses can be subverted as well. So I think Marx uh as a colleague and I've worked together for about 20 years, I think has been a very important part of that travel. But together with many, many other people who've been, and you know, many of whom are members of ASBMR angle, ANZBMS have been uh with us on the journey and testing us and encouraging us and so on.

SPEAKER_00 7:00

Um that kind of leads into another question, which is which is the impact of of societies and journals on on your career and and uh and things that are important about particularly ASBMR and the JBMR. So can you say some words about the impact of JBMR and ASBMR on your field and what you value about those two institutions that are linked?

SPEAKER_01 7:28

Yeah, and actually everything positive I say about ASBMR will probably apply to ANZBMS as well, because they came into existence at almost the same time. And if you go back to that time, no, there were no bone societies if you go back to the 1980s. I think ASBMI came into existence, I think, in 1986, and and I was um at one of their early meetings and have been to virtually all of them since then. Um, and so it we got out from being under the wing of various endocrine societies or rheumatology societies or whatever, and got our own distinctive um uh place. But I think also what happened at that time, and if you think back to the meetings that we had, particularly during the 90s and the early 2000s, every meeting ASBMI would do when you went to, you went home. Um, you know, doing a journal club next week was an absolute dawdle because there were major new things to discuss. And that applied to the basic biology of bone uh as well as to the clinical stuff. And the two were just bouncing off one another. Um, and uh, and so those meetings were extraordinarily exciting because um people went to great pains to have their best stuff ready in time for the ASBMR rather than anywhere else. Um and so bone and osteoporosis as a clinical discipline really came from nowhere in the mid-80s to the place they have today. I I think meetings now are less exciting than they were because the pace of uh advancement in our area has slowed. You know, we have worked out the basic building box a bunch. No one could do anything with osteocytes, they uh, you know, they knew they existed in the 1980s, but no one could actually culture them or characterize them. We didn't know what most of the molecular factors were that sent signals backwards and forwards between the various bone cells. Um, in therapeutic terms, we were talking about calcin vitamin D and HRT. Um, and bisphosphonates were sort of around, but they were something used in Paget's disease and didn't work very well anyway. Um, and so you know it's easy to forget just how rudimentary the field was and how dramatic the explosion was that took place subsequently. Yeah, I I think one of the sad things about ASPMR just in the current political situation is that some of us don't feel very comfortable coming to the United States at the present time. And I think that's a major threat to all academic medical societies because America really has been the central focus uh of the bone field and meetings, but I think probably much, much more broadly across all the medical epidemic.

SPEAKER_00 10:08

Yeah, that's true. Um while we're talking about big findings that have shaped the field, um what what do you see when you look look at your career so far? Because you're still going. What do you think of about your discoveries? Which ones do you think move the field forward the most? What are you most proud of, Ian?

SPEAKER_01 10:34

Well, I think I'm most proud of the first thing I ever did, which was my trial of amidrenate uh and steroid osteoporosis. Uh as I said, Panamat's it in 1988, and then we was sort of an extra year follow up a year later. Um, because it was the first randomized controlled trial in any form of osteoporosis that showed an effect. There'd been an earlier trial with the tidrinate that didn't really produce anything, but there weren't proper ways for measuring bone density when that was done back in the 70s. And I think our positive data with Pamidronate, not that that went on and became an osteoporosis drug, but was I think the key factor from what William Lagana said to me for Merck going off and finding the nearest molecule they could to pemydronate, uh, which was a lendronate, uh, which they licensed in, and then we all know what happened to a lendronate and phosphomax, and then everyone else got on that bandwagon. And then that ultimately led to a number of the companies, notably SIBA, but also um Roche and uh uh Procter and Gamble synthesizing hundreds of other bisphosphonate molecules, and so that led ultimately to zoutrinate. Um, and that's been a fascinating journey that I've sort of been on since I first encountered it in the late 1990s. And it continues to provide us with surprises in terms of what it can achieve. And a lot of those surprises sort of come or have come in entirely by accident. You know, the idea that you would give a bisphosphonate by injection when you're trying to treat a long-term disease type osteoporosis, I think that was born out of, I mean, that was obviously place idea that you're not to nosis, but um I think it was really because they felt the oral bisphosphonates were all pretty well sewn up, so they needed to find a new trick. And you know, what came with study to me is discovering that you can get a vastly longer duration of action if you use a very potent bisphosphonate intravenously and basically coat the entire skeletal surface and so you can give it once a year, but actually you can give it every five years, and maybe you can even give it every ten years, based on my wild's recent publication. So, you know, I I think that's sort of come by accident. I don't think anyone sat down with the first pistphosphonate and said, obviously, we should give this intravenously, it'll work much better.

SPEAKER_00 12:55

Yes, yes. What what what have been some of the the challenges that you've had in your field?

SPEAKER_01 13:03

Well, I think the whole calcium story has been challenging. Um and that was a very interesting if slightly uncomfortable to me. Um when we did the Auckland calcium study, uh the intention, because we previously had a New England Journal paper in the early 90s saying that calcium has positive effects on bone density. Um I'd always been brought up to be a good boy and believe in calcium. And so I thought, well, let's do a bigger study that will demonstrate that it um has uh that it prevents factors. And also there were some suggestions that it might have beneficial effects. We published papers showing that it had beneficial effects on lipids uh and maybe on blood pressure, small effects, beneficial effects on blood pressure. So we actually specify cardiovascular disease as an end point of that study. And the fracture data we found an increase in the risk of hip fractures, no change in total numbers of fractures. That was difficult and embarrassing. Uh, and then we found this increase in cardiovascular risk. And um they weren't what we were looking for, um, but they were important and we published them. And and the response to that was very interesting because um some people had built their entire careers on a belief in Gaussian. Um so some of the vitriol that came our way was quite extraordinary, and some of the scientific dishonesty as well. Um whereas a lot of other people said much of unless, well, I never knew never thought it would work anyway, or or basically, you know, stick to your guns, you know, do the studies, publish them objectively. And that was how we got into the whole meta-analysis, because despite of lots of people saying, well, you know, you've got to do a randomized control trial to prove that this stuff causes heart attacks. Well, of course, no drug adverse effect has no one's actually set up to do a trial to prove that a drug is is harmful. So that was what led us into meta-analysis because the only way to actually get more reliable data is to draw together all the other studies that have been done in that space. Um and and over time there has been collateral uh information coming in from um Mendelian randomization studies and others that suggest that calcium probably does have an adverse effect uh on uh palliovascular disease. But I think the more important thing that's happened through during the B trials as calcium, as it subsequently happened, is that you can see that it doesn't have any beneficial effect on bone density. So who cares what effect it has on cardiovascular disease because it's not something that has a therapeutic role to play. And so I think that's allowed a lot of the heat to go out of the area. But you know, some people, particularly some close to home in Australia, um were very vociferous because their whole careers had been based around that that tenor that calcium was going to be great stuff, and it it proved not to be. But it's interestingly um there's still quite a lot of calcium um prescribed around the world rather than there was. Um there are large commercial interests in calcium and it continues to be promoted even though the evidence of its use is basically negative.

SPEAKER_00 16:16

Yes. This is probably a good moment to ask you um what message you'd like to share with the next generation of bone researchers.

SPEAKER_01 16:30

Um I think with bone researchers, I think the answer is to think carefully about your questions. Um most of the questions that I've addressed, whether we've addressed them in the lab or using epidemiological databases or clinically, have come from clinical issues. Um so I think it's really good, even if you're a uh a pure lab scientist, have mates who work clinically, see what the clinical questions are, because I think that will lead you on to more interesting questions. Yes. And people who are laboratory-based or animal research based are often able to address questions that clinicians themselves can't actually address. Um, so I think have good questions. Um, design your studies with great care. Uh and again, I think Steve Cummings taught me how you write proper uh protocols and and how you write proper analysis plans and how you think through all of these issues before you've ever collected the first piece of data. And I think often lab people are a bit further behind in that aspect. But I think it's quite good to have thought carefully about what your questions are going to be, how you're gonna do the studies, what the proper statistical power is, and how you're gonna analyse them rather than just gathering a great mass of data and then zipping through it and doing as many t-tests or whatever as you can and saying we've come up with three significant B-values. This is really important because that's the way when I started out, a lot of science was done, and you do get these problems of spurious results because you haven't really thought of how you're going to do it. Or spuriously negative results because you do trials with 20 people in each group, and then you really need a hundred or a thousand or whatever. Um so do your trials, design them well, record everything with great detail, do the studies rigorously, and then stick to your guns when you've got the data that you can have confidence in. And I think the vitamin D area, I remember a colleague presenting a negative vitamin D study and saying, So why didn't it work? And that wasn't the question. The question was, we've done a properly powered study, there is no effect on bone density. So what does this mean clinically? But that wasn't the question that the people at that particular presentation were interested in addressing. And I think, you know, then we've gone on and done 25,000 person studies and shown that yeah, it doesn't work when you've got 25,000 people, just as it doesn't work when you've got 1500. Um, and and so you need to believe your own data if you have designed it and carried it out appropriately. If you've just taken a convenient example of 20 people in each loop and it doesn't work, then that's meaningless. So don't waste your time. So design your studies carefully do them properly, and then have the courage to um accept your results and see who you go to next. And in many ways, uh our calcium study was an example of that. But we some people say, Well, ignore heart effects can't possibly be real, it's ridiculous. Just ignore them. Why would you want to publish them in a proper journal? Well, I don't think that's the right approach. If you power the study to lock it harder with events and you get an answer, you've got a responsibility to publish it and then to pursue it and see where it goes to me.

SPEAKER_00 19:53

That's a great piece of advice, Ian. Uh believe your data and and stick to your guns if you've designed the experiment properly.

SPEAKER_01 20:02

Yeah, and and I think the sort of other way of stating that is don't believe, you know, that something is good or something is bad, or have hypotheses and then test them. And then when you get the opposite answer from what you expect, it's not a failure, it's a surprise. But have the courage to be surprised and go with it.

SPEAKER_00 20:20

Yeah. Sometimes I think the most exciting result is the one that's not what you expected. Because it means you're wrong. That's great.

SPEAKER_01 20:27

Yeah, that means you can move forward.

SPEAKER_00 20:28

Yeah. One final question, um, which is we we've talked about the message you might you'd want to share with the next generation in research, but what about the next generation in patient care? Clinicians.

SPEAKER_01 20:42

Yeah, well, I I'm actually as I sort of move into my quasi-retirement, I'm doing more clinical teaching than I was because I'm not questioning around being a uh an academic administrator in the way that I was. Um so I think clinically, um, take a careful history, uh, do a thorough examination and investigate appropriately and don't jump to conclusions too quickly. You know, I think there's um many students there's so much tech in medicine these days that let's just do a whole lot of tests. And tests are very important, um, but they also rack up the price of net of medical practice. But if you actually sit down and take a proper history, and one of the challenges I think in teaching medical students at the moment is making sure they actually are taught properly how to take a medical history. This sounds very antiquating, but actually it's very important because if you don't establish the proper facts at the upset, then you don't really know what the problem is that you're trying to solve. And you can spend uh tens of thousands of dollars on doing tests that maybe aren't actually headed in the right direction because you didn't actually get a proper database from the patient at the upset. I mean, there are all the other things that remain critical in medical practice of empathy and understanding and having time and the ability to explain what's going on to patients and basically treating patients. It's quite good being in your 70s because sometimes me and my uh immediate family are patients these days, and you can actually see who does these things for who doesn't. So practice medicine to your patients and the way you would like to have a practice to you because all of us wind up in patients at some stage and often repeatedly during our lives. But uh just skipping the old fashioned basics of history taking uh light are very important. You can actually work out what's going on with the heart through doing investigations and whatever. You can't get the history any other way except sitting and carefully talking to the patient.

SPEAKER_00 22:41

Excellent. Thank you so much, Ian. It's been really lovely having a chat with you this morning. Um, and I'll I'll end the interview there. Thank you very much.

SPEAKER_01 22:54

Thanks.