Transcript

Ep159: Iron infusions and fracture risk 

MIC CAVAZZINI: Welcome to Pomegranate Health, a podcast about the culture of medicine. I’m Mic Cavazzini for the Royal Australasian College of Physicians. In episode 154 you met one of the generous podcast reviewers, haematologist Dr Fionnuala Fagan. Not long after that recording she sent me an email that made me drop what I was doing. It went, “This needs to go straight to the top of the pile. I read this and immediately changed my own practice. This is the kind of thing that should be reshaping prescribing decisions across half a dozen specialties right now”.

Dr Fagan was referring to a study published in July in the journal Blood, where it was shown that the most commonly used intravenous iron supplement is associated with a long-lasting, increased risk of fractures and osteomalacia. You probably know ferric carboxymaltose by its brand name Ferinject, though now that it’s off patent, it’s also sold as Ferricarbo, Ferivo and other names. In this study, the risk of bone events over seven years after an infusion was two to three times higher compared to a cohort receiving ferric derisomaltose, commonly known as Monofer.

And as we’ll hear today, 1 in 20 Australian women of reproductive age are treated with IV iron, almost exclusively with ferric carboxymaltose. While this formulation was known to cause hypophosphataemia in 50 to 70% of patients taking it, this increase in fracture risk is a newly reported finding. And it’s a little ironic given that mitigating osteoporosis is one of the reasons that iron deficiency should be treated, although the presenting symptoms typically include fatigue, restlessness, mood disturbances and impaired concentration.

The observational data from Australia and other high-income countries indicate that more than half of women of reproductive age experience iron-deficiency and in a quarter of those it progresses to anaemia. Prevalence of iron deficiency goes up to 70% in pregnant women and it can cause complications for the foetus and the newborn.

This discussion about safe use of intravenous iron is a critical one for the many different clinicians who prescribe it in the community as well as in hospital. I hope you’ll forgive the fact that you’re about to hear four blokes talking about an issue that largely affects women. I did reach out to an academic obstetrician who co-authored the prescribing paper we address at the end of the podcast but wasn’t able to coordinate the recording with her.

To explain this novel safety signal linked to ferric carboxymaltose infusion, and the dazzling molecular pathways behind it, I was very lucky to get lead investigator Professor Heinz Zoller on the line from Austria.

HEINZ ZOLLER:   So, my name is Heinz Zoller. I'm a professor of hepatology here at the Medical University of Innsbruck, but I'm also directing research at the Christian Doppler Laboratory for Iron and Phosphate Biology.

MIC CAVAZZINI:                Thank you. And to help me keep this interview on track, we've also got Professor Ian Morrison in Dunedin. And it was Ian who flagged this finding with my reviewer who then passed it on to me. So, Ian, tell us about yourself.

IAN MORISON: Hello, I'm Ian Morrison. I'm a laboratory haematologist, so I work at the local diagnostic laboratory in Dunedin, Awanui Labs. I've been involved with a lot of research activity at the university.

MIC CAVAZZINI:                And it was only a couple of weeks after seeing Professor Zoller’s paper that I saw another headline in the medical press, that “IV iron use soars among Australian women.” And that was reporting the findings of a recently-published analysis of prescribing data led by Associate Professor Luke Grzeskowiak who is with us today from Adelaide.

LUKE GRZESKOWIAK:     Thanks for having me. So, my name's Luke Grzeskowiak. I am a clinical pharmacist based in South Australia, and I lead a reproductive and perinatal pharmacoepidemiology research group based at Flinders University.

MIC CAVAZZINI:                We're going to spend most of the time talking about Heinz's paper, but I do want set a little bit of background for all of our generalists. So, we’ve understood the association between iron deficiency and bone density for a couple of decades now. But even that is not straightforward, as demonstrated in a massive longitudinal study from Denmark also published just recently in Haematologica. Ian, do you want to say what we know about iron and vitamin D metabolism in bone health?

IAN MORISON: A little bit just to step back. You know, as a haematologist we think of iron as being really important in red cells, and of course it is, but over the last years we've realized how important iron is in so many different processes in the in the body, you know, and muscles in the brain. And more recently our awareness has been increasing about the role of iron in bone. It's important for collagen synthesis, it's important for vitamin D, and the hypoxia that comes from anaemia might be important as well. So, the low iron, iron deficiency and bone is becoming quite a big story that we're learning about all the time.

MIC CAVAZZINI:                Do we want to say something about this Danish study? 142,000 participants over 10 years and there was actually a U-shaped relationship between fracture risk and plasma iron or transferring saturation.

IAN MORISON:  I think we've seen that a lot, that iron's quite a toxic molecule, so both sides of it. Iron overload is not good for the bones and iron deficiency is not good for the bones. I think it's become very clear from this recent paper.

MIC CAVAZZINI:                Heinz, do you want to add a couple of textbook observations?

HEINZ ZOLLER:   I totally agree with Ian that as we need most of our iron to produce red blood cells, maybe the role of iron has been underestimated in different biological processes and certainly in the bone. And what I find so exciting about the recent paper that you have just shown, that previous reports stressed the impact of anaemia, the negative impact of anaemia on bone health. But this new report really shows that it may really be the iron deficiency, so, the low ferritin and the low transferrin saturation which are both associated with an increased fracture risk, not just the anaemia. It may really be the underlying deficiency, for the very reasons Ian just mentioned.

MIC CAVAZZINI: And Luke, would you be able to give us a brief background on how iron supplementation therapy has evolved over the past decades?

LUKE GRZESKOWIAK:     Yeah, I guess there's been quite significant shifts in in how we've gone about addressing iron deficiency over the last few decades. So, we know first line, traditionally, we're trying to use oral iron. We know that can be quite limiting for a number of reasons. People could have side-effects, it may not be appropriate for people with conditions that impact iron absorption. And I guess we're getting a better understanding of unique situations or settings in which going to intravenous iron as a first-line therapy has really robust efficacy data that it is actually superior to oral iron. So, if we look at patients with heart failure as an example, increased recognition that that early replenishment of iron is actually a much better strategy.

So, when we look at intravenous iron preparations, I guess we've seen a significant transition from our old sort of dextran-based intravenous products in the fifties, which had a lot of issues around people developing anaphylactic or allergic reactions to them. And then the introduction of newer low molecular weight agents that release iron a little bit slower and are less likely to elicit that that allergic response. So, particularly, in an Australian context, in the in the 2000s the introduction of iron polymaltose [Ferrosig], which can provide the highest dose, a full iron dose replacement depending on how much an individual needs. And, I guess, that's a point of controversy that I we may or may not discuss at some point as to how much iron is enough iron and how do we work that out because I think that's a significant point of uncertainty, particularly from my clinical practice.

Then we've got our iron sucrose type products that we use in in specific, relatively limited circumstances in my clinical practice, largely for people multiple repeat doses. And then I think the real game change has been the introduction of those intravenous ion therapies that can be administered in as short as five to sort of 15-minute, you know, maybe up to 30-minute intervals. And so that's really changed the entire landscape of going from a three to four hour infusion to a very short infusion. And I think that's one of the main reasons that we've seen such a rapid increase in in the use of intravenous iron therapies.

And so, in an Australian context, I guess we've seen carboxymaltose introduced in early 2011, listed on our government subsidy program a couple of years later and then just taken off in terms of its uptake. And then just a decade ago has been registration of derisomaltose which has also just been recently listed on our government subsidy program and will no doubt see an increase in in the use of that preparation as well.

Cohort studies showing fracture risk

MIC CAVAZZINI: Yeah, we'll come to your observations on that 17-fold increase in prescribing since 2013 later. Heinz, I imagine the prescribing trend is similar in Australia where you work. Can you tell us what was the first sign that there might be these adverse outcomes of use of ferric carboxymaltose, and what prompted your study in the first place.

HEINZ ZOLLER:   Yeah, just a brief comment maybe on the prescribing practices here. We do see a similar trend and many people have questions, what's the background for this? And I think the most conclusive answer to that is that reproductive health has changed over the last generations very much. There is a lower number of births giving for each woman meaning that the time with active menstrual bleeding is much longer. And when you do that calculations, we see that women of this generation really just lose much more blood than our grandmother's generation did. And I think that really is one of the aspects that pushes towards the need for IV iron. And generally, I think IV iron can be a blessing and the recent developments with shorter infusion times and allowing for higher doses I think are really a good thing.

But my first contact with the problem was actually back in 2010 when ferric carboxymaltose was introduced. And Ian, may comment on that, maybe. In our hospital, we still do electrolyte panels, and that means that phosphate is on the list of every blood test we get. And we were really surprised to see that patients treated with ferric carboxymalose developed hypophosphatemia and we didn't know what that was. And it was actually the very first report on that was from New Zealand where a patient was treated with a very similar drug, iron polymaltose, and I think this is still in use in Australia and in New Zealand. And just to conclude that sad patient story, we didn't realize what was going on, what was causing the hypophosphatemia because the leaflet, the product insert, it's not very clear what's going on with phosphate. And only when the patient then went on to develop fractures, we realized what was going on. And that's how I became interested in that.

IAN MORISON: I remember about ten years ago being called up by a GP and saying, “I've got this patient with hypophosphatemia after intravenous iron, what shall I do?” And I had no idea, but it piqued my interest so, I've been interested in the field ever since. Although there are many of my colleagues who are not aware of it at all. And while that's occurred frequently, occurs very frequently after ferric carboxymaltose, the fracture risk, the osteomalacia, is regarded by many as pretty unusual and a rare side effect and has been downplayed, I think, by just about everybody. So, do you think do you think it's reasonable that it's an acceptable drug because the osteomalacia, the hypophosphatemic osteomolacea, is in fact a very rare side effect, or is that incorrect interpretation?

HEINZ ZOLLER:   Well, I think the full blown clinical picture of hypophosphatemic osteomalacia may be rarely seen, but it's an incredibly difficult diagnosis to make. Because many patients have aches and pains somewhere in their body and we were really surprised that a plain film X-ray shows you nothing. But when you then do an MRI—and in this patient zero we did the MRI not because we were expecting a bone problem we did the MRI because the patient had underlying inflammatory bowel disease—and then we realized that the patient had bilateral hip fracture. And this is so unusual, these things, that we then pursued that. And really this is still unfolding in front of my eyes because the more closer you look, the more patients you will diagnose. So, the key question that emerges from that is, what is the clinical relevance of that hypophosphatemia? And you said, Ian, this was considered asymptomatic, transient, mild, not a big deal, it's just a change in the electrolytes. But our recent studies really indicate that the problem may be very, very severe in many patients, and we don't know the exact numbers.

MIC CAVAZZINI:                Let's get stuck into it. Heinz, the paper you published in Blood with 28 co-authors, starts by describing a retrospective study at your hospital in Innsbruck. You identified 357 patients who had been treated with either ferric carboxymaltose or ferric derisomaltose, Ferinject versus Monofer, and examined the relative incidence of fractures in these cohorts over 7 years post-infusion. Tell us what the analysis found.

HEINZ ZOLLER:   Yeah, so as mentioned earlier, this was triggered really by a single clinical observation and we were asking that question, what is the true clinical burden that emerges from that hypophosphatemia? And so, we went back to our records to identify patients who have been treated with ferric carboxymaltose, just to realize that we needed to include a control group. So, we used patients treated with ferric derisomaltose because those patients, as we've discussed before, requiring intravenous iron treatment are at an increased risk for developing bone problems in the first place.

And we were really surprised that in this initial analysis, we were actually just trying to understand what is the clinical phenotype that one could expect in patients treated with ferric carboxymaltose and who develop hypophosphataemia. So, we did not just look at fractures but we used a more broad endpoint. We used findings on radiology reports suggestive of osteomalacia, also pseudo-fractures were included. But the bottom line is that the incidence was significantly higher, and it was about threefold higher when we corrected for underlying osteoporosis, age and sex and severity of iron deficiency. So, there was an independent association with an increased risk of developing a bone event in patients treated with ferric carboxymaltose as opposed to patients treated with ferric derisomaltose.

IAN MORISON: Is my interpretation right that approximately one in ten recipients of a single infusion would get a fracture as a consequence of their ferric carboxymaltose?

HEINZ ZOLLER:   Yeah, that is approximately correct. I mean, it's difficult with these retrospective studies because you have studies because you have different lengths of follow up. Cutting it down to a single number is quite difficult. And that's why we need this control group. I would rather view it as a relatively increased risk because it really depends on the follow up and the age of the population.

MIC CAVAZZINI:                The numbers I've jotted down was just that, in the first six months, the incidence of bone events was 5 of 172 patients in the carboxymaltose group and 1 of 185 patients in the derisomaltose group. And Heinz, were those treatment decisions just left up to the clinician preference?

HEINZ ZOLLER:   Correct. I mean, we do have an era effect because ferric carboxymaltse came to the market a bit earlier, and later on our hospital has really stopped using ferric carboxymaltse altogether.

MIC CAVAZZINI:                And this association was validated in a further 20,000 patients in the TrinetX US collaborative network. Heinz, can you put a more concrete number to this increase in fracture risk?

HEINZ ZOLLER:   Yeah, so as with these small retrospective studies, one asks, are there any underlying other risk factors that have not been captured? All retrospective. Were those patients sicker treated with ferric carboxymaltose and so on? So, we were looking for independent validation. The largest database that is available to our knowledge is this TrinetX. It's a multinational database where real time electronic or health records can be interrogated for these questions. So, we assembled two cohorts. The patients, selection criteria were that those patients were only allowed—and that's very important—to have had a single treatment course with either ferric carboxymaltose or ferric derisomaltose. And in the United States, that would mean 2x 750 milligrams of ferric carboxymaltose, as opposed to 1x 1g ferric derisomaltose. So, there is a small difference in the iron dose that was given.

But still, when we ran the fully adjusted analysis in those patients who also could not have had a previous fracture, we saw that the curves—the Kaplan-Meier—curves immediately diverge and this divergence—what we would have expected is that they would come back together or run in parallel at a later point in time, but they seemed to diverge for the entire observation period of seven years. Again, with the limitation that the follow-up was not seven years for all patients included and so on. But essentially, we could validate the findings from our cohort. In this cohort we had a doubling of fracture incidents in patients treated with ferric carboxymaltose as opposed to patients treated with ferric derisomaltose.

MIC CAVAZZINI:                And remarkably, that's all the result of one infusion trailing out to seven years. Luke, feel free to chime in any time.

LUKE GRZESKOWIAK:     So, looking at the cohort in the TrinetiX data analysis, I can see that around 70% of patients had iron deficiency. So, I guess I'm just wondering who are those 30% that are receiving intravenous iron that don't have iron deficiency in the TrinetiX cohort?

HEINZ ZOLLER:   Yeah, so, this diagnosis is based on codes. So, it's not iron deficiency defined as a ferritin less than 30 or whatever cutoff you want to use. So, the explanation for this is that either iron deficiency was not coded or intravenous iron was given in patients who were considered to be iron deficient. And one wonders, why would you treat someone without iron deficiency with intravenous iron? And the answer to that would be in heart failure patients. We know that many of those are not really iron deficient. Also, in patients with restless leg syndrome, intravenous iron has been shown to be very effective and the most recent update of the guidelines also recommends that you should treat anyone with intravenous iron with restless leg syndrome, as long as the ferritin is less than 300. So, you don't really need the diagnosis iron deficiency. And the same applies probably to most renal patients where you treat to a ferritin of 5-600. So, these are the three explanations without iron deficiency, okay?

MIC CAVAZZINI:                We’re doing a real journal club on this. Ian, you and Heinz had an email exchange trying to tease out the role of renal function in these outcomes. Do you want to explore some of that here?

IAN MORISON: Yeah, in our discussion with some of our colleagues and specialists and some of the regulatory bodies in New Zealand, they sort of say, “Well, it's a retrospective observational study, there's going to be confounding and so on”. And I think people are not taking the study as seriously as I think they should be. So, I'd like to talk about that.

So, obviously it's a mixture of patients and they have different indications for their iron. Many have renal impairment. So, what is the role of renal impairment and how did you adjust for that? But also, there could be some other confounding, couldn't there, in the decision making about whether to use one agent or the other, and how effectively do you think you've excluded that?

HEINZ ZOLLER:   So, this is a great question. I think the renal issue is very important here because, first of all, I think the early adopters for ferric carboxymaltose and intravenous iron in general, were the renal physicians. And this is owed to the fact that anaemia in patients with chronic kidney disease used to be treated with erythropoietin and it was realized that the addition of intravenous iron really boosts the effects of erythropoietin, it’s very effective. And it is very well known that chronic kidney diseases or end-stage renal disease is associated with fractures.

But hypophosphatemia incidence is much lower in patients with chronic renal impairment, because the mechanism how we lose phosphate after ferric carboxymaltose treatment is via the kidney. So, if you have an impaired kidney function you're, strangely enough, protected from hypophosphatemia.

So, if you think that the driving force for the increased fracture risk is hypophosphatemia, then one would expect that chronic kidney disease also protects from fractures after being treated with iron. But what we found is quite the opposite. We were surprised to realize that the fracture risk was even higher in patients with chronic kidney disease.

So, we tried to adjust for that, because we have grouped the patients in mild, moderate and severe renal impairment and we ran a multivariably-adjusted Cox regression analysis for this. And what came out was that patients treated with ferric derisomaltose had a more severe impairment in their kidney function. And again here, the surprising finding was that although patients with impaired renal function would be expected to have a higher fracture risk, still, ferric carboxymaltose treatment increased the fracture risk further in those patients.

So, the conclusion that we draw from these findings is that it's not the hypophosphatemia that drives the fracture risk, but it's the drug itself and the negative effects on bone. And why we think that is because also in the animal model, which have a very different way how these mice handle phosphate as opposed to humans, we cannot replicate hypophosphatemia in the model, yet we still see very significant effects on the bones of these mice.

Mouse models and molecular pathways

MIC CAVAZZINI:                We're going to get stuck into the mouse models now. Adult mice given a low-iron diet and serial phlebotomy end up with decreased volume of trabecular bone compared with nonanemic controls and deposition of iron at the bone surface. Unsurprisingly you chose the mouse femur to analyse. And you found that IV iron supplementation changed the distribution of iron in bone within a couple of days of treatment. But the pattern was remarkably different for mice treated with ferric carboxymaltose compared to ferric derisomaltose. So, tell us what you saw.

HEINZ ZOLLER:   Yeah, so. As I said, we were chasing this effect and trying to understand what is the actual underlying pathophysiology. And it had been known that the hormone that controls phosphate, FGF23, sharply increases after the infusion of ferric carboxymaltose. So, we cannot even reproduce that in a mouse so, we were very disappointed. Although we thought we were very clever because we made the mice iron deficient, we induced iron deficiency anaemia by bleeding. We treated the mice with the iron formulations intravenously, not intraperitoneally, which is usually done, so it's very tricky. Sonja Wagner did a wonderful job in developing all the skill to get and develop the model as closely as possible to the human system, but we could not reproduce the hypophosphatemia in the mice. So, we were stuck in the project in a way.

And luckily enough, we have a dedicated micro-CT facility. So, we just took the bones of these mice and took it to our micro-CT facility. And we we're surprised to see how striking the effect of iron deficiency anaemia on bone was. And we actually wanted to study the recovery of the iron deficient bone after IV iron treatment, because we could not reproduce the effect. And since we had already treated the mice with both drugs, we of course looked and compared the effects and we could see that ferric derisomaltose seemed to cause a more rapid and more pronounced recovery of the bone structure. And then chasing the underlying physiology behind that we realized that the distribution is very different.

And the bottom line here again is that ferric carboxymaltose seems to be very bone-seeking. It really is preferentially taken up by developing osteoblasts. And we think that, again, is due to different physical chemical properties associated with the sugar moiety of these iron drugs. So, it has a very distinct surface charge, which makes the drug want to go to the bone and being taken up by the osteocyte there.

IAN MORISON: That was impressive data to see both in your mouse model and the cell model how the ferric carboxymaltose was adhering to the surface of the bone or to the osteocytes, depending on the model. Do you have any sense of how long it hangs around there? Because I'm thinking of the data from the heart model where they've recently reported that ferric carboxymaltose is still detectable in the heart and I've forgotten exactly how, a year after the infusion. How long do you think it hangs around in the bone for?

HEINZ ZOLLER:   Yeah, I mean, that is our worry. We think it will hang there forever because it, as you know, the osteocyte gets embedded into the matrix of the bone. So, it really is buried in the bone and probably the iron goes with it there. Do we have data to support that? Not yet, I have to say, unfortunately. So, we haven't done some bone biopsies on patients, but that is a subject of ongoing research.

MIC CAVAZZINI:                And I’m still not totally clear on this answer. If hypophosphataemia wasn't replicated in the mouse model, do you understand that the effects of ferric carboxymaltose on bone, are down to hyperphosphatemia, or some molecular pathway that’s going on in parallel?

HEINZ ZOLLER:   So, when we started the project and from the first observations, the paradigm was ferric carboxymaltose causes hypophosphatemia and if that persists, that can cause damage to the bone. I don't think that this paradigm is no longer valid. I think that the modern paradigm is that ferric carboxymaltose goes to the bone and does many things there: One of them, it impairs extracellular matrix formation; it impairs the proper development of osteoblasts into osteocytes. And among other things, it also can cause hypophosphatemia. And I don't think that we can safely assume that those patients who do not develop hypophosphatemia, who do not develop symptoms will not develop complications from this treatment

Other risks of hypophosphataemia

MIC CAVAZZINI:                I don’t think we’ve said it outright, though many listeners know this already. Ferric carboxymaltose is well known to cause hypophosphatemia in more than half of patients who take it. We’re talking reductions in serum phosphate of 40 to 80%. And iron polymaltose or Ferrosig, which has been funded in Australia since the early 2000s, was shown by researchers in Melbourne to affect an even greater proportion of patients. Meanwhile meta-analyses, including your own, Heinz, show that ferric derisomaltose, Monofer, causes hypophosphataemia in only 4 to 10% of patients. So, aside from everything else we’ve talked about, how heavily should phosphate weigh into prescribing decisions?

HEINZ ZOLLER: Well, if you have asked me this question a year ago, would have said hypoposathemia is not big issue, but I think for the muscle it really is a very, very big issue. So, mild hypophosphatemia is not a big problem, if you say have a drop in phosphate to anything between 0.8 and 0.6, millimoles per litre, most patients are asymptomatic.

But it's not just a question of incidence, it's also a question of severity. And that is the worrying number with iron polymaltose and ferric carboxymaltose that in one study that we did, 11% of our patients developed severe hypophosphatemia which is anything below 0.3 millimoles and those patients can have very severe muscular symptoms. They develop muscular weakness and again this is very difficult to pick up because in a patient with iron deficiency you expect that they are fatigued, that they feel weak. This can be easily mistaken as the ongoing effect of iron deficiency, but we do see increasingly patients who have muscular effects of hypophosphatemia. So, the hypophosphatemia in itself is a big problem.

We know that women with low body weight are at increased risk of developing severe hypophosphatemia. Preserved kidney function is a risk factor, but these effects are really dwarfed by the effect of the drug you choose. So, a 30-fold increase in the risk of severe or persistent hypophosphatemia if you choose ferric carboxymaltose. But even if you use ferric derisomaltose, if patients develop new onset muscular symptoms, the phosphate should be checked, definitely.

MIC CAVAZZINI:                Luke, thankyou for being patient while we get through…

LUKE GRZESKOWIAK:     Can I ask a quick question to Heinz.

MIC CAVAZZINI:                Yeah of course.

LUKE GRZESKOWIAK:     Touching back on the hypophosphatemia, if we can just continue that just a little bit in terms of the management side of things so, you make a couple of comments in the discussion of your paper around what optimal management might look like and particularly comments around the use of phosphate may actually be detrimental in the management of hypophosphatemia. So, I guess I'm just interested in your thoughts as to what does optimal screening look like. So, it sounds like the recommendation is that if you're giving intravenous iron, that it should be monitored as part of standard care, that that obviously comes at a cost. But then if it is detected, what's the optimal approach of management and what does that look like and are we getting that right in a clinical practice setting?

HEINZ ZOLLER:  Well, the Food and Drugs Administration, I think they only recommend specific measurements or measures to prevent hypophosphatemia or to detect it early in at-risk patients, and especially only if you choose to use ferric carboxymaltose. So, my preferred strategy, and I'm really happy that our hospital adopted that, is to go for primary prevention. So, if you avoid, whenever you can, ferric carboxymaltose, I think this is the best you can do.

The recommendations around how to prevent it if you have no other choice than using ferric carboxymaltose to start off with a normal phosphate. So, you should screen the patient beforehand. And there are recommendations that vitamin D deficiency should be avoided in patients receiving ferric carboxymaltose. But the evidence behind that is rather weak.

So, what do you do when you detect it? You need to at least to check if it goes away. That means repeated visits and if it persists, hypophosphatemia. And there have been also studies from Australia showing very nicely that especially patients who have anti-resorptive drugs additionally, bisphosphonates for the treatment of underlying osteoporosis, that those patients are particularly at risk of developing severe and persistent hyperphosphatemia and the management has turned out to be very, very difficult. It's like—Myles Wolf uses the metaphor of the hole in the bucket—you know, pouring in phosphate will not resolve this.

So, we have also gone to use burosumab rather early, so this is of course not approved. It's a therapeutic antibody against FGF23. It's not approved for the use of treatment of ferric carboxymaltose-induced hypophosphatemia, but it works. That has been documented very nicely and that is actually the only thing that really helps patients to recover from their muscular symptoms.

MIC CAVAZZINI:                Your article in the journal Blood was accompanied by an editorial that was authored by genetic pathologist Karen Finberg, and clinical haematologist Michael Auerbach, both from the US. They noted that this hyperphosphatemia and osteopenia associated with ferric carboxymaltose would be of even greater concern in children. However, a couple of studies that have looked at this have identified rates of hyperphosphatemia in the range of only 14 to 19 %, not half of patients like in the adults, and no severe outcomes. What else would you like to know about this cohort?

HEINZ ZOLLER:  This I only appreciate since I have seen a patient a couple of weeks ago. This was a young boy with phosphate in the normal range of an adult. It was 0.92. But the boy was 14 years of age and his bones were bent. So, what I'm trying to bring up with this point is, you know, there is an age-specific reference range for phosphate. And as a newborn, you should have a phosphate of 1.2. And I think the problem in children with a developing skeleton is grossly underestimated and we should really be particularly careful and sensitized to that, we just don't know it.

And the question for many years was, what is the clinical relevance? What is the evidence for hypophosphatemia causing problems? But I would really think that there is this strange reversal of evidence situation. I think that it should be shown that hypophosphatemia is safe in those patients who may not come up with symptoms. I think, as you've said, there are so many reports and so many horrible patient stories that have been reported in the last years that now the question is, we have enough evidence to still justify the use of this drug that can cause these side effects? And that's why I'm very happy that the FDA also reacted with their boxed warning for ferric carboxymaltose.

MIC CAVAZZINI:                I’m very impressed, Heinz, that you're able to respond so clearly without a single pause. That's all of the questions I have for your study. You might be in a hurry to get off to the lab now. The remaining questions are more about the prescribing in Australia and New Zealand.

LUKE GRZESKOWIAK:     Can I ask one more question to Heinz? Yeah before he runs away. I'm particularly interested in the role of calcium. And I'm just thinking at-risk populations, particularly where intravenous iron is increasing more rapidly than in other populations, and one of those is pregnancy and postpartum. And we know that that places significant demands on calcium, we see reductions in bone mineral density that are able to be restored some six to twelve months later. But I'm just interested in your thoughts of those that receive intravenous iron. Could it have issues for bone regeneration? I guess, the normalization of that bone mineral density? Or are we clear enough that they're separate pathways that there's not going to be interacting effects there?

HEINZ ZOLLER:   Yeah, this also relates back to a very interesting study from Australia. Huang was the first author and there the hypophosphatemia incidence and FGF23 responses were compared in three groups; patients with iron deficiency alone, pregnant women and patients with impaired kidney function. And interestingly, pregnant women seem to have a lower hypophosphatemia incidence and also a lower FGF23 response because it has the canon always was, that even in patients who do not develop hypophosphatemia and hypocalcaemia—because some patients, especially if they are treated with bisphosphonates, they can develop hypocalcaemia—that in those patients who do not develop hypophosphatemia and hypocalcaemia, that the phosphate levels are maintained at the expense of bone mass.

And that's exactly what's happening during lactation and pregnancy, that women are releasing the calcium from their skeleton. But that seems to be compensated for in the postpartum period with higher intake. So, to me, I think the ideal scenario is that patients get their IV iron pre-conception, and they start pregnancy with full and replete iron stores. If you treat iron deficiency anaemia during pregnancy, it's less than perfect, but it's even better than not treating it at all. Because another study from Tasmania has shown that the baby blues, the so-called baby blues, can be significantly improved or mitigated, the severity of the symptoms, if you treat iron deficiency anaemia appropriately in the postpartum period [see also this Cochrane review and this meta-analysis].

And the question now is which drug to use. And I would again say, you know, we don't have the evidence that the hypophosphatemia and the hypocalcaemia that can develop or may not develop in this period of time, but the havoc that is created with the mineral metabolism with ferric carboxymaltose, we don't have the evidence that this is safe. So, final comment, maybe, there are many, scientific questions that could be clearly answered with prospective trials. But I think the ethics around that are just impossible to resolve because it would mean that you deliberately treating patients with very carboxymaltose just to see what are the downstream effects. And we have, to my understanding, evidence to say, you know, we have an alternative, why don't we use these alternatives?

MIC CAVAZZINI:                Perfect, Heinz, you've been fantastic.

HEINZ ZOLLER:   Actually, I have to go to an endoscopy. I would leave now unless there are any other questions.

MIC CAVAZZINI:                No, please. You've been very generous. I'll keep in touch via email with how the production is going, but thank you so much.

HEINZ ZOLLER:   Thank you. Bye bye.

IAN MORISON: Thank you. Lovely to meet you.

MIC CAVAZZINI: That was a very tidy—well, I won't say tidy, we've been going for a while, but very comprehensive.

IAN MORISON: He's a very clear thinker, yeah.

Prescribing landscape

MIC CAVAZZINI:                Incredible, yeah, yeah. I mean, his warning there at the end was pretty unequivocal. And interesting that the FDA just recently slapped  a warning on ferric carboxymaltose, even if that’s specifically regarding serum phosphate, not these newly reported effects. To my knowledge the TGA hasn't made any such move yet. Luke, Ferinject has been publicly funded on Australia’s Pharmaceutical Benefits Scheme since around 2011. And ferric derisomaltose or Monofer was added to the PBS in 2017. So, is there anything stopping Australian prescribers from making the switch tomorrow and talking to their hospital pharmacist about it?

LUKE GRZESKOWIAK:     Very interesting question. I guess it depends on where you work. Some workplaces will have their own formularies. So, while you've got your national pharmaceutical benefit scheme and things can be prescribed a bit more freely in private practice, within some practice settings they have what's called their own sort of formulary. So, my clinical practice, we have specific products that are listed. And other products that are restricted even if they are listed on the pharmaceutical benefit scheme.

So, our first line for inpatients, particularly, is polymaltose, and then be using carboxymaltose. And one of the big challenges, I guess, is hospital formularies are often there's a there's a price aspect to it in terms of looking at affordability. And one of the big challenges is we've just seen carboxymaltose go off patent. So, it's become a third of the cost this year as to what it was, and it is a third of the cost of derisomaltose to the Pharmaceutical Benefits Scheme or to us public taxpayers. So, now we have this real challenge of, yes, we have alternatives but at three times the cost and at what cost are we willing to pay to avoid these potential risk factors that we don't still have a good full understanding as to what the long-term consequences of them are.

MIC CAVAZZINI:                I mean, what will you be telling your clinicians, your prescribers? Or will you be waiting for a lead from TGA and PBS/PBAC?

LUKE GRZESKOWIAK:     Our recent conversations were trying to push towards derisomaltose, but largely for a different reason of the ability to give the up to fifteen hundred milligrams in a single infusion. So, when you look at the majority of the doses we're prescribing, it didn't make sense to me to have a large proportion of people needing to come back a fortnight later. That was that was an additional burden to get that extra 500 milligrams of carboxymatose. So, if the average dose you're giving is around 1500, it kind of made sense to do that in a single infusion. That would minimize costs and the patient burden all around. But now because of this costing change of the underlying product, that's thrown a little bit of a curveball because that needs to be factored in.

Because lots of places don't want to have lots of different types of iron because it increases the risk of issues in prescribing. Because as you can imagine, if you've got five different things to choose from, you might make di you might make errors in in dosing or administration or things like that. Ian, it'd be interesting from a New Zealand perspective. You have a different national formulary and a different process. Are you able to just comment on what's the current state of intravenous iron and how is it managed and governed, I guess, at a national level and then more locally in your clinical practice?

IAN MORISON: So, in New Zealand, ferric carboxymaltose and the ferric derisomaltose are both available  but the funding is through Pharmac, which is our national drug funding agency, which is excellent in terms of providing good quality drugs at good prices, on average. Pharmac fund the carboxymaltose for everybody including the community, so for use by general practitioners. In February, in response to submissions, they funded derisomaltose for in-hospital use for patients who had documented hypophosphatemia or a severe adverse reaction.

So, they're extending the use of that and we're hoping that they will see this new evidence and change their practice. I've certainly myself have put a submission into Pharmac a couple of weeks ago to suggest that funding for carboxymaltose should be stopped and derisomaltose also should be funded. The other organization that's important for us is MedSafe. They sent me a short email and essentially were unconvinced by this data, but I was disappointed and we'll get back to them on that.

LUKE GRZESKOWIAK: So, the patent issues would be similar in New Zealand of Pharmac will now be weighing it up this year with product that's third of the cost now. And had they been deliberating last year, before it was off patent, I guess possibly that could change the whole way that you think about the product availability.

IAN MORISON: It could. We just hope that they see the bigger picture and the ethics of giving a drug which we've known for many years is suboptimal. There was the US expert guidelines that came out two, three years ago that said that ferric carboxymaltose is a suboptimal preparation and should be avoided. Now, so even before this this latest paper we're discussing, we were concerned about it. And now with this additional evidence, no matter how good the quality is, this additional evidence I think is compelling. And if I was a patient, I certainly want wouldn't want to have that, or at the very least, I would want to have a very extensive discussion about the risk of that therapy.

I think it pushes people back—Luke, I'll be interested in this—back to oral iron, because oral iron, even though it's got lots of side effects, is still good. Lower dose is better for many people and of course alternate day iron is much better than certainly you don't want to give it more than once a day, but alternate day can be improved. So, do you think we should see a bit of a move back to working a little bit harder with the oral iron?

LUKE GRZESKOWIAK:     I think that's definitely a consideration and I think we've learnt a lot in the last few years. There's been some really good papers comparing different dosing regimes and I think that's been quite eye opening to people to understand that, you know, pushing two, three hundred milligrams of oral iron a day is probably not an effective strategy long term. Rather than actually lower doses less frequently. Yeah, it might take a little bit longer to get to full iron replacement, but you can do so without the need for a intravenous iron infusion. And I think that's certainly something that we need to be pushing and promoting.

And I guess the flip side of that is the increasing proportion of intravenous iron where it's being given late, where there's not enough time for oral iron to be to be effective. So, of course there's a large number of patients where that's not going to be a suitable strategy. And Heinz has touched on that in the pregnant population where there may only be a few weeks left of the pregnancy, and if there's evidence to support immediate effects of intravenous iron—it's still limited now, but I'm sure that that will come—then, you know, telling someone to go slow and steady comes with its own potential risks or issues as well. So, I think it's a really challenging landscape and it's only going to get more challenging as we move to these different issues.

And I guess, Mic, one of the interesting things is around the informed consent process. And I've discussed this with GPs as to, are we are we getting that right? Are we actually ensuring that those—I'm sure there's people going to the GP and just directly requesting intravenous iron because they've read about it or seen it somewhere. But what's that informed consent process look like and where does hypophosphatemia and potentially fracture risk sit in amongst that? And is it well understood by everyone involved in that consultation to ensure that that people can make informed decisions about what the best therapy looks like? And I'm not sure we've got that informed consent process down pat or perfect yet.

MIC CAVAZZINI:                You've partly answered my next question. So, the main finding from your recent paper was this 17-fold increase in prescribing of intravenous iron in Australia between 2013 and 2024. You put that at a cost of $82 million in 2024. That was published in the Internal Medicine Journal before Heinz’s findings had come out but let's imagine that everyone was using ferric derisomaltose already. You and your lead author, Gizat Kassie, had a different issue with this rather than the side effects. Whether this huge increase in use of IV over oral formulations is consistent with clinical need in the first instance. Can you expand on that a little bit?

LUKE GRZESKOWIAK:     Yeah, I guess we were interested in a number of different aspects. One's around the variation, particularly interest around equitable access. And there's a number of issues that clearly point towards issues around affordability. And you know, putting that in context, we've got no Medicare benefit scheme specific items around iron infusions. So people who see a bulk-billing doctor can't get intravenous ion infusions. You're paying out of pocket upwards of three hundred dollars for a single infusion. If you need two over a fortnight, more than six hundred dollars. How many people can afford that out of pocket up front?

That's not including—we've just heard from Heinz—that you want phosphates done at baseline and you want a couple of phosphates done two and three weeks after. That's another couple of visits with additional out of pocket costs. Then you've got the 30% that have low phosphate that now are going to get treated. So, you start adding it all up and it's starting to really become a significant burden. So, I think there needs to be a serious conversation around how we improve equity and access and are we getting it right in terms of who we're promoting intravenous iron for. And I think we've got to really get that evidence down pat for to better understand what we should be doing in clinical practice.

MIC CAVAZZINI: It was interesting that there was a two-fold difference in the prevalence of IV iron use from one jurisdiction to the next. In WA, the dispensing occurred for six in every hundred women, while in the ACT, the rate was less than three. Do we know anything more about the culture and awareness of prescribers around the country?

LUKE GRZESKOWIAK:     Yeah, I think there's a number of different factors. I think what we're what we've got a good understanding of is there's a large sort of clinician variability and there's a clinician effect of, you know, you might have high profile researchers or people that are really pushing research or evidence around the role of intravenous iron and they can be quite influential in a jurisdictional aspect in terms of guiding practice. You've got large clinical centres that develop their own policies protocols. And at a population level that that can be evident, particularly in a you know, a pregnancy context. If you change your hospital's guideline that you're going to screen every single pregnant person for a ferritin and then you start going to you're going start intervening on many, many more people. You're going start seeing that come out in in national data as well.

So, I think it's highlighting that there's there are clinician differences in in the thresholds for treatment. No doubt there's individual differences. We know there's going to be ethnic differences across jurisdictions and risk factors for iron deficiency. So, you know, we can't rule out that there's that there are true clinical need differences. But yeah, we need to better understand what's going on and improve that the standardization of high-quality clinical care.

MIC CAVAZZINI:                And finally, there's another formulation, ferumoxytol, which, if we're looking at hypophosphatemia, performs even better than derisomaltose. That was approved by the US FDA in 2009 but is not registered by Australian or New Zealand regulators. It's described as a superparamagnetic iron oxide nanoparticle. So, I guess it's somewhat different to the carbohydrate formulations we've been discussing. Luke, be looking harder at that option on top of the derisomaltose, or might it come with other potential surprises?

LUKE GRZESKOWIAK:     Yeah, I mean, I guess there's limited scope for individuals as clinicians to guide this because ultimately these are sponsor decisions around market share. Is there a significant enough market to warrant all the costs associated with having a product registered for Australia or New Zealand compared to the US? And I think, you know, sponsors would be looking at history and what's actually going on in terms of the introduction of new products. And I guess what's striking is, you know, we're looking at 2013 to 2024 data, there's at least six years where derisomaltose is available. And yet we were expecting—our hypothesis was that we were going to see a shift and a massive uptake of derisomaltose at the expense of carboxymaltose and we just didn't. We just saw the overall line just skyrocket and yet carboxymaltose still accounted for 98% of prescribing. There was really no dent in the in the market for derisomaltose, despite extensive marketing from the company around our product has less hypophosphatemia. And I guess you pointing at a new product, they would be looking at that going, “Is that going happen to us? Is that our market share? How do we get in as an alternative to this other product that's absorbing 98% of a $80 million cap, so how do we get a significant enough portion of that pie to justify regulation costs?”

MIC CAVAZZINI:                Should we draw the conclusion that Australian prescribers are impervious to big pharma advertising or they're just lazy and stick with what they know?

LUKE GRZESKOWIAK:     Yeah, I wonder if there's I don't think anyone can be completely impervious to advertising and there's enough evidence to show that's not the case. But I think it's more around the impacts of ingrained practice. You get accustomed to a certain practice and you've been doing it for so long it's very hard to shift someone's thinking. And that's what's most I guess compelling with Heinz’s paper is I think there's enough data there to really start that process of shifting.

But convincing your regulatory bodies or your local health network to completely change all your policies and guidelines, I'm not sure the there's enough body of evidence. There's probably just another couple of papers that need to come out to really validate this work. And so, it's an interesting proposition as to what level of evidence would the TGA need to issue either a black box warning or at least include fracture risk as part of the product information, because it's not as part of it at the moment. That's not in there, so people aren't being informed about that aspect, only the hypophosphatemia side of things. Alternatively, the company can jump the gun and put something in there themselves, without it being forced by the regulatory body.

MIC CAVAZZINI: Many thanks to Professor Heinz Zoller for getting on the line at 7am in Innsbruck to discuss his important findings with us. Thanks also to Profs Luke Grzeskowiak and Ian Morison for their candid thoughts about prescribing down under.

Professor Zoller has received consulting fees, honoraria and travel supports from Pharmacosmos, which produces ferric derisomaltose or Monofer. He’s also received consulting fees from CSL Vifor, which produces the Ferinject/Injectafer brand of carboxymaltose. His research program through the Christian Doppler Society or the Medical University of Innsbruck has also been supported by both companies. [Others that have provided funding in different capacities are Novo Nordisk, Kedrion Biopharma, Pierre Fabre and Falk Pharma. Professor Grzeskowiak receives salary support from a Channel 7 Children’s Research Foundation Fellowship and Professor Morison has no declarations of interest].

The views expressed in this podcast are those of the guests and this is intended as a conversation starter about emerging evidence not as a replacement for guidance from consensus bodies or clinical regulators. The interview was recorded mid-August, 2026, and the scene may have changed by the time you listen to this.

At our web page, and even your pod browsing app, you’ll find a transcript of the conversation and links to all the research papers mentioned. [The fracture-risk paper was published in the journal Blood, Volume 148 Issue 1 and the first author was Dr Sonja Wagner.  The data on prescribing of IV iron in Australia was published in the RACP’s Internal Medicine Journal, volume 56 Issue 9 with first author, Gizat Kassie.]

Please share this podcast with a colleague. They can subscribe to Pomegranate Health in any podcasting app or sign up to an email list from our website, racp.edu.au/podcast. A special shout out to Dr Fionnuala Fagan who brought today’s story to my attention and to all the podcast reviewers who kindly provided feedback on drafts. They were Doctors Marion Leighton, Aidan Tan, Hugh Murray and Maansi Arora, as well as PhDs Paul Cooper and Kathryn Smith.

You can send feedback and ideas to us via the email address podcast@racp.edu.au. I’m Mic Cavazzini, thanks for listening.