and I'm very grateful for the invitation to give this session today on discontinuation of denosumab. So my plan is to present you with some data, first some data on denosumab, which I think is a really great drug for many patients with severe osteoporosis, and then of course discuss some of the findings that are out there and some of the theories about what happens when we discontinue treatment and what we possibly can do about it. So hopefully we'll have a good discussion at the end. I think this is the purpose of these Meet the Professor sessions. So thank you all for coming. So here are my disclosures. So as I said, I'll talk a bit about denosumab and then of course mostly about denosumab discontinuation and suggestions about management. And then if time allows, I can tell you a little bit about a study we did in Aarhus in patients, or men, with prostate cancer, discontinuing denosumab because we thought it would also be interesting looking at men. And then also a bit about what happens if we delay the denosumab injections. So first of all, I just thought I would start with this figure, which is from a review by Ian Reid, now seven years ago. But it was just to highlight that when we look at the short-time antifracture efficacy, what you can see here is that the effect of the bisphosphonates, or at least most of the bisphosphonates and denosumab, they are quite similar when it comes to prevention of non-vertebral fractures. And the same goes for prevention of hip fractures, very similar. But we do know that there are differences, and that is highlighted especially when we look at what happens with hip BMD when we treat long-term, with bisphosphonates and with denosumab. Whereas with bisphosphonates, we see an initial increase in hip BMD over the first three to four years, and then BMD is thereafter stable at the hip site, whereas it continues to increase at least for up to 10 years with denosumab. And we know that, of course, from the FREEDOM and the FREEDOM Extension Study, which I'm sure you're all very familiar with, where we had these up to 10-year data. And that is also where we know about this continuing increase here, BMD at the spine, and where you can also see that the reduction in clinical fractures, sorry, here it's vertebral fractures, clinical as well as radiology-determined fractures, it stays stable and low for at least up to 10 years. And also, when it comes to increases in hip BMD and the incidence of non-vertebral fractures, that is stable for up to 10 years in these patients treated for up to 10 years. But what could be the reason for this continuing increase of hip BMD with denosumab, which really makes it different from bisphosphonates? We don't know that yet very well from human biopsies, but this is a monkey study where they looked at what happened to bone turnover at trabecular and cortical surfaces. And what you can appreciate is that if, so at the top here, I'll just point over here, sorry, but up here you can see the sham-operated animals, where there's a lot of activity going on intercortically and at trabecular bone. Sorry, these are the sham ones. And here is the OVX animals, where there's a lot of bone remodeling going on. And here are the denosumab-treated animals, where you can see there's hardly any remodeling going on, as we would expect with denosumab. But the interesting thing is, and I'll point to the other side here, is when we look at cortical bone. So again, here we have the sham-operated and the OVX-operated. There's bone formation going on at the cortical sites. But you can see that is also present in the denosumab-treated animals, suggesting that modeling-based bone formation continues, despite denosumab treatment, at least in monkeys. And so therefore, the theory here is that when we oviectomize the monkeys and treat with viracle, we will have a lot of remodeling, and that remodeling will tend to decrease bone mass. But, and there will also be still bone modeling and bone modeling-based formation and bone modeling-based resorption continuing. Whereas when you treat with denosumab, so of course you'll take, you will tend to reduce remodeling, so that would lead to, so the formation might be going on for a little while, and that's the initial increase in BMDBC, but thereafter remodeling is closed to almost nothing. But modeling-based bone formation will continue, whereas remodeling, whereas modeling-based resorption will be inhibited by denosumab. So this is why we perhaps see this continuing increase in bone mass at the hip site with denosumab, because bone modeling-based formation is still happening. So therefore it is really an interesting treatment modality. What else have we learned about denosumab? So we have learned that maybe because our patients suffer a fracture on denosumab, maybe that is not reason to discontinue the treatment or change treatment, because it was shown in the FREEDOM study, as you can see here, that the risk of a second fracture in patients who suffered fracture on the trial was also reduced compared to patients treated with placebo. So one fracture, although it's worrying for the patient and the physician, should maybe not always make us change the treatment. And another thing is that it has been investigated in different subpopulation where it also has shown quite prominent effect, especially in patients with very low hip BMD and in older patients. So many good reasons to consider denosumab treatment for our patients. And this is, I think it's a very good overall snapshot of what we can expect and what we could talk with our patients about when we discuss denosumab treatment. It's constructed based on the FREEDOM trial. It uses the virtual twin model and compared what would have happened if patients stayed on placebo or denosumab for 10 years. And you can see that there's a significant reduction in all types of fractures, including hip fractures, over this 10 year period. And you can also appreciate that the risk of atypical femur fractures in O and J is still very low compared to the fractures prevented. So good reasons to consider denosumab as a treatment. I just wanted to just briefly mention that another reason to at least consider denosumab treatment in some patient is if we are aiming for treatment targets. Because if BMD is very low, we know we will not be able to reach minus 2.5 or much less, minus 1.5 or whatever treatment target we could go for. We will not be able to achieve that with a bisphosphonate. So, and the whole idea about the treatment target of course comes from different clinical trials. Here I just took some of the data again, constructed based on the FREEDOM trial, where they looked at the T-score immediately or as close as possible in the trial. The T-score just before a nonvertebral fracture occurred. And what can be seen from this analysis is that as BMD, the higher the BMD, the lower the risk of a fracture. But you can also see that there is a plateau. So when you reach the T-score of minus 1.5 or thereabouts, you will probably not reduce the fracture risk further by increasing BMD. And you can see the curves are similar, irrespective of age. They're actually identical, irrespective of low or high age. But you can also see what we know, that patients with a prior fracture, they will always have a higher risk of a new fracture. And therefore, we most of the time consider these patient at higher risk of fracture than patients without a prior fracture. But the curves are still the same. The BMD plateaus around minus 1.5. The other argument that increase in BMD is important comes from the FNIH Bone Quality Work Group project, where they actually investigated BMD change as a predictor of fracture risk reduction. And as you can see, it's really a huge undertaking. They included data from 22 clinical trials, almost 100,000 patients altogether. And what they showed here was that there was a very strong correlation between increase in BMD and fracture risk reduction. So that's another reason for why we should aim for increasing BMD. It's also important to reduce bone turnover if that is high. That also is a good predictor for fracture risk reduction, but it is very important to increase BMD if we want to prevent fractures. So that was some of the arguments for why we should use the Newsome app. So now we will turn to the topic of the professor, namely discontinuation of the Newsome app. And we've known it all along. This is very early data published 10 years ago, showing that this is clearly a reversible treatment. If you stop it, the patients will lose BMD rapidly within the first six to 12 months. And we also know that that is because of the rebound or something that rebound is not the right word, but that's what we now have come to call it, the rebound activation of bone resorption here, indicated by the increases in CTX that increases way above the baseline level in these women. This is the study where the patients were not treated after the Newsome app. And so you can see that the increase in CTX spontaneously is reduced towards baseline in the two years following discontinuation of the treatment. And it has also been known for quite a while that there probably is an increased risk of vertebral fractures, and especially multiple vertebral fractures when you discontinue the Newsome app, especially in patients with severe osteoporosis and pre-existing vertebral fractures. Here you can see the risk of vertebral fractures on treatment in the FREEDOM trial placebo and the Newsome app groups. And here you can see what happens with vertebral fractures and multiple vertebral fractures when you discontinue the treatment still in patients on trial. You can see that when you just look at vertebral fractures, it just looks as if the fracture risk returns to what it was in the placebo group. But when you look at the multiple vertebral fractures, there seems to be an even more prominent increase in multiple vertebral fractures after discontinuation. These data have been interpreted slightly different here and in Europe, because here there's a warning against multiple vertebral fractures if you discontinue the treatment. In Europe, the EMA is much more conservative, you can say, so they have not put that into the SPC as a warning, which I think is sad in a way, because of course, treating physicians should know about this. So what can we do? So the absolute first attempt to do something was done by Ian Reid and his colleagues. And this is a case series of six post-menopausal women who actually participated in the FREEDOM trial. And because we already at that time knew that bone loss would occur if you just discontinued the treatment, they decided that they would try to treat them with solitronate. So they had one infusion of solitronate and then they looked at BMD two years later. And as you can see, BMD was increased most prominently at the hip side. This was, of course, just this case series, but it generated a lot of discussion and it led us to do the SOLIMAP study, as we call it, the study of solitronate after dunusumab. And the only thing that was out there at that time was actually that Ian Reid study. So, and there was a lot of discussion about whether solitronate was given too early and if bone turnover was still too suppressed by dunusumab and that was why solitronate wouldn't work. Because there was no bone activity that could actually lead solitronate to attach to the bone. So therefore, we decided this study as we did. We are much wiser now, so maybe we should have done it differently, but that's always how it is. So we had these three groups. One group received solitronate six months after the last DMAP injection. And then we had a delayed group, the nine months group. And then we had what we called an observation group. It wasn't a true observation group because all patients received solitronate, if not before, then at month six, which is actually 12 months after the latest DMAP. But we were quite afraid of what would happen. So you can see we measured blood turnover or bone turnover all the time and had some rescue intervention in place. So it was a small study, 20 patients in each group. They were predominantly female. They were between 65 and 70 years of age. 50% had a prior fracture. You can only get reimbursement for denosumab in Denmark if you have a reason, if you have a reason to give denosumab. So that would either be that you actually tried alendronate and couldn't tolerate that, or if you had some kind of gastric ulcer or something. So that's why most of the patient had a short period of alendronate before starting denosumab. But then they were treated for an average of 4.6 years with denosumab. And they had very nice BMD, as you can see, in the osteopenic range, where we would really like the patients to be before we consider discontinuation. And it became a quite messy study in a way. So all the purple bars represent patients treated again, or prematurely, with alendronate because of high levels of CTX, and they were really high. So our normal level in postmenopausal women is between 0.2 and 0.8, and we had set the intervention level at 1.26. So really, really high. And that was one of the mistakes we made. It probably should have been lower. So we had to treat a lot of patients outside of the protocol, just to prevent this from going too far. But you can also see later on in the study, we predominantly treated patients not because of high CTX, but because of BMD loss, which is the orange bars. But despite all our efforts, the patient lost BMD. You can see in the early treatment group, the BMD loss at the spine, almost 5% after one year. And you can see similar loss in the delayed groups that was, the pattern was slightly different because they had a very rapid decline in BMD before they actually got treatment. And then it seems to slow down a little bit, but they also ended with a 4% decrease. And this is the observational group, which also lost 4%. So you can see, irrespective of what pattern we have used for the treatment with soletronate, all of them lose BMD. You can see all of them together. So we were not successful in preventing bone loss in these patients. And similarly at the total hip, there was also a loss of 2% to 3%. Again the slope of loss was less with the early treatment group, but all groups lost BMD. And the reason for this is clearly seen here, which represents the changes in CTX. So this is the early treatment group where you can appreciate that despite CTX being quite low in the patients coming off denosumab, we were able to further suppress CTX after one month, one month after the infusion was administered. But we were just not able to maintain that suppression. It escaped again and reached really, really high levels of CTX. And here you can see the different pattern, of course, in the delayed groups with a very prominent increase in CTX early on before the infusion of soletronate. And then it was even more prominent in the observation group where we delayed soletronate treatment. So there clearly is a very, very prominent increase in CTX that is very strong and very cannot, it can hardly be managed, at least in patients who've been treated 4.6 years as in our study with one infusion of soletronate. So here they are just put all together. We were also able to see that treatment with, the longer treatment with denosumab that resulted in a higher level of CTX at baseline. And that has also been seen actually in the FREEDOM trial. There's a bigger escape of CTX for every injection you get of denosumab. But we can also see that the CTX at baseline was actually predictor of bone loss from the spine two years later. So what is going on? We're still trying to investigate that. And any good ideas, of course, would be welcome. We have just analyzed actually RANK-LIGAND, OPG, TRAP, CTX, and P1NP. And we presented this at the ECTS meeting a month ago. And of course, what happens here during denosumab treatment is not from our study because we didn't measure it. But that's from other publications. So we think there's this increasing amount of RANK-LIGAND there. It's neutralized by denosumab, but there's a high level of RANK-LIGAND. We also know that that declines a little bit when, or that's what we see in our study, that RANK-LIGAND declines when the patients are coming off DMAP. But at the same time, we see a prominent increase in TRAP, 5B first as an indicator of recruitment of osteoclasts. Then there's an increase in CTX, and then there's an increase in P1NP. And then we can see when we reach the nine-month time period, there's hardly any RANK-LIGAND left, but CTX, P1NP, and TRAP are still high. The surprising thing to us is actually that nothing happens to OPG. So we've been thinking a lot about that, and there may be reasons for it. It may be because the osteoblasts are also influenced by the lack of osteoclasts that are there during DMAP. So they are not activated, they are not ready to respond. But it has actually also been seen in other studies that there's no real response in OPG. It could also just be because the majority of OPG in serum is not bone-derived. It could be from the other sources of OPG. So I'll just spend a little time on some of the other studies, because I think there are some interesting points that can be also picked up, especially Swiss groups have been very active also. So this is an observational study in 120 postmenopausal women who developed osteopenia during treatment with denosumab. So the duration of denosumab varied between two and five years, and they had one infusion of seletronate. And exactly as was seen in the INREAD study and in our study, you can see that there is a decrease in BMD spine and hip between discontinuation of denosumab and the follow-up at DEXA. The interesting thing maybe from this study is that because it was a clinical observational study, the interval between DEXA-2 and DEXA-3 was actually quite variable, as you can see here. But that allowed for the investigators to actually see whether the interval or the time between discontinuing of denosumab and injection of seletronate and the follow-up DEXA, if that was actually important. And as you can see, it did not affect the BMD loss, suggesting that all of the BMD loss happens within the first year. So it's not a continuing thing. It happens within the first to maybe one and a half year after discontinuation. And actually, a similar thing, I think, can be interpreted from this also retrospective study of almost 800 cases, again, from the Swiss Denosumab Study Group. Here you can see the number of fractures before denosumab, on denosumab, and after denosumab. And again, very clearly, increase in vertebral fractures was seen in this study. But again, if you look at the timing, you can see here, so the months here are months after the last DMAP injection. So you can see how all of these fractures, or almost all of these fractures, occur within the 12-month window from when denosumab effect disappears. So that would be six months after the last DMAP, and then the following year. That's where the main risk for our patients are for the fractures. And they also looked at these different scenarios, patients who had not had any bisphosphonates either before or after denosumab. These are, of course, the ones that do worse. And then there were different other ways of trying to prevent the fractures. But again, so again, here you can see the fractures occur between when denosumab, the effect of denosumab stops, and then the following year. Thereafter, it seems to be quite stable. So it's during that phase of very high turnover that our patients have the risk of fracture. So what can we do then, apart from what we've tried? Can we use a lendonate? It hasn't been studied in great detail or in a great systematic approach. These are data from the DAP study, which is actually a preference study comparing denosumab with a lendonate. And in this study, it could be seen that if you treat for one year with denosumab here in blue, the third column, and then follow on with a lendonate, you'll be able to stabilize BMD, at least at the spine. It seems like there's a small decrease at the hip site. So could that be something? And it probably could if you've been treated for a short period of time with DMAP. I just wanted to share a patient of mine with you. She was an 80-year-old woman diagnosed with osteoporosis in 2012, and she thought she couldn't tolerate a lendonate, so she was started on denosumab. And that went really well. So she responded quite well, but she still had pretty low BMD. But she decided she wouldn't have denosumab anymore. It was just a decision. She didn't want any treatment anymore. And we tried all we could to persuade her to do something, because we thought this could go really, really wrong. So the only thing we could get her to accept was actually a lendonate. So she started on a lendonate, I think, five months after the last DMAP injection. And you can see it actually could not at all control neither CTX or P1 and P. They really increased a lot. And of course, especially here, you can see at the hip, she had a quite prominent loss of hip BMD. So in the end, we were able to persuade her to go on to selendonates, and now we'll see how long she will stay on that, because she's really not keen on treatment, despite her very low T-scores. So I don't think a lendonate will work in patients who have been treated with denosumab for a really long time. This is another study, the study from Greece, where they randomized patients who've been treated for two years with denosumab to either continue denosumab for another year or have one infusion of selendonate. And here again, you can see the black curve is a very rapid increase in CTX once they discontinue denosumab, whereas that can be prevented with one infusion of selendonate in these patients who've only been treated with denosumab for two years, then it works quite well. You can also see, initially, it's able to maintain BMD at the spine. It seems to be declining a bit, and they have actually reported a follow-up publication showing a further decline in BMD. But it probably works better if you've only been treated for a short period of time. At the time when we wrote the ECTS precision paper on denosumab discontinuation, we tried to look at the trials that were out there at that time. And some of them, as you can see, are really trials, and some of them observational studies. And we compared the treatment duration of denosumab with the change in lumbar spine and social hip BMD. And all of these patients were either treated with selendonate or selendonate afterwards. And despite the treatment with bisphosphonate, there seems to be a larger decrease in BMD with the longer duration of denosumab treatment. So just before I come to what we may be recommending, I just wanted to also highlight this new study or relatively new study by McDonald and colleagues. This is a mouse model, but they wanted to figure out how can we explain this rebound activation of resorption after discontinuation of denosumab. And they did a lot of elegant studies. They were able to show that osteoclasts are actually able to split up again, to fission into smaller cells that they call osteomorphs. They still have some osteoclast characteristics, but they also have some specific gene expression. But most importantly, in this context, they were able to see that if you treat these mice with OPG, which is kind of what you can use in mice instead of denosumab, that led to a decrease in the trap-positive osteoclast. And discontinuation of the OPG led to a rebound increase. And they therefore think that this is because we have this huge amount of these osteomorphs or ready-to-fuse osteoclasts lying there. And once there's no inhibition of them fusing, they will all fuse at once and make a lot of active osteoclasts. That has not yet been demonstrated in human beings, but we and others are working at it. So maybe one day we will know whether this is also the mechanism in human beings. So what are the current recommendations? There are probably several recommendations out there. I will focus on the ECGS precision paper, where we gave our recommendation. First of all, it's important to let the patients know that they should expect bone loss, especially if they've been on denosumab treatment for a long time. And we should therefore aim for a higher BMD. So most of us considered discontinuation of alendronate or bisphosphonate anyway when we reach a T-score of minus 2.5. But here you should probably go for minus 2 or minus 1.5, so that the patient will not immediately have an osteoporotic T-score again. And if it's short-term, if the patient's only been treated for up to two and a half years, you might get away with alendronate for one to two years. But if possible, we suggest that you monitor the response with CTX. And if you cannot keep CTX in a reasonable level, then you should probably give seletronate instead. But if the patient's been treated for more than two and a half years, we think the best option to reduce the bone loss would be infusions of seletronate. And we will give it six months after the last DMAP. And that is based primarily on the SOLARMAP study where we saw, although a bone loss, but it was at a more steady rate and no fractures occurred in that group. And then what we do currently is we monitor CTX after three months. If it's not still low or acceptable, we give a second infusion after three months. And we do that again after six months. So some of our patients in the clinic end up having three infusions of seletronate within the first six months. And then we monitor them from there on. If you're not able to monitor with CTX, we recommend that you give two infusions of seletronate six months apart. And then a very important thing that we don't know too much about is that we should probably not expect our patients to be continuously protected against bone loss. Because they have not a skeleton full of bisphosphonate. So they will probably resume age-related bone loss. And so these patients should still be monitored. And some of them might need treatment again. So we should have time for a discussion. But I'll just show you this study we've done. It's still a small study. But it's, as I said, because the colleagues at the Department of Urology, they treat all their prostate cancer patients with denosumab when they give them antiandrogen treatment. And then they usually give the antiandrogen treatment for three years. And then the plan is also to give denosumab for three years. But they do accept that they have to continue denosumab until testosterone is in the normal range. So this is their idea. We were quite scared when we heard about them discontinuing denosumab in this relative large group of patients. So we said maybe we should have a look here. So we agreed that they should refer all the patients when they considered discontinuation. And this is quite busy, but this is just to show you how difficult it is to do clinical observational studies. Patients get referred for all kind of reasons. But we ended up with 52 patients who were actually referred because they were discontinuing denosumab after discontinuing the anti-androgen treatment in this group. And so we thought we had a protocol where patients, if these men had osteopenia, we would treat them with seletronate. If not, if they have normal BMD, we would just follow them. But it showed, real life showed that not all of the men with osteopenia got treated. But we treated nine men and we followed 42. And just to let you know here that the men treated with seletronate, they did lose a little bit at the total hip, but we prevented bone loss, which was clearly bigger in the non-treated patients. But the good thing about these men is that most of them, when we saw them first, actually, as you can see, 50% had normal BMD at the time. So normal BMD at total hip, femur, neck, and spine. So they are not nearly at the same risk as postmenopausal women, but it's still a group to look out for. Yeah, and finally, this is my final point here. It's a very complicated study to read and understand. It's done based on the Health Improvement Network in the UK. It's a primary care database. And they were able to look in this database on patients treated with denosumab. And then they looked at what happens if the next denosumab injection is delayed. And they had all kind of assumptions here. And they also defined that a short delay was four to 16 weeks. And a long delay is more than 16 weeks past the six months time point. And then they looked at fractures. And as you can see, there were no effect on all fractures combined. But there was an increased risk of vertebral fractures, especially in the long delay group. It was increased by a factor four. In the short delay group, it was increased. It was not significantly increased, but there was a trend. So clearly, patients are at risk of vertebral fractures if we delay the injection of denosumab too much. There were no significant effect on the other types of fracture either. So just to sum up here about denosumab, I think it's important to remember that this is the only anti-resorptive treatment we have where BMD continues to increase for up to 10 years. And where the risk of non-vertebral, vertebral, and hip fractures are significantly reduced and remain so also for up to 10 years. There are risks associated with long-term treatment, but the incidence of these adverse events are really low and should be put in perspective because the benefit-risk ratio is positive in patients at risk of fracture with osteoporosis. We should remember the discontinuation of denosumab, it results in a rebound activation of bone resorption, bone loss, and in some patients, increased risk of vertebral fracture. And I don't think we know, and also this morning we had another study about different ways of preventing this. So I don't think we at the time know the optimal transition from denosumab to bisphosphonate and a potential treatment pause or treatment break thereafter. But it clearly depends on the treatment length. I think bisphosphonate is probably the best tool we have at the moment, but it cannot completely prevent bone loss. And therefore we should aim for higher BMD before we consider it. And therefore we should also remember that these patients will most likely start losing bone again and therefore they should be monitored and maybe put on bisphosphonate for a period of time. So thank you very much for your attention. And thank you. And I hope there are some comments or suggestions or something we can discuss because that's the really interesting part. So please. Hi, excellent talk. All right, sorry. My name is Mona Al-Muqaddam. I'm from the University of Pennsylvania. And I'm sure there's gonna be a lot of people asking you questions. But I think the biggest question is, do you really consider denosumab as a first-line therapy? So the updated endocrine guidelines continue to list denosumab as a first-line therapy. And we recognize that the use of osteoanabolic therapy before antiresorptive is better. We also recognize that the risk of bone loss and fractures is higher in younger patients and people who were not pretreated with bisphosphonates. So do you think that these guidelines should be updated so that prolia is not always considered as a first-line therapy? Yeah, no, I totally agree. I think we need to have a much more individualized approach to treatment of osteoporosis. I think denosumab is a perfect drug for an 88-year-old woman staying in an institution where we would not ever consider treatment discontinuation. But of course, we need to secure so that you could actually get the denosumab every six months. There are also other patients. If you, for one reason or another, have a younger patient with very low BMD and you are not able to treat with a bone anabolic treatment of endothelioperatide or beloperatide for reasons that could be there, then I think if you have a T-score of minus four, I would still consider denosumab in that young person. But we would have to have a long-term plan because, of course, you shouldn't be treated with denosumab until she's 90 or something. So I just think we need to consider carefully what the different drugs can do and therefore why we should choose different drugs for different patients. Sandeep Khosla, Mayo Clinic. It was beautiful. I mean, it was nice to kind of see it all put together. You know, when you showed that rank ligand data and you put it together with the zolendronate, I mean, it seems to me that whether it's due to the osteomorphs or some other reason, you have this very high rank ligand environment that's driving osteoclastogenesis. And then you give the zometa or the zolendronate, you see this transient reduction in resorption and then it just comes back up. Now, when you haven't treated with denosumab, we know that when you give that, when you give zolendronic acid, the resorption stays down and that single infusion can last two years. And for most of us, that's been because the zolendronate has been incorporated into the skeleton. I mean, what this is suggesting to me is that you have that immediate reduction with the high dose that the osteoclasts are seeing, but then whatever is being released from the skeleton isn't enough to overcome that very high rank ligand environment. And the question then becomes, you know, are you just not, in that setting, dosing with enough bisphosphonate? So, I mean, cancer patients get zolendronic acid monthly. And maybe after denosumab, you know, you ought to be giving it monthly to see if the CTX stays down. And then, you know, we're monitoring rank ligand, so when rank ligand comes down, then you can back off when there's zolendronic acid. Or giving higher doses of oral bisphosphonates daily to really suppress it. I mean, I'm not suggesting this as a clinical practice, but something maybe to explore. No, no, I totally agree. And the next study we are gonna do, we are not gonna give it monthly, but we are gonna give it three monthly, irrespective of CTX, also to make it more simplified for everybody. So we will suggest to give three times. Oh my God, are all these questions also coming? Okay. So, yeah, no, so that's what we do. I think, and you can discuss whether it should be, like, months one, two, three, or whether it should be months zero, three, six, or whatever, but I totally agree. There's such a prominent recruitment of osteoclasts, and the whole bone environment changes so rapidly. So one infusion is probably not gonna do it. Yeah, yeah, could be, yeah. Hi, Rob Wormer, Mayo Clinic, Rochester. Could you give us a little insight into how you approach atypical femur fractures on danosumab or ONJ? Do you have any clinical recommendations on how you approach that? Yeah, so first of all, with atypical femur fractures, yeah, so of course we try, we have to discontinue danosumab probably, but I'm still not really sure whether we have to do it, because then we have to give something else, and why not then continue danosumab? So, but just because it's really difficult for a patient who suffered what the orthopedic surgeons tell them is all because of the drug, a fracture. So for, maybe mostly for that reason, we tend to go to put these patients on seletronate, at least for a year, and then see what the treatment need long-term is. And with osteonecrosis of the jaw, again, we try to do it individually, and because there's not really, there's also now a new publication coming out, and there's been a number of publications suggesting that it doesn't really help to discontinue treatment. So if these patients are still at high risk, I would probably not discontinue treatment. Hi, great talk. Alberto Gonzalez from Dominican Republic. Interested in osteoporosis in men, and so after they're done with the danosumab, what CTX level do you aim, and then when will you repeat then a second dose of seletronic acid in those patients? So we do, we have exactly the same regimen going for men and women. So we aim for a CTX in our lab, it would be 0.4, it's probably 400 in most other people's lab. So if CTX increases above that level, then we retreat with seletronate. But I think the reason why the prostate cancer men are better protected is actually because they have their testosterone back. So they are not like sex hormone deficient as postmenopausal women. Thanks. Hi. Hi. Suchitra Nunchala from Northern Virginia. So you mentioned that you would give Zol six months after starting danosumab, stopping it. Yeah. So meanwhile, are you doing anything? Are you giving them oral alendronate? No, so six months after the last DMAP injection. Yeah, no, we don't give, and it's also because, you know, in Denmark we cannot prescribe danosumab for patients who can tolerate oral alendronate. Of course, things can have changed over the time course of danosumab, but most of the patients are not able to tolerate oral alendronate. So it's not like really an option in, but it could be interesting. And also, as Sandeep said, you know, we might just need to give higher doses of oral alendronate or resitronate for a period of time. And I hope somebody will do that study because it's just not easy for us to do it in Denmark. And your first CTX, you're doing it at three months? Yeah. At three months. And if that's above 400, you'll give them Zol then? We will give another infusion of Zol. So we give all of them at six months, and then we follow with CTX every three months. And if it increases above 400, we will give another infusion. Yeah, you'll have to fight with the insurance companies because they are not- No, I know, I come from a totally different system. So I know, I know. And would you talk about an anabolic agent after denosumab? Yeah, no, but not directly. I think the data from the extension of the romososumab phase two trial shows that we will probably not get the most out of Ivenity during the rebound phase. So I think if I had a patient where I would go from denosumab to Ivenity, a teriperatide for that matter, I would at least intervene with a year of bisphosphonate to not kind of lose the effect of the bone anabolic treatment during the rebound period. I see, okay. Thank you. Phillips Emory, I had a patient who had had bilateral hip replacement, terrible osteoporosis, and then had atypical humeral fractures on denosumab. She did not heal the fracture well. So I added Tymlose on the advice of another bone expert, not myself, and she healed beautifully. So I wonder if some consideration could be made in some circumstances of adding a bone formation drug. Yeah, no, that's a really good suggestion. I thought that was difficult here with insurance to give two drugs, so I wouldn't mention that. But that's another way, and I've done that with teriperatide, adding it to denosumab instead of changing from denosumab to teriperatide. So giving it on top, and that works really well. Yeah. Thanks so much for the nice talk, and Keza from Tufts. So what do you think about CKD patients? For example, we put them on denosumab, and then after, let's say, eight years, we want to transition them. And nephrologists do not look keen to do zoledronic acid. So do you prefer PO, bisphosphonase, or any other thoughts on those? I think you need to consider very carefully why you want to discontinue denosumab, because that's really troublesome in these patients. But if you really think, yeah, we sometimes give zoledronate to EGFR down to 20, but we don't really give it below that. But we are now doing a study with all bisphosphonate for these patients down to minus 12, GFR of 12 or so. So maybe, but I think I would continue denosumab if it's not because of terrible hypercalcemia or something that is absolutely uncontrollable. I would probably continue because it's really difficult. Like atypical fractures or ONJ, let's say, on these people. Yeah, but then you don't really know if that risk will be reduced on an oral bisphosphonate. So, but you could probably then go with it for a period of time to take off the worst of the rebound, but it is really, really difficult. Yeah. Thank you. So I'm really sorry to all the people out there who submitted all these questions. And I know I can't even open the iPad, so I can't even see all the questions, but I think the time is up. And I think I'm really, really happy that the people in the audience had so many questions to ask and thank you for a very lovely discussion. And I hope we can continue it at coming meetings. Thank you very much.

denosumab

osteoporosis

fracture prevention

bone mass

FREEDOM trial

bone mineral density

vertebral fractures

bisphosphonates