Hello everybody, welcome to this session. We are very fortunate today to be to be joined by three internationally renowned experts to present on the important topic of today's session, treatment options in osteoporosis across the spectrum of fracture risk. Our first speaker today is Dr. Ian Reid from the University of Auckland in New Zealand. His talk is entitled Treatment Options for Individuals at Moderate Fracture Risk. I would also like to remind attendees to please place your questions into the Q&A section and also remember to upvote your favorite questions. Thank you very much, Dr. Reid. Thank you for the opportunity to talk to you about the treatment options for individuals at moderate risk of fracture. In the past we focused very much on treating people at high risk and in recent times particularly high imminent risk so this is now moving to the other end of that spectrum. I don't have any relevant financial disclosures to make. The first question I guess that arises is why would you want to treat women or other individuals who are only at moderate risk of fracture? The NORA study was the first intimation we got that treating women at moderate risk of fracture was probably quite important. So in this study almost 150,000 women from across the United States were followed over a period of about a year and the occurrence of fractures was documented in relation to their bone density t-scores and we see in this graph with the healthier bone density t-scores at the left and the lower density shown at the right that as your bone density goes down your risk of having a fracture climbs quite steeply. What's very interesting is what happens when we compare this with the distribution of bone densities. So bone density is normally distributed with the peak at around minus 0.5 to minus 1 t-scores. So then let's move on now and look at what actually happens with the distribution of fractures and we see that here in the white or yellow bars and what we find is that because there are many more women with bone densities in the osteopenic range than those in the osteoporotic range that the fractures, the greatest number of fractures, is actually occurring in the osteopenic range where women are at moderate risk of fracture but because there's so many more of them this group dominate the fracture statistics. So it's between t-scores of minus 1 and minus 2 that the great majority of fractures in the postmenopausal population occur. This finding is not unique to Nora. We see on this table that in the Nora study 18% of women who had fractures actually had osteoporosis in bone density terms. The very large Rotterdam study 21% of women with non-vertebral fractures had osteoporotic bone densities and similar in the studies from Australia the Dubbo study 11 to 20% prevalence of osteoporotic bone density and the Arvo study from Denmark 23%. So most of the people having fractures do not actually have osteoporosis. Now this difficulty with identifying who is likely to have fractures has bedevilled the three large screening studies that have been published in the last few years. So I've identified these three studies in the left-hand column. The duration of the study is shown in two columns over the number of people screened at baseline and then the basis for determining a treatment recommendation and then the number of individuals who actually received the treatment and then the hazard ratio for fracture across the whole population. So of those hazard ratios I've highlighted what was pre-specified as the primary endpoint. So in the Scoop study using fracs as the criterion for intervening they only recommended treatment in 14% of the women that they screened. This resulted in a non-significant 6% reduction in osteoporotic fracture though there was a much larger decrease in hip fracture and the reason for that is unclear. In the ROSE study and the SOS study both carried out in Europe primary endpoint major osteoporotic fracture really no impact on that but again the treatment was only recommended in 7% of the screened population and taken in 6%. And then in the SOS study treatment recommended in 25% taken in 18% and a non-significant 3% reduction in total fracture numbers. So each of these screening studies has the appears in retrospect to have the problem that not enough of the women at risk have been treated as a result of the particular targeting mechanisms that they were using here. All right so if precise targeting of osteoporosis interventions does not result in a significant decrease in the global burden of fracture this suggests that we should be going back to what the NORA study originally indicated which was that it's sensible to intervene across a broad range of osteopenic women. So what are the treatment options if we're planning to take this approach? Well this is a recent meta-analysis substantially that done by the Endocrine Society looking at the sorts of interventions that are available and this is the efficacy of these interventions in terms of non-vertebral fracture prevention in osteoporosis. So this brings up the critical question do any of these interventions have a similar efficacy if we give them to patients or individuals who would not have qualified for entry to most of these studies because they do not have osteoporosis they have osteopenia. Let's talk first then about calcium. When calcium is given as a supplement it does have an effect on bone density and this is Mark Bolin's meta-analysis which demonstrates that if you look one year down the track from randomization to calcium or placebo that there is a 1.4% benefit to those randomized to calcium. If you look two years from the beginning of the study the difference between groups is 1.3% and in three years it's 1.2%. So this is probably a remodeling transient if you like that the calcium supplement decreases rates of bone turnover to a modest extent and as a result there is a small one-off increase in bone density but it doesn't accumulate over time and we wouldn't really expect such a small one-off increase in bone density to lead to an enduring beneficial effect in fracture prevention. And this indeed is what the trials and community dwelling individuals indicate so this is data from the JAMA study. It was our study published in JAMA a couple of years ago. Hip fracture shown in the top half where the relative risk of hip fracture in those randomized to calcium is 1.53 and in those in looking at non-fatiguable fracture 0.95. So really no suggestion that calcium prevents fractures in community dwelling older adults. When considering using calcium supplements we need to think about their side effects. Gastrointestinal side effects are quite common and sometimes do increase the risk of people being admitted to hospital with gastrointestinal complaints. Renal calculi are increased in the Women's Health Initiative by 17% and there is ongoing controversy regarding the effects of calcium supplements on cardiovascular disease but a body of literature from randomized controlled trials suggesting that cardiovascular risk is increased and that's been bolstered in the last few years by three different Mendelian randomization studies that indicate that increases in serum calcium levels comparable to those seen following the use of calcium supplements are also associated with increased cardiovascular risk. So no clear evidence of benefit in terms of fracture prevention but significant side effects in the use of calcium supplements. What about vitamin D? If we simply pull the studies together as we did in this meta-analysis of ours from a few years ago we find no significant effect on bone density. A difference here of 0.2% across 20 something studies with a total of about 4,000 patients involved average duration two years. If we look at the fracture data again a very negative result. This is from Mark Bolin's study relative risk of total fracture 1.01 in those randomized to vitamin D and compared with placebo. However this might not be the best way of interpreting this literature and we have recently published two different studies in which we have looked at the response of bone density to vitamin D supplements in terms of what the baseline level of vitamin D was and the reason for doing this is that if people have clear deficiency of vitamin D to the extent that they are beginning to move towards osteomalacia then we would expect to see some increase in bone density as a result of vitamin D replacement because we know that we see profound increases in bone density when we treat osteomalacia with vitamin D supplements. And so this was an exploratory analysis that we carried out of a randomized control trial and what we found was that in individuals who had a baseline 25 hydroxy vitamin D less than 30 nanomoles per liter that ongoing loss of bone density was prevented by vitamin D supplementation. So we see in the spine for instance a 2% loss in bone density over two years in those randomized to placebo completely prevented by vitamin D supplementation. However in those who started above 25 hydroxy vitamin D levels of 30 nanomoles per liter no significant loss in the placebo group and therefore no treatment effect from vitamin D supplementation and similar differences between these two groups when we look at the hip as well. So what this is suggesting is that at a functional level for bone health maybe a end of winter 25 hydroxy vitamin D level of 30 nanomoles per liter is the definition if you like of vitamin D supplementation and as I said in a post hoc analysis of a further trial we confirmed that that same threshold applies. So the suggestion that vitamin D supplements are beneficial on those with demonstrable deficiency in terms of bone density is borne out by the fracture study. So we know the Shapwe study where calcium plus vitamin D was given to women with profound vitamin D deficiency and there was a substantial reduction in both hip fractures and nonvertebral fractures. We see that on the left hand side of this slide and that contrasts markedly with what happened in the Women's Health Initiative where the population was younger, healthier, predominantly community-dwelling and had healthier vitamin D levels at baseline and again a very similar supplementation made no difference to the number of total fractures. So I think vitamin D is clearly important for skeletal health but it's not something that all people benefit from because the great majority of the ambulant community-dwelling population already have satisfactory levels of 25-hydroxy vitamin D and they are of the order of 30 to 40 nanomoles per litre and not the 75 to 100 that has been suggested previously. Alright, what then of the drug interventions? Is there any evidence that the available pharmaceutical products that we have can prevent fractures in people with osteopenia as opposed to osteoporosis? Well over the last almost 20 years we have accumulated a number of quite substantial trials which have suggested that intervention in women who do not have osteoporosis results in fewer fractures and the first of these was the Women's Health Initiative where women randomized to conjugated estrogens showed reductions of about a third in hip fractures, vertebral fractures and other non-vertebral fractures. The Eugene McCloskey study of daily oral clodronate in elderly women given over a period of three years did not impact on their primary endpoint which is hip fracture but a 20% reduction in clinical fractures and a 30% reduction in osteoporotic non-hip fractures and those women like Women's Health Initiative women were not selected for bone densities being low. The Ruth study was actually aimed at individuals with increased cardiovascular disease, risk of cardiovascular disease, so again it was not a targeted osteoporosis treatment study. This study used riloxifene, no change in non-vertebral fractures were seen but that would not be expected because riloxifene does not decrease non-vertebral fractures in osteoporotic populations but in fact the clinical vertebral fracture protection was very comparable to what is seen with riloxifene use in osteoporotic populations. In the next two lines of the table are two breast cancer studies. The first of these was in post-menopausal women with early breast cancer who were taking aromatase inhibitors and they were randomized to receive tenosumab every six months or placebo and clinical fractures were reduced by about 50% in those randomized to tenosumab. In the Azure study again women with early breast cancer randomized to seletronate or placebo, 30% reduction in clinical fracture numbers and then our recently published study giving seletronate to women who were selected for being osteopenic and reductions in non-vertebral fractures of about a third and vertebral fractures of about a half. The right-hand column in this table is quite important because in each of these studies people looked at subgroups to determine whether there was a high-risk group that particularly benefited from the intervention and very consistently no significant interactions are found in this regard, suggesting that a uniform decrease in fracture numbers across the groups being studied. It's interesting to note in the tenosumab study in women with breast cancer that even those with T-scores greater than minus one benefit was seen and in the Azure study even in premenopausal women benefit in terms of fracture prevention was seen. In our own study this is the fragility fracture data which was the primary endpoint so this is a composite of non-vertebral fractures and of fractures detected with vertebral morphometry and we see about a one-third reduction highly significant in this group of 2001 randomized to seletronate or placebo. This produced a number needed to treat of 15 and here from that study we see more detailed data relating fracture incidence in the two groups the placebo group shown in pink and the seletronate group shown in blue in relation to baseline calculated fracture risk and we can see that there is a very uniform decrease in numbers of fractures in those treated with seletronate irrespective of what their baseline calculated fracture risk was and so the numbers needed to treat across the two tiles of the population kept categorized according to the calculated fracture risk at baseline are very consistent 18, 12 and 16 across the lower middle and upper tertile. All right so now if we're on the basis of the half a dozen studies that I've just reviewed with you if we're planning to advocate that we should provide mass medication for fracture prevention in osteopenic older women there are some important issues that we need to think about. How safe is this? How much is this going to cost? Are the individuals in this group going to be willing to take this? Will they adhere long-term and what is the acceptability of this to the participants, the patients themselves and to the groups that are funding this intervention? By far the greatest safety concern when using anti-resorptive agents either bisphosphonates or denosumab is the occurrence of a typical subtrochanteric fractures which may develop initially as we see on the left hand side as a stress fracture in the lateral cortex of the femur and then can subsequently become a completed transverse fracture of the femoral shaft. Dennis Black's group have provided us with some valuable new data in relation to this based on a large observational study within California and we can see here that duration of use of bisphosphonates greatly increases the risk of atypical femoral fractures particularly after three or four years of use and beyond five years the risk climbs really quite steeply. Importantly if the oral bisphosphonates which was the predominant agent used in these studies, if the oral bisphosphonates is discontinued and then beyond three months of discontinuation the risk of these atypical femoral fractures drops by about two-thirds and beyond 15 months by almost 90%. So the problem comes with time and is reversible with time which suggests that if we want to use oral bisphosphonates long-term then we should look at instituting drug holidays and obviously this is common practice now these drug holidays with alendronate anyway should probably be at least one year or possibly two and we should try and institute them about every five years. It's important when thinking and talking about atypical femoral fractures that we remember that these fractures are very rare particularly in European populations and that they are dwarfed by the number of hip fractures that are prevented by the use of these drugs. So if we look at this breakdown of the black data by racial group we can see that in whites there are about 80 times more hip fractures actually occurring than for every atypical femoral fracture that occurs. So the prevention of these hip fractures by bisphosphonates is a very important therapeutic benefit. In contrast if we look at Asian populations where hip fractures are less common and the predisposition towards atypical femoral fracture seems to be higher that there is still a substantially a greater number of hip fractures than of atypical femoral fractures but the ratio now is only about threefold rather than 80 fold so the need for caution in long-term use of oral bisphosphonates and the need for drug holidays is considerably greater in Asian populations than it is in a white or European population. In the case of intravenous seledronate the risk of atypical femoral fractures is much less clear. In the largest of the phase 3 trials, the black study, there were three sub-trochanteric fractures observed in the seledronate group and two in the placebo group but x-rays were not available so whether these were atypical femoral fractures is not at all clear. Radiology was carried out in the two extensions of the black study out to nine years and no atypical femoral fractures were observed with that prolonged use but the numbers of participants was considerably reduced. In our recent seledronate study, so that's a thousand women on seledronate placebo out to six years, we saw no atypical femoral fractures and as of last year the ongoing Swedish national database had not observed any atypical femoral fractures in patients who had only been treated with Zol. Some had occurred in those who'd been treated with oral bisphosphonates as well as Zol. The other major safety issue that gets talked about is osteonecrosis of the jaw but in fact this is predominantly an issue in patients with disseminated cancer who are treated with high dose intravenous bisphosphonates and whether this problem is any more common in patients treated with oral bisphosphonates or for that matter oral denosumab than it is in patients with osteoporosis treated with other agents is quite unclear and this is a very large study from Taiwan published a few years ago showing that the evolution of ONJ in patients treated with lentronate was if anything slightly less than that seen in patients with osteoporosis treated with calcitonin and or riloxifene. So I think for practical purposes osteonecrosis of the jaw is not a major concern but atypical femoral fractures clearly remains an issue. It's important to acknowledge that in our recent Zoledronate study and also in the Lyles Zoledronate study which was carried out in men and women after hip fractures there is a suggestion of other benefits from other than just fracture prevention so we appear to see a reduction in risk of cardiovascular events and we also saw a reduction in the incidence of cancers in this study. In the Lyles study there was a reduction in all-cause mortality. So it may well be that if these findings are real of effects on cancer and cardiovascular disease and mortality then these may swamp concerns regarding things such as atypical femoral fractures. The evidence remains uneven. The black study of Zoledronate did not find these beneficial effects and they haven't been consistently demonstrated with oral bisphosphonate so they have been suggested in some studies. What then of the cost of these interventions certainly if one's using generic agents with the numbers needed to treat that we demonstrated in our Zoledronate study this is a cost-effective intervention. Is this going to be acceptable to patients will they continue to take it and that is going to vary from agent to agent. Certainly something that requires daily dosing is most unlikely to be acceptable in a prophylactic role long-term and even weekly oral dosing may cause problems. This is one of the major advantages of Zoledronate and this has been made particularly clear in Andrew Gray's recent publication. This is a follow-up from a randomized controlled trial in which women were initially, osteopenic post-menopausal women, were initially randomized to receive a single dose of Zoledronate or placebo and followed for five years and we can see the top graph the substantial benefits to spine bone density that occurred following that single dose and total hip bone density in the lower graph and then at five years both the former placebo group and the former Zoledronate group were given an infusion of Zole and you can see that that led to maintenance of the beneficial effects on bone density at both the spine and the hip. So this suggests that an agent such as Zoledronate can maintain bone density long-term for as long as 10 years. In this particular study whether that's going to be associated with fewer fractures remains to be determined but in general prevention of bone loss is associated with fewer fractures. In conclusion what I've shown you is that most fractures occur in osteopenic women not in osteoporotic women. Highly focused interventions have little impact on total fracture numbers but there is evidence that a range of anti-resorptive treatments can reduce fracture numbers over a wide range of baseline bone densities and fracture risk. Zoledronate appears to be a safe intervention for broad use in older women. If generic denosumab becomes available that may be a further option but it doesn't have the same longevity of action that Zoledronate has and so continued dosing with a rigid six monthly inter-dose interval would be necessary for that to succeed. Thank you for your attention. Okay what we're going to do right now is we're actually going to move on to the next presentation and then hopefully if we are able to sort this out we can come back to some of these excellent questions and to hear Dr. Reed's answer. And so I think what I would like to do next is to introduce our next speaker. The next speaker is Dr. Benjamin Leder from the Massachusetts General Hospital and he'll be speaking on the topic of transitions in osteoporosis pharmacotherapy. So thank you very much for that for that introduction and the invitation to talk about sequential therapy. These are my disclosures. Antiresorptive and anabolic therapies increase bone density, they reduce vertebral fractures and as well as non-vertebral fractures although the effect on non-vertebral fractures is notably more modest than that in vertebral fractures. But none of our agents can restore skeletal integrity in most patients and especially those with established disease. This slide shows the various agents that are currently available to treat osteoporosis. Obviously we have both antiresorptive and anabolic agents. They all increase bone density significantly, they all decrease the risk of spine and non-spine fractures, but they do have differing effects particularly the difference between anabolic and antiresorptive agents with greater increases in bone density particularly at trabecular sites in amongst the anabolic agents. Now what is the rationale to using more than one drug in sequence? First of all that we have to understand that given the limitations of our therapies it's become much more common to do that and the limitations go beyond just efficacy. So we talked about some limitations to efficacy specifically as it relates to non-vertebral fracture, but there's also now an increased understanding of some rare but serious side effects that occur and they occur more frequently with longer-term use. So designing the optimal drug sequence for individual patients requires both an understanding of the long-term effects of the individual drugs as well as the properties of the drug sequences and they do differ depending on the individual agent used. Now first of all let's think about what the consequences are of discontinuing therapy because for the different agents and for the different classes of agents they are they're quite distinct. First of all bisphosphonates, the most commonly used drug to treat drug class to treat osteoporosis, have a very interesting effect when you discontinue them in that they continue to have efficacy probably for months to years after their use is discontinued. This is a study called the FLEX study which was a extension of the original phase 3 FIT study which looked at the efficacy of alendronate versus placebo. In the FLEX study about a thousand women were who were assigned to alendronate in the original FIT study were re-randomized to receive either a continued alendronate or placebo and then followed for an additional five years. And as you can see in terms of bone density this is what happens during the original four-year treatment during FIT and then in the extension those patients who continue on alendronate have a slight further increase in bone density but those who are then transitioned to placebo have essentially stable bone density. And at the femoral neck you see a similar but not identical pattern there is some bone loss in the group that's transitioned to placebo but that bone loss is quite modest. And then when you look at the fracture incidents in this same study you can see that even in those patients who transition to placebo there's really no difference between the alendronate and placebo treated patients in terms of non spine fractures, morphometric spine fractures, but there is a increase in incidence in the placebo group in clinical spine fractures. So there's the maintenance of some anti-fracture efficacy although not complete maintenance of that effect. Now denosumab which is the also an anti-resorptive of a completely different mechanism has a very different effect when you discontinue it. Shown here are the effects on bone density in patients who are treated with the denosumab and then transition to placebo. And you can see that unlike with bisphosphonates there's a rapid decrease in bone density that occurs as soon as the denosumab is discontinued and shown here in the lumbar spine, total hip and the one-third distal radius. Now that decrease in bone density is associated with very high bone remodeling rates with high levels of bone resorption as well as formation. And that has some clinical consequences which we've begun to understand much more clearly over the last several years. It started with individual case reports of patients who had discontinued denosumab and then experienced multiple vertebral fractures. That was summarized very well in a study by Lamy and colleagues and published in the JBMR which looked at the clinical features of 24 patients who had rebound-associated vertebral fractures after stopping denosumab. And you can see that in the vast majority of patients who were reported to have vertebral fractures, they had multiple vertebral fractures including in many cases three, four, five vertebral fractures. Now those are obviously case reports. You can't determine incidents from case reports. But a very important follow-up study was a post hoc analysis was published by Cummings and colleagues looking at the vertebral fracture rate in a thousand women who had discontinued denosumab in the original FREEDOM trial. And you can see here that if you look at the rate of vertebral fractures in the placebo group in the original trial and then after during the extension when they're off treatment, the rates are not particularly different. Whereas in the denosumab group where the on-treatment rate is quite low, as soon as that treatment is discontinued, there's actually a pretty rapid and significant increase in the vertebral fracture incidence. The placebo and denosumab groups here are not statistically different from each other. But if you look specifically at patients who experienced multiple vertebral fractures, there's actually a greater incidence of multiple vertebral fractures in the denosumab treated group. So as soon as denosumab is discontinued, the antifracture efficacy, at least as it relates to vertebral fracture, is lost. And then actually the rate of multiple vertebral fractures is greater than those patients who were treated with placebo initially. Now PTH and PTHRP analogs, the anabolic agents, are similar in some ways to denosumab in that as soon as they are discontinued, as shown in this study, bone density begins to decrease and eventually is lost if you follow them far enough and their bone density goes back to baseline. But it differs first in the case that there's not this accelerated bone turnover that you see with denosumab, but also that there appears to be a continued antifracture efficacy that extends beyond the treatment period. Shown here is the probability of fracture in the patients from the original phase 3 registration trial who were treated with placebo, as shown in the dotted line, versus the both doses of teriparatide, either 20 or 40 micrograms. And you can see that the probability of fracture continues to increase in the placebo group, but there's continued separation between placebo and teriparatide treated individuals that extends for several years after the teriparatide is discontinued. Now romazosumab, as I mentioned, is our newest approved agent. It has both anabolic and anti-resorptive properties, but when it comes to the effects of discontinuation, it looks a lot like the anabolic agents in that as soon as romazosumab is discontinued, the bone density pretty rapidly begins to decrease. That's shown here if you look at the patients, the green line, which are patients treated with romazosumab for two years, and then they either continue romazosumab, as shown in the blue, or transition to placebo, as shown in the black, there's pretty rapid separation between those two groups. That's both at the total hip and at the lumbar spine. So with that as background, let's now look at what happens when you transition from one drug to another. One of the sequences that can be used is switching from one anti-resorptive to another anti-resorptive, and in most cases now, these are patients who are transitioning from a bisphosphonate, either an oral bisphosphonate like alendronate, or intravenous bisphosphonate like solostatic acid, to denosumab. Now denosumab is a more potent anti-resorptive agent. It decreases bone resorption to a greater degree than the bisphosphonates, and when you transition from a bisphosphonate, in this case a study of 500 postmenopausal women who had been receiving alendronate for at least six months, but the mean was about three years, so many of them had been receiving alendronate for quite some time, when they're either continued on alendronate, as shown in this in the dotted line, or transition to denosumab, you can see that there's an increase in bone density, which is greater in the denosumab group, both at the total hip and at the lumbar spine. So going from a bisphosphonate to denosumab is associated with greater increases in bone density. The effect on fracture, however, has not been well studied, but it's not unreasonable, I think, in patients in whom fracture risk remains high, despite bisphosphonate therapy, to transition to denosumab, although that transition to denosumab has to be part of a more global plan, because of the effects of discontinuing denosumab down the line, as I just showed. Now, what about the opposite sequence? And this has become obviously extremely clinically important, because discontinuing denosumab is associated with this increased risk of multiple vertebral fractures. So can this be prevented by transitioning from denosumab to a bisphosphonate? Well, there's a variety of studies that have been done, both with oral bisphosphonates and intravenous bisphosphonates, and they show somewhat differing results, and I think that depends quite a bit on the design of the study. This is a study that our group published just a couple of months ago, looking at patients who had been treated with, first they had been treated with teriparatide and then combination therapy, but for the six months prior to transition had been treated with denosumab alone, and then they all receive zoledronic acid, a single infusion of five milligrams. And this is what happens to their bone density. So they had very large increases in bone density during the initial treatment with teriparatide, followed by denosumab, but then when they receive a single dose of zoledronic acid, you can see that their bone density in the lumbar spine is maintained for the first year, followed by a modest decrease after that first year in the next year and a half. Remember, they're only treated with the single dose, so they're not given a repeated dose here, and even that single dose appears to maintain bone density pretty well at the lumbar spine, but even better at the total hip and femoral neck. Now this study contrasts with a study that was published last year by Solring and colleagues, and it's a somewhat complicated design. I'm going to go over it, but because of the results, which I'll describe in a second, it's less important to think about these individual groups than the overall take-home message. So these are patients that were treated with denosumab for a longer period of time. The average was about four years. And six months after their last denosumab injection, so denosumab is given every six months, so you would expect that that would be the time that you're actually transitioning if you're going to transition to another medication. One group received zoledronic acid, five milligrams. A second group got zoledronic acid, but it was delayed by three months. And then the third group was observed without treatment until zoledronic acid was given later, and there were a variety of different points at which patients could be crossed over from one group to another based on degree of bone loss or increase in bone turnover. Now the important findings are shown here. You can see that regardless of the treatment group, and if you want to focus just on the group that received zoledronic acid essentially immediately after denosumab is discontinued, there is significant bone loss both at the lumbar spine and at the femoral neck, which occurs fairly immediately upon discontinuation, so different from the study that I just showed you. The reason that these studies look different isn't entirely clear, but may have to do with the length of treatment that denosumab was given. So in the prior study, denosumab was just given for a year, whereas in this study it was given for a significantly longer period of time. And it appears that perhaps the longer denosumab is treated, the more difficult it is to inhibit the post-denosumab bone loss, which would occur if you didn't transition to any other medication. There have been other studies that have been published, including those using oral alendronate, and the results generally are similar or intermediate these two studies depending on the agent used. Now, what about transitions from anabolic therapy to antiresorptive therapy? And I think this is one of the most important transitions to look at because it's been increasingly well understood that in many patients who have a very high fracture risk at baseline, the initial treatment with an anabolic agent is often optimal. But all of our anabolic agents, both the PTH analogs like the valiparatide and teriparatide as well as romasosumab, could only be used for a year to two years. So they're not drugs that could be used for a longer period of time. And thus, and as I showed you, as soon as they're discontinued, the bone density begins to decrease. So a transition is inevitable whenever an anabolic agent is used. So when you switch, and the good news is that when you switch from an anabolic agent to an antiresorptive, and in this case, what I'm showing you is the transition to a bisphosphonate, bone density actually increases quite well, quite vigorously, perhaps even in some cases, even more quickly than in patients on de novo therapy. And the reasons for that are not entirely clear, but may be because during the period of anabolic therapy, there's a lot of bone formation, which is under mineralized. And then when the bisphosphonate therapy or other antiresorptive therapy is given, you get rapid mineralization of that bone, which leads to the even more rapid increases in bone density. So this is a study by Dennis Black. Now it's over 15 years old. These are women who were treated with alendronate for a year, I'm sorry, with PTH1 to 84. So not teriparatide, but PTH1 to 84 for a year. And then they either receive a year of placebo or a year of alendronate. And you can see that the increases in bone density at the spine, total hip, femoral neck, and radius are very similar, if not somewhat greater, particularly at the total hip and femoral neck as to what you would expect in a patient who had never received therapy who was starting on alendronate de novo. The same is true really for the transition from abaloparatide to antiresorptive therapy. In this case, again, alendronate. This is a study by Bone and Colleagues that was published a couple of years ago looking at the effects of first abaloparatide versus placebo. This is the original registration trial. And then they receive either alendronate, they all receive alendronate. And you can see that the increases in bone density between placebo to alendronate and abaloparatide versus alendronate look essentially identical. And this is actually also associated with continued antifracture efficacy. Now, what about the opposite transition going from an antiresorptive agent to an anabolic agent? And this is actually pretty interesting because it's been now understood for a period of years that there's likely some blunting of the effect of an anabolic agent when used specifically after a bisphosphonate. This is a study by Ettinger and colleagues now also about 15 years old, where teriparatide was administered for 18 months to about 60 women who had previously either received alendronate or the selective estrogen receptor modulator raloxifene. And you can see that P1NP, which is a marker of bone formation, increases more in the group that had previously received raloxifene versus alendronate. And bone density also increases more in the raloxifene group than the alendronate group. So it appears that the bisphosphonates are blunting the effect on increase in bone density much in the same way that there's a blunting of the effect when alendronate or other bisphosphonates are given alongside or at the same time as the anabolic agent teriparatide. The variety of studies that have focused on this were well-reviewed by Felicia Kosman several years ago. And she focused specifically on the effects at the total hip. And you can see that in all of these studies, the increases in total hip bone density are really quite modest in patients who had previously received either alendronate or residronate. So there is, residronate, excuse me. So there is some blunting, but the effects are still positive. It's not as though the anabolic agent has no effects when given after a bisphosphonate. They're just blunted somewhat modestly. And for many of our patients, this is the sequence that is occurring right now. And a lot of this had to do with restrictions by payers. Oftentimes you couldn't use an anabolic agent initially. You had to start with a bisphosphonate and then only later could an anabolic agent be used if the patient did not continue to fracture or for some reason didn't tolerate or didn't do well on the bisphosphonate therapy. Now, the situation of transitioning from denosumab to anabolic therapy is actually different than the one that I just described for bisphosphonate transitions. And in some ways is actually even less positive. So this is a study that we published about five years ago. It was an extension to our original study that looked at teriparatide, denosumab, or the combination of both drugs for two years. And then after two years, those who had received teriparatide received two years of denosumab. Those who received denosumab received two years of teriparatide. And those who received both drugs received just teriparatide for an additional two years. And this slide shows the increases in bone density first in the combination group, but then in the denosumab and teriparatide group initially. And you can see what happens when those groups are switched. So if you focus first on the teriparatide group, you can see that in patients who go from teriparatide to denosumab, there's an increase in bone density that is really quite dramatic. So the transition from teriparatide to denosumab, much like the transition from teriparatide to alendronate is associated with pretty significant and large increases in bone density. And these increases, if you look at the slope here, are really even greater than what you might expect in a de novo patient. That contrasts with what happens when you go from denosumab to teriparatide. And what happens is not only is there a blunting, but there's actually significant bone loss. That bone loss continues for a year, and only after a year do you begin to see an increase in these denosumab-treated patients. And if you look at the bone turnover and markers, in the serum of these patients, this period of bone loss in this year after the transition is associated with very high bone turnover rates, high bone resorption, high bone formation. So there's this high bone turnover bone loss, which occurs, and that increase in bone resorption and formation is even greater than if you just stopped the denosumab and do nothing, which I described earlier is obviously associated with significant bone loss as well. So what about rhomazosumab transition? So as I mentioned, rhomazosumab has both anabolic and antiresorptive properties. And when you go from rhomazosumab to antiresorptives, you get an increase in bone density that you might expect. So this is a study also published by Felicia Kosman four years ago, looking at patients who are initially treated with rhomazosumab, shown in the dark line here, and then receive denosumab. And you can see that there's this continued increase in bone density that looks pretty similar to patients who are treated with placebo, followed by denosumab. That's both true at the lumbar spine and at the total hip. Now, what about going from a bisphosphonate to rhomazosumab? So I talked about blunting when going from bisphosphonate to anabolic therapy with teriparatide. But in this study, we're looking at what happens when you go from a bisphosphonate to rhomazosumab. So this was a study of 436 post-menopausal women who had taken an oral bisphosphonate for at least three years, but the last year had to be a lendronate. And you can see that there's an increase in bone density in those patients who transition to rhomazosumab, which is greater than the increase than with teriparatide, and about 10% of an increase in the lumbar spine, and a more modest increase at the total hip. These increases are quite substantial, but are likely still, if you look across studies, less than when a patient is treated with rhomazosumab who had not been treated with any antiresorptive agent earlier. And finally, there's no published data, but McClung and colleagues presented at the ASBMR meeting last year a study that included a very small number of patients, 14 patients who received denosumab followed by rhomazosumab. So if you remember, if you go from denosumab to teriparatide, you lose bone pretty rapidly. Now, when you go from denosumab to rhomazosumab, you do have actually an increase in bone density at the lumbar spine of about 5%, as shown here. That is less than the increase when you go from rhomazosumab from a lendronate, as I just showed you in the prior slide, which is about 10%. And it's also less than the average of the increase you get when you start rhomazosumab de novo. So there is blunting both with a lendronate and denosumab, but the transition from denosumab appears to be different. Again, we're comparing across studies, but then the transition from a lendronate. And if you look at total hip bone density in that year, there's actually no increase in bone density at all. There's no bone loss, like we saw with the denosumab to teriparatide transition, but no increase in bone density at the total hip in that year, or at least very little. Again, we're waiting for that data to be published, and it's a very small number of patients, so more work needs to be done clearly. So to summarize, the transition from anabolic therapy to antiresorptive therapy further increases bone density and sustained fracture reduction, whereas the bone density gains after the transition from ribosphosphonates to an anabolic agent are modestly blunted. And the transitions from denosumab to anabolic therapy results in accelerated bone remodeling and bone loss, and potentially an increased risk of fracture, although we don't know that. The transition from denosumab to bisphosphonates mitigates the expected post-denosumab high turnover bone loss, but the optimal agent, the dose, and the frequency of the use of these antiresorptives after denosumab have not yet been defined, and we have more work to do in doing that over the next several years. And finally, in patients with severe osteoporosis, in whom therapy with multiple agents is likely necessary, we wanna really encourage the initial use of an anabolic agent. And hopefully, as this becomes better understood, and this data becomes better understood, payers will allow physicians to use anabolic therapy initially, particularly in those patients who likely will need extended therapy and are at high risk for fracture. So this is just a list of some of the key references that were listed during the course of the study. And finally, I just wanna acknowledge those folks who helped, who were really responsible for our transition studies with denosumab and anabolic agents. And thank you very much. All right, I'd like to thank Dr. Benjamin Leder for that beautiful presentation on a very complicated topic. And again, thank you to all the attendees who are answering or putting the questions in the Q&A. Dr. Reed is answering, typing answers to the questions from the earlier presentation, so you can communicate with him through there. In addition, I'd like to recommend if the audience can please type in who the question is directed to in terms of the specific question, or in terms of the speaker, that would be very helpful. So Dr. Leder, thank you again for that presentation. I think one of the themes of the questions that I'm seeing here has to do with denosumab and dental work, and how do you manage denosumab transitions for patients who are undergoing dental procedures where they need to take a temporary break and balance that against the risk of rebound fractures? Right, so it is complicated. And as Dr. Reed discussed, the data in terms of what the actual risk would be for different types of dental work is not entirely known. It's clearly extremely small, even if you don't stop. So my preference would actually be to continue denosumab and not discontinue it for most cases of dental work. I mean, if you were going to be discontinuing denosumab in any case, and then starting up as phosphonate, you could make an argument, you could wait a couple of weeks to maybe a month. Most of the fractures that have been described are occurring at about eight months since the last injection, so two months after the transition would occur or the discontinuation occurs. But still in most cases, and this is something that sometimes has to be negotiated with the oral surgeon, my preference would be just to go ahead and do the procedure if it's necessary, if it's elective, then not, as opposed to stopping even for a short period of time. Great, thank you. And then another question that's come up is, how long can you treat with denosumab? Is there a maximum limit? And how would you then transition someone off denosumab if they've been on for a long time, especially if they have CKD? Yes, that's a great question. So there is no set limit for denosumab and the safety data really extends now beyond a decade for denosumab. But it's also true that there's really no set limit for bisphosphonates. 10 years ago, we were treating patients with bisphosphonates for decades as well. And so, and why are we not, there are differences between the two drugs, there's continued bone density increases with denosumab, whereas with the bisphosphonate, there's really much more of a plateauing. The reason we're considering stopping these medications often is to worry about AFF specifically. And we don't know what that risk is with denosumab as well as we do with bisphosphonates, only because as Dr. Riccio, the data is not as robust as it is, for example, for alendronate. So, I mean, there's a long-winded way of answering the question. You can continue it indefinitely knowing that there may be risks that you really can't quantify. If you look at certain guidelines that that's not, they don't recommend that. For example, the ACP guidelines that were published in 2017 suggest that, or state that everyone should stop antiresorptive therapy at five years regardless of what the agent is. I don't think that's supported by the data necessarily. And then the question, but if you've made the decision to stop, maybe the patient's no longer at high fracture risk, and you wanna, and the next step would be to use a bisphosphonate, what do you do if there's chronic renal insufficiency? So, again, what I can tell you what I do, this is off-label, because if the GFR is under a certain number, then obviously bisphosphonates are contraindicated. I will often use solatronic acid at a very low dose or at a lower dose. There's really very good data way back from the phase two studies of solatronic acid that very low doses of solatronic acid as low as 0.25 milligrams can increase bone density in a de novo patient. So using a very low dose, potentially you could even use a different intravenous bisphosphonate like promidronate, but I haven't done that in a long time. And then I've seen, and I've, other endocrinologists using the 35 milligram dose of oral alendronate in those patients, the prevention dose in patients with CKD. So I think those are all choices, realizing that there's not great data for any of them and you're sort of in an off-label scenario. Thank you, Dr. Levy, I appreciate that. I think in the interest of time, we need to move on to the next presentation. So the next speaker is Dr. Suzanne Jandeber from the Johns Hopkins University School of Medicine in Baltimore, Maryland. And the title of her talk is Sclerostin Inhibition for the Treatment of Osteoporosis. I'd like to thank the organizers and the chairs of this session for inviting me to present. Today, we're gonna talk about sclerostin inhibition for the treatment of osteoporosis. I have no relevant disclosures. Let's start with a case. This is a 76-year-old female whom I follow in my clinic and who's been particularly challenging. You can see she has a long history of osteoporosis and a long fracture history. But what you'll notice is that she has been on a number of osteoporosis medications, including alendronate, teriparatide, zoledronic acid, and genosumab. And despite being on all these therapies, she's fractured on teriparatide, she's fractured on alendronate, she's fractured on zoledronic acid, and most recently, she's fractured on genosumab. Her medical history is significant for Graves' disease and thyroid cancer. She received a thyroidectomy and underwent radioiodine treatment. She also suffers with spinal stenosis and has intermittent steroid injections to help control her pain. Her family history is significant for osteoporosis in her mother, and she's had a hip fracture. Her mother's had a hip fracture. She, her social history is significant for remote smoking and occasional alcohol. And currently, she's on levothyroxine, genosumab, duloxetine, and calcium, and vitamin D. On physical examination, she has lost height. She had a peak height of 67 inches, and now she's 64 and a half inches. She has myelokyphosis, but no pain to spinal palpation. She's had a thyroidectomy scar, but she has no cushionoid features. On imaging, her DEXA shows osteoporosis in her lumbar spine with a T-score of minus 2.6. Has osteopenia in the femoral neck, but also very low bone density and her 1 3rd forearm of minus 3.1. Her CMP was normal. Her vitamin D is 42, which is at target. Her TSH is also in the normal range. And she's had a previous evaluation for secondary causes of osteoporosis, which are negative. So my plan was fall prevention because many of these fractures happened in the setting of fall. But now, since she's fractured on denosumab and has had two years of teriparatide and a number of other osteoporosis agents, really needed to escalate osteoporosis treatment. And I am considering romazosumab. So let me talk about romazosumab in the context of severe osteoporosis. So why do we care about fracture? Well, we care about fracture because it leads to morbidity and mortality. And having a fracture is a powerful predictor of a future fracture. So if you can see in the bottom panel of this slide, having a non-spline fracture or spline fracture, or especially having multiple fractures, multiple spline fractures, is really a powerful predictor. The relative risk of having another fracture goes up dramatically. And as I said, we care about fracture because fracture leads to morbidity and mortality. And this is looking at age-adjusted relative risk for mortality as a function of having hip fracture or having a spine fracture. And you can see both hip and spine fractures really increase the age-adjusted relative risk of having, of mortality. So gratefully, we have a number of medications that are effective against fracture. And they fall into two major categories, anteresorptives and anabolics. Anteresorptives work primarily on osteoclasts to decrease bone resorption. Anabolics work on osteoblasts to increase bone formation. And I'll tell you the difference between the few of them because there's some difference in their effect on bone resorption. The three anabolic agents we have are teriparatide, also known as Forteo, abalaparatide, which is a PTHRP analog known as Tymlos, and romazosumab known as Avenity. So when do we consider anabolic therapy? Well, we consider anabolic therapy in those at very high risk of fracture. So anabolic therapy may have faster and greater anti-fracture efficacy. So we use those in very high risk. So those people with a recent fracture, those people with multiple clinical fracture, those people with a low T-score of minus 2.5 or lower and fractures. So certainly the patient that I described to you fits the criteria for needing anabolic therapy. So these are our three current anabolic therapies, teriparatide, PTH, abalaparatide, a PTHRP analog, and romazosumab, which is an antisclerostin antibody. So let's discuss a little bit about the Wnt pathway and antisclerostin antibodies. So the Wnt signaling pathway is very important in osteogenic differentiation and in bone formation. Wnt, when it binds to its co-receptors frizzled in LRP56, stabilizes beta-catenin. And when beta-catenin is stabilized, osteoblast precursors differentiate to osteoblast, and this increases bone formation. Stabilized beta-catenin also has a negative effect on osteoclast precursors. And osteoportegrin decreases osteoclastic precursor differentiation to osteoclast, so it decreases bone formation. So this pathway increases bone formation, decreases bone resorption. There are inhibitors of this pathway. Sclerostin made by the osteocyte can inhibit signaling down this pathway. And DKK1 made by osteoblast can also inhibit signaling down this pathway. So by inhibiting inhibitor of sclerostin, you can increase signaling down this pathway by inhibiting the action of sclerostin. So interestingly, the way we began to appreciate that Wnt signaling was so important in bone formation was through some human disorders of high bone mass. So disorders such as sclerosteosis and Van Bucum's disease, where there's this increased cortical thickening, increased bone mass to the point where you get cranial nerve palsies because the foramina compress the nerve because they're so overgrown with bone. You can see in this panel that three normal skulls are even lighter than one skull of a person with sclerosteosis. And individuals with sclerosteosis and Van Bucum syndrome have an absence of sclerostin. So they either have mutations in the SOST gene itself, or they have mutations in a regulatory domain that regulates SOST. So that there is sclerostin, SOST is the gene that encodes sclerostin, there's a sclerostin deficiency. So when there's no inhibitor of the Wnt pathway, that there is increased signaling down the Wnt pathway and unfettered bone formation. In individuals with high bone mass trait, these individuals have high bone mass, thickened cortices, this kind of telltale torus palatinus. I mean, these individuals, they really have just a high bone mass and very few other phenotypic features that's less severe than say sclerosteosis. And these individuals, there's a gain of function of this LRP56 co-receptor so that there's constitutive signaling down this Wnt signaling pathway. So you have increased bone formation. So through the study of these types of kindreds, we were able to appreciate that this pathway is really important in bone formation and that makes sclerostin and other inhibitors of this pathway good targets for osteoporosis therapies. So just to follow on that point, so sclerostin antibodies that inhibit sclerostin will inhibit the inhibitor of this pathway, Wnt can bind to its co-receptors and then signal down pathway stabilizing beta-catenin and then increasing transcription of those Wnt genes, increasing bone formation. And that's how this particular medication works. So it's also interesting when we look at romazosumab, which is the anti-sclerostin antibody and look at its bone formation and bone resorption using markers of bone formation and bone resorption. So for example, using P1NP in the blue and CTX in the red, we can see with romazosumab treatment that there's an increase in bone formation, but there's also a decrease in bone resorption as would have been predicted by looking down that signaling pathway and seeing those effects. However, with teriparatide, which is another anabolic agent, which is PTH, there's an increase in bone formation, there's also concomitant increase in bone resorption. With the anti-resorptive agent, alendronate, there's a decrease in bone formation and a decrease in bone resorption. So this window with romazosumab where you have both increased bone formation but decreased bone resorption really is an opportunity to build a lot of bone or form bone. So this leads to bone formation, bone modeling. Whereas something like teriparatide increases bone remodeling where there's a paired resorption and formation. So romazosumab, an anti-sclerosin antibody, activates osteoblasts on the cortical and trabecular surface and it promotes cortical bone modeling more than bone remodeling. So making new bone rather than breaking down old bone and replacing it with new bone. And it also reduces osteoclastic resorption. So let's take a look at some of the pivotal trials that led to the approval of romazosumab for osteoporosis therapy. So in the pivotal frame trial, this was the 7,000 women with postmenopausal osteoporosis randomized to either receive once monthly romazosumab subcutaneously for 12 months followed by denosumab for an additional 12 months or randomized to receive placebo for 12 months followed by denosumab for an additional 12 months. And these are the data for the bone mineral density and bone markers. So romazosumab is in black followed by denosumab in the black dashed line. Placebo is in gray followed by the gray dashed line which is denosumab. And we're looking at changes in lumbar spine bone density, total hip bone density, and femoral neck bone density. So you can see that compared to placebo, romazosumab increases bone density at the lumbar spine and it continues to increase with denosumab therapy. In the total hip, increases in bone density with romazosumab compared to placebo with continued increases followed by denosumab. And in the femoral neck, increase in bone density compared to placebo and continued increase in bone density followed with denosumab. You can see this characteristic change in the bone markers. So P1NP is a marker of bone formation against with romazosumab treatment, a nice increase in markers of bone formation that then start to come back to baseline around 12 months. And bone resorption, again, decrease in bone resorption seen with romazosumab that then further decreases when switched over to denosumab. So also in the frame trial, looking at the incidence of new vertebral fractures, placebo in blue, romazosumab in orange, placebo in purple here, romazosumab in green. This is 12 months and 24 months. And looking at incidence of new vertebral fractures, significant decrease in new vertebral fractures, about 73% reduction. And this is continued to be seen at 24 months. When you're looking at the first clinical fracture time to event analysis, again, here, placebo is in blue, romazosumab is in red. You can see that there's a decrease cumulative incidence of clinical fractures. And this is significant at the 12 month time point. Then when both are switched over to denosumab, there's no significant difference at 24 months. The first new vertebral clinical fracture time to event analysis in non-vertebral fracture, again, placebo is gonna be in blue, romazosumab in red. No significant difference at 12 months, but there is a significant difference out at 24 months after denosumab is added to romazosumab. And then again, looking in the ARCH trial, this is looking at romazosumab versus alendronate. So 4,000 individuals are randomized to either receive alendronate weekly for 12 months, followed by another 24 months of alendronate for a total of 36 months of treatment, versus romazosumab, 210 milligrams monthly, subcutaneously for 12 months, then switched over to alendronate for an additional 24 months. So this is romazosumab versus alendronate. Looking at the bone's mineral density, romazosumab is in black, alendronate is in gray. You can see that there was an increase in bone density compared to alendronate in the lumbar spine and in the total hip with romazosumab treatment. When romazosumab is switched over to alendronate, that you continue to have that increased bone density, but it plateaus off somewhat, both in the lumbar spine and in the total hip. When we look at incident of new vertebral fractures at 12 months and 24 months, alendronate versus romazosumab, alendronate in the white, romazosumab in the gray, you can see that there is a reduction in new reaching vertebral fractures, and this is a 36% reduction, significant reduction over alendronate treatment. So head-to-head, it looks like it's better at reducing new vertebral fractures, and that's also seen at 24 months. When we look at the first clinical fracture, time-to-event analysis, romazosumab is in black, alendronate is in gray, and you can see there's a lower cumulative incidence of clinical fractures with romazosumab, and the curve begins to start to split around six months. We're looking at non-vertebral fracture here, time-to-event analysis. Again, romazosumab has a lower cumulative incidence of non-vertebral fractures, and again, these begin to split around nine to 12 months between alendronate and romazosumab. What about romazosumab followed by placebo? What happens then? This is a study by Mike McClung and colleagues published in the JBMR of 419 post-menopausal women with a T-score of minus 2.5 to minus 3.5. They were treated with romazosumab, 210 milligrams monthly for two years, and then after two years, they were randomized to either placebo or denosumab. In this slide, we can see that romazosumab is in green, pooled placebo is in black, denosumab is in the blue dotted lines, and alendronate is in orange. When we look at lumbar spine, total hip, and 1 3rd radius, lumbar spine bone density with romazosumab goes up nicely. You can see there's a biggest increase in the total hip and 1 3rd radius. There's a biggest increase up to 12 months, and then it plateaus a little bit. But when you follow it on with placebo, you begin to lose bone, and you lose the bone that you gained. So really, this is to drive home the point that romazosumab needs to be followed by an antiresorptive therapy. In addition, you can see that when you use alendronate and then you follow it with romazosumab, that you get a blunting of that nice increase that you get when you first start to use romazosumab in individuals that have not been on antiresorptive therapy or have not been on alendronate. So use of alendronate before romazosumab somewhat blunts the effect on the bone density of romazosumab. So here, I just wanted to point out that the effect of romazosumab starts to plateau around 12 months, that you need to follow romazosumab with an antiresorptive or you will lose bone, and that bisphosphonates before romazosumab somewhat blunts the effect. What about romazosumab versus teriparatide? This was a nice study done by Bente Longdahl, published in The Lancet. These are just gonna look at bone density only. So about 400 individuals were randomized, 200 to receive romazosumab, 210 milligrams subcutaneously monthly for 12 months, versus those assigned to receive teriparatide subcutaneously 20 micrograms every day. And in these individuals, the time point was 12 months and the end point was bone density. So you can see, this is the total hip bone density. There's an increase in total hip bone density with romazosumab compared to teriparatide, where there was not much of an increase at 12 months. At the femoral neck, there was an increase in bone density in romazosumab compared to teriparatide, which there was not much of an increase at 12 months. And in the lumbar spine, there was increase in both romazosumab and in teriparatide at 12 months, but the increase in the lumbar spine was greater with romazosumab. So what about the side effects of romazosumab? So it looks like it's really effective at increasing bone density. It's effective at decreasing vertebral fracture and non-vertebral fracture. It seems like it's more efficacious than alendronate when head-to-head, and it improves bone density more than teriparatide when compared head-to-head. But what are the side effects? So it's interesting in the frame pivotal trial, it was found that there was no cardiovascular imbalance between groups, between romazosumab and placebo. However, in the ARCH trial, when romazosumab was compared with alendronate, there did appear to be imbalances in the first year of the ARCH trial. There was more cardiovascular deaths, there was more ischemic events, and there was more cerebrovascular events. And this has been somewhat puzzling, but has led to a black box warning on romazosumab. Some of the thoughts around these data are that perhaps that bisphosphonates might be protective against cardiovascular events. So you didn't see it when romazosumab was compared to placebo, but it did become evident when romazosumab was compared to alendronate. Nonetheless, there's a black box warning on romazosumab that you should be aware of. So the black box warning says that this is not appropriate therapy in individuals who have had a cardiovascular event or a stroke within the last year. And I use it in caution in people who are at high risk for cardiovascular disease or have had cardiovascular events in the past, if I have other things to use instead. Other side effects include arthralgia and myalgia, injection site reaction, hypocalcemia, and interestingly, even though this is an anabolic therapy, there were some incidences of atypical femoral fracture and osteonecrosis of the jaw that you should be aware of. So back to my patient. So she fractured on multiple antiresorptive therapies. She had a recent fracture and she's at very high risk for another fracture. So anabolic therapy is needed. She'd already been treated with two years of teriparatide. So really this makes it difficult to get either teriparatide or abaloparatide approved for second course. So my choice was to start romazosumab, 210 milligrams subcutaneously, monthly for 12 months. And then my plan is to follow it with denosumab. So in summary, understanding and targeting the WNT pathway has yielded potent anabolic agents for the treatment of osteoporosis. Antisklerosin antibody romazosumab increases bone density and reduces fracture. And romazosumab is a dual action agent that increases bone formation and decreases bone resorption. It's indicated in severe osteoporosis with a high risk of fracture. For treatment failure or for intolerance to other agents. Its effects wanes after a year and must be followed by an antiresorptive agent. And it is contraindicated in those at high cardiovascular or high stroke risk. With that, I'll thank you very much for your attention. And I look forward to your questions and further discussion. Thank you. Thank you, Dr. Zandiver for that illuminating talk on this important update in our osteoporosis treatment arsenal. There are several questions about the utility of romazosumab in various situations. For example, in somebody who has just sustained an atypical femoral fracture, would this be an agent that you would transition to? Another question is about the use with radiation therapy. Dr. Zandiver, what are your thoughts? So I don't know of any data on using romazosumab in radiation therapy. I don't know any data that would discourage me from using in that situation. Certainly I would might shy away from using teriparatide or beliparatide in that situation where there's been radiation and there could be increased risk of transformation. But for romazosumab, I know of no risk currently for using with radiation therapy. As far as using romazosumab for atypical fractures, in the trials, there were atypical fractures in the romazosumab group. So if you were thinking about treating for atypical fracture, that might not be the best choice. Although the numbers were very low and as we know that atypical fractures can happen even without anti-osteoporosis therapy. So I might lean towards another anabolic such as a beliparatide or teriparatide in that situation. Thank you. We have time for maybe one quick more question and quick answer. So there's a question about whether there's any data on transitioning from romazosumab to another anabolic agent such as teriparatide or beliparatide. You know, there's no data that I am aware of, although I do have a patient I'm considering doing it because she just fractures every time she goes on off of an anabolic agent. But I'm not aware of, there's case reports but not hardcore data about transitioning from one to another on anabolic to anabolic. Yes. Thank you so much. And thank you to all of the speakers today and for the audience for participating in this session on osteoporosis treatment across the spectrum of fracture risk. I hope you enjoy the rest of the Endocrine Society meeting.

osteoporosis treatment

fracture risk

NORA study

screening studies

calcium supplementation

vitamin D supplementation

drug interventions

bisphosphonates

denosumab

teriparatide

anabolic agents

antiresorptive agents