FAN eP2P_Apr26_Updated Video Presentation

>> Hello. My name is Bente Langdahl. I'm a Professor in Endocrinology. I work at Aarhus University Hospital, where I see patients with osteoporosis every week. I'm here today to talk to you about how to diagnose osteoporosis and choose the optimal treatment for your patients. Osteoporosis is an epidemic and it has been called, "The Silent Epidemic." We know that more than 200 million women are affected by osteoporosis. And that one in three women and one in four men suffer fractures due to osteoporosis. We also know it's a silent epidemic, but it still has a voice. And the voice is fractures. And although the voice is fractures, not all of the fractures come to our attention. And we know that only one in three patients with vertebral fractures have actually noticed the fractures. And because of that, some of these fractures are silent, more than 80% of patients at high risk of future fractures do not become diagnosed, and therefore, do not get any treatment. So let me tell you about a patient of mine. She's now 75 years old. She had her first DXA in 2013. And that DXA showed osteoporosis with T-scores of -3.4 and -1.7 at the spine and hip. She was prescribed Calcium and Vitamin D. A couple of years later, she was admitted to hospital due to back pain. And, they diagnosed her with a fracture of the 12th thoracic vertebrae. And she was hospitalized for three days, and treated with painkillers and physiotherapy. She also had a DXA that also again showed osteoporosis now with T-scores of -3.8 and -2.2 at the spine and hip. And she was then prescribed Risedronate 35 mg weekly and continued on Calcium and Vitamin D. A little more than one and a half year later, she was again admitted to hospital with severe back pain. This time, to my hospital. And she now had a new vertebral fracture of lumbar vertebrae number 2. We also repeated the DXA, which shows stable values at the spine, but further reduction of the BMD at the hip side. The patient asked me: Will I get my life back? Meaning, "Will I be able to work in my garden?" "Will I be able to play with my grandchildren?" So let's have a look of what happened to this patient. She actually had a new fracture and she also had BMD loss. So let me ask you, what would you do now? Would you reassure the patient, have her continue the current treatment? Would you change the treatment to Zoledronic Acid or Denosumab? Or would you change to a bone forming treatment - Teriparatide? Let us think a little bit more about the fracture cascade. It has been quite well demonstrated that there is an imminent fracture risk after a recent fracture, and also that the more fractures you suffer, the higher the risk of further fractures, as indicated in this slide. So do you have more, do you have two vertebral fracture? The risk of the third is increased 3-fold and so on. The other thing is that, also, as shown in this slide, already within the first year of the fracture, there's a very high risk of more fractures especially if you have multiple vertebral fractures. And also, the more severe your fractures are, the higher the risk the patient is at for further fractures. As you can see in, in this slide, where patient in the placebo group of the big clinical trial were divided into groups based on how severe their baseline vertebral fractures were. So we therefore need to examine our patients as good as possible, and that includes imaging of the spine. It can be done by spinal x-rays as you can see in this slide where there clearly are fractures at the lumbar spine. But it can also be done in many DXA centers by using the VFA option of the DXA machines. So, now we have the patient and we have examined our patient. We know about bone mineral density, we know about existing fractures. So now, our first and foremost goal is to prevent the next fracture because this is what is a threat to the life, and to quality of life to our patient. And how can we do that? Yeah, we want to improve bone mineral density because we know that that is an important factor in preventing fractures. We also want to take the best treatment we can find to achieve a better fracture outcome. And finally, we want to secure our patients that they understand why it's important to start treatment and how they should take the treatment and for how long. So what options do we have? As you all know, we have many, many antiresorptive treatments available. In some countries, Hormone Replacement Therapy is still an option. But apart from that, we have SERMs and both of these are weaker antiresorptives, and then we have the stronger antiresorptives which are the bisphosphonates and Denosumab. These are all in the category of antiresorptives. On the other side, we have one, bone-forming treatment Teriparatide. And let us have a second look on how they work and how they work differently. Let me tell you about the FACT Trial. The FACT Trial was done to investigate and compare the effect of a potent antiresorptive Alendronate and Teriparatide, a bone-forming agent. So in this study, bone formation and bone resorption markers as well as bone mineral density was examined. And as you can see in this slide, on the left-hand side, you can see how bone markers responded to treatment with Teriparatide, and you can see the blue line representing bone formation here as P1NP. You can see there's a rapid increase in bone formation and you can see that it stays up for up to 12 months. So, it's not a temporary increase in bone formation, it stays high through our treatment. We can also see that there's a secondary increase in bone resorption here measured by NTx. But still there's a huge difference in the increase between bone formation and bone resorption. On the right-hand side of the slide, you can see how the bone turnover responds to Alendronate treatment. There's a prominent decrease first in bone resorption, but secondarily in bone formation. This has been investigated further by looking directly on the bone surfaces using Histomorphometry. In this study, which is a recent study called, The SHOTZ Study, the authors compared the effect of Teriparatide with the effect of the very potent Bisphosphonate Zoledronic Acids. And let me just show you pictures because I think they tell the story quite clearly. So here, in this slide, you see the changes in the trabecular bone. On the left-hand side again, you see the effect of Zoledronic acid, and you could see there are hardly any Tetracycline labeling, suggesting that very little bone turnover is going on, and especially very little bone formation. On the other side of the slide, the right-hand side, you can see lots of activity. Many Tetracycline labeling suggesting large bone formation going on. And you can see that in 6 months, but you can also see all the lines at 24 months suggesting that the increased bone formation continues for at least up to 24 months. We can look at this in a bit more closer details and you can see, here you can see the lines laid down at six, after 6 months of treatment and the lines laid down after 24 months of treatment. And you can see the relatively big amount of bone that's been laid down in the intervening time. And then have us look at the cortical side because that's also of course of interest especially if you're thinking about preventing non-vertebral fractures. And here, you can see, again on the left-hand side, the response to Zoledronic acid and you can see after 6 months as well as after 24 months that there are hardly any labeling, suggesting that there's very little bone formation going on. On the right-hand side of the slide, it's the completely opposite picture with lots of Tetracycline labeling at the periosteal surface, the endocortical surface as well as intracortical surfaces. And, if we take higher magnification, look at this, you can see lots of labeling, intracortical as well as both of the cortical surfaces. So this and many other data have lead us to understand how Teriparatide works at the remodeling level. And this is what it's been, what you can see in this cartoon. So, bone resorption take place at the same rate and to the same extent as usual, some types even increased a little bit. And bone formation is then simulated. So it not only fills up the remodeling cavity, but it actually overfills the remodeling cavity so that there are much more new bone laid down than the bone resorpts. And this also reflected here in the BMD changes as seen in the FACT Trial where you can see when you measure areal BMD. The usual way we measure BMD, you can see there's a doubling in the increase in BMD after 18 months with Teriparatide compared to Alendronate. And if you specifically investigate trabecular bone BMD using QCT, you can see an even bigger difference between the two treatments. Looking at BMD changes, we have to realize that increases in BMD can come in different ways. So here we have made a sketch of the 3 different ways you can increase BMD. So first of all, starting from the top, you can increase BMD by increasing trabecular number. You could also increase BMD by increasing trabecular thickness. And then of course you can increase BMD by maintaining bone volume but building more mineral into the bone. And that is what we call, "Secondary Mineralization". Teriparatide, which is a bone-forming agent, uses the two upper mechanisms for increasing bone mineral density. Increases trabecular number and increases trabecular thickness, whereas antiresorptive treatments like Bisphosphonates and Denosumab predominantly uses the lower, the lowest cartoon way that is increasing secondary mineralization. So, to summarize, what are the therapeutic choices we are facing? that is increasing secondary mineralization. So, to summarize, what are the therapeutic choices we are facing? So we can choose a bone-forming agent like Teriparatide and we will see new bone formation because the drug stimulates osteoblast activity. We have some secondary osteoclast activity increase as well. We have increase of bone turnover. We have new bone formation, and that leads to increased skeletal mass and increased bone volume. Then the opposite, antiresorptive treatment, we have decrease in bone resorption due to a decrease in osteoclast activity. With secondary leads also to a decrease in osteoblast activity, that leads to decreased bone turnover. And that leads to a filling on of the remodeling space and increased mineralization of the existing bone. But there's no effect on bone volume. So let's have a look of how well these drug work in real life in clinical trials. So first of all, let me just remind you of the pivotal fracture trial investigating the effect on preventing fractures of Teriparatide. It was a study with two different dosages used. The 20 microgram we use in the clinic today but also 40 micrograms and it was compared with placebo. And as you probably recall, there was a very prominent 84% reduction in new, vertebral fractures in patients treated with Teriparatide compared to placebo. There was also a 50% reduction in new, non-vertebral fractures. So, very prominent antifracture efficacy in this placebo-controlled trial. Bone biopsies will also taken in that trial and you can just see from these reconstructions how bone is changed from the baseline where it's characterized by thin cortices and a rock-like structure of the trabecular bone to thicker cortices and a more plate-like structure of the trabecular bone, a structure that we know confers much more strength to the bone. Bone mineral density by areal DXA was also measured. And you can see again a very prominent increase in bone mineral density here at the lumbar spine. So this is nothing new, but why did I choose to show this picture? Anyway, it's because it's interesting to see what happens after Teriparatide. Because in the pivotal fracture study, treatment was ended after approximately 20 months of treatment. And in this slide, you can see, on the right part of the slide, you can see what happens after ending Teriparatide treatment. And you can see the patients that go on an antiresorptive treat and they have further increases in bone mineral density. And why is that? That is because all the new bone that is filled up during the Teriparatide treatment are now being mineralized and the antiresorptive also prevents osteoclasts from breaking down the new bone. So you have a further increase when you go from Teriparatide to an antiresorptive treatment. There were also, of course, observation of adverse events in that study. And the things that were more common in patients treated with Teriparatide compared to placebo were dizziness and also leg cramps, and there were cases of mild hypercalcaemia But they were not very frequent and I think we've all known, learned how to deal with these in clinical practice. And of course, many colleagues ask me, but do we know that this drug work in clinical practice? And that's been done a number of observational studies and I'll just show you one slide from one of those. The European Observational Study, called the "EFOS Study", where women who were chosen by clinicians to receive treatment with Teriparatide could be enrolled and monitored. And we just monitored fracture frequency in these patients. And as you can see, the study was done at a time where Teriparatide were only approved for 18 months of treatment. So we only have 18 months of observation on Teriparatide treatment. But you can see how in every 6 months interval the incident of new, vertebral fracture is reducing over time. And what is also important is to see that their reduction in new fractures continues when the patients go from Teriparatide to an antiresorptive treatment. Then, of course, many clinicians wondered, "Is this drug better than an antiresorptive?" Can I really advise my patients to go on Teriparatide, or would they do equally well on a strong Antiresorptive treatment? So, I'm happy to present to you with the outcome of the VERO trial. The VERO trial was a randomized, active-controlled, double dummy study assessing the outcome of fractures, comparing Teriparatide with Risedronate. The study was a two-year study and included postmenopausal women with severe osteoporosis that would be existing vertebral fractures. So, a little bit about the patients who went into the study. So they were, on average, 72 years old. They had osteoporosis. 100% of the patients in both groups had existing vertebral fractures. They had BMD in the osteopenic range which is not a surprise, as 60% of the patients have previously been treated with a Bisphosphonate. We can also see that almost 50% of the patient had had a previous non-vertebral fracture. And this is the main outcome. The primary endpoint was new, vertebral fractures and this was what the study was powered to investigate. And, as you can see, already after 12 months, there was a 50% reduction of new, vertebral fractures in patients treated with Teriparatide, in comparison with not placebo, but a very strong antiresorptive agent Risedronate And their difference in new, vertebral fractures was maintained throughout the second year of the study and we are 12% in the Risedronate who have suffered new, vertebral fractures compared to only 5.4% in the Teriparatide-treated group. Secondary endpoint were multiple, vertebral fractures and where there also was a 54% reduction which, if you remember, is very similar to what was seen in the near study, the pivotal fracture study. But again, we have to remember that this time, it's against an active treatment Risedronate And also, clinical vertebral fractures were significantly reduced in this study with the P value of 0.002. Coming to clinical fractures, that would be clinical vertebral fractures and non-vertebral fractures. You can see that there is a rapid difference between the two groups. After 6 months, the curves start to diverse and after 24 months, there's a prominent, almost 50% difference between the two groups. Finally, non-vertebral fractures didn't reach a significant difference. There was a reduction but as I said, none, not significantly different. And then, also, major non-vertebral fractures were investigated. And why specifically this group? This is because this is the group IMEA identified as the group of non-vertebral fractures that's especially important. And as you can see, it almost reads a significance with the P value of 0.06. And we have to remember that the study was not powered to look for non-vertebral fractures. But, despite of that, it almost made a significant reduction. This slide is very busy. But to summarize, it's the outcome of the VERO study. You can see that there was a prominent and significant reduction in new, vertebral fracture. In new or worsening of vertebral fractures in clinical fractures. And then there was a borderline trend for non-vertebral fractures as well as major, non-vertebral fractures. What about adverse events? Are there some things we need to consider here? You can see overall the ballot, it was very well balanced between the two groups. There were a few, adverse events that were more common among patients treated with Teriparatide. That would be dizziness and hypoglycemia as we know it. But also pain in hands and feet, and pain in general. And that is also a very well-known symptom in patients treated with Teriparatide, and it has been demonstrated that it is related to the increase in bone turnover that we see in these patients. But again, these adverse events that were more common in the Teriparatide-treated patients were still not very common. So to sum up, I hope you agree that in postmenopausal women with established osteoporosis who are at high risk for fracture, FORSTEO significantly reduced vertebral and clinical fractures compared with Risedronate. FORSTEO is better at preventing fractures in patients with severe osteoporosis and confirm previous data from clinical trials of Teriparatide or FORSTEO versus Bisphosphonates with fracture as secondary outcome. Clinicians should consider FORSTEO for optimal management of patients with osteoporosis who have prevalent vertebral fractures. Coming back to my patient. This 75-year-old woman who now has 2 vertebral fractures. She has a new one, and she also has a loss of BMD. What would you do now with all these new data in mind? Would you reassure the patient, have here continue on her current treatment? Would you change the treatment to Zoledronic Acid or Denosumab? Or would you change to a bone-forming treatment - Teriparatide? So here's my answer: I started my patient on FORSTEO because I think it's the best choice in patients with existing vertebral fractures and low BMD. So, to summarize, patients with osteoporosis have decreased bone strength which leads to increased risk of fracture. The first osteoporotic fracture leads to a considerable risk of subsequent fractures and the fracture cascade can start. So clinicians like you and me should consider FORSTEO for optimal treatment of osteoporosis who have prevalent vertebral fractures. And why should we do that? Because the benefits of Teriparatide or FORSTEO therapy include it that it stimulates the osteoblasts and that is what we want. We want new bone. We want more bone. We want a better structure of the bone. We know it reduces fracture risk. We know it improves BMD. And we know that the effect of Teriparatide is observed very early on in the treatment of the patients. And, it has now been demonstrated in the VERO trial that it's better at preventing fractures in patients with severe osteoporosis compared to a Bisphosphonate. Thank you very much for your attention, and I'm happy to take any questions you may have.