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Shifting Paradigms in Rare Bone Disorders: What Do New Treatments Mean for Outcomes?

  • Authors: Aliya Khan, MD, FRCPC, FACP, FACE; Richard Keen, PhD, FRCP
  • CME / ABIM MOC Released: 2/14/2023
  • Valid for credit through: 2/14/2024
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  • Credits Available

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    ABIM Diplomates - maximum of 0.25 ABIM MOC points

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Target Audience and Goal Statement

This activity is intended for pediatricians, orthopedists and orthopedic surgeons, hematology/oncology specialists, diabetologists and endocrinologists, and medical geneticists.

The goal of this activity is for learners to be better able to increase awareness of how care pathways for rare bone disorders may change with the advent of new therapies.

Upon completion of this activity, participants will:

  • Have increased knowledge regarding the
    • Impact of new therapies for rare bone disorders on patient outcomes
    • Clinical data for emerging therapy in fibrodysplasia ossificans progressiva (FOP)


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  • Aliya Khan, MD, FRCPC, FACP, FACE

    Clinical Professor of Medicine
    Division of Endocrinology and Metabolism, and Division of Geriatric Medicine
    Director of the Calcium Disorders Clinic
    Director of the Fellowship program in Metabolic Bone Disease
    McMaster University
    Hamilton, Ontario, Canada


    Aliya Khan, MD, FRCPC, FACP, FACE, has the following relevant financial relationships:
    Consultant or advisor for: Alexion Pharmaceuticals, Inc.; Amgen, Inc.; Ascendis Pharma; Takeda
    Speaker or member of speakers bureau for: Amgen, Inc.; Ultragenyx
    Research funding from: Amgen, Inc.; Ascendis Pharma; Chugai Pharma USA, LLC; Radius Health, Inc.; Takeda; Ultragenyx

  • Richard Keen, PhD, FRCP

    Consultant in Metabolic Bone Diseases
    Director of the Metabolic Bone Disease Centre
    Royal National Orthopedic Hospital NHS Trust
    London, United Kingdom


    Richard Keen, PhD, FRCP, has the following relevant financial relationships:
    Consultant or advisor for: Ipsen; Regeneron Pharmaceuticals, Inc.
    Speaker or member of speakers bureau for: Ipsen
    Research funding from: Incyte Corporation; Ipsen; Regeneron Pharmaceuticals, Inc.


  • Grace O’Malley, BSc, PhD

    Associate Medical Education Director, WebMD Global, LLC


    Grace O’Malley, BSc, PhD, has no relevant financial relationships.

Compliance Reviewer

  • Amanda Jett, PharmD, BCACP

    Associate Director, Accreditation and Compliance, Medscape, LLC


    Amanda Jett, PharmD, BCACP, has no relevant financial relationships.

Peer Reviewer

This activity has been peer reviewed and the reviewer has no relevant financial relationships.

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Shifting Paradigms in Rare Bone Disorders: What Do New Treatments Mean for Outcomes?

Authors: Aliya Khan, MD, FRCPC, FACP, FACE; Richard Keen, PhD, FRCPFaculty and Disclosures

CME / ABIM MOC Released: 2/14/2023

Valid for credit through: 2/14/2024


Activity Transcript

Aliya Khan, MD, FRCPC, FACP, FACE: Hello everybody. My name is Aliya Khan, and I'm a clinical professor of medicine in the Divisions of Endocrinology and Metabolism, and Geriatrics at McMaster University. And I'm the director of the Calcium Disorders Clinic at McMaster, and also the director of the Fellowship program in Metabolic Bone Disease at McMaster University. Welcome to our program, Shifting Paradigms in Rare Bone Disorders, what do new treatments mean for outcomes? And joining me today is Richard Keen, consultant in metabolic bone diseases and director of the Metabolic Bone Disease Center at the Royal National Orthopedic Hospital in London. Welcome, Richard.

Richard Keen, PhD, FRCP: Hi Aliya. Hi.

Dr Kahn: Richard, can you tell us briefly about how the treatment of rare bone disorders is changing?

Dr Keen: Sure. Yeah, I mean I think we're very fortunate that with our understanding of molecular biology we've been able to identify a lot of the basic pathophysiology underlying a lot of the diseases, we've identified the cell types that are involved and how the diseases are caused. And I think that's really helped our understanding about the disease processes. And what's been so exciting in the last couple of years is, the fact that we've actually developed some new treatments for a large number of conditions, hypophosphatasia, X-linked hypophosphatemia, and achondroplasia. So, these drugs are now in the clinical scenario. And also, we've got for some of the really rare diseases such as FOP and osteogenesis imperfecta. Again, there are ongoing clinical trials that are looking at getting treatments for these conditions both for children and for adults. So, it's a really, really exciting time.

So, I've given a brief overview of the number of diseases that where these drugs have actually come to light. Aliya, perhaps you just give us a little bit more detail on one of the conditions and perhaps how the availability of a treatment is actually changing things for the patients?

Dr Kahn: Yes, of course, Richard. And as you know, there's been a lot of advancing in XLH (X-linked hypophosphatemia), hypophosphatasia, achondroplasia. I'd like to just say a few words about XLH. We know this is also a rare disease and its estimated prevalence is about 1 in 20,000, 1 in 25,000. And as you know, it's due to loss of function mutations in the PHEX gene. And this results in a defective PHEX (Phosphate regulating gene with Homology to Endopeptidases located on the X chromosome) protein being made by osteocytes. And we don't understand the full mechanism for how this results in osteocytes producing excess FGF23 (fibroblast growth factor 23) hormone. But this hormone has 2 main effects. One of them is to increase renal phosphate loss by decreasing expression of the sodium phosphate cotransporters type 2 in the kidney. And this results in increases in urine phosphate loss. And the second main effect is in decreasing the formation of 1,25 dihydroxyvitamin D.

So, we're forming less 1,25 [dihydroxyvitamin] D and we are increasing catabolism. And so, we end up with decreases in 1,25 [dihydroxyvitamin] D and therefore decreased ability to absorb calcium and phosphate from the bowel. And at the same time, we're not able to reabsorb phosphate through the kidney, and this is associated with increases in urine phosphate loss. And as we know when we don't have the optimal calcium phosphate product, this will result in impaired mineralization of bones and teeth. And the lifelong impact of XLH is seen in the pediatric patient population and also in adults. In pediatric patients we see delayed and disproportionate growth. We can see cranial synostosis and this can result in increases in intracranial pressure and require shunting. We can see rickets; we can see bowing of the long legs and delays in important milestones such as walking.

And in adults, we can see the manifestations of osteomalacia. These patients are severely disabled. Their ability to walk can be significantly impaired. It can affect the inner ear, the small bones in the ear and affect hearing, and the disability really can impact their ability to function and their ability to work. And of course, they can also have dental abscesses. And this is a common problem both in children and unfortunately also in adults. And it is important for us to be aware of that and to advise our patients to ensure that they're receiving good dental health.

As you know, Richard, we do have advances in treatment. Our treatment goals really are to improve the mineralization of the bones, and try and reduce the dental complications, and to reduce pain. If patients get pseudofractures, we want these fractures to heal. We want to reduce renal phosphate loss and we want to improve that TmP/GFR. And conventional therapy consists of phosphate and active vitamin D, 1,25 dihydroxyvitamin D.

The problem with the phosphate is that in one and a half hours you're back down to baseline. So, in children we have to give multiple doses in the day, maybe 4 or 5 times a day. And remember too, that patients can develop secondary hyperparathyroidism and tertiary hyperparathyroidism as complications of the phosphate and the reductions in 1,25 [dihydroxyvitamin] D and also higher levels of FGF23, which will stimulate PTH (parathyroid hormone) release. We can see if cinacalcet is going to be able to help us. So, conventional therapy has a number of limitations.

And when we talk about new treatment goals, and you're asking me, Richard, about advances in treatment. Well, we do have burosumab, which is a fully human monoclonal antibody to FGF23, and we can neutralize this excess FGF23, and we can demonstrate improvements in bone mineralization and in many of the parameters that we discussed. And there was a very nice study published by Karl Insogna in 2019, and this was actually an open-label single arm study looking at XLH in adult patients, 14 patients, and they were given burosumab, 1 milligram per kilogram, subcutaneously every 4 weeks. And we can see improvements in osteoid volume, bone volume, osteoid thickness decreased, and we can see improvements in mineralization lag time. And if you look at these very nice pictures, because bone biopsies, Richard, were done as you know, at baseline and at week 48, and we can see a very nice reduction in the amount of osteoid that was present. And in our experience, burosumab is associated with significant improvements in the symptoms of bone pain, muscle pain, and weakness and improvements in gait. And we've really found this to be a valuable treatment option.

And it is a safe option as well. The side effect profile was really limited to injection site reactions. Some patients can get headaches, but in general the drug is very well tolerated. And as you know, the treatment emergent adverse events leading to study discontinuation or to treatment discontinuation or even to death was zero. So, that was really nice to see that we can make an impact on this particular rare disease. And I won't say it's just a bone disease because it's more than that. It really is a multisystem disease, and it is important for us to be able to recognize that treatments make a difference.

So, I'd like to ask you Richard, would you like to talk about how the availability of a new treatment can change care pathways?

Dr Keen: Sure, yeah. I mean I think, the example I'm going to use is FOP (fibrodyaplasia ossificans progressiva). This is an ultra-rare genetic disorder. It's characterized by abnormalities in the big toe, but the real thing for the patients is that the condition has these episodic flare-ups that result in the formation of new bone, which become more and more disabling. So, there are management guidelines out there which have been brought together by the great and the good in the field of FOP. And up till now the treatment really has been to just control the symptoms of these flareups with using high dose anti-inflammatories and steroid medicine. That's basically been the treatment goals to date. And I think what's really, well, for the patients is just how this condition is just progressive. So, it's a genetic condition, patients will often be diagnosed in their early years, probably around an average age of about 4 or 5.

But over time when they get these flare-ups, the bones being formed, then they become more and more restricted in what they can do. And so, over time their mobility is dramatically reduced, their activities of daily function are less good. And actually, there is early mortality in this patient group. So, they will often be dying in their 40s due to respiratory complications. So, it is a very devastating condition. And I think, what we've learned, again, once you start moving into the field of having a treatment or potential treatment of such a rare condition, you just start needing to be able to quantify some of the impact of the disease. And so, one of the things that's been really exciting, I think, is actually that we've been able to identify the natural history of the condition.

So, we've been able to demonstrate the number of flare-ups patients have, where the flare-ups are happening. They often happen around the shoulder girdle, to start with and around the hip area. And again, this diagram here is showing a heat map of where the condition is developing over time. So, I think, as you move into the concept of actually developing a drug treatment for the condition, you start actually wanting to characterize the condition in a much more scientific and useful way. We've also been able to identify, again, that the respiratory function is quite severely affected, particularly as they move into adulthood. And again, we know that that's one of the reasons for the early mortality that's seen with this sort of condition.

The other thing that we've gained much more experience of, when you have a disease where you are looking at the potential treatments is understanding how the condition affects different parts of the body. And we've been able to use whole body CT as a very good way to capture the amounts of new bone that's being formed. And again, these serial radiographs, not of the same patient, but you're able to see a skeleton that's very normal in a very young individual, and then you can start seeing the deformities that will arising, the extra bone that's being formed. But again, by capturing this information, we're starting to develop endpoints. A bit like you were talking with the burosumab, you've got your bone biopsies. In patients with FOP we can't get tissue biopsies because that will cause more flare-ups. But actually, getting a more systematic way of looking at the radiology has been really important for our understanding of the disease.

And you talk about what about the drugs? Well, what's so exciting for this ultra-rare disease is the fact that there are a number of clinical trials that are ongoing at the moment in this condition. We've got trials that have basically got to phase 3 and have completed. There are trials that are in the phase 2 component, and then other drugs that are in the slightly more early path of the development. But it's actually quite exciting.

And what we've been able to do with this condition is actually, again, when you're doing a trial, you need to capture information about the severity of the disease. So, one thing we now do with these patients is, we very systematically collect how restricted their joint function is. And there's a scoring system called CAJIS which basically goes with a score from zero in the joints that we think might be affected and not affected at all, up to a score of 30, where these 15 components, parts of the body are quite restricted and not moving at all.

And we've been able to show the correlation between age and disease severity. So, that's, again, a really useful tool to be looking at. And we've also been able to take the data that I showed with the whole body CTs and show that the amount of extra bone there correlates with the disease severity assessed with the clinical assessment, and then also with the number of body regions. And so, for a lot of the trials that are under development at the moment, we're looking both at the physical function of the patients but also the amount of bone that's assessed with the whole-body CT. And that will give us an assessment of where the potential drugs are working or not.

And I think again, what's happened in the last couple of months is the fact that we've actually now got results coming from these phase 2 and phase 3 trials. So, there's been data just recently published which is looking at palovarotene, which has been studied in just under a hundred individuals with FOP and compared them to patients who were basically in a natural history sort of observational study.

And essentially, it's been able to demonstrate a significant reduction in the amount of new bone that's been formed, assessed with the whole-body CT. And there were some side effects which have been reported. Some we'd expect because they are associated with retinoids and this is a sort of retinoid like drug, and also some other abnormalities or impacts that have been seen related to the epiphyseal growth plate. So, this might just lead to its use in certain patient age groups.

Another study that's just had data published, it was a phase 2 study of garetosmab, which was an intravenous monoclonal antibody against activin A. And again, this was a 28-week placebo control trial. The results from this trial demonstrated that there was a reduction in the number of new bone lesions and that flare-ups seem to be less reported in both the patients and assessed by clinicians in those who are on the treatment when compared to placebo. So again, very exciting preliminary data and this product is now going into a larger phase 2/phase 3 study.

Dr Kahn: Thank you so much, Richard. That was amazing. Can you tell us what does this mean for patients with rare bone diseases like FOP?

Dr Keen: I think, again, for an ultra-rare disease, I think the first thing it does is, it gives patients hope. And I think that's really, really important with any rare disease, to know that there are researchers, clinicians who are interested in their condition. I think also, we still have to remember that these drugs are still in development to a degree they're not yet licensed. So, we still have to manage the patients with the guidelines that we have. We have to obviously avoid doing any harm. So, things like biopsy, surgery, intramuscular injection, dental blocks, those are no-go areas because they can cause these disease flare-ups. But I do think the fact that we've got these trials being published, there are ongoing trials going through, I really do think this offers huge hope for patients, that within the next few years there will be drugs that are going to be available which are going to help this very devastating condition. And I'm sure, again, other diseases which is yet don't have drugs available will also be able to offer that same hope to those diseases as well.

Dr Kahn: Well, thank you so much, Richard. That was really amazing and a very comprehensive overview on what's new in FOP. And I really want to conclude by saying that we have very exciting emerging therapies for rare bone diseases which have developed in the recent past few years. And we've also seen that even though molecular genetics is in its infancy as a field, we have improved understanding of genetics and the molecular etiologies of these rare bone diseases. And with our improved understanding and our ability to apply this information to enhance our ability to diagnose this condition as early as possible and with improvements in access to drugs which can make a difference in rare bone diseases, we really can make a difference in our patients who have these conditions. And we've seen improvements in quality of life, mobility, overall function. So, this is really an exciting time for patients who have rare bone diseases and I'm really pleased to be able to see that there is hope. And I agree with you, Richard, there is hope for people who have these conditions. And we expect to see further advancements in the next few years.

So, Richard, thank you again for this great discussion. And I'd like to thank you all for participating in this activity. Please continue on to answer the questions that follow, and please complete the evaluation. Thank you so much.

This transcript has not been copyedited.

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