All right. Well, good afternoon. We are going to have a presentation on one of the rare endocrine disorders, and the topic of today's webinar is recognizing and treating X-linked lymphophosphatemia, a generic, progressive, and lifelong disease. And I'll quickly walk you through the agenda for today. Next slide, please. Here is the information about commercial support. Obviously, an activity like this, you know, has to be supported, and that's the information, the disclosure information. The faculty for today consists of Dr. Mike Lewicki, who has his disclosures mentioned here, his, you know, disclosures, and I'm Dr. Ranjot Gill, and I have no relationships to disclose. Dr. Basma Abdulhadi was also involved in developing this webinar. Unfortunately, she couldn't be present to give this lecture, to be part of this lecture series. And of course, Amy from ACE has been invaluable in developing this webinar. Next slide, please. So learning objectives for this afternoon's lecture. Upon completion of this webinar, you'll be able to, or the attendee will be able to describe the diagnostic and testing approach in evaluating a patient with possible, quote unquote, possible XLH. Utilize evidence-based guidelines, algorithms, and consensus statements to manage XLH. And then lastly, to identify and treat long-term complications and comorbidities of XLH. Next slide. Here's the outline, brief outline. We'll begin with the case presentation, and then go over background and pathophysiology of XLH, how to go about establishing a diagnosis, and then treatment, and finally discussion. A quick word about housekeeping announcement. For any questions that the attendees may have, please post them in the Q&A section of the Zoom link, or, you know, the Zoom format, and we'll try to answer them as we go along. And also, we'll discuss some of those in the end, after Dr. Luecke finishes his part of the presentation. So we'll begin with the case. The history and physical of this patient is that of a six-year-old female whose parents bring her to see you with concerns that their daughter seems to be shorter than her peers. And she complains of leg and ankle pain after walking or playing for extended periods of time. Over the past year, the parents have noticed her legs to be bowing outwards. She was born full-term with no significant complications, so birth was unremarkable. She had normal development milestones, at least early on. And then over the past two years, there has been a noticeable slowing of growth in her height compared to her peers. Next slide. Here are some of the examination findings. Her height is below the third percentile for her age. Weight is 15th percentile, so she is underweight. She has a mild waddling gait, and her legs show geno-worm deformity. Amongst other findings, she has a mild tenderness over the tibia and ankles upon palpation. Next slide. So here are some of the questions that might arise after reviewing that case. And the questions for us to answer or to discuss would be, what laboratory abnormalities does one expect to find in a case like this? Secondly, what type of radiologic features can be expected in this patient? Certainly, she has some deformity. Is there a genetic predisposition for this order? Actually, the more apt question would be, what is the genetic abnormality? Because we know this is a genetic... I mean, if it is XLH, it's a genetic disorder. And what treatment modalities are available? So here is some more information about this case. Some of the investigational findings. Her serum phosphate is low. The normal ranges are given. Calcium is normal. Serum alkafos is elevated. PTH is described as normal. FGF23 is elevated. Her serum 25-hydroxyvitamin D level is normal, whereas serum 125-dihydroxyvitamin D level is low. She has normal renal function. She has renal phosphate wasting by elevated urine phosphate, 24-hour urine phosphate. Radiographs of the lower limbs show bilateral leg bowing. There is radiographic evidence of osteomalacia. She has growth late abnormalities with widening and fraying of metaphyses in the femur and tibia. Genetic testing was done and shows a mutation in the FACS gene confirming the diagnosis of X-linked hypophosphatemia. And I'll hand over the presentation to Dr. Mike Lewicki to discuss this further. Thank you. Thank you, Ranjan. Well, one thing for all of us to recognize is that XLH goes by many other names, unfortunately. So historically, you may come across any of the names that you see here. And I think when I was in medical school, there was talk about vitamin D-resistant rickets, and that's because it wasn't fully appreciated that hypophosphatemia was the cause of this problem. It was getting confused with rickets due to vitamin D deficiency, but these patients didn't respond to very large doses of cod liver oil or whatever might have been given at that time. So you may well come across these in your reading of the literature, and some patients may actually use some of these names as well. So you've heard already about the idea that this is a whole body, whole life, and a whole family disorder. That phrase actually came from patients who gathered together to discuss the consequences of this disease and how to make others aware of all that it encompasses. And this was published in the Journal of the Endocrine Society, JES, with patients. And I was the scientific advisor on this, but it's the patients who did most of the writing. And they emphasized here the cause of the disease from a genetic standpoint. They talked a little bit about the pathophysiology and the prevalence being about 1 in 20,000. Now, talking about the pathophysiology of XOH, it is, of course, a mutation of the FEX gene that results in osteocytes producing more FGF23, which is high when it's measured. This has two consequences that are important in this disease, both of which involve the kidneys. So on the left, you see a representation that it increases 24-hydroxylase and decreases 1-alpha-hydroxylase, resulting in decreased production and more rapid degradation of 125-dihydroxyvitamin D, resulting in a reduction in phosphate absorption, mostly in the small intestine, contributing to hypophosphatemia. And what's probably far more important is what you see on the right side of the slide, where there's decreased production of the sodium phosphate co-transporters in the kidneys, resulting in decreased phosphate reabsorption. So this is a renal phosphate-wasting disease, and that is the number one contributor to hypophosphatemia and all of its consequences. So phosphorus is important for more than just bones, of course. It's essential for normal growth. It's essential for virtually all of our cellular activities, and we need it for strong teeth as well as bones. So teeth are not quite the same as bones, but in some fashion, they are both dependent on an adequate amount of phosphorus as well as many other micronutrients. Just a reminder here of some of the symptoms of XLH in children. You've heard about rickets already. Osteomalacia can also occur. This is what happens in more mature bones and can be responsible for bone pain. There is delayed walking in children. Irregularities of walking and balance, abnormalities of gait. You heard already about a waddling gait. That's a common occurrence in these diseases. There's muscle pain and weakness. Dental abscesses are common. These patients are generally short in stature. They have pain not only in the bones but in the joints. Bald legs and knocked knees, tooth loss. Irregularities of the shape of the head due to craniosynostosis and headaches that may be due to structural defects in the skull. So the image on the right, I think, is classical for rickets. That picture has been reproduced in many publications. On the left, you see the typical radiographic appearance. And more x-rays in children. So all different versions of what you see on x-rays. And you don't need an x-ray, of course, to know what's going on in these patients. So it's pretty clear when they walk in the room that they have a major skeletal deformity. And this might clue you into thinking about XLH. Now, adults have osteomalacia. So this can result in bone pain. So if you're trying to distinguish between a patient having osteoporosis and osteomalacia, you can do some simple exam room tests like pressing your thumb on the anterior tibia. If they go ouch, maybe it's fibromyalgia. Maybe they're exquisitely sensitive to pain. But it could be due to osteomalacia. And typically, that does not happen with osteoporosis patients. They tend to be short. They have pain in the bones and joints. Headaches. Enthysopathy, which is a calcification of the ligaments and tendons near the joint insertions. So this may be picked up on x-rays and sometimes is painful. There is an increased incidence of spinal stenosis in these patients. They can have bald legs and knocked knees that are just left over from childhood. These things do not correct themselves. Impairment of walking and balance. Muscle pain and weakness. Osteoarthritis, often probably due to excessive strain in the joints because of the bone deformities. They have fractures and pseudo fractures and often have loss of hearing. Inheritance is important to recognize since this is an X-linked dominant disorder. If the father has XLH, then the son who gets the Y chromosome will not have XLH. However, 100% of his daughters will. On the other hand, if a mother has XLH, there's a 50% chance of sons getting it and 50% chance of daughters getting it. Now, if there's a strong family history of the disease and a child or adult comes in with symptoms compatible with this, the diagnosis may be fairly simple. However, what's far tougher to deal with in clinical practice are the spontaneous cases. And there are many of those. It's estimated that about 20 to 30% of cases are spontaneous. This represents a clinical challenge to us. And as with all rare diseases, I think we have to think about it before we can diagnose it and we have to order the proper laboratory tests. So, what about diagnosis? So, we have clinical radiographic and biochemical findings. The clinical presentation can range from unappreciated hypophosphatemia to severe skeletal deformities. Now, you're not going to miss severe skeletal deformities. You will miss hypophosphatemia if you don't order a phosphorus. So, in my opinion, every patient who comes in with chronic musculoskeletal symptoms should have a fasting blood phosphorus measure at least once, at least once. And if you don't do that, in some of these spontaneous cases, you will have a hard time figuring this out. Typically, symptoms are in the first two years of life when symptoms of skeletal deformities and bowing is obvious. However, in some patients, because of the wide heterogeneity of this disease, the diagnosis may be delayed. Early diagnosis is very essential in children because early intervention can maximize growth and minimize lower extremity deformities and dental problems. Mike, can I interject for a moment? Yeah, please go ahead. So, amongst clinical manifestations, we often talk about skeletal symptoms and signs, but also it's a musculoskeletal disorder. So, muscle is involved as well. There's usually sarcopenia, there's muscle weakness, there's muscle wasting because of various reasons, and lethargy or fatigue also would be part of the constellation of symptoms. In adults, it may also manifest in sort of respiratory compromise because certainly phosphate is involved in the strep cycle and generation of ATPs. So, there may be several clues other than skeletal deformities. Thank you for pointing that out, and certainly when patients talk about this disease, chronic pain and fatigue is something that is often a big concern in their lives. So, if you measure a phosphorus, it should be fasting since there are some circadian rhythms. You should recognize that there are age-adjusted reference ranges, and phosphorus levels in infants and children are normally higher than in adults, and they have a wider range for the reference range. Sometimes we call it phosphorus, sometimes phosphate. I often use the terms interchangeably, although they're not exactly the same. So, be sure to get a fasting phosphorus and look at the age-adjusted reference range. Now, here is one scheme that was published a few years ago. Hopefully, you have measured a phosphorus in somebody who's got chronic musculoskeletal diseases, and if you find that it's low, I certainly agree that the next step is to determine whether they have renal phosphate wasting or not. So, you measure urine phosphate, and what normally is done is to measure a maximum tubular reabsorption of phosphate divided by GFR. Now, if you've never ordered this, don't panic. It's easy to do. I typically tell a patient to go into the lab first thing in the morning, and I tell the lab to get a serum creatinine and phosphorus and get a urine creatinine and phosphorus on the second void urine specimen, but it could be a random specimen as well. And there's a simple calculation to find out if they're wasting phosphate or not. Sometimes the lab will do that for you, but there are many website calculators you can go to, so you just plug in the four numbers, and they'll give you a value. So if they have hypophosphatemia and urine phosphate is low, then they probably have inadequate intake or malabsorption. If they have renal phosphate wasting, this algorithm suggests measuring PTH. It's a little different in my particular patient population because probably they've already had a PTH and calcium measured, so I generally feel pretty confident whether or not they have hyperparathyroidism before I launch into my hypophosphatemia workup. They typically will have low normal 125 dihydroxyvitamin D. Once you know that they have renal phosphate wasting, then you want to know if it's FGF23 mediated or not. So the next step after you find they have renal phosphate wasting is to measure FGF23. That's easy to do. That's a standard commercial laboratory test. If it's elevated or inappropriately normal, in that case, you may be highly suspicious that they have XLH. So, Ranjad, let me just turn it over to you. Any other thoughts that you have on how you think about evaluating people with low phosphate? And what's your normal process? Yeah, I like this algorithm and schema. It simplifies it. And the etiologies of hypophosphatemia, per se, are countless. And it's very, it'll be arduous to go over all the possible etiologies of hypophosphatemia. But rather than going on a wild goose chase, I think you can decide which way to go after obtaining urine phosphate value. And then you go either one way or the other way. And you can limit your differential diagnosis based on that. And if it's low urine phosphate, the causes are multiple. But if it's high, if there's wasting, there are fewer causes of hypophosphatemia. So that helps you to narrow and actually stray, not get any sort of incidental findings that you can't explain. So in my mind, this is a good approach. Yeah, thanks. I appreciate your input. So an example of non-FGF23-mediated renal phosphate wasting might be Fanconi syndrome. So I recently saw a patient on tenofovir for HIV who had hypophosphatemia as a result of the tenofovir. And that patient had medication stopped and problem resolved. So here is just another summary of the biochemical findings. So low fasting, age-adjusted serum phosphorus, reduced tubular reabsorption of phosphate divided by GFR. Elevated or inappropriately normal FGF23. FGF23 comes in two flavors. One is the C-terminal. One is the intact. They have different reference ranges. And people who deal with this a lot feel that it's inappropriately elevated in the setting of hypophosphatemia if the C-terminal value is greater than 100 or if the intact is greater than 30. So you can measure a 125 dihydroxy vitamin D or calcitriol level. That will be typically inappropriately low or normal. Alkaline phosphatase level may be high, which generally we think of as representing the osteomalacia component of this. PTH levels are often normal, but in some cases may be high. So some guidelines recommend confirming the diagnosis of XLH by genetic analysis and asking for the FEX gene in both children and adults. Genetic testing is getting much, much cheaper than it was years ago, so this is pretty easy to do. Now, it may not be necessary to do genetic testing if the patient has a strong family history of the disease and typical symptoms, although it may be required for insurance for subsequent treatment. If genetic testing is not available or if the patient doesn't want to do it, you may be perfectly justified in making the diagnosis based on IFGF23 and or family history. And if genetic testing is negative and they have hypophosphatemia and renal phosphate wasting, there are other hereditary causes and acquired hypophosphatemia, such as tumor-induced osteomalacia. So back to the concept of whole body, whole life, and whole family, this is what the patient group had to say. They wanted to emphasize that it's not just bones and teeth, but as Ranjat has said, muscles, also joints, impaired mobility, reduced hearing, fatigue, depression, and many more things. And it affects a whole life. It's not just a childhood disease. It persists into adulthood. So all the problems of childhood generally leave manifestations that persist into adulthood, plus new problems in adulthood. Often, there's difficulties with transition of care to adult positions. This can have effects on education, sports, income potential, family planning concern. And it affects the whole family, and not just the genetic family, but friends, peers, and colleagues who need to understand. So we talked about muscle pain, fatigue. People need to understand who deal with the patient that these things can be problems, and these aren't malingerers if they have symptoms like this. And like many chronic diseases, it requires a team to deal with it. The endocrinologist could be captain of the team, but it could be some of the other people. And probably, the primary care provider needs to be involved, perhaps a nephrologist, orthopedist, and dentist, certainly. Geneticists can play a role, especially with family planning. Physical therapy can be very helpful, a psychologist, and of course, many others. The handoff from pediatric to adult care is certainly problematic in many cases. There's two approaches to treatment. In the past, it's been conventional therapy, and now we have a drug that's FDA approved called burosumab for the treatment of XLH. There are some very helpful resources. One is the XLH network, which is very involved in patient networking and education. Another is XLH Link. If you are interested in taking care of these patients or you want to direct your patient to a database where they might find someone who can help with their care, this is a very helpful place to go. Keep in mind that the doctor database is not perfect. I've looked at it and found doctors who have died, doctors who have retired, doctors who have changed fields. So it's not always updated. I understand there's an intensive effort to do so. But certainly, you might want to go and see if your name is on the database. And if it's not, and you do want to care for these patients, then have your name added. So I mentioned transition of care. And with regard to this, I think it's important for the pediatric providers to be familiar with the adult care resources in the community. At some XLH pediatric centers, this is very well organized. But you may be in a place where not so much. The patient and parents should, I think, be ideally actively involved in the transition to adult care. Adult care providers, I think, need to make it known that they're willing and able to care for these patients. And if you're not an expert, you need to learn how to be a competent provider for this disease. And as I mentioned, you can register on the network. And if you want to learn more, I would strongly advise you to join the Rare Bone Disease Echo program. That is the link. We're getting to that. You can go to that link and register and get monthly notifications about this monthly Zoom meeting. If you can't remember any of that, just Google Rare Bone Echo. And I think this will pop up right at the top. It's the Osteogenesis Imperfecta Foundation that hosts the Rare Bone Disease Echo program. This is what it looks like if you go to the website. They do a terrific job at that. Laura Tosi, a pediatric orthopedist, is the one who organizes this. They line up expert speakers on a wide variety of rare bone diseases, many of which involve children. Some of them are directed to adults as well. And they cover XLH, OI, and many other rare bone diseases. This is a review of XLH that was published a few years ago on JES. And I think this is a terrific resource if you want to go to one place and one article and get a lot of up-to-date information about XLH sighting. I would encourage you strongly, if you want to learn more, and if you want one single source of information, this is a great place to go. In this review, they identify some important goals for children. It's to normalize phosphorus, heal rickets and osteomalacia, and prevent skeletal deformities and impaired growth. For adults, also to normalize phosphorus, to heal osteomalacia, and to prevent and heal pseudo-fractures and non-union fractures, and relieve bone pain. It's emphasized that it needs to be a multidisciplinary team to evaluate a treat. And there's a broad range of interventions that include nutritional support, pharmacological therapy, dental care, genetic counseling, and so forth. So this is conventional therapy. So this is conventional therapy. Multiple daily doses of phosphate, often in the form of K-phos neutral, which has to be given four to six times per day, as well as active vitamin D, which in the US is usually calcitriol. The benefits that have been well-documented in children are healing of rickets, improvement of osteomalacia, diminished deformities, and improvement in growth. Data are far more limited in adults, but there are some studies showing improvement in bone pain, healing of pseudo-fractures and non-union fractures, and a lower risk of dental disease. However, there are many limitations with conventional therapy, as any of you who have prescribed these medications are well aware. It's inconvenient. Nobody wants to be taking phosphorus four to six times a day. Phosphate is poorly tolerated. A lot of GI upset with it. Compliance is often poor. Also, it does not correct the high FGF-23 and may not be successful at normalizing the fasting phosphorus. And many adverse effects, in addition to GI intolerance, there may be hypercalcemia, hypercalciuria, nephrocalcinosis, and hyperparathyroidism. So Ranjad, what's your experience been with conventional therapy? So it's not optimal, obviously. There's the issue of multiple dosing of phosphorus. If you're able to get it at all, some pharmacists don't stock it. We've had challenges in procuring that. And then, obviously, taste and the adherence because of multiple dosing, need for multiple dosing. And then also, what's the optimal dose to give? What's the optimal requirement? How do you monitor it? How often do you monitor it? There's obviously the concern that if it's overaggressive, then you might cause hyperpara. It may be a stimulus for PTH to rise with its own attendant consequences. And then it doesn't correct the underlying disorder. It's just sort of symptom. It's treating the after effect of the abnormality, which is the FGF23. And then certain other mechanisms are implicated. Some yet to be defined. But it's not an optimal treatment. But that's what we have until we got this new intervention in the form of monoclonal antibodies to FGF23. But everybody doesn't have access to it necessarily. So the treatment is challenging. Management and treatment are challenging. Yeah, I certainly agree. And believe it or not, phosphorous supplements can be quite expensive. And sometimes it's hard to get insurance companies to cover the cost. So another challenge. So that leads us into burosomab. This is the one and only FDA-approved medication for treatment. It's a fully human monoclonal antibody to FGF23 that we've had available since 2018. So indications are treatment of XLH in adult and pediatric patients age six months and older. And also for treatment of FGF23-related hypophosphatemia in tumor-induced osteomalacia, affectionately called TIO, which is associated with phosphaturic mesenchymal tumors, usually small benign tumors that are hard to identify. And when they can't be identified or resected in adult or pediatric patients two years of age and older, burosomab should be considered. Ranjot, any comments on TIO? Yes. Thank you for actually letting me chime in there and anticipating my question and comment. So I'm an adult endocrinologist. Of course, I see some transitional patients that are transitioning from pediatric to adulthood. But when the symptoms and the presentation is sort of mild and the typical skeletal deformities of XLH are lacking, or you may have missed, or the patient may not have sought care until later in life, how do you distinguish XLH from TIO? That becomes an issue, because some of the laboratory findings are similar in both. So we've often, and genetic, of course, genetic testing would be very helpful in that scenario. But sometimes they're indistinguishable, and you have to rely on genetic testing. Yeah, you know, TIO is very rare, but there's a good chance you might come across at least one of these patients sometime in your career. And you don't want to miss one of these patients, because it's a curable disease. And one of the distinguishing clinical features is most of the time, these patients are pretty healthy up until six months ago, a year ago, six months ago, a year ago, two years ago, when they suddenly develop bone pain and weakness, difficulty ambulating. Quite different than adult XLH patients, who often have a many-year history of symptoms getting progressively worse. But as always, you have to measure the phosphorus if you're ever going to identify this disease. Now, there are contraindications for buosamab, concomitant use of oral phosphate or active vitamin D analogs. These should not be given due to the risk of hyperphosphatemia. You should not give it if phosphorus is within or above the normal range. Now, what they mean here is that you should not start it if the phosphorus is within the normal range. You can certainly continue it if the phosphorus is normal. You would not want to continue it in the same dose if the phosphorus is high, though. And avoid in severe renal impairment or end-stage renal disease because of the possibility of hyperphosphatemia. So here's the dosing. It's a little bit different with kids and adults, of course. The recommended dose for starting in children is 0.8 milligram per kilogram sub-q every two weeks. The minimum starting dose is 10 milligrams and goes up to a maximum of 90 milligrams. The dose can be increased up to approximately 2 milligram per kilogram every two weeks in order to seek out a normal serum phosphorus. In adults, it's recommended starting with 1 milligram per kilogram up to a maximum dose of 90 milligrams. And adults are treated once every four weeks, whereas children, it's recommended every two weeks. It's not always clear exactly when to make that transition from a pediatric dosing regimen to adults. But typically, it's around the age of 18 or so. But individual distinctions can be made there. The medication is supplied in single-dose vials of 10, 20, and 30 milligram per milliliter. It must be administered by a health care provider. There was actually some exceptions to that made during the time of the COVID global pandemic when some patients were self-administering. It's not recommended that that be done currently, although that may receive further consideration in the future. It's advised to discontinue oral phosphate and active vitamin D one week before starting. Fasting serum phosphorus should be below the normal range for age prior to starting. So this is a phase 3 trial in children with burosomab compared with conventional therapy. So this was randomized open-label study at 16 clinical sites with children 1 to 12 years of age, one-to-one randomization. There were 61 participants in this study, a few more girls than boys. And the primary endpoint was change in Ricketts severity at week 40. And this was assessed by something called radiographic global impression of change score. And these are the results. In the top graph, you see that there's significant improvement in radiographic global impression of change score compared with conventional therapy, whether looking at a global score or lower limb deformity score. On the bottom graph, you see the blue line representing a nice increase in phosphate levels that remained in the low end of the normal range throughout the study period here. And this particular graph goes out to 64 weeks. And along with this, there was improvement in Ricketts alkaline phosphatase levels, growth, glowing, and patient mobility. So very encouraging findings that encouraged further exploration of this medication. Now, for adults, this is a phase 3 study that was placebo controlled. So this was randomized and double blind at 25 investigational sites with adults age 18 to 65, one-to-one randomization, 134 participants. The primary endpoint here was the proportion of patients who had mean serum phosphate levels above the lower limit of normal, or 2.5. And here, you see the findings at the top. You see that phosphate levels were normalized with burosomab throughout the dosing interval. There was also improvement in fracture healing with burosomab, with about 43% fracture healing seen with burosomab versus 7.7% with placebo. In the bottom, you see phosphorus levels going to the end of the dosing interval, also staying in the normal range. And there was a significant improvement in bone turnover markers and increased bone turnover markers with burosomab. Here, we see data with regard to healing of fractures. So clearly better with burosomab than placebo. On the upper right, you see a pseudo fracture that has healed very nicely with burosomab. In the bottom left, you see P1NP, a marker of bone formation. On the right, CTX, a marker of bone resorption, both of these going up with medication. Of course, there are adverse effects that have been associated with this. For the pediatric patients, these include having fever, injection site reactions, cough, vomiting, extremity pain, headache, tooth abscess, and dental caries. With adults, AEs that have been identified are back pain, headache, tooth infection, restless leg syndrome, decreased vitamin D, dizziness, constipation, and increase in blood phosphorus level. For any of you who have been involved in clinical trials and understand FDA terminology, an adverse event does not necessarily mean something that has a causal relationship with the medication. So some of these reported symptoms may simply be related to the disease state. And sometimes, there's just statistical flukes that result in numerical differences in the rates of events in different groups. But nevertheless, these are considerations and the sorts of things you need in having a conversation with the patient. There have been hypersensitivity reactions reported. Hyperphosphatemia may increase the risk of nephrocalcinosis and increase PTH levels. There can be injection site reactions. There are no data in pregnant women. And no information available on the presence of the drug in human milk or milk production with breastfeeding. So as mentioned before, it's advised to discontinue phosphate supplements and active vitamin D a week before starting. Have phosphorus below the reference range. This should be administered by a health care professional. Rotate injection sites. So typically, the upper arms, upper thighs, buttocks, and abdomen are used. If the dose requires multiple vials, you can combine the content of two vials. But the maximum volume that's recommended is 1.5 cc's. If multiple injections are required on the dosing day, use different injection sites. And as with all injectable material, look at it before you inject. If there are any particular matter or discoloration that you notice, then it should not be given. How to monitor and how to dose. Well, for adults, we start with the 1 milligram per kilogram, round it to the nearest 10 milligram, up to the maximum dose of 90. It's recommended that you monitor a serum phosphorus. That would be a fasting serum phosphorus two weeks post-dose. And do that appropriately thereafter. If the phosphorus is in the normal range, keep doing what you're doing. If phosphorus is above the normal range, then withhold the next dose. Repeat a phosphorus in four weeks and resume treatment with half the previous dose when phosphorus is below the normal range. And monitor serum 25 hydroxyvitamin D and supplement with vitamin D or D2 as needed. This is something that's hot off the presses. Last week, the annual meeting of the American Society of Bone and Mineral Research was in Toronto. And this was presented at this meeting. These are brand new, just released global guidelines for diagnosis, management, and monitoring of XLH in children and adults. 43 international experts were involved in this study. The GRADE methodology was used to evaluate the level of evidence. And these issues were addressed. How to diagnose XLH, who to treat, how to treat issues with special patient populations, such as pregnant women and dental concerns, how to monitor, and a research agenda was developed. I understand none of you can read this, and I can't either. So I'm going to just highlight two of these sections so that they are legible. This has not yet been published, but hopefully, in the near future, it will be published. And this may help us all to have a little bit of guidance on how to manage our patients. So it was suggested in all adults that they have an initial assessment as follows. First, you want to document some important information, like family history, and understand that it's X-linked dominant inheritance. Evaluate for fractures or pseudofractures. If you're not certain of that, you may want to get some x-rays, do a skeletal survey, perhaps. And you may find that people have fractures that they weren't even aware of. You want to document the presence of dental abscesses or periodontitis. Measure height, weight, and BMI. Look for bone tenderness and range of motion and genetic testing when appropriate. For lab, you want to measure a phosphorus and albumin corrected serum calcium. And always remember, it has to be corrected for albumin. Measure ALKFOS or ALP, 25-hydroxyvitamin D level. Test the renal function. Get a PTH. Get 24-hour urine for calcium and creatinine. Look at maximal tubular reabsorption of phosphate divided by GFR. Get a baseline bone density test and baseline dental assessment. Now, in the bottom, in the middle, it states very clearly, all recommendations are weak. Very low certainty of evidence based on experts' clinical practice survey. So this is, by and large, expert opinion. But this is what people who see a lot of this disease recommend that we all do. What about treatment? Well, this is what was recommended. Number one is a strong level of recommendation, although certainty is moderate. And that is that in adults with fractures or pseudo fractures who have XLH, it's recommended that burosomab therapy is preferred over no therapy. On the other hand, number two, in adults without fractures or pseudo fractures, it's suggested that burosomab is better than no therapy. But this is a conditional recommendation with low certainty. And finally, number three, in adults with fractures or pseudo fractures, burosomab is suggested over conventional therapy. Again, this is a conditional recommendation with low certainty. So the general idea is that burosomab is superior to no therapy or conventional therapy. However, depending on the specific clinical circumstances, these recommendations are conditional, and the level of certainty is certainly not very high. So to summarize, XLH is a genetic, progressive, lifelong disease due to dominant X-linked mutation in the FEX gene, resulting in elevated levels of FGF23. Hypophosphatemia is due to FGF23-mediated renal phosphate wasting and reduced absorption of phosphate. Affected patients have multisystem disease, including rickets, osteomalacia, fractures, pseudo fractures, and chronic pain. Conventional therapy is with phosphate supplements and active vitamin D. However, there is a drug called burosomab that is a fully monoclonal antibody that is approved for the treatment of adults and children age six months and older who have documented XLH. So that's the end of the formal presentation. I'll stop sharing my screen. And Ranjit, if we have questions or comments, let's hold it up. So we have a few questions. I'll try to answer a few. But one of the questions pertains to fasting measurement of phosphate. Why fasting? Well, there's a diurnal variation, and there are postprandial variations. So it tends to be lowest first thing in the morning. And it also tends to go high after having a meal. So if you really suspect that a patient might have hypophosphatemia, it's possible that you may miss it if you get a random specimen, especially one later in the day and after a meal, where you might discover that it's normal when it would have been lower if it had been a fasting morning specimen. Certainly, other markers, such as PTH, also vary a lot depending on whether you're fasting or not. There's a question about the difference between phosphorus and phosphate. What's the correct term? Circulating phosphate is not all by itself. It's actually in the form of phosphate. Some people feel strongly that we should use one term over another. I think, technically, we're measuring the phosphate. In common usage, physicians and patients all use those terms interchangeably. So personally, I'm not too fussy about which term is used. But some of you may be, and you're entitled to do so if you want. Quickly, last couple of questions. What's the sensitivity and specificity of FGF23 measurement for diagnosis? Are there conditions where FGF23 levels cannot be relied upon for diagnosis? I'll quickly chime in. FGF23 can actually be elevated even without XLH in real disorder, certain inflammatory states. So you have to be cognizant of that because there's a stimulus to get rid of excess hyperphosphatemia itself. And I'll heavy chime in, Mike. Yeah, another important thing to recognize is that elevated FGF23 is a common occurrence in chronic kidney disease. So it can start to go high fairly early in chronic kidney disease. So that needs to be a consideration. If a patient has CKD, especially severe CKD, that's going to have an impact on FGF23. It can even be affected in acute kidney injury to some extent. And lastly, what's the prognosis of these patients' life? What's the effect on their lifespan? Well, certainly as with many genetic diseases of childhood that now have treatments, patients are living longer and longer. I think for severe forms, it may be very disabling and shorten the lifespan. I think for milder forms, people live well into adulthood. And in fact, sometimes they're not even diagnosed until middle age or beyond in very mild cases. And it's also the cases for other rare bone disease. There's another one called hypophosphatasia that is also a form of osteomalacia and is sometimes confused with X-linked hypophosphatemia. And I think some of the confusion is that hypophosphatasia is a funny name. It sounds a little bit like hypophosphatemia. And I hear sometimes that some people aren't sure whether their patient has one or the other. So keep in mind that hypophosphatasia patients do not have hypophosphatemia, but they do have a low level of alkaphos. So if you see an adult with normal phosphorus and a low alkaphos that's less than 40, for example, often very much less than 40, that is highly suspicious of hypophosphatasia. On the other hand, you may have a patient with similar symptoms with a normal or high alkaphos and a low phosphorus. And that would lead you to be suspicious of XLH. I've actually seen another term being used for hypophosphatasia, which is hypophosphatacemia. Somewhere I've seen that term. Anyway, there's one last question. Somebody has a patient who meets all lab criteria for either XLH or TIO, renal phosphate wasting, elevated FGF 23, hypophosphatemia, of course. But imaging on x-ray and PET scan shows diffuse sclerosis. Biopsy of a bony tumor showed woven bone. She had negative genetic testing for XLH. Are you aware of any conditions that fit these findings? There are other genetic disorders that can cause very similar clinical findings, hypophosphatemia with renal phosphate wasting. So that's beyond the scope of what we can cover here. And unfortunately, I think our time is up. But yeah, that could be another webinar to talk about non-XLH causes of hypophosphatemia. Well, thank you so much, Drs. Gill and Lewicki. We really do appreciate your time this afternoon. And thank you all for joining us. And this will conclude our webinar today. Have a great afternoon. Thank you so much. Thank you. Thank you, everyone. And thank you, Amy. Thank you, Mike. Thanks for enjoying it.

X-linked hypophosphatemia

genetic disorder

fibroblast growth factor 23

renal phosphate wasting

burosumab

early diagnosis

multidisciplinary approach

phosphate supplements

genetic testing

Rare Bone Disease Echo