Hello, everyone. I'm Lakshmi Menon. I'm an endocrinologist at the University of Arkansas for Medical Sciences, and I am happy to talk to you today about the topic of hypophosphenic rickets. This talk is really going to be kept as clinically relevant as possible. We are going to touch on a few basic science aspects as well, because they play a role in the clinical management of this condition. So I do not have any disclosures, and the objectives for the talk today are to describe the role of fibroblast growth factor 23 in phosphate metabolism. Next is to review the different forms of inherited as well as acquired FGF 23 mediated hypophosphenic rickets. And finally, we're going to discuss the treatment of hypophosphenic rickets, including conventional treatment with calcitriol and phosphate salt, the new treatment option, which is burosimab, as well as we're going to review the effect of iron deficiency on disease manifestations in autosomal dominant hypophosphenic rickets. So we'll first start with an overview of what exactly fibroblast growth factor 23 is. So FGF 23 is a 251 amino acid polypeptide that is synthesized within osteocytes. The N-terminal section has a signal peptide, which is cleaved to create the mature peptide, which is then further processed, and it can be secreted either intact as intact FGF 23, or it can be secreted following proteolysis into N and C-terminal fragments. Now the proteolysis of FGF 23 happens at only one specific location, which is between amino acid 179 and 180. And this actually becomes relevant later on when we talk about various disorders, including autosomal dominant hypophosphenic rickets, as well as IV iron-induced hypophosphatemia. Now here it's important to understand that it's only the intact FGF 23 which is biologically active and is capable of causing hypophosphatemia. Now the FGF 23 that is secreted into circulation has two direct effects on phosphate metabolism, both of which happen at the level of the proximal renal tubule. So the first role is that it reduces the tubular reabsorption of phosphate by decreasing the expression of the sodium phosphate cotransporters. And the second mechanism is that it decreases the expression of renal 1-alpha-hydroxylase, and it increases the expression of 24-hydroxylase. The net effect of this is that there is decreased production of 125-dihydroxyvitamin D. In states of FGF 23 excess, there is increased renal loss of phosphate, or in other words, renal phosphate wasting, as well as there is decreased GI absorption of phosphate related to the decrease in the 125-dihydroxyvitamin D. And the net effect of both of these mechanisms is that there is hypophosphatemia. Now the factors that regulate FGF 23 production and metabolism within the osteocytes, they are not fully understood as of this time, but there are still a few things that we know. There are certain factors that stimulate FGF 23 production, and these include 125-dihydroxyvitamin D, high phosphate diet, and hypophosphatemia. Now this makes sense if you think of it logically, because in states that are associated with phosphate excess, such as hyperphosphatemia, the increase in the FGF 23 basically helps the body to get rid of the excess phosphate. Now in addition to that, PTH, as well as iron deficiency, can both stimulate FGF 23 production. And among the factors that inhibit FGF 23 production, the one that we really know of at this time is only hypocalcemia. Now this is an overview of the different diseases that are associated with FGF 23-mediated hypophosphatemia. Here they're classified into inherited and acquired conditions. And we'll talk about all of these conditions in detail later on in the talk. But essentially, all of these conditions have hypophosphatemia as a presenting clinical feature, as well as the hypophosphatemia drives most of the disease manifestations. And the hypophosphatemia and all these conditions are mediated by the excess levels of intact FGF 23. Now before we talk about these disease conditions individually, I just wanted to go over the laboratory investigation of hypophosphatemia. So when you have a patient in clinic who's presenting for the investigation of hypophosphatemia, then these are the initial labs to get, which consists of the serum phosphorus, PTH, serum calcium, serum creatinine, vitamin D, and the alkaline phosphatase. Now typically in hypophosphatemic rickets, regardless of the etiology, this is the pattern of labs. So the serum phosphorus is going to be low. The parathyroid hormone level can be either high or it can even be high normal. The serum calcium is normal. Serum creatinine is normal unless the patient has pre-existing CKD. The vitamin D level is typically normal because FGF 23 does not have a direct effect on the levels of 25-hydroxy vitamin D. But occasionally, these patients can have coexisting vitamin D deficiency. And the alkaline phosphatase is typically high because of the underlying state of rickets or osteomalacia. Now this pattern of labs also helps us to exclude two common conditions that can result in low serum phosphorus. Namely, this can help exclude primary hyperparathyroidism because of the fact that the serum calcium level is normal. And it can also help exclude vitamin D deficiency as a cause of the low serum phosphorus because in this case, the serum calcium level is normal. And even after correcting the vitamin D deficiency, the serum phosphorus is not going to change. Now the next step after getting the initial labs is to calculate the maximal tubular reabsorption of phosphate per unit volume of glomerular filtrate, namely the TMP by GFR. This is basically a measure of what percentage of the phosphorus that is filtered by the glomerulus actually gets reabsorbed by the renal tubules. Low TMP by GFR means that there is impaired renal phosphate reabsorption. In order to perform this test, it has to be done in the morning after the patient has fasted overnight. The first urine that is passed in the morning is discarded. The second urine sample is collected. And at the same time, blood tests are also done. And both the serum as well as the urinary phosphorus and triadenine levels are measured. And the following equation is used to calculate the TMP by GFR. And I have also copied the table that has the normal reference values for TMP by GFR. And as you can see from the table, the TMP by GFR is the highest in infancy, and the levels decrease with increasing age. And then as we mentioned, if the TMP by GFR is below the reference range that's shown on this table, it means that there is renal phosphate wasting. Once we verify the presence of a low TMP by GFR, the next step is to obtain a serum FGF23 level. This can be either elevated or it can be inappropriately normal for the level of hypophosphatemia in diseases that are associated with FGF23-mediated hypophosphatemia. And in addition to that, you can also check a 125 dihydroxyvitamin D level, which is going to be either low or low normal in disease states associated with FGF23-mediated hypophosphatemia. Now, after we've gone through a laboratory overview, the next step is to talk about the individual diseases that are associated with FGF23-mediated hypophosphatemia, starting with the inherited conditions. Now, of the inherited conditions, the most common one is X-linked hypophosphatemia or XLH, which accounts for 80% of cases of hereditary hypophosphatemia crickets. The incidence of this condition is about 3.9 to 5 cases per 100,000 live births, and there are no ethnic variations in the incidence. Now, in terms of the clinical manifestations of XLH, it is typically diagnosed in infancy or early childhood, and the clinical manifestations in children consist of lower extremity bowing that starts with weight bearing. Both the tibia, fibula, as well as the femur are involved, and a large percentage of these children ultimately require surgery to correct the bony deformity. There is decreased height velocity relative to peers, and these children present with muscle weakness, which is related to the hypophosphatemia. There is increased risk of dental caries and dental abscesses, and this is because the dentin is somehow defective in this condition. And then finally, cranial abnormalities, such as Chiari malformation and craniosynostosis. These are a relatively rare feature in XLH. These patients typically complain of headaches or blurry vision, and this happens because of the increased intracranial pressure that happens with these bony abnormalities. Next, we move on to clinical manifestations in adults. The decreased height velocity that is seen in childhood, it ultimately results in adults who have short stature, and these adults actually have relatively short limbs in comparison to their torso. These patients can report joint pain, which can happen due to multiple reasons. There is increased risk of degenerative arthritis related to the bony deformity, and they also have increased risk of developing osteophytes, as well as endoscopy. Impaired mobility is again multifactorial and can be related to the muscle weakness resulting from hypophosphatemia from bony abnormalities, as well as from the joint pain. These patients have osteomalacia, and they are at increased risk of developing stress fractures or pseudo fractures, and then as with children, they are at higher risk for developing dental abscesses. Now, in addition to these specific manifestations, adults with XLH, they report increased rates of depression, decreased productivity, as well as overall poorer quality of life as compared to controls, and these are all related to the immobilities that result from the disease manifestations in XLH. Now, once we suspect that a patient has XLH based on history and physical exam findings, the next step is to perform biochemical analysis with the initial set of labs that we discussed. In XLH, these patients have low serum phosphorus, reduced TMP by GFR, as well as elevated FGF23. Now, this kind of pattern of clinical presentation, as well as the biochemical pattern, these can be seen with other conditions associated with FGF23 excess as well. So, in order to specifically diagnose XLH, the patient needs to undergo genetic testing, and in case of XLH, there is a pathogenic variant in the FEX gene, which stands for phosphate regulating endopepsidase X-linked. Now, commercial genetic testing is available for XLH, and typically, you have a whole hypophosphatemia panel, which checks for really all the genetic conditions that are associated with hypophosphatemia. Now, the FEX gene is present on the X chromosome, and the disease is inherited in an X-linked dominant manner, which means that males and females are equally affected. Now, the exact role of the FEX gene and the protein that it encodes is not known, but we do know that the protein that is encoded, it is a transmembrane endopepidase, so basically an enzyme that creates protein, and that this protein has a role in the phosphate sensing mechanism within osteocytes. So, whenever there is a loss of function mutation in FEX, there is impairment of the phosphate sensing mechanism within osteocytes, and the osteocytes basically respond to this by releasing more FGF23, which is responsible for the hypophosphatemia. Now, this disease has 100% penetrance by age one year, which is why typically the disease is diagnosed in childhood itself. Now, the initial management of XLH consists of understanding the full extent and the severity of the underlying bony deformity and the underlying rickets, and this is done by obtaining X-rays of the wrist and lower extremities in children to evaluate for the presence of rickets. Bone age is measured to evaluate what their final growth potential is likely to be. Then a dental examination needs to be done, because as we have discussed, these patients have increased risk of dental caries and abscesses, as well as a hearing evaluation needs to be done, because there are reports that these patients have higher chances of having both sensorineural as well as conductive hearing loss. The evaluation in adults consists of getting X-rays of skeletal sites where the patients report pain, and this is to evaluate for the presence of fractures and pseudo-fractures, and adults also require a dental exam and a hearing evaluation if it has not been done previously. Now, conventional pharmacotherapy for the management of XLH consists of combination therapy with an oral phosphate salt, such as potassium phosphate, and an active vitamin D analog, which is typically calcitriol. Now, there's a reason why we cannot use only oral phosphate to correct the hypophosphatemia, and this is because when you give the patient only oral phosphate, then the phosphate level rises in the bloodstream, it complexes with the calcium in the blood, and the calcium phosphate salt basically precipitates, leading to hypocalcemia. This hypocalcemia, in turn, acts as a stimulus for the release of the parathyroid hormone, and the parathyroid hormone, as we know, causes renal phosphate wasting. So, essentially, the oral salt that is given ends up getting wasted because of the effect of the increased parathyroid hormone. So, in order to reduce the risk of losing the oral phosphate salt, it is combined with the calcitriol. So, by giving calcitriol, there is increased absorption of calcium from the GI tract. So, this actually reduces the risk of developing hypocalcemia, as well as the calcitriol, it actually has a direct inhibitory effect on PTH secretion, which also reduces the chances of renal phosphate wasting. I've also listed the doses that we typically use for both the oral phosphate salt, as well as for the calcitriol. The key thing here is that with the oral phosphate, it needs to be given in multiple daily doses, typically three to five times a day. And this is because of the short half-life of the phosphate, as well as the fact that it is lost quickly from the body due to the ongoing renal wasting. Now, conventional pharmacological therapy, it does have some kind of positive changes on the patients. It is associated with improvement in the serum calcium, serum phosphate levels, but the serum phosphorus level typically is still not within the normal range. If we try to normalize it, typically we encounter other complications that we'll discuss in the next slide. Now, this combination therapy has been associated with increased growth velocity in children, but still their growth velocity does not catch up with that of peers who do not have XLH. In adults, conventional pharmacological therapy is associated with improvement in bone and joint pain in about 75% of patients, as well as it is associated with improved oral health, both in children as well as in adults. Now, there are a lot of limitations to conventional pharmacological therapy as well, which is what led to the need to discover newer therapeutic options, which is the Burosimab. So, let's go over what are the limitations of the conventional therapy. So, firstly, with the phosphate salts, they can cause abdominal pain and diarrhea, which can limit patient compliance with the treatment. Then, secondly, as we discussed, the oral phosphate salt can actually stimulate the release of PTH by causing hypocalcemia, and this can lead to the development of tertiary hyperparathyroidism. And if you have a prolonged period of secondary hyperparathyroidism, and when you have a prolonged period of secondary hyperparathyroidism, ultimately it leads to the development of parathyroid gland autonomy and the development of tertiary hyperparathyroidism. The calcitriol that is used can lead to the development of hypercalcemia, as well as hypercalciuria and increased risk for kidney stones, and it can also lead to the development of nephrocalcinosis. So, in order to monitor for the development of these complications and really to catch it early, these patients need labs every three to six months in which the following labs are checked. Again, our goal is not to normalize the serum phosphorus, it is really to improve the symptoms that are caused by the hypophosphatemia such as the muscle weakness, as well as the monitoring is done to screen for complications such as hypercalcemia and hypercalcemia. Now, given the limitations of the conventional treatment, burosomab actually presents as a very new and exciting treatment option for this condition. It is a monoclonal antibody that is directed against FGF23 and this in turn leads to inactivation of FGF23. It has been FDA approved and the approval came in 2018. Approval is for children aged six months and older, as well as adults with XLH. Now let's review some two studies that looked into the effect of burosomab treatment on children with XLH. The first study is a phase two open-label trial in children aged five to 12 years with XLH, most of whom had previously been treated with conventional therapy, but they continue to have rickets. Now these children were randomized one is to one to receive either burosomab subcutaneously every two weeks or burosomab every four weeks. Now, as you can see from the graph in the upper right section, when the burosomab is given every two weeks, there is sustained normalization of the serum phosphorus levels. But when the burosomab is given every four weeks, there are dips in the phosphorus levels below the normal range. And so for this reason, burosomab is dosed every two weeks in children. In addition to that, you can see that there is sustained improvement in the TMP by GFR with the Q two weeks dosing, as opposed to with the Q four weeks dosing, you still have the fluctuations in the TMP by GFR. Now both with the Q two week as well as Q four week dosing, both of these led to radiological improvement in the science of rickets, but the magnitude of the improvement was more in the children who received the dose in Q two weeks. Now, the second study is an open label phase three trial in children aged one to 12 years. And in this case, the children were randomized to receive either burosomab Q two weeks or conventional therapy with phosphate salt and calcitriol. Now, as you can see from the graphs, it's only the children who were treated with burosomab who had normalization of the serum phosphorus levels with conventional therapy, the serum phosphorus remained below the normal range. And 87% of children who were treated with burosomab, they had improvement in rickets at 64 weeks of treatment, whereas only 19% of children who were treated with conventional treatment, they had improvement in rickets during the same timeframe. The dosing for burosomab, as we discussed previously in children, it is dosed every two weeks. It's 0.8 milligram per kilogram subcutaneous up to a maximum dose of 90 milligram. And in adults, the dose is one milligram per kilogram subcutaneous every four weeks. The maximum dose again is 90 milligrams. Now, before starting this medication, the oral phosphate salts and calcitriol needs to be held one week before. And the serum phosphorus levels need to be below the normal range before the first injection can be given. Monitoring is done by checking the fasting serum phosphorus levels midway between injections in adults, that is two weeks after the injection. And the fasting serum phosphorus levels needs to be checked weekly for the first three months. And after that, if the level is stable, then the lab test can be spaced further apart. In terms of side effects of this medication, most of the side effects are related to injection site reactions and occasionally hypersensitivity reactions such as fever can also occur. Next, we move on to autosomal-dominant, autosomal-recessive hypophosphatemic rickets, which is actually a group of conditions with multiple genes involved, all of whom basically share a recessive inheritance patterns. So they are present in late infancy and there are three main subtypes. Autosomal-recessive hypophosphatemic rickets type one is associated with mutations in DMP1, dentin matrix protein one, and this is associated with impaired osteocyte maturation. In addition to the hypophosphatemia, these patients can also develop hyperostosis and increase in bone density by middle age. ARHR type two is associated with mutations in ENP1-1, that's the ectonucleotide pyrophosphate phosphodiesterase one and in this case, along with the hypophosphatemia, there is also the presence of muscular calcifications. And the type three form is associated with mutations in FPM20C and this is associated with the presence of cerebral calcifications as well as facial dysmorphism. Management consists of calcitriol and phosphate salt and the murosomab is not FDA approved for the treatment of any of these subtypes, but there has been one case report in the literature that showed that it was beneficial for the treatment of autosomal-recessive hypophosphatemic rickets type one and that it led to the normalization of serum phosphate as well as improvement in rickets in that case. Next, we move on to autosomal-dominant hypophosphatemic rickets, which is caused by genetic mutations that affect the cleavage site of FTF23. Like we discussed previously, the cleavage site of FTF23 is located between amino acid 179 and 180 and any missense mutations that affect the amino acid sequence can basically lead to the creation of a mutant peptide that is resistant to proteolytic cleavage. Now this mutant peptide, even though it is resistant to proteolytic cleavage, it retains its biological activity and that results in the increased levels of intact FTF23, which is responsible for the hypophosphatemia. Autosomal-dominant hypophosphatemic rickets has a few unique features in comparison to XLH and autosomal-recessive hypophosphatemic rickets. So one unique feature is the variable age of presentation. So in contrast to the other two conditions, this disease may not be apparent within infancy or early childhood itself. So only about 50% of patients with autosomal-dominant hypophosphatemic rickets, they present with hypophosphatemia as well as boring of legs at the age of one to three years. And even within these children who present with disease manifestations early on, some of them, they have spontaneous resolution of hypophosphatemia by late childhood or adolescence. And the rest of the patients, they can develop disease manifestations for the first time, either in adolescence or maybe sometimes even in adulthood. And in these cases, these affected individuals, they actually do not have boring of their legs. And so they can be mistaken to have an acquired cause of the hypophosphatemia in that case. In addition to that, this disease displays incomplete penetrance, which means that not everybody who has the mutation will develop disease manifestations. And finally, it is associated with periods of quiescence, which are basically time periods where there is spontaneous normalization of the serum phosphorous levels without any treatment options. So this disease basically goes into remission. And these periods of quiescence can basically go away and the disease manifestations can develop again. So the fact that this condition, it has a limiting relapsing course, that raises kind of the suspicion that there is something in the environment that is responsible for causing quiescence and then for causing the disease manifestations to develop again. And as far as what is that environmental factor, we know that it is iron deficiency. So iron deficiency, it is associated with the increased production of FGF23 mRNA within osteocytes, both in individuals with ADHR, as well as in normal subjects. But what's different is that in normal subjects, while there is increased FGF23 production within the osteocytes, there is associated increase in cleavage as well, so that the serum levels of intact FGF23 are maintained within the normal range. Now, when individuals with autosomal dominant hypophosphatemic rickets, since they have a mutant peptide that is resistant to proteolytic cleavage, the osteocyte is unable to break down the increased FGF23 that is produced. And this basically spills over and results in increased serum levels of intact FGF23. Now, given that iron deficiency is associated with increased FGF23 and disease manifestations, every patient with autosomal dominant hypophosphatemic rickets who presents with hypophosphatemia, they need to be screened for the presence of iron deficiency. Now, conventionally, this condition is treated with phosphate salt and calcitriol, which is the same treatment option as for XLH. But we do know that when these individuals are found to have iron deficiency, they can be treated with only iron replacement and calcitriol without needing phosphate supplementation. And this is because when these patients receive iron replacement, the iron replacement actually leads to decreased production of the FGF23. Ultimately, the FGF23 goes into the normal range and this results in the resolution of the hypophosphatemia. And obviously, this treatment option, it is more convenient because you don't have the multiple daily dosing of the phosphate salts that is part of the conventional treatment. Now, those were the three inherited conditions of FGF23-mediated hypophosphatemia. Next, we will go on to the acquired conditions. And there are three conditions that I'm going to talk about. Hypophosphatemia due to IV iron infusion, tumor-induced osteomalacia, and fibrous dysplasia. So starting with hypophosphatemia due to IV iron infusion. So the most important thing to remember here is that the hypophosphatemia is seen only with certain formulations of IV iron, the chief among which is ferric carboxymaltose. Now, this was a clinical trial that was a randomized control trial that compared the incidence of hypophosphatemia among patients with iron deficiency who received either two doses of ferric carboxymaltose, 750 milligrams each, or one dose of ferric derexamaltose, 1,000 milligrams once. And the labs were checked during all these days and the trial was continued for a total of 35 days. And what they found is that the incidence of hypophosphatemia was 74% with ferric carboxymaltose, but only 8% with ferric derexamaltose. In addition to that, severe hypophosphatemia with serum phosphorus levels below one milligram per deciliter was seen only with ferric carboxymaltose. Happened in about 11% of participants who received ferric carboxymaltose. As well as the hypophosphatemia that develops with ferric carboxymaltose, it can be prolonged. And about 45% of patients, they continue to have hypophosphatemia even on day 35 after the start of the first treatment dose. Now, what is the mechanism of hypophosphatemia due to IV iron infusion? So we know that iron deficiency itself is a state associated with increased FGF23 production within osteocytes. But in healthy individuals, typically there is a coupling of, there is increased cleavage, which basically maintains the serum FGF23 levels in the normal range. But certain carbohydrate moieties, such as that present in ferric carboxymaltose, it basically inhibits FGF23 cleavage. And so similar to what happens in autosomal dominant hypophosphatemic ligates, because of this uncoupling of the production and the cleavage, there is increased levels of intact FGF23 and decreased levels of the C-terminal fragment due to impaired proteolysis. And so the next effect is that you have hypophosphatemia due to renal phosphate wasting, as well as decreased 1,25-dihydroxyvitamin B production, which is responsible for the disease manifestation. Now, in mild cases, the hypophosphatemia that develops due to IV infusion, it can be completely asymptomatic. And we may not even realize that this patient basically developed hypophosphatemia. Typically the symptoms go away after a few months and they may never actually be labeled as having developed hypophosphatemia. In kind of more moderate cases, these patients can report fatigue and muscle weakness, but those symptoms can be attributed sometimes to the iron deficiency, or it can be attributed to the underlying disease process that was responsible for the development of the iron deficiency in the first place. In patients who receive repeated infusions of IV iron, there can be prolonged periods of hypophosphatemia, which can result in the development of osteomalacia. And these individuals can develop fractures as well as trugal fractures. To the right, you can see a radionucleotide bone scan where you see areas of increased activity in the ribs, the sacrum, as well as the feet, which represent the areas of fractures. Now, what are the risk factors for hypophosphatemia due to IV iron infusion? The biggest risk factor is basically the formulation of IV iron. As we discussed previously, ferric carboxymaltose is associated with a very high risk of causing hypophosphatemia, whereas the risk is very low with ferric dirizomaltose. The severity of iron deficiency also is a risk factor because the lower the baseline serum ferritin level, the higher the risk of developing hypophosphatemia. Individuals with normal kidney function, they have a higher risk of developing hypophosphatemia because in these individuals, there is more glomerular filtrate containing phosphorus, and there is more of the phosphorus that needs to be reabsorbed by the sodium phosphate-coarse transporters. In addition to that, if there is associated secondary hyperparathyroidism, either due to vitamin D deficiency, calcium malabsorption, or some other etiology, it can also compound the hypophosphatemia because the increased BDH causes renal phosphate wasting. Now, knowing that the hypophosphatemia in IV infusion, it is driven by FeF23 excess, it helps us to choose the management option. You can have a targeted treatment for this condition with phosphate, salt, and calciferol, and that's because phosphate monotherapy is not going to be helpful. And typically, that is the only treatment option that is needed. The hypophosphatemia is usually present for a few weeks, occasionally a few months, treat with the phosphate, salt, and calciferol, and typically the condition will resolve unless the patient gets another IV infusion of iron, and then you have to repeat the treatment option. Now, Burosimab, again, is not FDA-approved for treatment of IV hypophosphatemia in this situation, but there has been one case report which mentioned a patient who was getting repeated IV iron infusions, and it was intolerant to oral phosphate salts, who actually had resolution of the hypophosphatemia with Burosimab. And the key thing here is prevention. So whenever the patient is able to get an iron formulation that is associated with lower risk of hypophosphatemia, such as ferric adenosyl maltose, then it reduces their risk of developing the hypophosphatemia and osteomalacia. The next acquired condition is tumor-induced osteomalacia. This is a paraneoplastic syndrome in which the tumor cells secrete Fgf23. As with other causes of hypophosphatemia, these patients present with bone pain, muscle weakness, and osteomalacia, and they can have pathological fractures. The tumors that are responsible for Fgf23 secretion, they are typically small, slow-growing tumors. The median size of the tumor at diagnosis is only 2.7 centimeters. And pathologically, these tumors are generally classified as phosphatidic mesenchymal tumors of mixed connective tissue variant, and they have a spindle cell appearance with a basophilic cytoplasm. These tumor cells can be stained for Fgf23, which basically confirms that they are the source of the Fgf23 excess. These tumors are typically benign, and the risk of malignancy is only about 10%. Now, 95% of patients with tumor-induced osteomalacia, they report initially being misdiagnosed as having some other condition. And typically, that other condition is either a rheumatological disease or fibromyalgia. And this happens because the symptoms can be very nonspecific, myalgia, muscle weakness, fatigue, and it can be mistaken to be due to other conditions. But another reason why for the misdiagnosis is the fact that there is not enough awareness regarding this condition. And the decreased level of awareness, it's also responsible for the delayed diagnosis. And one study showed that the average duration from the onset of symptoms to the diagnosis of tumor-induced osteomalacia was 2.9 years. Now, once the diagnosis is made, the next step is localization of the tumor. Sometimes the tumor can be localized just based on a thorough history and physical exam. So the patient will be able to tell you localize the site of the pain, and physical exam may reveal a lump that represents the tumor. But this happens rarely. Much more commonly, the tumor is kind of occult, and you need some kind of functional whole body imaging to localize the tumor. This tumor can be located anywhere in the body from the head and neck to the lower limbs. The most common location of the tumor is within the lower limbs, and this is followed by the head and neck region. Now, these tumors have historically been extremely hard to localize, but recently there was a meta-analysis that came out that showed that using DOTATATE PET-CT, the tumor can be localized in 90% of cases. The second best imaging modality, which can be used if DOTATATE PET-CT is not available, is the Octreoscan. This was successful in localizing the tumor in 83% of cases. Now, once the tumor has been localized, the first line treatment option is complete surgical resection. The entire tumor needs to be removed, and this is to reduce the risk of recurrence of the condition. Now, if the tumor cannot be resected, either because it's in a location that's hard to access surgically, or because the patient is a poor candidate for surgery because of comorbidities, then the second line of treatment option would be radiotherapy. The reason that radiotherapy is not first line is that we don't have long-term outcomes data, and so we do not know what is the risk of recurrence in patients who are treated with radiotherapy. Then burosomab is FDA-approved for the treatment of tumor-induced osteomalacia in patients who are not candidates for surgery. And finally, a treatment with phosphate salt and calcitriol, it remains an option in patients who are not candidates for any of the other treatment options. And the final disease that I'm going to discuss today is fibrous dysplasia. Now, fibrous dysplasia can be either mono-osteotic, when only one bone is involved, or it can be poly-osteotic when more than one bone is involved. Fibrous dysplasia can occur as either an isolated entity, or it can occur as part of McEwen-Albright syndrome, when it is associated with the presence of cafe-au-lait macules and endocrine hyperfunction. In McEwen-Albright syndrome, there is a post-zygotic mutation in the GNAS gene, and this results in the increased generation of cyclic AMP. And the increased level of cyclic AMP, it actually drives increased FGF23 transcription. So basically, it is the dysplastic bone in fibrous dysplasia, which is the source of the FGF23 excess. And for that reason, the FGF23 levels basically correspond with disease burden and fibrous dysplasia. So patients who have more extensive fibrous dysplasia, they are more likely to present with hypophosphatemia and to have osteomalacia. Now, these are two X-rays from individuals with fibrous dysplasia. On panel A, you have the X-ray of the femur, and the red arrow points to a Shepard's crook deformity, which is the site of fibrous dysplasia. And the yellow arrow basically shows the splaying of the metaphysis, which corresponds to the area of osteomalacia that is associated with FGF23 excess. On panel B, you can see fibrous dysplasia involving the humerus. And in this case, there's a characteristic ground glass appearance, as well as you can see that there's bowing of the humerus, which happens because of a previous fracture in the mid-shaft. Okay. Now, that brings me towards the end of my talk. Now, as you might have realized, there are still a lot of unknowns in the field of FGF23-mediated hypophosphatemia, and there's still a lot of research that is being done and that will be done in the future. Now, in terms of what are the things that we need to understand, I've basically divided it into basic science aspects as well as clinical aspects. In terms of basic science aspects, we need to understand what are the different factors regulating FGF23 production. We know some of them, but possibly there are kind of other compounds involved as well. And also to understand what is the exact role of FEX in causing XLH. And in terms of the clinical standpoint, we need to understand how can we shorten the time to diagnosis of autosomal-dominant hypophosphatemic rickets as well as tumor-induced osteomalacia. Because if the patients are diagnosed early, we can reduce a lot of the morbidity that they suffer. And also we need to understand how to reduce the risk of IV iron-induced hypophosphatemia, which obviously one way is the formulation of IV iron, but we need to know other mechanisms as well. Now, this is a summary of my talk. FGF23 excess causes hypophosphatemia by two mechanisms. There is decreased tubular reabsorption of phosphate leading to renal phosphate wasting, as well as there is decrease in 125-dihydroxyvitamin D production, which leads to impaired phosphate absorption from the GI tract. XLH is associated with lifelong hypophosphatemia. Disease manifestations first start around within the age of one year, and then the hypophosphatemia is present throughout the lifespan. Now, in contrast to this autosomal-dominant hypophosphatemic rickets, it has a limiting and relapsing course. And this is driven by the fact that iron deficiency stimulates FGF23 production as well as the development of disease manifestations in autosomal-dominant hypophosphatemic rickets. There are certain IV iron formulations that can cause hypophosphatemia by increasing the levels of FGF23. The chief among this is ferric carboxymaltose, and virosumab is a monoclonal antibody against FGF23, which has been FDA approved for use in XLH patients who are not candidates for, sorry, in XLH, as well as in patients with tumor-induced osteomalacia who are not candidates for surgery. That brings me to the end of my talk. Thank you for your attention, and I'm happy to take any questions that you have. Thank you so much, Dr. Menon. A few questions did come up throughout the presentation. Thank you for those who are submitting throughout. To kind of kick off, and I think this touches nicely on the kind of future of research, is wanting to get your general thoughts on why our understanding of the regulation of phosphorus metabolism is currently lagging behind our understanding of other systems, such as calcium regulation. Kind of a multi-tiered question. Are there teams currently working on understanding that mineral homeostasis through the lens of phosphorus, and do you expect breakthroughs on the horizon? Okay, a lot of different questions combined. Yeah. And I mean, this is just kind of my conjuncture, really, regarding this. I would say one possible reason is that kind of, there are a lot of different players involved in phosphate mechanism, right? With calcium, we know there are kind of a few different factors, like parathyroid hormone that have a big role, but it looks like in phosphate mechanism, because there are so many different factors involved, it's hard to find out which ones are the key players, which ones are the minor players, and also if we know kind of all the players involved in the field. And I know there's a lot of work kind of going on in the basic science field. It looks like there's been a lot of advances in that area, but as to how much of that kind of becomes clinically relevant, I think we'll know with time. Thank you. So our next question is, given that calcitriol effect is mediated by alterations in protein synthesis, such that the biological effects should be longer than circulating serum, the half-life of calcitriol, are there any data suggesting that if it's not given in divided doses, the effects wear off, per se? So is that, sorry, I'm trying to read the question. So the idea is that, do you need to give calcitriol in divided doses, or can you just give it once daily, is that the question? I believe so. I think if they opted not to do a divided dose, do the effects wear off? Well, no. With the calcitriol, yeah, you can give once daily dosing. I don't see a reason why not. Again, conventionally, we've just done twice daily dosing. I don't know that I've ever done once daily dosing, but it should work. It's mainly with the phosphate that you have kind of the short half-life, and we have to dose it multiple times. Okay, great. We do have a case question. So does everyone with the FEX mutation need treatment? This individual has a patient whose only symptom is joint pain. They were diagnosed last year at the age of 23 based on family history and genetic testing, and she does have low phosphate levels. So the first thing would be that, obviously, we need to understand the kind of the disease burden. We want to make sure that the patient is not having some underlying muscle weakness that they may not realize that there is some muscle weakness or impaired mobility involved. So just seeing kind of asking them to kind of get up to a standing position from a chair, just observing them, it may help us evaluate objectively, is there somebody who may have some underlying kind of muscle weakness? And also in these individuals, if they are kind of completely asymptomatic, they do not have any underlying osteomalacia, no underlying fractures, you know, fractures, you don't need to treat these adults with the kind of burosomab, but it's really if they have symptoms, if they have fractures, or if they're going to be undergoing some kind of orthopedic procedure, in those situations, they will require treatment. Now, is there an optimal range of phosphorus and urinary calcium that we should be keeping the patients within? I mean, this phosphorus level, it just needs to be within the normal reference range, kind of whichever one that is. And same as with the urinary calcium, it just should not be above the normal reference range, typically taken as above 400, in order to reduce the risk of calcium-related kidney stones. Great. Now, I want to try and make sure that I'm tracking this particular submission as there are a couple of questions in here. So the first part is how to follow a patient who presented fractures with minimal trauma due to hypophosphatemia after sequential infusions of ferric carboxymaltose. And I get the sense that the phrase is also possibly, and this is after replacement of chelated phosphorus orally or the serum phosphorus normalized PTH. Okay, so I am trying to understand this question. So the idea is that, okay, so let's see. So the main thing is to monitor the fasting serum phosphorus levels in these patients, and then just follow them along serially while on treatment with the phosphorate salts and calcitriol to see when there is resolution of hypophosphatemia. Once the hypophosphatemia resolves, you do not need to kind of monitor those labs again, unless they receive another infusion, or for some reason you feel like the hypophosphatemia kind of precedes the IBI infusion, and there's some other reason, then you need to follow that up. This really, I would say it's not necessary to check the FGF23. If you strongly believe that this is all driven by FGF23, and you've proven that with basically a low TMP by GFR, then checking an FGF23, it's really not going to add any more information there. Now, in patients with tumor-induced osteomalacia, without a positive image, should clinicians do genetic studies, or is it not necessary? So that's, I like that question, because here there's a presumption that even without a positive imaging, the patient has tumor-induced osteomalacia. And that's something I've encountered in clinical practice as well, where you have a patient who presents in adulthood, in middle age, with hypophosphatemia for the first time, and there's a presumption that it has to be TIO possibly. But there's still a possibility that this is somebody who actually has autosomal-dominant hypophosphatemia ligates, who actually never developed disease manifestations until that age. So definitely you will need to do genetic testing, just to make sure, just to evaluate whether it is TIO, or is there a possibility that what this patient actually has is autosomal-dominant hypophosphatemia ligates? And then just a clarification question, if FGF23XS increases the production of 1.25 vitamin D, why do we treat with calcitriol? So sorry, FGF23XS, actually, it does not increase the production of 1.25 dihydroxyvitamin D. It actually decreases the levels of 1.25 dihydroxyvitamin D. Okay, wonderful, thank you. So how does one distinguish the normoplasmic primary hyperparathyroidism from hypophosphatemia ligates? Well, so normoplasmic primary hyperpara, it is a disease of exclusion. And so in the correct clinical scenario, you first have to exclude FGF23-mediated hypophosphatemia ligates before you label them as having normoplasmic primary hyperpara. Another question that we got is, is there an effective octreotide on phosphate in tumor-associated hyperphosphatemia or FGF23XS? That's interesting. I do not know the answer to that question. I'll have to look it up. Going back to borosumab as a possible treatment, what was the longest duration of borosumab use in the clinical trials? To my knowledge, the longest duration of use is 64 weeks. All right, so kind of going into another patient question that someone submitted, what do you do when a 55-year-old patient with tumor-induced osteomalacia clinically and on the biochemistry cannot be localized even despite the GADOTA scan? An MRI of the whole body and for most borosumab is not available. So thinking of those three factors. It says that she's currently on medical therapy with oral phosphate and calcitriol. However, they're running into complications with secondary hypoparathyroidism and chronic kidney disease. So would you repeat the GADOTA imaging or would you try an octreotide scan? Well, if you've done one imaging and it was not helpful, it would make sense to kind of check by another imaging modality there. And then here, again, I'm not saying that this is necessarily the right thing to do for kind of that patient, but there's been one case where in this case where you have basically recalcitrant kind of hypophosphatemia and basically nothing that was given was working. They intentionally went ahead and did a total parathyroidectomy. So they basically removed all the parathyroid glands, induced hypoparathyroidism. And so this basically also demonstrated that without PTH, FGF23 cannot act. So it's a kind of an extreme measure, not something you would typically do, but just kind of, I think it goes into the pathophysiology there. And just a pragmatic question, but can clinicians add phosphate levels to the CMP? This could possibly promote earlier identification of some of the issues addressed today. Yes, but then again, we get into other factors such as kind of cost-benefit analysis. So another question that we received is for XLH treatment, do you start with the phosphate salts and calcitriol before going to borosinab, or do you ever go straight to borosinab? I mean, in my experience, I deal with adult patients. So I really only get patients who have already kind of been treated with phosphate salts and calcitriol. And typically in all of these patients who have been treated with phosphate salts and calcitriol, I've not had somebody who is kind of completely happy with the treatment options. Typically there is some residual muscle weakness, some residual joint pain. And in that case, they do notice an improvement on treatment with borosinab. And our final question that we have time for this afternoon is what is the mechanism of developing calcification in the tendon and vessels in patients with hypophosphatemic rickets when the serum phosphorus is low? Yes, good question. And I don't know that we have the answer to that. We know that they develop kind of calcifications and endosopathy. But again, to my, I do not know the answer again. That's, yeah, that's what I'd say. But good question.

hypophosphatemic rickets

FGF23

phosphate metabolism

treatment options

X-linked hypophosphatemia

calcitriol

burosumab

autosomal dominant hypophosphatemic rickets

research