Speaker 1:

Welcome to AACE Podcasts. Thanks for tuning in as we elevate clinical endocrinology by taking deep dives into trends and topics that can help us improve our patient care and global health. Find the latest episodes on aace.com/podcasts. And now let's meet the endocrine experts who will be talking with us today.

Dr. Steven Petak:

Welcome to another episode of the AACE Podcast. I'm Dr. Steven Petak. I'm a past president of AACE and ISCD, and I just retired as chief of endocrinology at Houston Methodist Hospital. I've also been an endocrine consultant to NASA at the Johnson Space Center for about 18 years, and I specialize in rare bone disease. Today, we're discussing a commonly missed but clinically important topic, Hypophosphatemia.

Before we begin, I'd like to thank our sponsor, Kyowa Kirin, for supporting this important conversation. Joining me today are Dr. Laila Tabatabai and Dr. Basma Abdulhadi. Thank you both for being here. Laila, let's start with you. Could you introduce yourself and share your background and area of expertise?

Dr. Laila Tabatabai:

Thank you, Steve. I'm so pleased to be here tonight with you and Basma. I'm Dr. Laila Tabatabai. I'm an endocrinologist with a specialized focus in metabolic bone disease, including disorders of phosphate homeostasis, osteomalacia, and particularly advanced osteoporosis and fragility fractures. I'm associate professor of clinical medicine at Weill Cornell, and I also practice at Houston Methodist. We still miss you there. So I split my time between clinical care, education, and research.

Dr. Steven Petak:

Wonderful. Great to have you. Basma, could you introduce yourself?

Dr. Basma Abdulhadi:

Thank you, Steve. Yes, I'm very happy to be here. I'm Dr. Basma Abdulhadi. I'm an endocrinologist and an assistant professor of medicine at the University of Alabama. My interests include metabolic bone disease and osteoporosis. I work closely with our radiology department at UAB as the head of bone densitometry.

Dr. Steven Petak:

Perfect. Well, let's dive in. First, we see a lot of confusion between osteoporosis and osteomalacia. Can you explain the difference to us?

Dr. Laila Tabatabai:

So I frame it this way. Osteoporosis is a quantitative problem, so that's related to the amount of bone mass that we see. So it's reduced bone mass with normal mineralization. Osteomalacia, on the other hand, is qualitative. It has to do with bone quality, and it means that there's impaired mineralization of the osteoid.

That most commonly comes from vitamin D deficiency or phosphate deficiency. And clinically, osteomalacia can bring bone pain, muscle weakness, and what we call pseudofractures or what's known as Looser zone. And so on the other hand, osteoporosis many times is silent until a fracture occurs.

Dr. Basma Abdulhadi:

Lab work also helps in differentiating the two. In osteomalacia, alkaline phosphatase is typically elevated. And depending on the cause, you might see low phosphate levels and often low or inappropriately normal 1,25-dihydroxyvitamin D. In primary osteoporosis, calcium phosphate and alkaline phosphatase levels are usually normal.

Dr. Steven Petak:

That distinction becomes vital when a patient isn't improving on standard osteoporosis therapy when the true problem is osteomalacia. So it's very important to make a diagnosis. So let's talk about symptoms. What should raise the suspicion in children with Hypophosphatemia?

Dr. Basma Abdulhadi:

So in children, we usually think of Hypophosphatemia causing rickets. So they have growth delays, lower extremity deformity, genu varum/valgum, widened wrists, delayed tooth eruptions. They can also have some dental abscesses, especially in X-linked Hypophosphatemia. Some may have hearing issues, fatigue, bone pain, which are very common, but easy to overlook.

Dr. Laila Tabatabai:

In adults, it's important to look for diffuse bone pain, proximal muscle weakness. And the way you ask about that is it difficult to climb stairs? Is it difficult to get out of a chair? Adults can also have fatigue and pseudofractures. So they're commonly found in the lateral femur, in the ribs, in the pelvis. So many times they'll be complaining of that pain.

They'll have imaging, and the imaging will show that pseudofracture or Looser zone. And then in acute or severe Hypophosphatemia such that the patient might be hospitalized, you can see rhabdomyolysis, respiratory muscle weakness, paresthesias, and occasionally cardiac dysfunction, so cardiomyopathy.

Dr. Steven Petak:

So the clinical picture spans musculoskeletal, neuromuscular, and sometimes cardiopulmonary problems, which is important for our listeners to understand how this can be quite severe in some patients. So the key issue, of course, is the check phosphate message. The core messages will miss Hypophosphatemia if we don't measure a phosphate level.

Dr. Laila Tabatabai:

That's exactly right. Serum phosphate is not on the basic metabolic panel nor the comprehensive metabolic panel that we typically order. So if you're only ordering these types of metabolic panels, which is what our primary care physicians do, what we typically do for every kind of visit, we're going to miss Hypophosphatemia.

Very, very important to order a fasting phosphate whenever you see a patient with bone pain, proximal muscle weakness, atypical fractures, pseudofractures, rickets or osteomalacia, or risk factors such as malabsorption, chronic antacid use, Roux-en-Y Gastric Bypass, for example, is a cause of malabsorption, or as we'll discuss a little bit later, recent IV iron infusion.

Dr. Basma Abdulhadi:

Also, we have to remember that there's a diurnal variation in phosphate levels. The phosphate tends to be higher later in the day, so context matters. If the lab results don't fit the clinical fixture, it's important to consider an assay interference or sample and handling issues.

Dr. Steven Petak:

What about assay interference? What kind of things would be looking for?

Dr. Basma Abdulhadi:

So we sometimes see pseudo hypophosphatemia. Paraproteins and monoclonal gammopathies can interfere with the phosphate assays causing phosphate to falsely appear low. If the number doesn't make sense, you always have to ask the lab for dilution studies, deproteinization, or an alternative method of checking the phosphate levels. You would also need to correlate with clinical findings in other lab tests like alkaline phosphatase or tubular reabsorption of phosphate.

Dr. Laila Tabatabai:

And that's really critical. I want to emphasize we don't want to get fixated on a single lab value that contradicts the clinical picture. And back to what you said earlier, Steve, I think the take-home message really is check a phosphate. In these types of patients who are presenting with musculoskeletal complaints, I always tell my fellows, my trainees, if you're checking a vitamin D and you're checking a PTH, you must check a phosphate. Those labs, those metabolic bone labs, they go together, and it's really not a complete eval unless the phosphate is there.

Dr. Steven Petak:

So briefly, what about a differential diagnosis of Hypophosphatemia?

Dr. Laila Tabatabai:

So there's three sort of buckets when it comes to Hypophosphatemia. So we need to think about, first of all, redistribution. So that's when phosphate shifts inside of the cell, and that can happen in a few clinical scenarios, most commonly respiratory alkalosis, so hyperventilation. It can also happen in insulin treated patients, as well as those who have refeeding syndrome. So a lot of times those hospitalized patients will present with Hypophosphatemia.

And then hungry bone is a very common scenario as well. So patients with hyperparathyroidism who undergo parathyroidectomy, they will oftentimes have a post-surgical Hypophosphatemia presentation. And the next bucket to consider is decreased absorption. So again, going back to the malabsorptive patients, this would be celiac disease, inflammatory bowel disease, post-bariatric surgery.

And then we also have syndromes of vitamin D resistance, as well as vitamin D deficiency. Sometimes those patients will have Hypophosphatemia as well. And then phosphate binders. So remember your renal patients, end stage renal disease or advanced chronic kidney disease who are on binders such as sevelamer, calcium acetate, et cetera. And then excessive antiacid use. And then chronic alcoholism can also lead to decreased absorption.

And then the final thing to consider where most of our hereditary syndromes fall is the bucket for increased urinary losses. So this is phosphaturia, hyperphosphaturia, and that would be a renal phosphate wasting syndrome. So of course, we do have to consider our renal colleagues or nephrology colleagues will be looking for Fanconi syndrome and also proximal tubulopathies that can be caused by tenofovir, phosphamide, cisplatin, or heavy metals.

Post-transplant we can see tubular dysfunction. And then of course, hyperparathyroidism can cause increased renal phosphate loss. And then all of the FGF23-mediated syndrome. So we'll touch upon that a little bit later in this podcast. X-linked Hypophosphatemia, TIO or tumor-induced osteomalacia, and then the ADHR, ARHR subtypes. So we'll be getting into those a little bit later as well.

Dr. Basma Abdulhadi:

So the structure quickly narrows the differential diagnosis. If urinary phosphate excretion is high in the setting of low serum phosphate, then you're looking at renal wasting and FGF23-mediated causes rise to the top of the differential.

Dr. Steven Petak:

So what kind of an evaluation do you recommend for teaching our fellows and other physicians who are interested in this disorder who may encounter it?

Dr. Laila Tabatabai:

That's a fantastic question, Steve. I think it's really important also to recognize many endocrinologists, though they may be very familiar with osteoporosis, with hyperparathyroidism, Hypophosphatemia is not something that we commonly see. So I think it's great for everybody to be aware of this. And so we obviously start with a fasting serum phosphate level.

We also want to check a calcium, typically a full CMP. So that's going to include your calcium, your creatinine and estimated GFR, your alkaline phosphatase level, bicarbonate, and then of course, a 25-hydroxyvitamin D level, as well as a 125-dihydroxyvitamin D, and then the parathyroid hormone level, PTH. And then the renal handling, so the kidney handling of phosphate and assessing for hyperphosphaturia, we would want to check some additional urinary studies.

So a 24-hour urine phosphate collection can be done. Or in most cases, we'll want to get a spot urine to check for fractional excretion of phosphate or the tubular maximum reabsorption of phosphate. And so that TmP/GFR calculation is an important one to do. It's certainly not something I've memorized. I mean, I look this one up every time, but you would want to calculate that using the spot urine results as well as your serum labs.

And then a low TmP/GFR in the presence of Hypophosphatemia would be consistent with renal phosphate wasting. So that definitely helps narrow your differential.

Dr. Basma Abdulhadi:

Next, you would want to measure an FGF20 level. In the face of a low phosphate, FGF23 should be suppressed. So if it's normal or elevated, then that's inappropriately high and points to an FGF23-mediated disease.

Dr. Steven Petak:

So lab set the context, then you use your urine studies, and then FGF23 to define the mechanism. So FGF23, what exactly does it do?

Dr. Basma Abdulhadi:

So FGF23 decreases renal phosphate reabsorption by downregulating the sodium phosphate cotransporter in the proximal tubule. It also suppresses 1-alpha-hydroxylase, so lower is 1,25 vitamin D. With less active vitamin D, you also reduce intestinal phosphate absorption.

Dr. Steven Petak:

And what about FGF23-mediated disorders then as far as what the classic picture is for osteomalacia, Dr. Tabatabai?

Dr. Laila Tabatabai:

So the really classic picture for osteomalacia clinically would be a low serum phosphate, a low or inappropriately normal 1,25-dihydroxyvitamin D level, high alkaline phosphatase, and a low TmP/GFR. So that's the classic osteomalacia picture. And again, clinically you're going to see those symptoms of bone pain, possibly proximal muscle weakness, lots of pseudofractures or abnormalities on X-ray. So that complete picture starts to come together.

Dr. Steven Petak:

The practical pitfall that most physicians are not aware of, although hematologists are now beginning to become aware of it more, are the problems with certain iron infusions, particularly ferric carboxymaltose causing Hypophosphatemia.

Dr. Laila Tabatabai:

Yes, absolutely. This is definitely something that made it onto those rare clinical cases, case report type of thing, but now there's definitely a lot more awareness. It's still underrecognized. So in this case, what's happening is ferric carboxymaltose or FCM can cause marked Hypophosphatemia. And what it does is it's rapidly increasing intact FGF23. So intact FGF23 is what we measure and what the FCM is doing, the iron is inducing reduced cleavage of FGF23. So there's higher intact FGF23 levels with ferric carboxymaltose infusion.

So the risk of Hypophosphatemia is going to increase with repeated iron infusions, as well as low body weight, having a low phosphate at baseline, and vitamin D deficiency. So if you have a patient who is undergoing regular iron infusions, particularly with ferric carboxymaltose, very important to monitor their phosphate before dosing and one to two weeks after, especially if patients are reporting a lot of bone pain or weakness.

Dr. Steven Petak:

Doctor, what about XLH in particular?

Dr. Basma Abdulhadi:

So XLH is due to PHEX mutations. It's an X-linked dominant disease entity with variable expressivity. Clues include lifelong short stature, dental abscesses, family history of rickets, or leg deformities. Labs typically will show a low phosphate level, low tubular maximum reabsorption, normal calcium, high normal FGF23, and low or inappropriately normal active vitamin D. Genetic testing confirms the diagnosis and helps with family counseling.

Dr. Laila Tabatabai:

In terms of therapy, conventionally, we used to treat these patients with XLH with high doses of oral phosphate along with activated vitamin D, so calcitriol or alfacalcidol. The problem is those treatments had a very high pill burden. So rickets would improve, but it came at a cost. There was also the risk of secondary hyperparathyroidism and hypercalciuria and eventually nephrocalcinosis.

So long-term usage of oral phos and activated vitamin D requires really careful monitoring. And really, I think especially because there's an alternative that's extremely effective now available, the usage of oral phosphate and activated vitamin D, it is decreasing, I think. It's, as I mentioned, very, very high pill burden for patients, and that can be especially problematic for children, active adolescents, and adults.

So now, fortunately, we have burosumab. So burosumab is an anti-FGF23 monoclonal antibody. And what this does is it directly reduces FGF23 levels in the body and thereby essentially reverses and provides a biochemical cure, if you will, for the XLH process. So burosumab is a first-line treatment for children over the age of six months who have XLH. And it's also indicated for adults with symptomatic osteomalacia, pseudofractures, or significant pain and functional limitation.

So definitely an indication for usage of burosumab across the age spectrum. Really important to recognize that we don't stop treating XLH when growth plates are closed. Very, very important to keep treating XLH across the lifespan, so in adolescents and in adults as well. And burosumab will raise the serum phosphate and normalize the levels. In the vast majority of patients, it will improve the healing of rickets in children and promotes fracture and pseudofracture healing in adults, and it reduces pain.

So it's had really excellent outcomes that have been seen in the clinical trials. Now, it's very important to recognize that burosumab should not be combined with conventional phosphate or calcitriol therapy. And of course, there are serious side effects to monitor for, and it should be used under the care of a specialist.

Dr. Steven Petak:

And we don't want to forget dental and orthopedic co-management. This is a multidisciplinary disorder and we want to coordinate this care. So next, what about the differential among FGF23-mediated causes? There's some very rare disorders that we probably will not encounter typically, but we should at least know about them.

Dr. Basma Abdulhadi:

Yes, that is correct, Steve. So we have autosomal dominant hypophosphatemic rickets and we have autosomal recessive types. So in autosomal dominant hypophosphatemic rickets, we have FGF23 mutations that are resistant to cleavage. It typically can present in childhood or in adulthood, and it often worsens with iron deficiency. With the autosomal recessive hypophosphatemic rickets, it could be due to DMP1 variants or ENPP1 variants where we also have elevated FGF23 levels. Clinical patterns can hint at the subtype, but this is where genetic testing will clarify the diagnosis.

Dr. Steven Petak:

Then of course, we want to make sure we focus also on the differential that includes tumor-induced osteomalacia. How do you evaluate and localize these types of rare tumors?

Dr. Basma Abdulhadi:

So with tumor-induced osteomalacia, we have to start with the biochemical pattern. So typically we'll have low phosphate, low tubular maximum reabsorption of phosphate, inappropriately high normal FGF23, low or normal 1,25-dihydroxyvitamin D, and elevated alkaline phosphatase. If the labs fit, that's when we move to imaging. The first imaging mortality we can use is a cross-sectional imaging, so MRI or CT scan.

We typically will scan extremities, head and neck and the pelvis. We can also use functional imaging. So a DOTATATE PET scan is highly sensitive for these mesenchymal tumors. An FDG PET can also be helpful, but is less specific. Now, if the imaging is negative, we can consider repeat scanning. We can scan the patient from head to toe using an MRI, or we can use select venous sampling for.

Dr. Laila Tabatabai:

And when possible, the cure for TIO is always going to be surgical resection. So that's why identifying that tumor, as Basma said, is so critical. And it's a really curative surgery. So phosphate will normalize within days of surgical resection and symptoms will improve as osteomalacia heals.

Dr. Basma Abdulhadi:

Some of these tumors are unresectable or occult. So in that case, we can use burosumab, which is approved in many regions for tumor-induced osteomalacia. We can also use conventional phosphate plus calcitriol. Octreotide can also be used if the tumor is somatostatin receptor positive. Radiation or ablation can also be considered in some cases.

Dr. Steven Petak:

The key takeaway, of course, is don't stop at the low phosphate. You need to identify the mechanism so you can treat the cause. What about a checklist for clinicians as to how to proceed with this in summary?

Dr. Laila Tabatabai:

Yeah, absolutely. So hopefully, first and foremost, we're going to order a phosphate. So very, very important to remember, it's not on your typical panels unless there's some specialized lab testing by a nephrologist, for example. There may be a phosphate included there. But otherwise for the rest of us, we need to order a phosphate anytime we're evaluating patients who might be presenting with proximal muscle weakness, atypical fractures, rickets.

And also remember, after ferric carboxymaltose or IV iron infusions, we definitely want to order that phosphate level. And then if it's low, go ahead and proceed with a basic workup. So the alkaline phosphatase level, 25 and 1,25-dihydroxyvitamin D levels, PTH, calcium, and creatinine. And then it's important to calculate a TmP/GFR or do a fractional excretion of phosphate from a 24-hour urine to determine whether there's renal wasting of phosphate occurring.

And then if that wasting is present, absolutely you'd want to measure an FGF23 level. So intact FGF23 is available now on commercial lab assays, and that will help determine whether it's an FGF23-mediated Hypophosphatemia. And in the case that it is a suspected FGF23-mediated process, hopefully the family history and age at presentation will help guide you as to whether it could be XLH.

Many cases are spontaneous and actually are not detected or found via family history. But also if it appears that it could be a very recent onset or something suggestive of a rapid process, we should suspect and evaluate for tumor-induced osteomalacia. And in that case, as Basma mentioned, we would want to proceed with functional imaging, including a gallium DOTATATE PET scan when available because that type of test is highly sensitive for isolating these tumors.

Dr. Basma Abdulhadi:

And in XLH FGF23-mediated disease, consider using burosumab when indicated. If you're using conventional therapy, then monitor for PTH elevation, hypercalciuria, and nephrocalcinosis.

Dr. Steven Petak:

Well, this has been terrific. Hypophosphatemia is often underrecognized, but the downstream consequences such as osteomalacia, fractures, and functional decline can be substantial. To our listeners, a single most important, actionable message today is to check a phosphate. It's not on the typical chem panel, so you have to order it when the story fits. Laila and Basma, thank you so much for sharing your expertise and a special thanks to Kyowa Kirin for supporting this discussion. If you found this helpful, please follow the AACE Podcast and share this with your colleagues. Until next time.

Speaker 1:

Thanks for listening to another great AACE podcast. Join us for another episode at aace.com/podcasts and help us in our mission to elevate clinical endocrinology. Together we are AACE.