Hi, I'm Steve Harris from San Francisco, and it's my pleasure today to introduce Dr. Michael Collins. Dr. Collins is a Senior Investigator-in-Chief of the Skeletal Disorders and Mineral Homeostasis Section at the National Institute of Dental and Craniofacial Research at the National Institutes of Health in Bethesda, Maryland. He's a physician scientist trained in endocrinology and metabolism, whose research is broadly focused on the roles of PTH and FGF-23 in bone biology and mineral homeostasis. His primary approach to defining this biology is through translational and clinical studies in rare monogenic disorders of bone and mineral metabolism. Those include fibrous dysplasia, McEwen-Albright syndrome, hypopara, disorders of FGF-23 excess and deficiency, such as X-linked hypophosphatemic rickets, tumor-induced osteomalacia, and familial tumoral calcinosis. Through detailed studies, Dr. Collins has made incredible contributions to this field. I'm very much looking forward to his presentation. Good afternoon, everyone. My name is Michael Collins. I'm the Chief of the Section on Skeletal Disorders and Mineral Homeostasis at the National Institutes of Health. And I'm here today at the 2021 ACE meeting to talk to you about rare bone diseases you should never miss, in other words, when it's not just osteoporosis. I thought, though, that I'd first start with a case. This is a woman who was referred to us just a few weeks ago, and you can tell straight away since I'm calling her the pro-band that this ends up being a genetic case. But anyway, it was a typical 54-year-old woman referred for non-healing fractures and quote-unquote osteoporosis. Her DEXA scan readings were really unimpressive. The AP spine and femoral neck T-scores were minus 1.1 and minus 0.8. She did have a history, though, of dental issues. She had had multiple tooth extractions and several tooth abscesses. So this is suggestive of a deeper, more problematic skeletal disorder than just osteoporosis. She also had the intriguing history of premature hair graying starting at age 16. She had a medical history of upper and lower esophageal strictures that had started at a young age, 40, that both required dilatation. Family history was super interesting. So her mother also had had numerous fractures starting at the age of 47. She too had premature graying starting at 16 years of age. This woman had four children. Her 38-year-old son had had bilateral osteosarcomas, the first diagnosed at 22, the second at 30 years old. He too also had multiple fragility fractures and premature graying, again, starting at age 16. She has a 36-year-old son. He had had a few fragility fractures starting at around the age of 30, 32-year-old daughter with no significant history, and she had one son who had died at the age of 20 due to an osteosarcoma in the left leg that had been diagnosed at the age of 19. And before that, he had experienced bilateral femur fractures. So it's pretty striking that this woman had gone through the medical system for quite a bit of time with, quote-unquote, osteoporosis and these fractures, not referred to us until she had difficulty healing, so a non-healing fracture. When she had a medical history like this, there was clearly something going on and more needed to be done. We got plain x-rays on her, which we normally do, and I think are very often quite useful in patients like this whose case just doesn't really add up. And you can see in the left panel that I'll show you here that the bone, the cortical and the medullary part of the bone, there was really a significant amount of sclerosis. This was really quite evident in the femur shown here, and here's the rod in the femur for the fracture that she had had earlier. And so there's thickening of the cortices, there's sclerosis of the medullary space. Over here on the pelvis, she had this extra area of calcification, she had these really interesting punctate areas of sclerosis in the distal femurs here. I'm just realizing I say blue arrows here, but somehow my PowerPoint converted these to, I guess, what are orange arrows. And in addition, she had this very impressive emphysopathy on the plantar surface of the foot. So we'll come back to this fascinating patient and her family later, but I just wanted to go through first the causes of osteoporosis, because we're looking for stuff that's not osteoporosis, right? Okay. So this is a paper, this is from 2002, so quite a long time ago, but I think it's a really good paper. And this was a relatively large group of patients that were seen in a quote-unquote osteoporosis clinic. And what they did in this paper is they broke down the number of diagnoses, the percent of diagnoses they were able to make by just doing a history with a little bit of screening, etc. So right away, by just taking a good thorough medical history, they were able to identify about the likely cause, not always necessarily the case, but the likely cause of bone fragility in these patients by the medical history. So 36% of the patients had significant oral glucocorticoid treatment, 21% had premature ovarian failure, malnutrition, alcoholism, liver disease, etc., etc. You can see the various numbers there. Now keep in mind, this was an osteoporosis clinic, almost all of the patients here were postmenopausal women. But keep in mind, up to 30% of men with osteoporosis are hypogonadal. So for men, you need to take that history as well, a very detailed sexual history looking for evidence of hypogonadism. So then in this group of patients, the remaining 50% of patients in whom they didn't get an idea of the diagnosis based on the history, they did some laboratory testing. And now they were able to diagnose about 50% of the remaining patients. So 10% had hypercalciuria, which was probably contributing to the bone fragility these patients had, significant with malabsorption, hyperparathyroidism, vitamin D deficiency with the cutoff being a vitamin D level of less than 20, exogenous hyperthyroidism. So again, 49% of the patients, about another 50% of those patients, they were able to make the diagnosis on this fairly minimal laboratory testing. And so the laboratory testing for these underlying causes, well, first of all, review of medications, assessment of gonadal status, check the glomerular filtration rate, liver function tests, glucose, thyroid function tests, pretty straightforward. Now though, calcium, PTH, 25D, and in some cases, consider 125D, we'll maybe get to that later because you can think about malabsorption with vitamin D as well. If 24-hour urine for calcium. So I always do this in this group of patients, a 24-hour urine collection with calcium. It's a pain in the neck, I know that it often gets screwed up, but I think it's important because you saw 10% of these patients had hypercalciuria, which was possibly likely a contributor to their bone fragility. And then finally, if you suspect that they could have Cushing's disease, 24-hour urine for urinary-free cortisol, very, very, very important is always check the serum phosphorus in these challenging bone fragility patients. And I always get these, I get baseline bone turnover markers because they may be important either in the diagnosis or when you start treating them later. So by this relatively simple algorithm so far, we arrive down to about 25% of the patients that we're really going to call idiopathic or other causes of bone fragility fractures. And this isn't for screening, remember, these are the group of patients who are referred to you, the endocrinologist, because they have fractures, they have bone fragility, like the patient I talked about in the beginning. So what are the other causes of bone fragility? And as you can imagine, the list is quite long. I don't expect you, of course, to read these on the left, but I've given you the references of several papers that address this, and these are for different reasons. This is a relatively recent one, I think this is a really good paper. I like this one as well because of the way they break it down. Endocrine and metabolic diseases, most of which we've talked about. Genetic diseases, these are just a few, these are connective tissue disorders, and again, you'll pick up this sort of thing on physical examination, evidence of Ehlers-Danlos syndrome or Marfan syndrome. And chronic diseases, you'll get that by the history. Anyway, I like the way this was broken down. One of the best recent articles for this is Mike Lewicki's paper here in Indotex from 2015. So these are good references that give you the other causes of osteoporosis. And this is really important because I think when we go through this and get to the bottom of it, by the end of that, we will have diagnosed up to 80% of these patients or more, and there's really only a few percent, 5%, maybe 10% of patients at the end of the day that we can't figure out. And that's the proband that we talked about in the beginning. All right, so obviously I'm not going to be able to go through all of these things here, but I wanted to go through a few of them, and I selected them for specific reasons. One, because they're either common, and I think they're things that we often miss, like osteogenesis imperfecta, for example, but also diseases, conditions for which there are especially new medications that offer us an option for treatment, and we'll see which ones those are. So I'll start first with the osteomalasic disorders. So by definition, osteomalasia is not osteoporosis. Technically, the only way you can diagnose osteomalasia is a tissue diagnosis. You need to do a bone biopsy. But the fact is, is that most of these osteomalasic disorders, we can figure out from the history and the laboratory findings. So first off, though, you can get osteomalasic disorders from either low calcium or low phosphate. Because, in fact, the skeleton is really a crystal of calcium hydroxyapatite, calcium and phosphate. But anyway, the first bullet here, calciopenic ones. So I won't go into those, because these are the ones that we already will have picked up. We will have picked this up on the history and physical, where we get at malabsorption. We'll have picked this up on the laboratory, where we check vitamin D. So I wanted to start with these, the phosphopenic ones, and again, this really emphasizes the point of check the blood phosphate. So many of these patients who finally come to the attention by the endocrinologist and have gone through the hands of many doctors, they just never check the blood phosphate. As most of you probably know, phosphate used to be on a standard panel of blood tests. The CHEM-20 no longer is. So you have to check that box. You have to look at the blood phosphate. Just to orient us, though, I wanted to remind us of how phosphate is regulated. Because this is a relatively new finding within the area of endocrinology, and it's something that we as endocrinologists should know about, and it is something that for those who are taking the boards or retaking the boards, it'll definitely be on the boards. And this is FGF23. So FGF23, I like to think of as really the master regulate of phosphate homeostasis. So FGF23 is a hormone. It's made by bone cells. It circulates in the blood, acts at the kidney, and at the kidney it does two things. It regulates phosphate reabsorption by sodium phosphate co-transporter, and it regulates the formation of 125D, active vitamin D from vitamin D. And the action of FGF23 is to decrease phosphate reabsorption, to decrease 1-alpha hydroxylase. So if you have excess FGF23, you're going to have low blood phosphate and low 125D, and these act back at the bone in a classic endocrine loop. Okay. Let me first, though, talk about the acquired disorders of hypophosphatemia. And the major ones are shown here. So one is tumor-induced osteomalacia. So what is tumor-induced osteomalacia? These are little, teeny, benign, small, mesenchymal tumors that secrete FGF23. These patients show up with low blood phosphate, low 125D, and high FGF23. I'll make a brief comment about FGF23 levels now. So the measurement of FGF23 is widely available. There is some caveats with the assays, though. So most of the places at which you can order FGF23 give the results in what they call the C-terminal FGF23, which, in fact, is a mixture of full-length FGF23 and the C-terminal FGF23. It's a good assay. It picks up almost all the cases. But remember, you can have an FGF23 level that's in the normal range with a patient that's hypophosphatemic, and that high normal FGF23 is the cause of the hypophosphatemia. If a patient is hypophosphatemic, their FGF23 level should be low. So even a high normal FGF23 is inappropriate in the setting of hypophosphatemia. We'll go into this a little bit, but the diagnosis of tumor-induced osteomalacia. The best widely available study for this is a gallium-68 PET-CT scan. This is the best single study. If you don't have that, but you have Octreoscan, you can do an Octreoscan. If you don't have either of these, an FDG PET is pretty good too. Now, you can, of course, have osteomalacia disorders caused by calcium and vitamin D, and we talked about this. These are really the calcipenic ones. Now, this is interesting as well. This is a pretty rare thing, but you can see this. This actually causes a form of osteomalacia as well. These are patients with weird diets, where they have places where there's high fluoride in the levels. It's not very common. Some of the inexpensive instant teas have high levels of fluoride. There are these patients who are habitual tea drinkers, who will drink gallons of tea a day, and they can have atypical fractures. In these patients, you'll get this from the history, and you can check fluoride levels. What are the drug-induced causes of this? Certain chemotherapies can do this. This is damage to the proximal tubules that causes phosphate wasting. The biggest one for these is isospamide, which is more common in children. Heavy metals can also do this, cadmium, strontium, lead. These are patients who have high levels of exposure to those, either in places where they're high in the water, well water, or where they work in places where they're exposed to high levels of heavy metals as well. I wanted to point this one out as well, because this is really a fairly significant cause of osteomalacia. This is tenofovir. Tenofovir is either a single medication given for hepatitis, or it's part of the medication PrEP that's used for HIV prophylaxis. This is not, I don't think, widely enough appreciated. Tenofovir can cause a tubular phosphate wasting by damage to the tubules in about 15% of the patients. The manufacturer recommends that you get a dexascam. This is really a poor way to pick up osteomalacia, so checking blood phosphate and checking the tubular reabsorption of phosphate, which there are apps that do that, or you can find websites that will tell you how to do that. If your patient's on tenofovir, be aware of the fact that this can be a cause of bone fragility, hypophosphatemia. What about the genetic causes of osteomalacia? The most common is X-linked hypophosphatemia, the genes are shown here. These patients almost always present in childhood, but you can have patients that present in adulthood. They'll often have a history of enamel hypoplasia, having tooth abscesses, and a lot of dental problems, and will be, and the ones who hold out to adulthood to be diagnosed, they don't so much have the bowing, but they are short, so they're shorter than their parents. I think it's always important when you're seeing patients like this to make sure that you know the parent's height. Autosomal-dominant hypophosphatemia crickets. These patients also can present in adulthood, not so common, so be aware of this. Autosomal recessive, usually present in childhood, but also can be present in adulthood as well, because they have a variable course. The final common pathway for all of these patients is that they have an elevated serum FGF23. Assays are available. Remember, a high normal range FGF23 in the setting of hypophosphatemia is abnormal. I'll mention this here, but we'll talk about it more later, is that hypophosphatasia is also an osteomalasic disorder. It's caused by low serum levels of alkaline phosphatase, but we'll talk more about that later. We're going to first, though, go through the evaluation of hypophosphatemia, and that's shown here. So, patient walks in, low blood phosphate. Remember to check the age appropriate normally for normal levels if it's a young person. Blood phosphate levels are higher in children and young adults. Confirm that, in fact, it's renal loss, so this is by calculating the tubular reabsorption of phosphate, or the tubular maximum reabsorption of phosphate for GFR. There are apps that do this, MedCalc will do this, or there are websites where you can type in calculation, TMPGFR, TRP, and you can enter the numbers and do that. Then the question becomes, is this cause of hypophosphatemia because of a primary renal defects or the renal tubules broken, or is this hormonal? So therefore, you check plasma FGF23. If the plasma FGF23 is low, then that's a problem with the tubules. So sort of Fanconi-type tubulopathy. These patients, in addition to having low blood phosphate, will have amino acid urea, protein urea, bicarbonate urea with acidosis, and calciurea. So look for this if a patient is hypophosphatemic, low FGF23, genetic causes of Fanconi syndrome. Then there are the acquired ones. We talked about these, so toxins, lead, cadmium, et cetera, drugs, tenofovir, chemotherapy, they can do it. All right. So you check the FGF23 and the level's high. The genetic causes that we just talked about, you should think of, and then the acquired causes of tumor-induced ostimulation. What I didn't mention before, but I'll mention now, is that some patients with metastatic cancer can also have FGF23-mediated hypophosphatemia. This however, it's not a tricky diagnosis. This is almost always quite advanced metastatic cancer. Prostate cancer is the most famous for doing this, but you can see it in other cancers as well. So these are patients with really advanced cancer, potentially nearing terminal cancer, who by the way, in addition to their cancer, happen to have hypophosphatemia and a high FGF23. Not that we shouldn't treat them, because as the cancer therapies get better, these patients' life expectancy is better. Treatment for these will be the same, and we'll go over that now. So treatment for hypophosphatemia, well, if it's a case of tumor-induced ostimulation, the treatment is surgery, and this is curative. Again, you do an imaging study like a Gallium 68 scan, you find the tumor, you cut it out. This is very, very important. In the surgical excision of these tumors, it has to be wide margins. These look to be little teeny tumors, but if you leave anything behind, it's going to recur. If the tumor is in bone, and about 50% of them are, it's really important that you not do a simple curatage to get out what you think is enough. You really need to do an on-block resection. So sometimes these orthopedic surgeries can be quite extensive, but you have to get wide margins with those tumors to cure these patients, because they will recur, and the recurrence is a mess, and it will sometimes ultimately kill them. Now, for years and years, the traditional medical therapy that we gave was phosphate and calcitriol. It's a pain-in-the-neck treatment. You have to give the phosphate three to five times a day. If you don't, it's not effective. You have to give calcitriol, because their 125D levels are low, and when you give phosphate, you induce secondary hyperparathyroidism. So you add calcitriol, you titrate it to normalize parathyroid hormone, but in so doing, you can oftentimes induce in these patients hypercalciuria, so you have to watch that as well. So you get the impression this is really a difficult treatment. Calcitriol, by lowering PTH, can raise blood phosphate, so sometimes sinicalcet is used as an adjunct therapy to the traditional standard care medical therapy. But the new treatment that was recently just approved for X-linked hypophosphatemia in tumor-induced osteomalacia is borosumab, Crisvita. It's approved for adults with XLH, also approved for TIO as well. It's an expensive drug, 200K per year, but the company has done a great job of making sure that just about everybody who needs this drug can get it. They work with the insurance companies. They have a program. It's a great drug, very effective. It turns this nightmare therapy of phosphate and calcitriol into a once- or twice-a-month injection, and it works great. Okay, I wanted to come back now to hypophosphatasia, which I mentioned earlier. So hypophosphatasia, these are patients with low alkaline phosphatase. So again, most of these patients present in childhood, and there's a wide spectrum of this disease. So the worst of these is lethal. These kids have practically no bone, and they can die shortly after birth. I'll skip ahead and come back to the rest of it in a minute. So there is a drug, STRINZIC, asphatase alpha, which is enzyme replacement therapy for hypophosphatasia. This saves the lives of these patients. This is really a triumph of modern bone therapy. These kids routinely died with the bad forms of this, and this drug saves their life, and they walk, and it works great. But that's not who's going to come and see most endocrinologists. Most of these will be the patients that present in adulthood. And how do you find these patients? Well, first of all, they'll have a low alkaline phosphatase level. But as you and I often know, patients who present with fractures to present to their primary care doctor or their OBGYN, they straightaway get put on antiresorptive therapy with bisphosphonate. So a lot of times we miss this, because this is a patient who has been treated with bisphosphonate. Alkaline phosphatase level is low, so we, oh, it's low alk-phos, you know, that's from the bisphosphonate they got. So patients untreated have low levels of alkaline phosphatase. The other thing that can tip you off to these patients is they have a very unusual dental problem in childhood. And again, this really stresses the importance of a good dental history in these patients, because the teeth are really sort of a specialized bone, and for these systemic disorders that affect bone, they also affect the teeth as well. So these patients have a history of early tooth loss. First kid in their class to lose their teeth, and the tooth often falls out root and all. So they lose the entire tooth in childhood, root and all. Now, you know, most adults don't have a clear history of what their tooth loss was like. And if you're a little kid and your tooth falls out and the root's there, you think, well, that's everybody's teeth fall out that way. So sometimes you have to dig for this history. You have to maybe ask the parents or ask the patient, ask the parent, and say, oh, yeah, your tooth were weird. They fell out root and all. Anyway, the other thing, and this is more common for adults with hypophosphatasia. One of their most common presentations is with metatarsal fractures. Well, you know, metatarsal fractures are common. So most, the vast majority of metatarsal fractures are not hypophosphatasia. However, you have a patient presents with a metatarsal fracture. They have this unusual low alkaline phosphatase level. Think about hypophosphatasia and do the work up for that. One of the most inexpensive and revealing tests for the diagnosis of hypophosphatasia is to measure a B6 level. Because this enzyme, alkaline phosphatase, T-N-S-L-A-P, is involved also in, it's a phosphatase for vitamin B6 as well. So these patients have high levels of B6. Anyways, how does this work? Pyrophosphate is a mineralization inhibitor, and this circulates in micromolar concentrations in our blood. It's a really, really important blood product in all of us. This pyrophosphate is what keeps you and I from calcifying our vessels, what keeps us from calcifying our muscles after trauma. So it's really important. What happens is you have pyrophosphate circulating in the blood, but you want to keep pyrophosphate away from the bone because you want the bone to mineralize. So bone cells produce alkaline phosphatase. They break down pyrophosphate and they allow mineralization to proceed. So if you have low levels of alkaline phosphatase, you have low levels of pyrophosphate breakdown, high levels of pyrophosphate, you inhibit mineralization, and you get osteomalacia. So again, remember, a lot of these patients get treated with antiresorptives. Antiresorptives in fact make this worse. So giving these patients an antiresorptive medication like bisphosphonate or denosinone is a bad thing. You don't want to do this. Now, this is the drug I talked about. At this point in time, it's only approved for these more severe forms. But there are adults that will benefit from this. So this is a really expensive drug. This is up to $200,000 per month. So that can be over a million dollars a year at the highest doses. So are there adults that should be treated with this? Probably. Should every adult be treated with this? Probably not. But anyway, you don't want to miss hypophosphatase. It's an important diagnosis. You can make it worse by giving the wrong medication. All right. So that was a recent disease, the etiology of which was recently revealed to us. So this now is an old bone disease, and this is Paget's disease. Sir James Paget, these are his drawings of what a patient with Paget's disease looked like. The hallmarks of this are bone deformity, skull enlargement, their hat no longer fits, and they have pain and fractures. So what causes Paget's disease? Well, there's still a debate about this. So there was this big breakthrough a number of years ago where they saw that there were viral inclusion particles in these Pagetic bones. And in fact, the prevalence of Paget's disease has gone down with some of the immunizations for some of the viruses that were associated with it. So clearly, there is a viral component to that. But the other new thing is that it's also been made clear that there's a number of forms of Paget's disease that are associated with mutations, mostly in the rank-rank-login pathway, which is the pathway that's targeted by denosumab. Most of these patients, again, will present in childhood, but there are patients who can present in adulthood with this. And if you have a patient with severe Paget's disease, it's probably worth checking for these mutations. We'll go into genetic testing a little bit towards the end. What does Paget's look like? This is what an X-ray in Paget's look like. And again, I just want to emphasize, I think it's really important to get X-rays on these patients. I always get skeletal surveys on this group of patients who are towards the end of that algorithm where you're not sure what's going on. These patients, in contrast to the hypophosphatasia patients, have high alkaline phosphatase. They have pain, deformity. These are hypervascular lesions. When you put your hand over the bone, it's warm, and they can even have sweating over that bone. Now, the sort of late complications of severe Paget's disease, probably for those patients who aren't treated, they can get compression of cranial nerves, so they can get deafness, they can get other cranial nerves compressed, they can get spinal stenosis, and they can get fractures. So where do they get this and what happens? So really, it can occur almost in any part of the skeleton. It doesn't affect the entire skeleton. It is a mosaic condition. And so most common sites are sacrum, spine, femur, pelvis, skull. So it can be anywhere. These light up on bone scan. Bone scans are quite useful for diagnosis, and you get pain, deformity, fractures. Arthritis is quite common, and I'll come to this in a minute. A small portion of these can transform into cancer, and some can have hearing loss, as they talked about. And this is what it looks like. So if you're taking the boards or retaking the boards, and they show you a micrograph that looks like this, and a really massive giant cell with dozens and dozens of nuclei in it, this is Paget's disease. You get these giant, giant, giant cells, giant osteoclasts, you get fibrosis, and they get a particular type of fracture, which is called a chalk stick fracture. So it's like if you break a piece of chalk. Okay. What are the indications for treatment? So bone pain. Some people say that if you can turn down the disease activity prior to an orthopedic surgery, that's a good thing. Fracture is obviously an indication. A patient with Paget's disease, where the bone turnover is really revved up, and they get put to bed rest for whatever reason, surgery or some other thing like that, they can get hypercalcemic and hypercalciuric. So that's an indication of treatment. Orthopedic deficit, cranial nerve deficit, indication of treatment. If you had really widespread Paget's disease, you could even get a high output heart failure, congestive heart failure. I've never seen a case of that, in fact, I've never known anyone who's seen a case of that, but it's in the books, it's on the list, could be on the boards, that sort of thing. And then, of course, you would treat them if you want to prevent fracture, future complications. So treatment for Paget's is actually pretty easy. It's bisphosphonates, and zoledronic acid works really great. A single infusion can last for up to five years. So the way it's done, or if you can't get zoledronic acid, you need to give an oral bisphosphonate, that works also not quite as well. Anyway, you give zoledronic acid, the alkaline phosphatase almost always comes down with a single infusion, and then you just wait for the alkphos to come back up. Now one thing to think about, I told you that Paget's gives you bone disease, that's true. You get an intrinsic bone disease in patients with Paget's that's almost always relieved with bisphosphonate treatment. So in an older patient with Paget's, let's say their alkphos is high, they have bone pain, you treat them, the alkaline phosphatase goes down to normal, but they still have pain. Think about osteoarthritis. These patients often will develop secondary osteoarthritis because of malalignment of the bone. So you can give alkaline phosphatase till the cows come home, you're not going to treat that osteoarthritis. So you need to treat that osteoarthritis as you would treat osteoarthritis. So this is something to remember in the older Paget's patients, osteoarthritis is common. Okay, this is one that you won't see so often in adults, again usually presents in childhood, but you know these patients who are treated as children, followed by children, do come to us in the adult clinics, so we do need to know about this and know how to treat these patients. These patients present with pain, fracture, and deformity. Fibrous dysplasia, like Paget's disease, is a mosaic disease, so you can see this patient's left leg, left tibia, left side of the body is affected, right side is spared. On x-ray it often has what's typically called a ground glass appearance, so if the radiologist uses that term ground glass, suspect that they're talking about fibrous dysplasia. Again this diagnosis is usually already made for you, but sometimes you'll need to make this diagnosis in the adult patient. Patchy intense uptake on bone skin, and different than Paget's disease, there's rarely neurologic sequelae. The thing to remember about fibrous dysplasia is that it can be part of the McKeown-Albright syndrome, and so these sorts of cafe au lait marks that sort of respect the midline have these jagged borders. This is really a classic birthmark for a patient with McKeown-Albright syndrome. We know the cause of this, it's a mutation in GNAS. You're not going to find this on a blood test though, because this is a mosaic disorder, so you have to do the genetic testing on affected material, and there are places in the country that will do that. The other thing to remember about this is these patients can have a number of other issues as part of the McKeown-Albright syndrome. They can have hyperthyroidism, they can have hypophosphatemia, they can have growth hormone excess. All of those make the fibrous dysplasia worse, so you have to think for those, you have to screen for those, and treat those. They can really be a whole endocrine textbook in a single patient. They're really fascinating, fun patients to take care of. They too can get hypophosphatemia. Again it's FGF-23 mediated, and again the treatment for all these FGF-23 mediated diseases is the same. Standard therapy, as I told you about, barosumab is the better drug. It's not approved, it's not an approved treatment for this indication. But often you can get the insurance companies to pay for this. The bisphosphonates are very effective at relieving pain in these patients, so think about using bisphosphonates. They however don't change the natural history of the disorder. So what about denosumab? Well denosumab is effective, usually, but you have to be careful. These patients have really high bone turnover disorder, and so patients, the higher the bone turnover, the more the risks of treating these patients with denosumab. So high bone turnover, you start treating them, they can develop hypophosphatemia and hypocalcemia, and these can be quite striking. But the biggest thing about denosumab and treating high bone turnover disorders like fibrous dysplasia is the rebound that can happen with discontinuation. These patients can develop threatening profound hypercalcemia with either discontinuation or even if they're missing doses. So I would not recommend denosumab in treating these patients you really have to follow them closely, you really have to have some experience. The bisphosphonates work fine in most patients and that's what I would use typically speaking. Okay, this is a diagnosis that I think we adult endocrinologists miss a fair amount and that's osteogenesis imperfecta. We don't miss these the type 3, type 4, type 5. These are the ones who show up in childhood and are in a wheelchair from an early age and are cared for typically by geneticists but the ones that we do miss are type 1 OI and this can be subtle. They can present in adulthood, usually young adulthood. They often have a family history of fractures. These patients again the dental history have multiple dental periods and they often get scoliosis as you can see in this patient here. If you're lucky you'll be able to make the diagnosis on the blue sclera. That happens quite commonly and also it's the case that for example if you have a young adult who's seeing you in the clinic and you really do a thorough history of the parents you'll see that they also had a lot of fractures. A lot of times these patients the parents will just write these fractures off as oh well that's what happens to all active kids but no not all active kids get 10 fractures. Anyway it's a molecular diagnosis. These are quite easy to do now. Now in these adults with type 1 OI if they have fractures yes I would treat them. I'd treat them with bisphosphonates. I think they work. They seem to work. There are trials with parathyroid hormone with dinosumab and other medications as well. These are ongoing. We don't know about these yet but in a type 1 patient who's having fractures I would treat them with bisphosphonates. And again think about the dental history and the dental examination to make the diagnosis. Okay we're coming down to the end here and so you never want to miss a fracture as caused by a cancer. So multiple myeloma your SPEP, UPEP. Think about hematologic malignancies often presented with hypercalcemia. You can get fractures as cause of infection so these are usually pretty sick patients with tuberculosis etc. There is this rare condition where you have something on the bone that looks like osteomyelitis but it's sterile. This is chronic recurrent multifocal osteomyelitis. It's an auto-inflammatory disease. You think about this refer them to a rheumatologist. Peripheral neuropathies can cause this as well. I just wanted to quickly go through skeletal dysplasias. They're not really so much for us but it is at least important to know about them. There are hundreds of these skeletal dysplasias and so a general approach to them is good. History and physical, skeletal survey again, bone scan sometimes. And so it's important to be able to describe the location of the lesions in the skeleton and the bone and to describe the characteristics of the lesion. Are they hot or cold on bone scan? And sometimes you need to do a biopsy with these. So we often describe the skeletal dysplasia as affecting the craniofacial skeleton or the axial skeleton or the appendicular skeleton. And then we further characterize it as to which part of the bone that it evolves. Is this a metaphyseal dysplasia, a diaphyseal, an epiphyseal skeletal dysplasia? It helps to figure it out although probably most of these patients in clinical practice you'll refer to geneticists. This was a patient that we saw as a normal volunteer in the study and complained of bone pain. They got an x-ray and he had this weird x-ray here. We didn't know what it was. We ultimately figured it out. This was an autosomal dominant skeletal dysplasia, painful late onset sclerotic diaphyseal lesions hot on bone scan. So this was ribbings diaphyseal dysplasia. Okay so now we've gone through all of our work and we come down to this few patients who we still can't diagnose. And this is really where you get the skeletal survey. It'd be great if you have a skeletal radiologist. They're sometimes hard to find. If you find a skeletal radiologist somewhere make sure that that person reads these x-rays. A lot of help are skeletal dysplasia geneticists. So geneticists who specialize in skeletal dysplasias. And then of course nowadays the big thing is you can do genetic testing. This one right here is my favorite genetic testing place right now. Connective tissue gene testing, CTGT. They do a great panel. You can test dozens of these metabolic and genetic disorders in a single test. Baylor, GeneDx, Carlos Ferreira, my colleague here at the NIH, is an excellent skeletal dysplasia person. He's always looking for new cases, undiagnosis of skeletal dysplasias. And there are dozens of them that remain to be diagnosed. Let me return now to our patient, our program. This is a case. So we try to think about this case. Remember this woman had esophageal strictures, sclerotic appearing bone lesions, bone fragility, and early graying. Dyskeratosis congenitum is associated with it. And this is a telomere mutation. But osteosarcomas aren't known to be part of that. There's a whole slew of telomeric genes that are involved with skeletal dysplasias and other neoplasias. So it's a long list. Familial osteosarcomas, Leigh-Fraumeni syndrome, p53 mutation. So this is another possibility. These have abnormal bone and osteosarcomas, diaphysial medullary stenosis, and malignant fibrosis histiocytoma due to MTAP mutation. So I should have told you in the beginning, I don't know what the diagnosis is in this late in her family, but we have it cooking. So we got two affected people and an unaffected sister, so triad as it's known. And now we're doing whole exome sequencing on the proband and the affected and unaffected children. Actually, I had hoped to have the results back by the time of this recording, but unfortunately, I don't. But nonetheless, I think this is really an illustrative case of how to approach these patients. So thank you for your attention. And I hope that you will not miss any of these cases that come to you, referred to as osteoporosis that aren't osteoporosis. Feel free to contact me anytime if you have difficult cases. We love difficult cases at the NIH. Thank you very much. And that's it for me. And we'll take questions right now. Michael, thank you very much. That was really a masterful review of a very confusing set of diseases that we all encounter every once in a while and always struggle to figure out what to do with. Having said that, just a couple of very, very practical questions. I think there's a lot of interest in the aspects of laboratory testing. And one of the things that comes up actually with some interest is the issue of using a spot calcium to creatinine urine as sort of a screening test. Do you have any biases about spot urines as opposed to those sort of punitive 24-hour urines that we do all the time? Or looking at this in terms of calcium to creatinine ratio, I mean, how do you use urinary calcium measurements? Yeah, that's a really good question. It's a question that comes up all the time. And fortunately, there's a pretty accurate answer to that question. And the answer is that a spot calcium to creatinine ratio correlates very poorly with a 24-hour urine calcium. So it is, in fact, not an adequate screen for hypercalciuria. And I'm afraid that we are stuck with what, as you describe, is the punitive 24-hour urine calcium collection if we're really interested in knowing if a patient has hypercalciuria. So you know, for a long time when I was more junior, I used the calcium creatinine ratio all the time and I was quite happy about it. But as time has passed, and there have been several articles that were very convincing, very well done, showing pretty clearly that it doesn't correlate and therefore it does not reflect an adequate test for hypercalciuria. So, you know, it's a pain. I know it's a pain. It's terrible for the patients. It gets screwed up, you know, more often than we'd like. But if you want to check for hypercalciuria, and I think in patients who have fragility and fragility fractures, I really do think that it's incumbent upon us to check for hypercalciuria and you have to do the 24-hour urine calcium. Let me add one caveat to that, and that is this. So if a patient has bone fragility and fractures and you measure the 24-hour urine calcium and they're hypercalciuric, I treat those patients with thiazide diuretic, but I have to confess there's not good evidence to support that normalizing urinary calcium will further prevent fractures. There is evidence that it increases bone density on dexa and therefore I think it's probably safe to assume that decreasing or getting rid of hypercalciuria in a patient with bone fragility will have a beneficial effect. Yeah, that certainly sounds very reasonable. I mean, just a very practical point we run into all the time also, Michael, is that when we order these 24-hour urines, we need to have some sense of what's going in the patient's mouth. So the 24-hour urinary calcium really cannot be interpreted unless you have some handle on dietary calcium plus supplement use. And we certainly have plenty of people who are taking 87 different supplements, and when you add up the amount of calcium, it's really quite extraordinary. I just wanted to add one thing. You're absolutely right. So it's important to know what your patients are taking. The other thing, other situation or time when I find the 24-hour calcium useful is in those patients who you do it on and you identify that they have very low, sometimes even undetectable urinary calcium. And then it's quite clear that those patients don't have an adequate dietary calcium intake. And then, you know, so you're right, there's the two ends of the spectrum. There's those people who aren't taking enough and there's those people who are taking all kinds of supplements. So yes, you're right. So continue with these thoughts about laboratory testing. When we're assessing the hypophosphatemic patient, do you insist that people have their blood phosphoruses drawn fasting? So that's a good question. And that's the most accurate is to get a fasting phosphate first, you know, in the morning. However, you can calculate. So there's two ways to determine, because what you're trying to get out really typically is if the patient has a renal phosphate leak, whether they have hypophosphaturia. And so if you can do a tubular reabsorption of phosphate, which requires a urinary phosphate, urinary creatinine and serum phosphate and creatinine, and you can do that any time of day. So TRP can be done any time of day. TMPGFR, tubular maximum phosphate for GFR, has to be done fasting. So it's not always essential to do it fasting if you calculate the TRP, but the morning fasting phosphate is the most reflective of a patient's urinary phosphate reabsorption. We have a somewhat open-ended question here about how do you interpret serum CTX? Do you want to riff a little bit, Michael, on how you use CTX? So, you know, we have used a number of bone turnover markers over the years. And the two that seem to, that the field seems to have settled on are P1NP and CTX. And CTX is a bone resorption marker. And the reason I say the field has settled on those, and the reason why I think it's a good bone turnover marker, and one that I often use, is because nowadays, in almost all the studies of bone diseases, in particular osteoporosis, and in specifically osteoporosis treatment studies, the two bone turnover markers that are most commonly used are CTX and P1NP. And therefore, I think that they are good markers to use, and I like to use CTX. Now, that said, there is a diurnal variation to CTX as well. And it can change, if I can remember accurately, I think it can change up to 30% or more throughout the course of the day. So it is best for you to get a morning CTX. And because the reason is, that's the time of day when the normal range for the CTX, the age-appropriate normal range for CTX, is most reliable. So yes, I think CTX is a great bone turnover marker. I think it's important to get it fasting, if you can, in the morning, because there is a diurnal variation. And I find it quite useful to monitor, for example, the effects of treatment. So if you have a patient taking an oral bisphosphonate, which patients are notoriously not compliant with, and they come in and they have a high CTX, and you start treating them, and their CTX stays high, they're either not taking it or not absorbing it. And that might be a situation where then you would change from an oral bisphosphonate to an intravenous bisphosphonate to obviate the issues of non-compliance or poor absorption. Thank you. We have a little bit more than four minutes left, so there are a number of questions still in the queue here. So let's try to move relatively quickly with a few Qs and As here. You commented in passing about FGF23 assays and the C-terminal assay versus other assays. Any other comments you want to make about just the practicality of assessing FGF23? Yeah, I know there is an evolving field. The Mayo Clinic, which many of us use, has recently added an intact FGF23, and I personally think there's some confusion as to whether or not they still offer the C-terminal FGF23 assay. Generally speaking, except in rare circumstances, the C-terminal FGF23 assay is very good and quite adequate. Now, if you have a patient, who is hypophosphatemic, and they have a normal FGF23, a high normal FGF23, that's abnormal. That's like a patient who has a high PTH when they have a high calcium. So it does need to be interpreted in the context of the blood phosphate as well. A few other questions here. Put polyostatic Paget's disease in a young patient. Did you ever see this? What actually might you use for the basis of a more definitive diagnosis in that setting? Yeah. So this is, again, where the genetic testing is getting better and better and better all the time. When you go to one of these places like the connective tissue gene test, CTGT, now you can order panels of tests. So you don't need to order specific tests. Actually, you can order a whole bone panel, and in there will be the Paget's disease test. So yes, most of the time, these young ones are picked up in childhood, because these are usually genetic conditions that present quite early. So polyostatic Paget's is possible, and those are usually associated with known genetic tests, mutations as well. Good. Do you have a favorite thiazide that you use when you're trying to treat hypercalciuria? What kind of dose? What kind of drug? What are we talking about here? Yeah. So I typically start with hydrochlorothiazide at a low dose for several reasons. One, because first of all, to see if the patient can tolerate it, both in terms of their blood pressure and for the purpose of looking at its effects on potassium as well. So if they can tolerate a low dose of thiazide once a day, and they tolerate it well, but I still haven't achieved the effect on urinary calcium, then I'll increase that to twice a day and also increase it. Now, reach the point where that's tolerated, and then I'll go to a once a day drug like chlorthalidone. Thank you. Sadly, we only have about a minute left, so let's have a couple of quick questions and answers here. If the estimated GFR in a patient with Paget's disease is 28, can you still use zoledronic acid? Good question, and you probably shouldn't. Okay. If you have a patient who actually has hypophosphatasia, is it possible with a fracture to get the alkaline phosphatase to go up into the normal range? That's a good question, and I don't have a ton of personal experience with hypophosphatasia, although I don't know the answer to it, although I've been impressed at how relatively small fractures or osteomyelitis even can increase the alkaline phosphatase pretty significantly, but I don't know the answer to that specific question. Sorry. One other question about lab testing here, I think this is probably going to be the last question, bone-specific alkphos versus total alkaline phosphatase. So, in most cases, the total alkaline phosphatase is fine. It's cheap. We have years of experience with it. It's easy to interpret. In circumstances, for example, where there's liver disease, then you have to go with bone-specific alkphos, but I generally like to do alkphos until there's a reason why, when I think it's not reliable. Thank you. Michael, sadly, I think we're out of time right now. I just wanted to thank you for all the time and expertise that you've devoted to this programming. I think that was terrific. That was incredibly helpful. Thank you. Thank you. Thank you. It was my pleasure. Thank you for having me.

rare bone diseases

osteoporosis

tumor-induced osteomalacia

FGF23 hormone

hypophosphatasia

osteogenesis imperfecta

Paget's disease

fibrous dysplasia

skeletal dysplasias