Good evening, everyone. And thanks for joining us today for the ASAP Live Bone and Parathyroid Session. This is the second webinar that we are holding for the Bone ASAP Live Session, and the first one this year. Just to introduce the course leadership, Dr. Suraj is the Editor-in-Chief of ASAP. He's Professor of Medicine, as well as Division of Endocrinology, and Associate Dean for Clinical Research at the Eastern Virginia Medical School. And Dr. Gopalakrishnan is Chair of the Fellows Education Subcommittee in ACE, and Associate Professor of Medicine and Division Chief at Alpert Medical School of Brown University. I will be your presenter for the day. My name is Dima Diab. I'm Professor at University of Cincinnati, and I will also be tackling moderating the session as well. So what I plan to do for the next hour or so is hopefully go through six cases from ASAP 2021. These will be bone cases. And just remember that after the STEM and the question part, there'll be a poll for the Q&A answers, and then I'll address the correct response and the rationale after that. And then I'll try to kind of look through the Q&A box for any questions that you may have. So please remember to type your questions during the case presentation if you have any of those. We'll try to address the questions for each case in real time. And so once we move on, I won't go back to questions from the prior case. And we'll try to get through as many questions as possible. Maybe five to six would be the goal. Hopefully we'll see how many we can go through. So without further ado, I'm going to go ahead with the first case, which is a hypercalcemia case. This is a 60-year-old woman with a longstanding history of nephrolithiasis since her 20s, and she presents for evaluation for hypercalcemia. This also has been a longstanding problem, intermittent but longstanding, and associated with a low normal parathyroid hormone level. She has been taking 4,000 units of vitamin D3 daily for the last six months because she had a 25-hydroxy vitamin D level of 18. She denies taking any calcium supplements, and her only medication is the telepramp for depression. Her dietary calcium intake is roughly about 800 milligrams daily, which is slightly above average. The average tends to be 600 to 700 milligrams daily. Her bone mineral density on a DEXA scan shows T-scores of minus 1.6 in the femoral neck and a minus 1.0 in the lumbar spine. She has no fragility fractures. Her menopause occurred at 51, and she has never taken estrogen replacement therapy. Her family history is significant for kidney stones in three out of six siblings, and a niece and a nephew, and they all started at young ages. Physical examination findings are unremarkable. So these are the laboratory findings. You can see the labs, the results, as well as the reference ranges here on the right. So the serum calcium level is 10.6, which is slightly elevated. The serous level is normal at 3.5, parathyroid hormone level is slightly low at 14, normal albumin, creatinine, just slightly elevated at 1.2, 24 urine calcium, high at 406 milligrams per day. Her 25-hydroxy vitamin D level now is at 69, and her 125-dihydroxy vitamin D level is high normal at 70. So this is the question, which of the following management options is most likely to significantly improve this patient's hypercalcemia? Is it A, intravenous bisphosphonates, B, ketoconazole, C, glucocorticoid therapy, or D, parathyroidectomy? So please enter your answers. All right, the results are in from the poll. So about 50% of you chose intravenous bisphosphonates, 25% chose ketoconazole, and that is in fact the correct answer. We'll go through why. 13% chose glucocorticoid therapy and parathyroidectomy. So that was an equal response for those two. All right, so let's keep going. I think the key in this case that is really important when you're answering board questions is to look at the clinical presentation. And whenever you see something that's really longstanding with a strong family history, you should always think about an inherited disorder. And so what this patient actually has is a loss of function mutation in the CYP24A1 gene, which impairs the 24-hydroxylase enzyme that inactivates vitamin D. So that can result in hypercalcemia, hypercalciuria, high normal or elevated 125-dihydroxyvitamin D, and I know in her case it was on the high end of normal, but that wasn't appropriate. And then low normal or suppressed PTH and a history of kidney stones. This is your typical presentation of somebody with this type of mutation. This is not a common condition, but it's always something important to think about when you have active vitamin D-mediated hypercalcemia that seems to be due to some inherited disease. So again, the second point here is just making sure to remember that looking at longstanding nature of the disease and family history are really critical in making the diagnosis. The next slide just shows a brief figure looking at vitamin D metabolism, and you know that vitamin D undergoes 25-hydroxylation in the liver and then 1-alpha-hydroxylation at the level of the kidney to become active calcitriol. And the main enzyme that is involved in inactivating vitamin D is this 24-hydroxylase enzyme, which leads to, you know, 124-25 vitamin D, which is inactive. And so if you have a mutation here that results in accumulation of the precursor and hypercalcemia related to that, and that will always be a PTH-independent presentation. So the PTH levels in these patients will tend to be either low or frankly suppressed. In patients who have this mutation, ketoconazole has been shown to actually inhibit the 125-dihydroxyvitamin D synthesis and lead to improvements in their hypercalcemia. So in terms of the options given here in this case, that would be the correct answer. However, practically, if you see these patients, and again, these are not common patients, but the general management strategy initially is really a reduction in calcium and vitamin D intake to avoid that hypercalcemia. Ketoconazole has associated toxicities, including on the liver, as well as can affect multiple steroidogenic pathways. And so it leads to reductions in cortisol and sex steroid production. So it's not something that people tolerate long-term because of toxicity. And again, the initial strategies would always be the ones listed down here. But definitely in terms of the options presented, this would be the correct answer. As far as intravenous bisphosphonates, these would be effective in patients who have hypercalcemia related to malignancy, humoral hypercalcemia of malignancy, as well as osteolytic metastases. And so that's where you would prescribe an antiresorptive, subcutaneous denosumab, as well as subcutaneous calcitonin can be given for these indications as well. But the primary source of calcium excess in this individual is related to excess active vitamin D. And so this type of medication would not be effective in this case. Would not be a primary treatment strategy. Hopefully that makes sense because that was the answer that the majority of you chose. As far as other causes of PTH-independent hypercalcemia, which could be also due to 125-dihydroxyvitamin D excess, the most common is granulomatous disease, which of those sarcoid would probably be the most common. Less commonly also TB, histo, or even some lymphomas have been associated with hypercalcemia due to excess 125-dihydroxyvitamin D. And the reason that's high in these patients is the 1-alpha hydroxylation of vitamin D by the macrophages. And the 1-alpha hydroxylase in those cases is not regulated by PTH. So the biochemistry would be similar in situations like this, but again, the family history and the longstanding findings in this patient go along with an inherited disease. So that's what deviates that from that. If you had suspected sarcoid, glucocorticoids would be the mainstay of therapy. And then finally, in terms of primary hyperparathyroidism, I'm glad the majority did not choose this because you should see right off the bat that the PTH level is low, and that should move you completely away from thinking about PTH-dependent or primary hyperparathyroidism causes of hypercalcemia. And so parathyroid activity would not be the right answer in this case. So hopefully that clarified that one. This is a tough case. We don't see these patients a lot, but it's definitely important to know for boards. These are some references that I have listed here for you, and let's see if you have any questions in the Q&A. So I don't see anything from my end. Oh, and Dr. Obeid is here. Okay. I don't see anything either. Okay. All right. So maybe I'll move on. We'll see if we can kind of go through all six questions today. So the second case is an osteoporosis case. This is a 76-year-old woman who comes to the clinic to discuss treatment options for osteoporosis. This was diagnosed with a recent DEXA scan. She is concerned because her mother had a hip fracture at age 76, and she died of complications related to that fracture. The patient personally has not sustained any fractures that are known, but she has had significant height loss over the years. She has a significant intake of calcium through her diet and takes a multivitamin every day. She completed a five-year course of aromatase inhibitor therapy three years ago for her breast cancer, and she's never used tobacco or alcohol. She has an active lifestyle. She had menopause at age 40, did not take hormone replacement therapy after that. She has no history of glucocorticoid use. She has a noted history for barrett esophagus and a myocardial infarction six months ago in addition to her remote history of breast cancer. Physical exam findings, she has some thoracic kyphosis. Her BMI is 25. There we go. These are her laboratory test results. She has a normal calcium level with a normal GFR. 25-hydroxyvitamin D is 32, so in the sufficient range on the low end. Her thyroid hormone level is normal, SPEP and UPEP are normal, and her 24-hour urinary calcium is 150 milligrams per 24 hours, which is also normal. Her bone density reveals T-scores of minus 3.2 in the lumbar spine, minus 2.5 in the left femoral neck, and minus 2.5 in the left total hip, consistent with osteoporosis. Which of the following medications would you recommend for this patient as a treatment option? Is it A, oral alendronate, B, intravenous zoledronic acid, C, raloxifene, or D, romosozumab? I'll give you a few minutes to put in your answers. Oh wow, all right, the poll's ended. We have 100% for intravenous zoledronic acid, that's excellent. So maybe I don't need to spend as much time on this one, that is the correct answer. And so this slide, I just show the medications that are currently approved for treatment of osteoporosis by the FDA in the U.S., and I highlighted in blue the answers that were given as options in this case. So we have alendronate on the top, zoledronic acid here, and both of these, as you can see, have been shown to have broad-spectrum efficacy, meaning a reduction in the risk of fractures at all sites, vertebral, hip, and nonvertebral fractures. Raloxifene down here has really only been shown to decrease the risk of vertebral fracture, we'll go into that in a little bit, and then romosozumab, both vertebral and nonvertebral fracture, although the trials that looked at this probably weren't powered enough to show a reduction in hip fracture for romosozumab. All right, so we all know that osteoporosis is a common disorder, and one in two women older than 50 will have a fracture related to osteoporosis, and this is significant. Although the majority of fractures are typically vertebral and may just present with height loss, the most devastating fractures are the hip fractures, which are associated with a mortality range of anywhere between 20 and 40 percent. This patient has multiple risk factors for osteoporosis, including her race, advanced age, her parental history of hip fracture, theromatase inhibitor use, and history of untreated premature menopause as well. For her, intravenous laldronic acid is the best choice. You all chose that. So, the advantages to the other options listed here are, one, of course, broad-spectrum efficacy. The other nice, you know, finding with laldronic acid trials is that it has been shown to reduce mortality and skeletal recurrence in patients with breast cancer treated with aromatase inhibitors. So, I think in women who have breast cancer, I tend to favor laldronic acid as far as the bisphosphonates go. But in this particular case, there's a main reason why oral alendronate would not be a great choice, and it's really herbaric esophagus. You want to try to avoid using oral bisphosphonates in patients with esophageal or upper GI pathology. Otherwise, it may have been a reasonable option, but that really, in my mind, excludes that in patients who have Barrett. Raloxifene is a selective estrogen receptor modulator. It's really considered second line because of the efficacy just being shown in terms of reduction of vertebral fracture risk. So, this patient who has low T-scores at the hip, as well as a parental history of a hip fracture, you really want to make sure that you use an agent that's been shown to prevent hip fractures. So, this would not be a good choice. And then finally, as far as ramosozumab goes, so it's a monoclonal antibody against sclerostin. This was one of the more recently approved medications. And the nice thing about ramosozumab is that it has a dual benefit of having both anabolic and antiresorptive properties. It's approved for use to treat postmenopausal osteoporosis in women for one year, but it has a black box warning for cardiovascular risk. And so, anybody that has had a myocardial infarction or stroke within the past year would not be a candidate for this. And you may want to be cautious in people who are high cardiovascular risk when you think of using ramosozumab. So, that eliminates that as the best option in this case. And always in boards, you know, think about comorbidities and reasons why medications may be contraindicated. That would eliminate them as the best option. Because many times, you know, outside of the comorbidity or the contraindication, another option would have been reasonable. Hopefully, that was a clear enough question, because I think most all of you got that right. These are some references. I don't see any questions, Dr. Diaz, but can I ask a question? Sure. So, I noted that on the question stem, they mentioned this patient had a myocardial infarction in the past six months, and which is, as you mentioned, was a big clue that excluded romososumab. What would be the indication, what would be the contraindication for using romososumab? Is it NMI ever, or a high SCAVD score, or what do we use to assess for that? So the black box warning states, am I or stroke in the past year? And that's what I usually go by. Now, that being said, you know, I would, you know, clinical judgment always plays a role. So if somebody is at very high risk, even if they haven't sustained that, that would be a discussion to have with the patient. I don't know that it would absolutely exclude it, but it would be something that I would discuss in the risk and benefit. But the contraindication would be NMI or stroke within the past year. Thank you. All right, we'll move on to case three. So this is a 30-year-old man who was referred for evaluation of hypophosphatemia. He has longstanding fatigue, muscle weakness, and bone and joint pain. Again, young patient with longstanding symptoms, reporting dental problems as a child. And he's currently treated with phosphate and calcitriol supplementation. He has no nausea, vomiting, or diarrhea. On physical exam, he is five feet tall, has mild bowing of his lower extremities. Laboratory results show a calcium of 10.2, which is on the high end of normal, a low phosphorus of 1.5, a creatinine of 1.0, a PTH level of 75, slightly elevated, 25-hydroxyvitamin D of 43, a 125-dihydroxyvitamin D level of 10, which is low, and a normal albumin. Which of the following is the most likely diagnosis? Is it A, hereditary resistance to vitamin D, B, tumor-induced osteomalacia, C, vitamin D deficiency, or D, X-linked hypophosphatemia? Okay. Oh, wow. Nice. All right. So maybe, yeah, this is great. 100% chose X-linked hypophosphatemia. That is, in fact, the correct answer, and let's review this rationale a little bit. So whenever you see a hypophosphatemia case, it's important to think about, you know, differential and deficient intake or use of phosphate binders definitely would be on there. You think about whether it's PTH-dependent or not, or whether it's FGH, FGF23-dependent or not. And so for this patient, the low FOS with the lowish 125-D is really the key to think about FGF3-dependent, FGF23-dependent hypophosphatemia. And the two most common ones that I think you should know for boards are tumor-induced osteomalacia and X-linked hypophosphatemia crickets. And whenever, again, you see someone with longstanding history, young age, with dental problems, always think about XLH. Those are some other, a lot less common, you know, inherited disorders that are also associated with osteomalacia and hypophosphatemia. And then there are some kidney disorders as well that are independent of FGF and PTH. So the patient in this vignette has XLH, and the gene responsible for XLH, which is FEX, is expressed predominantly in bone and teeth. If you have an inactivating variant in FEX, that increases the production of fibroblast growth factor 23 or FGF23, which is a phosphatonin. And so that results in hypophosphatemia, increased phosphate excretion, as well as a low normal circulating 125-dihydroxyvitamin D. And that's really the key to answering these questions. The low 125-dihydroxyvitamin D level is thought to be the result of decreased expression of 1-alpha-hydroxylase, as well as increased catabolism of 125-dihydroxyvitamin D. So XLH has an X-linked dominant pattern of inheritance. Some main clinical features of it include fatigue, muscle weakness, stiffness, bone pain, and gait abnormalities. Also dental problems in childhood are common. The major clinical findings are short stature, leg deformities, teeth defects, and osteomalacia related to the impaired mineralization, usually the low FOS. And these patients also can present with accelerated osteoarthritis, as well as enthesopathy. And that usually begins in the second or third decade of life. And that's part of why they develop the stiffness, calcification, and the tendons that you see with this condition. So tumor-induced osteomalacia, which is also known as oncogenic osteomalacia, is also rare, but it's an acquired disorder. And biochemically, it looks exactly the same as XLH. So really the key in differentiating these two is the clinical presentation. These tumors in oncogenic osteomalacia secrete FGF23 and other phosphatory proteins. And that increases the risk of osteoarthritis and other phosphatory proteins. And that increased circulating FGF23 leads to the same biochemical and mineralization abnormalities that you see in genetic forms of hypophosphatemia crickets. So again, it's really the clinical presentation that's gonna point you to one or the other. This is a table that I'm not gonna go through, but just include it for your references to kind of compare. But all the FGF23-mediated conditions will really have very similar biochemistry as you see here, as opposed to hyperparathyroidism, where you have a high PTH and a normal to high 125D. Okay, so what about the other options? Hereditary resistance to vitamin D is typically caused by end-organ resistance to 125-dihydroxy-D. And that's usually because of a loss of function variant and the gene encoding the receptor. So when you have a resistance, you typically would have high serum 125-dihydroxy vitamin D levels, not low. And you would have hypophosphatemia, typically also hypocalcemia and a significantly elevated serum PTH levels. And this patient does not have the high serum 125-dihydroxy vitamin D levels. So that value is critical in interpreting these cases. And then finally, vitamin D deficiency to cause hypophosphatemia and or hypocalcemia, you typically will need to see really low 25-hydroxy vitamin D levels, typically below 10 to lead to osteomalacia. And associated with that, most of these patients will also have a secondary hyperpara and elevated alkaline phosphatase levels, as well as low urinary calcium excretion. So we know that based on this patient's laboratory values, the vitamin D level was not low. And then the 125-dihydroxy vitamin D levels, just as a side note, could be normal low or high in vitamin D deficiency. We don't typically check it in that scenario. It depends on the severity and the duration of the vitamin D deficiency. And 25-hydroxy vitamin D is really the main storage form and circulating form of vitamin D. And that's how you would define deficiency. And so that's the level that you would check to screen for a vitamin D deficiency. All right. And let's see if there's any questions. You know, while we're waiting for questions, it's interesting that everybody got it correct. And I think probably, you know, the fact that this is a young guy and the bone pain and short stature is definitely a big sign. But so one of the things that's mentioned here is iron. One of the things in the hypophosphatemia causes is iron infusion. How is that? Do we see it often? Is it all iron supplements? What are your thoughts on that? It's being, actually, it's being described more often now, and it's mostly with the ferric carboxymaltose preparations and less so in patients with CKD because they have some impairment of phos expression. So it's more in patients with good renal function where we're seeing this. Typically, you know, within a few weeks of getting that, that's where the nadir happens, and it may take up to three months for it to recover, but there's definitely been more reports about this. I wonder if that could be, you know, down the road, probably something that would be a question on boards. It's definitely being described more often, but mostly with the ferric carboxymaltose preparations is my understanding. So that would be in the question main stem, probably. Yes, yes. If that was part of the answer. Yes, that's a great point. If you see anything related to an iron infusion and hypophosphatemia, those definitely could be linked. And it is also something that seems to be mediated by FGF23 as well. And so that's another interesting finding. And one last thing about XLH, and I didn't go into treatment much here. This was a diagnosis question, but just be aware that there is now an antibody, borosimab, that is a monoclonal antibody to FGF23 that's approved to treat both XLH as well as TIO in cases where you can't find the tumor and take it out, which is usually, of course, the main course of treatment. Sometimes they're small or they can't be located that could improve outcomes in terms of bone mineralization, healing of fractures, things like that. And I think another thing is, so what do you think about the PTH being elevated? You mentioned the low 125D and then with the normal kidney function, the calcium being upper limit of normal. Do you see this often? Yeah, because the issue is this patient's being treated with phosphate and calcitriol, and that can actually kind of worsen the secondary hyperpara process. So it becomes a vicious cycle because you're excreting that FOS and you're trying to treat it by giving FOS and that leads to transient reductions in calcium and that drives the PTH up. That's part of the challenge with the traditional treatment of XLH is that hyperpara process that can become hard to control. And in those patients, spirozumab may be a better option. Yeah, and I think some of these patients can end up with hyperpara where they require surgery if they're on conservative treatment with calcitriol and phosphate. I don't see any other questions here. Okay, I'm gonna move on then to case four. This is a 72-year-old man who underwent combined liver kidney transplant 10 years ago. He's being evaluated for osteopenia. He takes cyclosporine, mycophenolate, and prednisone, five milligrams daily. His current creatinine is 1.12 with an EGFR of 65. His liver function tests are normal. His DEXA scan shows the hip T-score of a minus 0.8 and a lumbar spine T-score of a minus 1.4, which is stable from two years ago. He has no history of fragility fractures. He denies the history of parental hip fractures, alcohol use, smoking, and rheumatoid arthritis. His 10-year risk for a major fracture based on FRAX is 8.4% and for a hip fracture is 1.9%. His estimated dietary calcium intake is 800. He's not taking calcium or vitamin D supplements. His calcium, FOS, 25-hydroxyvitamin D levels are normal. He has no current issues with his dental health. And physical exam reveals a normal one-legged stents test. Let me take that away. Stable dentition, really no remarkable findings. So based on current U.S. guidelines for the prevention and management of glucocorticoid-induced osteoporosis, which of the following is the most appropriate recommendation for this patient? Is it A, Elendrin A, 70 milligrams once weekly combined with lifestyle modifications, adequate calcium and vitamin D supplementation? Is it Denosumab, 60 milligrams every six months with lifestyle modifications as well as adequate calcium and vitamin D or lifestyle modifications, calcium and vitamin D supplementation or an 8 a.m. total and bioavailable testosterone level assessment with consideration of androgen replacement therapy if low on two consecutive measurements? So please enter your answers. Okay, so it looks like there's a 50-50 split between Elendrin A with lifestyle modification or just lifestyle modifications and calcium and vitamin D. And so this is, I guess, good to go over this. Be aware that in patients who are on glucocorticoids, the thresholds to treat are lower. And we all know that glucocorticoids have a negative effect on the skeleton and there's a rapid reduction in bone mineral density within the first six months of using oral glucocorticoids and it becomes a slower progressive decline thereafter. This reduction is more pronounced in trabecular bone, mostly in the lumbar spine. And we know that fractures are increased with glucocorticoid use and that's independent of bone density. And so in the FRAX calculator, that's why they're included there as a risk factor. There we go. So the guidelines from 2017 basically recommend that in patients who are on glucocorticoid therapy, it is recommended to treat if they have one of these following criteria. So either a history of an osteoporotic fracture or a T-score that's consistent with osteoporosis or a FRAX 10-year overall fracture is for a major fracture that's greater or equal to 10% or a hip fracture is that's greater than 1%. And this is different from the three and 20 cutoffs that we typically would use in someone that's not on chronic glucocorticoid therapy. And finally, very high doses of glucocorticoids are also included there as a recommendation to treat. So in this patient, the 10-year hip fracture risk was 1.8%. So he would meet treatment guidelines for considering an oral bisphosphonate, which is a lendronate option A. That would be the correct answer. For patients who are on doses that are greater than 7.5 milligrams per day, there is an adjustment that could be made in the FRAX tool and I didn't include it here, but it will be in the references to increase that risk based on a higher dose of prednisone. So there are multiple therapies that are currently approved and the ACR guidelines, which was the ones that I presented here, recommend oral bisphosphonates as a first-line therapy with other therapies in order of preferences. I've listed here intravenous bisphosphonates, theriparatide, denosumab, and riloxifene. Denosumab, in one study at least, was associated with an increased overall risk of infections and specifically UTIs after kidney transplant within the first year. So that's just something to keep in mind. And although calcium and vitamin D would be appropriate for all of these patients, it would not be adequate just to do that in this patient because of that HIPFRAX score being above 1%. And finally, regarding the testosterone, remember that testosterone therapy has not been shown to reduce fractures. So it would not be recommended as a standalone therapy. However, if this patient had hypogonadism and was considered as a treatment to treat the symptomatic hypogonadism in addition to the other osteoporosis therapies, that would be reasonable, but it would not be the best answer in this case. Your references will include the ACR guidelines reference. And this is the table that lists the recommendations for the treatment for patients at moderate to high risk based on age. And our patient fell in this category here where the FRAX and your adjusted risk for hip fracture was greater than 1%. Thank you. All right, questions. Gosh, we see these patients all the time, right? You know, they come in with 7.5 milligrams of Pregnizone, some 20 milligrams and you know and the guidelines and the FRAX we have is on anything above 5 milligrams. Do you typically adjust for higher doses? I would if it's above 7.5 I would use the recommended adjustment and there's a calculation that needs to be made and then you add that number to the percent that you have. I did not include it in the slides here but it is in that guide guideline and I do typically use that adjustment for anybody that's at a dose greater than 7.5 milligrams a day. I think the other patient populations which you would consider potentially treating at a lower threshold would be patients on androgen deprivation therapy as well as women on aromatase inhibitor therapy and there are guidelines from the cancer societies actually looking at those and not waiting until they're you know full-blown osteoporosis before you would treat because you know these therapies would lead to declines in bone mineral density as well. So again many of this many of the decisions we make are individual clinical judgment cases but those would be situations where I would have a lower threshold to treat. And you know my understanding is so if this patient you know if they gave us a different scenario this patient is has is on the same medications transplant patient on pragnism five milligrams but his bone density is normal and yet somehow he got an x-ray that showed a fracture you know vertebral fracture or he had a hip fracture would that change your management? Absolutely so you can make a clinical diagnosis of osteoporosis with a history of a fragility fracture and I think spine and hip are you know critical and so regardless of the t-score that points to poor bone quality and would be somebody that should be treated yes. Yeah and I think some advocate for you know doing a spine x-ray since about 40 percent of patients can have asymptomatic vertebral fractures when you see these steroid-induced osteoporosis patients. And then one last question I have if there are no other questions because this is a very interesting topic at least to me is so if is your bisphosphonate always the go-to drug for these patients or would you add teriparatide potentially as an option? I mean in this guy you know no fractures frac score is you know in the middle although it reached a threshold but how do you manage or if they had added teriparatide how would you differentiate how would you pick this over alendrinoid over teriparatide? Yeah I think that's probably why it wasn't given as an option. So the primary defect with glucocorticoids is an anabolic defect and so in patients who are very high risk in my mind if they've had already a fracture or they have lower scores to begin with that would be probably somebody I would like to start off with an anabolic as opposed to a bisphosphonate. I think you know part of the challenge is getting getting it covered for people with not so bad scores and in real life you know you got to show a t-score below minus 3.0 or a fragility fracture or patients have a really hard time affording this but I think with a primary defect being initially at least an anabolic defect and people who are higher risk I would I would go the anabolic route. Yeah that's my understanding too is that in steroid induced osteoporosis and you know high risk patients if you found a fracture if their t-score is a lot lower teriparatide is much more effective than bisphosphonate. So if you on the question stem you know if you're asked about somebody who's had a fracture their bone density is just an osteopenia range and they gave you those two options potentially teriparatide may be a better option. Would you agree or? Yes yes the Vero trial I believe directly compared an oral bisphosphonate to teriparatide yeah so yeah I definitely would agree with that. Okay all right. So I'm gonna keep going with case five um also an osteoporosis case 57 year old man who's referred for evaluation of osteoporosis and he does not have a history of fractures kidney stones or glucocorticoid use. He also does not have any symptoms of musculoskeletal pain, polyuria, polydipsia, constipation, difficulty concentrating. He does not take any supplementation spends a good amount of time out in the sun on weekdays and weekends and has no other complaints. So this is a younger you know gentleman. He has a DEXA scan which shows a lumbar spine t-score of minus 2.3 femoral neck minus 2.7 total hip minus 2.6 and it is the one-third radius of a minus 2.8 and as you can see the z-scores as well which are on the lower end down to minus 2.5 in the forearm. These are his labs. Normal calcium at 9.9, phosphorus at 3.2, normal kidney function and albumin as well as unremarkable liver function. Parathyroid hormone level is mildly elevated at 83, normal 25 hydroxy vitamin d level of 49 and a total testosterone level at and a total testosterone level at ADM of 308 which is within the normal range. So what is the most appropriate next step in management for this patient? Is it a measurement of 24-hour urine calcium and creatinine, b measurement of 125 dihydroxy vitamin d, c systematic scan of the parathyroid glands or d serum c telopeptide. Okay so the results are in. Majority chose measurement of 24-hour urine calcium and creatinine and that is the correct answer and then another choice that was minority measurement of 125 dihydroxy vitamin d. All right. So things to remember in this case, so this is a 57-year-old man who does not provide a history of any of the common causes of osteoporosis in men as far as hypogonadism, glucocorticoid use or excess alcohol which are the three big ones that we always look at for men. Men especially those with disease scores below minus 2.0 you should always think about secondary causes of osteoporosis and it's important like with everything else to get a complete history and a physical exam. We know he has osteoporosis with these scores that are abnormally low for his age, sex and race and we also know that he has a cortical bone loss given the forearm findings on the DEXA scan. So the basic workup for osteoporosis in men would always include a complete metabolic panel, 25-hydroxy vitamin D level, an AM testosterone level and a 24-hour urine calcium and that's the correct answer. So his labs in particular show a mildly elevated PTH and whenever you see that and you think about secondary causes of parathyroid elevation in the setting of a normal calcium, you think about low vitamin D or impaired kidney function but in this patient those were fine and so then you need to think about other reasons for a secondary hyperparathyroidism which would include inadequate calcium intake or absorption so that would be hypocalciuria on a 24-hour urine test or hypercalciuria that can also lead to secondary hyperparathyroidism and the only way to make that determination is by getting that 24-hour urine. Once you exclude secondary causes for hyperpara, you may think about you know normal calcemic hyperpara slash early primary hyperpara and especially in this patient who has low scores in the forearm on the DEXA scan. So the most appropriate option in this patient is a 24-hour urine calcium which the majority of you got correct. Since this patient has not received a biochemical diagnosis of primary hyperparathyroidism, there is not enough information to proceed to assist the MIBI scan. The only indication for that really is to after making a biochemical diagnosis of primary hyperparathyroidism to localize the disease and so that's where we would get imaging but without that biochemistry first we do not really go to the imaging route. 125-dihydroxyvitamin D which is the active form of vitamin D is important for maintaining serum calcium and typically is measured in workups of hypocalcemia but not routinely in the workup for osteoporosis. There's really no relevance for that here. And then finally the serum C-telepeptide which is a bone resorption marker may be useful in some cases for example in patients with kidney disease where you're looking at low BMD or if you're monitoring response to therapy or if you're discontinuing denosumab, there may be some indication to look at these things but again not the best next step in this case which is really trying to find out if there is any issue with calcium excretion or intake leading to a secondary hyperparapicture. So those are the references and we'll see if any of you have any questions. You know I'm curious for those of you who picked 125-D, I wonder what the what your thought process was. If anybody's willing to speak or put something in the chat. I'm assuming it's because of the suspecting primary hyperparathyroidism and perhaps you know PTH increasing vitamin D to 125-D and you can see elevated 125-D but okay no takers. Okay, all right I think we may have time to go through the last case. Yeah all right let's try that. This is a little bit of a switch in gears from osteoporosis to hypocalcemia. So this is a 32-year-old woman with no significant past history who was admitted to the hospital for hypocalcemia. She's had a one-week history of paresthesias, muscle cramping, and had a recent gastrointestinal illness with nausea, vomiting, and diarrhea. Despite treatment with calcium and vitamin D supplements, she remains hypocalcemic. She has no family history of calcium disorders. Her body mass index is 18 and the schwastik site is elicited on exam. Her labs include a calcium of 7.2, a phosphorus of 3.5, a creatinine of 0.8, intact PTH of 18, and a 25-hydroxy vitamin D of 32. Measuring which of the following is the best next step in the evaluation of this patient's hypocalcemia? Is it A, 125-dihydroxy vitamin D, B, magnesium, C, parathyroid hormone antibodies, or D, tissue transglutaminase antibodies? I don't think those are updated from what I'm seeing. Oh, that's right. So, I'll just, A is 125-dihydroxy, D, B is magnesium, C is parathyroid hormone, and D is parathyroid hormone, and C is parathyroid hormone, and D is parathyroid hormone. So, I'll just, A is 125-dihydroxy, D, B is magnesium, C is parathyroid hormone, and D is 125-dihydroxy, D, B is magnesium, C is parathyroid hormone antibodies, and D is tissue transglutaminase antibodies. You can probably answer in the chat. There you go. Okay, someone entered B. Anybody else? Okay, we have a second B. And we have a third B in the Q&A. All right. So, it looks like majority are entering B. We have one A. Oops, the slides are going. Okay, I'm going to proceed. Thank you for whoever entered the answer. So, the answer is B. It is magnesium. And let me go through this. So, this patient has symptomatic hypocalcemia. She's young. She has no history of neck surgery and has had a recent gastrointestinal illness. And you know that her hypocalcemia is refractory to treatment with calcium and vitamin D. So, we're going to look at vitamin D. And it's associated with a low normal PTH. So, once you see a low normal PTH in somebody that's had a recent GI illness or who's on chronic EPI or diuretic therapy, always think of hypomagnesemia because that can cause refractory hypocalcemia by impairing PTH release in response to hypocalcemia, and also sometimes can impair PTH action. So, you have a functional hypoparathyroid state. And despite this, most of these patients will have normal or even low FOS levels because of poor intake. So, the typical manifestation in your hypoparathyroid patient is a high FOS. But in these patients, it tends to be normal or sometimes even low. And MAG is not measured routinely on the blood tests that we do. So, you really have to think about it to order it. And I think anybody with refractory hypocalcemia, you should have a low threshold to have that checked. So, risk factors for this would include diarrhea, malabsorption, PPI therapy, diuretic use, alcoholism, malnutrition, and severe illness. And in addition to refractory hypocalcemia, clinical manifestations can include neuromuscular disturbances and cardiac arrhythmias. So, generally, once you fix the MAG, the patients respond to the treatment for the hypocalcemia. Now, if you have the same findings in the absence of hypomagnesemia, that would have been consistent with a diagnosis of primary hypoparathyroidism. And in somebody without a history of neck surgery, you would think about autoimmune, especially if they have a personal or family history of autoimmune disease. This could be a manifestation of polyglandular autoimmune syndrome type 1, which is rare. And measuring PTH antibodies may be useful to screen patients suspected of having this, but not in this patient where a low magnesium check should be the next step. Now, in patients treated with immune checkpoint inhibitor therapy, there have been reports of patients developing activating calcium-sensing receptor autoantibodies leading to autoimmune hypopara. So, that's one thing to keep in mind as well. 1,25-dihydroxyvitamin D would be appropriate if you're suspecting either an inherited disorder leading to a deficiency in the production or a defect in the receptor, which are both rare conditions associated with secondary hyperpara. But it really would not be helpful in this clinical scenario. And then finally, transglutaminase antibodies, which you would get if you were worried about celiac, is really not a concern in this patient. Her 25-hydroxyvitamin D level is normal. So, it doesn't suggest a chronic malabsorption problem. And so, magnesium is always good to think about in patients who look like they may have hypopara, but have reasons to have a low mag and have refractory hypocalcemia to treatment. And these are some of the references here. So, we're right on time. I mean, just a couple of minutes left. I don't see any questions, but I'll wait for that. I think before we wrap up, I do want to mention we did not present here. We do have some cases in the ASAP about PAGET, which I think is important to know for boards. And we did not include that in the six cases we discussed here, but that would be something to be aware of. And then also FHH, familial hypocalcemic hypercalcemia would be something to know how to, you know, how they clinically present and how to make the diagnosis. So, those would be two other important conditions to keep in mind for boards. All right. Thank you very much, everyone. Have a great evening. Thank you. Thank you. Bye. Bye.

Bone ASAP Live Session

hypercalcemia

parathyroid hormone

osteoporosis

hypophosphatemia

glucocorticoid therapy

osteopenia

hypocalcemia

evaluation