Good morning, everybody. My name is Alia Khan, and it really is my pleasure and honor to chair this morning's session. We will be presenting the Endocrine Society Clinical Practice Guideline on the Treatment of Hypercalcemia of Malignancy in Adults. This guideline has been published in JCENM in December of 2022, along with the supporting reviews informing the guidelines. This was an evidence-based guideline following GRADE methodology. We have an internationally acclaimed faculty, and Ghada El-Hajj Fuleihan was the chair of the guidelines. She's a professor of medicine at the American University of Beirut in Lebanon. Matthew Drake was the co-chair associate professor of medicine at Mayo Clinic in Rochester, Minnesota. Gregory Clines, associate professor, University of Michigan, Ann Arbor, Michigan. Claudio Marcocci, professor of endocrinology, University of Pisa in Italy. The guideline development panel included Ghada, Matthew, Hassan Murad, Thomas Piggott, Gregory Clines, Mimi Hu, Claudio Marcocci, who was also the representative of the Endocrine Society, European Endocrine Society, Kathy Van Posnack, who was a representative of ASCO, Joy Wu, and Freddie Smith, patient representative. And these are the disclosures, and nobody had relevant disclosures to this guideline. So I'd like to ask you all to join the session by scanning the QR code below. If everybody's got their phones out, and scan the code. I'll give everybody five more seconds. Okay, so let's do some test questions, and just to warm up everyone so you're comfortable and familiar with the polling. So where are you located? A, in the U.S. B, international. Responding to the live format. Okay, very good. Who is in the audience? Where do you work? Clinical practice, academia, or other? Okay, so we've got a good mix. How long have you been in practice? Are you in training less than five years post-training, five to 10 years post-training, or more than 10 years post-training? Again, it's a good mix with experienced individuals as well as early graduates. And what is your focus? Basic science, clinical science, or other? Lots of clinicians in the audience. So this is our agenda. We're going to present the framework and give an overview on the background and the scope of the guidelines, the grade methodology that was employed to develop these guidelines, the ungraded good practice statements, and then the clinical practice guidelines recommendations will be presented in a case-based format, and the recommendations and workflow will be presented, and then there'll be additional Q&A at the end with all the panelists. So let's begin with the framework, background, and scope. So I'm going to hand it over to Matthew. Over to you, Matthew. Okay, well, thank you for joining us today for this clinical guidelines overview. We know that hypercalcemia of malignancy is the most common metabolic complication associated with cancer. It occurs anywhere from two to 30% of patients and really depends on the type of malignancy present as well as the stage at which the cancer is. Importantly, cancer cells secrete various molecules, including PTHRP, as well as other cytokines, which result in bone resorption and calcium release from the skeleton. Submalignancies, however, such as lymphomas, also increase intestinal calcium absorption due to enhanced calcitriol production, which is the active vitamin D metabolite. Serum calcium levels further increase when renal calcium excretion is impaired, which happens frequently due to dehydration or with renal failure. Overall, hypercalcemia of malignancy leads to decreased quality of life, systemic bone loss, as well as local osteolysis, and this increases the risk for fractures, renal failure, and unfortunately, mortality. The median length of an inpatient stay is now estimated to be about four days, and importantly, with improvements in anti-cancer treatments and the use of medications to treat hypercalcemia of malignancy, in-hospital mortality has decreased dramatically, from a previous level of about 50% to somewhere around 7% now. Importantly, the symptoms associated with hypercalcemia depend on both the severity and the rapidity at which the serum calcium level has risen, so mild chronic increases to levels which are typically less than 12 may be asymptomatic for many patients or cause only fatigue and mild constipation. However, more rapid increases or more moderate, less than 14 milligrams per deciliter, or severe, which we define as 14 milligrams per deciliter or higher, levels of hypercalcemia can induce polyuria, polydipsia, cardiac arrhythmias, cognitive dysfunction, confusion, and in some cases, even coma. Treatment of the primary disease, including surgery if warranted, particularly in cases of parathyroid carcinoma, is absolutely instrumental for presenting and treating hypercalcemia malignancy. However, for us, for most of us in the audience, medical management is very important. The approaches have included hydration, potent IV bisphosphonate therapies, and sometimes the use of calcitonin. These have been the cornerstone of treatments for many years. Leukocorticoids have long been used to treat calcitriol-mediated hypercalcemia malignancy, and more recently, use of denosumab and calciumimetics for parathyroid carcinoma have been added as potential medications to treat hypercalcemia malignancy. However, despite the advent and approval of multiple different medications, including antiresorptive agents, guidelines or clinical care pathways to guide stakeholders caring for patients with hypercalcemia malignancy have been lacking. Further, evidence for head-to-head comparisons for the efficacy of various medications has been missing, and as a result of these concerns, the Endergan Society gathered a multidisciplinary panel of clinical experts, as you've seen in the past several slides, as introduced by Dr. Kahn, together with experts in systematic literature review to develop clinical practice guideline for the treatment of hypercalcemia malignancy. And I will just give a brief overview in this slide, which will show sort of the mechanisms by which hypercalcemia malignancy occurs. So pre-osteoclasts bind rank ligand, produced largely by osteoclasts at the rank receptor. This then generates multinucleated osteoclasts, which sit down on the surface of bone and cause bone resorption. We have largely two classes of medications for preventing this. The first is denosumab, which we know is a monoclonal antibody directed against rank ligand, which binds rank ligand, inhibiting its interaction with rank ligand. As a result, pre-osteoclasts do not develop into multinucleated osteoclasts, and therefore osteoclast formation, function, and survival are inhibited. Alternatively, we have bisphosphonates. So bisphosphonates work at a different step in the osteoclast pathway. Bisphosphonates bind to the surface of bone, where activated osteoclasts start to resort bone. They then endocytose the bisphosphonates, and as a result, the osteoclasts undergo apoptosis. And with that, I'll turn it over to my colleague, Dr. Ghada El-Hajfoulyan. Thank you, Matthew. I'd like to go over the GRADE methodology, which is central to the development of trustworthy guidelines. So we will start with our question, which is the treatment of hypercalcemia of malignancy, search for the evidence, and then develop and formulate statements that include the recommendations that we will review with you today. GRADE starts with questions. The questions have to be pertinent for decision-making between patients and clinicians, not necessarily questions that have been commonly answered by available and well-known research, and importantly, comparing treatment options. So the question should describe the population in as much detail as necessary, including age, gender, comorbidities, hospitalization or outpatient for the guideline question. For evidence review, one should define how narrow or broad the included population can be. For the intervention, we describe the intervention or multiple intervention in as much detail as necessary, the medication, the program, et cetera. Comparator describes the alternative, either no active treatment or a different treatment, and the outcomes, of course, describe the patient-important outcomes that will inform decisions about the intervention, mortality, morbidity, quality of life. And we actually have outcome prioritization by the guidelines panel. In addition, had in parallel outcome prioritization by the patients, and they were fairly congruent. This is a typical PICO table for PICO-1, treatment of hypercalcemia of malignancy in adults. So the population are the adults with HCM. The intervention here, for example, is bisphosphonate or denosumab. The comparator is placebo, control, hydration, and the outcomes are listed here. Normal calcemia, time to normal calcemia, duration of normal calcemia, skeletal-related events, adverse events for some PICO questions. Allow me to walk you through this busy slides. I don't think my pointer shows on the screen, but I'll try. We're gonna go color code, moving up and down. So we start with the scope of the guidelines, and of course, the Endocrine Society set up this clinical practice guidelines panel after a very thorough vetting of conflict of interest, and you've heard none of us had any. We then sat together remotely, formulating each PICO question and selecting the outcomes. We then moved on to providing the Mayo with our questions, and the Mayo Evidence Center would retrieve the evidence, assess the quality, and synthesize, based on a very extensive literature review of multiple databases. They also graded the certainty of the evidence, and then we had to meet to review each PICO question one by one, virtually, and sometimes a question would take more than two Zoom calls lasting a couple of hours each, to formulate our recommendation using the evidence-to-decision framework, and I'll go over that in a minute. And then after that, we will basically formulate the recommendation, provide the justifications for them, reviewing the evidence, send the manuscript for external review, get comments back, big tables, lots of comments. We had to review them, respond to them, send them back, and then it gets launched to the public for input from the public before final acceptance and dissemination through the publication. Now, allow me to walk you through this. This illustrates the evidence-to-decision framework, and you can see listed on the left nine different domains that were assessed for each single PICO questions, and these domains included assessing desirable effects, how substantial are the desirable effects, undesirable effect, again, how substantial were they, what is the certainty of the evidence for making the recommendation for that specific PICOS, what are the values to be considered, is there important uncertainty and variability about how much people value the outcome, the balance of the effect, looking at desirable versus undesirable effect, the resources required, outpatient, inpatient, et cetera, the cost, equity, would this recommendation impact health equity, acceptability, do we think that this is gonna be acceptable to key stakeholders, and finally, feasibility. So the first five of these are evidence on health effect, and the last four are evidence on what we call the contextual factors and ETD approach. Again, I would like to conclude with one more piece of data to understand the process. This is, again, for one PICO. You can see on the left the desirable and all the way down to feasibility, so these are the nine domains, and for each of these domains, for each PICO, we would decide whether the desirable effect is trivial, small, moderate, large, unknown, or varies, and we would go down the list for the nine domains. At the end, we will get a color picture like this, a matrix, if I may say. If most of the boxes that light up are on the left, that means there is not a whole lot of certainty about recommending a certain treatment. On the other hand, if you have more moving to the right side, then there would be more certainty, and of course, we have to examine that carefully and come up with a recommendation balancing desirable and undesirable consequences for the recommendation. On the left is in favor of the intervention. On the right is in favor of the alternatives, and these are the five choices we had for each PICO questions, either a strong recommendations against or a conditional recommendations against the intervention, a conditional recommendation for either intervention or control, we try to stay away from that because that's basically a flip of a coin, conditional recommendation for the intervention, and strong recommendation for the intervention. We have one of five choices. We try not to go for the middle choice, and if we have a strong recommendation against the intervention, that means that we assessed that the undesirable consequences would clearly outweigh the desirable one. Conversely, if we go for a strong recommendation for the intervention, the desirable clearly outweighs the undesirable. A conditional recommendation against the intervention means that the indesirable consequences probably outweigh the desirable, and in parallel, the conditional recommendation for the intervention, the desirable probably outweigh the undesirable recommendation. So this is the thorough process that we had to go through for each PICO. I'm gonna move on and allow Dr. Clines to explain some of the ungraded practice statements behind the recommendation before we move to the cases and the recommendations with evidence. Great, thank you, Gada. So we formulated eight ungraded good practice statements, and so these statements are, we thought, are common sense recommendations when there's really high certainty that the desirable effects of an intervention clearly outweigh its undesirable effects, but the body of evidence is indirect or lacking. So here's the first, here's eight recommendations here. So in patients with hypercalcemia malignancy, adequate hydration with IV fluids is first-line therapy. This is important because many patients, most patients who have severe hypercalcemia malignancy are volume deplete due to the diuretic effect of high calcium in the blood. So these medications, bisphosphonates, don't work immediately, so it's really important to hydrate these patients immediately. The second one is dental hygiene and oral health. These patients are at risk for developing osteonecrosis of the jaw, and if there's any concern about that, these patients should be referred to a dentist or a surgeon, so there's something to consider. Vitamin D levels should be monitored just because if their vitamin D levels are low, they're at risk of developing hypocalcemia after treatment. The fourth statement is in patients with hypercalcemia malignancy, renal function should be assessed, obviously, before prior administration of IV bisphosphonates, being cautious or being nearly contraindicated for GFRs that are less than 30. The fifth one is in patients with hypercalcemia malignancy and renal insufficiency who are treated with IV bisphosphonates, consider the GFR in these patients, reducing the dose of pomidronate or zoledronic acid, and increasing the time of administration to reduce the risk of further renal dysfunction. Six, in patients with hypercalcemia malignancy, serum magnesium and phosphorus levels should be monitored and completed if determined to be low because these could go even lower with antiresorptive therapy. Seven, in patients with hypercalcemia malignancy, clinical oncology consultation for treatment of the underlying malignancy should be undertaken, obviously, and then finally, the eighth one, in patients with hypercalcemia malignancy due to parathyroid carcinoma, surgical consultation should be pursued for definitive treatment. So we're gonna move on to cases. In case there's some late joiners, we'll give us, everybody, about 15 minutes, or 15 seconds, rather, to scan the QR code. For those who came in late, we'll have some audience polling questions. Okay, are we good? All right. Okay, we're gonna kick off with our first case, and out of the eight recommendations, three of the recommendations are embedded in this first case. So the first case is a 39-year-old female who presented to her primary care provider with fatigue, weight loss, polydipsia, and polyuria. She was found to have hypercalcemia with a quite elevated serum calcium of 14.8 milligrams per deciliter, a lower phosphorus, an elevated creatinine of 2.7 milligrams per deciliter, and an elevated urea nitrogen. She was then sent to the emergency department, a repeat lab, showed something very similar, calcium elevated at 14.1, creatinine was 2.6. She had a chest X-ray, but this was normal. So it's really important, as I said before, in patients who have hypercalcemia that they are usually volume deplete due to the diuretic effect of high calcium in the blood. So it's really important to restore uvulemia because the kidney has a really great capacity to remove excess calcium, assuming that if their kidneys are actually perfusing. So this patient got one liter of bolus of normal saline followed by the two to 300 cc's an hour of normal saline. I wanna comment about furosemide. You see this in some recommendations. This is really unproven. These patients are already volume deplete and giving them furosemide, even though we do know it does cause calciuresis, it's not gonna work well if the kidneys aren't being perfused anyway. We would consider this in patients who might be volume overloaded due to congestive heart failure, but generally for most cases, we do not recommend, furosemide is not recommended. So this patient was admitted to the hospital on day two. Her calcium was better, it was 12.4. Creatinine had improved as well, but her PTH was suppressed. All right, so here's the first real polling question. So what therapy would you prescribe next? A, calcitonin, B, denosumab, C, zoledronic acid, or D, sinicalcid? You just go to the next slide. Yeah, that's it. Okay. Slowing down. All right, so looks like zoledronic acid one, denosumab second, calcitonin third, and this isn't a calcit, very little. Okay. Actually, zoledronic acid, denosumab, each are both correct answers, at least in this initial case. So this patient received zoledronic acid, four milligrams IV over 30 minutes. So this leads us to our very first recommendation. So in patients with hypercalcemia malignancy, we recommend, I wanna use the word recommend, I'll come back to this, treatment with IV bisphosphonate or denosumab compared with management without IV bisphosphonate or denosumab. And so we give this a strong recommendation, and the evidence for this are four reports that were published in the late 80s and early 90s of using IV bisphosphonates compared to saline in patients with hypercalcemia malignancy. Two of these studies used IV atidronate, one used clodronate. Many of the trainees have never heard of these medications because we don't use them that often. But one, the last one by Gukalp et al. used pomidronate, and it's something we do use commonly these days. But these are the only four who compared it directly with bisphosphonate or any antiresorptic compared to placebo. So this is one of the ETD tables, and so, does my, I guess our pointer doesn't work, it's okay. So in the first row is, what was significant is resolution, what is that? It's the red star. Oh, great. Doesn't work, that's okay. So in the first row, what was significant is that the risk of bisphosphonate or denosumab or antiresorptive, the relative risk was higher for the resolution of hypercalcemia compared to without medication. And the relative risk for this was 2.22, and this was significant. Mortality was not different between the two groups. Adverse events were obviously higher in bisphosphonates, and adverse events in these studies included infusion reactions, fever, hypocalcemia, hypophosphatemia, and change of taste as well. This is a different view of the same data. This is a forest plot showing a combined analysis of all four studies showing that the relative risk for resolution of hypercalcemia was better with bisphosphonates in this case, again, with a relative risk ratio of 2.22, and this was significant. I include the figure here on the left from Gukalp et al, and this is the group that studied IV pomidronate, and the top line is saline, and there was two other treatment groups was pomidronate 60 milligrams given over four hours or 24 hours, and as you can see, that there was a more rapid resolution of hypercalcemia in those who received pomidronate. I also like to note, and this was not included in our guidelines, that there is one report comparing pomidronate to zoledronic acid, and it was noted that zoledronic acid did lead to more rapid resolution of hypercalcemia compared to pomidronate. So what are the justifications for this decision? Again, I said there are no trials comparing zoledronic acid or denosumab to placebo evaluating treatment for hypercalcemia malignancy, so the justification for this came from grade guidance when low-quality evidence suggests benefit in a life-threatening situation, and again, many patients with hypercalcemia malignancy die of hypercalcemia. So the panel discussed the hypercalcemia malignancy is often a life-threatening situation and noted that the consideration justifies the strong recommendation. Okay, so this goes to recommendation two. So in adults with hypercalcemia malignancy, we suggest, and I wanna make this a difference, but the previous one we recommend, this is suggest treatment with denosumab over an IV bisphosphonate. We gave this a conditional recommendation. We found five prospective phase three clinical trials. We enrolled patients with solid tumors, bone metastases, multiple myeloma, and they were randomized to treatment with either zoledronic acid, four milligram dose, or denosumab, 120 milligram dose. Only one study evaluated for the prevention of hypercalcemia malignancy as endpoint. We were looking at the treatment, so we considered this indirect evidence. There was another study that also looked at prevention of hypercalcemia malignancy, but this was a secondary endpoint. And again, because of this, this is not direct evidence. We consider this indirect. And the paper below is the one I'm referring to that looked at hypercalcemia malignancy as the primary endpoint. Skeletal-related events in two of the studies was the primary outcome in two of these comparing denosumab to zoledronic acid. So what are skeletal-related events? So these are endpoints that are often used in bone metastasis studies. And so these include pathologic fracture, need for radiation, needs for surgery to repair an impending fracture, and spinal cord compression. As you can see here in this pooled analysis, in these two studies, that denosumab was superior in preventing skeletal-related events compared to zoledronic acid, and this was significant. So the strength, again, is conditional recommendations. The panel based its recommendation on very low certainty evidence demonstrating lower incidence of skeletal-related events and increased rates of hypocalcemia, both implying higher potency of denosumab versus a bisphosphonate. And so the panel actually had a lot of discussions about this, is that what is the balance between desired effects and undesired effects? We didn't wanna come out with a neutral recommendation as Gada had said earlier. So the desired effects of using denosumab over a bisphosphonate include better efficacy, fewer skeletal-related events, ease of administration, and more safety data in patients with chronic kidney disease. The undesirable effects include hypocalcemia and rebound hypercalcemia if patients aren't continued on denosumab. We completely recognize the fact that denosumab is FDA-approved in the United States for bisphosphonate refractory hypercalcemia malignancy. And then many of you know, if you've ever tried to get denosumab in the hospital, it's difficult or nearly impossible because it's not on inpatient formularies. I also like to say is that denosumab is currently not approved by the European Medicines Agency for treatment of hypercalcemia malignancy. All right, continue on with the case. So day three, this patient's calcium had improved 11.1 or creatinine improved as well. So next, so what therapy would you prescribe next? A, calcitonin, B, denosumab, C, continue with current therapy, or D, sinocalcite. Okay. All right. There's a clear winner here. So continue with current therapy. Based on our recommendations, we agree with that. So in patients with severe, this is the third recommendation. In patients with severe hypercalcium malignancy, meaning a serum calcium greater than 14 milligrams per deciliter, we suggest, not recommend, we suggest a combination of calcitonin and an IV bisphosphonate or denosumab as initial treatment compared with IV bisphosphonate or denosumab only. And the strength of this recommendation is conditional. And this is based on a single report of using modern dosing of calcitonin combined with bisphosphonate compared to bisphosphonate only. And I remind you, this is a retrospective study, not a prospective. And this is a figure from this paper from Kahn et al. showing that bisphosphonate plus calcitonin is in red, bisphosphonate alone is in blue. And that there was similarities in the resolution of hypercalcemia malignancy in both groups. But I want to point out, is those who received a combination of therapy started with a higher calcium in the first place. And so really the degree of decline was actually larger with the combination of therapy. The medium duration of calcitonin was about 72 hours. And you can see as time went on, those in the combination therapy, those who actually started with a hypercalcemia had a higher calcium, assuming they had bigger, larger tuber burden, actually increased. So this is our ETD table showing that the resolution of hypercalcemia, this is in the first row, with the addition of calcitonin or not was really no different between the groups. We did note that mortality was actually higher in the combined group. We discussed this quite extensively and our belief is that these patients who got combined therapy were sicker, had a higher calcium and a higher tumor burden. We don't think that calcitonin itself led to, itself led to increased mortality. So again, this is a conditional recommendation. So in patients with severe hypercalcemia malignancy and possibly in those with renal dysfunction, calcitonin in addition to IV fluids to temper the hypercalcemia. And again, while waiting for more important antiresorptives such as bisphosphonates and genoseptor work may be considered. So this is day number four. The patient's calcium is much improved. Creatinine is now normal. Patient was found to have an elevated PTHRP and a mammogram did show that she had a breast mass and she was eventually diagnosed with breast cancer. So that's the end of my case. If anybody, late comers again, wanna scan, be our guest. And then our next speaker. We can take questions from the audience. Yeah, we're gonna take questions. Feel free to come up to the microphones. We're gonna take questions after every case rather than. Yeah. Please. So I think you already discussed this about the CKD and we know that the GFR is calculated from the creatinine. And in individuals in whom we do not know the baseline and let's say they come in with an AKI and the GFR is like 20 or 15, then would that help you go choose denosumab instead of zoledronic acid? Yes. Because we don't know the baseline? Yes. So I think most of us, at least in the patient setting, would have a hard time or pharmacy, inpatient pharmacists would not allow us to prescribe an IV bisphosphonate if the GFR is less than 30. So in that situation, at least my anecdotal experience that in patients who do have CKD, we can in that situation do use denosumab. But it takes a little bit of work to convincing the pharmacist that's needed. But maybe some of you have better success. So I noticed that, Mitch Harmon, Phoenix, I noticed that about 25% of us wanted to start with calcitonin and I was one of them. And the reason is we did not know yet that this patient had hypercalcemia of malignancy as opposed to some other form of hypercalcemia. We only knew that her PTH was suppressed. So she might have had granulomatous disease. She might have had one of the malignancies that produces a high 125. And so I would want to know that before I gave a bisphosphonate because the treatment, in my opinion, if it's one of the others, would have been steroids, not a bisphosphonate. Fair enough. I don't know how quickly your 125 dihydroxyvitamin D values come back, at least at my institution. Well, that's why I think the calcitonin buys you a day or two to find that out. I mean, that's a fair comment. We're actually gonna come, actually, we have another recommendation based on this. So if you wanna hold that thought, we're gonna actually discuss this again in one of the recommendations. But I appreciate your comment. Yes. Jackie James from Toronto. Your recommendation for denosumab slightly over a bisphosphonate, did you consider in patients with existing osteoporosis that actually giving them a few doses of denosumab and then not following it up may actually be deleterious to their fractures? I mean, that, I mean, we, I appreciate that comment very well. I mean, that was your, this is kind of outside our PICO question. And, you know, we had the PICO question, at least initially, with you, is denosumab more efficacious than bisphosphonate in treating hypercalcemia malignancy? And again, we didn't think that it deserved, you know, against. We did not wanna be neutral. And again, we struggled, we did talk about this quite a bit, but ultimately we decided that we favored slightly that there was, you know, greater benefits of using denosumab over bisphosphonate. But that's a fair, your comment is very fair. Yeah. Did the patient have lytic bone lesions or PTHRP? This particular patient did not have lytic bone lesions. Yeah. Thank you so much for putting together wonderful guidelines. I'm Misha Zilberman. I'm actually an endocrine hospitalist. So the minute the guidelines were published, actually took it to our P&T committee, pharmaceutical therapeutic, and showed it to them. So now denosumab is in our hospital formula. Oh, congratulations, it's terrific. There is one person who is not too thrilled about is our pharmacy director because of the cost. She's like, well, denosumab costs $1,400 for zoonotronic acid, I don't know, $50, something like this? $15 for generic. But thank you. But again, you also have to, you know, consider the administration costs of IV especially, maybe that's not such important in the inpatient, but more outpatient. Oh, thanks. Hi, how are you doing? Cheyenne from New Hampshire. In regard to one of the good practice statements, you recommended in setting of monitoring vitamin D levels and treating as any other vitamin D level. So frequently you get patients with severe hypercalcemia and undetectable 25 OHD levels. Especially we live in Michigan. Yeah, so I guess the suggestion of the panel would be give no pause in giving zoonotronic acid as long as you are supplementing D in the same way you normally would. Right, I mean, I don't think, I mean, as I said before, patients with severe hypercalcemia are at risk of death because of the hypercalcemia. That's something you have to consider and replace vitamin D at the same time. And again, we know that using at least cholecalciferol, the effects are not immediate. So obviously it's something you need to monitor very carefully. And this is a known adverse effect in the clinical trials of hypocalcemia in patients who do receive bisphosphonate. It is tricky and basically you need just to monitor calcium levels very closely and do your best to replace vitamin D. Sure. Subhash Gokreja, Chicago. I have a concern about your conditional recommendations on dinosumab as the preferred over zoonotronic acid. The only studies, as you pointed out, is in zoonotronic acid resistant hypercalcemia. That's how it's FDA approved, right. Right, but even the data is very weak outside of the FDA. And the concern is, I know they use it for skeletal related events, but for hypercalcemia it is one week, two week, and four weeks. As opposed to every four weeks for the skeletal related events. So I think hypocalcemia, and I'm sure all of us have seen hypocalcemia due to dinosumab. So I would be very concerned. And I think the data, based on what you're making the recommendation, does not exist. That would be my concern. I totally appreciate your comment. And again, that's why we gave it a conditional recommendation. So it's not as strong. But it should maybe in the middle. The other comment, if I may make another comment. Yeah, do we have time? We have one more minute. One more minute. Related to the FDA, the package insert, zoledronic acid as Zometa is approved for creatinine below three. If you look at the package insert. So I think there is, even though we are saying EGFR of 35 for zoledronic acid, potentially, according to the package insert, it could be used even in patients with lower GFR. Okay, thank you for that comment. We have one more. Last question. My question was the dose of dinosumab. Is it, are you talking about 60 or 120? 120. Because 120 is approved for hypercalcemia. It is. We're talking about the 120 milligram dose. It's XGVA. Yes. Thank you. Okay, thank you. So Dr. Drake is next. Again, the same QR code for anyone who arrived a few minutes late. Otherwise, didn't change. Okay, so we'll move on to the second case here. This is a 77-year-old woman who presented with anemia, acute renal failure, and multiple vertebral compression fractures. Calcium was elevated at 14.2. Phosphorus was near the upper normal limit. Creatinine was also elevated in B1, was 58. An evaluation revealed multiple myeloma. She had 85% IgG lambda plasma cells in her bone marrow, which is fairly high, but certainly not out of the realm that we see. PET-CT imaging showed multiple lytic lesions in both the axial and appendicular skeleton. She was initiated on chemotherapy with medications, including daratumumab, lenalidomide, and dexamethasone, and achieved what the hematologists call a partial response. Importantly, from our perspective, her renal function improved significantly, and we were able to initiate her on treatment with IVs of aldronic acid provided once monthly. After 14 months, unfortunately, she had a biochemical relapse and an increase in her monoclonal protein and her free light chain values. Repeat CT imaging did not show any new osteolytic lesions, but her serum calcium, unfortunately, had increased to 13.1. Renal function remained acceptable, by cystatin C, with an estimated GFR of 51. So the polling question for the audience would be, in addition to optimizing hydration, what therapeutic approach would you consider? Do I need to? Oh, sorry. Okay. Looks like we've mostly finished here. Okay. So recommendation four from our guidelines are in hypercalcemia refractory resistant to intravenous bisphosphonate therapy. In adults with refractory recurrent hypercalcemia malignancy on already being treated with the intravenous bisphosphonate, we suggest the use of denosumab compared to management without denosumab. This was a conditional recommendation with the evidence cited there below. There were in fact three studies which we were able to include, one by Dr. Mimi Hu, who was actually part of our guideline panel, and this actually included the majority of the patients. This was actually a phase two study. The other two studies listed below as numbers two and three were actually case series. So this study, this is the evidence that we were able to look at. The study designs, they were all observational studies. Risk for bias was not serious across each of the studies. There was a concern for serious inconsistently in one of the studies. The indirectness was very serious in each of the studies, imprecision was not serious in two of the studies, and serious in one of the studies, and overall there were not other things which we needed to consider. So this is the forest plot again, which shows that, so if you look at the bottom there, the majority of the weighting was from the study by Dr. Hu on the top there, and it showed overall that following intravenous bisphosphonate by denosumab led to improvements in hypercalcemia and in fact resolution. So with the proportion was 0.67. So justification for this, the guideline panel made its recommendation by assessing indirect evidence. These were single arm studies in patients with hypercalcemia refractory to IV bisphosphonate, were then subsequently treated with denosumab. Overall, across these three studies, they included a total of about 45 patients. I believe about 35 of those, 36 of those were in that first study against small case series of three and four patients in the other studies. The panel identified as important both resolution of hypercalcemia and reduced mortality in patients with hypercalcemia refractory to IV bisphosphonate, who then received denosumab therapy. Importantly, no studies in patients refractory to denosumab therapy, there were no studies in patients who were refractory to denosumab therapy who were then transitioned the other way to IV bisphosphonate. There was just a lack of evidence of that. And the panel also noted the United States as Dr. Klein's already mentioned, denosumab is FDA approved for the treatment of hypercalcemia malignancy following IV bisphosphonate treatment only. So that was our justification. And with that, we can open this again to questions. We can take questions from the floor. Please come up to the microphones. Do you want him to give a microphone? Dr. Hershkovich, UMass. I would like to comment a little bit about the denosumab after the bisphosphonates. So the FDA couple of months ago, right after you guys put the guidelines, issued a warning regarding the use of denosumab in patients with elevated creatinine and or GFR. So we're not gonna go into the details of the cystatin-related GFR. But what I wanna say is that there was an elevated risk of hospitalizations both for hypo as well as for hypercalcemia in patients who received denosumab in this category of patients. What is your comment with regards to this guidelines? So the question is, what is our comment in response to the FDA guidance? I mean, we have conditional recommendations based upon the evidence that we have. I guess I can't really say a whole lot more than that. I can say in my clinical practice, which doesn't vary widely from this, patients who actually have received, who have received ibuprofen and then are followed by denosumab, I think have a little bit less rebound hypercalcemia. I've seen in my practice when the denosumab is discontinued, I think because a lot of their skeleton is actually coated with bisphosphonate. But again, that wasn't part of our guideline recommendation here. So again, I can't really say a whole lot more. Yes. Thank you, I'm one of the endocrinologists from London. Just a quick question about multiple myeloma. Does the guideline address the use of ionized calcium in this, in treating? In the sense, we often get very enthusiastic and continue to switch treatment or escalate to denosumab and eventually there's a risk of hypercalcemia and things. So we did not address ionized calcium per se specifically in the guideline. Typically in our clinical practice, my clinical practice typically recommend getting albumin and a total serum calcium and correcting that way. I think a lot of places, hospitals can use, do ionized calcium well, but some places perhaps not. If it sits around for a while, if the pH gets off or something, then it can be different. So we typically like to use an albumin-corrected calcium, at least in my clinical practice. But again, the guidelines specifically did not address. Yes. Hi, Carlos Botero from Orlando. Can you please define what refractory means? Like is that, what's a reasonable amount of time to- Yeah, good question. So what is actually defined as refractory? So earlier we described sort of different levels of their sort of mild hypercalcemia, moderate and severe. Probably if the person is in the mild category, probably not, and they're relatively asymptomatic, that would probably be not too much of concern. But if the moderate or severe category, clinically I would consider that to be refractory. Is there a time period where you should wait for on bisphosphonates before considering switching to denosumab? So bisphosphonates and denosumab each take at least probably three or four days until you're probably gonna start to see good effects. So I wouldn't sort of, if you treat it day one, I wouldn't sort of consider them refractory. I'd probably consider them after at least a week or maybe two weeks or something like that while you let everything else sort of play out and normalize. Yes. Your comments about vitamin D and hypocalcemia with these drugs, are those anecdotal or do we actually have evidence? Because based on the NEJM articles in osteoporosis, we really don't need to bother about vitamin D anymore, either to check it or to give it in people who are on prolia, for example. So like in the hospital setting, if you have someone with hypercalcemia, would you start them on vitamin D along with Xgeva? And how much? Would you look at their level? Would you base it on that or, I mean? Yeah, so the question becomes, what about vitamin D replacement in a patient who has evidence for hypovenrosis D while hospitalized with hypercalcemia? Is that the question? Who has evidence for what? I mean, I don't know that there's really evidence in the setting of hypercalcemia malignancy, but again, we would typically, in our clinical practice, like to replace those patients to limit the risk for developing hypocalcemia. But again, that was not part of our guideline. Because my impression is that if hypercalcemia is going to happen, it's going to happen, irrespective of whether someone's on vitamin D or not. It's usually mild. Okay. I mean, I'm not sure. I mean, is it like you guys have a dose of vitamin D or like, or something, anything? I mean, there are endocrine society guidelines that have been in place for vitamin D replacement. And I'd probably refer you there. Again, it was outside the scope of our guidelines per se. Hi. I've had a couple of patients who did develop hypocalcemia after denosumab or Xgeva. And it was a little bit of a dilemma on what to do on discharge. Of course, it happens right when they're about to go home and you don't want to send them home on calcium. And sometimes the oncologists don't want to start vitamin D in someone who has a high risk of recurrence and they could break through. So I think sometimes, I'm just not sure, do oncologists manage this just as much as endo or what's, because sometimes what we want to do differs a little bit. And I almost feel like their infrastructure for redosing might be better than we have in our own clinics. Sure. So I'm trying to sort of get a question from there. Sure, like a little bit, like should this be managed by us or oncology? Well, I mean, personally, I feel that endocrinologists are well-versed in this, probably better than oncologists in terms of understanding vitamin D. But again, I would refer to the guidelines that are in place for vitamin D. And if you can ideally address that upfront, I think the risk of developing hypocalcemia, it should be less. Thank you. All right, and I'd like to then bring back Dr. Gada El-Hajfouliam for the next section. I'd like to address the issue of lymphoma and hypercalcemia raised by one of our colleagues. This case is actually lifted from the literature and it perfectly illustrates the lack of evidence from modern drugs. This is a 77-year-old man who presented with hypercalcemia, had a normal vitamin D, a suppressed VTH, and slightly elevated calcitriol level. And typically their levels are one and a half to two times normal. Liver was six centimeter below the costal margin. CT showed massive retroperitoneal lymphadenopathy. He was suspected to have lymphoma and given prednisolone 40 milligrams a day one week before admission. This slide actually, can I have the pointer, illustrates on the right hand some of the biochemical parameters in this gentleman. And on the top panel is, I don't know why from distance it doesn't work. I'm sorry. On the top panel is calcium. Bear with me because you have the values in the table. So the calcium in admission was 13.3. The SI units are bolded two columns down. Phosphate was normal. Creatinine was elevated at 1.5 upper limit. 25 D was 48. 125 D was again one and a half times normal. PTH was relatively mid normal. It's an older assay. And urine calcium was elevated. Serum calcium started rising again to 13.8 milligram per deciliter soon after glucocorticoid discontinuation. So the question is, what drug would you use now? IV bisphosphonate, denosumab, glucocorticoids and IV bisphosphonate, glucocorticoids and denosumab, either glucocorticoids with bisphosphonate or glucocorticoids with denosumab. Okay. Perfect. So, we're right on with the audience in agreement here, and that's the right answer is E. I'd like to point out that the hypercalcemia and calcitriol-mediated hypercalcemia has a dual mechanism. One of them, of course, is increased intestinal calcium absorption, and therefore steroids, glucocorticoids, would be the perfect drug to start with. But in addition, there is a direct effect increasing bone resorption, thus justifying the use of anti-resorptive agent, and I hope that addresses our colleague's question. So, recommendation five. In adults with hypercalcemia of malignancies from tumors associated with high calcitriol levels, such as lymphoma, who are already receiving glucocorticoid therapy, since it's a primary therapy in these patients, but who continue to have severe or symptomatic hypercalcemia, we suggest the addition of an intravenous bisphosphonate or dinosumab compared with management without an intravenous bisphosphonate or dinosumab, and our patients actually had a fairly high calcium level. The strength of the recommendation was conditional, very low-quality evidence, and I'd like to just start by saying, giving the evidence for the glucocorticoid, which was not a PICO question, but just to show you what the data is. Of course, we all know that these are first-line therapy to address major mechanisms. What I've shown you in these three consecutive panel graphs are a quick response of calcium to glucocorticoids in patient one, who had adult-onset T-cell leukemia lymphoma, two who had histiocytic lymphoma, and three who had a mixed histiocytic and lymphocytic lymphoma. So quick effect within a couple of days and normalization, and then rebound upon discontinuation is not unusual. So what's the evidence for recommendation five? They were the four same trials that Dr. Clines had mentioned comparing the effect of IV bisphosphonate or dinosumab to placebo in patients with HCM in general. We did not find any data for the use of these agents from randomized trials in the case of calcitriol-mediated hypercalcemia. And again, I show you the same effect size estimates. On the left is resolution of hypercalcemia, which was 2.2 times more likely to happen. And of course, what you've seen from Dr. Clines' presentation is an increase in the incidence of adverse events, and the references are below. This is actually the evidence table, resolution of hypercalcemia 2.2 times. The total number of patients was 306 in four randomized trials. Mortality was actually 1.52. This was not significant. It crossed the confidence interval. It was just one randomized trial, which were described by the authors to have more severe disease. And the adverse events, again, were higher in the treatment with the randomized trial with bisphosphonates. The systematic review did not identify any direct evidence evaluating the effect of bisphosphonate or dinosumab in patients with calcitriol-mediated hypercalcemia, who were already receiving glucocorticoid therapies but continued to have severe or symptomatic hypercalcemia. We therefore drew upon case reports from the literature on patients with lymphoma and calcitriol-mediated hypercalcemia treated with glucocorticoid therapy, who were also treated with IV bisphosphonate, and thus very, you know, conditional recommendations with very low-quality evidence. What I've done here is tabulate the three case reports. They were one in one publication, two in another, and one in the third. And you can see their age was above 55, going all the way to 81. It was a mixture of mostly male, one female. The calcium levels were between 12 and 14. Creatinine was at the upper limit of normal. And the 125D was not, frankly, elevated. It was 1.5 times the upper limit in that de Volageur study. The doses used were actually the older bisphosphonate, pemidronate, that some of us still use because of low cost and efficacy. The doses were quite variable. It was 10 milligram in the first case with prompt response. The glucocorticoids were given before the bisphosphonate. The second series had two patients. One received 15 milligrams of pemidronate five days in a row over two cycles, and the effect was within two to three days. The glucocorticoid in one patient was post, and the other one was pre with a higher single dose, with a higher dose given as 30 times three days twice. The last case actually received one dose of pemidronate 60. There was a response within one week, and glucocorticoids and CHOP were administered post-bisphosphonate. These are the references. So not very convincing evidence. That's all we could find, and this is why we used an older case. So this is clearly a conditional recommendation with very low quality evidence. The justification is that IV bisphosphonate and dinosumab are both effective antiresorptive medications for inhibiting the osteoclastic mediated bone resorption that occurs as one of the mechanism with excessive calcitriol production. The panel concluded that the balance of effects, resources required, cost effectiveness, and equity all varied, but that the treatment will probably be feasible and accessible. The patient remained normal calcemic after 30 milligram of pemidronate given three days in a row, and then also starting prednisone five milligrams a day. And I'm sorry, I don't have a pointer. The top panel, you see these three arrows, and then gradual normalization of the calcium. Of course, in conjunction with treatment of the primary disease, which is instrumental in addressing hypercalcemia of malignancy, no matter what the etiology is. So I'm going to stop here and see if there are any questions. Please feel free to come up to the microphones for questions from the floor. Got it. I take it that the panel did not consider a, say something like keroconazole under these circumstances. Something would directly block the one hydroxylase, which is used effectively in a variety of granulomatous diseases. Not necessarily something like this, but it works. That was not included in our PICO question. We clearly specified the agents to be used as more potent. Your point is well taken. We usually don't think of ketoconazole in the setting of hypercalcemia, as you said, but mostly in granulomatous diseases, and that was the reason. It works. Thank you. Hi. I'm with Rochester Regional Health. So I had a question. So, for example, for this patient with the lymphoma, let's say he developed, he or she developed hypercalcemia and then eventually pancreatitis. Would you still recommend steroids, or would you hold off, because we know steroids can worsen pancreatitis in these patients? Well, hopefully. I mean, the steroids we would like to keep, depending on the dose, you've seen the dose variability of steroids used. I mean, we've seen cases or clinical experience with as little as five. So it depends on the severity. I mean, if the steroid dose is high and the patient clearly has pancreatitis, of course we're going to have to inch down and rely more on the antiresorptive effect. But that's, again, an expert approach, certainly not supported by any of the evidence we could find. Thank you. In this case, you repeated Pemidronate for three days. I didn't. They did. We had to go to the literature to illustrate that this is very old literature. Before, like, I don't know how frequently can we repeat Zomeda. I mean, do you guys have any comment on that? Or, and when do you call something bisphosphonate refractory then? When would you call it bisphosphonate refractory? Right. Refractory. Refractory. I think that question, let me start with that first. Refractoriness depends on the time since the administration of the drug. We usually like to give a week to 10 days. So, and again, the urge to treat what we call refractory is also driven in part by severity and symptomatology. So if a patient is very symptomatic and the calcium is rising, we may go before the week or 10 days. So that's, that refractoriness was not per se addressed in our guidelines, but I think this is how we would clinically approach it. Well, with regard to the first question? Well, I know that Pemidronate can be repeated. Right. Right. But what about Zomeda? I mean, if you were to repeat it, how long would you wait? Right. So we did provide, and I'm sorry, I don't have the table here. We did provide a table, which is one of the resources you have for the mode of administration and the frequency of administration. But Zoledronic acid, we probably could potentially treat within a week and two weeks if it's a very severe hypercalcemia. My experience has been we can do well with, you know, once monthly like the skeletal metastasis, but yeah. Okay. So did the panel have any recommendations for after the initial treatment of this hypercalcemia in the hospital, what is the long-term or the longer-term? Because their malignancy is ongoing, so they have risk of recurrence, and how do we monitor or manage? Well, I think if we're lucky and can, first of all, we would want to work with the oncologist and treatment of the primary tumor is essential, and we underscore that in the recommendations on graded practice statements that Dr. Clines had mentioned. And, you know, how do we consider, you know, if they recur or if they're not responding to their treatment? I think there's absolutely no data. We're in the data-free zone of what to do on the long run. I mean, what we had, as you saw, are studies that are the most of short duration. So, again, you're going to have to resource to expert opinion, and we did not tackle that in the guidelines because of the lack of data. Thank you. Two last short questions and short answers. We have one minute left. Very short. So, given the cost of one versus the other, why the recommendation is you give is equal weight for either or bisphosphonate or denosumab, given cost? So, I'm sorry. Say the question. Given the cost? The question is, you know, for these patients with malignancies and hyperglycemia, in this particular case, you recommended glucocorticoids plus IV bisphosphonates or glucocorticoids plus denosumab. Given the different, given the cost of one versus the other, why you gave equal weight to both recommendations? Okay. Thank you. I just want to clarify, first of all, that the recommendation for patients on glucocorticoid who have persistent hyperglycemia, what do we do? So, we assume they're already on glucocorticoids. And I think it depends on the setting. Some patients may be treated at home. And admission, per se, is quite costly. Some patients may live far away from where hospitals are available. And these were some of the considerations that I tried to illustrate in one sentence about the context. Where is the patient being treated? If he or she is an outpatient, far away from a hospital, and IV is not convenient, I think the travel cost, the cost of getting admitted, nursing cost, administration, may in some countries. And we left it very, that's where the varies come in by context and availability of the drug. So, your point is well taken. And that's where the physician taking care of the patient uses the guideline as a premise and then uses his or her judgment to decide what would work best. But in terms of efficacy, I think they would be equally expected to have the same effect. Yes? Lawrence Hofbauer, Germany. Yes. Question, hemodialysis as the ultima ratio, question mark. Thank you so much. So, we did not have that. Thank you so much for raising that, Lawrence. We did not have that as a question in our PCOS. I refer you, and I'm sure you're well aware of the beautiful review by Dr. Theresa Geis and Dr. Walmosky in the New England Journal, bringing that as an additional potential avenue to treat this patient. It was not included in our PCOS. Thank you so much. Thank you. And I'm going to hand it to my colleague, Dr. Makocsi, who's going to go over the last three recommendations on parathyroid carcinoma. Thank you, Gada. Good afternoon. So, we'll discuss the treatment of hypercalcemia related to parathyroid carcinoma. And I will start with this case, a 15-year-old man with a history of one year of nausea, constipation, increased thirst, severe pain at knees, and recurring bilateral nephrolithiasis, who presented at the emergency unit. Routine tests included serum calcium and PTH, and as you see, there was a markedly elevated serum calcium, 16.4 milligrams per deciliter, and PTH of 1,471 nanograms per liter. So, this biochemical signature is pathognomonic of primary hyperparathyroidism, of severe primary hyperparathyroidism, and the patient actually had clinical feature that were suggested for parathyroid carcinoma, namely male gender, highly symptomatic with disease, severe hypercalcemia, serum calcium above 14 milligrams per deciliter, and serum plasma above 3 to 10 times the upper normal limit. So, the question I would like to pose to you is, what would you be, would you consider as therapeutic approach? Urgent parathyroidectomy, parathyroidectomy followed after control of hypercalcemia with senacalcet, parathyroidectomy after control of hypercalcemia with hydration, or parathyroidectomy after control of hypercalcemia with intravenous bisphosphonate? I think we can stop here. And I see that there are major review that consider hydration as a first option, and bisphosphonate, particularly zoledrolic acid. I'm a little bit surprised to see sinacalcet because we are faced by a patient with severe hypercalcemia and we know that sinacalcet has a low begin-onset-advancet, has to be titrated. So let's see what we did. And first of all, I would like to mention that in patients with parathyroid carcinoma, the most appropriate approach to manage hypercalcemia, as long as it's feasible, is surgery. And of course, in our patient, that has to be considered. But because of the severity of hypercalcemia, we actually choose to treat the patient with isotonic saline, one liter over two hours, and then 200, 300 milliliters per hour, followed by furosemide. And as we mentioned before, there is no agreement and evidence that furosemide is effectively useful in this context, but this is what must be done in the emergency unit in PISA. And then the patient was admitted to the hospital and we started intravenous zonal electronic algorithms with progressive reduction of sinucalcin up to 12 nanomilligrams per deciliter over three to four days. The workup of the patient revealed a six-centimeter right parathyroid mass with a strict adherence to the thyroid lobe, and multiple brown tubules were detected by x-ray. One month later, the patient was admitted to right inferior parathyroidectomy together with ipsilateral thyroid lobe, and this kind of surgical approach is the gold standard when I have a suspicion of parathyroid carcinoma. The inferior laryngeal nerve was partially resected because of strong adherence to the parathyroid mass. At that time, there was no mention of local invision in the surgical report. Histology was consistent with parathyroid carcinoma and surgery was followed by resolution of hypercalcemia and development of a severe angry bone syndrome that was treated with calcium trihydrate and calcium. Afterward, serum calcium remained in the upper part of the normal range for about one year, and then progressively increased up to 12 milligrams per deciliter. At clinical evaluation, we performed necrotasound, and total body contrast enhancing CT did not show any residual parathyroid tissue or distant metastasis. What would you do at this time? Start synacalcic therapy, hydration, IV zoledronic acid, or denosumab. I think I can stop the voting and go after and see what we did. We started oral Xenocalcite and it was titrated to 60 mg twice daily with partial control of hypercalcemia that range in the follow-up between 11.2 and 11.4 mg per deciliter. What's the recommendation 6 says? In patients with hypercalcemia or malignancy due to parathyroid carcinoma, we suggest treatment with either a calcimimetic or an intravenous bisphosphonate or adrenosumab. And after remembering that surgery should be considered as long as feasible, so when no longer is feasible, the remarks say that in adults with mild hypercalcemia and related symptoms, we suggest starting therapy with calcimimetic. Conversely, for adults with moderate to severe hypercalcemia-related symptoms, an intravenous bisphosphonate or adrenosumab should be the initial therapy. And the recommendation consider the more rapid onset of action of bisphosphonate or adrenosumab and this has to be considered, of course, in case of severe hypercalcemia and generally a better tolerability profile than a calcimimetic that, as you know, as long as you try to increase the dose, often appear side effects, particularly at the gastrointestinal site. The recommendation is conditional for intervention. And there are some evidence that are all indirect evidence. We know that normalize serum calcium in 70% to 80% of patients with primary hyperparathyroidism with mild to moderate hypercalcemia. In a population with more severe primary hyperparathyroidism, namely three single harm observational studies in patients with intractable primary hyperparathyroidism or parathyroid carcinoma with moderate to severe hypercalcemia treated with sinacalcet, hypercalcemia normalized in 14 of 43 patients. And here you see the forest plot that summarized the data. These reports have also shown transient reduction of serum calcium in patients with incomplete response to sinacalcet treated with intravenous bisphosphonate or adrenosumab. I want to mention also a paper that was not included in our literature review. This is a phase three trial comparing sinacalcet 30 milligram by AD, then adjusting the dose according to serum calcium to a maximum of 90 milligram twice a day in patients who had primary hyperparathyroidism and contraindication to surgery. And also in this case serum calcium normalized in 75% is very similar to the first study I mentioned to you. The strength of magnation is a conventional intervention and the justification is that the panel agree that based on low, very low certain evidence, non-important difference were seen in the outcomes with any of the three regimens. And the panel concluded that the balance of effect, resources required, and the equity all varied, but that the treatment would probably be feasible and accessible. I want to make a comment at this point. Please remind that the remark were to consider sinacalcet in mild cases and EIV bisphosphonate or adrenosumab in moderate or severe cases. So the patient was treated with sinacalcet and we lost the patient follow-up probably mostly because he was living far from our country. But we had some mail with him and he was always complaining of side effects of sinacalcet. When you see the patient three year after, three, four year after, he came with serum calcium of 13.2 milligram per deciliter and PTH3178 nanomoles per liter. So what will you do at this time? Increase the daily dose of sinacalcet, go back to hydration, add intravenous teledronic acid or add adrenosumab. Okay, most, the large majority, prefer go back, go to an antiretroviral drug. And this is what actually we did. We started intravenous zoledronic acid, added to sinacalcic with partial control hypercalcemia. And that time, however, contrast anaesthetic CT showed two continuous neck lesions, 10 and 18 millimeter at the site of prior parathyroid surgery. Also in this case, no distant metastasis were detected. In a recommendation we are referring is recommendation seven, in adult patient with hypercalcemia due to parathyroid carcinoma, not adequately controlled despite treatment with calcimimetic. We suggest the addition of an intravenous bisphosphonate or DMAP compared to management without intravenous bisphosphonate or DMAP. The strain group recommendation is conventional recommendation for intervention. And also in this case, we do not have any direct evidence. Anyway, there are cases reports that show transient reduction of serum calcium in patient with incomplete response to sinacalcic treated with intravenous bisphosphonate. We have more data concerning denosumab. We have a one case series and nine case reports that included a total of 19 patients, 11 of whom have parathyroid carcinoma with hypercalcemia refractory to sinacalcic and or bisphosphonates, and 11 patients with parathyroid carcinoma at the resolution of their hypercalcemia after denosumab treatment. I have to inform you that this was a short-term treatment, and we do not have other information concerning long-term use of denosumab in parathyroid cancer with uncontrolled hypercalcemia. There are a few case report that show actually persistence of effect after months and even years. Justification, the adverse event often observed during the detrition of sinacalcin frequently prevent reaching the effective dosage needed to control hypercalcemia. In this constant, we expect that the addition of either intravenous bisphosphonate or denosumab therapy will lead to a decreased sinacalcic dosing, improvement in control of hypercalcemia, and decreased hospitalization, and will eventually exert positive impact on outcome of interest, including reduction of adverse event. The panel concluded that the balance of effect, resource required, and equity all varied, but that the treatment would probably be feasible and accessible. So two months later, following the finding on the CT scan, the patient was submitted to further surgery with radical restriction of the lesion in the right extending to the mediastinum with no sign of invasion into adhesion tissue. Histology consisted with the diagnosis of parathyroid cancer, and also in this case after surgery, there was a remission of hypercalcemia, and serum calcium, the average serum calcium was 9.8 milligram per deciliter. Four years later, the patient was seen again, and at this time, serum calcium was mildly elevated and the same true for PTH. The patient, with the exception of the initial observation, has never made major complaint related to symptom of hypercalcemia. Four months later, serum calcium increased again to 13 milligram per deciliter, and PTH to 336 nanogram per liter. Following the recommendation six, we started zoledronic acid, four milligram that was given every one to two months, with incomplete control of hypercalcemia. So at this point, the question is whether to increase the frequency of zoledronic acid at senacalcet, replace intravenous zoledronic acid with DMAP, consider further surgery. Oops, excuse me. I want to go back. No, no. Okay. So, the large majority was in favor of adding or using an antiresorbent drug, intravenous zoledronic acid or consider further surgery. At that time, we didn't have any kind of information. What we knew is that the surgeon that did the latest operation said that would have that concern in doing further surgery. But what is, of course, reasonable to do is, as I said before, this approach. What about considering the placement of intravenous zoledronic with DMAP? As was mentioned before, DMAP was not approved in Europe for treatment of hypercalcemia or malignancy, so that option was not available for us. And what we did, we actually considered to adding sinacalcet since the hypercalcemia and the bisphosphonate was not so severe. And the reason why sinacalcet can be added to bisphosphonate is because it acts in a different way as compared to bisphosphonate because hypercalcemia and hyperparathyroidism is, in large part, mediated by the action of PTH on bone and on the kidney and indirectly by hydroxidation or 25-hydroxidase in the intestinal absorption. Sinacalcet acts at the kidney, in this case, as well as the PTH and the parathyroid level. But as we know, the effect on the parathyroid secretion is rather modest, whereas the treatment with sinacalcet could increase urinary calcium excretion. So we thought that that could be an option. And as you see, we get a little bit more effect going down to 11 milligram per deciliter. Recommendation eight says that in adult patient with hypercalcemia or malignancy due to parathyroid carcinoma who are not adequately controlled with an intravenous bisphosphonate or DMAP therapy, we suggest the addition of a calcium emetic comparing to no addition of a calcium emetic. The strong recommendation, again, is conditional recommendation for intervention. And we did not have any evidence to support the recommendation because there are no studies looking at this specific issue. And the justification was that the panel noted very low certainty of evidence and lack of high-quality studies on import outcomes. And the panel concluded that the balance of effects probably favor the intervention, that the cost of resources may be moderate, and that the equity would vary, but that the treatment would probably be feasible and accessible. I think I have finished, so. We do have time for two short questions from the audience. And while people are coming up to the microphones, I'd like to ask Claudio to comment on the use of senacalcet for metastatic disease with tumors that are not of parathyroid origin. Well, my comment was already mentioned before because we may take advantage of the effect of senacalcet on the renal tubule where it decreases calcium absorption so may increase urinary calcium excretion. Thank you. Thank you. We know that, you know, in severe hyperparathyroidism, postoperative hungry bone syndrome is almost inevitable. And then if we were to block osteoclast activity further with denosumab preop, are we putting them at risk of refractory hypocalcemia postop in that situation? In other words, will it be easier to use senacalcet or calcitonin preop? Will that be an ideal option? Well, you mean that you will be able to decrease bone turnover? But in this instance, we have emergency to do surgery. So I don't think that can be taken into consideration. This difference could be in a programmed treatment or a patient with moderate hypercalcemia, whether this could be a vote. As far as I know, there are no studies that show this to be advantageous. And another issue is that the hungry bone syndrome is related to the fact that the bone turnover, the AISH remodeling unit, is due by reabsorption. That usually is rather short. And formation that takes much long time. So the question is whether you will be able to intervene on bone formation if you want to take an advantage of denosumab or bisphosphonate in this setting. And I'm not sure that this is going to be the case. One last very short question, please. Short answer. So we also have patients with parathyroid carcinoma which cannot approach surgery because of financial restraints. So we're kind of like stuck in the time where we can apply surgery and we have to treat them with these solutions. So are there any developments in conventional chemotherapy or maybe immune chemotherapy for parathyroid carcinoma instead of applying surgery only and controlling hypercalcemia? Thank you. Well, there is very little in this setting. There are only case reports showing moderate effect of TKI inhibitors, sorafenib, or as well as FGF1 receptor 1, levantinib. And also recently studied using pembrolizumab which is a checkpoint inhibitor. That all have been effective in reducing serum calcium but are very short-term studies. So we don't know whether that could be able to cure the patients. I have one. We can take the questions at the end. We have only like one minute left. There's a typing error on your leaflet. That's what I wanted to mention. Thank you. I will show you. Gada? Thank you so much for those of you staying. I'll wrap up quickly. This is a very nice flow diagram that's available in the pamphlet and on the website. There are a lot of resources. Basically to summarize, we went by severity of hypercalcemia mild, moderate, severe, and whether it's refractory. And basically embedded the recommendation in that flow diagram. For Dr. Bickley, I want to mention that also we did not have ketoconazole of one of the alternative strategies. We certainly did not come across any studies comparing denalchimab or bisphosphonate to ketoconazole because our review of the evidence would have picked that up. We have two special populations outlined there. And I'm going to really close for the sake of time. We will stay beyond the session at the podium for all of you who have questions. Dr. Kahn? I'd like to thank all of the speakers for exceptional presentations. Thank you. And I'd also like to thank Christopher McCartney and Marie McDonnell from the Clinical Practice Guidelines Committee Chairs, Suzanne Jandabur, Karen Smith, wife of late patient Freddy Smith, patients from Lebanon, Italy, and the U.S. who took part in the survey, Andrea Hickman and Maureen Corrigan. I'd like to thank you all for your attention and your participation. Thank you.

Endocrine Society

Clinical Practice Guideline

Hypercalcemia of Malignancy

Adults

Alia Khan

Guideline Development

Evidence-based

GRADE Methodology

Treatment Options

Denosumab

Zoledronic Acid

Refractory Hypercalcemia

Hypercalcemia in Parathyroid Carcinoma