Welcome, everyone, to the ACE ASAP Live. This is the bone and parathyroid disorders section, and these are our illustrious ASAP course leaders. Dr. Cyrak is a professor of medicine at Eastern Virginia Medical School, and we'll just call Geetha. She's the associate professor of medicine at Brown University. This section here, we have, hopefully, Dr. Diab will be here. Dr. Diab is a professor of medicine at the University of Cincinnati and also the fellowship associate program director and VA site director. And I'm Rob Wormers. I'm a consultant and chair in the Division of Endocrinology, Diabetes, Metabolism, and Nutrition at Mayo Clinic, Rochester. These are our disclosures. So the way this will work is that we will go through a series of cases today, and you'll have a chance to vote on the right answer. These are questions from ASAP. The Zoom poll opens, select your answer, and then we can, at the end of each case, we can discuss questions that you might have. So with no further ado, we'll go ahead and proceed with case one. So case one is a 55-year-old woman who's referred for persistent hyperparathyroidism after a parathyroidectomy one and a half years previously. Her current calcium level is 8.8 with a parathyroid hormone level of 133 picograms per mL. Preoperatively, her calcium level was 9 milligrams per deciliter, and that was on several measures. She was in that kind of range. Her PTH then ranged in the 88 to 106 picogram per mL range, and she had a parathyroid scan done by her provider, and they said there might be a left superior adenoma. She subsequently went for a parathyroidectomy, and pathology revealed a small normocellular parathyroid gland. She does have osteoporosis based on her bone density, and despite good compliance with raloxifene over the past three years, she was started on Alendronate. She subsequently stopped Alendronate because her bone density declined, even though she was taking it correctly, and her current bone density shows osteoporosis with a femur neck T-score of minus 2.7 and lumbar spine T-score of minus 2.1. She denies kidney stones, fractures, and has many symptomatic concerns, including cognition, fatigue, arthralgias of her feet, and constipation. Other pertinent medical history includes Graves' disease, treated with radioactive iodine 12 years prior. She's had difficulty regulating her levothyroxine dose, and currently is taking 112 micrograms alternating with 125 micrograms daily, even though she takes her medicines correctly. She's not had any abdominal surgery. She denies radiation exposure other than radioactive iodine for Graves' disease. She denies lithium or thiazide diuretic use, and she had menopause at 45 years of age. Her family history is unremarkable for parathyroid disease or endocrine syndrome, such as MEN1. And current medications include calcium citrate, two tablets twice daily, 315 milligrams, 250 IUs. She has an estimated 600 milligrams of dietary calcium intake. She takes medication for constipation in addition to her levothyroxine and vitamin D3, 4,000 IUs daily. Physical examination shows a normal weight, healthy-appearing individual, and really other than a collar scar, her examination is unrevealing. Laboratory tests now show a normal complete blood count, sedimentation rate, B12, folate, electrolytes, creatinine, and protein electrophoresis. And these are her laboratories, so I'll give you a second to look at that. Calcium is 9.2, phosphorus 3.9, PTH slightly elevated at 66, and 25-deoxyvitamin D is in a sufficient range at 37 nanograms per mL. Okay, so now is the big moment. So based on this patient's history and laboratory results, which of the following is the most important test to perform? Parathyroid scan with SPECT-CT, markers of bone turnover, cystatin C with estimated GFR, or 24-urine calcium and creatinine. So I think this is your chance to vote. Yes, exactly, so that is the right answer. Everyone got this right. 24-urine calcium and creatinine. So in this particular individual, the 24-urine calcium did come back on the lower end at 46, despite a good collection based on her 24-urine creatinine and generous calcium intake and high vitamin D intake. And subsequently, she was screened for celiac sprue and had positive IgA tissue transglucaminase, upper endoscopy confirmed, malabsorptive pattern consistent with celiac. And so rather than normal calcemic primary hyperparathyroidism, this patient was diagnosed with secondary hyperparathyroidism. There are many clues in the patient's history, including her autoimmune thyroid disease, her unexpected response to osteoporosis medicines. Remember that most patients treated with oral bisphosphonates will respond with either a stable or increase in their bone density, especially if they're taking it correctly. Her thyroid history with difficulty stabilizing your thyroid hormone was another clue. So I agree with the group that the 24-urine would be a good way to screen for malabsorptive issues in calcium. Now, normal calcemic primary hyperparathyroidism is really defined by normal serum calciums with an elevated PTH and no other causes of hyperparathyroidism. Typically, you want to have a vitamin D level at least 20 nanograms per mL, and some would suggest 30 nanograms per mL to suppress PTH maximally. And that would be what the most recent guidelines would suggest in the International Hyperparathyroidism Workshop. GFR should be above 40, and the 24-urine calcium should be not too low but also not high, where you might get another cause of secondary hyperparathyroidism. There are many other causes of secondary hyperparathyroidism. I'm going to cover those in just two seconds to think about. In this case, we wouldn't recommend option A, which is a parathyroid scan, unless you confirmed the primary hyperparathyroidism, and really here we were more suspicious it was secondary, so that wouldn't be appropriate. Markers of bone turnover are nonspecific and wouldn't be diagnostic in this particular case, so they really wouldn't be recommended. Cystatin C sometimes can actually be a good test if you're trying to assess renal function, especially in patients who have sarcopenia or conditions where you're concerned their EGFR may not be accurate through Cockroft-Galt or an MDRD calculation. So, yes, I'm sorry, very obese, so older adults, malnourished patients might be a situation to get a cystatin C. So I just wanted to show you this algorithm. This was just published in January in JES. Joe Shaker and myself published this review article on how to approach patients with persistently elevated PTHs and persistently normal albumin-corrected serum calcium levels and ionized calcium without a known cause of secondary hyperparathyroidism. A couple of highlights I want to point out, and I would encourage you, if you see these patients, this, I think, is a pretty reasonable article. I guess since I wrote it, I'm highly biased, but with that said, sometimes just checking PTH on a different platform or at a different reference lab can give you different answers. So consider checking PTH on a different analytic platform if you're seeing a persistent elevation in a single lab with normal calcium. If you do that and the numbers are staying elevated, then you need to think about other causes of hyperparathyroidism outside of primary hyperparathyroidism, and this includes chronic kidney disease, medications. You need to do medication reconciliation, as there are several medications that can do this. We have a list within this table that you might have interest in. Hypercalceria can be associated with secondary hyperparathyroidism, and in this case, it would be reasonable to think about a trial of a thiazide diuretic. Vitamin D deficiency, and here we actually suggest less than 30 being kind of the threshold where maybe you'd want to augment their vitamin D level and get it above 30 and reassess. Malabsorption, remember that after both gastric sleeve and Roux-en-Y, you can have elevated PTHs years after that procedure, thought to be due to gastric calcium malabsorption with low gastric acidity. Malnutrition or low calcium intake can lead to secondary hyperparathyroidism. There can be FGF23-mediated disorders, can sometimes be associated with hyperparathyroidism with a normal calcium. They should really have a marked hypophosphatemia, and then a couple of others we outline and cover more in that chapter or in this article. There are some other references for your review if you'd like. So let's move on to case two. So case two is a 57-year-old man being evaluated for recurrent insufficiency fractures. He developed subacute left hip pain four years ago that was initially treated with a, I'm sorry, do we have, I think maybe, do we have questions? Okay. Sorry, I just got a chat on here, so I had to look. Anyway, so left hip pain four years ago that was initially treated conservatively, but due to unresolving pain, an MRI was done and showed a left subtrochanteric insufficiency fracture. He was treated with teriparatide for 15 months with initial improvement in pain. About two years ago, he developed pain in both femurs and in the right femur. About two years ago, he developed pain in both femurs and MRI showed insufficiency fractures involving the subtrochanteric regions of the right and left proximal femur. The whole body scan showed increased uptake in the left posterior rib and right posterolateral 11th rib, so 10th and 11th ribs. He denied any issues with diarrhea, kidney disease, skeletal deformities, or a family history of bone disease, and he reports normal skeletal growth during childhood and young adulthood. So these are the laboratories, and you can see the, I'll let you take a peek at those, but calcium is normal. Phosphorus is low at 1.5 milligrams per deciliter. Magnesium is normal. Renal function is normal. Alkaline phosphatase is at the high end of normal, but bone alkaline phosphatase is about twice normal. PTH is at the high end of normal. Vitamin D was generous at 83. 125 D was in the lower normal range. 24 urine calcium was 75, and urine phosphorus was 728 milligrams. Her laboratories indicated the following ranges over the past five years. Serum phosphorus in the 1.7 to 2.1 range. Serum calcium within the lower normal range to mid-normal range. PTH was in the upper end of normal at 51 to 64 picograms per ml. And this is the bone density. Femur neck T-score in the osteopenic range, as is the total hip and lumbar spine. So what's the next best step in evaluating this patient's metabolic bone disease? Genetic testing for a PEX mutation. Obtain parathyroid scan, cestamib scan. Measure fibroblast growth factor 23. Obtain urine studies for pH, glucose, and amino acids. So please lock in your answers. Okay, so this one, the majority answered measure FGF23 level. So let's go through this one. I'm going to cover this one in a little bit more detail, but when you have FGF23, you're going to want to look at the FGF23 level. I'm going to cover this one in a little bit more detail, but when you have this patient's history would be consistent with osteomalacia, and it would be due to the hypophosphatemia. Now, to develop osteomalacia with hypophosphatemia, you really need to have chronically low phosphorus levels, because it takes time to develop osteomalacia. And remember, but if you have osteo, if you have impaired mineralization before pubertal development, it's rickets where you get bulging of the femur, commonly known as extremities, with weight bearing. But in adults, we call it osteomalacia, which is, again, impaired skeletal mineralization. So this is your differential diagnosis. This is always good to know for board exams, but dietary deficiency, malabsorption, it's been associated as well with a certain elemental formula that babies have used. Dietary phosphate binders, hyperparathyroidism, rarely could be associated with this. But in this bucket, really, we're more suspicious of an FGF23 dependent mutation. And then if FGF is normal, and PTH is normal, then we get into things like renal tubular acidosis, hereditary hyperphosphatemic rickets with hypercalceria, and certain medications can do this as well in heavy metals. So this is a, these are kind of the features of the FGF23, and some of the most common, I guess, FGF23 and hyperparathyroidism-related laboratories. So the key distinguishing feature is that FGF23, when it's high, in the two most common conditions, and the one you'll need to know for your board exams, are TIO and XLH. And the distinguishing feature is when generally will be when did they present and is there a family history of this? XLH is an autosomal dominant disorder, so it should be strongly penetrant in the family. And women, as it turns out, even though it's an X-linked disorder, women and men are affected pretty much the same clinically. And the key feature here is that both of them will have inappropriately elevated FGF23 levels. Remember that FGF23 inhibits the sodium phosphate transporter in the proximal renal tubule, which leads to urinary phosphorus wasting. In addition, FGF23 impairs the second step to form active vitamin D. So you'll see that 125D will actually be low or low normal. And this is a clue that it's an FGF23 media disorder, which this patient clearly had on their laboratories. 25D will be normal. PTH can either be normal or slightly elevated, and obviously phosphorus will be low. So for board purposes, I would say these top three disorders are the ones you're gonna have to really know because those are the most common ones by far. So I talked already about XLH. It's an autosomal dominant disorder. It's the most common genetic cause of hypophosphatemia due to increased FGF23 production. Most patients who have FGF23 due to XLH, excess due to XLH will present with Bowling, signs of Bowling of the lower extremities, have a family history, and it should be readily apparent, although there are some mild sub-variants where maybe it may present in adulthood, but those are less common for sure. So if there's any doubt, you can always do genetic testing to sort that out if you're not sure. And typically when you do genetic testing, there's a hypophosphatemia panel that's done to screen for all of these different things that we've mentioned that are inherited. TIO, on the other hand, can present the same, except that it presents in adults. It usually has a more rapid onset. And the key thing here is with TIO, these tumors can be quite difficult to localize. And at the current time, the test that we go to in Mayo Clinic Rochester is really the DOTATATE scan. Fanconi's is a proximal RTA type two that can be associated with proximal wasting of phosphorus. There, they should have other signs within a urinalysis or their bicarb may be abnormal. And in this particular case, the other clue was that the 24-hour urine was inappropriately high for somebody who has a low phosphorus. And you can calculate the tubular resorption of phosphate to confirm that either through 24-hour urine, or you can do a morning void and calculate the fractional excretion or the tubular resorption of phosphate. This particular case, this patient had a rapid onset and just given the clinical presentation, it would suggest they have TIO. So, and likely not an inherited rickets, so option A is incorrect. FGF23 would be the go-to test, which was the correct answer. This really was not a story suggestive of hyperparathyroidism. If they have hypophosphatemia, they should really have, usually have more significant hyperparathyroidism. Anyway, and there was nothing here to suggest that this patient had Fanconi's, but it may be something to consider, especially if FGF23 came back normal or even lower normal. So these are references in that regard. And we'll move on to case three. So this case three is a 73-year-old woman referred for evaluation of multiple atraumatic vertebral compression fractures. She was initially diagnosed with osteoporosis at 61 years of age. Her lowest T-score was minus 3.2 at the lumbar spine. She was treated with a Lendronate for one year, but because of significant GI irritation, she was switched to zoledronic acid once yearly for the next three years, and then she had a three-year drug holiday. Her primary provider reviewed an updated bone density, which showed some decline in bone density at spine. And so she was switched to denosumab, 60 milligrams every six months. Her bone density increased significantly after four years of denosumab treatment, and therefore her primary provider stopped denosumab. One year after her last dose, she developed sudden severe back pain without a fall or other injury, and spine radiographs showed a new vertebral compression fracture at L1, L3, and L4. So we'll queue up a question again. So, which of the following management options would be recommended to best treat the patient's osteoporosis and decrease the risk of future fracture? A, vertebroplasty. B, a Lendronate, 70 milligrams once a week. C, zoledronic acid, five milligrams intravenously. Or D, teriparatide, 20 micrograms subcutaneously daily. Okay. Okay. Well, this one's a little bit all over the place, so this'll be a good one to go over. So this is an important, important case, so I'm glad that there's something at least maybe to be taught here. So as you all know, denosumab is a potent antirank ligand monoclonal antibody that bonds rank rankle, and thereby prevents osteoclast activation, which reduces bone resorption. Now, when you use this medication, it can effectively reduce bone turnover. Also, it can lead to significant increases in bone density, both at the spine, hip, and wrist. In addition, it's been shown to reduce fractures, fragility fractures. The problem with denosumab is is that when it's stopped, there can be a rapid rebound in bone turnover with bone resorption exceeding baseline levels before starting denosumab for up to two years after discontinuation of this medication. And the current thinking is, is there are two kind of mechanisms that this is caused by. One is, is when you are on denosumab, cells called osteomorphs are formed. And once these osteo, once you stop denosumab, these osteo, fission occurs, and these osteomorphs will turn into an army of osteoclast that lead to aggressive bone resorption. Furthermore, OPG levels are markedly decreased because not only do you reduce bone resorption, but you reduce bone formation and osteoblast function. And OPG secreted by osteoblast is a key negative inhibitor of osteoclast. So the loss of your brakes, i.e. OPG, and an army of these fission of these osteomorphs leads to aggressive bone resorption. So this rebound bone loss can reduce bone strength and reports of multiple spontaneous vertebral fractures have occurred. And I just saw one this week with this exact scenario where somebody actually had the same thing happen after it was stopped about seven months ago. So the Endocrine Society recommends, and not only the Endocrine Society, it's just recommended that you really shouldn't stop Denosumab without considering antiresorptive therapy. Now, going through the choices on this particular question, you could use oral or intravenous bisphosphonates, or you could restart Denosumab potentially. But for this patient, the best option was zoledronic acid. And typically what I do when I have a patient on Denosumab and we wanna try to transition them off of it, I'll give that zoledronic acid six months after the last DMAP injection. There have been studies looking at different ways to do this such as treating based on bone turnover markers or giving it six months, and then again, when bone turnover markers go up. But when you look at bone density response, none of those appear to be superior to just giving it at six months after the last injection. The duration of DMAP treatment's important, and it's well known now that the longer you use this medication, the more aggressive the bone loss is. And cutoff points that have been proposed are somewhere around three to four years. If you use Denosumab beyond that three to four year mark, it's unlikely that even with zoledronic acid, you're going to be able to, you'll still see bone loss once you transition. It's not a reason to not try to get off the medication, Denosumab, if you think it's appropriate for sure, or if the patient wants to. But another key point here is you really wanna make sure your patients know this, and that they have to get their injections every six months, and they should never stop this medication without a transition plan. And that, you wanna tell them up front before you start this medication. We wouldn't recommend necessarily doing vertebroplasty in this particular setting. We really wanna try to prevent future fractures, especially since often the pain can improve, but it really doesn't address the main issue. Given her upper GI issues, restarting Lendronate really wouldn't be a good option. There is data with the Lendronate in patients who say that it's not a good idea to use Lendronate There is data with the Lendronate in patients who stop Denosumab, but the only data we have so far are patients who've been on shorter courses of Denosumab one year, and then transitioning to a Lendronate, and that works fine in maintaining bone density. It may be that a Lendronate once a week where you get exposed to the bisphosphonate more frequently than just once a year actually works better than Reclast, but nobody knows. We'll need more research to determine that. Now, an important point is, is that if you take a patient on Denosumab and switch them to teriparatide based on the data switch trial, you're going to actually see accelerated bone loss, especially at cortical sites. So switching from Denosumab to teriparatide is not a good strategy. And we do have several references there for your review. Okay, so we'll move on to case four. So this is a patient who you've met in a medical mission. It's an 18-year-old Gambian woman residing in a refugee camp for the past three years. She was complaining of muscle weakness and bone pain. Her diet varies depending on what she gets in food packages and what she can purchase with food, perishable items such as milk, orange juice, eggs, and fish are scarce. Bread and cereal are intermittently available, but the patient admits that she gives many of her rations to her other younger siblings. She denies loss of teeth, alopecia, fracture, statorrhea, or seizures. She has a lot of issues with her teeth. Her blood pressure, you can see, is normal, 112 over 62, weights 102 pounds, BMI is 17.5. And physical examination is significant for a waddling gait, enlarged costochondral junctions, and a positive shvastic sign. So I can't read this entire question, but here we go. Although you do not have a laboratory on site, what would be the expected laboratories in this individual? And you're gonna need to take a look at this. I'll give you a minute to look at this. A, low calcium, high phosphorus, high alkaline phosphorus, and B, high pH, high pH, high alkalinity. And C, high pH, high alkalinity. A, low calcium, high phosphorus, high alkaline phosphatase, high PTH, normal 25-hydroxyvitamin D, normal 125 D. B, high calcium, high phosphorus, low alkaline phosphatase, normal PTH, normal 25 D, normal 125 D. C, low calcium, low phosphorus, high alkaline phosphatase, high PTH, high 25-hydroxyvitamin D, high 125 D. Or D, low calcium, low phosphorus, high alkaline phosphatase, high PTH, decreased 25 D with an increase in 125-dihydroxyvitamin D. So, everybody's answered D. So, let's go through the answer here. And I, so in this particular case, refugees, and especially breastfed infants, are at increased risk for nutritional vitamin D deficiency, which is what we're seeing here. Also, patients with malabsorptive disorders, such as celiac, cystic fibrosis, inflammatory bowel disease, malabsorptive gastric surgeries, biliary, severe biliary tract disease, intestinal small bowel overgrowth, can all increase the risk for vitamin D deficiency. There can be some other risk factors, including sun exposure, certain medications like anticonvulsants, which can accelerate catabolism of the active form of vitamin D. Same thing with antiretroviral drugs, same thing with antiretroviral therapy, glucocorticoids. Ketoconazole can inhibit production of vitamin D. Obesity reduces vitamin D levels, and prematurity and low maternal vitamin D levels. So, in this particular case, option A was wrong. It would be more suggestive of CKD, where you get secondary hyperparathyroidism. So, in this particular case, you'll often see a low calcium, a higher phosphorus, high PTH in that setting, and decreased 125-dihydroxyvitamin D. And you can sometimes, especially with more severe disease, and especially with stage five CKD on renal replacement therapy, you can see high alkaline phosphatase. Option B would be more suggestive of possible hypophosphatase. The clue there is gonna be a low alkaline phosphatase. So, this is an inherited mutation of the ALPL gene, which encodes for tissue nonspecific alkaline phosphatase enzyme. This results in accumulation of pyrophosphate, which impairs calcium and phosphorus, mineralizing the skeleton, and ultimately can lead to osteomalacia, especially in more severe forms of this disorder. Classical kind of stories you would see on a board question might be early tooth loss with the root intact in a younger individual. Metatarsal stress fractures. Atypical femur fractures can be seen in this group, and also chondrocalcinosis is another clinical manifestation. Now, option C was a case of vitamin D dependent Ricketts type 2, which is an autosomal recessive disorder where you have resistance to 125D at the receptor level. And there you'll see the classic findings of low calcium, low phosphorus, but PTH will be high and as is 125 and 25. You can also have individuals with vitamin D dependent Ricketts type 1, which typically these individuals will have a one alpha hydroxylase gene mutation that leads to inability to produce 125D and hence can lead to osteomalacia through that mechanism. So you were correct, vitamin D, option D for vitamin D was the correct answer. And so what I might do is just go over to the kind of this nice, a couple of nice charts that I think you'll find kind of useful. This is one of those board questions that you just have to review. And there are often questions that will give you calcium and phosphorus and PTH and vitamin D findings. And you need to just be able to review or be able to see those and recognize those. So we talked about type vitamin D resistant Ricketts type 2 which is that inability to activate the 125D receptor versus type 1A where you can't convert 25 to 125D. This is actually a defect of 25 hydroxylation vitamin D resistant Ricketts type 1B. And vitamin, there's a newer form now called vitamin D resistant Ricketts type 3 which is an accelerated catabolism of vitamin D as the main mechanism here. So these patterns can all be seen. They usually make, especially you need to be able to distinguish between 1A and 2. That's gonna be your board question. Now in individuals with vitamin D deficiency you could see them at many different stages early on versus intermediate versus later. And I'll just point out to develop osteomalacia from vitamin D deficiency, you have to have severe vitamin D deficiency that's longstanding. And it should be pretty dramatic when you see this. And so the key here though is even an early vitamin D deficiency you can have a lowish calcium and a high PTH. Alkaline phosphatase can be high and urine calcium can be low. Now, the key thing that you should recognize is that 125D may not be a good marker for deficiency and can actually be elevated in many patients who have underlying vitamin D deficiency that's significant. And so 125D would not be a recommended test really for vitamin D deficiency. And that's important to recognize. And there's a reference for you. So let's move on to case five. So this is a 72 year old. And I think I might've been muted this whole time. I apologize. Oh, sorry about that. This is a 72 year old. Sorry about that. This is a 72 year old woman with stage 3B chronic kidney disease who's referred for evaluation and management of postmenopausal osteoporosis with a recent low trauma fracture after taking a Lendonate 70 milligrams for a week, once a week for three years. Three years ago, she fell on the ice and fractured her left wrist. She has tolerated a Lendonate without difficulty and specifically has not had any issues with gastroesophageal reflux, osteonecrosis of the jaw, atypical femur fractures or other side effects. But last week she fell again after tripping over a loose rug at home and fractured her right hip. Her bone density has been stable with a Lendonate over the last three years. Her most recent bone density of the spine showed a T-score of minus 2.5, femur neck bone density was minus 1.5 and her left total hip T-score was minus 1.3 when checked six months ago. So what would you expect with regard to this patient's bone turnover markers? Elevated bone specific alkaline phosphatase and elevated beta CTX. Elevated bone specific alkaline phosphatase and decreased beta CTX. Decreased bone alkaline phosphatase and elevated beta CTX or decreased bone alkaline phosphatase and decreased beta CTX. Okay, so we have a few different answers here, but most picked choice A, which is elevated bone alkaline phosphatase and elevated beta cross-slaps. And that is the right answer. So a couple of things about bone turnover markers. These are obviously, as you all know, we have coupled bone formation and bone resorption and normal bone remodeling, where you dig out old bone via osteoclast and then osteoblast follow and lay down osteoid, which then subsequently is mineralized and forms our skeleton. Now, these can be useful in some situations to monitor. And a couple of the classic markers of bone formation include bone specific alkaline phosphatase, which will be your cheaper one. I usually utilize this, but you can also do a P1MP or a propeptide of type one collagen. Bone resorption markers, on the other hand, such as beta CTX, are the breakdown products of collagen that can be detected in both serum and urine. NTX would be a urine breakdown product. And these can be useful markers of bone resorption. Now, it's important that you measure these typically in the morning. They can be altered by food intake, the time of the measure. So if you're doing a urine measure, we typically recommend a morning second, or I'm sorry, that should be morning fasting levels. Whoops. Morning fasting levels for serum. And then a second void morning sample, actually, for the urine. Now, a couple of things. There are different, you can get different results depending on your reference lab. So if you're using them for comparison purposes to check a baseline level with a follow-up level, you should do those at the same lab. It's also important to know that in patients with chronic kidney disease, that we don't have any good bone resorption markers. So in patients with chronic kidney disease, you really wanna do bone-specific alkaline phosphatase, or you could do P1NP, as they are not affected by renal clearance like bone resorption markers, which will be elevated if you measure them in patients with significant chronic kidney disease. Now, in this particular case, they both would be elevated because when you fracture a large bone like a hip, you're going to have fracture repair ongoing, which is typically associated with, part of it is remodeling that fracture and then bridging that fracture. And that will be associated with high bone turnover markers. And in fact, these turnover markers can stay elevated for several months after a fracture. So in patients who fracture, the key message here is, if you wanna assess whether or not they're getting adequate benefit from an anti-resorptive standpoint, it's gonna be hard to do that in a patient who's had a recent fracture. And there's some references for your review. And we'll move on to the last question here. So this is a 47-year-old African-American woman with polymyalgia rheumatica who's been treated with prednisone, 30 milligrams daily over the last three months with a plan to continue high-dose steroids with a slow taper over the next six months. She was unable to tolerate rituximab. She sustained an atraumatic L1 vertebral fracture while lifting groceries a week ago. She has no prior history of fractures. Her dairy and dairy products Her dairy intake is low and she does not take any calcium supplements or vitamins. Her menses are regular. She's premenopausal. She has a history of Hodgkin's lymphoma and was treated with chemotherapy and radiation. She's had a tube of ligation. She doesn't smoke or drink. She walks 7,500 steps a day. BMI is 24. She has no history of an eating disorder and her only medication is prednisone. And she has a strong family history of osteoporosis. Physical examination is consistent with polymyalgia rheumatica, in addition to back pain, consistent with her fracture. And her bone density shows a lumbar spine T-score of minus 3 and a femur neck Z-score of minus 2.1. So aside from calcium and vitamin D, what's the next best step in her bone health management? Tenosumab, 60 milligrams every six months. Romazosumab, 210 milligrams every month for one year. Melendronate, 70 milligrams once weekly. Teriparatide, 20 micrograms subcutaneously every day. Okay, let's see if we have an answer here. Okay, so this is a little bit all over the place. So I have some for DMAB, a couple for a lendronate. Okay, well, let's go through this. So, DMAB is a drug that's used to treat osteoporosis and osteoarthritis. It's a drug that's used to treat osteoarthritis and osteoarthritis. So, glucocorticoid-induced osteoporosis is a very common form of secondary osteoporosis. This patient has a history of a fragility fracture, and this combined with a low bone density puts her at a high risk for future fracture. Her bone density obviously fits with osteoporosis. So based on the American College of Rheumatology guidelines for the prevention and treatment of osteoporosis, the preferred first-line treatment for this woman of childbearing age with a high risk of future fracture without a plan for pregnancy and a disindividualized tubal ligation as your clue is an oral bisphosphonate. So option C would be the best answer. Oral bisphosphonates are preferred given their safety profile, evidence in regard to fracture reduction, low cost, and really lack of evidence other than with teriparatide in a head-to-head trial and reduction of fractures and improvement in bone density. Now, the FDA has approved both bisphosphonates and teriparatide for treatment of premenopausal women taking glucocorticoids with low bone mass. In younger individuals, we don't have the same fracture data we have in older individuals, but clearly these are high-risk patients. In one study that I just referenced earlier, in patients age 22 to 89, treatment with teriparatide for three years did show a better increase in bone density and fewer vertebral fractures compared to alendronate. Now, if an oral bisphosphonate isn't appropriate for whatever reason, then according to ACR guidelines, you can consider other therapy. Teriparatide, though, would be a good choice because this patient had radiation exposure. So for board exam purposes, they're really gonna want to know when to treat and which drugs to treat with, which shouldn't be treated, what drugs shouldn't be used. So the American Society of Bone and Mineral Research has a little stronger recommendation that teriparatide may be an alternative to bisphosphonates if a woman is considering future pregnancy because it wouldn't be expected one stop to affect fetal bone development. So donosumab, I'm gonna show you the newest guidelines that haven't even been published yet, but according to the last published guidelines, donosumab was considered a fourth-line therapy. It has approved for treatment of glucocorticoid-induced osteoporosis, but there are other issues that we talked about earlier with using donosumab and stopping it in the future. Romazosumab hasn't been studied in glucocorticoid-associated osteoporosis, so really it would be a drug I typically wouldn't use until we have more data in this setting, although it should work, but we'll see. So FDA-approved medicines for GIO include alendronate, recidronate, ibandonate, zolandronic acid, donosumab, and teriparatide. We only have fracture data, though, for alendronate, recidronate, ibandonate, and teriparatide. So this is the new, and this question was actually written just before these guidelines came out. They haven't even been published yet, but they should be published any time now. But in this particular individual who was greater than 40 years of age, who obviously had an osteoporotic fracture as well as osteoporotic bone densities, she met all these, she'd meet all these criteria, even very high dose. If they plan 30 milligrams or more for three months or longer, this we'd wanna use, consider treating even without some of those risk factors or fractures. This case that she's not of childbearing age, or she's not gonna bear children because she's had tubal ligation. First line recommendation then is to treat with an oral bisphosphonate. And they've gotten rid of the different levels of therapy, first line, second line, third line. They've really just said, if you can't use an oral bisphosphonate, you can consider an IV, teriparatide, or botuloparatide, or donosumab. And so these are the newest guidelines that should be published any time now. And these are some references, and we'll add the new reference once it's published. So with that, I apologize, I didn't have my, or my, I was muted for a portion of that. I guess I missed that, but, and I'm happy to answer any questions. I do see here a question about how long to continue reclassed after donosumab. So it's not known for sure. I typically will treat maybe three years after they stop, just because that's how I usually use reclass in a lower risk patient. I'm worried that if you give them one reclass, they may still have some bone resorption occurring, especially longer term donosumab use. Some of my colleagues, I'll just say, may give a dose, not only at baseline, after six months after stopping, but then again in another six months. But I typically, if I typically favor maybe three reclass infusions personally. And there's no data on that, by the way. Any other questions? Okay, hearing no other questions, I think it's time for dinner for many of us. I do appreciate your attention and hope you learned a few pearls here that you'll find useful in your practice and for taking boards, or if you have to take boards in the near future, I hope that helps. Have a good night.

bone disorders

parathyroid disorders

hyperparathyroidism

insufficiency fractures

zoledronic acid treatment

malabsorption

muscle weakness

alkaline phosphatase

oral bisphosphonate treatment