Hello, good afternoon, and welcome to the session titled Osteoporosis Conundrums. My name is Jennifer Kelly, and I will be the moderator. Just a couple housekeeping notes, if you could please silence your cell phones, and then after the three presentations, we will have time to answer questions, and we will have people please come up to the microphones in the middle of the aisles, and we ask if people could please limit to one question to give others a turn. So it's my pleasure to introduce our speakers for today. Our first speaker will be Dr. Gigi Abate. She is an assistant professor of medicine at the Mayo Clinic, Florida, in the division of endocrinology. Dr. Abate's research and clinical interests are in metabolic bone disease and transplant-related bone disease. She completed medical school at Loma Linda University Medical School, Loma Linda, California, where she obtained her medical degree. She subsequently completed an internal medicine residency and endocrinology fellowship at the Mayo Clinic College of Medicine. She has conducted multiple studies to investigate the unique bone health issues that organ transplant recipients encounter before and after transplant. She is currently conducting clinical trials to identify optimal imaging modalities in order to understand the unique fracture challenge that transplant recipients experience. Our next speaker will then be Dr. Vin Tengpreetcha. He is a professor of medicine and the program director for the endocrinology fellowship program in the division of endocrinology, metabolism, and lipids at Emory University School of Medicine in Atlanta, Georgia. Dr. Tengpreetcha received his medical degree from Tufts University School of Medicine and completed his internal medicine residency and endocrinology fellowship at Boston University Medical Center. He completed his PhD degree in molecular medicine on the topic of vitamin D at Boston University School of Medicine. He serves on the Endocrine Society Guidelines Committee for the Hormone Treatment of Gender-Nonconforming and Gender-Incongruent Patients, which has published two international guidelines on transgender patients. He served on the World Professional Association for Transgender Health Guidelines for the Standard of Care for Transgender People in 2011, and he currently serves as the chair of the Hormone Chapter and Updated Guideline SOC 8. He served as a committee member for the 2019 ISCD Official Position Statement on Bone Densitometry Measurement in Transgender and Gender-Nonconforming People. He is the immediate past president of the World Professional Association for Transgender Health. He has received funding from the Cystic Fibrosis Foundation and the NIH, and he has published over 250 peer-reviewed manuscripts on transgender medicine, vitamin D, and cystic fibrosis. And then our last speaker today will be Dr. Albert Hsieh. He is an endocrinologist whose clinical practice focuses on osteoporosis and calcium disorders. He currently sees patients in Westwood, Torrance, and Santa Monica, and is board certified in endocrinology, diabetes and metabolism, and internal medicine. Dr. Hsieh received his medical degree and completed his internal medicine residency at the Weill Cornell Medical College in New York. He then moved to Los Angeles, where he completed his endocrinology fellowship at UCLA. He grew up in the greater Boston area and underwent his undergraduate degree from the Massachusetts Institute of Technology, where he majored in biology. In addition to his clinical work, Dr. Hsieh is actively involved in osteoporosis research and has published in top journals in the field, including the Journal of Clinical Endocrinology and Metabolism, the Journal of Bone and Mineral Research, and Osteoporosis International. His research was recognized by the American Society for Bone and Mineral Research through a Young Investigator Award. He has also served as guest editor of the Bone Disorders Issue of Endocrinology and Metabolism Clinics of North America, and is currently a reviewer for Osteoporosis International. So thank you for everyone for attending, and I welcome our first speaker. Okay, good afternoon, everyone. Thank you for coming, and I understand this is the last bit of the talk, so thank you for staying behind. So I'm delighted to talk about a topic that's dear to my heart, which is transplant-related bone disorders. And then, red, so I'm trying to push it, yeah. Is it moving, or? Oh, here we go, okay, so my mistake. So the learning objectives of this talk are to discuss the risks of osteoporosis in transplant patients, and how to best assess transplant patients for risk of fracture, work up an evaluation for osteoporosis in this population, and when and how to treat transplant patients, and then briefly about management of kidney transplants, which are separate. So I'll be talking about solid organ transplant primarily. So we'll start with the first case of a 66-year-old white male with history of end-stage liver disease comes into your pre-transplant clinic, and he has, his liver disease is due to NASH, and he was diagnosed about five years ago. His complications include variceal bleeding, ascites, hepatic encephalopathy, and he has high MELD score of 22. These are all consistent with decompensated cirrhosis. And upon further questioning, he has no prior history of fractures. He had a past medical history significant for NASH, and hyperglycemia, and hypertension. He's on PPI, hydrochlorothiazide, spironolactone, lactulose, and rifaxamine, and he doesn't drink much alcohol, no tobacco use. And we always get a DEXA scan, or our hepatology friends get a DEXA scan on all patients coming in for transplant evaluation because we know that bone disease is prevalent in this population. So his DEXA scan shows he has osteopenia at all sites, with the lowest being his spine or the T-score of minus 2.0. And you review his labs, and he has the typical hyponatremia related to his liver disease, but the rest of his labs are pretty normal. His total 25-hydroxyvitamin D is 32, his PTH is normal, and his serum calcium is kind of in a low normal range, and his 24-urine calcium is normal. So how would you approach this patient? And this is in a pre-transplant center. So in addition to calcium and D, you know, would you get a, you know, he has osteopenia, no prior fracture, would you just watch him and recommend calcium and vitamin D, and see him back in six months with another DEXA scan, and then again in 12 months, or would you get a spine X-ray, or would you decide to treat before or after transplantation, or you wouldn't do anything? So I'm just going to move forward and tell you what we've done. So in this patient, we got a spine X-ray, which showed he had a T12 compression fracture. And it was chronic. He did not have any back pain at the time of his X-ray. And we felt that he likely has osteoporosis, and treated him with soledronic acid prior to his transplant. So what is the data behind that? So one of the data that we have from Cohen in 2004, published in JBMR, rate of fracture and osteoporosis extremely high in pre-transplant and post-transplant population. So in liver transplant, osteoporosis is about 16 to 46%. And fracture is, you know, close to almost 50%. And lung is similar, heart, kidney transplant. So they tend to be in that high group. So our initial, when you look at this, the initial thought is, okay, this is from 2004. So things have changed since 2004. We have less glucocorticoid we're using in this population. We have more glucocorticoid-sparing drugs. And they're transplanted faster now. So maybe this data has changed. So another thing I wanted to point out is the location of fracture is also slightly different in this population. So this paper from Elizabeth Shane back in 1996, they did a prospective trial of cardiac transplant, men and women undergoing cardiac transplant evaluation. And when they did a spine x-ray, they found that thoracic and lumbar spine tend to be the most common site of fracture, and hip and ribs being less likely to be location for fracture. And then when they looked at when do these fractures occur, and they tend to occur mostly after transplant within the first 12 months, and the first three months being the most common time, the highest risk of fracture time. So this is all from 1990s and early 2000s. So what's going on in the current transplant era? So we wanted to look further into that. And we published an endocrine practice in 2021 at Mayo Clinic in Florida. We looked at our retrospectively liver transplant patients who received transplant between 2011 and 2015, around 400 liver transplants. And we looked at their x-rays, CTs, MRIs, looking for any fractures that we can identify. The average age was 60, and time to transplant was about 90 days, which is pretty common now. And when you look for new fractures that occur within the first year after transplant, about 38 out of... The number of people who have fracture within the first year was 41 out of 286 of post-liver transplant recipients. So it's about 14%. And most of those were vertebral fractures, and some of those were multiple vertebral fractures. And when we delved in a little deeper, and they had x-rays because they had symptoms. So these were symptomatic fractures. And there were some that were picked up by x-rays, and those were new compared to their pre-transplant fracture. So the number of fractures have not seemed to be... Have gotten any lower with our current transplant regimens. And then we also wanted to look at, okay, so when we see these patients before transplant, so what would be the most predictive factors that we should be looking for? And what we found was that the presence of fracture before transplant was the most predictive to post-transplant fracture. So that was one of the most important risk factors. Use of glucocorticoid was not really significant determinant of post-transplant fracture. So we concluded that the risk of fracture in after transplant is multifactorial, likely, and it's from glucocorticoid use combined with use of other immunosuppressants such as tacrolimus, cyclosporine, hyponatremia, we know increases risk of falls, and also osteoporosis and fracture, sarcopenia. These patients are malnourished, poor nutrition, calcium and vitamin D deficiency. Use of certain medications like proton pump inhibitors, which can lower calcium use and fall risk tend to be high because of the sarcopenia risk and lifestyle. So some people may have had extensive tobacco use or alcohol use. So take on point in 2021 is about 14% of fractures are after transplant, which is quite significant. And the most predictor of post-transplant fracture is the presence of pre-transplant fracture. And BMD can be normal in these patients, as I've showed you quickly that a lot of our patients had normal or osteopenia on a bone mineral density. So what would be a best way to assess these patients? So this is from Kroll and 2014, they did a prospective study where they did a spine x-ray along with bone density, and they looked for fracture and pre-transplant patients. And they found that the rate of fracture was quite high on spine x-ray, suggesting that maybe we should add a spine x-ray to our pre-transplant evaluation. So in our practice, and there's no guideline for transplant evaluation, and these patients fall in between glucocorticoid and, you know, regular osteoporosis. So they have their own bone disorder, and we do complete history and physical. So, you know, identifying those who've had fracture is the most important factor. So whether by history or getting a spine x-ray, or even reviewing any CT or MRI images you have available on their chart would be useful. And then consider treating patients prior to transplant. And this is sort of the protocol we use is if somebody has osteopenia on a bone density, then we investigate further for fractures. And if they do have fractures, then we, you know, we treat them with azoledronic acid before transplant. And we know that there's some data to show that that reduces risk of post-transplant fracture. And some of these are the typical bone workup that we do, which is common to osteoporosis workup. So what are the treatment options? So bisphosphonates are the mainstay treatment for these individuals, and that's where we have the most studies for. And if somebody has a creatinine clearance greater than 35 and they meet criteria, whether they have osteoporosis by bone density or you identify their high risk for fracture because you identify a fracture, treating them before they go to transplant seems to be quite effective in preventing fracture post-transplant. And oral bisphosphonates have limitations, especially in these individuals, you know, if they have esophageal varices, et cetera. It's contraindicated. How about denosumab? We don't have any studies using denosumab in pre-transplant individuals. This particular one looked at, you know, post-transplant patients and seems to be safe to use, but in pre-era that's, we don't have that data. And then I would caution you that there's risk of hypocalcemia with denosumab. And what happens when you stop it? Can you continue it after transplant? So there's a lot of unanswered questions. How about using teriparatide? As Dr. Wormers mentioned this morning in the review, teriparatide is superior in glucocorticoid induced osteoporosis. So, you know, I've used it, but again, you know, you've got to use caution as to they're also sick individuals. So what do you do after using teriparatide? So bisphosphonates remain the mainstay treatment. We know that calcineurin inhibitors can affect the bone, but overall we think of them as bone sparing because they allow us to use less glucocorticoids. So they tend to have less effect on the bone, although tacrolimus probably have a little bit more than the cyclosporine. And then briefly about CKD. So kidney disease is extremely, you know, it's completely different than the other solid transplant. And just to, this can take on its own talk, but to briefly mention that, you know, there's a lot of things that are dysregulated in patients who are kidney, end stage kidney disease and after kidney transplant. So you have to, those are treated differently. So in pre-kidney transplant, we look at their metabolic profile. So what's their phosphorous level? What's their calcium? Can you regulate their vitamin D, PTH level? So that would be the focus. And be very cautious to use any medication in these individuals without getting a bone biopsy. And because you want to determine whether or not they have adynamic bone. And adynamic bone means that their bone turnover is very low or nonexistent and antiresorptives would be harmful. And as you can see, and the percentage of adynamic bone disease is high in hemodialysis and peritoneal dialysis patients. So bone biopsy is typically required prior to treating these individuals. And if a bone biopsy indicates that they have high bone turnover before or after transplant, then using medications like denosumab would be useful. So in post kidney transplant would be where I would consider treatment. The KDGO guidelines in 2017 is what we use. And they do recommend getting bone density after kidney transplant. And if they do have low bone density, consider treatment with either bisphosphonates or denosumab in those individuals. If they have normal metabolic, you know, PTH, calcium, and those things have been maximized. So in summary, osteoporosis and fracture risk is high pre and post organ transplants. And the best predictor of post transplant fracture is presence of pre-transplant fracture. There are multiple factors that play a role here. So I think it should be seen as its own separate entity when you're treating these patients. So, you know, using x-rays and history and trying to identify who are high risk regardless of bone density is the first step. And if you determine that they're high risk because of high risk for fracture post transplant, then using bisphosphonate would be the first line of treatment. If you can use that with their kidneys, and if not, perhaps waiting after a transplant rather than denosumab use, unless they do have a lot of fractures, then you may want to consider teriparatide or denosumab pre-transplant. But mostly we usually wait until after transplant because of lack of data in using denosumab in pre-transplant individuals. And as I mentioned, only consider denosumab or anabolic therapy in those patients with multiple fractures that occurs before a transplant. After we treat them just the same as we would for any non-transplant individuals. And management should also include, you know, making sure maximizing nutrition, physical therapy, improving mobility, and really assessing for fall risk and metabolic derangement evaluation. And thank you very much. Thank you for asking me to speak on this important topic of skeletal health and transgender patients. My name is Vintang Preach and as you heard, I'm a professor at Emory University. These are my disclosures. I don't have any commercial financial relationships to the content of this talk. I was the past president of WPATH and I'm currently editor-in-chief of Endocrine Practice and I get funding from NIH and the CF Foundation. So my learning objectives today are to list the factors for low bone health and below bone density in transgender people, describe the approach in screening and diagnosis of low bone density in transgender people, and to discuss the fracture risk in transgender people following the initiation of gender-affirming hormone therapy. So I'm going to start with a case and this is a case I saw in my clinic a few years ago. A 50-year-old transgender woman presented for osteoporosis evaluation. She has been on gender-affirming hormone therapy for three years prior to her appointment today. She unfortunately developed a DBT following orchiectomy due to inadequate DBT prophylaxis so she had to discontinue her gender-affirming hormone therapy as recommended for at least a year. Her bone density demonstrated osteoporosis with its lowest T-score of negative 2.9 at the spine. She has no prior history of fractures or falls, no family history of fractures. She's not currently on steroid medication. She doesn't currently take VIMD or calcium. She's mostly sedentary and not currently employed. These are her lab tests, her sex hormones, estradiol now off of the gender-affirming hormone therapy, 27, testosterone undetectable after her orchiectomy, and her DEXA report shows a spine L1 to L4 T-score of negative 2.8. Her right femoral neck T-score is negative 2.1 and her right total hip was negative 1.9. So before we discuss what happened to her, what do we know about bone health of transgender people prior to starting gender-affirming hormone therapy? So I'm going to highlight two studies. One was from Europe, mostly from the Belgian, and they looked at 25 transgender women, 25 age-matched cisgender men, and a reference population of over 900 men. They measured bone marrow density prior to the initiation of estrogen in the transgender women, and this was an age group in the late 30s. And so this was one of the first studies looking at bone health in transgender women prior to starting gender-affirming hormone therapy, and you'll see on this slide, I've highlighted in red the transgender women, and to the right of the transgender women are the two different controls, and you'll see that in all the bone sites, the femoral neck, total hip, and spine, the bone density is lower. In fact, if you look at the spine T-score, between negative 1 and negative 2.5, 32% had bone marrow density T-scores that could be compatible with osteopenia, low bone density. If you looked at the spine T-score of less than negative 2.5, 16% of the transgender women had very low bone marrow density. And it's a little bit surprising. This is even before starting hormone therapy. These women did not receive any gender-affirming hormone therapy prior to this point. The authors measured 25-hydroxyvitamin D, and it was significantly lower than the two populations, so they hypothesized perhaps transgender women are not getting outdoor physical activity, their diet is not as good, maybe that explains why the bone density is lower in the transgender women, even before starting hormone therapy. Subsequently, I don't think you can see it very well, but subsequently this study has been replicated in Brazil, and I've just highlighted in yellow pretty much the same pattern. The spine, femoral neck, and total femoral bone marrow density is lower in transgender women compared to cisgender women, and this is prior to starting gender-affirming hormone therapy. Again, the authors conclude perhaps it's decreased physical activity, inadequate diet, including vitamin D. So what happens when transgender women start on gender-affirming hormone therapy? So fortunately, bone density seems to be improved with start of gender-affirming hormone therapy. This is a study from Belgium. They looked at about 50 transgender women, and they started on estradiol valerate, four milligrams a day, or a patch, and all these women were greater than age 40, the women who were on the patch were greater than age 45, and they received a oral progesterone cyproterone, something we don't use in the United States, but you should use that to interpret these data, but we use spironolactone in the United States. Nevertheless, you'll see the same pattern on the figure. Compared to control men, for some reason, again, the bone density is much lower, but with the initiation of hormone therapy, there seems to be improvement of bone marrow density. So fortunately, it seems like gender-affirming hormone therapy does improve bone density and somewhat reverses this low initial bone density state that transgender women have before starting gender-affirming hormone therapy. The Endocrine Society commissioned a systematic review to look at this issue, and I mean, unfortunately, there are not a lot of studies looking at this topic, but you can see the data that we do have over 24 months demonstrate an improvement in lumbar spine bone density. There are only about three studies in this meta-analysis, and so that's pretty consistent with the two studies that I presented earlier, that there is improvement in bone health after starting gender-affirming hormone therapy. It's somewhat neutral on the femoral neck. At least there's preservation of bone health in the femoral neck, but it's not improved after 24 months. What about transgender men? I wanna highlight this study. This was a study I did when I was a fellow, and I had concerns that when you start transgender men on testosterone, you're lowering their estradiol, and maybe that's detrimental. And this was a very small case series. We looked at testosterone-naive transgender men, so those were transgender men prior to starting testosterone and transgender men already on testosterone. Pretty small study, but the average age was in the 30s and 40s. You can see the average dose of weekly testosterone was 60 to 70, and half of them smoked, so that's an important caveat. Nevertheless, this is the data for the transgender men that were newly started on testosterone, my hypothesis was incorrect. They actually had improvement in bone density. So you can see on the left side, the hip bone density improved significantly by two years, and the spine bone density had a slight improvement by year one, but it was not statistically significant by year two, but you can see in general, their bone density was preserved. I guess looking back on this study, I should have known that the testosterone is aromatized to estrogen and bone, and I probably had the wrong hypothesis when I started the study. But I think this is good news for transgender men, that the testosterone is protective of their bones. Again, the Endocrine Society did commission a meta-analysis and found that the testosterone therapy in transgender men was neutral in terms of preserving bone density. Didn't significantly improve it, but at least kept it about the same after 24 months. We've been wanting to have long-term data in this field for many years, and we finally got some in 2018, and this is data from the Dutch, looking at bone density changes in transgender populations. And their protocol is to get a bone density at time zero, two years, five years, and 10 years. And let's focus on the top two squares of this figure. You'll see the transgender women in the top left, and transgender men on the top right. And you'll see the same pattern in transgender women. There's an initial bump-up of the bone density. This is the, I think this is the, must be the spine. And you see that initial bump-up in bone density. So there's some recovery, reversal of that low initial bone density state. And then over time, the bone density seems to be preserved after 10 years. In the transgender men, it seems to be stable over 10 years. So this is the first time that we've received some good news that the bone status seems to be preserved with gender-affirming hormone therapy. This is the first time we've had fracture data. And this is a study from Amsterdam. They looked at the rates of fracture in transgender men and women. And the way they defined fractures were fractures seen in the emergency room. So we have to take that into account. It may not have all been fragility fractures. But nevertheless, they compared the rate of fractures seen in the emergency room to control men and women. They divided the group into transgender women greater than 50 and transgender women less than 50. For the transgender women less than 50, you can see in the dark bar, the rate of fracture is in between cisgender men and women. And it wasn't significantly different. So that's good news. There isn't an increased rate of fracture in cisgender women less than 50. I mean, transgender women less than 50. If you look at transgender women greater than age 50, the rate of fracture is greater than cisgender men and is the same as cisgender women. The easiest way to keep, to interpret this data is that the transgender women assume the rate of fracture of their affirmed gender. So it matches cisgender women. So I think that's seen as positive. So the rate isn't more than cisgender women. The transgender men, their rate of fracture, you can see in the dark bar, are less than both cisgender women and cisgender men. So that is very positive. So there's no increased risk of fracture. I wanna talk a little bit about trans youth who start on gender affirming hormone therapy. There's been a lot of discussion about this. And you'll briefly go over this slide and the circles somewhat got shifted. But the brief summary is that when trans youth start on puberty blockers or GNH agonists, there is a state of hypogonadism. You can see the lines go down. And that middle set of bars is when they, the first bar is when they start, before they start gender puberty blockers. The middle is after they've started. So you can see in the rate, the phase of hypogonadism, bone density goes down. And when they start gender affirming hormone therapy, there seems to be recovery only in the trans boys. But the concern is, the lowest bar, is the trans girls don't quite catch up to their peers. So you may hear in the literature, there is a concern that the trans girls may be having a prolonged period of hypogonadism, which may impact future bone health. So what are the reasons for low bone mass in transgender and gender diverse people? We've discussed possibly low VIMD status, low physical activity, there may be prolonged hypogonadism prior to starting sex hormone therapy. During the time of starting sex hormone therapy, there may be inadequate hormone adherence, or they may discontinue sex hormone therapy. There may be other things like lifestyle, diet, due to gender minority stress, and HIV risk, particularly in transgender women. I only have about two minutes, I'm gonna just quickly go through the ISCD guidelines in terms of screening. This was published a few years ago, and they recommend that bone density testing is indicated for transgender women, based on the data that I showed you, that there are increased risk for having low bone marrow density. And especially those who've had gonadectomy, who have hypogonadism due to orchiectomy and don't plan to be on gender affirming hormone therapies, and other ISCD indications where bone density could be low. The second statement is for follow-up screening, those transgender women should have follow-up bone density if they have pre-existing risk for low bone density. Keep in mind statement one and two didn't mention transgender men, because it seemed that transgender men are protected from low bone density. Statement three suggests that we should use T-score, using the Caucasian non-race adjusted normative database, it's because it was felt that there's more fractured data using T-score, but using Z-score that matches the gender identity of the individuals. And we can discuss that later, I don't have time right now to why they decided that. In terms of the report, the parameters that should be in a report, should include Z-scores, according to both male and female databases to help the clinician. And there was still a lot of questions what else should be included in the ISCD report. So in inclusion, despite limited data, fractures in transgender population do not appear to exceed the expected rate of the affirmed gender or the sex assigned at birth. Gender affirming hormone therapy seems to be protective and associated with maintenance of bone density, especially in transgender men. Screening for low bone density should be performed in high risk individuals, or those who are no longer taking gender affirming hormone therapy or interrupt their use of gender affirming hormone therapy. I think we need more fractured data, especially in the United States, we don't really have that data here, we base everything from the European data. And I'm one minute over, but just back to our case, our transgender woman was treated with vitamin D 1500 units a day, received calcium, she was encouraged to participate in weight bearing activities for at least 20 minutes a day. After a year of anticoagulation, after she stopped anticoagulation therapy, she was reinitiated on transdermal patch of estrogen, which was thought to be less thrombogenic. And then her dose was slowly increasing, she didn't have any recurrent thromboembolic disease. This is her bone density response, as you can see baseline, she had a decrease after stopping the gender affirming hormone therapy, and then fortunately she had a pretty decent response, about 13% increase in her spine bone density. And I thank you very much for your attention. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. And so here's an outline of the things we're gonna cover. First I'll just briefly review the bone remodeling cycle, and then go over a list of commonly used bone turnover markers. Then we'll talk about overarching limitations of using bone turnovers in clinical practice, and then we'll discuss two specific clinical scenarios where bone turnover markers have been better studied. All right, so first this is a picture from Greenspan's, which all of us read to varying degrees. This shows the bone remodeling cycle. So first we start with the resting trabecular surface, and then the osteoclast comes, it digs a resorption pit, and then the osteoblast comes, and then fills the pit with unmineralized matrix, and then the matrix is then mineralized. So bone turnover markers are basically biochemical reflections of this underlying process. So they're bone resorption markers, and then they're bone formation markers. So commonly used bone resorption markers include the C and N-terminal fragments of type I collagen. These are CTX and NTX, deoxypyridinylene, and then also tartrate-resistant acid phosphatase. On the bone formation marker side, P1MP, or the N-terminal propeptide of type I collagen, is commonly used. Bone alkaline phosphatase and osteocalcin are others. So currently, the recommended reference bone turnover markers are CTX for bone resorption and P1MP for bone formation. So the first major limitation of using bone turnover markers in clinical practice is that single BTM measurements are not predictive. And this is because 10 people could have the same BTM level, but they'll be losing bone at different rates. And so this is a classic demonstration of this point. So here, we're looking at the distributions of rate of bone density change, depending on whether people had NTX or CTX values above or below the sample median. And you can see here that the rates of bone density change basically overlap, regardless of whether you have higher versus lower NTX or CTX values. The second major limitation is that there are multiple sources of variability. So there is pre-analytical variability, which occurs before the assay is performed. And then there's analytical variability, which occurs during assay performance. So to minimize pre-analytical variability, bone resorption markers, including CTX, should be measured after an overnight fast between 730 and 10 o'clock in the morning. This is because these markers are highest in the morning and then come down in the afternoon. And they're also suppressed by food intake. To reduce analytical variability, serial measurements should be done using the same assay. All right. So in order to maximize the clinical utility of BTMs, two major criteria should be met. The first is that we should track them over time within the same person. That way, you can reference subsequent measurements to the patient's own baseline. The other criteria is that we should use them in scenarios where we expect very large changes in bone turnover over short periods of time. So relevant to this is the concept of least significant change, or LSC. The LSC is defined as the minimum amount of change that is considered statistically or physiologically significant. And for a given test, there are two different LSC thresholds. There's the bidirectional threshold, which assumes you don't know whether the test result will go up or go down. And then there's the unidirectional one, which assumes you know the direction of change. So the bidirectional LSC thresholds are 38% for P1MP and 56% for CTX. And then the unidirectional thresholds are 18% for P1MP and 30% for CTX. So now that we know the basics, I have three clinical scenarios to kind of go over some of the available data. So let's say we have a 63-year-old female who had a prior ankle fracture, no family history of hip fractures, and bone density T-scores of negative 2.7 at the lumbar spine, negative 1.7 at the femoral neck, and negative 1.5 at the total hip. The patient reluctantly agrees to start a Lendronate, but wants to know how she will know that the drug is working. So the question here is, how do you determine response to treatment? So there are two major objectives to this case. The first is I just wanted to review some of the limitations of using DEXA to monitor treatment response. And then the second is to discuss whether a decrease in CTX or P1MP greater than the LSC is a clinically useful criteria for response. This is also called the LSC criteria or LSC approach. So first, a little bit about bone density. So we all use bone density to monitor response, but there are limitations. When we interpret DEXA scans, the concept of LSC is also relevant. And according to the ISCD, the maximum allowable LSC thresholds are 5.3% at the lumbar spine, about 5% at the total hip, and nearly 7% at the femoral neck. The problem with this is that change in bone density is relatively slow compared to these thresholds. And so on the right, we're looking at change in femoral neck and lumbar spine bone density on a Lendronate. I've also marked these LSC thresholds in red. And we can see here that the average increase in bone density at the femoral neck never reaches that maximum allowable LSC threshold. At the lumbar spine, it takes about one to two years to reach this threshold, which is good. But we also know that adherence to oral bisphosphonates is poor. And by one year, adherence can be quite low. So one of the potential advantages of using bone turnover markers is that they change rapidly in response to treatment. Here, we're looking at data from the TRIO study, which randomized 172 postmenopausal women to a Lendronate, Rizedronate, or a Bandronate. And we can see change in bone resorption on the left and change in bone formation on the right. And we can see here that all three bisphosphonates lead to large changes in both bone resorption and bone formation markers within 12 weeks. So to test the clinical utility of this LSC criteria for response, the TRIO investigators looked at the percentage of participants who had a decrease in CTX or P1NP more than the LSC after 12 weeks of treatment. In the original version of the study, they used the bidirectional LSC threshold. So again, these were about 60% for CTX and about 40% for P1NP. Using these thresholds, between 75% and 98% of participants were considered responders. This is a lot of people, but it's roughly a quarter, about a quarter could have been taking their medications and then were not considered responders using this criteria. It turns out that the bidirectional LSC thresholds were probably a little too stringent in this scenario because we know that bisphosphonates decrease bone turnover, so the unidirectional thresholds are probably more appropriate. So when the data were reanalyzed using these thresholds, over 95% of participants were considered responders. So based on these data, the International Osteoporosis Foundation proposed the following algorithm for assessing adherence to oral bisphosphonates. Basically, you check a P1NP and CTX before treatment, then you start treatment, three months after treatment, you check the same markers, and if you see a significant increase that suggests adherence in general response to therapy, and then you continue for the rest of the treatment course, if you do not see a significant response, then you assess for things like adherence and whether there are underlying secondary issues that were missed. Now, it's important to note that we are talking about general response to therapy. Change in bone turnover markers has not been shown to actually predict bone density gain or fracture risk reduction on treatment. For example, one systematic review of 14 randomized trials of various bisphosphonates and CERMs found that although change in P1NP was associated with vertebral fracture reduction, it was not associated with a nonvertebral or hip fracture reduction. Moreover, change in CTX was not associated with fracture reduction at any site. So now on to case two. So let's say we have a 72-year-old female with osteoporosis who recently completed five years of alendronate. She's establishing care with you now because she just moved. We do have bone density measurements from before treatment and then now, but they were done on different machines. And using these measurements, there was a, quote unquote, apparent decline in bone density with T-score at the lumbar spine going from negative 2.7 to negative 2.9, and then the T-score at the femoral neck going from negative 1.8 to negative 2.1. The patient did not have any fractures while on treatment. So the patient is very concerned about the apparent loss of bone density. So the purpose of this case is to talk about whether or how to handle situations where we don't necessarily have a baseline bone turnover marker measurement. And so in these scenarios, the reference interval criteria has been proposed. And basically, this suggests that if a patient's CTX or P1NP values are below the premenopausal mean, then it suggests adherence in response to treatment. So the physiologic basis for this reference interval criteria or approach is that bone turnover increases from pre- to postmenopause. Therefore, postmenopausal women who are untreated will have relatively high bone turnover levels. And then when you put them on antiresorptive therapy, then bone turnover should suppress to the lower half of the premenopausal range. So to test the utility of this reference interval approach, the trio investigators looked at the percentage of participants who would be categorized as responders if the criteria for response was a CTX or P1NP value below the respective means for the assays. So the premenopausal mean value for CTX is 312 nanograms per liter. And the premenopausal mean value for P1NP is 35 micrograms per liter. Using these criteria, about 85% of participants were considered responders. So again, this is a lot of people. But it also means that almost 15% of people who were taking the medication were not properly classified as responders. And so I think this is one major limitation of this approach. Two other limitations of the reference interval approach is that different labs will have different reference ranges. And also, the reference ranges for pre- and postmenopausal women can overlap. So here, I've compiled the CTX and P1NP reference ranges for three popular clinical labs. And as you can see, they all have different reference ranges, although there is some overlap. In the case of the Quest, they don't even report the reference range based on pre- versus postmenopausal status. So this approach would be challenging with that assay. You'll also see that pre- and postmenopausal reference ranges do overlap to quite a degree. And that's a problem, because that means that there will be a portion of postmenopausal women who already meet the reference interval criteria for response before they start treatment. OK, so last case. Let's say we have a 76-year-old who just completed five years of alendronate. She had a wrist fracture before starting treatment. She has not had any fractures while on treatment. And her bone density T-scores at the five-year time point are negative 2.4 at the lumbar spine, negative 2.7 at the femoral neck, and negative 2.5 at the total hip. So you decide to put her on a bisphosphonate holiday, the question now is how will you determine when to restart her bisphosphonate? Okay, so the the purpose of this case is to really understand that although bone turnover does start to increase after stopping bisphosphonate therapy, change in bone turnover markers has not been reliably shown to be predictive of bone density loss or fracture incidence off treatment. Okay, so there's interest in whether BTMs could be useful in this situation because bone turnover goes up, so when you stop anti-resorptive therapy. So here again are data from the TRIO study, we see that when participants are on their bisphosphonate CTX and P1MP are low, and then once you stop the treatment CTX and P1MP go up. So to test whether the bone turnover markers can be clinically used to monitor for the offset of bisphosphonate treatment effect, the TRIO group looked at the rates of bone density change depending on two criteria. The first was whether CTX or P1MP increased more than the least significant change off of treatment, and then the second was whether CTX or P1MP was more than the premenopausal mean off treatment. And as you can see here in this table, bone loss was indeed faster in people who met either or both of these criteria. However, the correlation between change in bone turnover markers and change in bone density was only moderately strong, with correlation coefficients between negative 0.4 and negative 0.6. So although this is statistically significant, it does not necessarily translate into clinical utility. In a different study from the fracture intervention trial long-term extension or FLEX, the investigators found that neither change in NTX nor bone alkaline phosphatase predicted incident fracture off of alendronate after three to five years of treatment. Okay, so to summarize, two broad limitations of using bone turnover markers in clinical practice. The first is that for a given bone turnover marker level, different people will be losing bone at different rates. So to maximize the utility of these markers, we should use them, we should track their change over time within the same person. The second overarching limitation is that there are multiple sources of variability, and to reduce these sources of variability, we should check bone resorption markers such as CTX, fasting between 7.30 and 10 o'clock in the morning. We should also use the same bone turnover marker assay for serial measurements. And then ideally, we're using these markers in clinical scenarios where we expect large changes in bone turnover. The most supported clinical scenario in which to use bone turnover markers is to monitor adherence in general response to therapy. And for this purpose, the LSC criteria I think is pretty well supported. The reference interval criteria you can also use if you don't have a baseline measurement, but we should recognize the potential limitations there. In terms of monitoring for or assessing the offset of treatment effect after stopping bisphosphonate therapy, change in CTX and P1NP and others have not been shown to predict rate of bone loss or incident fracture sufficiently for clinical practice. Okay, so that's it. Thank you very much. Oh, Dr. Shea, do you want to just stand there? Okay. Great. Well, thank you so much for those wonderful lectures. So, I guess we'd like to open the Q&A, please. Hi. Thank you. Nice review. The first question is regarding the transplant patients, any experience or data with raloxifene and for the transgender woman. I'm still kind of puzzled and not satisfied with the possible explanation for the lower BMD for transgender woman, because those patients are genetically men. They are supposed to have bigger bones. So, their T-scores, when compared with Caucasian women, it should be, if anything, better. And if we are going to explain the lower vitamin D, lower mobility, then we have to screen many cis men who are in their 30s, 40s, 50s, just because their vitamin D is 15, because then we are going to expect much lower BMD. So, I can answer the question about the transplant. So, there's no data I know of regarding use of raloxifene in pre- or post-transplant recipients. Thanks for the question on transgender women. So, just to remind you, the two studies that showed lower bone density in transgender women were compared to cisgender men. So, it was a matched control, and they were lower bone density and a reference population. So, two different control groups in the study from Belgium and Brazil. Now, I think you're referring to the ISCD guidelines. The ISCD guidelines recommended screening for low bone density because of the low bone density compared to cisgender men. We're not comparing them to cisgender women, but they recommended screening because of the low bone density. And in that case, they recommend using T-scores to fracture risk stratify. I don't know if there's a subtle difference. Does that answer the question? Sure, that explains partially, but still, the vitamin D is lower. Yeah, we just don't really know. I mean, I think the two studies that show lower bone density in transgender women before starting hormones, I mean, I think there's a multitude of issues. It's not just low vitamin D. I mentioned it briefly. I didn't have time to talk about gender minority stress. Transgender women smoke more, drink more, have many things. Because of this very stressful situation, maybe don't seek adequate health care or are blocked to getting adequate health care. There's probably a multitude of reasons why transgender women have lower bone density before starting. It's not just vitamin D. Sorry, I wish. In regards to the post-transplant patients, is there any concern with using the denosumab because of its rank ligand inhibitor and its possible effects on the immune system? I've had a couple of patients who were not post-transplant. These were individuals with Crohn's disease or rheumatoid arthritis. They're on biologic agents. They're on glucocorticoids. At least the GI specialists and rheumatologists raise this as an issue of trying to eschew denosumab in that setting. Is there a similar concern for the post-transplant population? Yeah, that's a good question. You're correct that denosumab is the least studied medicine for post-transplant patients. But the one study I quickly went through, there's only been one study that I know of in post-transplant, post-liver transplant patients using the denosumab. And they seem to do just as well as those who did not, you know, who are not on immunosuppressants. So the risk is there, but, and we know that even without transplant, there's some data with RA patients on immunosuppressants that denosumab doesn't seem to increase risk of complications. So it seems to be safe, but it's very limited. So I personally, you know, that would be my second or third choice. Thank you. Thank you. Great talks for all three of you. The first question is for the first speaker and it is regarding the use of densitometry vertebral fracture assessment. Because I noticed that in your cases, you put regular lumbar hip determinations and you're going to miss a lot of the fractures that you can get on a vertebral fracture assessment scan. So the question is, do you normally use those scans, even if you didn't put them on the slide? Yeah. So that's a really good question. And that is, so we don't have that data, but that's one of my research. So we are looking at it's not validated VFA vertebral fracture assessment is not validated in transplant patients because it just hasn't been looked at. But that's one of the things we're looking at prospectively. It's blinded. So I don't have that data yet, but that's a really, you know, it makes sense. I believe that regardless of being validated or not, it will save a lot of time to start the treatment. I agree with you. Absolutely. We just need data and hopefully we'll have that published soon. So the second question and a comment is for the second speaker. And it's about the question is, how do you deal with the youth transgender women in terms of trying to preserve the bone mineral density during the pubertal years when they are still on the accrual phase of bone? Yes, that's a very important question right now. There are people trying to figure out, I mean, the, we know that the puberty blocker medication, GRNH agonists are going to cause a period of relative hypogonadism. And so in the past, before the data I presented came out, there would be many years of this phase, which people realize was going to impact bone health. So now the more recent guidelines say limit that to less than a year. If you're going to start puberty blockers, you probably should make a decision on the gender affirming hormone therapies within a year, if you can, to preserve bone health and catch up. So the reason I'm asking the question is because there's a kind of an analogism with girls with endometriosis that start treatment with GRNH analogs pretty much at the same age, you know, in 13, 14 years of age, even less sometimes. And they are added estrogen to the GRNH antagonist treatment in a very low quantity so that they do not trigger, you know, worsening of the endometriosis, but that they can assure the bone accrual in the patients. This would be much easier in the transgender women because number one, estrogen is one of the parts of the treatment. And second, you don't have the issue of the endometriosis that you have in the other condition. Yeah, I agree with that. But I think it's the timing of when started estrogen is very complicated. I mean, the blockers give the family time to make sure the gender identity is solidified and that when the estrogen is started requires a multidisciplinary approach. So it can vary. Thank you. Did you want to do the last question, please? We're at time. I just wanted to ask our last speaker about the utility of bone turnover markers with other treatments. You talked a lot about bisphosphonates, but how would you use them to measure response to patients on Prolia or anabolic agents or Avenidae? Yeah. So there are a decent amount of data on bone turnover markers in response to teriparatide and avaloparatide. With those agents, a P1NP increase more than 10 has been suggested to be a positive predictor. So that's those drugs. In terms of denosumab, you know, I mean, we know that when you take denosumab, the bone turnover markers go way down really quickly. So the question is, you know, does knowing that necessarily change your management? You know, most of us would be monitoring whether they're getting it. So I don't think adherence is as much of an issue for the denosumab patients as it is for the oral bisphosphonate or the self-injectable patients. One scenario in which you could consider, I think, using bone turnover markers in denosumab patients is to determine when you want to start consolidation therapy with the bisphosphonate towards the end. There's some suggestion that, you know, a significant increase in the bone turnover markers would be a good indicator for when to start the bisphosphonate. So I don't think there's a clear cut answer on the denosumab question. As for eventity, we know the bone formation goes up, bone resorption goes down. But again, you know, I don't know if knowing that necessarily helps you clinically in terms of decision making. So if it's something that the patient wants, sort of reassure them that, wow, look, bone turnover went up and, you know, it could be potentially useful that way. But I don't know if it changes your management that much. Thank you. The question about transplant patients, where do you factor the age and frax? I didn't see it in your algorithm in the treatment, similarly to, let's say, steroid-induced osteoporosis. Aren't we missing, then, cases which are osteopenic? Absolutely. So the reason why I didn't mention it is because frax has not been, you know, they look at the hip. So frax includes hip BMD. And the calculation, we know that spine is the most common location for fracture. And, you know, they fracture even with a normal BMD. So it's not been validated for transplant recipients. And I don't think it'll be that helpful. So that's why I didn't include it. I use it sometimes if someone is in osteopenia range and just to kind of get an idea. But I think what we've shown is that presence of fracture age is one of the risk factors. So the older age groups are going to be higher risk. So those are more of a predictor than frax. But we need more data to include frax as a predictive model. Any other questions? Yes. Thank you so much. But I just want to try to understand something about the transplant talk. So pre-transplant fractures by definition, osteoporosis, is that correct? If it is like spine fracture, are we talking about fragility fractures? Yeah. So that's a good question. So I see what you mean. So when you look at pre-transplant fracture, these are asymptomatic. So we don't know. All we know is radiographically, if you look at an x-ray of any sort, they have a CT of the chest. And you look at their spine and it says there's T12 compression fracture. And the patient doesn't recall any major trauma. So we're assuming based on the limited data we have that those could be risk for fracture. So in our study we did, we included all fractures because it was retrospective. So any fracture that was detected either by history or by any imaging. So we consider those as fragility fractures. So there is limitation when you do retrospective. Yeah. So does this mean, does the transplant then is a risk factor for those specific population? Because we know in osteoporosis, a previous fracture is already high risk, right? So would the transplant here add in more risk? No, no. It's just the presence of fracture before transplant. So it's good to go back and really get those patients before they're transplanted and really assess them. That seems to be the critical time to kind of strengthen their bone to get them ready for after transplant. So itself, no. Thank you. Any other questions at this time? Yes, please. Thank you for the talks. For, in terms of using bone turnover markers for patients on Prolia and you want to switch them to a bisphosphonate, you know, typically, you know, the studies have shown that the bone turnover markers increase when you switch them. Does that really, I mean, how much does that really change your management in terms of whether or not, if you're kind of expecting the bone turnover markers to increase anyway, whether that would change your management in terms of to keep them on bisphosphonate or put them back on the denosumab? Yeah, that's a very interesting question. So there was a study that kind of gets at the question you're asking, which is, does just starting the bisphosphonate make sense? And is it equally as good as waiting until the bone turnover markers to go up to start it? And so in that study, it was pretty small. It randomized 20 people to various groups, one of which was just automatically starting zoledronic acid nine months after the last denosumab dose. And then another group was waiting until the bone turnover markers increased significantly to start the, to start the zoledronic acid. And in that study, the outcomes are similar, you know, so from, you know, so it kind of supports, I think, what you're suggesting, which is, you know, maybe you don't even need to do it. You know, but that study was smaller. And so I think that's an area of interest. Sorry, I have a question. It kind of crosses over transplant patients and bone turnover markers. So I take care of a few transplant patients. I'm at UCSD. And especially with liver transplant, post liver transplant, I've happened to have checked some of these bone turnover markers in patients with normal GFRs, with and without lumbar, like compression fractures. And I have noticed in several of my patients, almost like Paget's like high P1NP and CTX levels. My question is, I guess it's two part, like one, do you see that often? And is there, is this even clinically meaningful? And should I just stop checking these turnover markers in these, this kind of particular group of patients? And number two, would those high P1NP CTX bar these patients from receiving something like Forteo, especially in the setting of like prior vertebral fractures? So these are post liver transplant patients. Okay. And it's within the first year then. So we are, so there's no bone turnover data. We are doing a study looking at, and it hasn't been published yet, but looking at bone turnover markers. We find that high beta CTX, especially the resorptive marker, is seen more in certain group of patients like alcoholic liver cirrhosis. They tend to have higher beta CTX than P1, and also high P1NP versus NASH tend to have lower if they've been transplanted for NASH. We're trying to figure out where that difference and how, you know, how does that correlate with bone density? I don't think checking it is that useful, honestly, because we don't know what to do with it yet. But we are noticing that there's a difference with the type of liver disease. So that may be what you're seeing is what was the reason for the initial transplant. And we're seeing that alcohol tend to have high bone turnover marker. Yeah. I mean, I don't have that much experience with the transplant population. I'm also curious though, how long in the liver transplant patients before their kidney function recovers do these higher BTM levels reflect maybe poor underlying kidney function? Yeah. So bone turnover markers are affected by CKD as well. So you have to have a normal kidney function to really make a good assessment. So that would be one thing is they should have a normal kidney function. So in our study, we excluded those with a GFR that's low. Are anabolic drugs contraindicated in all patients that have had external beam radiation therapy, such as to a brain tumor? They would be contraindicated? I believe so. That's my... I think it's, I think the label has been updated to say specifically radiation to the bone, I believe. Okay. That's what I wondered if there was... That would be also including, right? The skull was part of the bone. My understanding is it's excluded in all external beam radiation too. I don't know if anybody else has any thoughts. No, you know, and I'm glad that you brought that up because when you had that on your slide there, I think a lot of us kind of think now differently, a little bit about teriparatide with the, as you mentioned that the labels changed where we no longer have the black box warning. We no longer have the two year lifetime limit. So it gives us a lot more reassurance. So I know in my practice, I don't necessarily have the big nose that I used to feel for the use of that medication. Thank you. Any other questions? So I have a question thinking about the patients with renal osteodystrophy or CKDMBD, because as you mentioned, the CAID to go guidelines, I was so happy when they had put in there that we not, people don't necessarily need a metabolic bone biopsy. Just, I mean, it's certainly it's gold standard, but it can be difficult to obtain an invasive. And they mentioned that perhaps we could use PTH and BSAP as guidelines. Do you use those? Oh, that's very difficult. That's very contra and it's, it's hard to do. So yeah, there's some, the CAID to go 2017 guidelines do say, you know, PTH levels greater than three times upper limit of normal kind of gives you if it's high, then maybe, you know, they're, they do have, you know, increased bone turnover or normal bone turnover. So that could be useful, but there's that gray areas, you know it's not really, or a BSAP bone specific alkaline phosphatase of greater than 12, I believe is. So that could be a marker, but it's not really the best marker to, to determine bone turnover. So gold standard still remains bone biopsy. Sure. But, and at least for the patients that are going to receive a transplant, then, you know, things are going to change. You feel more comfortable down the road that you can treat them. After transplant, they do recommend, you know, you treat them like everybody else. So that shouldn't make a difference. As long as their kidney function goes back and their metabolic profile goes back to normal. Sure. Well, thank you so much for the wonderful speakers and lectures today, and thank you all for attending and enjoy the rest of the meeting.

bone health

transplant-related bone disorders

transgender individuals

bone turnover markers

osteoporosis

fractures

organ transplant patients

bone density scans

bisphosphonates

hormone therapy

glucocorticoid-induced osteoporosis