My name is Jad Sfeir. I'm an endocrinologist and gerontologist at Mayo Clinic in Rochester. This afternoon, Dr. Rob Wormers and myself will be presenting to you the year-end review for bone, metabolic bone diseases and parathyroid disorders. Just waiting for our slides. There you go. As I mentioned, I'm an endocrinologist at Mayo Clinic, and Dr. Rob Wormers is the chair of the DSN bone, but also chair of our division in endocrinology at Mayo Clinic. We will both be talking to you today about what we saw in the past year in terms of relevant bone and parathyroid disorder publications that are relevant to our practice. We'll discuss important findings in the management and treatment of osteoporosis in the past year. There are pivotal studies in vitamin D, but also in hyperparathyroidism and hypoparathyroidism that we will review, and then highlight advances in our knowledge in rare bone disorders. The way this came together, we reviewed the literature between January 2021 and December 2021, systematically reviewed the main endocrinology and particularly main bone publications, but we also looked at other journals with key publications, and then we looked at the abstracts of bone, mainly American Society for Bone and Mineral Research, ASBMR, ACE, and Endocrine Society. We will divide the talk into multiple categories within the bone field. We'll start with the largest piece, which is osteoporosis. Within osteoporosis, let's start with patients who fracture while on therapy. This is a study by Ian Reid. This is a re-evaluation of the study where they provided zoledronic acid infusion at an 18-month interval over six years. Patients received four infusions of zoledronic acid once every 18 months for six years. These patients had osteopenia at the hip and not osteoporosis. And then they re-evaluated those who had fracture while on zoledronic acid. Subjects who had fracture in study had a lower baseline bone density, were older, and then they had a history of nonvertebral fractures. The change of bone density while on zoledronic acid did not predict whether the patients will fracture on therapy or not. What predicted it was the baseline BMD. So no matter what the bone density looked like while on therapy, they still fractured on therapy if they started with a low bone density. Similar findings were also noted in untreated individuals in terms of risk factors, low baseline BMD. This suggests that what matters really is the main assessment of the patient that we have. Their change in bone density may not matter. And certainly monitoring BMD while on therapy may not provide you with information regarding whether they're going to fracture on therapy or not. Another study, which is revisiting the WHI data, about 70,000 postmenopausal women aged between 50 and 70 years of age. They were followed over an average of eight years, mainly collected from three clinical centers. And what they looked at in those who had a fracture, and they looked at the mechanism of the fracture. Is it traumatic or non-traumatic fracture? Now, mind you, this was self-reported by the patients. So the patients determined whether they had trauma or not to cause the fracture. Nonetheless, they followed these patients over time, and they noticed that the risk of having a future fracture is elevated both in patients who had a traumatic fracture and non-traumatic fracture. Obviously, those who had a fragility fracture had the highest risk of having future fractures, but even traumatic fractures predicted the incidence of future fractures. At the bottom of the slide, you can see the hazard ratios for both types of fractures. This is important because this is the WHI and postmenopausal women data, adding to more data that we're seeing in orthopedic journals is telling us that even traumatic fractures certainly predict risk for future fractures. Take-home points. All fractures, including traumatic increase, the risk of subsequent fracture, and should warrant consideration and evaluation for osteoporosis. What increases the risk of fracture? Remember the seven Fs of fracture failure. Food, low BMI, falls, fracture, a prior history of fracture, frailty or older age, forgetting medication, mainly noncompliance, secondary factors, and then frightening low BMD, which is a low baseline BMD. So for those of you who like mnemonics, hopefully this was helpful. We talked earlier about serial BMD measurements. They do not really predict fracture on therapy. So what data do we have about serial BMD? This is a study from the Manitoba group that looked at a large registry of patients who had DXA scans, and they compared the intervals. So at the bottom of the screen you're seeing the intervals at which the BMDs by DXA were repeated, two to three years, three to four years, up to ten years in between bone density and the next. And then they looked at what is the annual percent loss of BMD that is noted. And what you can see is that there is really no difference in terms of the percent bone density change per year, no matter how long you do the bone density or how long the interval is. And we know that, that the percent change is going to be the same. But what was different is the standard deviation. The standard deviation at the earlier interval, having short interval with repeat BMD, was significantly high, telling us that there is a higher chance of noticing a rapid loss when there is really not true rapid loss. And this is data in patients who did not have osteoporosis, patients who did not receive any type of treatment. So they were not high-risk patients to begin with. But serial BMD, the shorter you do it, the highest risk of being within a standard deviation that's quite wide, telling you the highest risk of overestimating the loss that happens in untreated individuals with near-normal bone density. Another study by the same group, but this is looking at those who are receiving treatment. So this is bone density repeated while on therapy in patients with osteoporosis. This is a little bit tricky, so I'll guide you through this slide. What this is showing us, they looked at patients who received a bone density on treatment. So that dotted line in the middle, this is at the time they received that bone density. Three years before the bone density and three years after, they looked at the adherence to medication. And the way they calculated adherence to medication is by something called the medication possession ratio. Basically looking at the pharmacy data and calculating how many refill days the patient had during a certain period of time. So for example, the patient got 60 days of refills during a 90-day period. That's 60 over 90, that's two-thirds. If they got 90-day refills in a 90-day period, that's 1.0, that's 100%. So this is how they calculated the MPR, medication possession ratio. Those patients who had a decline in their bone density at the three years after starting therapy are shown in the orange line. These are patients who had a low, below 40% possession ratio. So low adherence to medication. Notice that after the dotted line, after they got the BMD and they came for a follow-up, that compliance increased the year after, and then it dropped again. Telling us that that bone density kind of reminded the patient to adhere more to the medication. Those who had a bone density that was stable over time, so the repeat bone density on therapy did not change, those were the most compliant. They were noted in the blue above, and this is almost 80% compliance over a six-year period of time. And then the same data looking at the risk of fracture, having any fracture, major osteoporotic fracture in those patients. And then this is showing us those patients who had a stable bone density, meaning that they were at least 80% adherent to medication in the dark blue, had a lower risk of rate of fracture compared to those who did not adhere to the medication, those orange that we saw in the previous slide, had a higher risk of fracture. So obviously with the decreased medication compliance, there was an increased risk of fracture. But more importantly here, remember those patients who were not compliant eventually became compliant maybe for about a year after the bone density. It didn't matter. It was too late. They still fractured at a higher rate. This is bringing us to, so what about serial BMD? Is it helpful? Maybe it's not helpful in terms of us evaluating the actual response, but more helpful to the patient to remind them of adherence. Take-home points for this part. The first BMD is the most important one in assessing risk of fracture. There is limited value for serial BMD monitoring in untreated patients or those patients who are compliant. The question is how do you check compliance of these patients? And this brings the issue, should we get earlier follow-up than a two-year bone density maybe with turnover markers, which we will not go into right now. This certainly does not apply, serial BMD data does not apply to those who are on a drug holiday where serial BMD is quite important or in those who you decided they failed therapy, you need to switch therapy. The first response to a decreased bone density should always be review adherence because that's more likely than not to be an adherence problem. This is not a study but rather a review by two experts that was published in JAMA Insights and they just gave recommendations on how often to repeat bone density based on the data that I just showed you, how often to repeat it, and then they look at what was the initial BMDT score, what is their FRAX calculated MOF and hip fracture to determine the interval of therapy, something I invite you to take a look at. The second part we're going to talk to within osteoporosis is denosumab discontinuation. So what happens after denosumab? This first study looked at zoledronic acid. Patients received zoledronic acid six months after the last denosumab injection but they split them into two categories. Those who received less than six injections of denosumab, on average they received about four, so that's two years of denosumab therapy and then zoledronic acid. And those in the dark blue were those who received more than six injections, on average this was eight injections, so four years of denosumab therapy. And look at the difference. The less they have been on denosumab before receiving zoledronic acid, the less chance of losing bone after zoledronic acid. So in the dark blue you see a significant drop in bone density even after zoledronic acid for the group that have been on Prolea for an average of four years. And this applies to both the lumbar spine and the femoral neck. So it looks like duration of denosumab mattered here. The same study looking at the change in turnover markers. Turnover markers increased in both groups. So there was a significant increase in turnover markers of formation and resorption in both groups. So this was not attenuated by the zoledronic acid but this did not necessarily reflect on the bone density changes in the patients who received only two years of denosumab. What about rhomososumab after denosumab? This is the phase two trial of rhomososumab. So they took the patients who received placebo, which is seen in black, followed by rhomososumab, which is noted in green. And then those patients who received placebo and then denosumab and then rhomososumab, you can see at the top, and I'm talking about group two with three colors, at the top of the screen you can see that there has been an increase in the lumbar spine and the increase in lumbar spine bone density continued even after stopping denosumab while on rhomososumab. But there was no increase in the hip, but at least it was maintained. There was no loss after denosumab when receiving rhomo. Remember, those patients only got two injections of denosumab, only one year of therapy, as opposed to many of our patients who received longer duration before you decide to transition them. So again, the first point here, what about long courses, those who are on longer duration of denosumab? There is a study from Japan that looked at some patients looking at rhomo after denosumab who received denosumab for a longer period of time, and they did not see the improvement in bone density that was noted in this trial. Take-home points, a couple of mouse data that we did not go into, but they show that the rebound increase of bone loss that happens after discontinuation of denosumab may not only be related to the increase in osteoclasts, but also increase in osteoblasts because OPG was noted to be significantly suppressed while on denosumab, and OPG increase from the osteoblasts is activating the osteoclasts. So it seems to be an interaction after you remove the denosumab, both osteoclasts and osteoblasts increase, but moving more towards resorption because of the crosstalk of these two cell lines. Longer duration of denosumab reduces the efficacy of switching to rhomo, as I mentioned earlier. It seems that duration matters. The shorter the patient has been on denosumab, the more likely you will have offset of the bone loss that happens with zoledronic acid. It's unclear whether this happens with alendronate or not. Some of these trials are underway. Parathyroid hormone therapy for osteoporosis. So transitioning to antiresorption. This was a very interesting study, and there's a typo on the slides. Please note I'll mention it to you in a little bit. So this looked at the Medicare data and looking at teriparatide prescription. Teriparatide was prescribed and patient continued it in terms of the refills with a median of 7 months only. 35% stopped it within 3 months, 47% stopped it within 6 months, and only 37% continued beyond 1 year. Only 41% of patients who received teriparatide and discontinued it were switched to an antiresorptive therapy. 60% were left with nothing after teriparatide. 42% within 60 days received an antiresorptive. 50% of these were denosumab and 31% were oral bisphosphonates. Patients who were treated by endocrinologists had longer teriparatide continuation. On average was 9 months, and more often, not less often as is seen on the slide, more often were transitioned to antiresorptives, 46%. Still that 46% is not something to be proud of. 60% of patients or 54% of patients even within endocrinology are not transitioned to antiresorptive after teriparatide. And then something that's coming on is oral parathyroid hormones, so oral PTH. This is a phase 2 study only for 6 months duration looking at oral PTH. Oral PTH did increase over 6 months lumbar spine bone density compared to placebo. Less so total hip and femoral neck. And this is something to look forward to in the future. And this is looking at turnover markers with the oral PTH significantly increased turnover markers, particularly formation markers with suppression of resorption markers. Take home points. Real world use of teriparatides shows suboptimal persistence and transition to antiresorptive after stopping. Oral PTH appears to be effective with early clinical trial data. I'll turn it over to Dr. Wormers to talk to us about vitamin D studies. Thanks, Jad. Thank you, Jad. This is truly a labor of love. This is the most work I have to put into any talk every year. We get a little out of our comfort zone, so you did a great job. Just to be honest. Okay, so let's see if I can move this. Oh, yeah, we're doing conventional now. Okay, so one, there's going to be two really emerging things in vitamin D that I want to stress. And this is the first kind of bucket of things to think about. And that are, does vitamin D really provide clinically significant outcomes? And so this is data from the VITAL trial. And this was in primarily healthy community-dwelling adults, large number, randomized placebo-controlled trial, half men, half women, 50 years of age and older. And they were put on 2,000 IUs of vitamin D3 versus placebo. And last year we presented some data from the same trial. But this year the news is that when you look at these healthy patients followed for five years, there was no effect on reducing fractures. Not surprising, but you can see the hazard ratio is nearly one. Both for total, non-vertebral, and for hip. And also the same study last year we showed you showed no reduction in falls. Now, an important study just published in the Annals of Internal Medicine last year was called the STERDI trial. And I honestly can't remember what that acronym stands for. But it was a well-done trial. It was a control group that used 200 IUs of vitamin D3. And they compared it to three different doses, 1,000 IUs of D3, 2,000 IUs of D3, or 4,000 IUs of D3. And they followed them over a period of two years on the average. And the important outcomes they were following were mortality and falls. Now, these were older individuals, 75 years of age and older, and they were at risk for falls. And these patients actually had vitamin D levels that ranged from 10 up to 29. So they were kind of falling to that mild vitamin D deficiency range. Now, one important message from this trial is they actually stopped the 2,000 IU trial about three years into the study because of an increased risk of falls and an increased risk of, I'm sorry, increased risk of death and an increased risk of hospitalization. And then about three months after that, the same thing was seen with 4,000 IUs per day. And those two groups then were transitioned to 1,000 IUs per day and they didn't enroll any more patients in that 2,000 and 4,000 arm. So what you see in this particular side essentially is that the 2,000 IU was associated with the higher risk of falls and then like the 1,000 IU in this particular case. And here was the heart outcome that was looking at the primary outcome of the study which was falls. And what you can see is when you compare 200 IUs to 1,000 IUs per day over two years, there was no reduction in fall in patients with mild vitamin D deficiency at high risk for falls who were 75 years of age and older. Now the other thing I want to point out from this study that's very interesting is the 200 IU group actually got vitamin D levels up to a mean of around 28 nanograms per ml. So even that low dose of vitamin D made a pretty significant impact on the actual vitamin D levels that were seen in these patients. Okay. Now this is a meta-analysis and, you know, these sometimes can be a little metaphysical in nature but this was an important meta-analysis published in JBMR. Now I don't know how many of you are aware but there was a group in Japan, Sato and colleagues in southern Japan, that had one of the biggest, I guess, fraudulent number of studies published in the history of medicine and these were on vitamin D showing remarkable outcomes in all kinds of things, fractures and falls and so on. As it turns out, some investigators, actually Ian Reed and colleagues, thought the data couldn't be real. They challenged it and it turned out it was falsified data. This particular meta-analysis then excludes all of the previous data from Sato and colleagues and to make a long story short, when you do a meta-analysis and look at the studies, randomized placebo-controlled trials of vitamin D and muscle health and look at timed up and go, basically the outcome did not show significant benefit. They also looked at knee flexion, the ability to, I guess, strength with knee flexion and actually vitamin D supplementation was associated with a reduction in knee flexion. So not beneficial but actually potentially harmful on muscle strength. The other hot topic in vitamin D is around the metabolomic profile of vitamin D metabolites and there's some really smart people, way smarter than me, who are very interested in this and looking at these various vitamin D metabolites. So we know a lot about vitamin 25-hydroxyvitamin D, which has a longer half-life, two to three months and that's why it's the preferred test for checking for vitamin D deficiency. But with that being said, we know that vitamin D that's bound to vitamin D binding protein isn't the active form, it's free vitamin D and we don't really have a good way to measure that. We know the active form of vitamin D is 125-dihydroxyvitamin D but the problem with measuring 125-dihydroxyvitamin D, it has a half-life of about six to eight hours and is in very low concentrations and difficult to measure. So we, and the other thing that's being realized is that there's all these different metabolites that may give a better picture of what's actually going on at the cellular level. Now this is probably the hardest, one of the hardest studies I've read in the last year from a really smart guy in Canada named Glenville Jones. I think he must be one of the smartest people in the world. What he did is he looked at a group of patients who had idiopathic hypercalcemia. So we do know there's some variants of patients with non-PTH mediated hypercalcemia due to 24-hydroxylation mutations in the CYP24A1 gene and also there's a subgroup that get hypercalceria, hypophosphatemia due to SCL3 or 34A1 mutations which leads to sodium phosphate transport dysfunction and proximal renal tubule. But what they did is they ruled out those patients and they looked at every other patient where we couldn't identify the cause of hypercalcemia and we see these patients periodically in our bone clinic. And what they did is they looked at some of the downstream metabolites and surprisingly what they found was that the 125D level was low and they had an elevated 12425, that shouldn't be 35 level. And essentially these are genes that, or these are byproducts that indicate 125D activation of the vitamin D, of the vitamin D receptor. And so what this suggests is that these people with idiopathic hypercalcemia have this hypersensitivity at the level of 125D action on the vitamin D receptor. And as it turns out, this mimics what's seen in this Williams-Beroon syndrome which is another form of hypercalcemia that's not well understood. So I think in the future the message here isn't to know about the actual levels but to see that there's going to be some more data coming out on metabolites helping define mechanisms of hypercalcemia that we don't understand. The other hot topic I would say in the metabolites is this thing called VMR. So obviously we talk a lot about 25 hydroxy vitamin D levels. We've talked about some of the deficiencies in 25 hydroxy vitamin D. But VMR is the vitamin D metabolite ratio. And it specifically refers to the ratio of 2425 dihydroxy vitamin D which is the product that 24 hydroxylase takes 25D to the 2425D level. And what they do is they look at that ratio of that metabolite to 25 hydroxy vitamin D, multiply it times 100 and they come up with a VMR. And as it turns out in this study from Ginsberg and colleagues, the VMR actually showed a better relationship to bone density and fractures. And actually that's the next study. You can see how complicated this is. So oh yeah, this is the next slide, sorry. So VMR actually showed that it was more associated with the bone density than the vitamin D level itself. And the lower the VMR, the higher association it had with fracture risk. And so the concept here is that rather than just 25Ds to determine skeletal health, we may be using vitamin D as kind of like the TSH which is actually a receptor level kind of biomarker that we use in thyroid disease. And I think we're going to hear more about VMR and we may be in the future using that rather than 25D to assess skeletal health. So here's the take home points. Vitamin D, 1,000 units once or more once daily compared to 200 IUs in community dwelling adult older adults at increased fracture or fall risk doesn't prevent falls and actually may increase falls at higher doses. Vitamin D supplementation does not improve muscle function strength or mass and may actually have an adverse effect on muscle health based on the timed up and go in knee flexion. Vitamin D metabolites or profiles may be helpful identifying the underlying cause of idiopathic hypercalcemia and also those individuals at greatest risk for bone loss and fractures. So Jah's going to do hypoparathyroidism. Moving on to the calcium disorders, I'll start with hypoparathyroidism and then Dr. Wormers will cover hyperpara. And the reason I wanted to cover this is remember we talked about oral parathyroid hormone in terms of treatment for osteoporosis and that was PTH 1 to 84. Here we have oral PTH 1 to 34 in treatment of hypoparathyroidism. This was a 16 week open label pilot trial involving 19 adult subjects with hypopara for over one year. And then oral PTH 1 to 34 was given four times daily. This comes as an injection. I'm sorry, the oral comes oral and then gives in four times daily and titrated to a maximum of 12 tablets a day. This has a half-life of 20 minutes compared to the human parathyroid 1 to 84 which has a half-life of three hours. And then the effect in this study extended beyond just the time that 20 minutes after taking it. They had more sustained response. It was significantly reduced the intake of calcium supplementation starting from week four up to week 16 from taking it. In 40% of the subjects the reduction of calcium supplementation was over half. And there was no change in calcitriol dose but that was by design. The design of the study was to stabilize the calcitriol and just play around with the calcium supplementation. There was significant decrease in the phosphate level in these patients. And then interestingly 24-hour urine calcium decreased by 21% with oral PTH. The main adverse event was GI issues as you would expect taking so many pills a day. It was up in 30% and the nasopharyngitis in 32%. This is another study transcon PTH and this is the PTH that comes as an injection. So transcon PTH comes as an injection treatment for hypoparathyroidism. Last year in the DSN bone both Dr. Wormers and I presented the initial results of this study. You can refer back to it. But this is an extension of transcon PTH. By week 26, 91% of patients were able to go off of calcitriol and then were on less than 500 milligrams a day of calcium supplementation. But the more important part here and this is what you see on the graph is the decline in 24-hour urine calcium. 24-hour urine calcium went from an average of 400 milligrams per 24 hours down to 178 within the normal range. This is very important for these patients with hypoparathyroidism. At 58th week of the open label extension patients did remain, 91% of them did remain off of conventional therapy and the 24-hour urine at 58 weeks was also still on average within the normal for calcium at 152. So take home points here. The two types of PTH that are upcoming for treatment of hypoparathyroidism now that we cannot, we don't have Natpara anymore that was pulled from the United States market. Hopefully these will come in sooner than or at some point maybe before Natpara is back on the market. Oral PTH in the early clinical trial that we saw has efficacy in treating hypoparathyroidism but requires many pills a day as I mentioned. Transcon PTH in this phase two that we presented seems to be quite efficacious, reducing the pill burden of both calcium and calcitriol and improving urinary calcium mostly because of its long half-life. Rob. Okay, so now we'll move on to the most important disease in the world, hyperparathyroidism. So if you read our last parathyroid session you've already seen this but I think it's worth highlighting. There was a meta-analysis done in JAMA otolaryngology, head and neck surgery that compared different localization strategies for primary hyperparathyroidism and from this meta-analysis it suggested a very high sensitivity for choline, the choline PET CT scans compared to other more conventional measures. Obviously this is more expensive and not a first-line imaging technique but it does suggest that this might be a really good localization tool. I also mentioned these guidelines came out last year on intraoperative PTH monitoring from the UK that suggested that really there's little evidence to suggest that intraoperative PTH needs to be routinely used because of its potential limited benefit, especially if you have an experienced surgeon, high-volume centers. And it suggested that the cost effectiveness may not be worth doing as well. But in the same year, this again in the same journal, I think it was even the same issue, there was another meta-analysis looking at intraoperative PTH in minimally invasive parathyroidectomy and obviously that's the sweet spot for intraoperative PTH where you can do a limited access surgery and this actually suggested benefit in doing intraoperative PTH measuring for our surgeons. And they suggested that the cure rate was higher and that, you know, 3 or 4% may not seem like a lot but if you think about all the parathyroidectomies done, that's quite a few patients who may have to go back for another surgery. You do have more bilateral neck explorations if you do intraoperative PTH mainly because you're going to find a gland that you didn't identify or a multi-gland disease. So you have less re-operations. OR time is lower and my surgical colleagues tell me and the people who, I talked to one of the scrub nurses in these procedures and they hated intraoperative PTH but, you know, it's all right. And then there's no difference in morbidity. Now I want to switch gears to parathyroidectomy because that's kind of one of the other main themes that's happened over the last year as far as clinically significant outcomes. And I'm going to show you three of these large database mining trials and the first one here is from Dr. Sieb and colleagues looking at parathyroidectomy versus observation and effect on fracture risk in older individuals. And this was from a Medicare, large Medicare database, so not a lot of granular data. But what they found was that in the non-operative group on the top versus the parathyroidectomy there appeared to be some limited benefit, some benefit in reducing fractures in patients who underwent parathyroidectomy. What about kidney stones? So this is data from the same group, the Sieb group, where they actually used the Optum database for commercial pairs and looked at parathyroidectomy and benefit as far as kidney stones goes. And they broke it into two different groups, a group who had a history of stones and a group that had no history of stones. And they looked at parathyroidectomy versus observation. And essentially what they found was no significant difference in kidney stones when you did observation compared to parathyroidectomy in this cohort from the Optum database. That includes one stone or if you had more than one stone. This is where it gets a little bit confusing because now there's another database study from Kaiser Permanente that looked at kidney stones from Huang et al. where they looked at patients who were observed versus patients who before surgery and then patients after surgery. And what they found was in the observation group compared to the post-surgery group that there was a difference in kidney stone risk in this particular study. Now as it turns out, the rate of kidney stones in that post-surgery group was about similar to those patients who have a history of kidney stones in general. So it kind of suggests that these patients who are prone to stones may have not only primary hyperparathyroidism but other factors that contribute to their stone risk. And I think that's a lot of people, including myself, believe that. At our last session, this question about quality of life was brought up. And all of us have seen remarkable patients who, I can tell you anecdotes all day long about patients who, you know, from one day to after the parathyroid surgery within a very short time feel remarkably better. But to look at that in a more, I guess a more randomized scientific way, this European cohort from Denmark, Sweden, and Norway did this study called the SIP study. And they looked at a lot of important outcomes. And what they did is they had patients with mild primary hyperparathyroidism, and they had about 95 patients in each group observed versus surgery, and they were randomized. So it is a randomized trial. So in this particular trial, they had a long-time follow-up of about 10 years. And they looked at—this quality of life study looked at SF36 and this thing called the Comprehensive Psychopathological Rating Scale, or the CPRS. And they saw some subtle differences with parathyroidectomy, maybe giving some mild improvement in vitality, but you can see the P value there was not significant. And a trend towards an overall score improvement, again, the P value didn't meet statistical significance. Now I know my surgeons that are out in the audience, including some really good surgeons, and they're going to say, well, you know, listen, they had 90 patients in each arm. And they're right, this is not a highly powered trial to be able to potentially see differences, but it's the best randomized trial we have in this. What was interesting in this particular cohort, and I think just throws a little bit of caution in the wind, is this particular figure from the same study. And when you look at that parathyroidectomy group in the darker blue, what you see is that first year there was a pretty significant drop, but then after the first year these quality of life measures, or the CPRS in this case, moved back towards the observation group, suggesting that some of those early changes may not persist with longer term follow-up. And so that's kind of, I guess, the one caution I would throw out there. Now since I'm giving this talk, I can put out one of my studies. So there you go. This was a mortality study we published in Bone this last year. And we looked at survival compared in our cohort over 45 years of patients from Rochester, and we compared them to expected in Rochester. And the overall survival was no different from the general population. So we didn't see any decrease in life in patients with primary hyperpara. But when we looked at the quartiles of serum calcium, we did see a nice separation, such that higher calciums were associated with increased mortality, and the cutoff was around 10.8 milligrams per deciliter. And so when you looked at those patients at 10.8 or higher, they did have a reduced survival compared to the general population of Rochester, which has to be one of the healthiest populations in the world, I would imagine. Now, when we look at survival after parathyroid surgery, this is another big question. Does parathyroidectomy actually improve survival? And we found no overall benefit in surgery reducing survival. And this is important because the same SIP study just came out with a publication about two months ago in the Annals of Internal Medicine in that randomized cohort, showing no difference in survival in their group as well. With that being said, what we did find was that, again, that calcium, when it was 10.8 or higher, there was a significant reduction in mortality if they had parathyroidectomy versus observation. So here's some take-home points from that. Parathyroidectomy may be associated with a reduction in fractures and a reduction in mortality if the serum calcium is higher. Parathyroidectomy may not be associated with long-term, and I stress long-term, benefits and quality of life compared to observation in mild primary hyperparathyroidism. It doesn't mean you shouldn't operate on patients because of this, because if they have a high chance of cure and a lifelong follow-up, it may be very reasonable to still operate. The reduction in clinical stones within… There are reduced stones within five years after parathyroidectomy, but I'll just stress that these patients, I always give them information on other ways, lifestyle ways to reduce kidney stones. And so the secondary prevention measures should be important. And recurrent, the other important point is that these patients still get stones even after kidney surgery. And that stresses, again, why the focus on lifestyle measures. And it may just take longer to see that benefit. Choline PET-CT appears to be an excellent localization tool, but its cost and limited availability keeps it as a second line imaging procedure, in my opinion. Interoperative PTH, in conjunction with experienced surgeons, really appears to improve the outcome of surgery. So we'll finish with rare malabolic bone diseases, and, because this really, I'll just say from a bone field, this is one area that our field is clearly going into. Prevention of drugs for rare bone disease is going to be a hot topic in our future. So a couple of things about pretty important papers. This is a paper published in the New England Journal of Medicine that described acquired PTH resistance due to blocking antibodies to the PTH1 receptor. Now what they noted in this family, or these, I'm sorry, these patients, was that they actually had normal calcium levels, and then they were found to have profoundly low calcium levels. And you can see 5.7 milligrams per deciliter. Not very often I've seen a calcium that low. Phosphorus was very high, 5 to 10. Magnesium was low. And PTH was over 1,000. And they also had a high bone mass, because if you get resistance at PTH at the receptor level, PTH1 receptor, you're not only going to lower calcium, but it also happens at the skeletal level. And so these patients also had high bone mass. And I don't think it's ever been reported that this is a cause of a high bone mass phenotype until this. They were very difficult to control with calcium and calcitriol. They also, the other important historical point of these patients is that they also had other autoimmune disorders, and that's an important clue in this particular family. The investigators for this particular study did an elegant, used elegant technology to detect the antibodies, not to the PTH, but to the PTH1 receptor. They found no PTH antibodies, and they actually had very high serum levels of PTH against PTH1R. And so this is the first report that I guess I've ever seen with this. So now it's one of those things we can add to our extensive differential diagnosis, I guess, of hypocalcemia. Now another hot area of drug development is in what's called autosomal dominant hypocalcemia type 1. So autosomal dominant hypocalcemia type 1 is a genetic disorder of the calcium-sensing receptor, where you have an activating mutation in CASR that basically leads to decreased sensitivity at the calcium-sensing receptor level in the parathyroid. And the result of this is that you get low calcium, high phosphorus, and in this case you don't actually get a high PTH like you do with the other case I just showed you with the antibodies to the PTH1R receptor. Now this was published again in the New England Journal within the last year from Raj Thakkar's group in the UK, where they actually had these patients who were having refractory seizures, and what they did is they gave them basically subcutaneous pump administration of PTH1-34. And they showed very nicely that when they gave PTH1-34 continuously via pump, they could nicely increase calcium in the orange bars. They could nicely reduce phosphorus, again, in the orange bars. The calcium phosphate product went down, and they also improved magnesium. As it turns out, there's also a drug being developed for autosomal dominant hypocalcemia type 1, which is Encalaret. So Encalaret is a calcilitic that is being developed where it actually impairs the action at the calcium-sensing receptor and thereby increases the sensitivity of the calcium-sensing receptor. And this is a—I think this is a phase—either phase one or it could have been an early phase two trial where they gave the—did a proof of concept where they gave calcilitic to patients with this genetic condition, and I know it's now moving on to phase two trials. And what they did is they started with a 30-milligram dose, and they escalated that. And as it turns out, this calcilitic—calcilitic Encalaret nicely increased serum calcium, nicely—actually increased PTH, improves the sensitivity at the PTH receptor for calcium, and it lowered 24-hour urine calcium. So for these patients with ADHR1—or ADH1, this appears to be a promising therapy and is currently, again, undergoing further studies. Now the other thing I wanted to mention was this remarkable cohort of patients. So this is a condition called chronic nonbacterial osteomyelitis, or CNO. Now many of you may have heard of CNO and know it as SAFO syndrome. SAFO syndrome is sternoclavicular hyperostosis, where patients get painful sclerosis of the sternum and inflammation of the sternum. And that's where I've seen this in my own—in my own practice. With that being said, I was amazed when I saw that there were 213 adult patients in this Dutch cohort, and they were primarily women. They're actually pretty young, and the ones I've seen have been young. It's often not diagnosed. It's kind of a—one of these things that's rare and often missed. And they also looked at pattern of development. In many—a lot of patients, it's isolated to the clavicles and the sternum. And the most common presentation is chest pain—chest pain. And so they also can get local redness, edema, and bony prominence of the sternoclavicular region. And the interesting thing was—and we actually looked at this a few years ago and found the same thing—was that smoking appears to be a risk factor. There can be restricted mobility of the upper arms and upper girdle—shoulder girdle. A clinical clue on these patients will be this sterile pustulosis they can get, and it's classically on the palms and on the plantar region. And many of these patients will have an underlying autoimmune disease as well. And so based on this, what they've done is they have proposed the CNO classification, and I think it's pretty reasonable, actually, and they break it down into adults and children. The most common one that I've seen is SAFO syndrome, which, again, is going to be that—the skeletal lesions, typically in the sternoclavicular region. But they're going to have the palmar plantar pustulosis, acne, and other autoimmune joint diseases. And this is one where I work very closely with my rheumatology colleagues. These are patients that I send to rheumatology, and we work together on treating this. Hypophosphatase is another hot topic, mainly because we have a drug now. So pharma certainly drives a lot of our practice, and they have in this particular condition. And I'm going to finish with just a couple of studies on hypophosphatase. So as you all know, hypophosphatase is a deficiency in tissue-nonspecific alkaline phosphatase, which essentially leads to an accumulation of pyrophosphate, which impairs mineralization and can lead to rickets and osteomalacia. Now in this particular study, what they did was look at 15 adults. They were relatively young. Some of them were on enzyme replacement therapy, and they compared them to the general population. And they actually—what was interesting is, is not only did these patients have some physical manifestations with gait speed and physical function, but they also had a higher amount of depression, anxiety, and stress. Now one of the interesting concepts is that when you have tissue-nonspecific alkaline phosphatase deficiency, you're unable to take pyridoxal phosphate. You can't dephosphorylate it. And that pyridoxal actually crosses the blood-brain barrier and has important augmentation of central neurotransmitters. And so there's some thinking that maybe this could—you know, could this be real, or is it because of their pain? But there could be some plausibility biologically to why they would have this kind of manifestation. But what I'll throw out there is—and I'm seeing these patients now where they have hypophosphatasia, but they don't have the classical manifestations. And they may have osteoporosis, and how do we treat those patients? And I wish I could tell you I knew the answer. I don't. So I think there's more to be learned in this condition. So that begs the question of these mild forms of hypophosphatasia, and there were a couple of abstracts out on this within the last year at our ASBMR meeting where they actually looked at adults with HPP, and they compared those with skeletal features to those without skeletal features. And they actually found that pain, disability, and quality of life was reduced whether or not you had the classical skeletal manifestations. And again, I don't know. I mean, would these patients benefit from giving replacement therapy? We don't know the answer to that question, but we certainly are seeing these patients. And again, a lot of them complain that they don't feel well. The last study that I want to review is just briefly this study where they looked at parents of HPP patients who had the same pathogenic mutation as their children. And they didn't have the classical abnormal biochemistries, but they did have the biomarkers which might include elevation in urine phosphoethanolamine or elevations in PLP. But what they found was even though they didn't have the classic clinical manifestations, they did have some clinical features that were subtle in nature that were undiagnosed. And so I think what we're learning is with a lot of these rare bone diseases, you see the extreme forms of the disease, and those are the ones that the drugs are being developed for. But there's a lot of grayness, and there's a spectrum of not normal and slightly abnormal findings in patients with all kinds of skeletal genetic disorders, skeletal dysplasias. And I think we're going to learn more about how these might contribute not only to function in those individuals who are termed carriers, but also in how these mutations might be important in other diseases that we see in the general population. So I think with that, it's been our pleasure to present, and we thank you for your attention. Thank you. Yes. We have time for questions. We have time for questions. So please go ahead. Hi. Victoria from Chicago. Have you guys noticed in the last two years an uptick in hyperparathyroidism cases? Hyperparathyroidism? Hyper. Hyper. Hyper. Yeah. Yeah. I've been in practice for 10 years, and I've never seen as much hyperparathyroidism as I've seen in the last two years. We always see a lot of it. I think the thing we're seeing a lot of right now are elevated PTHs with normal calciums. And I think that the whole thing of normal calcemic hyperparathyroidism has been really – it's created a flux of patients into our practice. I don't know if that's what you're seeing, but... I'm seeing actual hypercalcemia, like just on screening labs. I mean, I've got people with diabetes, hyperdisease, just rolling in so much more. And I'm wondering if – and, you know, the woo – you know, do we see maybe COVID-related pro-inflammatory? Something's different. Well, what we – I mean, we did – we have looked in our population, and Dr. Ye, who's in the audience, has also looked at this. What we think is is we saw this big increase in primary hyperparathyroidism when automated chemistry screens were in 1974 – June of 1974, to be specific. So we swept out all these previously unrecognized cases. The incidence then went way down. And then in – let me see if I can remember the exact date. It was around 1990-somewhere, 90-somewhere, they introduced the National Osteoporosis Foundation Screening Guidelines for Osteoporosis. And also there were drugs being put in the market then to treat osteoporosis. So we saw this big increase in primary hyperpara. So we hypothesized that that increase was due to increased screening in patients at risk, because the highest risk group for primary hyperpara are going to be older, you know, women. So that may be what you're seeing. In regards to the denosumab, when I came in, I thought that I would get an information because of all these patients who have now been on for three to five years on denosumab, and then I would be able to take them off. But it seems like I got them addicted to the drug. So while that conceptually may be okay, but mechanistically, why do you think that the longer we use the agent, is it altering some kind of bone marker – the bone mechanism there? Why should it be that if I use a drug longer, if it is just a six-month effect of the drug where it skips off and then I use the second dose, but then I use it for three years and I suddenly lock something into it? So it's a very good question, and I don't think we have a very good answer for that. We have more mechanistic studies that are coming on. What we know is that there is so much profound suppression of the osteoclast by blocking the rank ligand, that after you remove the suppression, even with alendronate or zoledronic acid, you're not getting as much suppression, and then you have this rebound increase. The osteoclast numbers start to increase, possibly the osteoblasts, and there is more crosstalk giving you this rebound formation. There is much more for – rebound resorption, I'm sorry. There is much more for us to learn why the longer you are, the more suppression you have, and then this rebound thing happens. I don't know if we have any better answer right now. No, and I mean the skeletal activity is so quiescent. When you're on denosumab, you'll see about a third of the – if you do a bone biopsy of these patients, only about a – you'll see 30% of the patients without any skeletal label – we call it label uptake, but meaning your bone is very, very quiescent. It may be that when you give a bisphosphonate once a year, for example, it doesn't get into where it needs to go and it's renally excreted, and so I think we just have a lot to learn. Prolia, denosumab is a tricky drug to use, and it's something endocrinologists should really be experts at. Microphone to my right. In patients with hypophosphatasia, could you talk about the prevalence or incidence of parathyroid hyperplasia and hyperparathyroidism and how to manage that long-term? Oh my God. Okay. Yeah. Yeah, that's a good question. You can get hypercalcemia in this condition, and it's thought that you're not able to get calcium to where it needs to go maybe. I don't know the incidence of hyperparathyroidism with that, to be honest, but you can see hypercalcemia, and I don't remember PTH being that big of a factor in hypophosphatasia, but I'd probably plead ignorance otherwise. Yeah. Sorry, I don't know if I have any good answers to your question, but you can get hypercalcemia, and I think that could be just part of the disease. Okay. Yeah. Thank you. Go ahead. Bone density seems to drive a lot of our treatment of osteoporosis, and I am one of those people who has an employer, so I'm required to go to the bone densitometry courses periodically. I just wanted to be brought up to date if you know if this has changed at all, but they told us that if you have a bone density on your patient in one hospital one year, and then the next year he goes to another hospital, same whole logic, bone density machine. You cannot compare those two bone densities. And furthermore, if you look at the bone mineral density in a femlec and a woman in Sweden and try to compare that to somebody in Spain, you can't do that because the normative data is different between those two countries, and yet we compare people from Maine to Florida with one single normative data group. So do those things make you wonder about our bone density test? So yes. So to answer your first question, yes, bone density on the same machine is very essential to be able to look at longitudinal changes with BMD because there is a lot of variability from machine to machine, from center to center. So yes, it is still recommended that patients go through the same machine every year, which sometimes is hard to do. Sometimes they haven't had it in five years. They moved, but we try to do as much as possible. To answer your second point, sorry, what was it again? Normative data between different latitudes. Oh, the normative data. Absolutely. I invite you to listen to the disparities in bone density talk that is happening by Nicole Wright from UAB. She has a lot to say about that because not only you're talking within the continental U.S., but within the continental U.S., you have a lot of ethnic variability in terms of yet we're comparing all our patients to white women. And is that the best way to do it or not? That's a very good question. So please listen to the health disparities talk. I believe it's this afternoon or tomorrow afternoon. Go ahead. I had a practical question about the vitamin D. I live in Pittsburgh. My patients are heavy, so I have a ton of patients on 4,000 IU of vitamin D. What do you tell your patients given that data? Yeah. Well, in general, I don't encourage high doses like that. Now, obviously, people with obesity have, it's thought to be they have more of a depot for the parenteral form of vitamin D before it's hydroxylated, and maybe they need higher doses potentially. With that being said, you know, I would favor lower and reassess, and it seems like maybe lower doses can actually get you into a good range rather than the higher doses. Right now, I think we're going to be moving from a number-based treatment regimen, and maybe in the future we'll go to more based on the evidence on the dose, the data, and maybe we'll use a VMR instead in the future. But I just don't, I think vitamin D seems to be, 25D seems to be a bit of a blunt instrument from what I'm seeing now. I guess my question is, to get them to 30, it's taking me 4,000. So what do you do for those patients where you deliberately would have to undertreat their vitamin D? Yeah, first I would say maybe do we really need to get them all to 30? That's based on PTH. So we call normal at our lab at Mayo 20, you know, anything above 20, 20 or higher. Now you could argue PTH is maximally suppressed at 30, but if they're 30 or 32 or whatever with 4,000, I wouldn't necessarily change that. So I guess if that, because I don't think there's so much uncertainty in the whole field right now, I guess what I'd say is that's fine. Certainly bariatric patients need higher doses. So there are some patients, and to be honest, there's a lot of individual variation in vitamin D catabolism and metabolism. Last year at this same talk, we showed that the closer, you know, the, just based on your, where you lived in regard to the, where you get more sun exposure, we have, you're more likely to have less hydroxylation of vitamin D, and you're going to have changes in vitamin D, you know, and it's probably a mechanism to protect us from hypervitaminosis D. So there's just a lot of ethnic variation. So we may be going more to precision medicine ratios and things to determine in the future. Thank you. Thank you. I'm sorry, but we're out of time. Thank you all for your attention.

bone

metabolic bone diseases

parathyroid disorders

osteoporosis

vitamin D deficiencies

rare bone disorders

oral PTH

denosumab

parathyroidectomy

precision medicine