Good afternoon. Welcome to the session, Mild Forms of Hypercarotiditism, including normal calcium. What's an endocrinologist to do? My name is Joana Miragai, and I'll be serving as your moderator today. You'll be hearing a lecture from Dr. Natalie Cusano on this very fundamental subject. Dr. Natalie Cusano is an Associate Professor of Medicine at the Zucker School of Medicine at Hofstra, Northwell, and Director of the Bone Metabolism Program in the Division of Endocrinology at Lenox Hill Hospital in New York. She received her undergraduate training at Massachusetts Institute of Technology and her medical training at the Boston University School of Medicine. She completed residency training in internal medicine at Beth Israel Dickens Medical Center, and fellowship training in endocrinology, diabetes, and metabolism at the College of Physicians and Surgeons, Columbia University. She serves on the editorial board of endocrine practice, and she lists over 100 publications of original research, invited articles, chapters, and abstracts in the field of metabolic bone disease. My name is Natalie Cusano, and it's my pleasure to speak with you today on mild forms of hyperparathyroidism. What's an endocrinologist to do? These are my disclosures. The key points I wanted to address today are, first, are most patients with primary hyperparathyroidism asymptomatic? Second, how do you evaluate normal calcemic primary hyperparathyroidism? Third, what medical management can we offer? Fourth, who should we refer for parathyroid surgery? Then this is an outline of the talk, so we'll go through a brief introduction, look at the clinical presentation of the disease, and then look at various aspects of the guidelines to date. Just a brief foray into the history of the parathyroid glands. They were first discovered by Richard Owen in 1852 when he performed an autopsy on the great Indian rhinoceros. That was kept by the Zoological Society of London. Parathyroid hormone, or PTH, is made by the usually four parathyroid glands that sit posterior to the thyroid. Primary hyperparathyroidism is a disorder traditionally characterized by elevated levels of PTH and hypercalcemia. Primary hyperparathyroidism is one of the most common endocrine disorders with an estimated prevalence of 0.1-1 percent in postmenopausal women. The prevalence is about three times greater in women than men, and it is more common with increasing age. It is a very common secondary cause of osteoporosis and one that we often scream for, or that we discover incidentally on routine blood tests. This is data taken from the Kaiser Permanente group where they looked at the prevalence of primary hyperparathyroidism over 15 years, and they found that the prevalence in the United States tripled over this time of monitoring both in women and in men. The prevalence in women by 2010 was 233 per 100,000, and in men, 85 per 100,000. To look at the phenotypes of the disease, before the advent of the multichannel autoanalyzer, it was a highly symptomatic disease of bones, stones, brims, and moans. This is the early clinical picture of the disease. This is Captain Charles Martel in 1918. Then unfortunately, just eight years later, after he developed multiple vertebral fractures as part of the disease. In terms of symptomatic primary hyperparathyroidism, kidney stones do remain the most common complication of the disease. But we really rarely now see osteitis fibrosis cystica, which is the classic bone disease associated with primary hyperparathyroidism. It's manifest clinically by bone pain, and then radiographically by a salt and pepper appearance of the skull, tapering of the distal clavicles, subperiosteal bone resorption of the phalanges, and cysts and brown tumors of the long bones. Symptomatic disease does remain common in certain regions of the world, as you can see here by multiple reports. But really now, we are mainly seeing this other phenotype, which is a disease with primarily biochemical and density metric signatures, a more subtle form of the disease. Looking at the modern clinical profile of primary hyperparathyroidism in four cohorts over time, the most recent cohort here reported from 2000-2014. Nephrolithiasis remains a more common symptom of the disease, and it was present in 19 percent of patients in this cohort. What's interesting is looking for the prevalence of kidney stones in quote-unquote asymptomatic patients, so patients who don't have a clinical history of kidney stones. In this one study from Italy, actually in this cohort, 36 percent of patients were known to have kidney stones on a history. But when they actually looked for kidney stones, over half of the patients in this cohort were actually noted to have kidney stones when they looked for them. Overall, in this cohort, 22.4 percent of the patients who had been classified as, again, quote-unquote asymptomatic at baseline, were then found to have kidney stones or vertebral fractures on imaging. Then another study from the same cohort reported by Walker and colleagues, where they looked at 96 patients who had known primary hyperparathyroidism, but without a known history of nephrolithiasis, they did find a cold kidney stones in 21 percent of patients. Yes, kidney stones are relatively rare, about 20 percent of patients in this cohort, but they are much more common if we look for them. Hypercalciuria was found in about 17 percent of patients in this cohort. None of them had overt skeletal disease, and 81 percent had been classified as being asymptomatic. When we look at the biochemical profile of the disease, so serum calcium in the cohort from the 80s to 90s to the more recent from 2000 to 2014, serum calcium is still within one milligram per deciliter of the upper normal limit, so that was not different. But one thing that was different was 25 hydroxy vitamin D levels were much higher in this more contemporary cohort. Here, none of the patients in the prior cohort were taking vitamin D supplements compared to 64 percent for contemporary cohort, and there is a median of 800 international units a day. Associated with this increase in vitamin D, there was a decline in the parathyroid hormone level and an increase in the 125 dihydroxy vitamin D level which is driven by the disease. Here, if we look at the bone density signature, primary hyperparathyroidism, so we know from multiple studies looking at the disease that lumbar spine bone density is relatively preserved. Trabecular bone is relatively preserved. The hip, which is an admixture of trabecular and cortical bone, also relatively preserved. But here, the radius composed primarily of cortical bone is relatively low. What's interesting was that in this newer cohort of patients, when they stratified patients by vitamin D levels, they actually found that patients who had a vitamin D level of 30 nanograms per mil or higher, actually did not have this classical finding of low one-third radius bone density. It might be that this classical finding might be less common as time goes on and more patients are taking vitamin D supplementation. In terms of the management of asymptomatic patients with primary hyperparathyroidism, main questions are, who needs surgery and who doesn't need surgery? For symptomatic patients, it's not necessarily a question of whether to recommend surgery. It would be recommended as long as there were no medical contraindications. But there are a number of guidelines statements to help us manage the question of asymptomatic patients. It's also important to note that even though patients may not meet any specific criteria for surgery, parathyroidectomy is not an inappropriate course of action, as long as there are no medical contraindications. Looking at this question, there's been a number of international workshops. The fourth international workshop findings were published in 2013, and the fifth international workshop is currently ongoing. The American Association of Endocrine Surgeons also published guidelines in 2016. The guidelines address a number of different aspects of the disease and are definitely worth reading if you are further interested in any of these features or findings. Here are the citations where they've been published. Looking at the diagnosis, a patient who has hypercalcemia and a normal or high PTH, not taking drugs that are associated with this. One thing here, if you are suspecting primary hyperparathyroidism and a patient has a low PTH, you might want to exclude biotin supplements because various assays use a biotinylated antibody, and sometimes high-dose biotin supplements can interfere and cause a falsely low PTH. There are very few assays where that might be the case, but again, if you are suspecting primary hyperparathyroidism, a patient is on high doses of biotin, and has a low PTH, you might ask them to stop the biotin before repeating. But if that's not the case, you first want to assess for family history of the disease and for syndromic forms of the disease. If that's the case, you want to proceed with genetic testing. But if not, then you want to measure urinary calcium to creatinine ratio. Look at the serum 25-hydroxyvitamin D and the estimated GFR. This is how we calculate the urinary calcium to creatinine ratio. Looking at the 24-hour urine calcium times the serum creatinine, divided by the serum calcium over the 24-hour urine creatinine. If that level is greater than 0.02, then the patient most likely has primary hyperparathyroidism. If that ratio is relatively low, so between 0.01 and 0.02, then you're not able to distinguish between primary hyperparathyroidism and familial hypercalcemia. It's important to note that in order to make or to adequately assess that ratio, patients should have a replete vitamin D and should have good renal function. If EGFR is low or vitamin D is insufficient, then you might get a lower urinary calcium to creatinine ratio because of that. But if you do have this relatively low ratio, then you'll want to do genetic testing to assess for FHH1, 2, and 3. Looking at the genes for the calcium sensing receptor, looking at GNA11 and AP2S1. If the ratio is less than 0.01, then the patient most likely has familial hypocalcemia or hypercalcemia. You can still consider genetic testing to facilitate screening of relatives. But you would proceed as if the patient had FHH in which you would not consider surgery for these patients. If you have a patient with the disease and who has any one of these findings, so your young age, which from the international workshop guidelines was classified as age less than 45 years, multiglandular disease, which is defined as two or more glands, parathyroid carcinoma, an atypical adenoma, which had cysts or iverspans or positive family history. Then you would want to do mutational analysis in order of the likely frequency. Blue are the recommendations from the Fourth International Workshop, and pink is an additional gene that was recommended by the American Association for Endocrine Surgeons. Obviously, if you detect a mutation, you want to follow up with regular screening for other tumors, such as MEN syndrome or hyperparathyroidism, jaw tumor syndrome, and screen first-degree relatives. If not, then the likelihood of these genetic diseases is very low. The endocrine surgeons recommended genetic counseling be performed for patients younger than 40 years with primary hyperparathyroidism and multiglandular disease and consider for those with a family history or syndromic manifestations. Looking at the surgical guidelines, the Fourth International Workshop continued the age and serum calcium criteria here. Age less than 50 years or serum calcium greater than one milligram per deciliter above the upper normal limit. Those patients have been shown in some studies to progress more faster than other patients. The endocrine surgeons also recommended for these criteria. They said that parathyroidectomy was indicated when the serum calcium level is greater than one milligram per deciliter above normal, regardless of whether objective symptoms are present or absent. That was a strong recommendation with low-quality evidence. Also recommended that parathyroidectomy is indicated when the disease is diagnosed 50 years or younger, regardless of whether the patient had symptoms. That was also a strong recommendation with moderate quality evidence. Moving on to fracture risk in the disease. Bone density, we discussed earlier, as well as bone biopsy data, showed a decreased cortical bone, but relative preservation of the trabecular skeleton. With this, we would expect fracture risk to be decreased at vertebral sites but increased at non-vertebral sites. This is older data from the Mayo Clinic, looking at the expected number of fractures based on age and sex match data versus the observed number of fractures in patients with primary hyperparathyroidism. You can see for all fractures, there was a higher than expected number of fractures in patients with primary hyperparathyroidism. When we looked at vertebral fractures alone, however, there was a much higher than expected number of fractures, of vertebral fractures in patients with primary hyperparathyroidism. This is data from Italy, where they looked at controls versus patients with primary hyperparathyroidism. They screened everyone with vertebral imaging to look for vertebral fractures. Patients with symptomatic primary hyperparathyroidism had a very high rate of vertebral fractures, close to 35 percent. But again, these quote-unquote asymptomatic patients with the disease also had a pretty high rate of having a vertebral fracture. If we look at the body of data in patients with primary hyperparathyroidism, actually most studies show that fracture risk is increased at both vertebral and non-vertebral sites. It shows that trabecular bone is also affected in patients with asymptomatic primary hyperparathyroidism. We can look at this further with high-resolution peripheral quantitative computed tomography, or HRPQCT, which is a non-invasive method to look at bone quality. It's a non-invasive bone biopsy. You can see a patient with healthy bone here on the left versus a patient with osteoporosis here on the right. Just qualitatively, you can see that this bone is more porous. The cortex is thinner, there are many fewer trabeculae. Using HRPQCT, actually, two groups have shown abnormalities in both cortical and trabecular bone in women with primary hyperparathyroidism. Again, this is just looking qualitatively at a patient with the disease versus a match control. You can see thinner cortex and really a profound abnormality in the trabecular space. Then quantitatively, you can see this looking at various aspects of skeletal microstructure. Patients with primary hyperparathyroidism had lower cortical parameters, but also a lower trabecular volumetric bone density, lower trabecular number, lower trabecular thickness, as well as a higher separation and heterogeneity, all of which are overall bad for trabecular bone. These findings were noted most predominantly at the distal radius, but also in many cases at the tibia as well. We found that cortical and trabecular indices were reduced at the radius and the tibia in patients with asymptomatic primary hyperparathyroidism. Basically, it looks like these parameters are overall able to be improved following successful parathyroid surgery. This was looking at patients through two years after successful parathyroid surgery. We found very good improvements at both the radius and tibia and a number of these parameters that had been. Volumetric bone density, cortical parameters, trabecular bone density, and stiffness and failure load, which are associated with bone strength. They all improve after successful parathyroidic surgery. The most recent guidelines recommended as well, consideration for parathyroid surgery if a patient had osteoporosis at any site, had a history of a clinical fragility fracture, or had a vertebral fracture via vertebral fracture assessment, x-ray, CT, or MRI. We recommended screening for vertebral fractures with any one of these modalities. The surgeons also recommended parathyroid surgery in patients who had osteoporosis, fragility fracture, or evidence of vertebral compression fracture on imaging, and this is a strong recommendation with high-quality evidence. Looking at the renal data in the disease, kidney stones are still the most common complication, primary hyperparathyroidism, and they can be detected by non-invasive imaging. Following successful parathyroid surgery, the probability of developing new stones just seem to decrease, although there's a small risk that remains likely due to coexisting idiopathic hypercalceria. Skeletal involvement is more evident in the disease when the EGFR is low, so when patients have stage 3-5 chronic kidney disease. The fourth international workshop did recommend surgery for patients who had an EGFR less than 60 cc's per minute. Patients who had a kidney stone by x-ray CT or ultrasound, and again, it was recommended a screen for stones in quote-unquote asymptomatic patients. Then it was also recommended to look at hypercalciuria plus other urinary indices of increased stone risk. Probably this will be removed from the guidelines that are coming out from the most recent conference. The surgeons also recommended parathyroid surgery for patients who had evidence of renal involvement, patients with kidney stones, nephrocalcinosis, hypercalciuria, increased stone risk, or impaired renal function, although for them this was a weak recommendation with low-quality evidence. Looking at the other aspects of the disease with neurocognitive and cardiovascular complaints as well as calcium and vitamin D. There are a number of issues that patients have with primary hyperparathyroidism. Patients often say that they are weak, have a lot of fatigue, have depression, brain fog, increased sleep requirements. But unfortunately, these findings can be present in a number of other chronic conditions. They lack specificity, are difficult to quantitate, and unfortunately, adequately controlled studies have been a big challenge. There were three randomized controlled trials looking at the effect of parathyroidectomy on psychiatric and cognitive symptoms of quality of life. Despite a similar trial design and assessment tools, they found inconsistent data. One found that parathyroidectomy prevented worsening of quality of life and improved psychiatric symptoms. The other demonstrated a clear improvement in quality of life. The third really indicated no benefit. Then looking at cardiovascular manifestations. In the past with symptomatic disease, there were a number of known cardiovascular manifestations of primary hyperparathyroidism. But with the more mild disease that we see now, there have been some subtle abnormalities noted in various parameters like blood pressure, vascular reactivity, left ventricular hypertrophy and cardiac function or carotid intimal thickness. But the functional significance of these findings is unknown and uncertain. And their reversibility after successful parathyroid surgery is also not clear. So a meta-analysis of 15 studies found a decrease in left ventricular mass by 12% all in parathyroidectomy, but no consistent improvement in other parameters. So the fourth international workshop found that with regards to neurocognitive and cardiovascular complications, there still was not enough data for decisions on surgical management. But this is where the surgeons did have a different recommendation. So they recommended surgery for patients with neurocognitive and or neuropsychiatric symptoms that are attributable to primary hyperparathyroidism. Again, it's hard to provide a clear attribution in some cases, but for them, this was a strong recommendation with low quality evidence. They also recommended offering surgery to patients with cardiovascular disease who might benefit from mitigation of potential cardiovascular sequelae other than hypertension. This was a weak recommendation with low quality evidence. And they recommended that the non-traditional symptoms of muscle weakness, functional capacity, and abnormal sleep patterns be considered in the decision for parathyroidectomy. This was a weak recommendation with moderate quality evidence. And then they also spoke on the non-traditional features of gastroesophageal reflux, fibromyalgia. They said to consider in decision making, but this was insufficient evidence. So looking at calcium intake and primary hyperparathyroidism. So a lot of patients have been told to stop taking dairy or calcium, but there's really no data to support a dietary restriction of calcium in patients with primary hyperparathyroidism. And actually low dietary intake has been shown to stimulate PTH secretion. There's a prospective trial of patients with asymptomatic disease treating with daily, so they had a daily calcium intake of less than 450 milligrams. So they were subsequently supplemented with 500 milligrams of calcium a day. And there, there was no significant increase in serum calcium levels after four and 12 weeks. There was actually a decrease in serum PTH after four weeks and an increase in femoral neck bone density after 52 weeks. So looking at vitamin D deficiency in primary hyperparathyroidism, a meta-analysis and literature review of 10 studies with 340 patients showed preoperative vitamin D repletion in patients with primary hyperparathyroidism and vitamin D deficiency produced no significant change in serum calcium levels, despite a significant increase in 25-hydroxyvitamin D. So here are five patients developed worsening hypercalcemia requiring cessation of vitamin D, but no patient developed a hypercalcemic crisis. There was a double-blind randomized control trial that demonstrated that cholecalciferol 2,800 international units daily versus placebo significantly decreased PTH levels by 17%, increased bone density by two and a half percent at the lumbar spine, and decreased bone turnover markers. There were no differences in adverse events between groups, no differences in any time point in serum or urinary calcium levels between groups. So the fourth international workshop recommended that calcium intake follow national guidelines, that 25-hydroxyvitamin D levels be maintained at least 20 nanograms per ml using initial doses of 600 to 1,000 international units daily, and to monitor serum and urine calcium with vitamin D repletion. The surgeons stated that most patients with primary hyperparathyroidism follow instituted medicine guidelines for calcium intake, and that prior to parathyroidectomy, patients with a disease for vitamin D deficient can safely begin vitamin D. So now shifting to the newer phenotype, so a disease that presents at first with a more subtle biochemical signature, elevated PTH levels with normal serum calcium. So this is known as normal calcemic primary hyperparathyroidism. It was first recognized at the time of the third international workshop, but diagnostic criteria and management recommendations were first made at the time of the fourth international workshop. Unfortunately, there's still really no evidence to guide physicians regarding management decisions in this phenotype. So looking at the diagnostic features, so patients must have an elevated parathyroid hormonal, as well as normal albumin-adjusted serum calcium and normal ionized calcium. So studies have shown that four to 64% of patients with a diagnosis of normal calcemic primary hyperparathyroidism may be reclassified as having traditional hypercalcemic disease with measurement of the ionized calcium. And it's important to note that the corrected and ionized calcium should be always normal to make this diagnosis. So sometimes patients with traditional hypercalcemic disease may have a lowering of the serum calcium into the normal range at times, but they still have traditional hypercalcemic disease if they have been hypercalcemic in the past. So here it's very important to exclude secondary causes of hyperparathyroidism, most common being vitamin D deficiency. So the minimum goal level for vitamin D should be 20 nanograms per ml, but most experts think it's desirable to have a level of over 30 nanograms per ml. And certainly you can try and get their level up to the 40s if you can do it safely. Obviously patients who require very high vitamin D levels to suppress PTH might not have a completely normal physiology or calcium-sensing receptor, but again, if you can get their vitamin D levels up safely and that normalizes the PTH, then you've excluded the normal calcemic form of the disease. So we know that parathyroid hormone levels go up as EGFR declines, and so renal insufficiency has to be excluded. A number of medications have been shown to be associated with secondary hyperparathyroidism. In the literature, lithium and thiazides have been consistently excluded in studies, but loop diuretics and anti-resorptives, especially more potent anti-resorptives, denosinam, can cause secondary hyperparathyroidism. Hypercalciuria can potentially increase PTH levels, as can calcium malabsorption. So before making this diagnosis, you want to make sure that you've excluded these other causes of elevated PTH levels. So I'm looking at the natural history of the disease. So we don't have that much data, but here are the studies that have looked at the natural history. So the first 20 patients who had the disease were followed for 4.1 years, and none of those patients developed hypercalcemia. 12 patients who had a positive localization study underwent parathyroidectomy, and were found to have a single adenoma, or hyperplasia. In the Columbia cohort, 40% of patients who were followed developed other signs of primary hyperparathyroidism with a mean follow-up of three years. And here, 19% of patients actually did develop hypercalcemia during the monitoring course. Seven patients in total underwent parathyroid surgery, so three patients who became hypercalcemic, as well as four patients who were persistently normal calcemic. And there, they were found to have a single adenoma, or hyperplasia. The largest study, which was published most recently, followed 111 patients for at least four years. And here, 19% became hypercalcemic over the monitoring period, the majority becoming hypercalcemic within two years of diagnosis. And there are nine hypercalcemic patients underwent parathyroidectomy, and eight who were found to have an adenoma and were cured. So this last study was a population-based study looking at 100 women where they were completely asymptomatic, and they identified six of 100 who had normal calcemic disease. But there, none of those patients developed symptoms or hypercalcemia in a short follow-up period of one year. There's also another interesting population-based study from Denmark, where they can store blood from a large number of patients from the population. And this was a retrospective study looking at 117 patients who were subsequently diagnosed with primary hyperparathyroidism. And so this study, again, they had stored blood over time, and they found 44 of the 117 patients did not have hypercalcemic primary hyperparathyroidism at the time of study entry based on the stored blood, but 30% did have a high PTH with normal calcium at the time of study inclusion. Okay. So moving on to medical management of the disease, and we're gonna talk about for all patients with asymptomatic primary hyperparathyroidism very shortly, but particularly for normal calcemic disease, there's really only two studies looking at medical management, and both were quite small. So the first was looking at bone density effects in patients with normal calcemic primary hyperparathyroidism treated with the lendronate, so 15 patients versus cholecalciferol alone in 15 patients. And so they found that there was a bone density improvement with the lendronate at the lumbar spine of 4.7% in the treatment group versus a decline of 1.6% in the vitamin D group, and also an improvement at the hip of 4% versus a decline in the vitamin D alone group. So these improvements are what you might expect in patients without primary hyperparathyroidism treated with lendronate. There was also a small unblinded pilot study of six patients with normal calcemic disease using sinicalcet at the dose sufficient to decrease PTH levels, and there they found a decrease in the number and diameter of kidney stones. Really, the majority of data on normal calcemic primary hyperparathyroidism is regarding surgical management, and it's just important to note that many studies have shown that imaging studies are less likely to localize a parathyroid lesion in patients with the disease, so there's potentially a decrease in sensitivity. So 40 CT performed best for patients with normal calcemic primary hyperparathyroidism, but it was only positive in 56% of patients with normal calcemic disease versus 75% of patients with hypercalcemic disease. Ultrasound was only positive in 22% normal calcemic versus 58% with hypercalcemic, and scintigraphy positive only in 11% versus 75% with hypercalcemic disease. The reason for this might be due to two few causes, one being an increased risk of multiglandular disease. So there's a two to three-fold increase in multiglandular disease in patients with normal calcemic versus hypercalcemic disease, and also a decrease in adenoma size. So a few studies have shown an approximate 50% decrease in adenoma size in normal calcemic versus hypercalcemic patients. This is important because for gland exploration, which is a more challenging approach with higher surgical risk, is required if a patient does have multiglandular disease or fails to localize on imaging. One study also did show an increased need for conversion from a minimally invasive approach to bilateral neck exploration in patients with normal calcemic versus hypercalcemic disease of 13% versus 4%. The good news is that if a patient with normal calcemic disease does have a successful parathyroid procedure, there are data showing that there's an improvement in bone density, nephrolithiasis, cardiovascular parameters, as well as quality of life. So the fourth international workshop recommended checking calcium and PTH annually, as well as dexa every one to two years in patients with normal calcemic disease, and if there was progression to hypercalcemic disease to follow those guidelines. And if they remain normal calcemic, and there is progression of the disease in other ways, such as worsening bone density or fracture, or kidney stone or nephrocalcinosis to then proceed with surgery. So just to briefly touch on this, so now we may even be finding a disease before there's really any biochemical signatures. So the parathyroid incidental loma. So these are incidental parathyroid nodules noted at the time of an imaging study or during neck surgery. And they may be relatively common, but very few cases reported in the literature that they're actually related to the disease. But very few cases reported in the literature. The majority of reported cases are biochemically silent. So there's really no data here on monitoring or other management. But I think that a number of us are probably monitoring these patients who were found to have an incidental parathyroid adenoma on some imaging study that lit up with scintigraphy and again, maybe biochemically silent, no symptoms and just following. Just to go back to more established issues in the disease, so looking at medical management. So looking at observation versus pharmacologic approaches. So the longest study looking at the natural history went through 15 years without surgery. And so with regards to serum calcium, it did remain relatively stable over the course of 15 years within one milligram per deciliter above the upper normal limit. But you can see there was a trend over time towards an increase. The other biochemical parameters remained overall stable. Looking at bone density over 15 years. So it remained relatively stable at the lumbar spine, but at the femoral neck and the radius between years 10 and 15, there was a decline in the population of patients without surgery. So you can see that there was this decrease between years 10 and 15. So overall, 30% of patients developed one or more indications for surgery during 15 years of monitoring. So nephrolithiasis, hypercalcemia or reduced bone density. But if you are an optimist, then you would say that 63% of patients did not develop an indication for surgery during 15 years of monitoring. So it all depends a little bit on your outlook, I suppose. So when do we consider pharmacologic approaches? So when surgery is indicated, but medically contraindicated or the patient declines. And the agent that we use, we look at the surgical indication. So either severe hypercalcemia or reduced bone density. It's important to note that senocalcet is the only approved agent for therapy of hypercalcemia in the US and the European Union. But other agents that have been studied include estrogen, riloxepine and lindronate. And most of these studies were very small. And this is just looking overall at what was found. So estrogen really had no effect on calcium parathyroid hormone or bone density. Riloxepine may have had a slight lowering of serum calcium, but no effect on PTH or bone density. A lindronate did improve bone density as you would expect. Unfortunately, with lindronate, there was no change in calcium or parathyroid hormone levels. And it's important to note that the study did not look at fracture, specifically only bone density. So senocalcet really does decrease serum calcium. Unlike in renal hyperparathyroidism, it doesn't decrease PTH levels as much in primary hyperparathyroidism for some reason. And unfortunately, there was no effect on bone density. So there's one study looking at the combination of syncalcine and lendronate, and here the effects work together to improve bone density and decrease calcium and PTH as one might expect. Here are the recommendations from the fourth international workshop. For the control of hypercalcemia, syncalcine is the treatment of choice. To improve bone density, bisphosphamate therapy is recommended, and the best evidence is for the use of a lendronate. Then to reduce the serum calcium and improve bone density, combination therapy with both agents is reasonable, but strong evidence for efficacy is lacking. Also, there is a difference here with the surgeons where they said that operative management is more effective and cost-effective than either long-term observation or pharmacologic therapy. This is a strong recommendation on their part with moderate quality events. Briefly addressing the surgical management. Surgical approaches include the minimally invasive parathyroidectomy with intraoperative PTH and full exploration. In the modern era, the minimally invasive parathyroidectomy with intraoperative PTH has helped achieve cure rates of 97-99 percent. Here, preoperative localization is necessary. That localization can be any one of these modalities. Really, the ideal study depends on local availability and expertise, the preference for the surgeon, and possible need for re-operation. My mentor, John Pelosikian, would always quote John Daltman, who said that the most important preoperative localization challenge in primary hyperparathyroidism is to locate the parathyroid surgeon. You definitely want someone who has very good experience. The American Association for Endocrine Surgeons said that patients who are candidates for parathyroidectomy should be referred to an expert clinician to decide which imaging studies to perform based on their knowledge of regional imaging capabilities. They recommended cervical ultrasonography to localize parathyroid disease and assess for concomitant thyroid disease. Following successful parathyroid surgery, a number of these biochemical parameters that we've looked at as well as risk of nephrolithiasis, bone markers, bone density, and bone microarchitecture seem to normalize or return towards normal. So just looking at the monitoring guidelines for patients who are not undergoing surgery, it was recommended to check serum calcium annually, check DEXA every 1-2 years, as well as imaging for vertebral fractures if clinically indicated, and annual monitoring of EGFR, and abdominal imaging if clinically indicated for kidney stone. Then indications for surgery if a patient is just undergoing monitoring, so a rise in the serum calcium of one milligram per deciliter above the upper normal limit, if the bone density declines into the osteoporosis range, or if there's a significant reduction in bone density, or if a patient develops vertebral fracture. Renal guidelines, so if a patient's EGFR declines to stage 3-5 chronic kidney disease, or if there's the development of a kidney stone by imaging or history. So are the scales tipping towards surgery? Obviously, there's a number of findings that may indicate this, but obviously both options are important to consider in each patient. I guess it's important to think about what a non-invasive method of parathyroidectomy, such as ultrasound guided microwave ablation, further tip the scale. We just need more data. So to circle back to the key points, so are most patients with primary hyperparathyroidism asymptomatic? Yes, but we should screen for kidney stones and vertebral fractures in quote-unquote asymptomatic patients because we might find that they are in fact symptomatic. How do you evaluate normal calciumic primary hyperparathyroidism? We need to monitor serum total and ionized calcium, as well as exclude the secondary causes of hyperparathyroidism, vitamin D deficiency, renal failure, drugs, malabsorption, and hypercalceria. So what medical management can we offer? So senocalcet for hypercalcemia and anti-resorptive therapy for osteoporosis. Who should we refer for parathyroid surgery? Any symptomatic patients or asymptomatic patients who have kidney stones or osteoporosis, younger patients less than 50 years, and patients with a serum calcium greater than one milligram per deciliter above normal. So just to summarize, primary hyperparathyroidism is a very common endocrine disorder. Non-surgical management may be appropriate for individuals who do not meet surgical criteria, or if there are contraindications for surgery. But surgery may also be appropriate for individuals who do not meet surgical criteria as long as there are no medical contradictions. I'd just like to acknowledge my mentor, and I'd like to thank you for your attention. Thank you, Dr. Cusano, for this very important lecture. It was a great lecture. We will now go ahead and open the floor for the Q&A. Please type your questions into the chat box. We'll do our best to answer all the questions. So I think we have some questions here, Dr. Cusano, for you, and I'm going to start with, when should we refer for parathyroid surgery, or should we wait for those patients with normal calcium and hyperthera? Right. Unfortunately, we're picking up most of these patients with normal calcium and primary hyperparathyroidism due to complications that the parathyroid hormone level was measured because of a kidney stone or because of osteoporosis. I think it depends. Obviously, if you've well-established the diagnosis, the patient has had elevated parathyroid hormone levels over six months, you've evaluated and ruled out all of their secondary causes of hyperparathyroidism, then you should discuss with the patient about surgical referral to consider parathyroidectomy. How common it is to see in those patients after surgery hypocalcemia risk? In normal calcium in patients, I mean, it depends on a lot of factors, including the parathyroid surgeon. That's why it's very important to find a good parathyroid surgeon to decrease that risk. Unfortunately, patients with normal calcemic disease do have a higher prevalence of parathyroid hyperplasia, which again is a more complicated surgery with potential higher risk for hypocalcemia postoperatively. You really want to make sure that you have a good parathyroid surgeon and counsel the patient as well before surgery. Is there any benefit of using thiazide diuretics in normal calcemic hyperplasia? For hypercalciuria, some experts have recommended using thiazide diuretics as a trial to see if the hypercalciuria resolves with the thiazide diuretic, in which case, they've made a diagnosis of normal calcium. If it persists, they made this diagnosis of normal calcemic primary hyperparathyroidism. But certainly, it's not necessarily universally recommended. I'm going to try to combine two questions in one here. Let me see, how can I do that? One of them, it talks about, so how can you best differentiate normal calcemic hyperpara from idiopathic hypercalciuria with normal or high PTH? The next question would be, how common is to see hypercalciuria, normal calcemic hyperpara, and how can you differentiate from idiopathic hypercalciuria since both of them can cause elevated PTH? Well, I guess the first question, if they have a normal PTH, and I would not consider the diagnosis of normal calcemic primary hyperparathyroidism since that's the main diagnostic feature that we need to look for. If a patient does have hypercalciuria with a high PTH, again, you could do a trial of a thiazide diuretic to see if that resolves the hypercalciuria, and if not, then some experts have said that that is a diagnosis with normal calcemic primary hyperparathyroidism then. Then I apologize, I did not quite get the second part of the question. How to, since both of them can cause elevated PTH, how would you differentiate the normal calcemic hyperpara from the idiopathic? Oh, I see. Then I answered that one. Yes. How would you distinguish if there is chronic kidney disease? If the patient presenting with a chronic kidney disease, how can you differentiate between the two? Right. Chronic kidney disease, stage 3-5 and EGFR less than 60 milliliters per minute, is an exclusionary criteria for the diagnosis of normal calcemic primary hyperparathyroidism. All patients have to have that PTH level be above 60 to make the diagnosis, because we do know that PTH levels rise as EGFR goes down. Those patients that do go for surgery and they have normal calcemic hyperparathyroidism with osteoporosis, when do you expect improvement on their T-scores? Clinically, I don't necessarily check before a year. But in studies, certainly, patients have had an improvement in bone density within six months of having a successful parathyroid surgery. If a patient met the criteria for osteoporosis and had a successful parathyroid surgery, I would wait for at least a year before repeating the bone density. If at that one-year mark, they still had osteoporosis, I would consider starting treatment at that time. We do still see an improvement in some patients in terms of their bone health through at least two years after parathyroid surgery. They usually start treatment if they need it at one year after parathyroid surgery. Certainly, patients who've had primary hyperparathyroidism for a shorter amount of time, do seem to improve more in terms of bone density after surgery. Would you change and do it sooner if the patient presents with fracture by the time of diagnosis of normal calcemia hyperparathyroidism? Well, yeah. Again, you do want to make sure that you've established the diagnosis, that you've made sure that they do continue to have high PTH levels over time and that you've ruled out everything else. Yeah, if they are already presenting with complications of the disease, then you might want to refer for surgery sooner rather than later. Then I think we have a few more minutes for questions too. Then how well does Xenocalcite can prevent complications of hyperpare compared to parathyroidectomy? Xenocalcite is indicated for patients who have serum calcium levels that are elevated, but who have medical contraindications for surgery or who decline surgery. That's really the main indication for it. In terms of whether it helps prevent nephrolithiasis, there's some small case studies, case reports, series that might indicate that. But otherwise, we don't have that clear data. Then unfortunately, Xenocalcite does nothing for bone density or would be expected to do anything for fracture. It's not as good as parathyroid surgery for those bone outcomes. I think that's a question that most of the endocrinologists have is, can you comment on albumin-corrected calcium and ionized calcium when we get a discrepancy in the labs, which one should we follow and why is there a discrepancy? Yeah, it's interesting. I think unfortunately, ionized calcium is a little hard to measure in some labs. It needs to follow some very certain processing guidelines. Yeah, I think it depends on what the discrepancy is. Obviously, ionized calcium depends on other things within the blood, pH and protein levels. It is highly recommended to look for it in patients with normal calciumate disease because it might mean a reclassification of the patient from a normal calciumate to a traditional hypercalciumate patient. Yeah, I think you have to acknowledge what some of your specific lab issues might be. If you think that your lab does have issues with measurement of ionized calcium, you might want to refer the patient to central lab where you're more sure to have a more accurate result. In terms of a parathyroid incidentaloma, we tend to find sometimes parathyroids in ultrasound in normal labs. How should we follow those patients? Again, here we're in a data-free zone, as I said. I have some patients that I do follow and really there's no guidelines. I haven't really identified any patients who had an incidentaloma that had any issues with kidney stones or any issues with their bones. I have checked, but again, in terms of how often to monitor after that, really we have no idea. Then someone posted a case, younger patient, 40s, normal calcium levels, normal bone density, no kidney stones, mild elevation of ionized calcium with a PTH around 120, and a high 125 vitamin D. It looks like 25-hour calcium was normal. Is that a patient you would recommend surgery? I'm wondering why the PTH was measured in the first place, I guess, if the mild elevation of ionized calcium, I guess. I'm assuming this is a normal corrected calcium, and then the mild elevation of the ionized calcium. Yeah. I'm not sure. Again, I don't know how those labs have trended or tracked over time. With any lab, I just want to repeat and make sure that it is indeed off, because obviously we've all had patients where we checked labs, the patient was hypercalcemic, maybe the patient was dehydrated that day or other reasons. Again, there's other reasons to have a high PTH. I definitely wouldn't rush to surgery in this patient unless they had a well-documented history of high PTH without other causes, especially since they don't have any complications related to the disease. In terms of imaging to diagnose Dr. Cusano, can you comment about the PET-Colin versus the cestamide? Yeah. We don't use imaging to make the diagnosis. We would just use it if a patient were being referred for surgery. In that case, yeah, you just want to refer to your surgeon or to your radiologist for local imaging expertise because some centers are better than others at whatever imaging study, and so you want to rely on what's best at your center. I actually usually just let the surgeon order what study they prefer, because they're the ones who are going to be doing the surgery, so they can order whatever imaging study they know to prefer prior to that. What would be a good vitamin D level prior to proceeding with a 24-hour urine calcium collection? What would be your threshold, or your minimum, actually? Yeah. I like to have it around 30, but certainly at least above 20. About 20, okay. Let's see here. There's a bunch of questions. I just got a little bit lost on some of them. Does the level of hypercalcinia in primary hyperpair correlate to the degree of osteoporosis in hypercalcium and hypercalcium? That's an interesting question, but really, I don't think studies have formed that out. I mean, yeah, with the natural history data, again, two-thirds of patients over 15 years did not develop an indication for surgery over that prolonged timeframe. Yeah, in terms of degrees of hypercalcemia, I mean, yeah, people who tend to have more active disease may tend to have. From what we know from other countries where there's a high degree of vitamin D deficiency, those patients tend to have much larger adenomas, tend to have more active disease, tend to have osteitis fibrosis cystica, the classic bone disease that we don't tend to see these days. But in terms of osteoporosis, not necessarily worse in those patients. One final question before we finish. Should all normal calcemic hyperpair have spinal imaging and how common it is to find spinal fractures on those patients? Yeah, I definitely do recommend that all patients who've made a diagnosis of primary hyperparathyroidism, either hypercalcemic or normal calcemic, you look for spine fractures. If you can, it's easy to do at the time of the bone density testing with a vertebral fracture assessment, and that's very low radiation. In terms of how common it is, we don't have studies to necessarily look at that. Again, most patients with normal calcemic disease are very symptomatic because we're investigating them because they've been referred for some kind of complication. It's hard to say exactly because we're seeing referral populations. But again, at least in these referral populations, a lot of patients do have complications. Thank you so much for your time today, Dr. Cassano, and thank you all for participating today. It was my pleasure. Thanks for all the great questions.

mild hyperparathyroidism

normal calcium levels

primary hyperparathyroidism

asymptomatic patients

medical management options

parathyroid surgery

complications of hyperparathyroidism

individualized patient care

bone density

Dr. Natalie Cusano