Hypercalcemia

1 Improving precision in parathyroid surgery 18F-choline-PET-CT vs ultrasonography and 99-technetium sestamibi scintigraphy in preoperative localization for pHPT - A randomized trial Martin Almquist, 2022-03-08 Purpose and aims The purpose of the present open, single-center, prospective, randomized, clinical study is to investigate whether precision imaging with \[18F\]fluoromethyl-dimethyl-2-hydroxyethylammonium (18F-choline) positron-emission-tomography - computed-tomography, 18F-ch-PETCT, is superior to conventional imaging in localizing diseased parathyroid glands in primary hyperparathyroidism, pHPT. Our overall objective is to improve precision in parathyroid surgery, increase cure rates, minimize complications and shorten operation times. State-of-the-art Primary hyperparathyroidism (pHPT) is a common endocrine disorder, causing kidney stones, renal insufficiency, and osteoporosis, which increases the risk of fractures, especially hip fractures, which carry a substantial mortality risk (1). PHPT is caused by increased production of parathyroid hormone (PTH) in one or several enlarged parathyroid glands. Surgical removal of the pathologic gland(s) cures the disease (2). Successful preoperative localization of such glands limits the surgical dissection, increases the cure rate, minimizes complications, and decreases operation time (3). However, there is no perfect imaging method, which in all patients correctly identifies each and every pathologic gland (4). Commonly used imaging methods are neck ultrasonography and 99-technetium sestamibi scintigraphy (5). In patients with inconclusive imaging, multiphase four-dimensional computed tomography, 4DCT, can further help localize diseased parathyroids (6). The rate of inconclusive or negative studies is high (5). The current first-line imaging strategy with ultrasound and scintigraphy causes up to a half of patients to undergo no less than three localization procedures, adding to costs and inconvenience for patients. Replacing the current strategy with one modality might thus be beneficial for patients and cost-effective for the health care system. Imaging with \[18F\]fluoromethyl-dimethyl-2-hydroxyethyl-ammonium- PET-CT, 18F-ch-PET-CT, previously used for detection and staging in prostate cancer, might more precisely localize parathyroid glands than ultrasound and scintigraphy (7). However, 18F-ch-PET-CT is also more expensive than ultrasound and sestamibi scintigraphy, and not available at all centers. Hence, 18F-ch-PET-CT has mostly been used as a second-line method, for instance in patients with inconclusive ultrasound and/or scintigraphy, or in patients with persistent disease after previous parathyroid surgery (7). Significance and scientific novelty 18F-choline-PET-CT has not been used as the first-line modality in localizing parathyroid glands, and there has been no randomized trial comparing its efficacy to conventional imaging in this setting. A randomized trial would yield solid evidence and its results would be both novel and clinically important. 2 Preliminary and previous results Between 1st January 2017 and 31st December 2020, a total of 241 patients with first-time, nonhereditary pHPT were operated on at the Department of Surgery at Skåne University Hospital, Lund. Out of these, 225 patients (93 %) underwent ultrasonography, and 223 patients (92 %) underwent 99-technetium sestamibi scintigraphy. Ultrasound was inconclusive in 39 % of 225 patients, and sestamibi scintigraphy was inconclusive in 47 % of 223 patients. Hence, 116 patients (48 % of all patients) also underwent 4DCT. 4DCT was inconclusive in 28 % of patients. Thus, a total of 42 (17 % of all patients) had inconclusive results in all three investigations. In patients with localized disease, the cure rate was 95 %; in patients where all three examinations were inconclusive, the cure rate was only 81 %. Thus, precision in preoperative localization is needed. At the Department of Clinical Physiology and Nuclear Medicine, Skåne University Hospital, 18Fch- PET-CT has been used in 5,500 patients between 2008 and 2019 for imaging of prostate cancer. No adverse reactions were reported. An on-site cyclotron, PETtrace 880, GE Healthcare, is used to produce the radiotracer \[18F\]fluoromethyl-dimethyl-2-hydroxyethylammonium. Project description Theory and methods This is a non-blinded, single-center, prospective, randomized, clinical study comparing 18F-ch- PET-CT to 99-technetium sestamibi scintigraphy and ultrasonography for localizing parathyroid glands in primary hyperparathyroidism. Inclusion and exclusion criteria Adult patients with primary hyperparathyroidism referred to the Department of Surgery at Skåne University Hospital, Lund, deemed candidates for surgery by the attending surgeon, using criteria specified in clinical national and international guidelines, patient preferences, and surgeon judgment of indication and operability, are invited to participate. Invited patients are given oral and written information. After signed informed consent, patients are randomized to either 18F-ch-PET-CT or ultrasound and scintigraphy. Allocation is open, since blinding is not possible, neither for providers nor for patients. Patients with previous parathyroid or thyroid surgery, or with the need for concurrent thyroid surgery, or with lithium therapy, hereditary parathyroid disease, such as multiple endocrine neoplasia type 1, MEN1, or with severe renal insufficiency, are not eligible. Outcomes Since cure rates are high, even after negative imaging, 18F-ch-PET-CT might only increase cure rates slightly. However, more precise preoperative localization with 18F-ch-PET-CT should decrease operation time, facilitating surgical planning, with similar or higher cure rates than conventional imaging with ultrasound, scintigraphy, and (in half of the patients) 4DCT. The primary outcome, therefore, is operation time, measured from incision to the last suture. Secondary outcomes are cure rates, defined as normocalcemia without treatment with calcium or vitamin D at first follow-up, one month postoperatively; rates of complications such as damage to the recurrent laryngeal nerve and hypocalcemia; rates of persistent disease, i.e. hypercalcemia at one month postoperatively; sensitivity, specificity, positive and negative 3 predictive values, per-lesion and per-patient; the total amount of irradiation; and total imaging and procedure costs. Safety Patients randomized to the conventional arm are not at increased risk due to the study. Patients randomized to 18F-ch-PET-CT are at risk for side-effects of this investigation. Potential side effects include adverse reactions to the radionuclide 18F-choline, radiation, and incidental findings. The mean effective dose of radiolabelled choline PET, ranging from 2.5 to 3.8 milliSievert, mSV, was lower than that of parathyroid scintigraphy performed with different techniques in the metaanalysis by Treglia et al. The addition of low-dose CT imaging for the hybrid approach yielded minimal further radiation exposure, 0.8 mSv (7). Thus, patients randomized to 18F-ch-PET-CT will not be subjected to more irradiation than the patients in the conventional arm. Adverse reactions to \[18F\]fluoromethyl-dimethyl-2-hydroxyethyl-ammonium (18F-choline) are rare; none were reported in a meta-analysis on 18F-ch-PET-CT for prostate cancer, and none have been reported at the Department of Nuclear Medicine, Skåne Lund University Hospital, in a series of 5,500 patients. Power Currently, patients with pHPT have a mean (SD) operation time of 45 (25) minutes, whereas those with well-localized disease have currently a mean (SD) operation time of 31 (15) minutes. To show a difference of 45 vs 30 minutes or greater, with alpha set to 0.05 and 80 % power, 44 patients in each arm are needed (8). To account for attrition, an extra 6 patients in each arm will be included. Thus, the trial will need to include and randomize 100 patients, 50 to each arm. Feasibility and time plan During the last 3 years, a mean of 80 patients annually fulfilling inclusion criteria were operated on at the Department of Surgery at Skåne University, Lund. Assuming an inclusion rate of 85 %, inclusion would take 18 months. Given current wait times for surgery at the department, all patients would be expected to be operated on within 24 months. We will be able to analyze their outcomes within two and half years. A report of the study should be expected within 3 years. Project organization Logistics Referrals to the surgical department are checked daily by one of the attending surgeons. Referrals on patients deemed candidates for this study will be marked, and the research nurse will send patients a letter informing them about the study, and answer relevant questions by phone. Patients potentially eligible for the study will be seen by the PI. Patients' inclusion and exclusion criteria will be checked and noted, and eligible patients will be invited to participate. It is estimated that the PI will use 10 % of working time to oversee the study, inform and randomize patients. The research nurse will use 10 % of working time to further inform patients and managing referrals and appointments for imaging. Two specialist nuclear medicine physicians will devote 5 % of their time to management of the study, more specifically for image interpretation. 4 Data collection All data for the study will be collected using the Scandinavian Quality Register of Thyroid and Parathyroid Surgery, SQRTPA (9). This quality register is recognized by the Swedish Association of Local Authorities and Regions, the National Board of Health and Welfare, the Swedish Surgical Society, and the Swedish Association for Otorhinolaryngology and Head and Neck Surgery. The SQRTPA is managed by AddPro AB (10), a specialized IT-consulting company based in Lund, Sweden. All data are securely stored on servers located in Sweden. The PI will have full access to the study data. Randomization Patients will be randomized using the built-in function of the SQRTPA (9). Data analysis and statistics With an expected difference of 45 (SD:25) and 30 minutes in the experimental and conventional arm, and alpha 0.05, beta 0.80, a total of 44+44 patients are needed (8). To account for attrition, 100 patients will be included. Primary and secondary outcomes will be analyzed using the intention-to-treat model, where patients are compared according to the group they were randomized to. We will also conduct multivariable regression models to identify factors associated with high and low specificity and sensitivity of 18F-ch-PET-CT, to further understand potential strengths and weaknesses with the method. Equipment No special equipment will be needed. Need for research infrastructure. This study will not need any extraneous research infrastructure. International and national collaboration This is a single-center study. No national or international collaboration will be sought for this study. Other applications or grants. Local grants will be sought after ethical approval (Skåne University Hospital Funds, Funds of the Southern Health Care Region, ALF) Independent line of research. This an independent line of research. The PI has no relations with other researchers or projects that will affect the present study. Clinical significance. Currently, a precise method to localize the parathyroid glands preoperatively is lacking. Precision imaging with 18F-ch-PET-CT has the potential to reduce the number of investigations necessary to localize and identify the diseased gland and will decrease operation time, with maintained or improved cure rates, lower hospital stay, and lower costs. If successful, this precision imaging modality will be immediately implemented into the clinical routine at the Departments of Surgery and Nuclear Medicine in Lund; likely, other hospitals in Sweden and internationally will follow. 5 References 1. Kristensen PK, Perez-Vicente R, Leckie G, Johnsen SP, Merlo J. Disentangling the contribution of hospitals and municipalities for understanding patient level differences in oneyear mortality risk after hip-fracture: A cross-classified multilevel analysis in Sweden. PLoS One. 2020;15(6):e0234041. 2. Wilhelm SM, Wang TS, Ruan DT, Lee JA, Asa SL, Duh QY, et al. The American Association of Endocrine Surgeons Guidelines for Definitive Management of Primary Hyperparathyroidism. JAMA Surg. 2016;151(10):959-68. 3. Bergenfelz A, van Slycke S, Makay O, Brunaud L. European multicentre study on outcome of surgery for sporadic primary hyperparathyroidism. Br J Surg. 2020. 4. Bunch PM, Kelly HR. Preoperative Imaging Techniques in Primary Hyperparathyroidism: A Review. JAMA Otolaryngol Head Neck Surg. 2018;144(10):929-37. 5. Kunstman JW, Kirsch JD, Mahajan A, Udelsman R. Clinical review: Parathyroid localization and implications for clinical management. J Clin Endocrinol Metab. 2013;98(3):902- 12. 6. Kluijfhout WP, Pasternak JD, Beninato T, Drake FT, Gosnell JE, Shen WT, et al. Diagnostic performance of computed tomography for parathyroid adenoma localization; a systematic review and meta-analysis. Eur J Radiol. 2017;88:117-28. 7. Treglia G, Piccardo A, Imperiale A, Strobel K, Kaufmann PA, Prior JO, et al. Diagnostic performance of choline PET for detection of hyperfunctioning parathyroid glands in hyperparathyroidism: a systematic review and meta-analysis. Eur J Nucl Med Mol Imaging. 2019;46(3):751-65. 8. https://clincalc.com/stats/samplesize.aspx. 9. https://sqrtpa.se 10. www.addpro.se

Study Description: To evaluate participants with bone and mineral disorders at the NIH Clinical Center and obtain tissue and clinical specimens from outside institutions Objectives: Primary Objective: Provide a protocol within which participants with common and rare disorders of bone and mineral metabolism can be studied, evaluated and treated at NIH. Secondary Objectives: To obtain tissue and clinical specimens (including but not limited to blood, urine, nucleic acids, skin and bone) and data collected at outside institutions and the NIH Clinical Center from participants with various bone and mineral disorders. Tertiary/Exploratory Objective: Generate a pool of participants with bone and mineral disorders, from which research questions could arise and future clinical research studies may be generated. Endpoints: Primary Endpoint: Medical evaluation with clinical assessments performed at time points specific to each participant s diagnosis. Analysis of research and participant outcome data will be performed. Secondary Endpoint: Genetic and/or biochemical assessments of surgical waste material from the NIH Clinical Center or other medical facilities. Tertiary/Exploratory Endpoint: Development of a database containing information from enrolled participants with bone and mineral disorders and annotated specimens and data.

Brain calcification is a common neuroimaging feature in patients with metabolic, neurological, or developmental disorders, infectious diseases, traumatic or toxic history, as well as in otherwise normal older people. To understand the clinical and genetic characteristics of brain calcification, we establish a cohort of brain calcification to follow up patients with brain calcification.

Goal of this trial: To test a new tool called VISOR in adults (aged 18-80) with 1-3 cm kidney or ureter stones. We want to see: 1. If it's safe and works well 2. If its built-in features (flushing/suction, pressure control, and stone-breaking/removal) help clear stones better while keeping surgery safe. Main questions: 1. Can the VISOR clear stones successfully (with fragments \<4 mm left) for at least 9 out of every 10 people within 24 hours after surgery? 2. Will serious problems (like severe infections or ureteral injuries) happen to no more than 1 in 20 people (5%)? 3. Can the device keep pressure inside the kidney below 30 mmHg (a safe level) during the entire surgery? What participants will do: Have stone removal surgery using VISOR (breaks and removes stones at the same time). Get a CT scan within 24 hours after surgery to check if stones are cleared. Return 4 weeks (±1 week) after surgery for: An imaging test (CT or ultrasound) A check for any health problems related to the surgery.

This is an open-label study to evaluate the effect of DensityTM, amorphous calcium carbonate (ACC), in postmenopausal women, compared to FREEDOM substudy. Subjects with a BMD T-score between -4.0 to -2.5 will be invited to enroll into this study. After signed ICF, eligible subject who meet NHI reimbursement criteria for use of denosumab will be assigned to A arm, and subject who does not meet NHI reimbursement criteria for use of denosumab, or who is no willing to receive denosumab treatment during study period, even meet NHI reimbursement criteria will be assigned to B arm. A total of 205 subjects will be enrolled into this study, in which 142 subjects in A arm and 63 subjects in B arm. In A arm, subject will receive 5 DensityTM tablets (equal to 1000 mg calcium element) daily with injections of 60 mg of ProliaTM (denosumab) every 6 months at study site, while in B arm, eligible subject will receive 5 DensityTM tablets (equal to 1000 mg calcium element) daily only. DensityTM tablets will be administered as follows: 5 tablets will be taken after meal. In addition, all subjects with a baseline 25-hydroxyvitamin D level of 12 to 20 ng/ml will be given 800 IU of vitamin D3 daily, while those with a baseline level above 20 ng/ml received 400 IU of vitamin D3, both administered after meal. The study will consist of 7 clinical visits. Subjects will come to the clinics at Visit 1 (screening visit, Month -1), Visit 2 (regimen start, Day 0 in Month 0), and Visit 3 to 7 (follow-up visits, Month 1, 6, 12, 18, 24). BMD assessment and blood drawing will be performed before study medication administration and at Month 1, 6, 12, and 24.

Acutelines is a prospective biobank including patients with a broad spectrum of acute conditions. Its aim is to facilitate interdisciplinary research on the etiology and development of acute diseases with the aid of systematically collected biomaterials and medical data over various timepoints, both during the course of the patient's disease and after recovery. Clinical data, imaging data and biomaterial (i.e. blood, urine, feces, hair) are collected for patients presenting to the Emergency Department (ED) with a broad range of acute disease presentations. A deferred consent procedure (by proxy), is in place to allow collecting data and biomaterials prior to obtaining written consent. The digital infrastructure in place and the software used ensures automated capturing of all bed-side monitoring data (i.e. electrophysiological waveforms, vital parameters), and the secure importation of data from other sources, such as the electronic health records of the hospital, ambulance and general practitioner, municipal registration, health insurance companies and pharmacy. Follow up data are collected for all included patients during the first 72-hours of their hospitalization and 3-months, 1-year, 2-years and 5 years after their ED visit. Data and materials to be collected includes: * Demographic and health data (i.e. \[experiences\] health, quality of life, functional status) * Medical history (i.e. co-morbidity, intoxications, medication use) * Admission reason to emergency department * Physical examination and vital parameters * Clinical diagnostic data (i.e. \[point-of-care\] ultrasound, X-ray, CT-scan, laboratory results) * Electrophysiological waveforms (i.e. electrocardiogram \[ECG\], plethysmography) * Biomaterials * Treatment (i.e. medication use, non-pharmacological treatment, treatment decisions, length-of-stay in hospital, admission to intensive care unit \[ICU\])

Subjects with various AATS-related disease (Primary Hyperparathyroidism, Glioma, et al) patients underwent 11C/18F-MET/FET PET/CT either for an initial assessment or for recurrence detection. Lesions uptake was quantified by the maximum standard uptake value (SUVmax). The sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) and accuracy of 11C/18F-MET/FET were calculated.

Aim The overall aim of this study is a physiological investigation of the effect of bisphosphonate treatment versus placebo at time of parathyroidectomy (PTX) in patients with primary hyperparathyroidism (PHPT) on bone, kidney and the cardiovascular system one-year post-surgery. Hypothesis: In patients with PHPT and low areal bone mineral density (aBMD), treatment at time of PTX with zoledronic acid (ZOL) compared to placebo: 1. does not improve aBMD 2. does not improve bone microarchitecture 3. does not improve volumetric bone mineral density (vBMD) 4. does not influence changes in BTM 5. does not improve coronary artery calcium score (CACS) 6. does not improve arterial stiffness (pulse wave velocity \[PWV\]) 7. does not improve degree of renal calcifications or urinary parameters Background: PHPT is a common endocrine disorder characterised by hypercalcemia and inappropriately high levels of parathyroid hormone (PTH). In most cases, PHPT is caused by hypersecretion of PTH from a single adenoma (80-90%). It is a chronic disease, which may lead to several complications such as osteoporosis, renal calcifications, cardiovascular disease, and neuropsychiatric symptoms. Surgical removal of the parathyroid gland/-s causing the hypersecretion of PTH is the only definitive cure for PHPT. It is a disease that mostly affects women with a ratio of 3:4 in the age group 40-70 years. Even though many patients are asymptomatic up to one third of the patients have osteoporosis at the time of diagnosis. Hypersecretion of PTH affects bone causing an increase in bone turnover markers (BTM), a decrease in BMD and an increased risk of fractures. Successful PTX normalises the calcium homeostasis and increases BMD one-year post-surgery at both lumbar spine and total hip, whereas the BMD increase at the distal forearm is minor. Accordingly, in Denmark, patients with PHPT and osteoporosis are most often treated with PTX only and "watchful waiting" is employed regarding BMD. If osteoporosis is sustained one year post surgery treatment (typically with a bisphosphonate) is, then initiated. To date, limited data on the effect of bisphosphonates if administrated at time of PTX is available. A retrospective study comparing 24 PHPT patients treated with PTX alone to 26 PHPT patients treated with both bisphosphonates and PTX found no beneficial effects on BMD of adding bisphosphonate to PTX. In another retrospective study however, co-treatment with bisphosphonate prior to PTX in patients with both PHPT and osteoporosis was associated with a decreased risk of fracture whereas, adding bisphosphonates after PTX did no reduce fracture risk. In contrast, a RCT in patients with PHPT comparing treatment with ZOL 1-3 months after PTX to PTX alone and found a significantly higher increase in BMD at the lumbar spine and femoral neck in the group treated with ZOL. At the total hip, however, BMD increased more in the group that only received PTX. Taken together the studies so far have shown conflicting results. Moreover, as the lumbar spine and femoral neck are sites relatively rich in trabecular bone with higher turn-over, whereas cortical bone is more prominent at the total hip, the effects of bisphosphonates and PTX may differ according to bone site. Therefore, it is unclear if treatment with bisphosphonate at time of PTX strengthens bone or impairs the natural recovery of bone during the first year after PTX. Only very few studies have addressed this issue. As up to one third of the patients with PHPT are diagnosed with osteoporosis, it is essential to clarify which treatment approach is optimal for the recovery of bone in this patient group. To clarify bisphosphonates effect on bone metabolism at the time of PTX, the investigators will perform a mechanistic study in patients with PHPT and either osteopenia or osteoporosis to study the pharmacodynamic effects on bone prior to PTX. Several studies have reported an increased mortality compared to the general population in patients with classic PHPT with moderate to severely elevated ionized calcium levels whilst studies with focus on mild PHPT found no increased mortality. Overall death was reported from cardiovascular diseases (CVD) and malignancy. ZOL is a well-known drug used for decades to treat osteoporosis and malignancy-related bone disease. However, possible positive effects such as reduced mortality and cardiovascular events of ZOL used have been discussed. In a RCT study investigating the effects of ZOL infusion every 18 months on BMD in postmenopausal women observed a lower rate of myocardial infarction and composite cardiovascular outcomes (defines as myocardial infarction, need for coronary revascularization, stroke or sudden dead) but not stroke in the group receiving ZOL compared to placebo. In contrast, meta-analyses looking at cardiovascular safety of ZOL , found no beneficial effects on major cardiovascular events with ZOL used, however, in one meta-analysis an increased risk of arterial fibrillation was observed.\[22, 23\] In a large cohort study from Denmark and Sweden investigating the safety of ZOL against oral bisphosphonate also observed a higher risk of atrial fibrillation, other arrhythmias, and heart failure compared to untreated individuals whereas the cardiovascular mortality among ZOL users was lower. Studies investigating effects of ZOL on cardiovascular outcomes are all made in population with osteoporosis or in patients with low BMD. However, no one have investigated ZOLs effect on cardiovascular indices in patients with PHPT. Coronary artery calcium score (CACS) and pulse wave velocity (PWV) are strong predictors of CVD in healthy individuals. Only few studies have investigated the CACS in PHPT patients. A cross-sectional study of 130 PHPT patients compared to a cohort of population-based control subjects found a greater positive CACS in PHPT patients compared to controls. However, another cross-sectional study of only 20 PHPT patients found no increased CACS compared to healthy controls.\[28\] Central arterial stiffness measured as PWV has been established as a predictor of cardiovascular events and all-cause mortality in both the middle-aged and elderly population. A few prospective studies have reported an increased arterial stiffness in PHPT patients compared to healthy individual and a decreased arterial stiffness following PTX. A RCT study investigating short-term effect of PTX on arterial stiffness observed a significant decrease in PWV 3-month after PTX in PHPT with moderate-severe hypercalcemia. As patients with PHPT have increased CVD mortality is it of great interest to investigated if ZOL infusion in PHPT may have a proactive effect on the cardiovascular system as well as beneficial effects on bone architecture. Renal calcifications are common in PHPT and in many studies the prevalence is determined to be around 20-25%. However, effects of PTX on the remission on renal calcifications are sparser. The risk of nephrolithiasis declines following PTX, although the risk remains increased compared to the general population. Hypercalciuria is of importance for the development of calcifications, however it does not fully explain the increased stone risk. Other metabolic factors in the urine may play a role in the increased risk of renal calcifications. One study with 51 PHPT patients found normalization of urinary calcium excretion following PTX but not on all other urinary metabolic parameters. As only few studies have evaluated the effect of PTX on urinary parameters and renal calcifications one-year post-surgery the investigators want to assess a metabolic urinary profile and a CT-scan of the kidneys and urinary tracts in PHPT with renal calcifications compared to PHPT without calcifications and effects of PTX as well as the potential effects of treatment with ZOL. Methods Design: A randomized, double-blinded placebo-controlled trial Patient flow: Patients referred to Aarhus University Hospital (AUH) for PTX due to PHPT will be included prospectively. The investigators aim to include 140 patients with PHPT - 70 patients in each group. Patients will be enrolled consecutively until the required number of participants have been achieved. The enrolment period will be approximately 1 years. Enrolled participants will be randomized to intervention- or placebo group and receive either ZOL or placebo (saline water) 2-4 weeks prior to PTX. Enrolled participants will be examined as detailed below (table 1). Participants who did not archive normocalcemia following PTX may not have to continue their participation in the study after (unsuccessful) PTX. One-year post-surgery a control visit will be held for all participants. The participants finish the study at the 12- month follow-up visit after PTX. Participants will be excluded from the study if a ionized calcium \>1,35 mmol/l is measured at day 28. Intervention: ZOL 4 mg vs. placebo (100 ml saline water) as a single intravenous (iv) infusion. Participants will receive ZOL or saline water at the outpatient clinic of Endocrinology, Aarhus University Hospital approximately two-four weeks prior to PTX (baseline). According to standard of care at the hospital, all patients will be recommended a daily oral supplement with 800 mg of elementary calcium in combination with 38 micrograms of cholecalciferol following PTX. Double blinding: A nurse with no association to the project will mask both ZOL and saline water prior to randomisation with non-transparent bags so that both patients and investigators in the trial are blinded to the content of the infusion bags. At time of inclusion, participants will be randomised (double blinded) to receive either ZOL or placebo (saline) 2-4 weeks prior to PTX. ZOL and saline water will be administrated as an iv. infusion over 15 minutes by a study nurse without any other relation to the study. Randomization will be performed using a computer algorithm. Overall, participants will be stratified based on gender and ionized calcium ≤ or ≥ 1,45 mmol/l into 2 approximately equally sized groups. One of the groups will also have BTM performed at day 14 and at week 8, 16 and 24. Overall medical records: ZOL and placebo (saline water) are supplied by the hospital pharmacy and delivered to the investigation site. The investigators will document and keep a record of experimental drug delivered to the site with the following information: name, strength, amount received, date of receipt, batch number, expiration date, amount of experimental drug on the investigation site, date and initials on the person which has updated the records of the experimental drug delivered. The delivery note from the pharmacy may be used as documentations provided it contains the above information and will be signed upon receipt. Individual medical records: Medical records for each participant will be carried out thoroughly. A separate document will be used for the individual medical records to obtain blinding. Before the experimental drug is delivered to the investigator a second person with no association to the project will double check that is it the correct experimental drug delivered to the investigator according to the randomisation. The medical records will contain the following information: Patients ID, name, strength, and amount of the experimental drug, batch number, expiration date, amount of drug delivered and administered, date and initials of persons delivered and administrated the drug, amount of experimental drug returned, date and initial of person receiving returned experimental drug. Unblinding: The investigator has the responsibility and the possibility to unblind participants in case of emergency. Measurements: aBMD are measured by dual energy x-ray absorptiometry (DXA) and high-resolution peripheral computed tomography (HRpQCT) scans at baseline and end of study. Volumetric bone mineral density is measured by bone assessment included in the Cardiac CT-scan (see below). Biochemistry includes blood teste of plasma levels of PTH, vitamin D metabolites (including 25-hydroxyvitamin D \[25(OH)D\] and calcitriol \[1,25(OH)2D\]), total and ionized calcium (Ca2+), phosphate, magnesium, albumin, sodium, potassium, creatinine, estimated glomerular filtration rate (eGFR), cystatin C (CysC), aldosterone, renin, angiotensin 2, arginine vasopressine, insulin, glucose, glycated HbA1c, total cholesterol, low density lipoprotein (LDL), high-density lipoprotein (HDL) and triglycerides. At some time points blood is also analyzed in terms of a "BTM package" which includes analyses for C-terminal telopeptide of type I collagen \[CTX\], N-terminal propeptide of type I procollagen \[PINP\], bone specific alkaline phosphatase \[BSAP\]), and fibroblast growth factor 23 \[FGF-23\] as well as analyses of plasma Ca2+ and creatinine. In approximately half of the participants (who accept extended BTM measurements), BTM are also measured after 2 weeks and after approximately 2, 4 and 6 months (Table 1). In 24-hour urine, volume is measured, and the urine is analyzed for excretion of calcium, phosphate, sodium, potassium, magnesium, oxalate, uric acid and citrate. Some analyses are performed in batches for which samples will be frozen in a research biobank and not analyzed before all samples have been collected which includes PTH, vitamin D metabolites, BTM, insulin, aldosterone, renin, angiotensin 2, arginine vasopressine and CysC as well as urinary citrate. Cardiac CT-scan is performed at the Department of Cardiology at Gødstrup Regional Hospital and will include the heart, kidney and proximal femur. A cardiac ultrasound (ECHO) will be performed together with the CT-scan. An eGFR ≥ 35 mL/min must be measured within three months prior to the scan. Otherwise, a blood sample will be performed prior to the scan or on the day. From the Cardiac CT-scan the coronary artery plaque burden will be measured as a CAC-score. Furthermore, the CT-scan will provide data on vBMD at the lumbar spine and hip, vertebral compression fractures and renal calcifications. Tonometry: The SphygmoCor system (Xcel; AtCor Medical, Sydney, NSW, Australia) is an ultrasound examination used to assess arterial stiffness and pulse wave analysis (PWA). For measurements of PWV an inflated femoral cuff will be placed on the right-upper thigh combined with carotid applanation tonometry. Questionnaires: Parathyroid assessment of symptoms score (PAS) and primary hyperparathyroidism health related quality of life (PHPQoL) will be handed out at baseline and at 12-month follow-up. Furthermore, all participants will receive a questionnaire about possible side-effects to infusion 1-week and one month after receiving either ZOL or placebo (attachment 1). Statistics: Assuming a mean BMD of 0.9 g/cm2 at the lumbar spine and an estimated differences of 2% in BMD between groups one year after surgery (5% significant level, 90% power, SDdiff 0.03 g/cm2) 59 participants are needed in each group. To accounts for dropouts 70 participants will be included in each group. QQ-plots will be used to check for normality. The difference between the two groups will be assessed using either a paired t-test or Mann-Whitney U-test depending on distribution for continuous variables. The investigators will use intention to treat analysis including all randomized participants with a successful PTX (i.e., analysis will be restricted to participants archiving normocalcemia following surgery). Side effects 1. Intervention ZOL is a well-known drug that has been used for many years in treating osteoporosis and other metabolic bone diseases. It is well tolerated. However, there are some known side effects. Some participants may experience fever and muscle pain after infusion of ZOL (flu like symptoms). The side effects are benign, last only a few days and discomfort can be reduced by administration of paracetamol. Furthermore, some participants may experience joint pain which often disappear again after weeks. Allergy towards bisphosphonate is a very rare and an uncommon side effect. ZOL acid given as a single infusion is not expected to give any long-term side effects. Furthermore, infusion of 100 ml of saline water is not expected to give any short- or long-term side effects. 2. Other side effects During the project, less than 300 mL of full blood will be drawn and should not give any unpleasantness for the participants. Furthermore, to infuse ZOL or saline water an i.v. access is necessary. However, some may find it uncomfortable to have a blood test taken and an i.v. access established. There is only a minimal risk of infection at the injection sites. The cardiac CT is implemented in everyday clinical work, and to evaluate possible coronary stenosis it includes a contrast-enhanced sequence with an iodine agent. Participants' renal function is evaluated with a blood sample prior to the scan (e-GFR ≥ 35 ml/min/1.73 m3) for safety reasons. Furthermore, in very rare cases, participants develop an allergic reaction to iodine contrast and therefore participants are asked about prior allergic reactions to iodine before the CT scan. Moreover, a medical doctor will be present during the CT scan. Betablockers (atenolol administered orally 30 min-2 hours before the scan or metoprolol administered intravenously during the scan) or ivabradine (administered orally 30 min-2 hours before the scan) are used to lower the heart rate during the cardiac CT. Likewise, a vasodilator (nitroglycerin) is administered sublingually immediately prior to the scan. Both betablockers, ivabradine, and nitro-glycerine are administered to lower radiation doses and improve image quality. This standard procedure is also used in a clinical setting, and it is considered safe. The potential side effects are nausea, headache, dizziness, abdominal pain, or obstipation, and are considered minimal and short term. A medical doctor with experience in cardiac CT will evaluate the scans for critical cardiac disease (defined as a \>50% stenosis in left main coronary artery (CT angiography) or left ventricular ejection fraction below 30% by ECHO). Each CT-scan will cause a radiation of 10.0 mSv which corresponds to 3 years of background radiation. DXA- and HRpQCT scans are without discomfort for the patients. At each DXA-scan patient receive a total radiation dose of maximal 0.2 mSV which correspond to 30 days of background radiation. At each HRpQCT scan, a patient receives a total radiation dose of maximal 0.003 mSV which correspond to less than one day of background radiation. Accordingly, at baseline each patient will receive a total dose slightly higher than 10.2 mSv corresponding to 3.1 years of background radiation. As the examinations are repeated after one year, the total radiation will correspond to 6,2 years of background radiation and increase the risk of dying from cancer from 25.0% to 25.1%. However, the actual risk is probably less, as this study is performed in an elderly population (all \> 50 years of age) with an estimated median age of 64 years. As the investigation will provide important information on whether surgery should be encouraged in this patient population and the presence of potential debilitating comorbidities that require attention and further treatment, this risk is considered as reasonable, and the investigators believe the potential gains from this study outweigh the risks. Tonometry and ECHO are non-invasive procedures using ultrasound, and no direct harm or discomfort is caused to the participants. Management of incidents and side effects Product summary for ZOL will be used as a reference document in case of side effects. All adverse events (suspected or unsuspected) will be documented in case report forms (CRF) and handled in accordance with the general practice of the hospital. Registration of incident and side effects starts at the initiation of experimental drug for each participant and ends at the last control visit 12-month post-surgery. The participants will therefore be followed for approximately 12-13 months after administration of the experimental drug (which is administrated 2-4 weeks before surgery). Definition in according to the notice for clinical trials are: * Incident: Any adverse incident in a patient or a participant in a clinical trial after treatment with a medical product without there necessarily being a connection between this treatment and the adverse incident. * Side effect: Any harmful and unwanted reaction to an investigational drug regardless of the dose. A side effect that is inconsistent with the product information. * Seriously incident and side effects: An incident or side effect that regardless of the dose results in death, is life-threatening, entails hospitalization or prolongation of hospital stay, which results in significant or permanent disability or leads to a congenital anomaly or deformity. It is the investigator who has the responsibility to investigate and evaluate reported incidences and assess whether these incidences are adverse reactions (AR) or adverse events (SAR). Within 24 hours the investigator must report all serious incidences/side effects to sponsor. Sponsor will immediately report to EudraVigilance in case of any suspected unexpected serious adverse reactions (SUSAR). Sponsor must ensure that all SUSAR that are life threatening or deadly/results in dead are registered and reported to EudraVigilance as soon as possible and no later than 7 days after the SUSAR is registered. All other SUSAR must be reported to EudraVigilance no later than 15 days after the SUSAR has been registered. It is the sponsor who evaluate whether a seriously incidence/side effect is expected, or none expected according to the product resume and thereby a SUSAR or an expected seriously incidence/side effect. SUSARs will be reported electronically to the SUSAR database (EudraVigilance Clinical Trial Module E2B) using the e-form. Once a year throughout the trial period, the sponsor must prepare a list of all serious suspected adverse events (SAR) that occurred during the trial period and a report on the safety of the participants. The list and reports will be submitted to the competent authorities, i.e., the EU Clinical Trial Information System (CTIS) and The Central Denmark Region Committees on Health Research Ethics. End of trial: Results of the trial will be reported in EudraCT as soon as possible and no later than one year after the end of the trial. Research biobank Only blood and urine are collected. Approximately 300 ml of full blood will be drawn from the participants during the 1 year of trial which will be used for biochemical analyses. Collected biological material will be stored in a research biobank, under the premise of written consent from the participant. Blood samples are collected using standard methods and stored in a freezer (-20/-80C). Analysis will be carried out at the end of the study at the Department of Biochemistry, Aarhus University Hospital. At the end of the project excessive biological material will be transferred to a biobank for future research. It will generally require a new consent if excessive biological material is used for other research in the future. Furthermore, new research on excessive biological material will be reported to the Central Denmark Region Committees on Health Research Ethics. Clinical data The following information will be disclosed from the medical chart to the research project: Patient demography, co-morbidities, use of medications, smoking history and use of alcohol, indication for surgery, fracture history, results of DXA scan, X-ray of the spine, and CT scans of the kidneys and urinary tracts, histological diagnosis of the resected parathyroid gland/-s and the following biochemistry; P-PTH, P-ionized and total calcium, P-phosphate, P-magnesium, P-alkaline phosphatase, P-albumin, P-creatinine, estimated glomerular filtration rate (eGFR), 1,25-dihydroxyvitamin-D and 25-hydroxyvitamin-D. This information will be used to validate the diagnosis and possible complications following PHPT. Economics The trial is initiated by the applicants. Financial support has been granted by the Novo Nordic Foundation and additional support will be applied for from public and private funds. Financial support will be used to cover medical expensive and remuneration of staff. Recruitment Patients fulfilling the inclusion criteria will be enrolled after oral and written informed consent. Patients will be thoroughly informed about effects and possible side effects of ZOL. Patients will be approached by medical doctors either at the Department of Endocrinology and Internal Medicine, AUH during their diagnostic work-up for PHPT or during their appointment about PTX at the Department of Oto-Rhino-Laryngology, AUH. The conversation will be held behind closed doors. If a participant wants an assistant during the interview the meeting can be rescheduled on a following day. Possible participants have up to 2 weeks to decide. Publications The investigators will aim to publish results from this project - negative, positive, as well as inconclusive results in international peer reviewed journals. Ethical aspects Participants will be informed thoroughly about the project's aim, execution, and possible side effects both orally and in written. The project is voluntarily, and the participants can withdraw their consent anytime during the project. If a participants decide to withdraw, it will not affect their ongoing and future treatments. Participants will only be enrolled in the project by given full consent orally and in written. ZOL is a well-known drug that have been used for many years in treatment of osteoporosis. Typical side-effects observed after a single dose are often mild and transitory. Long-term side effects are not expected after a single dose of ZOL. Placebo (100 ml of saline water) is used in the project of methodological reasons. All patients enrolled in the project will all undergo PTX and therefore receive treatment for their hyperparathyroid hypercalcemia without any delays. If the investigators find signs of unknown diseases including critical coronary artery disease or severe heart failure, participants will be offered further investigation and/or treatment. Image-based findings unrelated to the heart, kidneys (excluding adrenal glands), and spine will not be a part of the study, and this will be stated in the participant information. In prior studies, single participants were diagnosed with lung cancer after their participation in the screening and a retrospective evaluation of CT images revealed that the cancer disease could have been observed at an earlier stage. This has led to a principal evaluation at the Danish Agency for Patient Complaints (file number: 2018-3464) and the Board of Appeal (file number 2019-6646), which both concluded that no criticism could be held against the study. CAC measurements may be useful to optimizing CVD risk stratification by identifying persons with undiagnosed subclinical disease, who should receive multifactorial intensified preventive treatment, but also to identify true low-risk persons in whom reduction of expensive medication with potential side-effects would be appropriate. Clauses There are no clauses to inform. Insurance The project is covered by Aarhus University Hospital patient insurance.

Cohort: All coronary CTO patients who underwent a PCI attempt and also underwent CTCA at our centre in the last 5 years. Method of identifying and consenting patients: Screening of our local database to identify suitable patients who fulfil the inclusion/exclusion criteria. These patients will be telephoned and the consent form and participant information sheet will be maile dot them along with a self addressed stamped envelope.On receipt of the consent form, we will countersign it and return a copy to the patient. Consented patients' images and reports of the CTCA and CTO PCI will be reviewed. Characteristics of calcification in the CTO on the CTCA will be evaluated including site, density and quantity of calcification. This will be correlated with CTO PCI outcomes of success and failure. Also this will be correlated with use of calcium modification tools for the CTO PCI. * Baseline and demographic as well as procedural data will be compared with CTO PCI outcomes and presence/characteristics of calcification. * Characteristics of calcification in the CTO assessed will include: site, density in Hounsfield units and quantity. * Site of calcification (proximal, body or distal) will be correlated with the CTO PCI outcome by chi square analysis. * Calcium density (in Hounsfield Units) on the CTCA will be correlated with successful versus failed CTO PCI by ROC curve analysis. * Quantity of calcification will be assessed as a percentage of the cross section of the CTO body (as \<50%, 50-75% and 75-100%) and correlated with CTO PCI success by contingency analysis. * Use of calcium modification tools will be correlated with CTO PCI outcome (success or failure) and density of calcification on CTCA (ROC curve and ANOVA). * Categorical variables will be compared by the chi square or Fisher's test and continuous variables will be compared by the Mann Whitney U test. In addition, based on CTO PCI outcome of success or failure, patients will be compared for demographics and procedural variables. * Categorical variables will be presented as percentage and compared with the chi square or Fisher's test * Continuous variables will be presented as median (range) and compared with student's t-test or Mann Whitney test.

Patients with biochemically confirmed primary hyperparathyroidism and non-localizing SPECT-CT exam within the past year will be included. Subjects will be treated with calcitonin to lower calcium levels immediately prior to reimaging. The goal of this study is to determine whether lowering calcium will improve uptake/retention of sestamibi and improve sensitivity of SPECT-CT to localize parathyroid adenoma.