The efficacy and safety of cinacalcet in primary hyperparathyroidism: a systematic review and meta-analysis of randomized controlled trials and cohort studies.

Cinacalcet, a positive allosteric modulator of the calcium sensing receptor (CaSR) reduces parathyroid hormone (PTH) secretion by increasing the sensitivity of the CaSR on parathyroid cells. We conducted a systematic review and meta-analysis on the safety and efficacy of cinacalcet in Primary Hyperparathyroidism (PHPT). MEDLINE, Embase, BIOSIS, and the Cochrane Library were searched for published articles (from database inception to Sept 2020). All double-blind RCTs and cohort studies that reported data on the efficacy and safety of cinacalcet therapy in individuals ≥ 18 with PHPT were included. Random effect meta-analysis was performed to estimate the efficacy of cinacalcet in lowering serum calcium and PTH levels compared with placebo. 4 RCTs (177 participants) and 17 cohort studies (763 participants) were eligible for final analysis. Pooled results from the RCTs suggest that, when compared to placebo and administered for up to 28 weeks, cinacalcet normalizes serum calcium (≤ 10.3 mg/dl) in patients with PHPT [RR 20 (95% CI 6.04 - 68.52, I2 = 0%, pheterogeneity < 0·00001)]. Serum PTH levels decreased significantly after 2 weeks and up to 28 weeks after treatment with cinacalcet. In the pooled analysis of the 17 cohort studies, serum calcium levels normalized in 76% (95% CI 66% to 86%; I2 = 92%, pheterogeneity < 0·00001) of patients regardless of the duration of treatment. In most studies, PTH levels decreased by 13% to 55%. No RCT reported on BMD as a primary or secondary outcome, and no improvement in BMD was noted in the 2 non-randomized studies that reported densitometric findings. No significant difference in urinary calcium was noted with cinacalcet therapy in either the RCTs or non-randomized studies. There was no significant difference in overall adverse events (AE) (RD 0.01, 95% CI -0.07 to 0.26) compared to placebo noted in the RCTs. In the non-randomized studies, pooled weighted AE rate was 45% (95% CI 32 to 59%). Risk of bias was low in 2/4 RCTs and 6/17cohort studies; risk was intermediate in 2/4 RCTs and 8/17 cohort studies, and risk was high in 3/17 cohort studies. In PHPT, cinacalcet lowers serum calcium and PTH with greater effects on calcium than on PTH in the short term. In the doses reported, the drug is safe with tolerable side effects. These findings can help inform targeted medical therapy of PHPT in those for whom lowering the serum calcium is indicated and for whom parathyroidectomy is not an option.

Skeletal effects of combined bisphosphonates treatment and parathyroidectomy in osteoporotic patients with primary hyperparathyroidism.

INTRODUCTION: Bone loss caused by primary hyperparathyroidism (PHPT) is an indication for parathyroidectomy (PTX). However, whether adding bisphosphonates would be superior to PTX alone to increase bone mass remains unclear. We thus aimed to compare the skeletal effects of the combination treatment of bisphosphonates and PTX with PTX alone. MATERIALS AND METHODS: In this retrospective analysis, bone mineral density (BMD) changes after 1 year of combination treatment and PTX alone were compared. We also analyzed the correlation between changes in serum biochemical parameters and BMD after 1 year of treatment in both groups. RESULTS: The baseline characteristics of patients treated with PTX alone (n = 24) and combination treatment (n = 26) were comparable. BMD significantly increased after 1 year of treatment in both groups (all p < 0.001), and the increase in BMD at the femur neck was higher in the PTX alone group than in the combination group (p = 0.011). There was a decreasing trend in serum alkaline phosphatase (ALP) levels in PTX alone compared to the combination treatment group (p = 0.053). In the study cohort, lower BMD and higher ALP levels at baseline were associated with higher 1-year BMD changes at all sites. Interestingly, a significant association was found between changes in ALP and BMD at the femur neck in the PTX alone group (p = 0.003), but abolished in the combination group (p = 0.946). CONCLUSIONS: There is no additional benefit of BMD in combination treatment with bisphosphonates and PTX over PTX alone in osteoporotic patients with PHPT. Combined bisphosphonate treatment might interfere with the increase in bone mass caused by PTX.

Withdrawal of Denosumab in Patients With Primary Hyperparathyroidism: A Follow-up Report of the DENOCINA Study.

OBJECTIVES: We investigated the development in the primary outcomes: changes in bone mineral density (BMD) measured by dual x-ray absorptiometry at the lumbar spine, total hip, and femoral neck after 2 years. METHODS: In patients with primary hyperparathyroidism, we investigated the effects of 30-mg cinacalcet per day plus 60 denosumab every 6 months for 1 year (Deno group), versus denosumab plus placebo for 1 year (DenoPlacebo-group), versus placebo plus placebo injection for 1 year (Placebo group). After the study's termination, most patients receiving denosumab were switched to bisphosphonate treatment. RESULTS: Forty-three out of 45 participants were subject to follow-up. A total of 35 patients completed a 2-year follow-up dual x-ray absorptiometry-scan (Deno: n = 13; DenoPlacebo: n = 12; and Placebo: n = 10). None of the groups showed statistically significant changes in BMD or experienced decreases in mean BMD below the study's baseline level. Overall, the changes in T-scores from the final study measurement to follow-up were similar among the groups (P = .38 for lumbar spine T-score, .63 for total hip, and .97 for femoral neck by 1-way ANOVA). P-calcium was not different over time (P = .20 for change over time and P = .08 for the difference between the groups by repeated measures ANOVA). A total of 5 participants suffered a fracture during the study or follow-up periods, all but one was in the placebo group. CONCLUSION: Evidence suggests that it is possible to at least maintain BMD, and thus potentially lower the fracture risk by a short course of denosumab followed by antiresorptive therapy, where applicable in patients with primary hyperparathyroidism.

Etelcalcetide decreases the PTH-calcium setpoint without changing maximum and minimum PTH secretion in mice with primary hyperparathyroidism.

INTRODUCTION: Etelcalcetide binds to the extracellular domain of the calcium-sensing receptor (CaSR), while cinacalcet binds to the 7-transmembrane domain of the CaSR; however, it is unknown, whether etelcalcetide has similar effects to cinacalcet on parathyroid hormone (PTH) secretion. MATERIALS AND METHODS: The PTH-calcium setpoint and maximum and minimum PTH secretion were determined using an 'in vivo setpoint analyses.' The PTH-calcium setpoint was obtained in a mouse model of primary hyperparathyroidism (PC) and wild-type (WT) mice, with PC mice divided into two groups. The setpoint was obtained after 7 days of etelcalcetide (3.0 mg/kg BW/day) or vehicle administration via anosmotic pump. After 7 days of crossover administration, the setpoint was obtained again. Parathyroid glands were obtained after crossover administration, and CaSR expression was analyzed by immunohistochemistry. RESULTS: Etelcalcetide administration significantly decreased the setpoint from 9.03 ± 0.56 mg/dL to 6.80 ± 0.28 mg/dL, which was restored to 8.81 ± 0.38 mg/dL after vehicle administration. In the second group of mice, vehicle administration did not alter the setpoint (8.84 ± 0.69 mg/dL to 8.98 ± 0.63 mg/dL), but subsequent etelcalcetide administration significantly decreased it to 7.10 ± 0.72 mg/dL. There was no significant change in maximum and minimum PTH secretion. Expression levels of parathyroid CaSR were lower in PC mice than in WT mice; however, no significant differences were observed between the two mouse groups. CONCLUSION: Etelcalcetide decreased the PTH-calcium setpoint without changing maximum and minimum PTH secretion in PC mice, suggesting that like cinacalcet, etelcalcetide has calcimimetic potency.

Normocalcaemic primary hyperparathyroidism: An update on diagnostic and management challenges.

Normocalcaemic primary hyperparathyroidism is a condition that can present with intermittent hypercalcemia or may evolve into hypercalcemic primary hyperparathyroidism. This milder biochemical entity remains incompletely understood because of a lack of long-term health outcomes regarding both medical and surgical approaches to its management. Medical therapies have shown some efficacy. A limited number of studies have found that bisphosphonates increase bone mineral density, and calcimimetics may decrease the risk of nephrolithiasis in patients with normocalcaemic primary hyperparathyroidism. Studies have also described patient outcomes after applying the same surgical criteria used for patients with hypercalcaemic primary hyperparathyroidism to those with the normocalcaemic form of the disease. These studies suggest that parathyroid surgery appears to be effective in normalizing elevated serum parathyroid hormone concentrations and decreasing adverse renal and skeletal outcomes in patients with normocalcaemic hyperparathyroidism. Given the available data and overall lack of consensus regarding the optimal management of these patients, a reasonable approach is to tailor treatment to the individual patient by considering their risk factors for new or accelerated bone loss, kidney stones, diminished quality of life, and cardiovascular disease.

Evocalcet in patients with primary hyperparathyroidism: an open-label, single-arm, multicenter, 52-week, dose-titration phase III study.

INTRODUCTION: Primary hyperparathyroidism (PHPT) is caused by parathyroid adenoma, primary parathyroid hyperplasia, or parathyroid carcinoma. For some patients with PHPT controlling serum calcium levels is critical. MATERIALS AND METHODS: We conducted an open-label, single-arm, 52-week, phase III study in Japanese patients with hypercalcemia due to PHPT to demonstrate efficacy and safety of evocalcet, a new calcimimetic. Patients with intractable PHPT (n = 13), postsurgical recurrence (n = 2), and parathyroid carcinoma (n = 3) were enrolled. Evocalcet administration started at a dose of 2 mg once or twice daily and was titrated to achieve the target serum corrected calcium (cCa) concentration (≤ 10.3 mg/dL) for two consecutive weeks (maximal dose 24 mg/day). RESULTS: Fourteen patients achieved the target (77.8%; 95% confidence interval [CI] 52.4-93.6). The lower limit of 95% CI exceeded the predetermined reference limit (11%), and thus, efficacy was confirmed. Of 18 patients, 12 (66.7%; 95% CI 41.0-86.7) showed decreased serum cCa of ≥ 1.0 mg/dL from the baseline for two consecutive weeks during the titration phase. Sixteen patients entered the maintenance phase, and 15 patients completed the study. Treatment-emergent adverse events (TEAEs) were recorded in 18/18 patients (100%) and drug-related TEAEs in 8/18 (44.4%). The most commonly observed drug-related TEAE was nausea (2/18 patients). No unexpected drug-related TEAEs were observed. All drug-related TEAEs were mild in severity. No patient discontinued the study because of drug-related TEAEs. CONCLUSION: Evocalcet demonstrated long-term effectiveness in reducing serum cCa concentrations and safety without any unexpected drug-related TEAEs in PHPT patients.

Case report of a cystic parathyroidal adenoma with rapid growth induced by cinacalcet.

BACKGROUND: Primary hyperparathyroidism is a rare condition of disease which can seldomly present as giant retrotrhyroideal cysts, complicating the localization of the adenoma to resect. CASE PRESENTATION: A 56-year old female presented with hypercalcaemia of 3.38 mmol/L (2.2-2.65 mmol/L) and a history of breast cancer. A fast growing cystic parathyroidal adenoma was diagnosed by a multimodal approach including comprehensive diagnostic imaging (ultrasonography, scintigraphies, dynamic MRI) and cytopathological investigations after ultrasonography-guided puncture. The patient was cured by surgical extraction of the whole adenoma. In retrospect, the rapid growth was most likely induced by cinacalcet (initially 30 mg/d, later 60 mg/d) therapy which the patient received for few months only. Primary hyperparathyroidism was ascertained because surgical removal of the solitary adenoma cured the patient. Furthermore, there was no relevant renal insufficiency or history of prolonged calcium-level deregulation. CONCLUSIONS: This phenomenon of cystic degeneration of parathyroidal adenoma under therapy with cinacalcet has previously been described in secondary hyperparathyroidism, but not in primary hyperparathyroidism and should be considered in diagnostic approach.

18F-fluorocholine PET/CT in MEN1 Patients with Primary Hyperparathyroidism.

BACKGROUND: Primary hyperparathyroidism (HPT1) is the most frequent endocrinopathy in multiple endocrine neoplasia type 1 (MEN1). Its surgical management is challenging. We aimed to describe and compare the imaging findings of parathyroid ultrasound (US), sestaMIBI scintigraphy (sestaMIBI), and 18F-fluorocholine (FCH) PET/CT in a series of MEN1 patients with HPT1. METHODS: Retrospective analysis of a cohort of MEN1 patients with HPT1 assessed by parathyroid US, sestaMIBI scintigraphy and SPECT/CT, and FCH-PET/CT for potential surgery between 2015 and 2019. RESULTS: Twenty-two patients with a confirmed diagnosis of MEN1 who presented with HPT1 and were assessed by the 3 imaging modalities were included. After imaging workups, 11 patients were operated on for the first time, 4 underwent a redo surgery, and 7 did not undergo an operation. The overall patient-based positivity rate of imaging was 91% (20 of 22) for parathyroid US and 96% (21 of 22) for both sestaMIBI and FCH-PET/CT. The 3 imaging modalities demonstrated negative findings in 1/22 patient who did not undergo surgery. Overall, 3 pathologic glands were not detected by any imaging technique. SestaMIBI and FCH-PET/CT both resulted in the same 3 false-positive results in ectopic areas with a significant uptake on two thymic carcinoid tumors and one inflammatory lymph node. FCH-PET/CT provided more surgically relevant data than sestaMIBI in 4/11 patients with initial surgery and in 1/4 patient who underwent redo surgery. CONCLUSIONS: Compared to sestaMIBI scintigraphy, FCH-PET/CT provides additional information regarding the number of pathologic parathyroid glands and their localization in MEN1 patients with HPT1.

Effectiveness and safety of cinacalcet for primary hyperparathyroidism: a single center experience.

Primary hyperparathyroidism (PHPT) is a common endocrine disease. Although surgical treatment is curative in most cases, there are few alternative therapies for the hypercalcemia caused by PHPT. Cinacalcet is a positive allosteric modulator of the calcium sensing receptor and was conditionally approved in Japan in 2014 to treat PHPT cases. However, there have been few reports on the outcomes. In our present study, we investigated the efficacy and safety of cinacalcet in 61 PHPT patients who were treated with this agent at our hospital between January 2014 and March 2017. The corrected serum Ca and intact PTH levels were significantly reduced by this treatment, whereas the serum phosphorus levels significantly increased. There were no significant differences in the eGFR or urinary Ca to urinary creatinine ratio between baseline and the maintenance phase. In terms of bone mineral density, there were significant increases observed in the 16 cases for whom a baseline value was available, 11 of whom had been treated for osteoporosis. The most common adverse events from cinacalcet treatment were gastrointestinal symptom, such as nausea and appetite loss. Other adverse events included severe dehydration due to hypercalcemia, myalgia, hypocalcemia, and increased urinary calcium excretion. Seven patients were switched to surgical treatment, and the drug was discontinued in 9 other patients, due to adverse effects. Our present study findings demonstrate that cinacalcet is an effective therapeutic option for PHPT from the perspective of hypercalcemia improvement but that adverse gastrointestinal effects of this drug occur at a frequency of about 10%.

The Relationship of Parathyroidectomy and Bisphosphonates With Fracture Risk in Primary Hyperparathyroidism: An Observational Study.

BACKGROUND: The comparative effectiveness of surgical and medical treatments on fracture risk in primary hyperparathyroidism (PHPT) is unknown. OBJECTIVE: To measure the relationship of parathyroidectomy and bisphosphonates with skeletal outcomes in patients with PHPT. DESIGN: Retrospective cohort study. SETTING: An integrated health care delivery system. PARTICIPANTS: All enrollees with biochemically confirmed PHPT from 1995 to 2010. MEASUREMENTS: Bone mineral density (BMD) changes and fracture rate. RESULTS: In 2013 patients with serial bone density examinations, total hip BMD increased transiently in women with parathyroidectomy (4.2% at <2 years) and bisphosphonates (3.6% at <2 years) and declined progressively in both women and men without these treatments (-6.6% and -7.6%, respectively, at >8 years). In 6272 patients followed for fracture, the absolute risk for hip fracture at 10 years was 20.4 events per 1000 patients who had parathyroidectomy and 85.5 events per 1000 patients treated with bisphosphonates compared with 55.9 events per 1000 patients without these treatments. The risk for any fracture at 10 years was 156.8 events per 1000 patients who had parathyroidectomy and 302.5 events per 1000 patients treated with bisphosphonates compared with 206.1 events per 1000 patients without these treatments. In analyses stratified by baseline BMD status, parathyroidectomy was associated with reduced fracture risk in both osteopenic and osteoporotic patients, whereas bisphosphonates were associated with increased fracture risk in these patients. Parathyroidectomy was associated with fracture risk reduction in patients regardless of whether they satisfied criteria from consensus guidelines for surgery. LIMITATION: Retrospective study design and nonrandom treatment assignment. CONCLUSION: Parathyroidectomy was associated with reduced fracture risk, and bisphosphonate treatment was not superior to observation. PRIMARY FUNDING SOURCE: National Institute on Aging.

The influence of thiazide intake on calcium and parathyroid hormone levels in patients with primary hyperparathyroidism.

OBJECTIVE: The effects of thiazide medication in patients with primary hyperparathyroidism (PHPT) have so far not been elucidated. The aim of this study was to analyse the extent to which the administration of thiazides may influence biochemical parameters and therefore the diagnosis of PHPT in a large cohort of patients. DESIGN AND PATIENTS: The biochemical parameters of 1066 patients with PHPT were analysed, and drug history was documented. Calcium (Ca)/creatinine clearance ratio (CCCR) was calculated. The results of patients given thiazides (n = 170) and those not given thiazides (n = 896) were analysed and compared. MEASUREMENTS: Twenty-four-hour urinary calcium excretion (24hU), albumin-corrected serum calcium, PTH, creatinine, 1,25OH- and 25OH-vitamin D were measured, and CCCR was calculated. RESULTS: 24hUC a and CCCR were significantly lower in patients on thiazides (P = 0·02 and P = 0·0068, resp.), and serum creatinine was significantly higher in those subjects (P < 0·0001). Serum Ca levels only proved different in an analysis of covariance among patients younger than 60 years (P = 0·003). Nevertheless, PTH was not different in both groups (P = 0·917). CONCLUSIONS: According to recently published guidelines, 24hUCa measurement is necessary to give indication for surgery in asymptomatic patients and to distinguish between PHPT and familial hypocalciuric hypercalcaemia [FHH]. Thiazides significantly decrease 24hUC a , yet neither increase serum Ca nor influence PTH levels in patients with PHPT. However, discontinuing thiazides is crucial for a correct CCCR calculation to pre-operatively rule out FHH. As a consequence, the withdrawal of thiazide medication must be recommended for the diagnosis of PHPT prior to surgery.

[A Case of Primary Hyperparathyroidism Complicated with Hypercalcemic Crisis during Treatment with Cinacalcet and Improved by Active Treatment].

A 77-year-old man was referred to our department for surgical treatment of a right ureteral stone identified on computed tomography (CT) during intensive examination for spondylolisthesis of L4-L5. At the initial visit, performance status was 4, and renal dysfunction was identified (Cr 1.3 mg/dl). Corrected calcium level was 11.8 mg/dl, and intact parathyroid hormone level was 555 pg/ml. A CT scan showed a well-defined mass measuring 22×16×20 mm on the right side of the esophagus, along with 99mTc-MIBI uptake in the lesion. Based on these findings, we diagnosed the patient with primary hyperparathyroidism. Considering his general condition, we determined that parathyroidectomy was difficult, and we started treatment using cinacalcet. A temporary therapeutic effect was observed, but the turning point was occurrence of hypercalcemic crisis with aspiration pneumonia. After recovery of his general condition and improvement of blood data by multidisciplinary therapy, we performed parathyroidectomy. Histopathological examination showed that the tumor was a parathyroid adenoma. He is free of reccurence at one year postoperatively. In addition, surgery for spondylolisthesis was performed, and he started to walk independently.

[Nonsurgical management of mild primary hyperparathyroidism].

Primary hyperparathyroidism (PHPT) is one of the common endocrine disorders, which results clinically in nephrolithiasis, osteoporosis, muscle weakness, cardiac and psychiatric abnormalities even in a mild or asymptomatic disease. Parathyroidectomy (PTX) is the only definitive treatment for PHPT, however, some patients with sporadic PHPT refuse surgery, are medically unfit, or have residual or recurrent disease inaccessible to further surgery. These patients may require intervention for management of symptomatic or moderate to severe hypercalcemia, bone loss or kidney calculi.

Effects of alendronate and vitamin D in patients with normocalcemic primary hyperparathyroidism.

UNLABELLED: No data on the pharmacological treatment of normocalcemic hyperparathyroidism (NPHPT) are available. We treated 30 NPHPT postmenopausal women with alendronate/cholecalciferol (treated group) or vitamin D alone (control group). Over 1 year, bone mineral density (BMD) increased significantly in treated group, but not in control group. Both treatments did not affect serum or urinary calcium. INTRODUCTION: Normocalcemic primary hyperparathyroidism (NPHPT) is defined by normal serum calcium and consistently elevated PTH levels after ruling out the causes of secondary hyperparathyroidism. It is likely that subjects with NPHPT may develop kidney and bone disease. As no data on the pharmacological treatment of NPHPT are available, we aimed to investigate the effects of alendronate and cholecalciferol on both BMD and bone biochemical markers in postmenopausal women with NPHPT. Safety of vitamin D was evaluated as secondary endpoint. METHODS: The study was a prospective open label randomized trial comparing 15 postmenopausal women with NPHPT (PMW-NPHPT), treated with oral alendronate plus cholecalciferol (treated group) and 15 PMW-NPHPT treated only with cholecalciferol (control group). Blood samples were obtained at baseline and after 3, 6, and 12 months. Bone turnover markers (BTM) were measured at baseline, 3, and 6 months, respectively. BMD was assessed at baseline and after 12 months. RESULTS: After 1 year of treatment, BMD increased significantly at the lumbar, femoral neck, and hip level in the treated group, but not in the control group (p = 0.001). No differences were found between or within groups in serum calcium, PTH, and urinary calcium levels. BTM significantly decreased in the treated group but not in the control group, at 3 and 6 months (p < 0.001), respectively. No cases of hypercalcemia or hypercalciuria were detected during the study. CONCLUSION: The results of this study indicate that alendronate/cholecalciferol increases BMD in postmenopausal women with NPHPT. Alendronate/cholecalciferol or vitamin D alone does not affect serum or urinary calcium.

Use of cinacalcet in nephrolithiasis associated with normocalcemic or hypercalcemic primary hyperparathyroidism: results of a prospective randomized pilot study.

OBJECTIVES: To evaluate, by means of a prospective randomized study, the efficacy of cinacalcet in the forms of nephrolithiasis associated with primary hyperparathyroidism in both the hypercalcemic and normocalcemic variant. MATERIALS AND METHODS: Ten patients suffering from active nephrolithiasis associated with primary hyperparathyroidism (4 hypercalcemics and 6 normocalcemics), equally divided between males and females, were randomly but not blindly addressed to treatment with potassium citrate and allopurinol, or to the same therapeutic regimen in combination with cinacalcet. The dosage of cinacalcet was optimized for each patient in order to obtain a reduction of parathyroid hormone (PTH) within normal limits while enabling the maintenance of adequate calcemic values. All study participants were given the same diet based on a reduction in sodium intake, oxalate-rich foods and animal protein with standardized intake of calcium and an increase in hydration. After a follow up period of 10 months , cinacalcet was associated to standard therapy and diet in patients who were not taken it, conversely cinacalcet was withdrawn in the remaining patients who remained on standard therapeutic regimen and diet. Follow up was continued for a second period of observation of the same duration of the first. RESULTS: At the end of the period of treatment with cinacalcet, for both variants of hyperparathyroidism, a statistically significant reduction in the overall number and in the diameter of renal stones was found. CONCLUSIONS: This prospective randomized study shows the effectiveness of cinacalcet used in combination with a diet with normalized calcium intake, in reducing the number and size of urinary stones in hypercalemic and normocalcemic forms of primary hyperparathyroidism.

[A clinical example of conservative management of a female patient with manifestation of primary hyperparathyroidism].

The problems of the timely diagnosis and treatment of primary hyperparathyroidism (PHPT) have recently attracted more and more attention because this disease now ranks third in incidence rates among endocrine diseases. Older women form a group at risk for this disease. Surgical removal of the source of parathyroid hormone hypersecretion is the only radical treatment option for this disease, which is performed in the majority of patients with PHPT. Occasionally, surgical treatment is contraindicated or unadvisable. In these cases, the possibilities of long-term medical treatment become relevant. For this, there are several groups of drugs available, such as bisphosphonates to maintain bone tissue, calcium-sensing receptor agonists (calcium mimetics) that are effective in reducing blood calcium levels. The patients frequently require combined therapy to control the major manifestations of the disease. There are limited data on the long-term medical management of patients with manifest PHPT in the literature.

Computational drug repurposing for primary hyperparathyroidism.

In hyperparathyroidism (hyperPTH), excessive amounts of PTH are secreted, interfering with calcium regulation in the body. Several drugs can control the disease's side effects, but none of them is an alternative treatment to surgery. Therefore, new drug candidates are necessary. In this study, three computationally repositioned drugs, DG 041, IMD 0354, and cucurbitacin I, are evaluated in an in vitro model of hyperPTH. First, we integrated publicly available transcriptomics datasets to propose drug candidates. Using 3D spheroids derived from a single primary hyperPTH patient, we assessed their in vitro efficacy. None of the proposed drugs affected the viability of healthy cell control (HEK293) or overactive parathyroid cells at the level of toxicity. This behavior was attributed to the non-cancerous nature of the parathyroid cells, establishing the hyperPTH disease model. Cucurbitacin I and IMD 0354 exhibited a slight inverse relationship between increased drug concentrations and cell viability, whereas DG 041 increased viability. Based on these results, further studies are needed on the mechanism of action of the repurposed drugs, including determining the effects of these drugs on cellular PTH synthesis and secretion and on the metabolic pathways that regulate PTH secretion.

[Association between preoperative cholecalciferol therapy and hypocalcemia after parathyroidectomy in patients with primary hyperparathyroidism].

BACKGROUND: Primary hyperparathyroidism (PHPT) is a endocrine disorder characterized by excessive secretion of parathyroid hormone (PTH) from parathyroid gland tumors. Parathyroidectomy (PTE) is the main treatment for PHPT, but it can lead to hypocalcemia in up to 46% of cases. Hypocalcemia is associated with seizures and life-threatening cardiac arrhythmias, and vitamin D deficiency can exacerbate PHPT severity and contribute to «hungry bones syndrome,¼ resulting in severe and persistent postoperative hypocalcemia. AIM: To evaluate the association and determine the strength of the relationship between preoperative cholecalciferol therapy and the occurrence of hypocalcemia within 1-3 days after PTE in patients with PHPT. MATERIALS AND METHODS: The study was conducted at the Endocrinology Research Centre, during the periods of 1993-2010 and 2017-2020. The inclusion criteria consisted of patients diagnosed with PHPT who required PTE, had a serum 25-hydroxyvitamin D (25(OH)D) level below 20 ng/mL, and a serum total calcium level below 3 mmol/L. The exclusion criterion was the use of medications that affect calcium-phosphorus metabolism, including cinacalcet, denosumab, or bisphosphonates, either as monotherapy or as part of combination therapy. RESULTS: There were 117 patients, including 110 (94%) females and 7 (6%) males. The median age and interquartile range were 58 [49; 65] years. Among the participants, 21 (18%) received cholecalciferol supplementation for a duration of 2 weeks to 2 months prior to PTE, aiming to address vitamin D deficiency. The remaining 96 (82%) participants did not receive -cholecalciferol supplementation. Both groups, i.e., participants receiving cholecalciferol and those who did not, were similar in terms of anthropometric factors (sex and age at the time of surgery), preoperative clinical characteristics (BMD decrease), and laboratory parameters (PTH, total calcium, phosphorus, ALP, OC, CTX-1, and 25(OH)D levels). The occurrence of postoperative hypocalcemia was significantly lower in participants who received cholecalciferol supplementation (10% vs. 63%, p<0,001, FET2). Cholecalciferol intake showed a negative association with hypocalcemia development (RR=0,15, 95% CI (0,03; 0,51)). CONCLUSION: Preoperative cholecalciferol supplementation for 2 weeks to 2 months before PTE reduces the risk of postoperative hypocalcemia in patients with PHPT by 2-33 times.