J Bollerslev and others Unmet needs in parathyroid 181:3 P1–P19 Consensus Q1 disorders Statement Unmet therapeutic, educational and scientific needs in parathyroid disorders: Consensus Statement from the first European Society of Endocrinology Workshop (PARAT) Jens Bollerslev1,2, Camilla Schalin-Jäntti3, Lars Rejnmark4, Heide Siggelkow5, Hans Morreau6, Rajesh Thakker7, Antonio Sitges-Serra8, Filomena Cetani9 and Claudio Marcocci9 on behalf of the PARAT Workshop Group† 1 Section of Specialized Endocrinology, Oslo University Hospital, 2Faculty of Medicine, University of Oslo, Oslo, Norway, 3Division of Endocrinology, Abdominal Center, Helsinki University Hospital and University of Helsinki, Helsinki, Finland, 4Department of Endocrinology and Internal Medicine, Aarhus University Hospital, Aarhus, Denmark, 5Endokrinologikum Göttingen, Georg-August-University Göttingen, Göttingen, Germany, 6Pathology, Leiden University Medical Center, Leiden, Correspondence Netherlands, 7Academic Endocrine Unit, Radcliffe Department of Medicine, University of Oxford, Churchill Hospital, should be addressed Oxford, UK, Endocrine Surgery Unit, Hospital del Mar, Universitat Autònoma de Barcelona, Barcelona, Spain, and 8 to J Bollerslev 9 Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy Email † (Details of the PARAT Workshop Group is presented in the Acknowledgements section) jens.bollerslev@medisin. European Journal of Endocrinology uio.no Abstract PARAT, a new European Society of Endocrinology program, aims to identify unmet scientific and educational needs of parathyroid disorders, such as primary hyperparathyroidism (PHPT), including parathyroid cancer (PC), and hypoparathyroidism (HypoPT). The discussions and consensus statements from the first PARAT workshop (September 2018) are reviewed. PHPT has a high prevalence in Western communities, yet evidence is sparse concerning the natural history and whether morbidity and long-term outcomes are related to hypercalcemia or plasma PTH concentrations or both. Cardiovascular mortality and prevalence of low energy fractures are increased, whereas quality of life is decreased, although their reversibility by treatment of PHPT has not been convincingly demonstrated. PC is a rare cause of PHPT, with increasing incidence, and international collaborative studies are required to advance knowledge of the genetic mechanisms, biomarkers for disease activity and optimal treatments. For example, ~20% of PCs demonstrate high mutational burden, and identifying targetable DNA variations, gene amplifications and gene fusions may facilitate personalized care, such as different forms of immunotherapy or targeted therapy. HypoPT, a designated orphan disease, is associated with a high risk of symptoms and complications. Most cases are secondary to neck surgery. However, there is a need to better understand the relation between disease biomarkers and intellectual function and to establish the role of PTH in target tissues, as these may facilitate the appropriate use of PTH substitution therapy. Management of parathyroid disorders is challenging, and PARAT has highlighted the need for international transdisciplinary scientific and educational studies in advancing in this field. European Journal of Endocrinology (2019) 181, P1–P19 Introduction Disorders in the parathyroid glands spans a huge variety among postmenopausal women (1, 2, 3, 4), some orphan of clinical important diseases, some with a very high like chronic hypoparathyroidism in adults (HypoPT) prevalence as in primary hyperparathyroidism (PHPT) (5, 6), with increasing awareness due to new treatment https://eje.bioscientifica.com This work is licensed under a Creative Commons © 2019 ESE PARAT Workshop Group https://doi.org/10.1530/EJE-19-0316 Attribution 4.0 International License. Published by Bioscientifica Ltd. Printed in Great Britain Consensus Statement J Bollerslev and others Unmet needs in parathyroid 181:3 P2 disorders algorithms (7). Parathyroid carcinomas (PC) are extremely pathologist in a standardized fashion. A main challenge is rare, but might potentially be underdiagnosed (8, 9, to distinguish PC from an atypical parathyroid adenoma. 10). By far most of parathyroid diseases are sporadic as PC is usually sporadic, but may be part of familial most cases of PHPT, some are part of well-known genetic syndromes such as hyperparathyroidism-jaw tumour conditions. As such, PHPT is linked to the multiple syndrome (HPT-JT), isolated familial hyperparathyroidism endocrine neoplasia (MEN) syndromes (11), and familial (FIHP) and, rarely, MEN1 or MEN2A (18, 19). CDC73 hypocalciuric hypercalcemia (FHH) ) is a well-described, germline mutations cause HPT-JT and, in 20–40% of the rare autosomal dominant inherited condition most often cases sporadic PC. In contrast to parathyroid adenomas, due to a loss-of-function mutation in the calcium sensor a majority of PCs are characterized by somatic CDC73 and partner proteins (12, 13). Thus, parathyroid disorders mutations (20, 21). CDC73 is a tumour suppressor gene are heterogeneous conditions with the organs (the glands) that encodes parafibromin. In PC, vascular tumour in common and with clinical awareness and interest often invasion and loss of parafibromin expression associate reflecting new developments in diagnostic procedures or with more aggressive behavior and impaired patient treatment possibilities. survival (10, 18, 22). Genetic testing should be offered The European Society of Endocrinology (ESE) recently to all patients with PC and when mutation positive, also established a new program focusing on parathyroid first-degree relatives should be screened. For patients disorders – the PARAT program – aiming to identify unmet with inoperable disease, treatment options are limited. scientific and educational needs in parathyroid diseases. Treatment of hypercalcemia is crucial; however, no The first workshop in Santpoort, The Netherlands in evidence-based disease-specific treatment exist. Given the European Journal of Endocrinology September 2018 invited European Top-experts within the rarity of PC, a collaborative approach is needed in order to three main topics, PC, PHPT and HypoPT, based on State develop novel diagnostic markers and targeted drugs, and of the Art Presentations by international experts followed hopefully improve outcomes. by break-out sessions to identify the needs in each area and a further discussion in plenum on prioritizing the way Preoperative diagnosis of parathyroid carcinoma forward in a 2- to 4-year perspective. The aim of this review is to summarize and discuss the recent achievements on The diagnosis of PC is challenging due to the lack these three defined topics. of reliable clinical diagnostic criteria and is in the majority of cases made postoperatively by histological examination. Local invasion of surrounding structures Parathyroid carcinoma (trachea, inferior laryngeal nerve, strap muscles) and the occurrence of distant or lymph node metastases PC is one of the most rare known malignancies and are the only unequivocal criteria of malignancy. The accounts for less than 1% of PHPT. Reports from the latter, however, usually develop late during follow-up. United States, Australia and Finland indicate increasing Patients who present with a palpable mass, a serum incidences (8, 9, 10). Preoperatively, PC cannot be calcium level higher than 3.5 mmol/L and markedly distinguished from benign causes of PHPT, as no disease- elevated PTH levels, severe renal and/or bone disease specific markers are available. PC should be suspected in involvement and/or laryngeal nerve palsy should be patients with severe PTH-dependent hypercalcemia or its suspected of harboring PC (18). Very rarely however, PC complications (14), but may be overlooked because it is so is nonfunctioning, that is patients have normal levels of rare. PC is rather aggressive with a high recurrence rate in plasma calcium and PTH (23). more than 50% of the cases and the 5-year survival rate in Currently, no standard imaging studies are able patients with metastatic disease is less than 50% (15, 16, to distinguish PC from a benign parathyroid lesion. 17). Patients suspected to have PC should have primary Nonetheless, some ultrasound (US) features may raise radical en bloc surgery, performed by an experienced the suspicion for PC, namely a large (i.e. >3 cm large) surgeon (18), as this is the only treatment that can ensure lobulated hypoechoic/heterogeneous parathyroid gland, cure. Diagnosis is confirmed by histopathology, which with irregular borders, thick capsule, suspicious vascularity also is demanding. Therefore, some patients are correctly and calcifications (24) (Fig. 1). However, these features diagnosed only because of persistent disease after surgery may also be seen in benign tumors (25). Conversely, Hara or later recurrent/metastatic disease. Histopathology et al. observed that the depth/width ratio of the lesion >1 should always be performed by an expert parathyroid suggest a PC, while <1 a benign tumor (25). Occasionally, https://eje.bioscientifica.com Consensus Statement J Bollerslev and others Unmet needs in parathyroid 181:3 P3 disorders Thus, in a given patient with suspicion for PC combined preoperative imaging studies are recommended. The role of FDG-PET is still debated; of note, the lesions of osteitis fibrosa cystica, which can be present in patients with PC, are hypermetabolic and positive at FDG-PET and, therefore, could be misdiagnosed as bone metastasis (27). Preoperative fine-needle parathyroid biopsy is not recommended because it cannot distinguish a benign from a malignant lesion and has a risk of tumoral rupture and seeding (28). Pathogenesis and histopathology Pathogenesis PC can arise in the context of the CDC73 related disorder (or HPT-JT syndrome and anecdotally in the context of MEN1 and MEN2A syndromes). Sporadic inactivation of CDC73 and other genetic factors are driving parathyroid cancers, but there are no data why these DNA variations European Journal of Endocrinology would occur in these relatively oligo-dividing parathyroid cells, with a relatively low chance of replication errors and less environmental influences (including lifestyle) than seen in other tumor types (29). However, a history of radiation exposure has been reported in PC (30). Proliferation of parathyroid cells due to renal failure with secondary hyperparathyroidism might occasionally drive Figure 1 parathyroid tumorigenesis towards malignancy (31). An Ultrasound image of a parathyroid carcinoma. The tumor alternative explanation for which there is no formal proof (arrows), located at the upper pole of the thyroid, shows a is that in metabolically hyperactive cells increased reactive heterogeneous pattern, irregular shape and halo sign oxygen species might lead to subsequent DNA damage (longitudinal view) (from Cetani et al. JEI 2016, with targeting crucial pathways in parathyroid homeostasis. As permission (18)). also postulated by Tomasetti and Vogelstein for cancers in the infiltration into surrounding tissues and cervical general, possibly bad luck is another valid explanation for lymph node enlargement can be identified (or suspected). PC tumorigenesis (29). 99mTc-sestamibi (MIBI) scan is routinely used for imaging abnormal/ectopic parathyroid lesion but cannot predict Histopathology malignancy. When there is a strong suspicion for PC higher resolution studies can be useful, namely contrast The correct histopathological diagnosis of malignancy computed tomography (CT), including 4-dimensional (WHO Classification of Tumours of Endocrine Organs, computed tomography (4DCT), magnetic resonance 2017) is primarily based on two strict criteria, that imaging (MRI) with gadolinium or positron emission is, ingrowth of tumor cells beyond the preexistent tomography (PET)/CT with 2-[fluorine-18]-fluoro-2- parathyroid capsule into surrounding tissues and the deoxyD-glucose (18F-FDG) (26). CT and MRI can accurately presence of lymphangio-invasiveness. The presence of locate the lesion and its relationship with or invasion into atypical mitotic figures and fibrous septa may be helpful adjacent tissues. Both are commonly used when planning as they are often associated with malignancy. An example en bloc resection of the lesion and surrounding structures. of PC is given in Fig. 2. Other criteria like nuclear atypia The sensitivity of a single preoperative imaging (US, CT or and the lack of uniformity of the cells are being more MIBI) has been reported to be ~80% but this increases up circumstantial. Additional immunohistochemical staining to 95% when the three procedures are used together (26). may help to support the diagnosis and the ones that are https://eje.bioscientifica.com Consensus Statement J Bollerslev and others Unmet needs in parathyroid 181:3 P4 disorders Figure 2 Histopathology: Parathyroid carcinoma in the context of CDC73-related disorder. Concerns index patient III.2 of family G described by van der Tuin et al. (Supplementary Fig. 1 and Supplementary Table 1 in the reference (38)). This male patient was diagnosed with PC at the age 45 years after he presented with primary hyperparathyroidism and a right-sided mass in the neck of 6 cm with European Journal of Endocrinology lymph node metastases. The patient eventually died of this disease. Germ line CDC73 (HRPT2) analysis showed a large deletion of the q-arm of chromosome 1 including the complete CDC73 gene. In the upper part of the figure, a hematoxylin and eosin stained histological slide is presented. The tumour showed pleiomorphic parathyroid hormone positive staining cells with anisokaryosis and prominent nucleoli. Broad fibrous bands were between tumour cell islands. Occasionally mitoses were observed. The Ki-67 index was focally around 5%. Lymph angio-invasiveness outside the tumour mass was seen. Parafibromin immunohistochemistry showed vague positive and focal complete lack of nuclear staining of tumour cell in comparison with internal reference cells. There was enhanced cytoplasmic staining of tumour cells. In the lower part of the figure somatic CDC73 (HRPT2) Sanger DNA- sequencing results are depicted showing a forward reference sequence above the tumour sequence. This region was not well covered in a targeted CDC73 containing gene panel for next-generation sequencing that was also analysed. In the tumour as a second hit on the wild type allele a pathogenic CDC73 exon 1: c.91_92delinsGGAA, p.(Ser31Glyfs*7) gene variant was identified. used currently are Ki67, Galectin 3, protein gene product Germline mutation testing 9.5 (PGP9.5) and parafibromin (encoded by CDC73) (32). Furthermore, loss of parafibromin expression and the Testing for germline mutation of the CDC73 gene is finding of inactivating CDC73 DNA variants can be found strongly recommended in patients with apparently in aggressively behaving parathyroid cancers (33, 34), and sporadic PC. The mutation detection yield ranges from 6 as such provide prognostic information. to 38% according to the different studies (10, 21, 33, 35, At this moment, there are no well-established tissue 36, 37, 38). The sample size, the selection bias and, not biomarkers that can delineate parathyroid carcinoma less important, the challenging of the histopathological (unequivocal carcinoma) from atypical adenomas diagnosis, could account for these differences. However, (or equivocal carcinoma). For example, there is no the latter is of utmost importance because it determines evidence that recently described limited gene panels for the prognosis of the patients. The majority of these PC (as outlined in the section titled 'Germline mutation mutations is widespread throughout the coding region, testing') or larger commercial gene panels can be but most are located in exons 1, 2 and 7 (10, 21, 33, 35, helpful to answer such diagnostic questions. Probably 36, 37, 38). Gross deletions within the gene have been only finding CDC73 pathogenic variants would point identified in a few cases of patient with PC (37, 38, 39). to a more aggressive potential although only in cases Therefore, in CDC73-negative cases for point/small with histological confirmation. Finding MEN1 variants mutations, the research of CDC73 gross deletions should would shift the odds to a more benign potential. be considered. Other biomarkers, such as microRNA profiles might be Germline mutations in additional genes including thought of. PRUNE2, CCD1, ADCK1 and genes of PI3K/AKT/mTOR https://eje.bioscientifica.com Consensus Statement J Bollerslev and others Unmet needs in parathyroid 181:3 P5 disorders pathways have been detected in patients with PC (40, and increase urinary calcium excretion, and occasionally 41). Therefore, gene panel testing using next-generation loop diuretics to enhance the calciuresis (16, 18, 45). sequencing should be considered because it would However, such measures are of temporary success only, improve the genetic analysis. and other approaches (e.g. drugs such as cinacalcet) are In clinical practice, the genetic testing for germline required for longer-term success. Cinacalcet, a calcimimetic mutations is helpful in the index case and, if positive, binding to the calcium-sensing receptor and thereby first-degree relatives of all patients with PC in order to decreases PTH secretion, is a potent oral calcium-lowering agent. The starting dose is 30 mg twice daily, with dose (i) identify the germline mutation in a given patient  adjustments every 2 weeks until calcium concentrations with PC; are acceptable (17). Nausea is a common side effect that (ii) identify asymptomatic family members carrying the may prevent the usage of higher doses. Cinacalcet can mutation and thus requiring a clinical evaluation be combined with zoledronic acid (44), the most potent for early detection of the tumor and appropriate known bisphopshonate (4 mg i.v every 3–4 weeks) or, with treatment; denosumab, a monoclonal antibody that binds to RANKL (iii) relieve the anxiety of developing the disease family (120 mg s.c monthly), especially in refractory cases and members who do not carry the mutation; patients with impaired kidney function (46, 47). There are (iv) start the screening for HPT-JT-related tumors in the however, no evidence-based specific treatments. Anecdotal index case and healthy carriers. Indeed, patients with positive responses to adjuvant radiotherapy (10, 48, 49, CDC73-related disorders might develop ossifying 50), PTH immunotherapy (51, 52) and alkylating agents fibromas of the maxilla and/or mandible and uterine European Journal of Endocrinology as iv dacarbazine (53) and oral temozolomide have been tumors and renal lesions. reported (44). Surgery of parathyroid carcinoma Future networking, biobanking, future joint efforts for a deeper understanding of Successful surgery depends on preoperative suspicion of pathogenesis, to enable tailored treatments PC and intraoperative recognition of malignant features, such as size (often >3 cm), firmness, grayish-white color It is of paramount importance to refer patients with and adherence/invasion to surrounding tissues. Local suspicion of PC to tertiary care centers with skilled excision is not acceptable, the only way of ensuring cure endocrine surgeons who are familiar with the treatment is complete removal of the tumor while avoiding capsule of this rare disease. It would be very desirable to set-up rupture and including all surrounding tissues involved European prospective registries and biobanks to collect (en bloc resection) (22). Achieving microscopically large number of patients with PC and bio-specimens disease-free margins improves disease-free survival (42). (tissues, blood, serum, urine, etc). Such a project Prognosis is influenced by surgeon performance (43). If would ensure an adequate sample size to improve our PC is suspected, surgery should thus be performed by an understanding on not yet clear clinical preoperative, expert parathyroid surgeon in a large-volume center. If surgical and histological findings. One of the main the patient has not undergone primary en bloc resection goals would be to define preoperative biomarkers to and histopathological confirmation of PC comes as a differentiate between malignant lesions and the much surprise, timely further expert parathyroid surgery must more common benign counterpart, and subsequently be considered. Surgery is first-line treatment also for a better understanding of the pathogenesis of PC. This recurrent disease and, in selected cases repeated operations would lead to better planning the initial surgical procedure in combination with other systemic treatments may as this greatly influences the prognosis of patients with PC improve the prognosis (44). and their management. Extensive epidemiological data on the occurrence of PC have so far not been compiled from all countries in Systemic treatments Europe and results on treatment outcomes have not been Most patients with inoperable PC ultimately succumb to evaluated. Treatment options for recurrent PC are so far severe hypercalcemia and kidney failure rather than tumour limited. Being a rare disease, the treatment of recurrent PC burden. The management of acute severe hypercalcemia can benefit from the developments in personalized cancer includes intravenous saline infusion to restore fluid volume care. These developments encompass the elucidation https://eje.bioscientifica.com Consensus Statement J Bollerslev and others Unmet needs in parathyroid 181:3 P6 disorders of relatively rare but targetable DNA variations, gene (64). In adults, chronic HypoPT is most often secondary amplifications and gene fusions across many cancer types to neck surgery, having a surprisingly high prevalence of (54, 55). For example, DNA alterations of the PIK3CA- 10–24/100.000 inhabitants (6, 64, 65). From a therapeutic PTEN-mTOR-AKT pathway, gene amplifications (HER2, aspect, HypoPT is the last endocrine deficiency syndrome FGFR3 etc.) or gene fusions (involving ALK, ROS, RET, not replaced by the lacking hormone in standard care (7, NTRK) are seen in different cancer types, although with 66). The indirect standard treatment or an un-physiologic different frequencies. Indeed, recent studies reported substitution therapy might give challenges affecting potentially targetable ROS1, TSC1, AKT1, MTOR, PTEN, quality of life (QoL) for the patients but also potential PIK3CA, NF1, KDR, ERBB1, NTRK1, IDH1 and FGFR3 long-term complications (6, 67, 68, 69, 70, 71). DNA variants in PC in the presence or absence of CDC73 mutations, with rationally matched targeted agents (41, The diagnosis of hypoparathyroidism 56, 57). Single PC cases showed clinical benefit from tyrosine kinase inhibitors (56). In PC cases with high HypoPT has been clearly defined in the guidelines on mutational loads or burdens, the applicability of different 'Treatment of chronic hypoparathyroidism in adults' by forms of immunotherapy (for example anti PD1 immune ESE as ‘a disease with hypocalcaemia and inappropriately de-blockade therapy) might be envisioned. Although low parathyroid hormone (PTH) levels’ (7). A similar the median total mutational burden in PC is relatively definition has been suggested by other expert groups low (1.7 mutations per megabase (m/Mb), about 20% (66, 72). Despite this general consensus, it seems that demonstrated high mutational burden (>20 m/Mb)) (40, HypoPT is defined in many different ways in the scientific European Journal of Endocrinology 56). The latter translates into a higher neo-antigen load literature. In 2010, Mehanna et al. (73) published a review with a chance that abnormal tumor peptide fragments on papers reporting risk of postoperative hypocalcemia. are presented on the tumor cell surface in the context Based on a systematic literature search, a total of 62 of HLA and thereby leading to cytotoxic T-cell responses papers were identified. The majority of the papers did not (58, 59). Repurposing existing drugs can be thought of as specifically define hypocalcemia and the papers reporting shown by the effectivity of temozolomide in an isolated this used ten different definitions. By applying these 10 PC case (44). As stated, there is a relatively high frequent different definitions to the same cohort of 202 thyroid inactivation of CDC73 in PC. The parafibromin protein surgery cases at a single institution, it was found that that encoded by CDC73 is part of the PAF1 complex involved the incidence of hypocalcemia varied widely (0–46%) in cell cycle regulation. It should be studied whether the depending on the definition used. Most recently, another latter would impose increased sensitivity to cell cycle systematic literature review has been published on papers inhibitors. Similarly cyclin D1 might be targeted as reporting on risk of permanent postsurgical HypoPT CCND1 is found to be amplified in PC cases, reviewed between 2010 and 2011 (74). The review identified 89 recently by Costa-Guda (60). In human cancers with articles using 20 different definitions and reported an P16 loss (encoded by CDKN2A), cell cycle inhibitors are incidence varying from 0.0–20.2%. None of the definitions given (CDK4/6 inhibitors) (61). To bring this field further, used were in accordance with the generally accepted PC-specific comprehensive integrative molecular analysis definition. Accordingly, there is a need for standardization (of the mutome, transcriptome, methylome, miRNAome, of the definitions used for reporting hypocalcemia rates. etc.) is lacking. So far, isolated relatively small series of Otherwise, patients are not diagnosed in a proper manner PC have been studied by extensive genomic analysis and thereby may not receive appropriate treatment. including exome analysis (40, 41, 56, 62, 63). There are no well-characterized cell lines available to facilitate HypoPT is a complicated disease biological research. For this purpose, future networking is of utmost importance to improve research and the It has become more and more clear that HypoPT is more treatment possibilities in recurrent PC. than just a matter of supplying calcium and activated vitamin D. HypoPT is a complicated disease with deficiency of two hormones, PTH and 1,25 (OH)2Vit D (64) (Fig. 3). Chronic hypoparathyroidism in adults In addition to hypocalcemia, HypoPT is associated with other biochemical disturbances, such as hypercalciuria Hypoparathyroidism (HypoPT) is a rare disease with an and hyperphosphatemia, as well as an impaired quality estimated prevalence of ~30 patients per 100,000 people of life and an increased risk of co-morbidities, including https://eje.bioscientifica.com Consensus Statement J Bollerslev and others Unmet needs in parathyroid 181:3 P7 disorders contrary, a Danish controlled cohort study reported the risk of renal stones to be ‘only’ four-fold increased (OR 4.0; 95% CI, 1.6–9.9), compared to the general population (65). In the Italian study, renal calcifications were assessed by ultrasound examinations and most patients were asymptomatic, whereas hospital discharge codes were used in the Danish study and most patients were symptomatic. Accordingly, HypoPT seems to be associated with a four- and eight-fold increased risk of symptomatic and asymptomatic renal calcifications. Figure 3 Hypercalciuria Overall calcium homeostasis in chronic hypoparathyroidism. Idiopathic hypercalciuria occurs with a prevalence of In chronic hypoparathyroidism in adults, overall calcium 5–10% in the general population and is associated with an metabolism is reflected by the lack of PTH. Bone turnover is increased risk of renal stones (76). Due to the lack of PTH, markedly decreased as is the net release of calcium from the renal calcium excretion is increased in HypoPT (Fig. 3) and stores in bone. Levels of active vitamin D (1.25-(OH)2–Vit D) are a prevalence of hypercalciuria as high as 25–50% has been low due to lack of the PTH driven 1-α-hydroxylase followed by reported (75, 77, 78). Although no good data are available European Journal of Endocrinology decreased intestinal absorption of calcium. The renal tubular on associations between renal calcium excretion and the reabsorption of calcium is decreased. Moreover, phosphate risk of renal stones in HypoPT, it seems likely to consider levels are high – not illustrated in the figure. hypercalciuria as a causative factor for the increased risk renal stones/impairment, neuropsychiatric diseases and of renal stones in HypoPT. infections. In general, it is recommended to aim at serum calcium levels in the low-normal range when treating HypoPT (7). The reason is the well-known association Renal stones between serum and urinary calcium that is, renal Huge variations in the prevalence of renal stones have calcium excretion increases with increased serum been reported, varying from 1.9–40%. As shown in calcium levels (79). Furthermore, thiazide diuretics Table 1, the presence of renal stones has been assessed have been shown to decrease urinary calcium in by different methods, which at least in part may explain HypoPT and may increase serum calcium levels, thereby this variability. Only few studies have compared the risk lowering needs for calcium supplements and activated of renal stones in HypoPT with the general population. vitamin D analogues (80). In idiopathic hypercalciuria, A recent cross-sectional study from Italy reported renal thiazides have been shown to reduce the risk of renal calcifications in 30% of patients with HypoPT, which stones and it seems likely that thiazides may exert a was eight-fold higher than that in an age- and gender- similar effect in HypoPT (81). However, the precise matched control group (odds ratio (OR) 8.2; 95% indication for use of thiazides in HypoPT needs further confidence interval (95% CI) 3.4–19.9) (75). On the evaluations. Table 1 Prevalence of renal calcifications in hypoparathyroidism as reported in studies from different countries. Country No of patients Type of examinations Prevalence of renal calcifications (%) Underbjerg 2013 (64) Denmark 688 ICD codes 1.9 Arlt 2002 (66) USA 25 Ultrasound 8 Rubin 2008 (152) USA 33 ? 15 Hadker 2014 (153) USA 374 Self-reported 25 Meola 2018 (74) Italy 82 Ultrasound 30 Lopes 2016 (154) Brazil 40 Ultrasound 25 Mitchell 2012 (77) USA 54 Renal imaging 31 Winer 2003 (155) USA 27 CT scans 40 https://eje.bioscientifica.com Consensus Statement J Bollerslev and others Unmet needs in parathyroid 181:3 P8 disorders Sodium restriction treated with conventional therapy (calcium and calcitriol) met the biochemical targets defined by the ESE guidelines Salt restriction has been associated with decreased 24-h (75). The best treatment option to reach these goals is still renal calcium excretion in subjects with hypercalciuria, to be established. as a high sodium intake increases calcium excretion which also may lower serum calcium levels in HypoPT (82). Some patients with HypoPT are prone to develop Quality of life sudden episodes of hypocalcemia without any obvious explanation. It should be further investigated whether Optimal control of HypoPT should not be restricted an intermittent high intake of sodium may contribute to simply to restoring biochemical markers. In a number of fluctuations in serum calcium levels in HypoPT. chronic diseases, quality of life (QoL) of the patients is supposed to be a hallmark of therapy (86, 87, 88) and is regarded as essential also for HypoPT patients by the ESE Biochemistry and risk of complications evidence-based guideline (7). Several instruments for the In a recent study, risk of complications to HypoPT characterization of QoL in HypoPT patients were used, has been associated with the biochemical profile (83). including the Short Form-36 (SF-36), the Hospital Anxiety Accordingly, relatively high plasma phosphate levels and/ and Depression Scale (HADS) and the WHO-5 Well- or a high calcium-phosphate product was associated with Being Index survey (WHO-5) (6, 68, 70, 71, 85). These an increased mortality as well as an increased risk of renal different questionnaires revealed large deviations from diseases and infections. Low levels of ionized calcium were the norms observed in the general population (6, 68, 85). European Journal of Endocrinology associated with an increased risk of cardiovascular diseases However, when involving patient control groups instead and episodes of hypercalcemia were associated with of population norms studies were less encouraging (67, increased mortality and risk of infections, cardiovascular- 69). Also treatment studies using rhPTH[1–84] using the and renal-diseases, beyond kidney calcifications. Whether generic SF-36 tool proved unable to detect any difference improving the biochemical control can lower risk of in the quality of life when compared to a control complications of HypoPT needs to be investigated in group treated with placebo (67, 69, 71). Symptoms of further prospective studies. hypoparathyroidism are diverse and frequently hard to classify (69, 89). The knowledge and characterization of symptoms is thus essential to establish and validate tools Are our patients well treated? that help to define optimal disease control (7, 90, 91, 92). A comparison of different treatment forms in HypoPT Hence, the importance of hypoparathyroidism-specific on biochemical parameters or complications are not instruments to assess symptoms has been regarded lately available to date. Treatment seems rather to depend on the as crucial to improve our understanding of the nature availability of active vitamin D compounds in different and the degree of impairments to QoL (71, 90). These countries. In a Danish study, alfacalcidol was exclusively should also take into account patients’ compliance with used (84), in the USA calcitriol (78), in Norway both treatment which may be influenced by drug cost and active compounds were given (6), whereas in Germany a multiple tablet burden. Findings from a 13-Country in addition to calcitriol and alfacalcidol, the long-acting patient survey highlight the substantial burden of illness dihydrotachysterol is available (67). Furthermore, the that negatively impacts health-related QoL (HRQoL) and use of supplemental calcium differs geographically, health status in patients with chronic HypoPT. The degree being highest in the USA (78), whereas higher doses of of HRQoL reduction reflected the magnitude of symptom active vitamin D are used in Europe (6, 67, 84, 85). The severity reported by patients; the greater the symptom European guidelines and international recommendations severity level, the lower the HRQoL (93). In addition, (7, 66) propose an standardized treatment with the aim a disease characteristic questionnaire was developed of reducing symptoms and complications by control of in comparison with control groups (94). With these multiple biochemical parameters beyond serum calcium, instruments, individual differences, and their relationship including serum phosphate, calcium–phosphate product, to biochemical variables (if any) and treatment modalities magnesium and urinary calcium excretion (7). A cross- need to be investigated in the future to identify the best sectional study from Italy indicated that only 34.1% treatment option for the well-being of our patients. https://eje.bioscientifica.com Consensus Statement J Bollerslev and others Unmet needs in parathyroid 181:3 P9 disorders Further perspectives and unmet needs in Chronic be used by the patients themselves would not only support HypoPT in adults the intended studies but also help to better understand the significance of value control by the individual patient There has been an increasing awareness on chronic on their burden of symptoms. HypoPT in recent years, primarily driven by epidemiologic and systematic clinical studies focusing on QoL, morbidity and co-morbidities, as indicated in the newly published treatment guidelines (7, 66). Most patients do develop Primary hyperparathyroidism chronic HypoPT following neck surgery, and there is a PHPT has become a common disease in developed need for a better understanding of the pathophysiology countries, where the diagnosis often is made by chance of post-thyroidectomy parathyroid failure (95, 96). As in patients without specific symptoms, whereas the most of the current knowledge is based on cross-sectional severe classical findings of PHPT most often are diagnosed or short-term intervention studies, prospective studies on in developing areas (100), potentially reflecting a real modern treatment modalities are warranted and needed. under diagnosing of the disease in these countries. With Such studies should be based on strict diagnostic criteria the change in clinical presentation, the question of and include prospectively defined endpoint also taking management of asymptomatic patients (mild PHPT) has comorbidities and late complications into account. PTH been discussed, often based on sparse evidence (101). replacement therapy has been marketed as adjunctive Given PHPT as a common disease, most often in peri- treatment of adult patients with chronic HypoPT, and postmenopausal women (1, 2) with a prevalence of who cannot be adequately controlled with standard European Journal of Endocrinology 2–5% in Scandinavian women, and most data derived therapy alone. Intuitively, substitution with the missing from observational and case control studies, we will here hormone seems an attractive approach. However, data concentrate on some areas of the disease spectrum that from randomized clinical trials (RCT) have so far only should be focused on in the immediate time to come. documented that PTH therapy lowers serum phosphate levels and doses of calcium supplements and activated vitamin D needed to maintain normocalcemia (77, 97). Qualitative aspects of bone tissue in PHPT Neither an improved QoL, nor lowering of urine calcium has been documented in RCTs. Currently, only treatment Due to the high PTH levels (Fig. 4), bone turnover is regimens using once-a-day injections are available. Such increased in PHPT leading to an, in principle reversible regimens cause a sharp rise in plasma PTH levels. However, bone loss based on the coupling principle and an due to a short plasma-half life, PTH is only present in enlargement of the remodeling space (102). Thereby, the circulation for 8–12 h after an injection. Data from bone mass should be normalized by successful surgery studies using twice-a-day injections as well as continuous and fracture frequency also be controlled. Based on large infusion by pump delivery have been publish showing a cohort studies, the fracture prevalence seemed to decrease plasma profile more similar to normal physiology (98). compared to the pre-surgery situation in PHPT, but it was Further studies are needed to elucidate the importance of still increased compared the background population (103, different PTH treatment regimens on its effects. 104). These data refer primarily to appendicular fractures, More information on transition from childhood as vertebral fractures classically are underdiagnosed (101). to adult care, on pregnancy and the early puerperium Studies based on histomorphometry of iliac bone biopsies is essential. QoL seems to be very low in patients have indicated a preservation of trabecular bone, but also with chronic HypoPT, but so far mostly based on a trabecularization of the endosteal envelope leading to generic questionnaires, disease specific tools should be a thinning of the cortical shell (105, 106, 107, 108). In implemented, and also studies including the burden of trabecular bone, the increased turnover is followed by an symptoms as perceived from the patients perspective. The increase in the activation frequency, a shortening of the prospective and randomized clinical trials with QoL as bone resorption period and of particular interest, a decrease an endpoint have so far not given a clear answer on the in the resorption depth. The bone formation phase is also benefit of substitution with PTH as once-a-day injections decreased, and the overall bone balance has been found compared with standard treatment (69, 99), a further to be even positive (reviewed in (102)). These findings unmet need at all levels. The future development of new are in accordance with an increased risk of peripheral technology for instant calcium determination which can fractures, but also indicating an unaltered or even reduced https://eje.bioscientifica.com Consensus Statement J Bollerslev and others Unmet needs in parathyroid 181:3 P10 disorders strength in both bone compartments, as demonstrated indirectly by finate element analyses (117). Is the cardiovascular burden increased in mild disease and potential reversible? Based on epidemiologic studies, PTH reflects cardiovascular (CV) risk in elderly men, even in the normal PTH range (118). PHPT is associated with a state of insulin resistance (119) and PTH is directly positively correlated to Left Ventricular Mass Index in PHPT (120). PHPT is also related to arterial hypertension, but reversibility by surgical treatment has not been demonstrated (116, 121, Figure 4 122). CV-mortality is increased in PTHP and a threshold Overall calcium homeostasis in primary hyperparathyroidism. effect for calcium levels has been discussed based on case- Due to a set-point error in PHPT, circulating PTH levels are control studies (104, 123), below which an increased CV inappropriately increased leading to a new steady state with risk could not be demonstrated. A recent meta-analysis increased PTH and calcium levels. Bone turnover, the renal on the effect on echocardiography measures of surgical tubular reabsorption of calcium, the activation of vitamin D treatment in PHPT could not demonstrate signs of followed by calcium absorption from the gut are all increased European Journal of Endocrinology reversibility neither in observational nor randomized leading to the new steady state, which in principle is able to be studies (124). The findings are in accordance with regulated – just at a higher level. biochemical markers of insulin resistance and CV-risk based on 2 and 5-year data from the randomized risk of vertebral fractures, also in agreement with findings Scandinavian study of PHPT (121, 125). Even though a by DXA (102). Conversely, recent studies have found a positive treatment effect of surgery on vitamin D levels high prevalence of vertebral fractures in patients of both (25(OH)D) was demonstrated, no effect was seen on body sexes in both younger and older patients with PHPT, and composition and various measures of insulin resistance even in patients with mild PHPT (109, 110). In the recent 5 years following randomization (116, 125). Danish study, the overall prevalence of vertebral fractures The increased CV-risk in PHPT is influenced by was around 22% for all age groups, and of interest higher traditional CV-risk factors and these might therefore in men compared with women in younger patients less partly explain the lack of reversibility of CV-endpoints by than 60 years. Most of the fractures were mild to moderate surgical treatment in PHPT (122). At the third international and only 28.7% had severe fractures by the method of workshop on management of mild (asymptomatic) PHPT, Genant (111, 112). When compared to patients with it was stated that demonstration of CV-risk reversibility postmenopausal osteoporosis, patients with PHPT seemed by surgery could change overall recommendations (126). to fracture at a higher BMD level (112). These findings Even though data from long term randomized studies have are supported by microarchitectural analyses by HRpQCT now emerged, the data have not indicated a change in imaging, showing decreased trabecular and cortical bone the recommendations for management based on CV-risk. microstructure in active PHPT (113, 114). Randomized Thus, increased CV-risk is at present not considered to be controlled studies have indicated a treatment effect of an indication for parathyroidectomy in PHPT (11). surgery on bone mass by DXA in the 5-year perspective, but not for cortical bone as seen in the proximal forearm Will patients with mild disease improve QoL (115, 116), of importance for the risk of low energy fracture with treatment? (116). Microarchitectural analyses have supported these data, showing an improvement in bone mass indices in Patients with mild or asymptomatic PHPT have decreased both trabecular and cortical bone by HRpQCT, starting QoL based on generic QoL questionnaires (2, 127, 128, already 6 month after surgical cure of PHPT in both sexes, 129, 130). Numerous observational studies including the and continuing up to 2 years following surgery (117). most recent have indicated a positive treatment effect of These improvements were attributed to a decrease in bone surgery on QoL (131, 132, 133). Randomized controlled turnover and leading to a presumably increase in bone studies have shown ambiguous results (128, 129, 130), https://eje.bioscientifica.com Consensus Statement J Bollerslev and others Unmet needs in parathyroid 181:3 P11 disorders demonstrating no significant effect of surgical treatment the variability is in the order of 0.02 mmol/liter (139). on QoL in patients not fulfilling the surgical criteria for Thus, to be certain that the measured serum calcium PHPT, as summarized in a recent meta-analysis (134). A is normal, we should know the range of variability of disease specific questionnaire (PHPQoL) has recently been each individual subject. Therefore, facing a subject with developed (135). The tool seems reliable with good internal the biochemical signature of normocalcemic PHPT, consistency and sensitive to changes over time. It was particularly when ionized calcium is in the upper normal also demonstrated that PHPQoL correlated significantly range, we cannot exclude that the correct diagnosis could with generic, traditional questionnaires and the tool was be classical PHPT, which is much more common than sensitive to the degree calcium related symptoms (135). normocalcemic PHPT. Before making a definite diagnosis So far the experience with PHPQoL tool is limited, but a of normocalcemic PHPT, the patient must be replete for recent observational study demonstrated an improvement calcium and vitamin D intake for several weeks before in PHPQoL following parathyroidectomy, independent of the diagnostic sample. A second problem is the exclusion calcium levels (136). PHPQoL has so far not been tested in of secondary hyperparathyroidism, particularly when randomized, controlled studies. ionized calcium is in the lower normal range, on the Due to ambiguous results from controlled studies and basis of the cut-off values identified for serum 25(OH) few data based on disease specific questionnaires, low QoL D, eGFR and 24-h urinary calcium. The relationship alone has not been an indication for surgical treatment of between plasma PTH and each of these variables differs PHPT (11). in different individuals. Therefore in the same individual, the coexistence of increased plasma PTH associated with European Journal of Endocrinology values of serum 25(OH)D and eGFR above, and 24-h Normocalcemic PHPT: How can the diagnosis urinary calcium below the relative cut-offs, might be be secured? compatible with a form secondary hyperparathyroidism. Normocalcemic PHPT is defined by the finding of plasma A third problem is to exclude subtle gastrointestinal PTH consistently (at least three determinations) elevated disorders that may cause calcium malabsorption. A associated with normal total (albumin-corrected) and fourth problem emerged from data from the Dallas Heart ionized calcium, after the exclusion of any other cause of study, in which, after the exclusion of subjects with eGFR secondary hyperparathyroidism: <60 ml/min and thiazide diuretics and lithium use, the prevalence of normocalcemic PHPT dropped from 3.1% (i) serum 25(OH)D <75 nmol/l, to 0.6%, when many of these subjects were reinvestigate (ii) eGFR <60 ml/min per 1.73 m2, 6 years later (137). Finally, a low calcium intake could (iii) 24-h urinary calcium >8.75 mmol (350 mg), also contribute to increasing plasma PTH. In conclusion (iv)  gastrointestinal disorders associated with calcium cautions should be recommended before concluding that and/or vitamin D malabsorption, and a biochemical signature translates into a disease entity. (v)  medications that could alter calcium homeostasis, Nonetheless, these subjects should be followed because including lithium, thiazide- and loop-diuretics, some of them may develop the classic hypercalcemic bisphosphonates or Denosumab (137). form of PHPT (140). These patients should be distinguished from patients with classical hypercalcemic hyperparathyroidism, who Risk factors for nephrolithiasis and value of the occasionally may have normal total and ionized serum ‘biochemical urinary stone risk profile’ calcium. We should also remind that about 10-15% of patients with classic PHPT may have albumin-corrected Recent studies have shown an increasing prevalence serum calcium in the normal range, but elevated ionized (7-35%) of silent kidney stones in patients with PHPT (112, calcium (138). 141). Hypercalciuria is a risk factor for nephrolithiasis and Several critical issues should be considered to secure a higher mean urinary calcium excretion has been shown the diagnosis of normocalcemic PHPT. The first problem in patients with PHPT and kidney stones compared with is the definition of normocalcemia using the range those without (112). On the other hand, nephrolithiasis of serum calcium in the normal population (usually may occur in the absence of hypercalciuria, suggesting 2.15 – 2.55 mmol/l (8.6-10.2 mg/dl)). The individual that factor(s) other than hypercalciuria may contribute variation in serum calcium is four times narrower that to stone formation. In this regard, the latest guidelines the inter individual variability, and for ionized calcium for the management of asymptomatic PHPT recommend https://eje.bioscientifica.com Consensus Statement J Bollerslev and others Unmet needs in parathyroid 181:3 P12 disorders a more complete biochemical urinary stone risk profile Further perspectives and areas of uncertainty evaluation, when 24-hour urinary calcium excretion is Although bone as target tissue has been a matter of clinical above 10 mmol (400 mg) (11). The rational for choosing and scientific interest for decades, the biomechanical this cut-off value is unclear and does not consider that the properties of bone in PHPT is still a matter of uncertainty upper limit of normal urinary calcium excretion differs and debate. The most recent studies have indicated between men and women (7.5 mmol vs 6.25 mmol (300 mg increased risk of low energy fractures even in mild PHPT, vs 250 mg daily)). Tay et al. (142) recently reported that only but also that patients with PHPT might fracture at a higher 31.6% of patients with asymptomatic PHPT and occult BMD level than expected and compared with patients nephrolithiasis had U-Ca >10 mmol/24 h (400 mg/24 h). with postmenopausal osteoporosis (110). The continuous Similarly, we found urinary calcium above this cut-off in loss of bone mass in non-operated patients calls for 18 of 38 (47.4%) patients with asymptomatic PHPT and consideration of a more active approach towards fracture silent nephrolithiasis (unpublished data), confirming a protection, being surgery or antiresorptive therapy (115, poor sensitivity of this cut-off. Therefore, the question 116), than recommended by the most recent international arises, whether other cut-off values could be more workshop (11). Another question arise when to start appropriate. Some, but not all, studies in mixed cohorts protective bone active treatment even before considering of symptomatic and asymptomatic PHPT have shown surgery both in classical or mild PHPT. that high 24 h urinary oxalate and low citrate excretion Several international guidelines and consensus are associated with nephrolithiasis (143). Further studies reports have been published on the management of PHPT, with a more complete assessment of urinary parameters and it is worrisome that the recommendations often not European Journal of Endocrinology that might be involved in stone risk formation in patients are followed. Recent long term data have emerged from with asymptomatic PHPT are warranted. randomized studies of mild PHPT without significantly demonstrating a treatment effect by surgery on CV-risk, presumable because of the importance of other CV-risk Why are International guidelines not followed factors. Thus, at present the proposed threshold for as expected? calcium levels in PHPT given by epidemiologic studies has Cohort studies as well as retrospective reviews of group’s not been challenged. Most probably, the increased CV-risk records have shown that parathyroid surgery was performed is a combination of traditional risk factors for CV disease, in almost half of patients with symptomatic PHPT, in and as well the increased calcium as PTH levels (151). 30-40% of those with asymptomatic PHPT who met at QoL is another area of controversy, as patients with least one criterion for surgery, and in about one quarter of PHPT have decreased scores by generic QoL tools and patients with asymptomatic PHPT who did not meet any disease specific questionnaires only recently have been criterion for surgery (144, 145, 146). A prospective study developed (135). So far, no benefit of parathyroidectomy carried out in Italian tertiary referral centers in patients on QoL from randomized studies has been demonstrated, with newly diagnosed PHPT confirms that international and data from disease specific questionnaires are guidelines are not obeyed over a follow-up period of warranted. one year after diagnosis. Indeed, parathyroidectomy was performed in 55.1% of patients with symptomatic PHPT and 53.7% of those with asymptomatic PHPT with at least Discussions and conclusions one criterion for surgery. In both subgroups surveillance was advised when parathyroid imaging studies were The presentations and discussions from the first PARAT negative. Parathyroidectomy was also performed in 25.7% workshop held in Santpoort, The Netherlands in of patients with asymptomatic PHPT and no surgical September 2018 are described in the present review, criteria, especially in those with positive parathyroid focusing on parathyroid disorders from an organ imaging studies (75%) (147). Therefore, in view of perspective with emphasis on unmet needs of importance the well-established selective approach to parathyroid for modern patient care. surgery (148), imaging studies could be considered in Whereas benign parathyroid adenomas and the therapeutic decision-making process in patients with hyperplasia are common in the clinic, PC are rarely seen asymptomatic PHPT, as suggested by some guidelines and do call for special attention and transdisciplinary (149, 150). collaboration, the parathyroid surgeon and pathologist https://eje.bioscientifica.com Consensus Statement J Bollerslev and others Unmet needs in parathyroid 181:3 P13 disorders having central roles. The understanding of the decades, but safely for how long time still remains to be pathogenesis and natural history of PC is virtually answered. The natural history of fractures in PHPT is also unknown. Due to the rareness, no center can claim high controversial and need to be covered (112) in prospective experience on PC, and there is a need for central registries studies. QoL is another controversial area in PHPT, where at different levels, for example through the European the recent developed disease specific questionnaire might Reference Network on Rare Endocrine Conditions (ENDO- be a step forward for a better understanding of the burden ERN). From the perspective of the PARAT project, such a of the disease (135). Several international consensus registry should have priority, but it is equally important statements on the management of PHPT have been to join forces to increase experience and knowledge, and published. With the accumulation of recent knowledge, moreover to avoid parallel registries. Lessons should be a systematic and strictly evidence based clinical guideline learned for improving preoperative diagnosis, but at the should be considered. moment no reliable biomarker for PC has been developed or validated. A multinational registry could be a way Declaration of interest forward, also giving possibilities for second opinion at The PARAT program of activities 2018–2019 has been supported by the the histopathological level, and for long-term follow-up European Society of Endocrinology (ESE) applying for and receiving an of patients. independent educational grant from Shire PLC. Shire has not had any opportunity to influence the agenda, planned activity schedule, choice There is an international need for stringent of faculty, participants, venue, delivery formats, distribution profile of diagnosing of chronic HypoPT in adults, and we suggest outcomes, scope of objectives or any other kind of engagement with the following the ESE definition of low calcium levels with low Steering Group or ESE Focus Area leads. European Journal of Endocrinology or inappropriate low levels of PTH (7), where the chronic state refers to 6-month duration, but 12 months could Funding be considered to allow recovery (96). There is a need for Further funding RVT is funded by a Wellcome Trust Senior Investigator a better understanding of the role of in situ parathyroid Award (grant number 106995/Z/15/Z); National Institute for Health Research (NIHR) Oxford Biomedical Research Centre Program and an NIHR gland preservation in the prevention of HypoPT Senior Investigator Award (grant number NF-SI-0514-10091). following surgery and to gain knowledge on the potential parathyroid reserve (95, 152). The burden of HypoPT is high for the patient with impairment in QoL and cognitive Acknowledgements properties, often with fluctuations within short time. The PARAT Workshop Group, except the core writing authors listed on the front page: Andrea Guistina – San Raffaele Hospital, Milan, Italy (giustina. There is a need for better understanding of the relation andrea@hsr.it). Wim Van Hul – Antwerp University Hospital, Belgium between biomarkers of the disease (calcium levels) and (wim.vanhul@uantwerpen.be). Karin Amrein – Medical University of Graz, intellectual function, but also to establish the importance Austria (karin.amrein@medunigraz.at). Tanja Sikjaer – Aarhus University Hospital, Denmark (Tanja.Sikjaer@aarhus.rm.dk). Elif Hindie – Bordeaux of the lacking hormone (PTH) in target tissues. The University Hospital, France (elif.hindie@chu-bordeaux.fr). Kyriakos optimal individual target of serum calcium concentration Vamvakidis – Henry Dunant Hospital, Athens, Greece (info@drvamvakidis. to be reached with therapy (within the low-normal range) gr). Sabrina Corbetta – University of Milan, Italy (sabrina.corbetta@unimi. it). Zhanna Balaia – National Medical Research Center for Endocrinology, may be un-physiologic and cause symptoms by some, as Moscow, Russia (jannabelaya@gmail.com). Marianne Astor – Haukeland the individual calcium level normally varies little within a University Hospital, Bergen, Norway (marianne.catharina.astor@helse- narrow range. Preoperative serum calcium concentration bergen.no). Ozer Makay – University Hospital, Izmir, Turkey (ozer.makay@ ege.edu.tr). Paul Newey – University of Dundee, UK (p.newey@dundee. could guide the management of patients with post- ac.uk). Fadil Hannan – University of Liverpool, UK (Fadil.Hannan@liverpool. surgical HypoPt. Most patients with chronic HypoPT are ac.uk). Lars Rolighed – Aarhus University Hospital, Denmark (larsroli@ females and in fertile age raising questions about optimal rm.dk). Natasha Appelman-Dijkstra – Leiden University Medical Center, Netherlands (N.M.Appelman-Dijkstra@lumc.nl). Corrina Wicke – Thyroid guidance during pregnancy and puerperium. Center, Kantonsspital, Lucerne, Switzerland (wickemedical@t-online.de). PHPT is a very common disease, especially in Stefan Pilz – Medical University of Graz, Austria (stefan.pilz@medunigraz. postmenopausal women (101). At present, we know little at). Federica Saponaro, University of Pisa, Italy (federica.saponaro@ gmail.com). Peter Vestergard, Aalborg University Hospital, Denmark about the natural course of the disease in the modern clinic, (p.vestergaard@rn.dk) and again it is virtually unknown whether morbidity and long-term outcome is related to the high calcium or PTH level or both (151). Cardiovascular morbidity is increased References in PHPT, but potential reversibility by surgery is still a 1 Lundgren E, Rastad J, Thrufjell E, Akerstrom G & Ljunghall S. matter of debate and an issue for further research (122). Population-based screening for primary hyperparathyroidism with Observation without intervention has been advocated for serum calcium and parathyroid hormone values in menopausal https://eje.bioscientifica.com Consensus Statement J Bollerslev and others Unmet needs in parathyroid 181:3 P14 disorders women. Surgery 1997 121 287–294. (https://doi.org/10.1016/S0039- Oncology 2018 25 2535–2540. (https://doi.org/10.1245/s10434-018- 6060(97)90357-3) 6559-6) 2 Siilin H, Rastad J, Ljunggren O & Lundgren E. Disturbances 16 Shane E. Clinical review 122: parathyroid carcinoma. Journal of of calcium homeostasis consistent with mild primary Clinical Endocrinology and Metabolism 2001 86 485–493. (https://doi. hyperparathyroidism in premenopausal women and associated org/10.1210/jcem.86.2.7207) morbidity. Journal of Clinical Endocrinology and Metabolism 2008 93 17 Wei CH & Harari A. Parathyroid carcinoma: update and guidelines 47–53. (https://doi.org/10.1210/jc.2007-0600) for management. Current Treatment Options in Oncology 2012 13 3 Wermers RA, Khosla S, Atkinson EJ, Achenbach SJ, 11–23. (https://doi.org/10.1007/s11864-011-0171-3) Oberg AL, Grant CS & Melton LJ 3rd. Incidence of primary 18 Cetani F, Pardi E & Marcocci C. Update on parathyroid carcinoma. hyperparathyroidism in Rochester, Minnesota, 1993–2001: an Journal of Endocrinological Investigation 2016 39 595–606. (https://doi. update on the changing epidemiology of the disease. Journal of Bone org/10.1007/s40618-016-0447-3) and Mineral Research 2006 21 171–177. (https://doi.org/10.1359/ 19 Cardoso L, Stevenson M & Thakker RV. Molecular genetics of JBMR.050910) syndromic and non-syndromic forms of parathyroid carcinoma. 4 Wermers RA, Khosla S, Atkinson EJ, Hodgson SF, O'Fallon WM & Human Mutation 2017 38 1621–1648. (https://doi.org/10.1002/ Melton LJ 3rd. The rise and fall of primary hyperparathyroidism: humu.23337) a population-based study in Rochester, Minnesota, 1965–1992. 20 Howell VM, Haven CJ, Kahnoski K, Khoo SK, Petillo D, Chen J, Annals of Internal Medicine 1997 126 433–440. (https://doi. Fleuren GJ, Robinson BG, Delbridge LW, Philips J et al. HRPT2 org/10.7326/0003-4819-126-6-199703150-00003) mutations are associated with malignancy in sporadic parathyroid 5 Underbjerg L, Sikjaer T, Mosekilde L & Rejnmark L. The tumours. Journal of Medical Genetics 2003 40 657–663. (https://doi. epidemiology of nonsurgical hypoparathyroidism in Denmark: a org/10.1136/jmg.40.9.657) nationwide case finding study. Journal of Bone and Mineral Research 21 Shattuck TM, Valimaki S, Obara T, Gaz RD, Clark OH, Shoback D, 2015 30 1738–1744. (https://doi.org/10.1002/jbmr.2501) Wierman ME, Tojo K, Robbins CM, Carpten JD et al. Somatic and 6 Astor MC, Lovas K, Debowska A, Eriksen EF, Evang JA, Fossum C, germ-line mutations of the HRPT2 gene in sporadic parathyroid Fougner KJ, Holte SE, Lima K, Moe RB et al. Epidemiology and carcinoma. New England Journal of Medicine 2003 349 1722–1729. health-related quality of life in hypoparathyroidism in Norway. (https://doi.org/10.1056/NEJMoa031237) European Journal of Endocrinology Journal of Clinical Endocrinology and Metabolism 2016 101 3045–3053. 22 Schulte KM & Talat N. Diagnosis and management of parathyroid (https://doi.org/10.1210/jc.2016-1477) cancer. Nature Reviews: Endocrinology 2012 8 612–622. (https://doi. 7 Bollerslev J, Rejnmark L, Marcocci C, Shoback DM, Sitges-Serra A, org/10.1038/nrendo.2012.102) van Biesen W, Dekkers OM & European Society of Endocrinology. 23 Cetani F, Frustaci G, Torregrossa L, Magno S, Basolo F, European Society of Endocrinology Clinical Guideline: treatment Campomori A, Miccoli P & Marcocci C. A nonfunctioning of chronic hypoparathyroidism in adults. European Journal of parathyroid carcinoma misdiagnosed as a follicular thyroid nodule. Endocrinology 2015 173 G1–G20. (https://doi.org/10.1530/EJE-15- World Journal of Surgical Oncology 2015 13 270. (https://doi. 0628) org/10.1186/s12957-015-0672-9) 8 Brown S, O'Neill C, Suliburk J, Sidhu S, Sywak M, Gill A, Robinson B 24 Sidhu PS, Talat N, Patel P, Mulholland NJ & Schulte KM. Ultrasound & Delbridge L. Parathyroid carcinoma: increasing incidence and features of malignancy in the preoperative diagnosis of parathyroid changing presentation. ANZ Journal of Surgery 2011 81 528–532. cancer: a retrospective analysis of parathyroid tumours larger (https://doi.org/10.1111/j.1445-2197.2010.05594.x) than 15 mm. European Radiology 2011 21 1865–1873. (https://doi. 9 Lee PK, Jarosek SL, Virnig BA, Evasovich M & Tuttle TM. Trends in org/10.1007/s00330-011-2141-3) the incidence and treatment of parathyroid cancer in the United 25 Hara H, Igarashi A, Yano Y, Yashiro T, Ueno E, Aiyoshi Y, Ito K States. Cancer 2007 109 1736–1741. (https://doi.org/10.1002/ & Obara T. Ultrasonographic features of parathyroid carcinoma. cncr.22599) Endocrine Journal 2001 48 213–217. (https://doi.org/10.1507/ 10 Ryhanen EM, Leijon H, Metso S, Eloranta E, Korsoff P, Ahtiainen P, endocrj.48.213) Kekalainen P, Tamminen M, Ristamaki R, Knutar O et al. A 26 Christakis I, Vu T, Chuang HH, Fellman B, Figueroa AMS, nationwide study on parathyroid carcinoma. Acta Oncologica 2017 56 Williams MD, Busaidy NL & Perrier ND. The diagnostic accuracy of 991–1003. (https://doi.org/10.1080/0284186X.2017.1306103) neck ultrasound, 4D-computed tomographyand sestamibi imaging in 11 Bilezikian JP, Brandi ML, Eastell R, Silverberg SJ, Udelsman R, parathyroid carcinoma. European Journal of Radiology 2017 95 82–88. Marcocci C & Potts JT Jr. Guidelines for the management of (https://doi.org/10.1016/j.ejrad.2017.07.026) asymptomatic primary hyperparathyroidism: summary statement 27 Andersen KF & Albrecht-Beste E. Brown tumors due to primary from the Fourth International Workshop. Journal of Clinical hyperparathyroidism in a patient with parathyroid carcinoma Endocrinology and Metabolism 2014 99 3561–3569. (https://doi. mimicking skeletal metastases on (18)F-FDG PET/CT. Diagnostics org/10.1210/jc.2014-1413) 2015 5 290–293. 12 Chou YH, Brown EM, Levi T, Crowe G, Atkinson AB, Arnqvist HJ, 28 Spinelli C, Bonadio AG, Berti P, Materazzi G & Miccoli P. Cutaneous Toss G, Fuleihan GE, Seidman JG & Seidman CE. The gene spreading of parathyroid carcinoma after fine needle aspiration responsible for familial hypocalciuric hypercalcemia maps to cytology. Journal of Endocrinological Investigation 2000 23 255–257. chromosome 3q in four unrelated families. Nature Genetics 1992 1 (https://doi.org/10.1007/BF03343718) 295–300. (https://doi.org/10.1038/ng0792-295) 29 Tomasetti C & Vogelstein B. Cancer etiology. Variation in cancer risk 13 Nesbit MA, Hannan FM, Howles SA, Reed AA, Cranston T, among tissues can be explained by the number of stem cell divisions. Thakker CE, Gregory L, Rimmer AJ, Rust N, Graham U et al. Science 2015 347 78–81. (https://doi.org/10.1126/science.1260825) Mutations in AP2S1 cause familial hypocalciuric hypercalcemia type 30 Christmas TJ, Chapple CR, Noble JG, Milroy EJ & Cowie AG. 3. Nature Genetics 2013 45 93–97. (https://doi.org/10.1038/ng.2492) Hyperparathyroidism after neck irradiation. British Journal of Surgery 14 Thakker RV. Genetics of parathyroid tumours. Journal of Internal 1988 75 873–874. (https://doi.org/10.1002/bjs.1800750914) Medicine 2016 280 574–583. (https://doi.org/10.1111/joim.12523) 31 Miki H, Sumitomo M, Inoue H, Kita S & Monden Y. Parathyroid 15 Lo WM, Good ML, Nilubol N, Perrier ND & Patel DT. Tumor size carcinoma in patients with chronic renal failure on maintenance and presence of metastatic disease at diagnosis are associated with hemodialysis. Surgery 1996 120 897–901. (https://doi.org/10.1016/ disease-specific survival in parathyroid carcinoma. Annals of Surgical S0039-6060(96)80101-2) https://eje.bioscientifica.com Consensus Statement J Bollerslev and others Unmet needs in parathyroid 181:3 P15 disorders 32 Erickson LA & Mete O. Immunohistochemistry in diagnostic surgery, radiotherapy, cinacalcet, zoledronic acid, and temozolomide. parathyroid pathology. Endocrine Pathology 2018 29 113–129. JBMR Plus 2019 3 e10114. (https://doi.org/10.1002/jbm4.10114) (https://doi.org/10.1007/s12022-018-9527-6) 45 Marcocci C, Cetani F, Rubin MR, Silverberg SJ, Pinchera A & 33 Cetani F, Banti C, Pardi E, Borsari S, Viacava P, Miccoli P, Bilezikian JP. Parathyroid carcinoma. Journal of Bone and Mineral Torregrossa L, Basolo F, Pelizzo MR, Rugge M et al. CDC73 mutational Research 2008 23 1869–1880. (https://doi.org/10.1359/jbmr.081018) status and loss of parafibromin in the outcome of parathyroid cancer. 46 Karuppiah D, Thanabalasingham G, Shine B, Wang LM, Sadler GP, Endocrine Connections 2013 2 186–195. (https://doi.org/10.1530/ Karavitaki N & Grossman AB. Refractory hypercalcaemia secondary EC-13-0046) to parathyroid carcinoma: response to high-dose denosumab. 34 Witteveen JE, Hamdy NA, Dekkers OM, Kievit J, van Wezel T, Teh BT, European Journal of Endocrinology 2014 171 K1–K5. (https://doi. Romijn JA & Morreau H. Downregulation of CASR expression and org/10.1530/EJE-14-0166) global loss of parafibromin staining are strong negative determinants 47 Thosani S & Hu MI. Denosumab: a new agent in the management of of prognosis in parathyroid carcinoma. Modern Pathology 2011 24 hypercalcemia of malignancy. Future Oncology 2015 11 2865–2871. 688–697. (https://doi.org/10.1038/modpathol.2010.236) (https://doi.org/10.2217/fon.15.232) 35 Wang O, Wang C, Nie M, Cui Q, Guan H, Jiang Y, Li M, Xia W, 48 Munson ND, Foote RL, Northcutt RC, Tiegs RD, Fitzpatrick LA, Meng X & Xing X. Novel HRPT2/CDC73 gene mutations and loss Grant CS, van Heerden JA, Thompson GB & Lloyd RV. Parathyroid of expression of parafibromin in Chinese patients with clinically carcinoma: is there a role for adjuvant radiation therapy? Cancer sporadic parathyroid carcinomas. PLoS ONE 2012 7 e45567. (https:// 2003 98 2378–2384. (https://doi.org/10.1002/cncr.11819) doi.org/10.1371/journal.pone.0045567) 49 Rasmuson T, Kristoffersson A & Boquist L. Positive effect of 36 Guarnieri V, Battista C, Muscarella LA, Bisceglia M, de Martino D, radiotherapy and surgery on hormonally active pulmonary Baorda F, Maiello E, D'Agruma L, Chiodini I, Clemente C et al. metastases of primary parathyroid carcinoma. European Journal CDC73 mutations and parafibromin immunohistochemistry in of Endocrinology 2000 143 749–754. (https://doi.org/10.1530/ parathyroid tumors: clinical correlations in a single-centre patient eje.0.1430749) cohort. Cellular Oncology 2012 35 411–422. (https://doi.org/10.1007/ 50 Tan AH, Kim HK, Kim MY, Oh YL, Kim JS, Chung JH & Kim SW. s13402-012-0100-x) Parathyroid carcinoma presenting as a hyperparathyroid crisis. 37 Bricaire L, Odou MF, Cardot-Bauters C, Delemer B, North MO, Korean Journal of Internal Medicine 2012 27 229–231. (https://doi. European Journal of Endocrinology Salenave S, Vezzosi D, Kuhn JM, Murat A, Caron P et al. Frequent org/10.3904/kjim.2012.27.2.229) large germline HRPT2 deletions in a French National cohort of 51 Bradwell AR & Harvey TC. Control of hypercalcaemia of parathyroid patients with primary hyperparathyroidism. Journal of Clinical carcinoma by immunisation. Lancet 1999 353 370–373. (https://doi. Endocrinology and Metabolism 2013 98 E403–E408. (https://doi. org/10.1016/S0140-6736(98)06469-1) org/10.1210/jc.2012-2789) 52 Horie I, Ando T, Inokuchi N, Mihara Y, Miura S, Imaizumi M, Usa T, 38 van der Tuin K, Tops CMJ, Adank MA, Cobben JM, Hamdy NAT, Kinoshita N, Sekine I, Kamihara S et al. First Japanese patient treated Jongmans MC, Menko FH, van Nesselrooij BPM, Netea-Maier RT, with parathyroid hormone peptide immunization for refractory Oosterwijk JC et al. CDC73-related disorders: clinical manifestations hypercalcemia caused by metastatic parathyroid carcinoma. Endocrine and case detection in primary hyperparathyroidism. Journal of Journal 2010 57 287–292. (https://doi.org/10.1507/endocrj.K09E-283) Clinical Endocrinology and Metabolism 2017 102 4534–4540. 53 Calandra DB, Chejfec G, Foy BK, Lawrence AM & Paloyan E. 39 Korpi-Hyovalti E, Cranston T, Ryhanen E, Arola J, Aittomaki K, Parathyroid carcinoma: biochemical and pathologic response to Sane T, Thakker RV & Schalin-Jantti C. CDC73 intragenic deletion in DTIC. Surgery 1984 96 1132–1137. familial primary hyperparathyroidism associated with parathyroid 54 Yu YP, Liu P, Nelson J, Hamilton RL, Bhargava R, Michalopoulos G, carcinoma. Journal of Clinical Endocrinology and Metabolism 2014 99 Chen Q, Zhang J, Ma D, Pennathur A et al. Identification of recurrent 3044–3048. (https://doi.org/10.1210/jc.2014-1481) fusion genes across multiple cancer types. Scientific Reports 2019 9 40 Yu W, McPherson JR, Stevenson M, van Eijk R, Heng HL, Newey P, 1074. (https://doi.org/10.1038/s41598-019-38550-6) Gan A, Ruano D, Huang D, Poon SL et al. Whole-exome sequencing 55 Bhangoo MS & Sigal D. TRK inhibitors: clinical development of studies of parathyroid carcinomas reveal novel PRUNE2 mutations, Larotrectinib. Current Oncology Reports 2019 21 14. (https://doi. distinctive mutational spectra related to APOBEC-catalyzed DNA org/10.1007/s11912-019-0761-y) mutagenesis and mutational enrichment in kinases associated with cell 56 Kang H, Pettinga D, Schubert AD, Ladenson PW, Ball DW, Chung JH, migration and invasion. Journal of Clinical Endocrinology and Metabolism Schrock AB, Madison R, Frampton GM, Stephens PJ et al. Genomic 2015 100 E360–E364. (https://doi.org/10.1210/jc.2014-3238) profiling of parathyroid carcinoma reveals genomic alterations 41 Pandya C, Uzilov AV, Bellizzi J, Lau CY, Moe AS, Strahl M, Hamou W, suggesting benefit from therapy. Oncologist 2019 24 791–797. Newman LC, Fink MY, Antipin Y et al. Genomic profiling reveals (https://doi.org/10.1634/theoncologist.2018-0334) mutational landscape in parathyroid carcinomas. JCI Insight 2017 2 57 Cui M, Hu Y, Bi Y, Wang W, Wang M, Zhang X, Zhang R, Wang P, e92061. (https://doi.org/10.1172/jci.insight.92061) Su Z, Gao X et al. Preliminary exploration of potential molecular 42 Schulte KM, Talat N, Galata G, Gilbert J, Miell J, Hofbauer LC, therapeutic targets in recurrent and metastatic parathyroid Barthel A, Diaz-Cano S & Bornstein SR. Oncologic resection carcinomas. International Journal of Cancer 2019 144 525–532. achieving r0 margins improves disease-free survival in parathyroid (https://doi.org/10.1002/ijc.31948) cancer. Annals of Surgical Oncology 2014 21 1891–1897. (https://doi. 58 Ribas A & Wolchok JD. Cancer immunotherapy using checkpoint org/10.1245/s10434-014-3530-z) blockade. Science 2018 359 1350–1355. (https://doi.org/10.1126/ 43 Villar-del-Moral J, Jimenez-Garcia A, Salvador-Egea P, Martos- science.aar4060) Martinez JM, Nuno-Vazquez-Garza JM, Serradilla-Martin M, 59 Samstein RM, Lee CH, Shoushtari AN, Hellmann MD, Shen R, Gomez-Palacios A, Moreno-Llorente P, Ortega-Serrano J & de la Janjigian YY, Barron DA, Zehir A, Jordan EJ, Omuro A et al. Tumor Quintana-Basarrate A. Prognostic factors and staging systems in mutational load predicts survival after immunotherapy across parathyroid cancer: a multicenter cohort study. Surgery 2014 156 multiple cancer types. Nature Genetics 2019 51 202–206. (https://doi. 1132–1144. org/10.1038/s41588-018-0312-8) 44 Storvall S, Ryhanen E, Bensch FV, Heiskanen I, Kytola S, Ebeling T, 60 Costa-Guda J. Commentary: next-generation sequence analysis Makela S & Schalin-Jantti C. Recurrent metastasized parathyroid of parathyroid carcinoma. Journal of the Endocrine Society 2019 3 carcinoma-long-term remission after combined treatments with 560–562. (https://doi.org/10.1210/js.2018-00315) https://eje.bioscientifica.com Consensus Statement J Bollerslev and others Unmet needs in parathyroid 181:3 P16 disorders 61 Schettini F, De Santo I, Rea CG, De Placido P, Formisano L, 76 Lerolle N, Lantz B, Paillard F, Gattegno B, Flahault A, Ronco P, Giuliano M, Arpino G, De Laurentiis M, Puglisi F, De Placido S et al. Houillier P & Rondeau E. Risk factors for nephrolithiasis in patients CDK 4/6 inhibitors as single agent in advanced solid tumors. Frontiers with familial idiopathic hypercalciuria. American Journal of Medicine in Oncology 2018 8 608. (https://doi.org/10.3389/fonc.2018.00608) 2002 113 99–103. (https://doi.org/10.1016/S0002-9343(02)01152-X) 62 Cetani F, Pardi E & Marcocci C. Parathyroid carcinoma. 77 Sikjaer T, Rejnmark L, Rolighed L, Heickendorff L, Mosekilde L & Frontiers of Hormone Research 2019 51 63–76. (https://doi. Hypoparathyroid Study Group. The effect of adding PTH(1–84) to org/10.1159/000491039) conventional treatment of hypoparathyroidism: a randomized, 63 Clarke CN, Katsonis P, Hsu TK, Koire AM, Silva-Figueroa A, placebo-controlled study. Journal of Bone and Mineral Research 2011 Christakis I, Williams MD, Kutahyalioglu M, Kwatampora L, Xi Y 26 2358–2370. (https://doi.org/10.1002/jbmr.470) et al. Comprehensive genomic characterization of parathyroid cancer 78 Mitchell DM, Regan S, Cooley MR, Lauter KB, Vrla MC, Becker CB, identifies novel candidate driver mutations and core pathways. Burnett-Bowie SA & Mannstadt M. Long-term follow-up of patients Journal of the Endocrine Society 2019 3 544–559. (https://doi. with hypoparathyroidism. Journal of Clinical Endocrinology and org/10.1210/js.2018-00043) Metabolism 2012 97 4507–4514. (https://doi.org/10.1210/jc.2012-1808) 64 Clarke BL. Epidemiology and complications of hypoparathyroidism. 79 Peacock M, Robertson WG & Nordin BE. Relation between serum Endocrinology and Metabolism Clinics of North America 2018 47 and urinary calcium with particular reference to parathyroid 771–782. (https://doi.org/10.1016/j.ecl.2018.07.004) activity. Lancet 1969 1 384–386. (https://doi.org/10.1016/S0140- 65 Underbjerg L, Sikjaer T, Mosekilde L & Rejnmark L. Cardiovascular 6736(69)91353-1) and renal complications to postsurgical hypoparathyroidism: a 80 Porter RH, Cox BG, Heaney D, Hostetter TH, Stinebaugh BJ Danish nationwide controlled historic follow-up study. Journal & Suki WN. Treatment of hypoparathyroid patients with of Bone and Mineral Research 2013 28 2277–2285. (https://doi. chlorthalidone. New England Journal of Medicine 1978 298 577–581. org/10.1002/jbmr.1979) (https://doi.org/10.1056/NEJM197803162981101) 66 Brandi ML, Bilezikian JP, Shoback D, Bouillon R, Clarke BL, 81 Fink HA, Wilt TJ, Eidman KE, Garimella PS, MacDonald R, Rutks IR, Thakker RV, Khan AA & Potts JT Jr. Management of Brasure M, Kane RL, Ouellette J & Monga M. Medical management to hypoparathyroidism: summary statement and guidelines. Journal of prevent recurrent nephrolithiasis in adults: a systematic review for an Clinical Endocrinology and Metabolism 2016 101 2273–2283. (https:// American College of Physicians Clinical Guideline. Annals of Internal European Journal of Endocrinology doi.org/10.1210/jc.2015-3907) Medicine 2013 158 535–543. (https://doi.org/10.7326/0003-4819- 67 Arlt W, Fremerey C, Callies F, Reincke M, Schneider P, 158-7-201304020-00005) Timmermann W & Allolio B. Well-being, mood and calcium 82 Carbone LD, Bush AJ, Barrow KD & Kang AH. The relationship of homeostasis in patients with hypoparathyroidism receiving sodium intake to calcium and sodium excretion and bone mineral standard treatment with calcium and vitamin D. European Journal density of the hip in postmenopausal African-American and of Endocrinology 2002 146 215–222. (https://doi.org/10.1530/ Caucasian women. Journal of Bone and Mineral Metabolism 2003 21 eje.0.1460215) 415–420. (https://doi.org/10.1007/s00774-003-0437-3) 68 Cusano NE, Rubin MR, McMahon DJ, Irani D, Anderson L, Levy E, 83 Underbjerg L, Sikjaer T & Rejnmark L. Long-term complications Bilezikian JP. PTH(1–84) is associated with improved quality of life in patients with hypoparathyroidism evaluated by biochemical in hypoparathyroidism through 5 years of therapy. Journal of Clinical findings: a case-control study. Journal of Bone and Mineral Research Endocrinology and Metabolism 2014 99 3694–3699. (https://doi. 2018 33 822–831. (https://doi.org/10.1002/jbmr.3368) org/10.1210/jc.2014-2267) 84 Underbjerg L, Sikjaer T, Mosekilde L & Rejnmark L. Postsurgical 69 Sikjaer T, Rolighed L, Hess A, Fuglsang-Frederiksen A, Mosekilde L & hypoparathyroidism – risk of fractures, psychiatric diseases, cancer, Rejnmark L. Effects of PTH(1–84) therapy on muscle function and cataract, and infections. Journal of Bone and Mineral Research 2014 29 quality of life in hypoparathyroidism: results from a randomized 2504–2510. (https://doi.org/10.1002/jbmr.2273) controlled trial. Osteoporosis International 2014 25 1717–1726. 85 Sikjaer T, Moser E, Rolighed L, Underbjerg L, Bislev LS, Mosekilde L (https://doi.org/10.1007/s00198-014-2677-6) & Rejnmark L. Concurrent hypoparathyroidism is associated with 70 Underbjerg L, Sikjaer T & Rejnmark L. Health-related quality impaired physical function and quality of life in hypothyroidism. of life in patients with nonsurgical hypoparathyroidism and Journal of Bone and Mineral Research 2016 31 1440–1448. (https://doi. pseudohypoparathyroidism. Clinical Endocrinology 2018 88 838–847. org/10.1002/jbmr.2812) (https://doi.org/10.1111/cen.13593) 86 Kuznetsov L, Griffin SJ, Davies MJ, Lauritzen T, Khunti K, Rutten GE 71 Vokes T. Quality of life in hypoparathyroidism. Bone 2019 120 & Simmons RK. Diabetes-specific quality of life but not health status 542–547. (https://doi.org/10.1016/j.bone.2018.09.017) is independently associated with glycaemic control among patients 72 Bilezikian JP, Khan A, Potts JT Jr, Brandi ML, Clarke BL, Shoback D, with type 2 diabetes: a cross-sectional analysis of the ADDITION- Juppner H, D'Amour P, Fox J, Rejnmark L et al. Hypoparathyroidism Europe trial cohort. Diabetes Research and Clinical Practice 2014 104 in the adult: epidemiology, diagnosis, pathophysiology, target- 281–287. (https://doi.org/10.1016/j.diabres.2013.12.029) organ involvement, treatment, and challenges for future research. 87 Porcu S & Mandas A. How to evaluate quality of life. Monaldi Journal of Bone and Mineral Research 2011 26 2317–2337. (https://doi. Archives for Chest Disease 2019 89 59–61. (https://doi.org/10.4081/ org/10.1002/jbmr.483) monaldi.2019.1033) 73 Mehanna HM, Jain A, Randeva H, Watkinson J & Shaha A. 88 Jitender S, Mahajan R, Rathore V & Choudhary R. Quality of life Postoperative hypocalcemia – the difference a definition makes. Head of cancer patients. Journal of Experimental Therapeutics and Oncology and Neck 2010 32 279–283. 2018 12 217–221. 74 Harslof T, Rolighed L & Rejnmark L. Huge variations in definition 89 Cho NL, Moalem J, Chen L, Lubitz CC, Moore FD Jr & Ruan DT. and reported incidence of postsurgical hypoparathyroidism: Surgeons and patients disagree on the potential consequences from a systematic review. Endocrine 2019 64 176–183. (https://doi. hypoparathyroidism. Endocrine Practice 2014 20 427–446. (https:// org/10.1007/s12020-019-01858-4) doi.org/10.4158/EP13321.OR) 75 Meola A, Vignali E, Matrone A, Cetani F & Marcocci C. Efficacy and 90 Mannstadt M, Bilezikian JP, Thakker RV, Hannan FM, Clarke BL, safety of long-term management of patients with chronic post- Rejnmark L, Mitchell DM, Vokes TJ, Winer KK & Shoback DM. surgical hypoparathyroidism. Journal of Endocrinological Investigation Hypoparathyroidism. Nature Reviews Disease Primers 2017 3 17055. 2018 41 1221–1226. (https://doi.org/10.1007/s40618-018-0857-5) (https://doi.org/10.1038/nrdp.2017.55) https://eje.bioscientifica.com Consensus Statement J Bollerslev and others Unmet needs in parathyroid 181:3 P17 disorders 91 Shoback DM, Bilezikian JP, Costa AG, Dempster D, Dralle H, after surgery for primary hyperparathyroidism. BMJ 2000 321 Khan AA, Peacock M, Raffaelli M, Silva BC, Thakker RV et al. 598–602. (https://doi.org/10.1136/bmj.321.7261.598) Presentation of hypoparathyroidism: etiologies and clinical features. 104 Vestergaard P & Mosekilde L. Cohort study on effects of parathyroid Journal of Clinical Endocrinology and Metabolism 2016 101 2300–2312. surgery on multiple outcomes in primary hyperparathyroidism. BMJ (https://doi.org/10.1210/jc.2015-3909) 2003 327 530–534. (https://doi.org/10.1136/bmj.327.7414.530) 92 Clarke BL, Brown EM, Collins MT, Juppner H, Lakatos P, Levine MA, 105 Christiansen P, Steiniche T, Brockstedt H, Mosekilde L, Hessov I & Mannstadt MM, Bilezikian JP, Romanischen AF & Thakker RV. Melsen F. Primary hyperparathyroidism: iliac crest cortical thickness, Epidemiology and diagnosis of hypoparathyroidism. Journal of structure and remodeling evaluated by histomorphometric methods. Clinical Endocrinology and Metabolism 2016 101 2284–2299. (https:// Aarhus Bone and Mineral Research Group. Bone 1993 14 403–408. doi.org/10.1210/jc.2015-3908) (https://doi.org/10.1016/8756-3282(93)90171-6) 93 Siggelkow H , Clarke BL, Germak J, Marelli C, Chen K, Dahl- 106 Christiansen P, Steiniche T, Vesterby A, Mosekilde L, Hessov I Hansen H, Glenister E, Bent-Ennakhil N, Judge D, Gibson K et al. & Melsen F. Primary hyperparathyroidism: iliac crest trabecular MON-521 impact of chronic hypoparathyroidism on health-related bone volume, structure, remodeling, and balance evaluated by quality of life: findings from a 13-country patient survey. Journal histomorphometric methods. Bone 1992 13 41–49. (https://doi. of the Endocrine Society 2019 3 MON-521. (https://doi.org/10.1210/ org/10.1016/8756-3282(92)90360-9) js.2019-MON-521) 107 Steiniche T, Christiansen P, Vesterby A, Ullerup R, Hessov I, 94 Wilde D , Wilken L, Stamm B, Happner C, Leha A, Hermann- Mosekilde LE & Melsen F. Primary hyperparathyroidism: bone Lingen C & Siggelkov H. Use of a disease-characteristic questionnaire structure, balance, and remodeling before and 3 years after surgical identified pain and cramps and neuro-vegetative symptoms as treatment. Bone 2000 26 535–543. (https://doi.org/10.1016/S8756- significantly elevated and affected by medication in mainly well- 3282(00)00260-X) controlled hypoparathyroid patients. Endocrine Abstracts 2018 56 GP 108 Parisien M, Silverberg SJ, Shane E, de la Cruz L, Lindsay R, 182. (https://doi.org/10.1530/endoabs.56.GP182) Bilezikian JP & Dempster DW. The histomorphometry of bone in 95 Sitges-Serra A, Gomez J, Barczynski M, Lorente-Poch L, Iacobone M primary hyperparathyroidism: preservation of cancellous bone & Sancho J. A nomogram to predict the likelihood of permanent structure. Journal of Clinical Endocrinology and Metabolism 1990 70 hypoparathyroidism after total thyroidectomy based on delayed 930–938. (https://doi.org/10.1210/jcem-70-4-930) European Journal of Endocrinology serum calcium and iPTH measurements. Gland Surgery 2017 6 109 Vignali E, Viccica G, Diacinti D, Cetani F, Cianferotti L, Ambrogini E, S11–S19. (https://doi.org/10.21037/gs.2017.10.04) Banti C, Del Fiacco R, Bilezikian JP, Pinchera A et al. Morphometric 96 Villarroya-Marquina I, Sancho J, Lorente-Poch L, Gallego-Otaegui L vertebral fractures in postmenopausal women with primary & Sitges-Serra A. Time to parathyroid function recovery in patients hyperparathyroidism. Journal of Clinical Endocrinology and Metabolism with protracted hypoparathyroidism after total thyroidectomy. 2009 94 2306–2312. (https://doi.org/10.1210/jc.2008-2006) European Journal of Endocrinology 2018 178 103–111. (https://doi. 110 Ejlsmark-Svensson H, Bislev LS, Lajlev S, Harslof T, Rolighed L, org/10.1530/EJE-17-0589) Sikjaer T & Rejnmark L. Prevalence and risk of vertebral fractures in 97 Mannstadt M, Clarke BL, Vokes T, Brandi ML, Ranganath L, primary hyperparathyroidism: a nested case-control study. Journal Fraser WD, Lakatos P, Bajnok L, Garceau R, Mosekilde L et al. Efficacy of Bone and Mineral Research 2018 33 1657–1664. (https://doi. and safety of recombinant human parathyroid hormone (1–84) in org/10.1002/jbmr.3461) hypoparathyroidism (REPLACE): a double-blind, placebo-controlled, 111 Genant HK, Li J, Wu CY & Shepherd JA. Vertebral fractures in randomised, phase 3 study. Lancet: Diabetes and Endocrinology 2013 1 osteoporosis: a new method for clinical assessment. Journal of Clinical 275–283. (https://doi.org/10.1016/S2213-8587(13)70106-2) Densitometry 2000 3 281–290. (https://doi.org/10.1385/JCD:3:3:281) 98 Winer KK, Zhang B, Shrader JA, Peterson D, Smith M, Albert PS 112 Ejlsmark-Svensson H, Bislev LS, Rolighed L, Sikjaer T & Rejnmark L. & Cutler GB Jr. Synthetic human parathyroid hormone 1–34 Predictors of renal function and calcifications in primary replacement therapy: a randomized crossover trial comparing pump hyperparathyroidism: a nested case-control study. Journal of Clinical versus injections in the treatment of chronic hypoparathyroidism. Endocrinology and Metabolism 2018 103 3574–3583. (https://doi. Journal of Clinical Endocrinology and Metabolism 2012 97 391–399. org/10.1210/jc.2018-00923) (https://doi.org/10.1210/jc.2011-1908) 113 Hansen S, Beck Jensen JE, Rasmussen L, Hauge EM & Brixen K. Effects 99 Vokes TJ, Mannstadt M, Levine MA, Clarke BL, Lakatos P, Chen K, on bone geometry, density, and microarchitecture in the distal radius Piccolo R, Krasner A, Shoback DM & Bilezikian JP. Recombinant but not the tibia in women with primary hyperparathyroidism: human parathyroid hormone effect on health-related quality of a case-control study using HR-pQCT. Journal of Bone and Mineral life in adults with chronic hypoparathyroidism. Journal of Clinical Research 2010 25 1941–1947. (https://doi.org/10.1002/jbmr.98) Endocrinology and Metabolism 2018 103 722–731. (https://doi. 114 Stein EM, Silva BC, Boutroy S, Zhou B, Wang J, Udesky J, org/10.1210/jc.2017-01471) Zhang C, McMahon DJ, Romano M, Dworakowski E et al. Primary 100 Khan AA, Hanley DA, Rizzoli R, Bollerslev J, Young JE, Rejnmark L, hyperparathyroidism is associated with abnormal cortical Thakker R, D’Amour P, Paul T, Van Uum S et al. Primary and trabecular microstructure and reduced bone stiffness in hyperparathyroidism: review and recommendations on evaluation, postmenopausal women. Journal of Bone and Mineral Research 2013 diagnosis, and management. A Canadian and International 28 1029–1040. (https://doi.org/10.1002/jbmr.1841) Consensus. Osteoporosis International 2017 28 1–19. (https://doi. 115 Lundstam K, Heck A, Godang K, Mollerup C, Baranowski M, org/10.1007/s00198-016-3716-2) Pernow Y, Aas T, Hessman O, Rosen T, Nordenstrom J et al. Effect of 101 Bollerslev J, Marcocci C, Sosa M, Nordenstrom J, Bouillon R & surgery versus observation: skeletal 5-year outcomes in a randomized Mosekilde L. Current evidence for recommendation of surgery, trial of patients with primary HPT (the SIPH Study). Journal of Bone medical treatment and vitamin D repletion in mild primary and Mineral Research 2017 32 1907–1914. (https://doi.org/10.1002/ hyperparathyroidism. European Journal of Endocrinology 2011 165 jbmr.3177) 851–864. (https://doi.org/10.1530/EJE-11-0589) 116 Lundstam K, Heck A, Mollerup C, Godang K, Baranowski M, 102 Mosekilde L. Primary hyperparathyroidism and the skeleton. Pernow Y, Varhaug JE, Hessman O, Rosen T, Nordenstrom J et al. Clinical Endocrinology 2008 69 1–19. (https://doi.org/10.1111/j.1365- Effects of parathyroidectomy versus observation on the development 2265.2007.03162.x) of vertebral fractures in mild primary hyperparathyroidism. Journal of 103 Vestergaard P, Mollerup CL, Frokjaer VG, Christiansen P, Blichert- Clinical Endocrinology and Metabolism 2015 100 1359–1367. (https:// Toft M & Mosekilde L. Cohort study of risk of fracture before and doi.org/10.1210/jc.2014-3441) https://eje.bioscientifica.com Consensus Statement J Bollerslev and others Unmet needs in parathyroid 181:3 P18 disorders 117 Cusano NE, Rubin MR, Silva BC, Tay YD, Williams JM, Agarwal S, asymptomatic primary hyperparathyroidism. Journal of Clinical Omeragic B, Guo XE & Bilezikian JP. Skeletal microstructure and Endocrinology and Metabolism 2004 89 5415–5422. (https://doi. estimated bone strength improve following parathyroidectomy in org/10.1210/jc.2004-0028) primary hyperparathyroidism. Journal of Clinical Endocrinology and 131 Bannani S, Christou N, Guerin C, Hamy A, Sebag F, Mathonnet M, Metabolism 2018 103 196–205. (https://doi.org/10.1210/jc.2017- Guillot P, Caillard C, Blanchard C & Mirallie E. Effect of 01932) parathyroidectomy on quality of life and non-specific symptoms 118 Hagstrom E, Hellman P, Larsson TE, Ingelsson E, Berglund L, in normocalcaemic primary hyperparathyroidism. British Journal of Sundstrom J, Melhus H, Held C, Lind L, Michaelsson K et al. Plasma Surgery 2018 105 223–229. (https://doi.org/10.1002/bjs.10739) parathyroid hormone and the risk of cardiovascular mortality in 132 Weber T, Eberle J, Messelhauser U, Schiffmann L, Nies C, the community. Circulation 2009 119 2765–2771. (https://doi. Schabram J, Zielke A, Holzer K, Rottler E, Henne-Bruns D et al. org/10.1161/CIRCULATIONAHA.108.808733) Parathyroidectomy, elevated depression scores, and suicidal 119 Bolland MJ, Grey AB, Gamble GD & Reid IR. Association between ideation in patients with primary hyperparathyroidism: results of primary hyperparathyroidism and increased body weight: a meta- a prospective multicenter study. JAMA Surgery 2013 148 109–115. analysis. Journal of Clinical Endocrinology and Metabolism 2005 90 (https://doi.org/10.1001/2013.jamasurg.316) 1525–1530. (https://doi.org/10.1210/jc.2004-1891) 133 Storvall S, Ryhanen EM, Heiskanen I, Sintonen H, Roine RP & 120 Persson A, Bollerslev J, Rosen T, Mollerup CL, Franco C, Isaksen GA, Schalin-Jantti C. Surgery significantly improves neurocognition, Ueland T, Jansson S, Caidahl K & SIPH Study Group. Effect sleep, and blood pressure in primary hyperparathyroidism: a 3-year of surgery on cardiac structure and function in mild primary prospective follow-up study. Hormone and Metabolic Research 2017 49 hyperparathyroidism. Clinical Endocrinology 2011 74 174–180. 772–777. (https://doi.org/10.1055/s-0043-118347) (https://doi.org/10.1111/j.1365-2265.2010.03909.x) 134 Cheng SP, Lee JJ, Liu TP, Yang PS, Liu SC, Hsu YC & Liu CL. 121 Bollerslev J, Rosen T, Mollerup CL, Nordenstrom J, Baranowski M, Quality of life after surgery or surveillance for asymptomatic Franco C, Pernow Y, Isaksen GA, Godang K, Ueland T et al. primary hyperparathyroidism: a meta-analysis of randomized Effect of surgery on cardiovascular risk factors in mild primary controlled trials. Medicine 2015 94 e931. (https://doi.org/10.1097/ hyperparathyroidism. Journal of Clinical Endocrinology and Metabolism MD.0000000000000931) 2009 94 2255–2261. (https://doi.org/10.1210/jc.2008-2742) 135 Webb SM, Puig-Domingo M, Villabona C, Munoz-Torres M, European Journal of Endocrinology 122 Walker MD & Silverberg SJ. Primary hyperparathyroidism. Nature Marazuela M, Fernandez D, Martinez G, Jodar E, Mangas MA, Reviews: Endocrinology 2018 14 115–125. (https://doi.org/10.1038/ Perulero N et al. Validation of PHPQoL, a disease-specific quality-of- nrendo.2017.104) life questionnaire for patients with primary hyperparathyroidism. 123 Vestergaard P, Mollerup CL, Frokjaer VG, Christiansen P, Blichert- Journal of Clinical Endocrinology and Metabolism 2016 101 1571–1578. Toft M & Mosekilde L. Cardiovascular events before and after surgery (https://doi.org/10.1210/jc.2015-3094) for primary hyperparathyroidism. World Journal of Surgery 2003 27 136 Ejlsmark-Svensson H, Sikjaer T, Webb SM, Rejnmark L & 216–222. (https://doi.org/10.1007/s00268-002-6541-z) Rolighed L. Health-related quality of life improves 1 year after 124 Best CAE, Krishnan R, Malvankar-Mehta MS & MacNeil SD. parathyroidectomy in primary hyperparathyroidism: a prospective Echocardiogram changes following parathyroidectomy for cohort study. Clinical Endocrinology 2019 90 184–191. (https://doi. primary hyperparathyroidism: a systematic review and meta- org/10.1111/cen.13865) analysis. Medicine 2017 96 e7255. (https://doi.org/10.1097/ 137 Cusano NE, Silverberg SJ & Bilezikian JP. Normocalcemic primary MD.0000000000007255) hyperparathyroidism. Journal of Clinical Densitometry 2013 16 33–39. 125 Godang K, Lundstam K, Mollerup C, Fougner SL, Pernow Y, (https://doi.org/10.1016/j.jocd.2012.12.001) Nordenstrom J, Rosen T, Jansson S, Hellstrom M, Bollerslev J et al. 138 Ong GS, Walsh JP, Stuckey BG, Brown SJ, Rossi E, Ng JL, Nguyen HH, The effect of surgery on fat mass, lipid and glucose metabolism in Kent GN & Lim EM. The importance of measuring ionized mild primary hyperparathyroidism. Endocrine Connections 2018 7 calcium in characterizing calcium status and diagnosing primary 941–948. (https://doi.org/10.1530/EC-18-0259) hyperparathyroidism. Journal of Clinical Endocrinology and Metabolism 126 Silverberg SJ, Lewiecki EM, Mosekilde L, Peacock M & Rubin MR. 2012 97 3138–3145. (https://doi.org/10.1210/jc.2012-1429) Presentation of asymptomatic primary hyperparathyroidism: 139 Pedersen KO. On the cause and degree of intraindividual proceedings of the third international workshop. Journal of Clinical serum calcium variability. Scandinavian Journal of Clinical Endocrinology and Metabolism 2009 94 351–365. (https://doi. and Laboratory Investigation 1972 30 191–199. (https://doi. org/10.1210/jc.2008-1760) org/10.3109/00365517209081110) 127 Lundgren E, Ljunghall S, Akerstrom G, Hetta J, Mallmin H 140 Lowe H, McMahon DJ, Rubin MR, Bilezikian JP & Silverberg SJ. & Rastad J. Case-control study on symptoms and signs of Normocalcemic primary hyperparathyroidism: further ‘asymptomatic’ primary hyperparathyroidism. Surgery 1998 124 characterization of a new clinical phenotype. Journal of Clinical 980–985; discussion 985–986. (https://doi.org/10.1016/S0039- Endocrinology and Metabolism 2007 92 3001–3005. (https://doi. 6060(98)70038-8) org/10.1210/jc.2006-2802) 128 Ambrogini E, Cetani F, Cianferotti L, Vignali E, Banti C, Viccica G, 141 Suh JM, Cronan JJ & Monchik JM. Primary hyperparathyroidism: Oppo A, Miccoli P, Berti P, Bilezikian JP et al. Surgery or surveillance is there an increased prevalence of renal stone disease? American for mild asymptomatic primary hyperparathyroidism: a prospective, Journal of Roentgenology 2008 191 908–911. (https://doi.org/10.2214/ randomized clinical trial. Journal of Clinical Endocrinology and AJR.07.3160) Metabolism 2007 92 3114–3121. (https://doi.org/10.1210/jc.2007- 142 Tay YD, Liu M, Bandeira L, Bucovsky M, Lee JA, Silverberg SJ 0219) & Walker MD. Occult urolithiasis in asymptomatic primary 129 Bollerslev J, Jansson S, Mollerup CL, Nordenstrom J, Lundgren E, hyperparathyroidism. Endocrine Research 2018 43 106–115. (https:// Torring O, Varhaug JE, Baranowski M, Aanderud S, Franco C doi.org/10.1080/07435800.2018.1431275) et al. Medical observation, compared with parathyroidectomy, 143 Rejnmark L, Vestergaard P & Mosekilde L. Nephrolithiasis and renal for asymptomatic primary hyperparathyroidism: a prospective, calcifications in primary hyperparathyroidism. Journal of Clinical randomized trial. Journal of Clinical Endocrinology and Metabolism Endocrinology and Metabolism 2011 96 2377–2385. (https://doi. 2007 92 1687–1692. (https://doi.org/10.1210/jc.2006-1836) org/10.1210/jc.2011-0569) 130 Rao DS, Phillips ER, Divine GW & Talpos GB. Randomized controlled 144 Yeh MW, Wiseman JE, Ituarte PH, Pasternak JD, Hwang RS, Wu B, clinical trial of surgery versus no surgery in patients with mild Liu IL & Haigh PI. Surgery for primary hyperparathyroidism: are the https://eje.bioscientifica.com Consensus Statement J Bollerslev and others Unmet needs in parathyroid 181:3 P19 disorders consensus guidelines being followed? Annals of Surgery 2012 255 150 Marcocci C, Brandi ML, Scillitani A, Corbetta S, Faggiano A, 1179–1183. (https://doi.org/10.1097/SLA.0b013e31824dad7d) Gianotti L, Migliaccio S & Minisola S. Italian Society of 145 Trombetti A, Christ ER, Henzen C, Gold G, Brandle M, Endocrinology Consensus Statement: definition, evaluation and Herrmann FR, Torriani C, Triponez F, Kraenzlin M, Rizzoli R et al. management of patients with mild primary hyperparathyroidism. Clinical presentation and management of patients with primary Journal of Endocrinological Investigation 2015 38 577–593. (https://doi. hyperparathyroidism of the Swiss Primary Hyperparathyroidism org/10.1007/s40618-015-0261-3) Cohort: a focus on neuro-behavioral and cognitive symptoms. 151 Bollerslev J. The important players in primary hyperparathyroidism. Journal of Endocrinological Investigation 2016 39 567–576. (https://doi. Clinical Endocrinology 2013 79 774–775. (https://doi.org/10.1111/ org/10.1007/s40618-015-0423-3) cen.12291) 146 Sharata A, Kelly TL, Rozenfeld Y, Hammill CW, Schuman E, 152 Lorente-Poch L, Sancho JJ, Ruiz S & Sitges-Serra A. Importance of in Carlisle JR & Aliabadi-Wahle S. Management of primary situ preservation of parathyroid glands during total thyroidectomy. hyperparathyroidism: can we do better? American Surgeon 2017 83 British Journal of Surgery 2015 102 359–367. (https://doi.org/10.1002/ 64–70. bjs.9676) 147 Saponaro F, Cetani F, Repaci A, Pagotto U, Cipriani C, Pepe J, 153 Hadker N, Egan J, Sanders J, Lagast H & Clarke BL. Understanding Minisola S, Cipri C, Vescini F, Scillitani A et al. Clinical presentation the burden of illness associated with hypoparathyroidism reported and management of patients with primary hyperparathyroidism among patients in the PARADOX study. Endocrine Practice 2014 20 in Italy. Journal of Endocrinological Investigation 2018 41 1339–1348. 671–679. (https://doi.org/10.4158/EP13328.OR) (https://doi.org/10.1007/s40618-018-0879-z) 154 Lopes MP, Kliemann BS, Bini IB, Kulchetscki R, Borsani V, 148 Mihai R, Barczynski M, Iacobone M & Sitges-Serra A. Surgical strategy Savi L, Borba VZ & Moreira CA. Hypoparathyroidism and for sporadic primary hyperparathyroidism an evidence-based pseudohypoparathyroidism: etiology, laboratory features approach to surgical strategy, patient selection, surgical access, and andcomplications. Archives of Endocrinology and Metabolism 2016 60 reoperations. Langenbeck’s Archives of Surgery 2009 394 785–798. 532–536. (https:// doi.org/10.1590/2359-3997000000221) (https://doi.org/10.1007/s00423-009-0529-1) 155 Winer KK, Ko CW, Reynolds JC, Dowdy K, Keil M, Peterson D, 149 Zini M, Attanasio R, Cesareo R, Emmolo I, Frasoldati A, Gianotti L, Gerber LH, McGarvey C & Cutler GB, Jr. Long-term treatment Guglielmi R, Piovesan A, Procopio M, Scillitani A et al. AME position of hypoparathyroidism: a randomized controlled study European Journal of Endocrinology statement: primary hyperparathyroidism in clinical practice. comparingparathyroid hormone-(1-34) versus calcitriol and calcium. Journal of Endocrinological Investigation 2012 35 2–21. (https://doi. Journal of Clinical Endocrinology & Metabolism 2003 88 4214–4220. org/10.1007/BF03345413) (https://doi.org/10.1210/jc.2002-021736) Received 27 April 2019 Revised version received 3 June 2019 Accepted 7 June 2019 https://eje.bioscientifica.com