Parathyroidectomy: still the best choice for the management of severe secondary hyperparathyroidism.

INTRODUCTION: Management of secondary hyperparathyroidism (SHPT) is a challenging endeavor with several factors contruibuting to treatment failure. Calcimimetic therapy has revolutionized the management of SHPT, leading to changes in indications and appropriate timing of parathyroidectomy (PTX) around the world. METHODS: We compared response rates to clinical vs. surgical approaches to SHPT in patients on maintenance dialysis (CKD 5D) and in kidney transplant patients (Ktx). A retrospective analysis of the one-year follow-up findings was carried out. CKD 5D patients were divided into 3 groups according to treatment strategy: parathyroidectomy, clinical management without cinacalcet (named standard - STD) and with cinacalcet (STD + CIN). Ktx patients were divided into 3 groups: PTX, CIN (cinacalcet use), and observation (OBS). RESULTS: In CKD 5D we found a significant parathormone (PTH) decrease in all groups. Despite all groups had a higher PTH at baseline, we identified a more pronounced reduction in the PTX group. Regarding severe SHPT, the difference among groups was evidently wider: 31%, 14% and 80% of STD, STD + CIN, and PTX groups reached adequate PTH levels, respectively (p<0.0001). Concerning the Ktx population, although the difference was not so impressive, a higher rate of success in the PTX group was also observed. CONCLUSION: PTX still seems to be the best treatment choice for SHPT, especially in patients with prolonged diseases in unresourceful scenarios.

Safety of cinacalcet in children and adolescents with chronic kidney disease-mineral bone disorder: systematic review and proportional meta-analysis of case series.

BACKGROUND: Mineral and bone disease in children with chronic kidney disease can cause abnormalities in calcium, phosphorus, parathyroid hormone, and vitamin D and when left untreated can result in impaired growth, bone deformities, fractures, and vascular calcification. Cinacalcet is a calcimimetic widely used as a therapy to reduce parathyroid hormone levels in the adult population, with hypocalcemia among its side effects. The analysis of safety in the pediatric population is questioned due to the scarcity of randomized clinical trials in this group. OBJECTIVE: To assess the onset of symptomatic hypocalcemia or other adverse events (serious or non-serious) with the use of cinacalcet in children and adolescents with mineral and bone disorder in chronic kidney disease. DATA SOURCES AND STUDY ELIGIBILITY CRITERIA: The bibliographic search identified 2699 references from 1927 to August/2023 (57 LILACS, 44 Web of Science, 686 PubMed, 131 Cochrane, 1246 Scopus, 535 Embase). Four references were added from the bibliography of articles found and 12 references from the gray literature (Clinical Trials). Of the 77 studies analyzed in full, 68 were excluded because they did not meet the following criteria: population, types of studies, medication, publication types and 1 article that did not present results (gray literature). PARTICIPANTS AND INTERVENTIONS: There were 149 patients aged 0-18 years old with Chronic Kidney Disease and mineral bone disorder who received cinacalcet. STUDY APPRAISAL AND SYNTHESIS METHODS: Nine eligible studies were examined for study type, size, intervention, and reported outcomes. RESULTS: There was an incidence of 0.2% of fatal adverse events and 16% of serious adverse events (p < 0.01 and I2 = 69%), in addition to 10.7% of hypocalcemia, totaling 45.7% of total adverse events. LIMITATIONS: There was a bias in demographic information and clinical characteristics of patients in about 50% of the studies and the majority of the studies were case series. CONCLUSIONS AND IMPLICATIONS OF KEY FINDINGS: If used in the pediatric population, the calcimimetic cinacalcet should be carefully monitored for serum calcium levels and attention to possible adverse events, especially in children under 50 months. SYSTEMATIC REVIEW REGISTRATION NUMBER (PROSPERO REGISTER): CRD42019132809.

Cost-effectiveness analysis of cinacalcet vs. paricalcitol in the treatment of hyperparathyroidism secondary to chronic kidney disease.

INTRODUCTION: For the reduction of PTH levels, two classes of drugs are available in the Brazilian market: non-selective and selective vitamin D receptor activators and calcimimetics. Among the mentioned drugs, the SUS provides oral calcitriol, paricalcitol and cinacalcet. OBJECTIVES: Develop cost-effectiveness (CE) and budgetary impact (BI) analysis of cinacalcet versus paricalcitol for patients on dialysis with SHPT, from the perspective of SUS. METHODOLOGY: A decision tree model was constructed for CE analysis, which considered the outcome of avoided parathyroidectomy and a time horizon of 1 year. As for the BI analysis, two scenarios were considered, one of which was measured demand and other epidemiological, based on data from the Brazilian Society of Nephrology (BSN). RESULTS: The CE analysis showed that the use of cinacalcet results in one-off savings of R$1,394.64 per year and an incremental effectiveness of 0.08, in relation to avoided parathyroidectomy. The incremental CE ratio (ICER) was - R$ 17,653.67 per avoided parathyroidectomy for cinacalcet, as it was more effective and cheaper compared to paricalcitol. As for the BI analysis, it was estimated that the incremental BI with the expansion of the use of cinacalcet in the SUS will be between - R$ 1,640,864.62 and R$ 166,368.50 in the first year, considering the main and the epidemiological scenarios. At the end of 5 years after the expansion of use, an BI was estimated between - R$ 10,740,743.86 and - R$ 1,191,339.37; considering the same scenarios. CONCLUSION: Cinacalcet was dominant to avoid parathyroidectomies, being cost-effective.

Medical management of primary hyperparathyroidism.

Primary hyperparathyroidism (PHPT) is an endocrine disorder resulting from the hyperfunction of one or more parathyroid glands, with hypersecretion of parathyroid hormone (PTH). It can be managed by parathyroidectomy (PTX) or non-surgically. Medical therapy with pharmacological agents is an alternative for those patients with asymptomatic PHPT who meet guidelines for surgery but are unable or unwilling to undergo PTX. In this review, we focus upon these non-surgical aspects of PHPT management. We emphasize the most studied and widely used pharmacological alternatives: bisphosphonates, denosumab, cinacalcet and hormone therapy, in addition to combined therapy. We also address the relevant aspects of perioperative management.

Cinacalcete para o tratamento de pacientes com hiperparatireoidismo secundário à doença renal crônica estágio 5D / Cinacalcet for the treatment of patients with hyperparathyroidism secondary to kidney disease chronic stage 5d

INTRODUÇÃO: O hiperparatireoidismo secundário (HPTS) à doença crônica renal (DRC) é caracterizado por elevados níveis séricos de paratormônio (PTH), hiperplasia das glândulas paratireoides, doença óssea de alto remanejamento e doença cardiovascular. O nível de PTH considerado adequado para pacientes com DRC estágio 5D está situado entre 150 e 300 pg/ml ou duas a nove vezes o valor limite do método de dosagem. Segundo o censo da Sociedade Brasileira de Nefrologia (SBN), em 2020, estima-se que 144.779 pacientes se encontram em tratamento dialítico no Brasil. Destes, aproximadamente 18% apresentavam níveis de PTH acima de 600 pg/mL em 2019, enquanto em 2014 eram em torno de 26%, sugerindo que houve certo impacto na redução dos níveis de PTH com a incorporação do paricalcitol e cinacalcete e implementação do PCDT em 2017. Para a redução dos níveis do PTH, estão disponíveis no mercado brasileiro três classes de medicamentos: ativadores não seletivos do receptor da vitamina D (calcitriol e alfacalcidol), ativadores seletivos de VDR (paricalcitol) e calcimi

Familial hypocalciuric hypercalcemia as a differential diagnosis of primary hyperparathyroidism with negative images / Hipercalcemia hipocalciúrica familiar como diagnóstico diferencial de hiperparatiroidismo primario con imágenes negativas / Hipercalcemia hipocalciúrica familiar como diagnóstico diferencial de hiperparatireoidismo primário com imagens negativas

Introduction. Familial hypocalciuric hypercalcemia is a rare inherited calcium metabolism disorder in which an alteration of the parathyroid hormone secretion set-point causes hypercalcemia with relative hypocalciuria. Some data suggest that its prevalence is around 74.1 per 100,000 inhabitants. Often, patients are asymptomatic. However, they can develop mild symptoms and an overactive parathyroid adenoma, its main differential diagnosis. The objective was to describe a patient's case and highlight the importance of clinical suspicion and diagnosis to avoid unnecessary surgical neck explorations for parathyroid adenomas. Case report. This is the case of a 40-year-old man with a biochemical profile compatible with primary hyperparathyroidism with anatomical and functional images negative for adenoma and a calcium/creatinine clearance ratio below 0.001, considering familial hypocalciuric hypercalcemia. Genetic studies evidence a mutation in the calcium sensor receptor gene and confirm the diagnosis. Discussion. Familial hypocalciuric hypercalcemia's main differential diagnosis is an overactive parathyroid adenoma. For both, mild or no symptoms may be present; serum calcium exceeds the upper limit, and parathormone is more than 25pg/ml. The calcium/creatinine clearance ratio should be used to differentiate one from the other and avoid unnecessary surgical neck explorations. Besides the lack of information on this topic, evidence supports the use of calcimimetics to treat symptomatic hypercalcemia. Conclusions. Patients with mild hypercalcemia with parathyroid hormone readings above 25pg/ml and a calcium/creatinine clearance ratio below 0.001, or patients with primary hyperparathyroidism with negative imaging, should not undergo surgical neck explorations. In these cases, familial hypocalciuric hypercalcemia is a reliable diagnosis; Cinacalcet may be administered in cases of symptomatic hypercalcemia.

Introducción. La hipercalcemia hipocalciúrica familiar es un trastorno hereditario poco común del metabolismo del calcio en donde una alteración del punto de ajuste de la secreción de hormona paratiroidea ocasiona hipercalcemia con hipocalciuria relativa. Algunos datos sugieren que su prevalencia es de alrededor de 74.1 por 100,000 habitantes. Los pacientes muchas veces son asintomáticos. Sin embargo, pueden desarrollar síntomas leves y un adenoma paratiroideo hiperactivo, que representa su principal diagnóstico diferencial. El objetivo fue describir el caso de un paciente y resaltar la importancia de la sospecha y el diagnóstico clínico para evitar exploraciones quirúrgicas cervicales innecesarias en búsqueda de adenomas paratiroideos. Reporte de caso. Este es el caso de un hombre de 40 años con un perfil bioquímico compatible con hiperparatiroidismo primario, con imágenes anatómicas y funcionales negativas para adenoma, además de una relación de depuración de calcio/creatinina menor a 0.001, con consideración de hipercalcemia hipocalciúrica familiar. Los estudios genéticos evidencian una mutación en el gen del receptor sensor del calcio y confirman el diagnóstico. Discusión. El principal diagnóstico diferencial de la hipercalcemia hipocalciúrica familiar es un adenoma paratiroideo hiperactivo. En ambos casos, es posible que no haya síntomas o que estos sean leves; el calcio sérico excede al límite superior, y la paratohormona es mayor de 25pg/ml. Se debe usar la relación de depuración de calcio/creatinina para diferenciar entre estas patologías y evitar exploraciones quirúrgicas cervicales innecesarias. Aparte de la falta de información sobre este tema, la evidencia apoya el uso de calciomiméticos para tratar la hipercalcemia sintomática. Conclusiones. Los pacientes con hipercalcemia leve, con valores de hormona paratiroidea mayores de 25pg/ml y con una relación de depuración de calcio/creatinina menor de 0.001, o los pacientes con hiperparatiroidismo primario con imágenes negativas, no deben ser sometidos a exploraciones quirúrgicas cervicales. En estos casos, la hipercalcemia hipocalciúrica familiar representa un diagnóstico confiable; se puede administrar Cinacalcet en casos de hipercalcemia sintomática.

Introdução. A hipercalcemia hipocalciúrica familiar é um distúrbio hereditário raro do metabolismo do cálcio, no qual uma alteração no ponto de ajuste da secreção do hormônio da paratireóide causa hipercalcemia com hipocalciúria relativa. Alguns dados sugerem que sua prevalência gira em torno de 74.1 por 100,000 habitantes. Os pacientes geralmente são assintomáticos. No entanto, eles podem desenvolver sintomas leves e um adenoma de paratireoide hiperativo, que representa seu principal diagnóstico diferencial. O objetivo foi descrever o caso de um paciente e destacar a importância da suspeita clínica e do diagnóstico para evitar exploração cirúrgica cervical desnecessária em busca de adenomas de paratireoide. Relato de caso. É o caso de um homem de 40 anos com perfil bioquímico compatível com hiperparatireoidismo primário, com imagens anatômicas e funcionais negativas para adenoma, além de relação depuração de cálcio/creatinina menor que 0.001, considerando hipercalcemia hipocalciúrica familiar. Estudos genéticos revelam uma mutação no gene receptor da sensibilidade ao cálcio e confirmam o diagnóstico. Discussão. O principal diagnóstico diferencial da hipercalcemia hipocalciúrica familiar é um adenoma de paratireoide hiperativo. Em ambos os casos, os sintomas podem estar ausentes ou leves; o cálcio sérico excede o limite superior e o hormônio da paratireóide é superior a 25pg/ml. A relação depuração de cálcio/creatinina deve ser usada para diferenciar entre essas patologias e evitar exploração cirúrgica cervical desnecessária. Além da falta de informações sobre esta questão, as evidências apoiam o uso de calcimiméticos para tratar a hipercalcemia sintomática. Conclusões. Pacientes com hipercalcemia leve, com valores de hormônio da paratireóide maiores que 25pg/ml e uma relação de depuração de cálcio/creatinina menor que 0.001, ou pacientes com hiperparatireoidismo primário com imagens negativas, não devem ser submetidos a exploração cirúrgica cervical. Nesses casos, a hipercalcemia hipocalciúrica familiar representa um diagnóstico confiável; Cinacalcet pode ser administrado em casos de hipercalcemia sintomática.

Judicialização do cinacalcete no estado do Rio de Janeiro / Judicialization of cinacalcet in Rio de Janeiro State

Objetivo: Analisar a judicialização do cinacalcete no estado do Rio de Janeiro e estimar o seu impacto no orçamento do estado do Rio de Janeiro no ano de 2015. Métodos: Estudo transversal descritivo que analisou os pareceres técnicos emitidos pelo Núcleo de Assessoria Técnica em Ações de Saúde do Tribunal de Justiça do Rio de Janeiro entre 2009 e 2016. Realizou-se uma busca no banco de licitações da Secretaria de Estado de Saúde do Rio de Janeiro para encontrar o valor pago por esse medicamento em 2015. Resultados: Entre 2009 e 2015, esse núcleo elaborou 23.852 pareceres, com 1.553 relacionados ao cinacalcete, sendo 359 em 2015. Entre os autores, 88% residiam na capital deste estado, 50,4% eram mulheres, 46% tinham renda entre 1 e 3 salários mínimos. A decisão judicial foi favorável ao autor em 100% dos processos. Conclusão: Em 2015, foram gastos cerca de 3,7 milhões de reais para compra desse medicamento, o que equivale a 2,5% dos recursos destinados à assistência farmacêutica do estado do Rio de Janeiro neste ano, caracterizando um elevado impacto no orçamento da saúde

Objective: Analyze the judicialization of cinacalcet in Rio de Janeiro and estimate its impact on the budget of Rio de Janeiro State in 2015. Methods: It is a cross sectional study that analyzed the technical reports issued by the Technical Advisory Core of the Court of Justice in Rio de Janeiro between 2009 and 2016. It was realized a search in the bids database of Health Secretary of Rio de Janeiro state to define the value spent for this drug in 2015. Results: Between 2009 and 2015, the Core Technical Advisory prepared 23,852 reports, 1,553 of them related to cinacalcet, 359 in 2015. Among the authors, 88% were living in the capital of Rio de Janeiro, 50.4% were women, 46% with income between 1 and 3 minimum wages. The court decision was favorable to the author in 100% of the processes. Conclusion: In 2015, about R$ 3.7 million were spent, which is equivalent to 2.5% of the resources destined to pharmaceutical assistance in Rio de Janeiro at that year, causing a high impact in the health's budget

Therapy for persistent hypercalcemic hyperparathyroidism post-renal transplant: cinacalcet versus parathyroidectomy / Tratamento do hiperparatireoidismo hipercalcêmico persistente pós-transplante renal: cinacalcete versus paratireoidectomia

ABSTRACT Background: Persistent hyperparathyroidism post-transplant is associated with increases in the incidence of cardiovascular events, fractures, and deaths. The aim of this study was to compare both therapeutic options available: parathyroidectomy (PTX) and the calcimimetic agent cinacalcet. Methods: A single center retrospective study including adult renal transplant recipients who developed hypercalcemia due to persistent hyperparathyroidism. Inclusion criteria: PTH > 65 pg/mL with serum calcium > 11.5 mg/dL at any time after transplant or serum calcium persistently higher than 10.2 mg/dL one year after transplant. Patients treated with cinacalcet (n=46) were compared to patients treated with parathyroidectomy (n=30). Follow-up period was one year. Clinical and laboratory data were analyzed to compare efficacy and safety of both therapeutic modalities. Results: PTX controlled calcemia faster (month 1 x month 6) and reached significantly lower levels at month 12 (9.1±1.2 vs 9.7±0.8 mg/dL, p < 0.05); PTX patients showed significantly higher levels of serum phosphate (3.8±1.0 vs 2.9±0.5 mg/dL, p < 0.05) and returned PTH to normal levels (45±51 pg/mL). Cinacalcet, despite controlling calcium and phosphate in the long term, decreased but did not correct PTH (197±97 pg/mL). The proportion of patients that remained with PTH above normal range was 95% in the cinacalcet group and 22% in the PTX group. Patients treated with cinacalcet had better renal function (creatinine 1.2±0.3 vs 1.7±0.7 mg/dL, p < 0.05). Conclusions: Surgical treatment was superior to cinacalcet to correct the metabolic disorders of hyperparathyroidism despite being associated with worse renal function in the long term. Cinacalcet proved to be a safe and well tolerated drug.

RESUMO Introdução: O hiperparatireoidismo persistente pós-transplante está associado a aumento na incidência de eventos cardiovasculares, fraturas e óbitos. O objetivo deste estudo foi comparar as opções terapêuticas disponíveis: paratireoidectomia (PTX) e o agente calcimimético cinacalcete. Métodos: Estudo retrospectivo de um único centro incluiu pacientes transplantados renais adultos que desenvolveram hipercalcemia devido a hiperparatireoidismo persistente. Critérios de inclusão: PTH > 65 pg/mL com cálcio sérico > 11,5 mg/dL a qualquer momento após o transplante, ou cálcio sérico persistentemente superior a 10,2 mg/dL um ano após o transplante. Os pacientes tratados com cinacalcete (n = 46) foram comparados aos pacientes tratados com paratireoidectomia (n = 30). O período de acompanhamento foi de um ano. Dados clínicos e laboratoriais foram analisados para comparar a eficácia e a segurança de ambas as modalidades terapêuticas. Resultados: a PTX controlou a calcemia mais rapidamente (mês 1 x mês 6) e atingiu níveis significativamente mais baixos no mês 12 (9,1 ± 1,2 v.s. 9,7 ± 0,8 mg/dL, p < 0,05); pacientes submetidos à PTX apresentaram níveis significativamente mais altos de fósforo sérico (3,8 ± 1,0 v.s. 2,9 ± 0,5 mg/dL, p < 0,05) e retornaram aos níveis normais de PTH (45 ± 51 pg/mL). O cinacalcete, apesar de controlar o cálcio e o fósforo no longo prazo, diminuiu, mas não corrigiu o PTH (197 ± 97 pg/mL). A proporção de pacientes que permaneceram com PTH acima da faixa normal foi de 95% no grupo cinacalcete e 22% no grupo PTX. Os pacientes tratados com cinacalcete apresentaram melhor função renal (creatinina 1,2 ± 0,3 v.s. 1,7 ± 0,7 mg/dL, p < 0,05). Conclusões: O tratamento cirúrgico foi superior ao cinacalcete para corrigir os distúrbios metabólicos do hiperparatireoidismo, apesar de estar associado a pior função renal no longo prazo. Cinacalcete provou ser um medicamento seguro e bem tolerado.

Therapy for persistent hypercalcemic hyperparathyroidism post-renal transplant: cinacalcet versus parathyroidectomy.

BACKGROUND: Persistent hyperparathyroidism post-transplant is associated with increases in the incidence of cardiovascular events, fractures, and deaths. The aim of this study was to compare both therapeutic options available: parathyroidectomy (PTX) and the calcimimetic agent cinacalcet. METHODS: A single center retrospective study including adult renal transplant recipients who developed hypercalcemia due to persistent hyperparathyroidism. Inclusion criteria: PTH > 65 pg/mL with serum calcium > 11.5 mg/dL at any time after transplant or serum calcium persistently higher than 10.2 mg/dL one year after transplant. Patients treated with cinacalcet (n=46) were compared to patients treated with parathyroidectomy (n=30). Follow-up period was one year. Clinical and laboratory data were analyzed to compare efficacy and safety of both therapeutic modalities. RESULTS: PTX controlled calcemia faster (month 1 x month 6) and reached significantly lower levels at month 12 (9.1±1.2 vs 9.7±0.8 mg/dL, p < 0.05); PTX patients showed significantly higher levels of serum phosphate (3.8±1.0 vs 2.9±0.5 mg/dL, p < 0.05) and returned PTH to normal levels (45±51 pg/mL). Cinacalcet, despite controlling calcium and phosphate in the long term, decreased but did not correct PTH (197±97 pg/mL). The proportion of patients that remained with PTH above normal range was 95% in the cinacalcet group and 22% in the PTX group. Patients treated with cinacalcet had better renal function (creatinine 1.2±0.3 vs 1.7±0.7 mg/dL, p < 0.05). CONCLUSIONS: Surgical treatment was superior to cinacalcet to correct the metabolic disorders of hyperparathyroidism despite being associated with worse renal function in the long term. Cinacalcet proved to be a safe and well tolerated drug.

Eficacia y seguridad de cinacalcet en el tratamiento de pacientes adultos con hiperparatiroidismo primario con hipercalcemia persistente pese a terapia quirúrgica / Efficacy and safety of cinacalcet in the treatment of adult patients with primary hyperparathyroidism with persistent hypercalcaemia despite surgical therapy

INTRODUCCIÓN: El presente dictamen expone la evaluación de la eficacia y seguridad de cinacalcet 30mg administrada VO, para el tratamiento de pacientes adultos con diagnóstico de Hiperparatiroidismo Primario (HPTP) con hipercalcemia persistente pese a terapia quirúrgica (Paratiroidectomía). El hiperparatiroidismo primario (HPTP) es una enfermedad que involucra a una o más glándulas paratiroides, responsables de la producción de la hormona paratiroidea (PTH) y que afecta directamente el control normal de los niveles de calcio en sangre. Un paciente con HPTP produce altos niveles de PTH y calcio en sangre (hipercalcemia) así como altos niveles de calcio en orina. Durante la hipercalcemia, el calcio liberado de los huesos con el tiempo puede desencadenar en osteoporosis, cálculos renales y reducción en la función renal. Este trastorno se da en aproximadamente 1 % de la población adulta, pero afecta a más del 2 % de la misma después de los 55 años y especialmente a mujeres. La paratiroidectomía (PTx) es la terapia de elección para el HPTP con una tasa de curación cercana al 95 %. Esta consiste en una intervención quirúrgica para extraer una o más glándulas paratiroides, realizando previamente un diagnóstico y evaluación por imágenes. No obstante, existe una proporción de pacientes que no responden a la terapia quirúrgica, persistiendo con la sintomatología propia de la enfermedad y la hipercalcemia, los cuales son diagnosticados como pacientes con terapia quirúrgica fallida (PTx fallida) o fracaso quirúrgico. Actualmente, en EsSalud no se cuenta con un tratamiento farmacológico alternativo para dichos pacientes, en quienes la terapia convencional y de mayor beneficio (i.e., PTx) no funciona. Es por ello que existe la necesidad de evaluar otras alternativas farmacológicas que podrían ser de beneficio para éstos pacientes. METODOLOGÍA: Se llevó a cabo una búsqueda sistemática de la literatura con respecto a la eficacia y seguridad de Cinacalcet para el tratamiento de pacientes adultos con hiperparatiroidismo primario con hipercalcemia persistente pese a terapia quirúrgica. Se empleó además un motor de búsqueda para las bases de datos de PubMed-Medline, the Cochrane Library, LILACS y SciELO. La búsqueda se enfocó en guías de práctica clínica (GPC), evaluaciones de tecnologías sanitarias (ETS) y revisiones sistemáticas (RS) con o sin meta-análisis (MA), identificándose términos en lenguaje simple, así como términos MeSH2 relacionados a la población de interés, la intervención según la pregunta PICO especificada". RESULTADOS: Los resultados se han obtenido a partir de los desenlaces que se encuentran en la pregunta PICO. No se incluyeron, por ningún motivo, resultados que no están enmarcados en la pregunta PICO. De acuerdo con la pregunta PICO, se llevó a cabo una búsqueda de evidencia científica relacionada al uso de Cinacalcet como tratamiento de pacientes con HPTP con Hipercalcemia persistente pese a terapia quirúrgica. En la presente sinopsis se describe la evidencia disponible según el tipo de publicación, siguiendo lo indicado en los criterios de elegibilidad (GPC, ETS, RS, MA y ECA fase III). CONCLUSIONES: El presente dictamen preliminar tuvo como objetivo evaluar la evidencia disponible en relación a la eficacia y seguridad de cinacalcet 30 mg VO para el tratamiento de pacientes con HPTP con hipercalcemia persistente pese a terapia quirúrgica.  Luego de realizar una búsqueda sistemática de la literatura, se identificaron y consideraron para el presente dictamen 4 GPC, una ETS y un solo ECA que evaluaron la eficacia de cinacalcet en pacientes con HPTP y con hipercalcemia no quirúrgicos. Tres de estas GPC coinciden en que cinacalcet es una opción terapéutica para el tratamiento de pacientes con HPTP con hipercalcemia que no se someten a terapia quirúrgica por algunas de las razones antes mencionada; y una GPC no reportó ninguna recomendación sobre el uso de cinacalcet u otro tratamiento más allá que realizar procedimientos más invasivos a fin evaluar mejor al paciente y buscar otras causas de hiperparatiroidismo secundario. Así mismo, la ETS elaborada por el NHS del Reino Unido, aprueba la disponibilidad del uso de cinacalcet para pacientes con HPTP con PTx fallida como opción terapéutica frente a la falla de la terapia convencional. El ECA desarrollado por Peacock, muestra la eficacia de cinacalcet comparada con placebo para la disminución de los niveles de calcio sérico llevándolo a niveles normales (8.5 ­ 10.5 mg/dl) y una reducción de 0.5 mg/dl (0.12 mmol/litro) del valor basal, estadísticamente significativos, mostrando que en el grupo que recibió cinacalcet los niveles de calcio bajaron hasta estar dentro de ,os valores normales dentro de las primeras 2 semanas y manteniéndose constante a lo largo de todo el periodo de seguimiento a diferencia del grupo placebo que mantuvo la hipercalcemia a lo largo del seguimiento (10.9 mng/dl). Se reportaron efectos adversos leves como náuseas y vómitos, los cuales fueron de igual proporción entre el grupo de intervención y el grupo control. Y que a pesar de las limitaciones existentes cinacalcet ofrece una alternativa de tratamiento para estos pacientes. Existe una proporción de pacientes que, a pesar de someterse a PTx, la terapia de elección para HPTP con una tasa de curación cercana al 95%, persiste con hipercalcemia. Frente a ello, actualmente EsSalud no cuenta con alguna alternativa de tratamiento farmacológico para controlar los niveles de calcio de manera gradual y segura, cuando la PTx es fallida, más allá de un seguimiento y evaluación constante del paciente por lo que surge la necesidad de evaluar otras alternativas de tratamientos. Consideramos en ese sentido, que a pesar de las limitaciones que pueda presentar la evidencia encontrada y teniendo el antecedente de aprobación de uso de cinacalcet para el tratamiento de hipercalcemia en pacientes con HPTS en la institución, se tiene experiencia de uso de este fármaco. Así podemos concluir que, cinacalcet supondría una alternativa de tratamiento para el control de los pacientes con HPTP que no responden a terapia quirúrgica. Por lo expuesto, el Instituto de Evaluaciones de Tecnologías en Salud e Investigación ­ IETSI aprueba el uso de cinacalcet para el manejo de los pacientes con diagnóstico de HPTP con hipercalcemia persistente pese a terapia quirúrgica. La vigencia del presente dictamen preliminar es de un año a partir de la publicación. Así, la continuación de dicha aprobación estará sujeta a los resultados obtenidos de los pacientes que reciban este tratamiento, a los reportes de seguridad que puedan surgir durante farmacovigilancia activa y nueva evidencia que pueda surgir en el tiempo.

The impact of cinacalcet in the mineral metabolism markers of patients on dialysis with severe secondary hyperparathyroidism / Impacto de cinacalcete em marcadores do metabolismo mineral de pacientes em diálise portadores de hiperparatireoidismo secundário grave

Abstract Introduction: Treating secondary hyperparathyroidism (SHPT), a common condition associated with death in patients with chronic kidney disease, is a challenge for nephrologists. Calcimimetics have allowed the introduction of drug therapies no longer based on phosphate binders and active vitamin D. This study aimed to assess the safety and effectiveness of cinacalcet in managing chronic dialysis patients with severe SHPT. Methods: This retrospective study included 26 patients [age: 52 ± 12 years; 55% females; time on dialysis: 54 (4-236) months] on hemodialysis (N = 18) or peritoneal dialysis (N = 8) with severe SHPT (intact parathyroid hormone (iPTH) level > 600 pg/mL) and hyperphosphatemia and/or persistent hypercalcemia treated with cinacalcet. The patients were followed for 12 months. Their serum calcium (Ca), phosphorus (P), alkaline phosphatase (ALP), and iPTH levels were measured at baseline and on days 30, 60, 90, 180, and 365. Results: Patients with hyperphosphatemia (57.7%), hypercalcemia (23%), or both (19.3%) with iPTH > 600 pg/mL were prescribed cinacalcet. At the end of the study, decreases were observed in iPTH (1348 ± 422 vs. 440 ± 210 pg/mL; p < 0.001), Ca (9.5 ± 1.0 vs. 9.1 ± 0.6 mg/dl; p = 0.004), P (6.0 ± 1.3 vs. 4.9 ± 1.1 mg/dl; p < 0.001), and ALP (202 ± 135 vs. 155 ± 109 IU/L; p = 0.006) levels. Adverse events included hypocalcemia (26%) and digestive problems (23%). At the end of the study, 73% of the patients were on active vitamin D and cinacalcet. Three (11.5%) patients on peritoneal dialysis did not respond to therapy with cinacalcet, and their iPTH levels were never below 800 pg/mL. Conclusion: Cinacalcet combined with traditional therapy proved safe and effective and helped manage the mineral metabolism of patients with severe SHPT.

Resumo Introdução: O tratamento do hiperparatireoidismo secundário (HPTs), patologia comum e associada à mortalidade na doença renal crônica, é um desafio para o nefrologista. Advento dos calcimiméticos propiciou terapêutica medicamentosa diferente da usual, baseada em quelantes de fósforo e vitamina D ativa. O objetivo deste estudo foi avaliar segurança e efetividade de cinacalcete no controle do HPTs grave de pacientes em diálise crônica. Métodos: Estudo retrospectivo 26 pacientes [idade: 52 ± 12 anos; 55% mulheres; tempo em diálise: 54 (4-236) meses], em hemodiálise (N = 18) ou diálise peritoneal (N = 8), com HPTs grave (nível de paratormônio intacto (PTHi) > 600 pg/mL), com hiperfosfatemia e/ou hipercalcemia persistentes, em tratamento com cinacalcete. Período de seguimento de 12 meses. Avaliados níveis séricos de cálcio (Ca), fósforo (P), fosfatase alcalina (FA) e PTHi no início do seguimento, 30, 60, 90, 180 e 365 dias. Resultados: Indicações para início do cinacalcete: hiperfosfatemia (57,7%), hipercalcemia (23%), ou ambos (19,3%) com PTH > 600 pg/mL. Ao final do seguimento, observada redução dos níveis PTHi (1348 ± 422 vs. 440 ± 210 pg/mL; p < 0,001), Ca (9,5 ± 1,0 vs. 9,1 ± 0,6 mg/dl; p = 0,004), P (6,0 ± 1,3 vs. 4,9 ± 1,1 mg/dl; p < 0,001) e FA (202 ± 135 vs. 155 ± 109 UI/L; p = 0,006). Eventos adversos: hipocalcemia (26%) e queixas digestivas (23%). No fim do estudo, 73% pacientes utilizavam vitamina D ativada associada ao cinacalcete. Três (11,5%) pacientes, todos em DP, não responderam ao cinacalcete, mantendo níveis PTHi > 800 pg/mL. Conclusão: Utilização de cinacalcete, associado à terapia tradicional, em pacientes com HPTs grave foi segura, eficiente e associada a melhor controle do metabolismo mineral.

The impact of cinacalcet in the mineral metabolism markers of patients on dialysis with severe secondary hyperparathyroidism.

INTRODUCTION: Treating secondary hyperparathyroidism (SHPT), a common condition associated with death in patients with chronic kidney disease, is a challenge for nephrologists. Calcimimetics have allowed the introduction of drug therapies no longer based on phosphate binders and active vitamin D. This study aimed to assess the safety and effectiveness of cinacalcet in managing chronic dialysis patients with severe SHPT. METHODS: This retrospective study included 26 patients [age: 52 ± 12 years; 55% females; time on dialysis: 54 (4-236) months] on hemodialysis (N = 18) or peritoneal dialysis (N = 8) with severe SHPT (intact parathyroid hormone (iPTH) level > 600 pg/mL) and hyperphosphatemia and/or persistent hypercalcemia treated with cinacalcet. The patients were followed for 12 months. Their serum calcium (Ca), phosphorus (P), alkaline phosphatase (ALP), and iPTH levels were measured at baseline and on days 30, 60, 90, 180, and 365. RESULTS: Patients with hyperphosphatemia (57.7%), hypercalcemia (23%), or both (19.3%) with iPTH > 600 pg/mL were prescribed cinacalcet. At the end of the study, decreases were observed in iPTH (1348 ± 422 vs. 440 ± 210 pg/mL; p < 0.001), Ca (9.5 ± 1.0 vs. 9.1 ± 0.6 mg/dl; p = 0.004), P (6.0 ± 1.3 vs. 4.9 ± 1.1 mg/dl; p < 0.001), and ALP (202 ± 135 vs. 155 ± 109 IU/L; p = 0.006) levels. Adverse events included hypocalcemia (26%) and digestive problems (23%). At the end of the study, 73% of the patients were on active vitamin D and cinacalcet. Three (11.5%) patients on peritoneal dialysis did not respond to therapy with cinacalcet, and their iPTH levels were never below 800 pg/mL. CONCLUSION: Cinacalcet combined with traditional therapy proved safe and effective and helped manage the mineral metabolism of patients with severe SHPT.

Osteoactivos en insuficiencia renal crónica avanzada: a propósito de un caso / Osteoactive in advanced chronic renal failure: a case report

El propósito de la terapia en el desorden del metabolismo óseo mineral asociado a la enfermedad renal crónica (IRC) consiste en restaurar el balance mineral, y, en la osteoporosis, mantener o aumentar la masa ósea. Ambas terapias tratan de evitar la fractura ósea. La mayoría de los osteoactivos están contraindicados en la insuficiencia renal crónica avanzada (estadios 4 y 5), y las terapias son empíricas. Algunos autores opinan que sin anomalías bioquímicas del desorden del metabolismo óseo mineral asociado a la enfermedad renal crónica avanzada se podría intentar el tratamiento estándar para la osteoporosis. Antes de intentar la terapia osteoactiva se debe corregir el desorden mineral óseo que pudiera presentarse asociado a la IRC, y en la indicación del tipo de osteoactivo se sugiere seleccionar al paciente según su estado óseo. Se aconseja que la administración de los antirresortivos se realice a dosis menores con respecto a los que tienen mejor función renal junto con aportes adecuados de calcio y vitamina D, antes y durante el tratamiento para prevenir el riesgo de severas hipocalcemias y un efecto óseo excesivo. Se presenta el caso clínico de una mujer de 65 años, con diagnóstico de osteoporosis de etiología multifactorial, fractura de pelvis, múltiples fracturas vertebrales e insuficiencia renal crónica avanzada, entre otras comorbilidades, y probable enfermedad ósea adinámica. Recibió inicialmente terapia con teriparatide y luego con denosumab, complicándose con hipocalcemia asintomática. (AU)

The purpose of therapy for the bone mineral metabolism disorder associated with chronic kidney disease is to restore the mineral balance; and to maintain or increase bone mass in osteoporosis. The goal of both types of therapy is to avoid bone fractures. Most antiosteoporotic drugs are contraindicated in advanced chronic renal failure (CRF) stages 4 and 5, and the therapies are empirical. Some authors believe that without biochemical abnormalities of the mineral bone metabolism disorder associated with advanced chronic kidney disease, standard treatment for osteoporosis could be attempted. Before attempting antiosteoporotic therapy, the bone mineral disorder that may be associated with CRF must be corrected, and in the indication of the type drug it is suggested that the patient be selected according to their bone status. It is advised that the administration of anti-resorptives be performed at lower doses in individuals with poor renal function compared to those with better renal function together with adequate calcium and vitamin D, before and during treatment to prevent the risk of severe hypocalcemia, and an excessive bone effect. We present the clinical case of a 65-year-old woman with a diagnosis of osteoporosis of multifactorial etiology, pelvic fracture, multiple vertebral fractures and advanced chronic renal failure, among other comorbidities and probable adynamic bone disease. The patient received initial therapy with teriparatide and followed by denosumab administration and exhibited asymptomatic hypocalcemia. (AU)

Un caso de hipercalcemia hipocalciúrica de causa genética en niño prepúber / Genetic hypercalcemic hypocalciuria in a prepubertal boy

Un paciente de 12 años consultó por vómitos recurrentes asociados con cefaleas, con varios episodios durante 7 meses, y retraso ponderal secundario a esa sintomatología. Había recibido previamente un tratamiento con antibióticos e inhibidores de la bomba de protones, por diagnóstico de gastritis a Helicobacter pylori, después de biopsia gástrica realizada durante una videoendoscopía digestiva alta. Se desconoce su historia familiar porque es hijo adoptivo. Al examen físico el paciente estaba adelgazado, sin tumoración a nivel de cuello; presentaba genitales prepuberales. Como el paciente continuó con vómitos cíclicos recurrentes, siguieron exámenes complementarios donde se constató en 2 oportunidades hipercalcemia (13,2-13,6 mg/dl), acompañada de hipofosfatemia (2,7 mg/dl). Con un diagnóstico presuntivo de hiperparatiroidismo primario se realizaron dosajes de laboratorio: calcemia total e iónica elevada (12,1 y 5,6mg/dl respectivamente), fosfatemia baja (2,8 mg/dl), fosfatasa alcalina sérica normal (151 mU/ml), PTH sérica normal (47,1 pg/ml), 25(OH)vitamina D sérica adecuada (22 ng/ml). La ecografía de glándulas tiroides y paratiroides mostró una imagen redondeada hipoecoica, avascular, de 4 mm axial por 4 mm cefalocaudal, por 3 mm ánteroposterior en topografía paratiroidea derecha, planteándose la posibilidad de hipertrofia paratiroidea versus adenopatía. Se realizó estudio de paratiroides por imágenes: centellograma con 99mTc-MIBI y PET-CT con 18F-colina, pero no se constató captación anormal. Se realizaron nuevos estudios de laboratorio: en orina de 24 horas el calcio era de 19 mg, el cociente calcio/creatinina urinaria 0,03 mg/mg, la reabsorción tubular de fósforo normal (82%) y el cociente de las tasas de depuración de calcio y creatinina muy bajo (0,00046). El CTX sérico era bajo. El diagnóstico clínico fue de hipercalcemia hipocalciúrica; ante la falta de antecedentes familiares, se realizó un estudio de posibles mutaciones puntuales en el gen del receptor de calcio (CaSR), hallándose la presencia en heterocigosis de la mutación p.Arg185Gln (p.R185Q) en la posición 554 (c.554G>A) del exón 4 del gene CaSR. Esto implica el cambio de una arginina por glutamina en el codón 185 de la proteína, y confirma el origen genético de la hipercalcemia hipocalciúrica en nuestro paciente. La edad ósea era de 12 años, y se indicó un tratamiento con testosterona i.m. a bajas dosis para acelerar el desarrollo puberal; luego de 4 aplicaciones mensuales su talla se ha incrementado en 4 cm y su peso en 3 kg. Una aplicación subcutánea de denosumab (60 mg) no controló la hipercalcemia. Continuó por un año con hipoorexia y un episodio de vómitos por semana, pero actualmente tiene buen apetito y excelente tolerancia digestiva. Se le ha prescripto cinacalcet oral (AU)

A 12-year-old patient who consulted for recurrent vomiting associated with headaches, with several episodes for 7 months, and low body weight. The patient had previously received treatment with antibiotics and proton pump inhibitors, due to gastritis with Helicobacter pylori, after gastric biopsy performed during videoendoscopy. His family history is unknown because he is an adopted son. At physical examination the patient was thin, without neck tumor; he had prepubertal genitalia. As he patient continued with recurrent vomiting, he was admitted for further evaluation. Laboratory studies revealed hypercalcemia (13.2-13.6 mg/dl), accompanied by hypophosphatemia (2.7 mg/dl). With a presumptive diagnosis of primary hyperparathyroidism, complementary determinations were performed: total and high total and ionized serum calcium (12.1 and 5.6 mg/dl, respectively), normal serum alkaline phosphatase (151 mU/ml), and PTH (47.1 pg/ml), and normal serum 25(OH) vitamin D (32 ng/ml). The ultrasonography of thyroid and parathyroid glands showed a rounded hypoechoic, avascular image, 4 mm in diameter in the lower right parathyroid topography. A parathyroid imaging studies were performed: scintigraphy with 99mTc-MIBI and PET-CT with 18F-choline, but no abnormal uptake was observed. New laboratory studies were carried out: in 24-hour urine the calcium was 19 mg, the urinary calcium/creatinine ratio was 0.03 mg/mg, the tubular reabsorption of phosphorus was normal (82%) and the ratio of clearances rates of calcium and creatinine very low (0.00046). Serum CTX was low. The clinical diagnosis was hypocalciuric hypercalcemia; in the absence of a family history, a study of possible point mutations in the calcium receptor gene (CaSR) was carried out; there was a heterozygous mutation: p.Arg185Gln (p.R185Q) at position 554 (c.554G)>A) of exon 4 of the CaSR gene. This involves the exchange of an arginine for glutamine at codon 185 of the protein, and confirms the genetic origin of the hypocalciuric hypercalcemia in our patient. Bone age was 12 years, and a treatment with testosterone i.m. at low doses to accelerate pubertal development was started; after 4 monthly applications height has increased by 4 cm and weight by 3 kg. Loss of appetite and a weekly episode of postprandial vomiting continued during one yeas, but now his appetite is normal and vomiting has subsided. A subcutaneous application of denosumab (60 mg) did not control hypercalcemia. He has been prescribed oral cinacalcet (AU)

Autophagy mediates calcium-sensing receptor-induced TNFα production in human preadipocytes.

Obesity is a major current public health problem worldwide due to the severe co-morbid conditions that this disease entails. The development of obesity-related cardiometabolic disorders is in direct association with adipose tissue inflammation that leads to its functional impairment. Activation of the Calcium-Sensing Receptor (CaSR) in adipose tissue contributes to inflammation and adipose dysfunction. Autophagy, a process of cell component degradation, is closely related to inflammation in many diseases, however, whether autophagy is associated with CaSR-induced inflammation remains unknown. Using LS14 and SW872 preadipose cell lines as well as primary human preadipocytes, we show that CaSR activation with the allosteric activator cinacalcet induces autophagosome formation. Cinacalcet-induced LC3II content elevation was precluded by knockdown of the CaSR and enhanced by CaSR overexpression, indicating a specific effect. Autophagy inhibition using 3-methyladenine prevented CaSR-induced TNFα production, indicating that autophagy contributes to CaSR-induced inflammation in human preadipocytes. Our results suggest that modulation of CaSR-induced autophagy is an attractive target in obese inflamed adipose tissue, to prevent the development of diseases triggered by adipose dysfunction. We describe a novel mechanism and possible new target to modulate and prevent adipose inflammation and hence the resulting disease-generating adipose tissue dysfunction.

Crisis hipercalcémica causada por adenoma paratiroideo: reporte de un caso clínico / Hypercalcemic crisis due to parathyroid adenoma: report of a clinical case

La hipercalcemia es un trastorno común que representa aproximadamente el 0,6% de todas las admisiones médicas agudas. El hiperparatiroidismo primario (HPTP) y las neoplasias malignas son las dos causas más comunes de elevación de los niveles séricos de calcio; constituyen, en conjunto, alrededor del 90% de todos los casos. La presentación sintomática clásica de la hipercalcemia se observa con relativa poca frecuencia en el mundo desarrollado; la presentación más común es la detección asintomática en las pruebas bioquímicas. Sin embargo, en casos raros, el HPTP puede desarrollar hipercalcemia aguda, grave y sintomática, llamada crisis hipercalcémica (CH). Esta condición se asocia a alteraciones profundas en el estado mental y las funciones cardíaca, renal y gastrointestinal en presencia de concentraciones marcadamente elevadas de calcio sérico y paratohormona (PTH). Mientras que algunas elevaciones en el calcio sérico pueden ser bien toleradas, los síntomas de la CH son severos. Si el tratamiento se retrasa, la CH puede provocar la muerte. Describimos el caso de un paciente masculino que ingresa en la unidad de cuidados críticos por una CH secundaria a un HPTP por adenoma paratiroideo. (AU)

Hypercalcaemia is a most common disorder, accounting for approximately 0,6% of all acute medical admissions. Primary hyperparathyroidism (PHPT) and malignancy are the two most common causes of increased serum calcium levels, together accounting for about 90% of all cases. The classical symptomatic presentation of hypercalcaemia is seen relatively rarely in the developed world, the most common presentation being asymptomatic and detected following on biochemical testing. However, in rare cases HPTP can result in acute, severe and symptomatic hypercalcemia, called hypercalcemic crisis (HC). This condition is associated with profound disturbances in mental status, and cardiac, renal, and gastrointestinal function in the presence of markedly increased serum calcium and parathyroid hormone (PTH) concentrations. While some elevations in serum calcium can be well tolerated, symptoms of HC are severe. If treatment is delayed, HC can result in death. We describe herein a case of a male patient who was admitted to the intensive care unit as a consequence of HC resulting from elevated PTH, secondary to a parathyroid adenoma. We describe the case of a male patient who was admitted to the critical care unit for a HC mediated by PTH secondary to a parathyroid adenoma. (AU)

Use of cinacalcet and sunitinib to treat hypercalcaemia due to a pancreatic neuroendocrine tumor.

Neuroendocrine tumors (NETs) can secrete hormones, including ectopic secretions, but they have been rarely associated with malignant hypercalcemia. A 52-year-old man with a history of diabetes mellitus was diagnosed with a pancreatic tumor. A pancreatic biopsy confirmed a well-differentiated pancreatic NET (pNET). The patient subsequently developed liver metastasis and hypercalcemia with high 1,25 OH vitamin D and suppressed parathyroid hormone (PTH) levels. Hypercalcemia was refractory to chemotherapy, intravenous saline fluids, diuretics, calcitonin and zoledronate. Cinacalcet administration (120 mg/day) resulted in a significant calcium reduction. Hypocalcemia was observed when sunitinib was added three months later and cinacalcet was stopped. Subsequently, the calcium and PTH levels normalized. After six months, we observed 20% shrinkage of the pancreatic tumor and necrosis of a liver metastasis. Cinacalcet is an allosteric activator of the calcium receptor agonist, and it is used for severe hypercalcemia in patients with primary (benign and malignant) hyperparathyroidism. In this patient, cinacalcet demonstrated a calcium lowering effect, normalized hypophosphatemia, and improved the clinical condition of the patient. The mechanism through which cinacalcet improved PTH-rp mediated hypercalcemia is still unclear, but studies have suggested that a potential mechanism is the activation of calcitonin secretion. Sunitinib is an oral multi-targeted tyrosine kinase inhibitor used to treat advanced pNETs. The hypocalcemic effects of sunitinib have not been previously described in a patient with pNET. Here, we report for the first time the successful combination of cinacalcet and sunitinib in the treatment of a pNET patient presenting with malignant hypercalcemia.

Use of cinacalcet and sunitinib to treat hypercalcaemia due to a pancreatic neuroendocrine tumor

SUMMARY Neuroendocrine tumors (NETs) can secrete hormones, including ectopic secretions, but they have been rarely associated with malignant hypercalcemia. A 52-year-old man with a history of diabetes mellitus was diagnosed with a pancreatic tumor. A pancreatic biopsy confirmed a well-differentiated pancreatic NET (pNET). The patient subsequently developed liver metastasis and hypercalcemia with high 1,25 OH vitamin D and suppressed parathyroid hormone (PTH) levels. Hypercalcemia was refractory to chemotherapy, intravenous saline fluids, diuretics, calcitonin and zoledronate. Cinacalcet administration (120 mg/day) resulted in a significant calcium reduction. Hypocalcemia was observed when sunitinib was added three months later and cinacalcet was stopped. Subsequently, the calcium and PTH levels normalized. After six months, we observed 20% shrinkage of the pancreatic tumor and necrosis of a liver metastasis. Cinacalcet is an allosteric activator of the calcium receptor agonist, and it is used for severe hypercalcemia in patients with primary (benign and malignant) hyperparathyroidism. In this patient, cinacalcet demonstrated a calcium lowering effect, normalized hypophosphatemia, and improved the clinical condition of the patient. The mechanism through which cinacalcet improved PTH-rp mediated hypercalcemia is still unclear, but studies have suggested that a potential mechanism is the activation of calcitonin secretion. Sunitinib is an oral multi-targeted tyrosine kinase inhibitor used to treat advanced pNETs. The hypocalcemic effects of sunitinib have not been previously described in a patient with pNET. Here, we report for the first time the successful combination of cinacalcet and sunitinib in the treatment of a pNET patient presenting with malignant hypercalcemia.