Calcimimetic Cinacalcet Research Articles

Front Cover Picture: Chemoenzymatic Approaches to the Synthesis of the Calcimimetic Agent Cinacalcet Employing Transaminases and Ketoreductases (Adv. Synth. Catal. 11/2018)

Front Cover Picture: Chemoenzymatic Approaches to the Synthesis of the Calcimimetic Agent Cinacalcet Employing Transaminases and Ketoreductases (Adv. Synth. Catal. 11/2018)

Effects of calcimimetics on long-term outcomes in dialysis patients: literature review and Bayesian meta-analysis.

Randomized controlled trials (RCTs) with clinical outcomes are considered the gold standard for regulatory approval. However, by design they are only able to answer a small number of clinical questions. Other high-quality studies are required for clinical decision-making. The EVOLVE was the largest RCT, evaluating the effects of cinacalcet on clinical outcomes among adult patients receiving maintenance dialysis suffering from secondary hyperparathyroidism. While the EVOLVE trial did not reach its primary end point, imbalance in subjects' age at randomization and discontinuation rates are two of the reasons that the lack of mortality benefit is in question. We undertook a systematic literature review and Bayesian meta-analysis combining randomized and observational studies on the estimated effects of the oral calcimimetic cinacalcet on clinical outcomes including all-cause mortality, cardiovascular-related mortality, hospitalization for cardiovascular events, fracture and parathyroidectomy among patients on maintenance dialysis. Data sources included MEDLINE, EMBASE and Cochrane Central Register of Controlled Trials databases. RCTs and observational studies were included. Data extraction was completed by two authors independently and in duplicate determined the methodological quality of the studies and extracted data. Of 564 unique citations identified, 16 studies were included: six observational studies and ten RCTs. Four high-quality studies (two observational and two RCTs) were deemed suitable for meta-analysis. Results indicated a statistically significant reduction in the risk of death associated with cinacalcet (hazard ratio: 0.83; 95% credible interval: 0.78-0.89). The results of this meta-analysis indicate that treatment of secondary hyperparathyroidism with calcimimetic therapy may in fact reduce mortality among patients receiving maintenance dialysis. This finding provides justification for a well-designed and adequately powered randomized trial to definitively address the question.

Incidence, predictors and therapeutic consequences of hypocalcemia in patients treated with cinacalcet in the EVOLVE trial

The calcimimetic cinacalcet is used to treat secondary hyperparathyroidism in patients receiving dialysis, and asymptomatic hypocalcemia is often observed following its initiation. Here we investigated the incidence, predictors and therapeutic consequences of hypocalcemia by a post hoc analysis of the randomized, double-blind, placebo-controlled EValuation Of Cinacalcet Hydrochloride Therapy to Lower CardioVascular Events (EVOLVE) trial. Hypocalcemia was classified as mild (total serum calcium 8.0-8.39 mg/dL), moderate (7.5-7.99 mg/dL) or severe (under 7.5 mg/dL). At least one episode of hypocalcemia developed within 16 weeks after the first administered dose among 58.3% of 1938 patients randomized to cinacalcet versus 14.9% of 1923 patients randomized to placebo. Hypocalcemia in the cinacalcet group was severe in 18.4% of the patients versus 4.4% in the placebo group. Severe hypocalcemia following administration of cinacalcet was associated with higher baseline plasma parathyroid hormone, lower corrected total serum calcium, higher serum alkaline phosphatase, geographic region (patients from Latin America and Russia had a higher risk relative to the United States) and higher body mass index. The median cinacalcet dose immediately prior to the first hypocalcemic episode was 54-58 mg/day and similar in the three hypocalcemia categories. In the majority of patients, hypocalcemia resolved spontaneously within 14 days without modification of background therapy. Among patients who received an intervention, the most common was an increase in the active vitamin D sterol dose. Thus, the occurrence of hypocalcemia is frequent following initiation of cinacalcet and the likelihood of developing hypocalcemia was related to the severity of secondary hyperparathyroidism. Hypocalcemia was generally asymptomatic and self-limited.

Managing hyperparathyroidism in hemodialysis: role of etelcalcetide.

Secondary hyperparathyroidism (SHPT) is common in patients receiving maintenance hemodialysis and is associated with adverse outcomes. Currently, SHPT is managed by reducing circulating levels of phosphate with oral binders and parathyroid hormone (PTH) with vitamin D analogs and/or the calcimimetic cinacalcet. Etelcalcetide, a novel calcimimetic administered intravenously (IV) at the end of a hemodialysis treatment session, effectively reduces PTH in clinical trials when given thrice weekly. Additional clinical effects include reductions in circulating levels of phosphate and FGF-23 and an improved profile of markers of bone turnover. However, despite being administered IV, etelcalcetide appears to be associated with rates of nausea and vomiting comparable to those of cinacalcet. Additionally, etelcalcetide, relative to placebo, causes hypocalcemia and prolonged electrocardiographic QT intervals, effects that must be considered when contemplating its use. Etelcalcetide likely has a role in treating hemodialysis patients with uncontrolled SHPT or with hypercalcemia or hyperphosphatemia receiving activated vitamin D compounds. However, its use should be at least partially constrained by consideration of the risk of hypocalcemia and resultant prolonged QT intervals in vulnerable patients. Because of its effectiveness as a PTH-reducing agent administered in the dialysis unit, etelcalcetide represents a potentially promising new therapeutic approach to the often vexing problem of SHPT in hemodialysis patients. However, whether its use is associated with changes in surrogate clinical end points, such as effects on rates of parathyroidectomy, fracture, vascular calcification, or mortality or on quality of life, remains to be studied.

Hypercalcemia of malignancy treated with cinacalcet.

Hypercalcemia of malignancy is the most common cause of hypercalcemia in hospitalized patients. It is associated with a poor prognosis, since it reflects an advanced cancer stage. Among all cancer in females, breast cancer is the most common malignancy, and it has the highest prevalence of hypercalcemia. Approximately 70% of patients with breast cancer have bone metastases and 10% of them will have hypercalcemia as a complication at some point in the disease. Herein, we report a 69-year-old female patient with metastatic breast cancer, who developed severe hypercalcemia in the course of her disease and was diagnosed with humoral hypercalcemia of malignancy (HHM). Intense hydration along with corticoisteroids and antiresorptive medication (calcitonin, bisphosphonates and denosumab) were administered to the patient. Despite the above treatment, serum calcium levels remain elevated and calcimimetic cinacalcet was added. Upon discontinuation of cinacalcet, calcium levels were raised and returned back to the normal levels following re-initiation of the calcimimetic. Her calcium level restored to normal, and she was discharged with the following medical treatment: denosumab monthly, and cinacalcet at a titrated dose of 90 mg per day. The patient is followed as an outpatient and 11 months later, her calcium level remained within the normal range.Learning points:Hypercalcemia of malignancy is the most common cause of hypercalcemia in hospitalized patients.Breast cancer has the highest prevalence of hypercalcemia.The cornerstone of therapy remains the intense hydration and intravenous bisphosphonates (preferably zoledronic acid).In case of persistent hypercalcemia of malignancy, the administration of calcimimetic cinacalcet could be an additional effective therapeutic option.

Cinacalcet corrects hypercalcemia in mice with an inactivating Gα11 mutation.

Loss-of-function mutations of GNA11, which encodes G-protein subunit α11 (Gα11), a signaling partner for the calcium-sensing receptor (CaSR), result in familial hypocalciuric hypercalcemia type 2 (FHH2). FHH2 is characterized by hypercalcemia, inappropriately normal or raised parathyroid hormone (PTH) concentrations, and normal or low urinary calcium excretion. A mouse model for FHH2 that would facilitate investigations of the in vivo role of Gα11 and the evaluation of calcimimetic drugs, which are CaSR allosteric activators, is not available. We therefore screened DNA from > 10,000 mice treated with the chemical mutagen N-ethyl-N-nitrosourea (ENU) for GNA11 mutations and identified a Gα11 variant, Asp195Gly (D195G), which downregulated CaSR-mediated intracellular calcium signaling in vitro, consistent with it being a loss-of-function mutation. Treatment with the calcimimetic cinacalcet rectified these signaling responses. In vivo studies showed mutant heterozygous (Gna11+/195G) and homozygous (Gna11195G/195G) mice to be hypercalcemic with normal or increased plasma PTH concentrations and normal urinary calcium excretion. Cinacalcet (30mg/kg orally) significantly reduced plasma albumin–adjusted calcium and PTH concentrations in Gna11+/195G and Gna11195G/195G mice. Thus, our studies have established a mouse model with a germline loss-of-function Gα11 mutation that is representative for FHH2 in humans and demonstrated that cinacalcet can correct the associated abnormalities of plasma calcium and PTH.

Parathyroid hormone contributes to the down-regulation of cytochrome P450 3A through the cAMP/PI3K/PKC/PKA/NF-κB signaling pathway in secondary hyperparathyroidism

Chronic kidney disease (CKD), which affects, not only renal clearance, but also non-renal clearance, is accompanied by a decline in renal function. Although it has been suggested that humoral factors, such as uremic toxins that accumulate in the body under CKD conditions, could be involved in the changes associated with non-renal drug clearance, the overall process is not completely understood. In this study, we report on the role of parathyroid hormone (PTH), a middle molecule uremic toxin, on the expression of drug metabolizing or transporting proteins using rats with secondary hyperparathyroidism (SHPT) as models. In SHPT rats, hepatic and intestinal CYP3A expression was suppressed, but the changes were recovered by the administration of the calcimimetic cinacalcet, a PTH suppressor. Under the same experimental conditions, a pharmacokinetic study using orally administered midazolam, a substrate for CYP3A, showed that the AUC was increased by 5 times in SHPT rats, but that was partially recovered by a cinacalcet treatment. This was directly tested in rat primary hepatocytes and intestinal Caco-2 cells where the expression of the CYP3A protein was down-regulated by PTH (1–34). In Caco-2 cells, PTH (1–34) down-regulated the expression of CYP3A mRNA, but an inactive PTH derivative (13–34) had no effect. 8-Bromo-cyclic adenosine monophosphate, a membrane-permeable cAMP analog, reduced mRNA expression of CYP3A whereas the inhibitors of PI3K, NF-κB, PKC and PKA reversed the PTH-induced CYP3A down-regulation. These results suggest that PTH down-regulates CYP3A through multiple signaling pathways, including the PI3K/PKC/PKA/NF-κB pathway after the elevation of intracellular cAMP, and the effect of PTH can be prevented by cinacalcet treatment.

Exploring the potential value of improved care for secondary hyperparathyroidism with a novel calcimimetic therapy

Aims: This study explored the use of a value-based pricing approach for the new calcimimetic etelcalcetide indicated for the treatment of secondary hyperparathyroidism (SHPT) in patients receiving hemodialysis. It used the US payer perspective and applied the cost-effectiveness framework. Because etelcalcetide is an intravenous therapy that can be titrated for individual patients, and because its utilization is yet to be assessed in real world settings, a range of plausible doses were estimated for etelcalcetide to define a range of prices. These were either in relation to the existing oral calcimimetic cinacalcet or compared to no calcimimetic treatment.Materials and methods: The value-based price of etelcalcetide was determined via a Markov model. This model combined data from the etelcalcetide trials and previously published cost-effectiveness models in SHPT, and allowed extrapolation of treatment effects on mortality, cardiovascular events, fracture, and parathyroidectomy. Several dosing scenarios were explored covering the dose ranges of 30.0–64.18 mg per day for cinacalcet and 1.07–3.11 mg per day for etelcalcetide. These included the mean dose from the etelcalcetide trials, the preliminary defined daily dose, and the expected most common dose in real world. An acceptable price range for etelcalcetide was assessed by comparing the incremental cost-effectiveness ratios obtained with the willingness-to-pay threshold range of $100,000–$300,000/quality-adjusted life-years.Results: Cost-effectiveness analysis supported value-based prices for etelcalcetide ranging from $21.15–$49.97/mg vs cinacalcet, and $13.79–$119.45/mg vs no calcimimetics.Limitations: There is uncertainty around what the real-world dosing will be for etelcalcetide. Another important nuance is that no studies have examined etelcalcetide effects on hard outcomes and, therefore, this modeling exercise relied on an extrapolation approach.Conclusions: This cost-effectiveness analysis, including scenarios to address uncertainties, allowed estimation of a value-based price range to aid reimbursement decisions in the US.

Paricalcitol and cinacalcet have disparate actions on parathyroid oxyphil cell content in patients with chronic kidney disease

The parathyroid oxyphil cell content increases in patients with chronic kidney disease (CKD), and even more in patients treated with the calcimimetic cinacalcet and/or calcitriol for hyperparathyroidism. Oxyphil cells have significantly more calcium-sensing receptors than chief cells, suggesting that the calcium-sensing receptor and calcimimetics are involved in the transdifferentiation of a chief cell to an oxyphil cell type. Here, we compared the effect of the vitamin D analog paricalcitol (a less calcemic analog of calcitriol) and/or cinacalcet on the oxyphil cell content in patients with CKD to further investigate the genesis of these cells. Parathyroid tissue from four normal individuals and 27 patients with CKD who underwent parathyroidectomy for secondary hyperparathyroidism were analyzed. Prior to parathyroidectomy, patients had received the following treatment: seven with no treatment, seven with cinacalcet only, eight with paricalcitol only, or cinacalcet plus paricalcitol in five. Oxyphilic areas of parathyroid tissue, reported as the mean percent of total tissue area per patient, were normal, 1.03; no treatment, 5.3; cinacalcet, 26.7 (significant vs. no treatment); paricalcitol, 6.9 (significant vs. cinacalcet; not significant vs. no treatment); and cinacalcet plus paricalcitol, 12.7. Cinacalcet treatment leads to a significant increase in parathyroid oxyphil cell content but paricalcitol does not, reinforcing a role for the calcium-sensing receptor activation in the transdifferentiation of chief-to-oxyphil cell type. Thus, two conventional treatments for hyperparathyroidism have disparate effects on parathyroid composition, and perhaps function. This finding is provocative and may be useful when evaluating future drugs for hyperparathyroidism.

Calcium-Sensing Receptor Genotype and Response to Cinacalcet in Patients Undergoing Hemodialysis.

We tested the hypothesis that single nucleotide polymorphisms (SNPs) in the calcium-sensing receptor (CASR) alter the response to the calcimimetic cinacalcet. We analyzed DNA samples in the Evaluation of Cinacalcet HCl Therapy to Lower Cardiovascular Events (EVOLVE) trial, a randomized trial comparing cinacalcet to placebo on a background of usual care. Of the 3883 patients randomized, 1919 (49%) consented to DNA collection, and samples from 1852 participants were genotyped for 18 CASR polymorphisms. The European ancestry (EA; n=1067) and African ancestry (AfAn; n=405) groups were assessed separately. SNPs in CASR were tested for their association with biochemical measures of mineral metabolism at baseline, percent change from baseline to 20 weeks, and risk of clinical fracture as dependent variables. There were modest associations of CASR SNPs with increased baseline serum parathyroid hormone and bone alkaline phosphatase primarily with the minor allele in the EA group (all P≤0.03), but not in the AfAn sample. In contrast, there was a modest association of decreased baseline serum calcium and FGF23 with CASR SNPs (P=0.04) primarily with the minor allele in the AfAn but not in the EA sample. The minor allele of two SNPs was associated with decreased percent reduction in parathyroid hormone from baseline to 20 weeks in the EA population (P<0.04) and this was not altered with cinacalcet. In both EA and AfAn, the same SNP (rs9740) was associated with decreased calcium with cinacalcet treatment (EA and AfAn P≤0.03). Three SNPs in high linkage disequilibrium were associated with a higher risk of clinical fracture that was attenuated by cinacalcet treatment in the EA sample (P<0.04). These modest associations, if validated, may provide explanations for differences in CKD-mineral bone disorder observed in EA and AfAn populations, and for differential biochemical responses to calcimimetics.

Mortality in dialysis patients with cinacalcet use: A large observational registry study

BackgroundSecondary hyperparathyroidism (sHPT) is associated with higher mortality in dialysis patients. The calcimimetic cinacalcet reduces intact parathyroid hormone (iPTH) in dialysis patients. The randomized controlled EVOLVE trial failed to unequivocally prove survival advantage of cinacalcet in dialysis patients. However, recent post hoc analyses suggested a benefit in subgroups of dialysis patients. Large observational cohort studies may represent an option to better determine such subgroups. MethodsData from the nationwide Austrian registry of dialysis patients between January 2004 and December 2009 were analyzed with follow-up until December 2010. All-cause and cardiovascular mortality analyses were performed using the Kaplan-Meier and Cox proportional hazards regression. To reduce confounding effects a propensity score (PS) based method (matching by stratification) was used for group comparison. ResultsThe cohort included 7983 dialysis patients, 1572 (19.7%) were prescribed cinacalcet. During a median follow-up of 2.7years, 3574 (44.8%) patients died, including 1342 (16.8%) deaths from cardiovascular causes. Survival analyses in the PS-matched study population (n=6109) showed lower all-cause mortality for cinacalcet-treated as compared to untreated patients only in subsets characterized by younger age, low prevalence of diabetes, iPTH levels between 300 and 599pg/mL, concomitant therapy with vitamin D and phosphate binders. ConclusionsOur data suggest that a subgroup of dialysis patients, namely those with moderate sHPT, younger age and without diabetes benefit from cinacalcet with reduced overall and cardiovascular mortality. These findings may help to identify populations for further controlled trials and may allow a more individualized sHPT treatment using cinacalcet in specific patient subgroups.

Etelcalcetide for the treatment of secondary hyperparathyroidism

ABSTRACTIntroduction: Calcium sensing receptor is an important target for the treatment of secondary hyperparathyroidism (SHPT). Etelcalcetide hydrochloride is a novel peptide calcimimetic agent that has a similar mechanism of action as cinacalcet hydrochloride. Clinical trials of etelcalcetide have been performed in the US, Europe, and Japan, and these trials demonstrated the safety and efficacy of etelcalcetide in dialysis patients. Etelcalcetide has recently been approved in Europe, the US and Japan.Areas covered: We review the development, pharmacokinetics, and clinical efficacy and safety of etelcalcetide for the treatment of SHPT in hemodialysis patients. We also summarize the clinical evidence regarding cinacalcet to forecast the potential clinical benefit of etelcalcetide.Expert opinion: Etelcalcetide is an injectable calcimimetic with a longer elimination half-life than cinacalcet. The injectable formulation improves adherence and reduces pill burden, while the frequency of gastrointestinal adverse events has been comparable between cinacalcet and etelcalcetide. The longer half-life of etelcalcetide reduces the fluctuation of biochemical markers of mineral and bone metabolism, but it remains to be determined whether such a sustained effect results in improved outcomes. Further studies are needed to determine the impact of etelcalcetide on clinical outcomes, particularly in comparison with the conventional calcimimetic cinacalcet.

Parathyroid hormone targets in chronic kidney disease and managing severe hyperparathyroidism.

Appropriate targets for parathyroid hormone (PTH) in patients with chronic kidney disease (CKD) stages 3-5D are controversial, as are the means by which these targets might be achieved. Secondary hyperparathyroidism is linked to symptoms like bone pain and itch, in addition to less clinically overt issues like bone fragility as well as vascular and soft tissue calcification which may lead to adverse hard endpoints, particularly fracture and death. Recognized therapies for managing a rising PTH include vitamin D analogues, with or without calcimimetic (where available), in addition to management of serum mineral concentrations with diet, binders and dialysis. Despite these interventions, many patients eventually develop refractory metabolic abnormalities of severe hyperparathyroidism (HPT). Treatment decisions in severe HPT in Australia previously centred around whether to perform parathyroidectomy or use calcimimetics in combination with calcitriol (or its analogues) with goals of symptom relief, fracture reduction and reducing vascular risk. The decision to remove Pharmaceutical Benefits Scheme reimbursement for the calcimimetic cinacalcet during 2015, means that parathyroidectomy has now become the only treatment likely to benefit most patients with severe HPT who are medically fit for operative intervention. Although improvements in care are apparent for patients with CKD, there remains an urgent need for basic science and large international trials to inform better ways to manage HPT.

Down-regulation of ABCG2, a urate exporter, by parathyroid hormone enhances urate accumulation in secondary hyperparathyroidism

Hyperuricemia occurs with increasing frequency among patients with hyperparathyroidism. However, the molecular mechanism by which the serum parathyroid hormone (PTH) affects serum urate levels remains unknown. This was studied in uremic rats with secondary hyperparathyroidism where serum urate levels were found to be increased and urate excretion in the intestine and kidney decreased, presumably due to down-regulation of the expression of the urate exporter ABCG2 in intestinal and renal epithelial membranes. These effects were prevented by administration of the calcimimetic cinacalcet, a PTH suppressor, suggesting that PTH may down-regulate ABCG2 expression. This was directly tested in intestinal Caco-2 cells where the expression of ABCG2 on the plasma membrane was down-regulated by PTH (1-34) while its mRNA level remained unchanged. Interestingly, an inactive PTH derivative (13-34) had no effect, suggesting that a posttranscriptional regulatory system acts through the PTH receptor to regulate ABCG2 plasma membrane expression. As found in an animal study, additional clinical investigations showed that treatment with cinacalcet resulted in significant reductions in serum urate levels together with decreases in PTH levels in patients with secondary hyperparathyroidism undergoing dialysis. Thus, PTH down-regulates ABCG2 expression on the plasma membrane to suppress intestinal and renal urate excretion, and the effects of PTH can be prevented by cinacalcet treatment.

Cinacalcet versus Parathyroidectomy in the Treatment of Secondary Hyperparathyroidism Post Renal Transplantation

Persistent hyperparathyroidism (HPT) with hypercalcemia is prevalent after transplant and is considered a risk factor for progressive bone loss and fractures and vascular calcification, as well as the development of tubulointerstitial calcifications of renal allografts and graft dysfunction. The subtotal parathyroidectomy is the standard treatment, although currently it has been replaced by the calcimimetic cinacalcet. The hypothesis of this study is that subtotal parathyroidectomy is superior to cinacalcet for treatment of persistent secondary parathyroidectomy post renal transplant, with minimal morbidity and significantly it reduces the cost of treatment after transplantation. We report our long-term clinical experience with either cinacalcet or parathyroidectomy in 59 kidney transplant recipients with hyperparathyroidism. Group one included medical treatment with cinacalcet and had 45 patients while parathyroidectomy patients (group 2) were 16 patients with two of them excluded because of surgical failure. No difference was found between groups for any parameter. A greater short-term change of calcium and phosphorus homeostasis obtained by surgery than by cinacalcet, and in long term change, no significant difference between the two groups. The main findings of this study are that correction of severe hyperparathyroidism was similar in both surgical and cinacalcet groups with the absence of a difference of long-term serum iPTH 1-84 levels between the two groups.

Calcium sensing receptor effects in adipocytes and liver cells: Implications for an adipose-hepatic crosstalk

The calcium sensing receptor (CaSR) is expressed in human adipose cells, and its activation may associate with adipose tissue (AT) dysfunction. We evaluated whether CaSR stimulation influences adipocyte triglyceride (TG) and fatty acid binding protein 4 (aP2) content, and hepatocyte TGs and proinflammatory cytokine expression. The effect of the calcimimetic cinacalcet on TGs (fluorimetry), lipogenic genes (qPCR) and aP2 (immunoblot) was evaluated in LS14 adipocytes or AT. In the human HepG2 hepatic cell line, we assessed CaSR expression and cinacalcet effect on TGs and lipogenic and proinflammatory genes. CaSR activation decreased adipocyte TG content by 20% and the expression of GPD and LPL by 34% and 20%, respectively. Cinacalcet increased aP2 protein expression by 60%. CaSR expression was shown in HepG2 cells and human liver samples. Cinacalcet-treated HepG2 cells in the presence of oleic acid exhibited a19% increased TG content. No changes were observed in the expression of lipogenic genes in HepG2 cells, however there was a 50%–300% elevation in the expression of proinflammatory cytokines. CaSR activation in adipocytes may associate with decreased TG storage ability and increased aP2. Hepatic CaSR stimulation may elevate steatosis and proinflammatory factors. We propose that CaSR may contribute to obesity-associated hepatic metabolic consequences.

Pharmacological characteristics of drugs targeted on calcium-sensing receptor.-properties of cinacalcet hydrochloride as allosteric modulator

Calcimimetics act as positive allosteric modulators of the calcium-sensing receptor (CaSR), thereby decreasing parathyroid hormone (PTH) secretion from the parathyroid glands. On the other hand, negative allosteric modulators of the CaSR with stimulatory effect on PTH secretion are termed calcilytics. The calcimimetic cinacalcet hydrochloride (cinacalcet) is the world's first allosteric modulator of G protein-coupled receptor to enter the clinical market. Cinacalcet just tunes the physiological effects of Ca(2+), an endogenous ligand, therefore, shows high selectivity and low side effects. Calcimimetics also increase cell surface CaSR expression by acting as pharmacological chaperones (pharmacoperones). It is considered that the cinacalcet-induced upper gastrointestinal problems are resulted from enhanced physiological responses to Ca(2+) and amino acids via increased sensitivity of digestive tract CaSR by cinacalcet. While clinical developments of calcilytics for osteoporosis were unfortunately halted or terminated due to paucity of efficacy, it is expected that calcilytics may be useful for the treatment of patients with activating CaSR mutations, asthma, and idiopathic pulmonary artery hypertension.

Hypercalcemia of malignancy and new treatment options.

Hypercalcemia of malignancy affects up to one in five cancer patients during the course of their disease. It is associated with both liquid malignancies, commonly multiple myeloma, leukemia, and non-Hodgkins lymphoma and solid cancers, particularly breast and renal carcinomas as well as squamous cell carcinomas of any organ. The clinical manifestations of hypercalcemia are generally constitutional in nature and not specific to the inciting malignancy. Such physical manifestations can range from malaise to lethargy and confusion. Constipation and anorexia are common. Acute kidney injury is likely the most frequently encountered manifestation of end organ damage. Symptomatology is closely linked to both the absolute elevation of serum calcium levels and the rapidity of calcium rise. The majority of cases are humoral in etiology and related to parathyroid hormone-related protein (PTHrP). Approximately 20% of cases are the result of direct bone metastasis with extra-renal 1,25-dihydroxyvitamin D (calcitriol) and ectopic parathyroid hormone production likely accounting for less than 1% of cases. The diagnosis of hypercalcemia of malignancy is confirmed either by an elevated PTHrP or by an evidence of bone metastasis in the appropriate clinical setting. Treatment is predicated on the patient’s symptoms and absolute serum calcium level. Interventions are aimed at lowering the serum calcium concentration by inhibiting bone resorption and increasing urinary calcium excretion, the former accomplished via bisphosphonate therapy and the latter with aggressive hydration. Novel therapies for refractory disease include denosumab, a monoclonal antibody against the receptor activator of nuclear factor κB ligand, and the calcimimetic cinacalcet. Finally, anti-PTHrP antibodies have been successfully deployed in animal models of disease. Despite the efficacy of the above therapies, hypercalcemia of malignancy portends an ominous prognosis, indicating advanced and often refractory cancer with survival on the order of months.

Lessons Learned from EVOLVE for Planning of Future Randomized Trials in Patients on Dialysis.

The effect of the calcimimetic cinacalcet on cardiovascular disease in patients undergoing hemodialysis with secondary hyperparathyroidism was assessed in the Evaluation of Cinacalcet Hydrochloride Therapy to Lower Cardiovascular Events trial. This was the largest (in size) and longest (in duration) randomized controlled clinical trial undertaken in this population. During planning, execution, analysis, and reporting of the trial, many lessons were learned, including those related to the use of a composite cardiovascular primary endpoint, definition of endpoints (particularly heart failure and severe unremitting hyperparathyroidism), importance of age for optimal stratification at randomization, use of unadjusted and adjusted intention-to-treat analysis for the primary outcome, how to respond to a lower-than-predicted event rate during the trial, development of a prespecified analytic plan that accounted for nonadherence and for cointerventions that diminished the power of the trial to observe a treatment effect, determination of the credibility of a subgroup effect, use of adverse effects database to investigate rare diseases, collection of blood for biomarker measurement not designated before trial initiation, and interpretation of the benefits-to-harms ratio for individual patients. It is likely that many of these issues will arise in the planning of future trials in CKD.

Molecular and Clinical Aspects of the Target Therapy with the Calcimimetic Cinacalcet in the Treatment of Parathyroid Tumors

Parathyroid tumors are almost invariably associated with parathormone (PTH) hypersecretion resulting in primary (PHPT) or secondary (SHPT) hyperparathyroidism. PHPT is the third most common endocrine disorder with a prevalence of 1-2% in post-menopausal women; SHPT is a major complication of chronic kidney failure, the prevalence of which is increasing. The calciumsensing receptor (CASR) is the key molecule regulating PTH synthesis and release from the parathyroid cells in response to changes in extracellular calcium concentrations. A potent calcimimetic, cinacalcet, has been developed in the last ten years and made available for medical treatment of both PHPT and SHPT. Cinacalcet has been demonstrated to be effective in inhibiting PTH secretion, though the drug fails to normalize PTH release, both in PHPT and SHPT patients with different degrees of disease severity, including patients with parathyroid carcinomas and with MEN1-related parathyroid tumors. Here we reviewed the molecular aspects of CASR target therapy and the effect of the CASR gene single nucleotide polymorphisms. Clinical data concerning the efficacy and safety of cinacalcet in controlling hyperparathyroidism are reported, focusing on the treatment of the different types of parathyroid tumors. Finally, limits of this target therapy are analyzed, pointing out the lack of efficacy in improving kidney and bone morbidities in PHPT and cardiovascular diseases in SHPT. Though cinacalcet is a target therapeutic option for parathyroid tumors, further approaches are warranted to fully control these metabolic disorders and the underlying tumors.