Cinacalcet Reduces Serum Calcium Concentrations in Patients with Intractable Primary Hyperparathyroidism

Department of Endocrinology and Metabolism, University of Pisa, Via Paradisa 2, Pisa, Italy.
The Journal of Clinical Endocrinology and Metabolism (Impact Factor: 6.21). 07/2009; 94(8):2766-72. DOI: 10.1210/jc.2008-2640
Source: PubMed

ABSTRACT Patients with persistent primary hyperparathyroidism (PHPT) after parathyroidectomy or with contraindications to parathyroidectomy often require chronic treatment for hypercalcemia.
The objective of the study was to assess the ability of the calcimimetic, cinacalcet, to reduce serum calcium in patients with intractable PHPT.
This was an open-label, single-arm study comprising a titration phase of variable duration (2-16 wk) and a maintenance phase of up to 136 wk.
The study was conducted at 23 centers in Europe, the United States, and Canada.
The study included 17 patients with intractable PHPT and serum calcium greater than 12.5 mg/dl (3.1 mmol/liter).
During the titration phase, cinacalcet dosages were titrated every 2 wk (30 mg twice daily to 90 mg four times daily) for 16 wk until serum calcium was 10 mg/dl or less (2.5 mmol/liter). If serum calcium increased during the maintenance phase, additional increases in the cinacalcet dose were permitted.
The primary end point was the proportion of patients experiencing a reduction in serum calcium of 1 mg/dl or greater (0.25 mmol/liter) at the end of the titration phase.
Mean +/- sd baseline serum calcium was 12.7 +/- 0.8 mg/dl (3.2 +/- 0.2 mmol/liter). At the end of titration, a 1 mg/dl or greater reduction in serum calcium was achieved in 15 patients (88%). Fifteen patients (88%) experienced treatment-related adverse events, none of which were serious. The most common adverse events were nausea, vomiting, and paresthesias.
In patients with intractable PHPT, cinacalcet reduces serum calcium, is generally well tolerated, and has the potential to fulfill an unmet medical need.

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    • "Hemodialysis can also be considered for calcium levels >18 mg/dL with neurological symptoms and a stable circulation [16]. Cinacalcet (sensipar), a calcimimetic drug, is available for the treatment of secondary hyperparathyroidism associated with renal failure, hypercalcemia in parathyroid cancer, and the treatment of severe hypercalcemia in patients with primary hyperparathyroidism unable to undergo parathyroidectomy [17–19]. In our patient we used it effectively as well. "
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    ABSTRACT: Context. Severe hypercalcemia is a life-threatening condition. Atypical parathyroid adenoma and parathyroid carcinomas are uncommon causes which can be difficult to differentiate. Objective. We report a case of a 36-year-old male with very high serum calcium due to a possible atypical parathyroid adenoma versus parathyroid carcinoma. Case Illustration. A serum calcium level of 23.2 mg/dl was noted on admission. He was initially treated with IV hydration, pamidronate, and salmon calcitonin to lower his calcium levels. He also underwent a surgical en bloc resection of parathyroid mass. Pathology showed a mixed picture consistent with possible atypical adenoma versus parathyroid carcinoma. However, due to the possible involvement of the recurrent laryngeal nerve, parathyroid carcinoma was more likely. Also after operation the patient developed hungry bones syndrome and his calcium was replaced vigorously. He continues to be on calcium, vitamin D, and calcitriol supplementation. Results. A review of the literature was conducted to identify previous studies pertaining to parathyroid adenomas and parathyroid cancer. Conclusion. We thereby conclude that hypercalcemia requires very careful monitoring especially after operation. Also it can be very difficult to distinguish between atypical parathyroid adenomas and parathyroid carcinomas as in our case and no clear cut guidelines yet exist to differentiate the two based on histology.
    Case Reports in Medicine 05/2014; 2014:473814. DOI:10.1155/2014/473814
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    • "Cinacalcet is an allosteric modulator of the calcium-sensing receptor and acts by sensitizing this receptor to the extracellular calcium [Nemeth, 2002], thus inhibiting the synthesis and secretion of PTH and the renal tubular calcium reabsorption. Cinacalcet was shown to decrease serum calcium levels across a broad range of PHPT severity, whereas PTH levels declined only modestly and generally remained elevated [Peacock et al. 2009, 2011; Marcocci et al. 2009]. No change in BMD was found in patients treated for up to 5.5 years. "
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    ABSTRACT: Nowadays, primary hyperparathyroidism (PHPT) is mostly a mild disease. Overt skeletal manifestations are rare but decreased bone mineral density (BMD) can still be demonstrated. Even in mild cases, excess parathyroid hormone (PTH) increases bone turnover leading to bone loss particularly at cortical sites. Conversely, a relative preservation of cancellous bone has been shown by histomorphometric analyses and advanced imaging techniques. An increased fracture rate has been demonstrated in untreated patients with PHPT at peripheral sites and in the spine. Parathyroidectomy (PTx) is the definitive cure for PHPT. With the restoration of normal PTH, bone resorption is quickly tapered down, while bone formation proceeds at the level of bone multicellular units, which were activated prior to PTx. The rapid refilling of the enlarged remodeling space and the subsequent matrix mineralization will result in an increase in BMD at sites rich in trabecular bone, such as lumbar spine and hip, which mainly occurs during the first 6-12 months after PTx. Cortical bone is less responsive to PTX because of the low rate of bone turnover, but sensible increases in BMD at the distal third of the radius can be observed in the long term. PTx seems to decrease the risk of fractures but more data are needed before a definitive conclusion on this important matter can be reached. Treatment with bisphosphonates can be considered for patients with low BMD who do not undergo PTx. Two-year treatment with alendronate has been shown to decrease bone turnover markers and increase BMD at the lumbar spine and hip, but not at the distal radius. Cinacalcet stably decreased serum calcium levels across a broad range of PHPT severity, but no change in BMD occurred in patients treated for up to 5.5 years.
    Therapeutic advances in musculoskeletal disease 10/2012; 4(5):357-68. DOI:10.1177/1759720X12441869
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    • "Acute regulation of CaSR by small molecule allosteric drugs, either agonists (calcimimetics) or antagonists (calcilytics), has been proposed as treatment for a variety of Ca 2+ handling disorders. Calcimimetics, which reduce PTH secretion by the parathyroid, have been used in treatment of primary hyperparathyroidism and parathyroid carcinoma (Marcocci et al., 2009; Padhi and Harris, 2009), and secondary hyperparathyroidism in end stage renal disease (Hebert, 2006; Nagano, 2006). Calcilytics have been proposed as an oral treatment for osteoporosis (Nemeth et al., 2001; Hebert, 2006; Marie, 2010). "
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    ABSTRACT: Calcium-sensing receptors (CaSR) are integral to regulation of systemic Ca(2+) homeostasis. Altered expression levels or mutations in CaSR cause Ca(2+) handling diseases. CaSR is regulated by both endogenous allosteric modulators and allosteric drugs, including the first Food and Drug Administration-approved allosteric agonist, Cinacalcet HCl (Sensipar®). Recent studies suggest that allosteric modulators not only alter function of plasma membrane-localized CaSR, but regulate CaSR stability at the endoplasmic reticulum. This brief review summarizes our current understanding of the role of membrane-permeant allosteric agonists in cotranslational stabilization of CaSR, and highlights additional, indirect, signalling-dependent role(s) for membrane-impermeant allosteric drugs. Overall, these studies suggest that allosteric drugs act at multiple cellular organelles to control receptor abundance and hence function, and that drug hydrophobicity can bias the relative contributions of plasma membrane and intracellular organelles to CaSR abundance and signalling.
    British Journal of Pharmacology 04/2011; 165(6):1670-7. DOI:10.1111/j.1476-5381.2011.01403.x · 4.84 Impact Factor
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