The discovery and characterization of the calcium-sensing receptor (CaR) has led to the creation of a new series of drugs known as the calcimimetics. Calcimimetic agents are small organic molecules that act as allosteric activators of the calcium-sensing receptor (CaR). They lower the threshold for CaR activation by extracellular calcium ions. By doing so, calcimimetics directly inhibit the release of parathyroid hormone (PTH) from the parathyroid glands (6). Calcimimetic compounds have been clinically tested and found to be useful in the treatment of diseases involving overly active parathyroid hormone release, most noticeably secondary hyperparathyroidism (12).
Secondary hyperparathyroidism is a disease where the parathyroid glands secrete too much PTH because of low serum calcium levels (15). Chronic kidney disease is a common cause of secondary hyperparathyroidism. It develops early in chronic kidney disease and is virtually present in all patients with end-stage renal disease (15). In the early stages of chronic kidney disease, decreased serum calcium levels contribute to a compensatory increase in the synthesis and secretion of PTH. This overly active secretion of PTH leads to hypercalcemia. Calcimimetic compounds are used to inhibit PTH secretion and maintain serum calcium levels at a normal range (15).
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The parathyroid glands are endocrine glands located on the posterior surface of the thyroid gland. Humans usually have four parathyroid glands, but the number can vary from person to person. Parathyroid cells are distinguishable from thyroid cells because they are small, densely packed cells compared to the large follicular cells of the thyroid. There are two main types of cells in parathyroid tissue: oxyphil cells and chief cells. The function of the oxyphil cells is unclear, but the chief cells produce and secrete PTH (8).
Parathyroid Hormone (PTH) and the Pathophysiology of Secondary Hyperparathyroidism
PTH is the most important hormone controlling calcium levels in the blood (8). It is secreted by the parathyroid glands as a polypeptide containing 84 amino acids. PTH secretion is triggered by low calcium levels and inhibited by high calcium levels (8). PTH targets three main organs to increase calcium levels in the blood. These organs are the bones, intestine, and kidneys. PTH stimulates osteoclast activity and inhibits osteoblast activity in bones. This leads to the breakdown of the bony matrix and the release of ionic calcium and phosphates to the blood. PTH also stimulates calcium absorption by the intestinal mucosal cells. In the kidneys, PTH increases calcium absorption and increases phosphate secretion. The overall effect of PTH secretion is increased blood calcium levels (8).
Secondary hyperparathyroidism is the excessive secretion of PTH from the parathyroid glands due to hypocalcemia. Chronic renal failure is a common cause of secondary hyperparathyroidism. Chronic renal failure is a progressive loss of kidney function over a period of months to years (15). There are five stages of chronic renal failure with the fifth stage being end-stage renal disease (ESRD) (8). A loss of kidney function results in several side effects. The kidney is unable to excrete enough phosphate (15). The free phosphate ions are then able to bind with calcium ions, forming insoluble calcium phosphate. This lowers the amount of free calcium in the blood circulation and causes the secretion of PTH (15). Failing kidneys are also unable to convert Vitamin D to its active form, calcitriol. The main function of calcitriol is to increase the absorption of calcium at the intestine. The failed production of calcitriol therefore leads to a decrease in absorption of calcium and a decrease in blood calcium levels. This signals the parathyroid glands to produce and secrete PTH (11). Secondary hyperparathyroidism has in the past been treated most commonly with calcitriol (4).
Calcium-sensing Receptors and Second Messenger Pathways
The ability of the parathyroid glands to sense small changes in blood calcium levels is due to calcium-sensing receptors (CaR) located on the cell surface of the chief cells (7). The CaR is a member of the G protein-coupled receptor family. It contains seven hydrophobic helices that anchor it into the plasma membrane (2). The amino terminal portion of the CaR forms a very large extracellular domain containing about 600 amino acid residues (2). The extracellular domain is able to interact with extracellular calcium ions, possibly through clusters of acidic amino acids located in this area of the molecule (2,6). The interaction of the extracellular domain with extracellular calcium ions modifies the receptor activation and signal transduction (6). Cysteine residues in the extracellular domain mediate the formation of dimers of the CaR, whereas other sites in this area serve as sites for N-glycosylation (13). Both of these processes affect receptor expression at the cell surface and the ability of the receptor to undergo ligand activation (13). The central portion of the CaR contains about 250 amino acids. This portion of the molecule forms the seven membrane-spanning domains that characterize G-protein coupled receptors and the intracellular and extracellular loops that connect them (2). Selected portions of the intracellular and extracellular loops are involved in phospholipase C activation (6). The carboxy terminal end of the CaR is composed of about 200 amino acids and forms the intracellular portion of the receptor (2). The intracellular domain has several sites that are available for phosphorylation by PKC and PKA. Phosphorylation by PKC diminishes the activation of the CaR, but it is unclear what phosphorylation by PKA results in (6,3).
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The activation of the CaR is linked to a broad array of intracellular signaling pathways that result in an array of physiological responses in parathyroid tissue. There are two major signal-transducing effects caused by the activation of the CaR. The Gq signaling pathway results in the activation of phospholipase C, which leads to the generation of the second messengers: diacylglycerol (DAG) and inositol triphosphate (IP3). IP3 results in the release of calcium from intracellular stores increasing the intracellular calcium concentration. DAG stimulates protein kinase C (PKC) which opens extracellular calcium channels, resulting in an influx of calcium into the cell. The Gi pathway results in the inhibition of adenylate cyclase. This lowers cAMP levels which stops PTH secretion. In general, the calcium-sensing receptors are spontaneously active and secrete PTH. When calcium binds to the extracellular domain, cAMP levels decrease and inhibit the secretion of PTH (13).
PTH Receptors and Second Messenger Pathways
PTH is able to promote calcium reabsorption through several different signaling mechanisms. Three main target tissues of PTH are bone, kidney, and intestine. PTH is able to bind to its receptor in these tissues and stimulate multiple intracellular signals. Two transduction pathways are the Gs and Gq pathways. The Gs pathway leads to the production of cAMP and therefore the activation of PKA. The Gq pathway stimulates phospholipase C to form the second messengers IP3 and DAG. IP3 stimulates increases in intracellular calcium levels and DAG stimulates PKC, which opens extracellular calcium channels (16).
In a study done at Harvard Medical School, the effects of PTH on cAMP levels, IP3 levels, and intracellular free calcium were observed. Intact rat bone cells were incubated with PTH(1-34) and PTH(1-36). (For the purpose of this paper, only the results of PTH(1-34) will be included.) The rat bone cells were incubated for various amounts of time ranging from fifteen minutes to forty-eight hours. Following incubation, depending on which of the three products was trying to be measured, different extraction procedures were performed. Analysis showed that there were increases in intracellular calcium levels, cAMP levels, and IP3 levels. Basal levels of cAMP were 8 +/- 3pmol per 15 min per well and maximal stimulated values were 125 +/- 8 pmol per 15 min per well. Basal levels of IP3 before incubation with PTH(1-34) were 349 dpm per plate and increased to 899 dpm per plate. Basal levels of intracellular calcium were 100 nm and increased to an average of 300 nm (1). The results of this study suggest that PTH does follow the two G-protein signaling pathways, Gs and Gq. Through these pathways, PTH is able to increase the amount of blood calcium concentration.
One of the challenges in developing a potential modulator of the CaR, and therefore control the release of PTH, involves accomplishing a high level of specificity for CaR binding. The term calcimimetics has been given to those compounds that can modulate the activity of calcium receptors. There are two types of calcimimetic compounds, Type I and Type II. Type I calcimimetics include inorganic cations, polyamines, and aminoglycosides that bind to the calcium-binding site on the receptor and are capable of activating the CaR in the absence of extracellular calcium. Some examples of Type I calcimimetics are Mg2+, Gd3+, neomycin, and spermine (2). Type II calcimimetics are organic compounds that bind to regions within the membrane-spanning domain of the CaR and have the potential to increase the sensitivity of the CaR to calcium. By increasing the sensitivity of the CaR to calcium, Type II calcimimetics lower the threshold for receptor activation by calcium and are considered allosteric modulators (6,10).
Effects of Cinacalcet On Secretion of PTH and Serum Calcium and Phosphorus Levels
A common calcimimetic compound used to treat patients with secondary hyperparathyroidism is cinacalcet, or AMG 073. A study was designed to evaluate the effect cinacalcet had on the bioactive form of PTH (whole PTH [wPTH]) and the truncated, fragment form of PTH (non-wPTH). In normal individuals 20%-60% of the PTH is in the non-wPTH form. In dialysis patients, the percentage of non-wPTH is generally higher. The study also looked at the wPTH/non-wPTH ratio in response to the induction of hypo- and hypercalcemia during hemodialysis. The study involved nine patients (five men and four women) ages 27 to 63 years old. All patients were on long-term hemodialysis for secondary hyperparathyroidism. PTH-calcium curves were measured before and after two months of treatment with cinacalcet. Table 1 below shows the levels of calcium and PTH before and after treatment with cinacalcet. There were significant drops in all three concentrations in the blood. It was found that cinacalcet increased the sensitivity of the parathyroid cells to calcium (14).
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Table 1. Levels of calcium, phosphorus, albumin, alkaline phosphatase, iPTH, and wPTH before and after treatment with cinacalcet (14).P
Basal calcium (mM)
1.190 ± 0.110
1.110 ± 0.200
1.740 ± 0.160
1.410 ± 0.090
3.960 ± 0.400
4.030 ± 0.500
Alkaline phosphatase (IU/L)
117.000 ± 20.000
134.000 ± 28.000
Basal iPTH (pg/ml)
645.000 ± 86.000
336.000 ± 55.000
Maximal iPTH (pg/ml)
997.000 ± 116.000
762.000 ± 107.000
Minimal iPTH (pg/ml)
148.000 ± 29.000
53.000 ± 10.000
iPTH basal/maximal ratio
0.640 ± 0.060
0.460 ± 0.070
iPTH set point
1.210 ± 0.020
1.100 ± 0.010
iPTH set point (midrange)
1.190 ± 0.020
1.090 ± 0.010
Basal wPTH (pg/ml)
358.000 ± 46.000
181.000 ± 11.000
Maximal wPTH (pg/ml)
624.000 ± 93.000
467.000 ± 65.000
Minimal wPTH (pg/ml)
56.000 ± 14.000
23.000 ± 5.300
wPTH basal/maximal ratio
0.530 ± 0.050
0.430 ± 0.050
wPTH set point
1.190 ± 0.020
1.075 ± 0.010
wPTH set point (midrange)
1.180 ± 0.010
1.060 ± 0.010
The mechanism accounting for the decrease in blood calcium and phosphorus concentration after doses of calcimimetics remains unclear. The decrease may simply be in response to the decrease of PTH-mediated calcium and phosphorus efflux from bone; a response similar to those that occur when plasma PTH levels are lowered abruptly after surgical parathyroidectomy. The finding that blood calcium and phosphorus concentrations drop after PTH levels fall following drug administration is consistent with this mechanism. Alternatively, the fall in blood calcium and phosphorus concentration could be a result of the activation of calcium-sensing receptors in bone, in the gastrointestinal tract, or in other tissues after the administration of calcimimetic agents (5).
The ability of calcimimetic compounds to lower serum calcium and phosphorus levels is particularly advantageous. Before cinacalcet was approved by the U.S. Food and Drug Administration in 2004, the main choice of drug for treatment of secondary hyperparathyroidism was Vitamin D sterols, such as calcitriol (12,4). Vitamin D sterols lower plasma PTH levels by reducing pre-pro-PTH gene transcription, making less hormone available for release from the parathyroid glands. To see reductions in PTH levels, several weeks or months of treatment are needed. Also, serum calcium and phosphorus levels often rise during treatment because of the affects calcitriol has on absorption of calcium and phosphorus at the small intestine. The increases in calcium and phosphorus levels limit the doses of Vitamin D sterols that can be given safely. As a result, significant decreases in PTH levels cannot be achieved in many secondary hyperparathyroid patients by treatment with calcitriols (4). The rapid effects of calcimimetic compounds on decreasing both plasma PTH levels and serum calcium and phosphorus levels therefore makes it advantageous in treating secondary hyperparathyroidism.
Study of the Effects of Cinacalcet Over Short Time Periods
Additional studies have been performed to show how quickly calcimimetic compounds are able to lower the levels of plasma PTH and serum calcium and phosphorus levels. A study was designed to test the effects of cinacalcet on fifty-two hemodialysis patients who were being treated for secondary hyperparathyroidism. The patients were given single orally administered doses of cinacalcet, AMG 073, ranging from 5 to 100 mg or the placebo. Patients were given the dosage orally within three hours after completing their hemodialysis treatment. Immediately following hemodialysis, patients were admitted to the hospital for three days. Administration of the study drug and the following monitoring procedures took place at the hospital as a safety precaution. Before administration of the drug, patients underwent physical examinations and had blood tests performed. These pretreatment procedures were done to determine baseline values for serum calcium levels and plasma PTH concentrations. Post treatment blood samples were taken 30 minutes and 1, 2, 4, 8, 12, 24, 48, and 72 hours after administration of AMG 073. Serum calcium levels and plasma PTH concentrations were compared to the baseline values for each individual patient.
Baseline values for plasma PTH and serum calcium levels did not differ among patients given the placebo or various doses of AMG 073. A decrease in plasma PTH levels was seen in patients who were administered single doses of 25, 50, 75, or 100 mg of AMG 073. Patients given 5 or 10 mg of AMG 073 or placebo had no change in plasma PTH levels. The largest drops in plasma PTH levels were seen 2 to 4 hours after administration of AMG 073 and the values differed significantly for the different groups, ranging from decreases of 40-60%. Maximum decreases in plasma PTH levels increased as dosage of AMG 073 increased. For patients who received 25, 50, or 100 mg doses of AMG 073, plasma PTH levels remained below basal values, but PTH levels of patients who received a 75 mg dose of the drug returned to the pretreatment value after 8 hours. Decreases in PTH levels were independent of the severity of the patients' secondary hyperparathyroidism. For instance, patients had a wide range of baseline plasma PTH levels, but values decreased by a similar percentage in each patient during the first 24 hours after drug administration.
Decreases in serum calcium levels were seen in patients who were given 75 or 100 mg doses of AMG 073 but no changes were observed in patients who received smaller doses or the placebo. Serum calcium concentrations were lowest 8 to 12 hours after administration of 75 or 100 mg doses of AMG 073 and remained below pretreatment values for 24 hours. After 48 hours, serum calcium levels returned to pretreatment levels (5).
This study shows the advantages of using calcimimetic compounds and how quickly they are able to lower plasma PTH and serum calcium levels. The faster PTH levels and serum calcium and phosphorus levels return to normal, the less likely it will be for the patient to develop parathyroid hyperplasia (9).
Calcimimetics in Treatment of Parathyroid Hyperplasia
Parathyroid hyperplasia is enlargement of the parathyroid glands and develops as a result of long-term hyperstimulation. In the beginning stages of chronic renal failure, proliferation of the parathyroid glands seems to be diffuse. In the more severe stages of chronic renal failure, nodular formations develop within enlarged parathyroid glands. This results in monoclonal nodular hyperplasia (9).
A study was done looking at the effects cinacalcet had on the morphology of the parathyroid glands of maintenance haemodialysis (MHD) patients. Nine patients, all awaiting a parathyroidectomy (PTX) were studied and treated with cinacalcet. A historical control group that consisted of 11 patients with signs of severe and refractory sHPT and treated with PTX were used for comparision reasons. The starting dose was 30 mg/day of cinacalcet and increased every 21-30 days. The maximum dose reached was 150 mg/day. A baseline value for the morphology and vascular pattern of the parathyroid glands was recorded before treatment and every six months thereafter, for a period of 24-30 months. High-resolution sonography was used to determine the glandular volume of the parathyroids. Significant decreases in the volume of glands that had a baseline volume less than 500 mm3 were seen. The mean percentage decrease in volume of these glands was 68%. Baseline volumes above 500 mm3 did not see significant decreases in mean volume during the study (9).
The preliminary findings of this study suggest that cinacalcet, in combination with conventional treatments, can lead to a decrease in glandular volume of patients with severe sHPT. Volume reduction was more significant in smaller glands, suggesting the importance of early detection and treatment of parathyroid hyperplasia. Larger, more prolonged studies need to be performed to examine these preliminary findings. If additional evidence is found supporting these studies, early use of cinacalcet could reduce the number of patients requiring a PTX (9).
Calcimimetic agents are allosteric activators of the CaR. Calcimimetics work by lowering the threshold for calcium activation, directly inhibiting the release of PTH from the parathyroid glands. Multiple studies have been performed looking at the effects of calcimimetic compounds on plasma PTH levels, as well as serum calcium and phosphorus levels. All studies show a decrease in all three concentrations, suggesting calcimimetics to be a good treatment option for secondary hyperparathyroidism. The quick ability of calcimimetics to decrease PTH release from the parathyroid glands makes them highly advantageous over past treatments. Chronic kidney failure patients now have a better prognosis and decreased need for surgical intervention.