University of Washington Seattle, Washington 98195
Address correspondence and requests for reprints to: Dr. Susan Ott, Division of Metabolism, Box 356426, University of Washington, Seattle, Washington 98195-6426.
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Searching Medline for the term "calcimimetics," I found only four references, but when I tried "EM Brown," I found an impressive list of related articles spanning the last twenty years. Some of his early work described families with hypocalciuric hypercalcemia and infants with neonatal severe hyperparathyroidism. He and his colleagues pursued parathyroid physiology and showed that parathyroid cells detect changes in extracellular calcium concentration. Hence, extracellular calcium was identified as a "first messenger." High levels of extracellular calcium resulted in release of intracellular calcium, which was already known as a second messenger. The parathyroid cells response was different from other endocrine cells: instead of increasing hormone secretion with increased intracellular calcium, the PTH secretion was decreased.
Further investigation showed that G-proteins were activated when extracellular calcium was increased. Thus it was logical to look for a membrane receptor similar to others that activate G-proteins. In 1993, Brown found and cloned the receptor he had been searching for (1). This was the first such receptor whose ligand was not a hormone, but an inorganic molecule. This receptor has joined the list of seven transmembrane domain G-protein-coupled receptors. It currently belongs to group II of Family C, the metabotropic glutamate receptors (2). The list of related receptors is growing rapidly, and investigators are still searching for the ligands for many of the receptors. (http://www.gcrdb.uthscsa.edu).
The calcium receptor was first identified on parathyroid cells. It was then found on several other kinds of cells, including thyroid C cells. This fit into the old paradigmthese cells should sense calcium because they make a hormone that regulates the calcium. Indeed, when the calcium receptor is activated on the C cells, calcitonin is secreted. Dual hormone control of a substance is a familiar concept.
But calcium receptors were also located on cells from organs that were thought to be the targets for the calcium-regulating hormones. These cells are the effectors in the feedback loops and were not supposed to have sensing receptors: renal tubular cells (3), gastric cells, bone marrow cells, and osteoblast precursors (4). Data is starting to accumulate that these receptors do influence cell physiology. It is time to revise the textbook model of the feedback loop for calcium metabolism and add a short-circuit. Cells that can alter calcium balance are regulated not only by hormones but also by calcium itself. These short-circuits are being explored in several other classical feedback loops, modifying the scope of endocrinology.
In the kidneys, the highest concentration of calcium receptors are found in the thick ascending limb, which controls reabsorption of calcium. Normally the transepithelial potential is lumen positive, favoring transport of calcium from the lumen into the interstitium via a peritubular pathway. The potential difference is maintained by secretion of K, which is recycled via the Na-K-2Cl cotransporter. Activation of the calcium receptor (on the basolateral membrane) inhibits the K permeability, which depletes luminal K concentration and inhibits NaCl absorption. This results in reduced calcium absorption. The net effect is similar to that of a loop diuretic (5).
Some renal tubular cells have receptors for PTH and others for calcium. Activation of the PTH receptor results in increased calcium reabsorption, whereas activation of the calcium receptor results in decreased calcium reabsorption. Under the usual physiologic stresses placed on the individual by the environment, this system will be complementary. During calcium deficiency the serum calcium is low, the PTH is high, and the kidneys will reabsorb calcium. During calcium excess the opposite occurs - serum calcium is high, PTH is low and the kidneys excrete the calcium. In pathologic situations where the messages are mixed, such as hypercalcemia and hyperparathyroidism, the PTH effect seems to predominate.
In addition to the effect on renal calcium transport, the calcium receptor is linked to water transport. Activation of calcium receptor leads to increased permeability of the distal collecting tube, so the urine is less concentrated. This explains how hypercalcemia can lead to nephrogenic diabetes insipidis. It is easy to remember this action, because it helps to prevent kidney stones. If the urine were allowed to reach normal maximal concentrations the high luminal concentrations of calcium would precipitate (6).
Cells in the bone marrow, including osteoblast precursors, also have calcium receptors (4). The function of these are not clear, but it appears that osteoblasts proliferate and form more bone when the calcium receptor is activated. Again, PTH itself has powerful actions on these cells, which usually dominate the clinical picture. In uremic rats, treatment with a calcimimetic reversed the osteitis fibrosis and decreased the rate of bone turnover, effects that were explained by the reduction in PTH (7).
Identification of the calcium receptor gene led to searches for mutations. Dr. Brown and colleagues had suspected that severe neonatal hyperparathyroidism and familial hypocalciuric hypercalcemia were related to calcium sensing, and again they were correct. Several mutations have been found that lead to loss of function of the calcium receptor (8). Heterozygotes have an increased "set-point" for PTH secretion (i.e. they require higher serum calcium to block PTH secretion). PTH is mildly elevated. The urine calcium is low despite increased serum calcium and remains low after parathyroidectomy. This condition is benign, and treatment consists of avoiding parathyroidectomy. The homozygous form, however, is severe neonatal hyperparathyroidism. The affected infants have marked hypercalcemia and hyperparathyroidism. Even when the parathyroid glands are removed, they still have hypercalcemia, because their kidneys do not excrete the calcium load. Loop diuretics such as furosimide, which enhance urine calcium excretion, are necessary in these patients.
If an inactivating mutation of the calcium receptor gene can cause hypocalciuric hypercalcemia, then an activating mutation should do the opposite. Recently families with hypercalciuric hypocalcemia have been found who did have mutations that resulted in gain of function (9).
The calcium receptor is not specific for calcium. Other cations can activate the receptor. In a search for pharmacologic activators, one compound was discovered (NPS R568) that can be given orally. This is the first calcimimetic that has been studied in humans.
Silverberg et al. (10) studied 20 postmenopausal women who had primary hyperparathyroidism. They were randomly given placebo or a single portion of the calcimimetic. Doses were varied so that each woman received a placebo and 2 other doses. They were followed for 3 days after each treatment, with at least 2 weeks between treatments. At the higher doses, 51% decreases in PTH were seen. Serum calcium decreased slightly, and urine calcium excretion doubled. These changes were maximal at 2 h, returning to baseline by 8 h. No adverse events were experienced.
Antonsen et al. (11) gave the calcimimetic drug to eight males maintained on chronic hemodialysis. Each patient received two identical portions, a day apart, and then several weeks later, two more identical portions at a higher dose. One portion was given just before dialysis, and the next day the patient did not receive dialysis. This study also showed a dramatic dose-dependent decrease in PTH. Six of 7 patients had more than a 60% decrease in PTH. Serum calcium declined modestly. The serum calcitonin increased. These changes were seen both during dialysis and on a nondialysis day. The serum calcium did not drop below the normal range, but the patients all were taking calcitriol. No adverse events were detected during the two days of giving the drug.
The study reported by Collins et al. (12) in this issue of JCEM (see page 0000) is important because it is the first case in which the drug has been given long-termin fact, very long-term for such a new drug. The patient had inoperable parathyroid cancer and had failed conventional therapy. Before treatment he had developed several complications leading eventually to hypercalcemic delerium. For two years on the calcimimetic his hypercalcemia has been controlled. He has felt well and been able to work full time. Readers will inevitably share the authors enthusiasm for the dramatic effects seen in their patient.
The case also raises several questions about the calcimimetics and the actions of the calcium receptors. One such question concerns the renal response. The overall excretion of calcium decreased when the patient was started on calcimimetic, which can be explained by the decreased filtered load of calcium. During the acute phase of therapy the drug did not alter the fractional excretion of calcium, even though activation of the calcium receptor would be expected to enhance the fractional excretion. Probably the furosemide effect was strong enough to over-ride other effects. Also, the patients renal insufficiency could have made him less able to respond to renal effects of the calcimimetic. Studies of patients with normal renal function are needed to answer this question.
A related question is the bone response. This patients bone density continued to decrease by a substantial amount, in trabecular bone and especially in cortical bone. This is the pattern seen with hyperparathyroidism, and suggests that his ongoing high PTH was still active on the bone cells. In this case the theoretical beneficial effect of activating the calcium receptors on the osteoblast was not manifest. The long-term urine calcium was not reported; it is possible that, during the later phases of treatment, he had enough negative calcium balance to explain the bone loss. This can happen without increases in serum calcium. If a bath tub is partially full of water, you can turn up the faucet and open the drain, while maintaining the water-level at the same position. Again, I wonder what would happen to patients who did not have the carcinoma, renal dysfunction, and other complications of this case.
This drug has great potential for treating patients with either primary or secondary hyperparathyroidism. Currently there are no satisfactory medical therapies for primary hyperparathyroidism. Patients must chose between surgery and observation. The drug would be particularly useful to patients who have an indication for surgery, such as hypercalcemia, but who have a high surgical risk.
In renal patients the need is even greater. Even with optimal medical management it is difficult to control secondary hyperparathyroidism, resulting in renal osteodystrophy as well as problems with metastatic calcifications. Parathyromatosis, an unusual complication of parathyroidectomy in dialysis patients, currently has no treatment, and it should respond to the calcimimetics (13). Calcitriol treatment can partially control the PTH, but it is limited by development of hypercalcemia. Phosphate control also involves giving oral calcium, which can cause hypercalcemia, but not enough hypercalcemia to turn off the PTH. The calcimimetic drugs should lower PTH even when there is already hypercalcemia.
Further progress in this area seems hampered by the lack of enthusiasm from the company that holds the patent on this drug. Clinical investigators are eager to learn more about the long-term effects of the drug, to understand more about the physiology of calcium metabolism and to develop treatment for their patients. I hope that in the future there will be more support for clinical studies of the calcimimetics.
Received February 5, 1998.
Accepted February 6, 1998.
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