EDITORIAL

Calcimimetics in action

The recent identification of a calcium receptor in the parathy-roid gland [1] has provided important new understanding of avariety of relatively uncommon metabolic disorders. Geneticdefects in this receptor clearly play an important role in familialhypocalciuric hypercalcemia [2], in which the receptor is lessresponsive to calcium, and in various hereditary forms of hypo-parathyroidism [3], in which responsiveness to calcium is in-creased and parathyroid hormone (PTH) secretion is suppressedby calcium levels substantially below normal.

While these discoveries have been enormously exciting andprovocative, for the clinician the development of agents thatactivate the receptor independent of calcium (calcimimetics)provides a therapeutic modality with wide-ranging possibilities.Scientists at NPS Pharmaceuticals have developed a compound,R-568, given by mouth, that activates the calcium receptor tosuppress PTH secretion. It also binds to several other sites ofinterest, specifically the thyroid C cell and the renal tubule. Atthese latter sites it may also simulate the effects of calcium itselfby stimulating calcitonin release from C cells and decreasing renaltubular calcium reabsorption (though there is as yet no directevidence of an effect at the renal tubule). For the first time, then,a potential therapy that decreases PTH secretion does not resultin an increase in serum calcium.

The focus of animal studies to explore these effects has been onPTH levels and the safety of effective doses. Numerous studies inrats and other species have been conducted that do not show anyunusual toxicity. The study by Wada et al in the current issue ofKidney International [4] extends studies of R-568 to a condition ofparticular interest to nephrologists, renal osteodystrophy. Afterinducing renal failure and hyperparathyroidism in rats, the inves-tigators assessed the ability of R-568 both to suppress PTHsecretion and to improve bone histology. The results met expec-tations, with improvement not only in PTH levels and bonehistology, but also in bone strength.

Of course, the questions clinicians will want answered is: arethese results achievable in humans as well? The answer is aqualified affirmative. Reports of single-dose studies in normalsubjects, patients with primary hyperparathyroidism and patientswith secondary (renal) hyperparathyroidism have been publishedrecently [5, 6]. In all cases, over a wide range of oral doses, PTHsecretion was suppressed. Larger doses produced greater suppres-sion and the effect persisted longer. No side-effects have beenobserved, but of course, these preliminary studies in fewer than100 patients cannot be presumed to address the safety issues.Larger studies of longer duration will be needed to delineate theseissues as well as define the clinical role of calcimimetic agents.

Use of these agents is likely to differ in the two patientpopulations investigated so far. In primary hyperparathyroidism

the drug should provide a medical equivalent to surgery. Forpatients in whom surgery may be risky or the benefits of it unclear,the potential exists to suppress PTH production to any degreedesired and to reverse the suppression at any point. Presumably,clinicians will want to suppress PTH sufficiently to control hyper-calcemia and/or hypercalciuria. Whether suppression to a greaterdegree is desirable remains to be demonstrated.

In patients with renal failure and secondary hyperparathyroid-ism, therapy will be more complicated than in patients withprimary hyperparathyroidism. In patients with the secondaryhyperparathyroidism of renal failure the calcium is likely to fall,perhaps too greatly, if a calcimimetic is used as the sole therapy.Indeed, successful suppression of PTH should lead to this out-come (as currently occurs with parathyroid surgery in suchpatients). Therefore, clinicians will need to regulate calcium andcalcitriol intake to maintain calcium when a calcimimetic isprescribed. At first blush this seems to complicate therapy. In myopinion, it actually simplifies treatment, since our current medicalapproach to this condition is limited by the development ofhypercalcemia. Using one agent to regulate PTH and another tocontrol calcium will produce better control of treatment strate-gies.

Calciphylaxis and parathyromatosis, two rare complications ofcalcium metabolism in renal failure that are exceedingly frustrat-ing to treat [7], may respond to calcimimetic therapy. Calciphy-laxis does not always respond to parathyroid surgery. The use ofa calcimimetic, by duplicating the effect of such surgery, shouldidentify patients who will respond to it (or provide an alternatetherapy for those in whom the operative procedure is deemedrisky). Currently we have no treatment for parathyromatosis.

In summary, the development of calcimimetics presents aremarkable therapeutic potential for a variety of difficult clinicalproblems. I look forward to the continued clinical evaluation ofthis class of drugs and their ultimate addition to extant therapeuticefforts.

DONALD J. SHERRARDSeattle Washington, USA

Reprint requests to Donald J. Sherrard, M.D., Department of VeteransAffairs, Puget Sound Health Care Systems, Renal Dialysis Unit (111A) 1660South Columbian Way, Seattle, Washington 98108, USA.

ACKNOWLEDGMENTS

Statement of potential conflicts: Dr. Sherrard has been a consultant toboth NPS Pharmaceuticals, Inc. and AMGEN, both of which have beeninvolved in the development of the calcimimetic agent R-568. He alsoreceived research support from NPS Pharmaceuticals, Inc., for the studiesdescribed above in reference 6. He currently is not receiving funding fromeither organization, nor does he have financial interests in either organi-zation.Key words: parathyroid hormone, osteodystrophy, calcium

© 1998 by the International Society of Nephrology

Kidney International, Vol. 53 (1997), pp. 510–511

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REFERENCES

1. BROWN EM, HEBERT SC: A cloned extracellular Ca21 sensing receptor:Molecular mediator of the actions of extracellular Ca21 on parathyroidand kidney cells? Kidney Int 49:1042–1046, 1996

2. HEATH H: Familial benign hypercalcemia—from clinical description tomolecular genetics. West J Med 160:554–561, 1994

3. PEARCE SHS, WILLIAMSON C, KIFOR O, BAI M, COULTHARD MG,DAVIES M, LEWIS-BARNED N, MCCREDIE D, POWELL H, KENDALL-TAYLOR P, BROWN EM, THAKKER RV: A familial syndrome of hypocal-cemia with hypercalciuria due to mutations in the calcium-sensingreceptor. N Engl J Med 335:1115–1122, 1996

4. WADA M, ISHII H, FURUYA Y, FOX J, NEMETH EF, NAGONO N: NPS

R-568 halts or reverses osteitis fibrosa in uremic rats. Kidney Int53:448–454, 1998

5. SILVERBERG SI, BONE H, MARRIOT T, LOCKER FG, THYS-JACOBS S,DZIEM G, KAATZ S, SANGUINETTI EL, BILEZIKIAN JP: Short-terminhibition of parathyroid hormone secretion by a calcium receptoragonist in primary hyperparathyroidism. N Engl J Med 337:1506–1510,1997

6. ANTONSEN JE, SHERRARD DJ, ANDRESS DL: A calcimimetic agentacutely suppresses parathyroid hormone levels in patients with chronicrenal failure. Kidney Int 53:223–227, 1998

7. STEHMAN-BREEN C, MUIRHEAD N, THORNING D, SHERRARD DJ: Sec-ondary hyperparathyroidism complicated by parathyromatosis. Am JKidney Dis 28:502–507, 1996

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