| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
Original Articles |
Developmental Endocrinology Branch, National Institute of Child Health and Human Development (M.T.C.), Metabolic Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases (M.C.S., A.M.S., S.J.M.), National Institutes of Health, Bethesda, Maryland 20892; and the Department of Medicine (S.J.S. J.P.B.) and Pharmacology (J.P.B.), College of Physicians and Surgeons, Columbia University, New York, New York 10032
Address all correspondence and requests for reprints to: Dr. Michael T. Collins, Developmental Endocrinology Branch, National Institute of Child Health and Human Development, National Institutes of Health, 10 Center Drive MSC1862, Building 10 Room 10N262, Bethesda, Maryland 20892; E-mail: collinsm{at}cc1.nichd.nih.gov
Abstract
Parathyroid carcinoma is one cause of primary hyperparathyroidism, a condition in which there is hypercalcemia and dysregulated hypersecretion of PTH. In normal, and in some neoplastic parathyroid cells, PTH secretion is mediated by the cell surface calcium-sensing receptor. We describe the first therapeutic use of a novel molecule, a calcimimetic, that has agonist action at the calcium-sensing receptor.
A 78-yr-old man with parathyroid carcinoma was admitted with hypercalcemia, markedly elevated PTH, and a change in mental status. He was treated for 17 days with conventional therapy, which included saline hydration, furosemide, pamidronate, and calcitonin. This was ineffective, and on hospital day 18, calcimimetic at a dose of 50 mg, orally, every 6 h was added. On hospital day 25, the dose was increased to 100 mg, orally, every 6 h, and on hospital day 30, saline and furosemide were discontinued. He was discharged on hospital day 40. With several dose adjustments, he has been treated with monotherapy calcimimetic for over 600 days and has not required any other interventions for his parathyroid carcinoma.
Mean daily precalcimimetic treatment values of serum ionized calcium and PTH were 1.83 mmol/L and 872 pg/mL, respectively. During hospitalization, at the lower dose of calcimimetic, calcium and PTH decreased to 1.67 mmol/L and 538 pg/mL; with the higher dose they further decreased to 1.51 mmol/L and 444 pg/mL. Since discharge, and despite increasing levels of PTH, serum calcium has remained high, but lower than the admission level and acutely responsive to changes in calcimimetic doses.
This compound, a calcimimetic, the first of a new class of compounds with activity at the calcium-sensing receptor, has been used to treat a patient with parathyroid carcinoma. During 2 yr of treatment, no adverse clinical effects have been observed, and it appears to have been effective at controlling hypercalcemia.
PARATHYROID carcinoma is a rare cause of primary hyperparathyroidism in which there can be marked elevations of PTH and serum calcium (1). Early surgery offers the only chance for cure. Complete surgical resection, however, is usually not possible, and recurrence is common. Medical therapies to treat this and other forms of primary hyperparathyroidism are directed at target tissue actions of PTH, such as osteolysis (2). None is directed at the underlying cause of the hypercalcemia, namely hypersecretion of PTH.
PTH secretion is negatively regulated by increasing serum ionized calcium concentrations (3), a regulation that is largely preserved by neoplastic parathyroid cells, at least in the case of benign tumors (4). Although the precise mechanism of calcium regulation of PTH secretion is not fully understood, identification and characterization of the parathyroid cell calcium-sensing receptor have provided insight about the first step of this pathway (5). The nucleotide sequence of the calcium-sensing receptor predicts seven hydrophobic transmembrane domains similar to other receptors in the G protein-coupled serpentine receptor superfamily, a large extracellular domain with potential calcium-binding clusters of acidic residues, and an intracellular tail (5). Similar or identical calcium receptors have been identified on some other cells known to be involved in calcium homeostasis, such as calcitonin-producing C cells of the thyroid (6) and renal tubular cells (7). Furthermore, the calcium-perturbing role of inactivating mutations, in the case of familial hypocalciuric hypercalcemia and severe neonatal hyperparathyroidism (8), and activating mutations, in the case of familial hypocalcemia with hypercalciuria (9), suggest that agonists and antagonists of this receptor have the potential to modulate PTH levels and, thus, calcium metabolism.
An allosteric modulator of the receptor that has calcimimetic properties has been developed (10) and has entered early clinical trials for the treatment of primary and secondary hyperparathyroidism. Preclinical data showed that this compound (N-[1(R)-(3-methoxyphenyl)ethyl]-3-(2-chlorophenyl)-1-aminopropane) is effective in lowering both serum ionized calcium and PTH in normal and uremic rats (11). In normal human subjects, single doses decreased PTH levels in a dose-dependent manner, and in a 2-week trial, there was a sustained reduction in serum calcium levels (data on file at Amgen, Thousand Oaks, CA). Single doses of the drug decreased PTH concentrations in patients with primary hyperparathyroidism (12). These data suggested that this drug may be effective in treating primary hyperparathyroidism.
This report describes the first therapeutic use of this drug, a calcimimetic with activity at the calcium-sensing receptor. It was used to treat a 78-yr-old man with parathyroid carcinoma, the form of primary hyperparathyroidism that is most refractory to treatment.
Case Report
History
The patient was 78 yr old when admitted to the NIH in 1995. He presented in 1988 with hypercalcemia and hyperparathyroidism. Neck exploration was performed, and a solitary tumor was resected. Immediately after the surgery, PTH levels returned to the normal range, and he became eucalcemic. However, 4 yr later, hypercalcemia recurred. He subsequently underwent four additional neck explorations. The patient was transiently eucalcemic after the first three operations, but not after operation 4 or 5. Resected parathyroid tissue from the first three operations was reported as "hyperplastic parathyroid tissue". However, tissue from the last two operations was consistent with parathyroid carcinoma. Over the last several years, his condition gradually worsened; he developed nephrolithiasis with renal insufficiency, osteopenia, anemia, lethargy, and a decline in functional capacity. Before transfer to the NIH, he was being treated as an in-patient at another facility. Treatment there for hypercalcemia included iv hydration and iv pamidronate, neither of which was effective at significantly lowering serum calcium concentrations. Given the degree of renal impairment at baseline, gallium nitrate and mithramycin were not used.
Measurements
Serum for PTH and calcium determinations during the in-patient treatment phase of therapy were drawn each morning approximately 2 h after drug administration. During chronic therapy, blood samples were taken between 1–4 h after drug administration. Serum ionized calcium (Nova, Waltham, MA) and total calcium (Hitachi-Boehringer Mannheim, Indianapolis, IN) were measured using standard techniques. PTH was measured using an immunoradiometric assay (13).
Twenty-four-hour urine specimens were analyzed for calcium using atomic absorption spectrophotometry and for creatinine using standard autoanalyzer techniques.
Acute treatment
On admission to the NIH, the patient was delirious, with marked
hypercalcemia and multiple laboratory abnormalities (Table 1
). The initial plan on admission was to
localize parathyroid tissue and perform a neck exploration to remove
PTH-producing tissue. However, five previous neck explorations and the
patient’s generally debilitated state made the risk of an additional
surgery unacceptably high. For that reason the use of the calcimimetic
agent was pursued. For the first 18 hospital days, he was treated with
conventional therapy. This consisted of hydration with normal saline
(175 cc/h, iv) plus furosemide (40 mg, iv, twice daily) from the time
of admission. He subsequently received three doses of pamidronate (60
mg each, iv), on hospital days 1, 7, and 10, and salmon calcitonin (100
IU, sc, daily) on hospital days 11–16. Studies to localize parathyroid
tissue revealed [131I]sestamibi uptake in the neck
without any evidence of metastases outside that region (not shown). The
patient was enrolled in a single use protocol approved by the
institutional review board.
|
Acute treatment response
Serum calcium. Despite aggressive conventional therapy, the
serum calcium level was very high and variable (Fig. 1), and the patient did not improve
clinically. It was not until the calcimimetic was added to his medical
regimen that a significant and sustained improvement was seen in serum
calcium concentrations. By the second day of treatment, a decrease in
the ionized calcium concentration was observed (Fig. 1). The patient
began to improve clinically by the third day of treatment,
demonstrating improved orientation and increased appetite. On hospital
day 25, the dose of calcimimetic was increased to 100 mg, orally, every
6 h; with this dose increase, there was a further decrease in
ionized calcium (Fig. 1). After 7 days at the higher dose, saline
hydration and furosemide were discontinued. Medical therapy at this
point consisted only of the calcimimetic. Serum calcium concentrations
remained stable on calcimimetic monotherapy (Fig. 1).
|
). The downward
trend in PTH is demonstrated by the average daily PTH concentration
(Fig. 2b). There were dramatic, if unsustained, decreases in PTH with
both the first administration of the calcimimetic on day 18 and the
doubling of the dose on day 25 (Fig. 2b).
|
). Urinary calcium excretion was quite
high during conventional therapy (saline, furosemide, pamidronate, and
calcitonin). With the addition of calcimimetic to the conventional
therapy, there was a decrease in urinary calcium excretion form
baseline that was statistically significant at the higher dose of
calcimimetic. Furthermore, there was a statistically significant
decrease in urinary calcium excretion between the lower dose of
calcimimetic (plus saline and furosemide) and the higher dose of
calcimimetic (plus saline and furosemide). When saline and furosemide
were removed from the medical regimen, and the treatment was
calcimimetic alone at 100 mg, orally, every 6 h, there was a
dramatic decrease in urinary calcium excretion to just above the normal
range.
|
Chronic treatment
The patient was discharged on treatment day 40, receiving calcimimetic at a total daily dose of 400 mg (100 mg, orally, 4 times daily). Approximately 1 month after discharge, his serum calcium level returned to the normal range, and the dose was decreased to 200 mg/day. Subsequent increases in serum calcium and PTH prompted several dose increases. At this writing, the patient is 80 yr old and has been treated with calcimimetic continuously for over 21 months.
Chronic treatment response
Serum calcium. Serum calcium values fluctuated over the
course of chronic treatment (Fig. 4a).
After approximately 1 month of treatment, while the patient was taking
400 mg/day of the calcimimetic, serum calcium fell into the normal
range. This prompted a decrease in the dose of calcimimetic to 200
mg/day to avoid hypocalcemia. Subsequently, serum calcium rose to 2.95
mmol/L (normal range, 2.05–2.50 mmol/L), and the dose of calcimimetic
was increased to 300 mg/day. This resulted in decreases in both serum
calcium and PTH that were only temporarily sustained (Fig. 4, a and b).
Serum calcium rose to 2.98 mmol/L, and the dose of calcimimetic was
increased to 350 mg/day. There was a transient decrease in serum
calcium, but by day 104, serum calcium had increased to 2.98 mmol/L,
and the dose of calcimimetic was increased to 400 mg/day. For
approximately the next 100 days, serum calcium was relatively stable
but eventually rose to 3.25 mmol/L, necessitating an increase in the
calcimimetic dose to 600 mg/day. For approximately the last year he has
continued to receive this dose. Although there have been fluctuations
in serum calcium levels, he has remained stable clinically.
|
). Of note, however, is the response of PTH to several of the
dose adjustments. With the initiation of calcimimetic on day 18, and
with the dose increases on days 90, 104, and 222, there was a marked
decrease in PTH. Furthermore, a time-course study performed
approximately 2 months into treatment demonstrated that a single 50-mg
dose of the drug was able to decrease serum PTH concentrations from
1655 pg/mL at baseline to 870 pg/mL 1 h after treatment, a 47%
reduction. Serum PTH values rose to 1185 pg/mL 2 h after the 50-mg
dose, a 29% decrease from the baseline. However, there continues to be
a steady rise in PTH with the passage of time. Other clinical indicators. Clinically, the patient has done well over the period of treatment. Except for the brief period of delirium and decompensation at admission and despite almost 10 yr of severe hyperparathyroidism, he remains highly functional. He is 80 yr old, working full time, and reports feeling well. Since discharge form our facility, he has not required medications other than the calcimimetic for the treatment of hyperparathyroidism or hypercalcemia. In addition, all measures of renal, cardiac, hepatic, hematological, and pancreatic functioning have remained stable over the entire treatment period (not shown). Serum 25 and 1,25-hydroxyvitamin D levels were normal at baseline and have remained essentially unchanged throughout treatment (not shown). He has had no complaints and has not experienced any side-effects that can be ascribed to treatment with the calcimimetic.
Discussion
This single patient study demonstrates the probable efficacy and lack of adverse clinical effects in 2 yr of treatment of a patient with parathyroid carcinoma with a novel calcimimetic. The patient had been progressively deteriorating for 1.5 yr before treatment with calcimimetic, with worsening hypercalcemia and declining functional status to the point where he was moribund on admission. Acutely, there was a marked decline in serum calcium after the administration of calcimimetic. This was paralleled by a decrease in average daily PTH values. There is a possibility that the acute response in serum calcium and PTH was not so much the result of the calcimimetic, but, rather, the cumulative effect of the conventional therapies. This seems unlikely because the patient had been treated with conventional therapy on a number of occasions just before admission without a similar effect. Furthermore, although conventional therapies can lower serum calcium, the indirect effect at the level of the parathyroid gland is to increase, not decrease, serum PTH. The temporal relationship to drug administration, the dose-response effect, and the sustained effect with the discontinuation of saline and furosemide all point to the likelihood that the calcimimetic was the cause of the acute and sustained decline seen in serum calcium over the first 40 days of treatment.
The acute response in PTH is not as clear-cut as the response of calcium. However, when the daily PTH values are pooled and averaged, a dose-dependent decrease, paralleling the decrease in serum calcium, is observed. The wider variability in PTH values is probably a result of the minute to minute fluctuations that can take place in serum PTH values (14).
The effect of calcimimetic on urinary calcium is difficult to interpret. With the addition of calcimimetic to conventional therapy, there was a statistically significant decrease in urinary calcium. With calcimimetic as monotherapy, there was a marked reduction in urinary calcium excretion. Activation of the calcium receptor in the kidney of patients with activating mutations produce hypercalciuria (9). Therefore, an exogenous activator of the receptor would be expected to raise urinary calcium. In fact, hypercalciuria would be a concern in the administration of this class of drug. The decrease in urinary calcium most likely reflects the net effect of the complex interaction of competing regulators of urinary calcium. As serum calcium is lowered, the load of calcium filtered by the kidney is decreased. This is probably the reason why there was a decrease in urinary calcium with the addition of calcimimetic. There was no difference in the fractional excretion of calcium between when the patient was receiving conventional therapy only and when the drug was added to conventional therapy or with an increase in the dose of the drug (data not shown). With the discontinuation of furosemide and saline, there was a significant decrease in the fractional excretion of calcium. Therefore, it is not likely that a drug effect by the calcimimetic on the fractional excretion of calcium is the cause of the changes in urinary calcium. When furosemide was stopped, there was a further marked reduction in urinary calcium, probably the result of withdrawal of the loop diuretic. In view of the theoretical concerns raised above, it is comforting to see that there is not marked hypercalciuria. It is not unreasonable to expect this degree of hypercalciuria in a patient with his level of hypercalcemia even in the presence of impaired renal function. Elucidation of the interacting mechanisms would require measurements with and without the drug. Given the severity of the patient’s disease, it would not be ethical to discontinue the drug.
During almost 2 yr of calcimimetic treatment, serum calcium has remained relatively stable. This is dramatically different from what occurred in the 1.5 yr before starting this therapy, when progressively worsening hypercalcemia became life threatening. The stabilization of serum calcium has occurred without the addition of other therapies. This may reflect the effect of the calcimimetic. Proof of this, however, would require stopping and restarting the drug, a course that is not appropriate in this case.
The response of PTH to the chronic administration of calcimimetic is less clear. The PTH level has had some of the predicted acute responses to the administration of a calcimimetic; i.e. with a dose decrease on day 47, PTH rose, and with dose increases on days 83, 104, and 222, PTH decreased. However, over the long term there has been a steady rise in the PTH. This is not surprising given the nature of the disease. Parathyroid carcinoma is the most severe and aggressive form of primary hyperparathyroidism and often loses responsiveness to interventions to which less severe forms of primary hyperparathyroidism respond (1). The escape of responsiveness to the calcimimetic could be explained by a number of scenarios, including further dedifferentiation of the cancer, increased growth of the tumor, or tumor metastases.
Perhaps the most surprising aspect of the patient’s response is the maintenance of a relatively stable serum calcium level in the face of an increasing serum PTH level. As the drug is apparently becoming less effective at the level of the parathyroid cell, one would have to evoke either renal or bone effects of the drug to explain this. The observations that there was a significantly higher level of urinary calcium during conventional therapy and that the level of urinary calcium decreased when the dose of calcimimetic was increased, suggest that an increase in urinary calcium secretion is not an explanation of the major mechanism of the drug. However, this remains to be studied in a more direct and controlled fashion. An effect of the calcimimetic on bone would be a plausible explanation of the lack of an increase in serum calcium in the face of increasing PTH. It is possible that the calcimimetic is inhibiting PTH action on bone via its action on the calcium-sensing receptor. There are reports that demonstrate the presence of the calcium receptor in chondrocytes (15, 16) and a recent report demonstrating the presence of the receptor in human and mouse bone marrow cells with osteogenic potential (17). In addition, there is evidence for a molecularly distinct calcium-sensing receptor present in a murine-derived osteoblast cell line (18) at which this compound could potentially have action.
Inhibition of osteoclastic bone resorption would explain a lack of increase in serum calcium. However, this is not likely either, given that there has been a steady decline in bone density at all sites in serial measurements of bone density. In 1 yr of calcimimetic therapy, bone density at the spine, hip, and radius decreased 11%, 13%, and 19%, respectively. This indicates that osteoclastic activity is intact, and that decreased osteoclastic activity is not the cause of the lack of increase in serum calcium. An alternative explanation would be that the tumor is now secreting a PTH molecule that is detected by the intact PTH assay but is less biologically active.
No adverse effects have been observed during the 2 yr of administration of this drug. This elderly and very ill patient has tolerated treatment well. All measures of hepatic, renal, gastrointestinal, pulmonary, and cardiac function have been stable. In fact, the patient, despite his age and now almost 10 yr of primary hyperparathyroidism (including parathyroid carcinoma), continues to work full time and generally feels well. The patient’s grave condition at presentation, the severity of his underlying disease, and his lack of responsiveness to conventional therapy all justified the use of this new drug. However, these same factors do not allow for the ideal study to prove efficacy or to delineate mechanisms of action. Given these limitations, we are able to say that the drug has caused no adverse clinical effects and that it is probably effective at controlling PTH-mediated hypercalcemia in this case of parathyroid carcinoma. Although the results in this patient were clinically dramatic and biochemically encouraging, further research will be required to establish the safety, efficacy, and mechanism of this class of compound in treating PTH-mediated hypercalcemia.
Acknowledgments
The authors would like to acknowledge NPS Pharmaceuticals, Salt Lake City, Utah, and Amgen, Thousand Oaks, California, for supplying the calcimimetic.
Received October 23, 1997.
Revised December 19, 1997.
Accepted January 8, 1998.
References
This article has been cited by other articles:
 |
|
 |
|
  A. Khan, A. Grey, and D. Shoback Medical Management of Asymptomatic Primary Hyperparathyroidism: Proceedings of the Third International Workshop J. Clin. Endocrinol. Metab., February 1, 2009; 94(2): 373 - 381. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P Iglesias and J J Diez Current treatments in the management of patients with primary hyperparathyroidism Postgrad. Med. J., January 1, 2009; 85(999): 15 - 23. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. J. Silverberg, M. R. Rubin, C. Faiman, M. Peacock, D. M. Shoback, R. C. Smallridge, L. E. Schwanauer, K. A. Olson, P. Klassen, and J. P. Bilezikian Cinacalcet Hydrochloride Reduces the Serum Calcium Concentration in Inoperable Parathyroid Carcinoma J. Clin. Endocrinol. Metab., October 1, 2007; 92(10): 3803 - 3808. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. J. Marx and W. F. Simonds Hereditary Hormone Excess: Genes, Molecular Pathways, and Syndromes Endocr. Rev., August 1, 2005; 26(5): 615 - 661. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. S Joy, A. V Kshirsagar, and N. Franceschini Calcimimetics and the Treatment of Primary and Secondary Hyperparathyroidism Ann. Pharmacother., November 1, 2004; 38(11): 1871 - 1880. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Betea, A. R. Bradwell, T. C. Harvey, G. P. Mead, H. Schmidt-Gayk, B. Ghaye, A. F. Daly, and A. Beckers Hormonal and Biochemical Normalization and Tumor Shrinkage Induced by Anti-Parathyroid Hormone Immunotherapy in a Patient with Metastatic Parathyroid Carcinoma J. Clin. Endocrinol. Metab., July 1, 2004; 89(7): 3413 - 3420. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
O. Kifor, F. D. Moore Jr., M. Delaney, J. Garber, G. N. Hendy, R. Butters, P. Gao, T. L. Cantor, I. Kifor, E. M. Brown, et al. A Syndrome of Hypocalciuric Hypercalcemia Caused by Autoantibodies Directed at the Calcium-Sensing Receptor J. Clin. Endocrinol. Metab., January 1, 2003; 88(1): 60 - 72. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. Shane Parathyroid Carcinoma J. Clin. Endocrinol. Metab., February 1, 2001; 86(2): 485 - 493. [Full Text]
|
|
|
|
 |
|
 O. M. Hauache, J. Hu, K. Ray, R. Xie, K. A. Jacobson, and A. M. Spiegel Effects of a Calcimimetic Compound and Naturally Activating Mutations on the Human Ca2+ Receptor and on Ca2+ Receptor/Metabotropic Glutamate Chimeric Receptors Endocrinology, November 1, 2000; 141(11): 4156 - 4163. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. Mihai and J. R. Farndon Parathyroid disease and calcium metabolism Br. J. Anaesth., July 1, 2000; 85(1): 29 - 43. [Full Text] [PDF]
|
|
|
|
 |
|
 J. R. Burgess, R. David, T. M. Greenaway, V. Parameswaran, and J. J. Shepherd Osteoporosis in Multiple Endocrine Neoplasia Type 1: Severity, Clinical Significance, Relationship to Primary Hyperparathyroidism, and Response to Parathyroidectomy Arch Surg, October 1, 1999; 134(10): 1119 - 1123. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. A. Tritos and P. Hartzband Rapid Improvement of Osteoporosis Following Parathyroidectomy in a Premenopausal Woman With Acute Primary Hyperparathyroidism Arch Intern Med, July 12, 1999; 159(13): 1495 - 1498. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. M. Ott Calcimimetics--New Drugs with the Potential To Control Hyperparathyroidism J. Clin. Endocrinol. Metab., April 1, 1998; 83(4): 1080 - 1082. [Full Text]
|
|
|
|
 |
|
 A. A. Jensen, T. A. Spalding, E. S. Burstein, P. O. Sheppard, P. J. O'Hara, M. R. Brann, P. Krogsgaard-Larsen, and H. Brauner-Osborne Functional Importance of the Ala116-Pro136 Region in the Calcium-sensing Receptor. CONSTITUTIVE ACTIVITY AND INVERSE AGONISM IN A FAMILY C G-PROTEIN-COUPLED RECEPTOR J. Biol. Chem., September 15, 2000; 275(38): 29547 - 29555. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| Endocrinology | Endocrine Reviews | J. Clin. End. & Metab. |
| Molecular Endocrinology | Recent Prog. Horm. Res. | All Endocrine Journals |
