Abstract
Context: Patients with persistent primary hyperparathyroidism (PHPT) after parathyroidectomy or with contraindications to parathyroidectomy often require chronic treatment for hypercalcemia.
Objective: The objective of the study was to assess the ability of the calcimimetic, cinacalcet, to reduce serum calcium in patients with intractable PHPT.
Design: 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.
Setting: The study was conducted at 23 centers in Europe, the United States, and Canada.
Patients: The study included 17 patients with intractable PHPT and serum calcium greater than 12.5 mg/dl (3.1 mmol/liter).
Intervention: 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.
Main Outcome Measure: 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.
Results: 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.
Conclusions: In patients with intractable PHPT, cinacalcet reduces serum calcium, is generally well tolerated, and has the potential to fulfill an unmet medical need.
In patients with intractable primary hyperparathyroidism, cinacalcet reduces serum calcium, is generally well tolerated, and has the potential to fulfill an unmet medical need.
Primary hyperparathyroidism (PHPT) is the most common cause of hypercalcemia in the outpatient setting and is usually discovered by routine laboratory testing (1). PHPT is frequently asymptomatic, but its clinical presentation ranges in severity from nonspecific complaints to life-threatening hypercalcemia. Increased serum calcium and PTH concentrations mediate the complications associated with PHPT, including skeletal and renal disease, gastrointestinal problems, and neuropsychiatric manifestations (2). Parathyroidectomy, the only curative treatment, has a high success rate when performed by experienced surgeons. Approximately 5–12% of patients with PHPT, however, may have persistent or recurrent hyperparathyroidism after parathyroidectomy (3,4,5). Repeat operations are associated with an increased incidence of complications, including recurrent laryngeal nerve damage or permanent hypoparathyroidism (6). Patients with persistent PHPT after parathyroidectomy or with contraindications to parathyroidectomy often require chronic treatment for hypercalcemia when it is moderate or severe or if symptoms are present. These patients can be considered to have intractable PHPT, and there are few treatment options currently available.
The calcimimetic cinacalcet is an allosteric modulator of the calcium-sensing receptor (CaSR), which is strongly expressed on the surface of parathyroid cells as well as in other tissues (7). Cinacalcet enhances the sensitivity of the CaSR to the prevailing extracellular calcium, resulting in an increase in the intracellular calcium concentration and a concomitant reduction in PTH released by the parathyroid gland. Cinacalcet reduces serum calcium and PTH levels in patients with mild PHPT compared with placebo (8) and significantly lowers serum calcium by greater than 1 mg/dl (0.25 mmol/liter) in more than 60% of patients with parathyroid cancer (9). In dialysis patients with secondary hyperparathyroidism (SHPT), cinacalcet reduces plasma PTH, serum phosphorus, calcium, and the calcium-phosphorus product (10,11,12). Cinacalcet has been approved by the U.S. Food and Drug Administration for the treatment of SHPT in patients with chronic kidney disease on dialysis and for the treatment of hypercalcemia in patients with parathyroid carcinoma (13). In 2008 cinacalcet was also approved by the European Commission for the reduction of hypercalcemia in patients with PHPT for whom parathyroidectomy is indicated on the basis of serum calcium levels (as defined by relevant treatment guidelines) but in whom parathyroidectomy is not clinically appropriate or is contraindicated. We report here the results of a multicenter study of cinacalcet in the treatment of patients with intractable PHPT. These patients were part of a larger study that also explored the efficacy and safety of cinacalcet as a treatment for patients with parathyroid carcinoma (9). The primary objective was to assess the ability of cinacalcet to reduce serum calcium concentrations in patients with intractable PHPT defined as unresolved PHPT after unsuccessful parathyroidectomy or in which parathyroidectomy was contraindicated. Secondary objectives were to assess the effect of cinacalcet treatment on plasma intact PTH (iPTH), serum bone turnover markers, health-related quality of life (HRQOL), and the safety of cinacalcet.
Patients and Methods
Patients
This study was conducted at 23 centers in Europe, the United States, and Canada. Patients were eligible if they had intractable PHPT, defined as PHPT unresolved after parathyroidectomy or contraindicated for parathyroidectomy, with a serum calcium concentration greater than 12.5 mg/dl (3.1 mmol/liter). Details of histological findings from previous parathyroid surgery were not collected. The percentage of patients with recurrent rather than persistent PHPT was also not recorded. Key exclusion criteria were malignancy (other than nonmelanomatous skin cancers or in situ cervical cancer); concurrent cancer chemotherapy; and use of tricyclic antidepressants (except amitriptyline) or flecainide [because these drugs are metabolized by cytochrome P450 2D6, which is inhibited by cinacalcet (14)]. The study was approved by the institutional review board or independent ethics committee for each center and was conducted in accordance with the Declaration of Helsinki. Each patient gave written informed consent.
Study design
This was an open-label, single-arm, dose-titration study. Ethical considerations precluded a control group of patients with PHPT not receiving cinacalcet. The study consisted of a variable length titration phase (2–16 wk) and a maintenance phase of up to 136 wk. Study visits occurred weekly during the titration phase and every 8 wk thereafter. Patients initially received 30 mg cinacalcet twice daily. The dosage was increased to the next sequential dosage (based on available tablet strengths) every 2 wk, depending on the patient’s serum calcium concentration during the previous week and an adverse event assessment (Fig. 1). Dosage escalation continued until the serum calcium concentration was 10 mg/dl or less (2.5 mmol/liter), the patient reached the highest possible dosage of 90 mg four times daily, or the patient experienced an adverse event that precluded further dosage increases. If a patient received all dosage levels, this titration sequence took 14–16 wk. During the maintenance phase, if serum calcium increased to an unacceptable level, dosage increases were permitted using the same algorithm (Fig. 1) as used in the titration phase. Investigators were allowed to prescribe treatments, including steroids, calcitonin, and bisphosphonates, deemed necessary to provide adequate supportive care.
Figure 1.
Algorithm for dose titration. During the study, new dose strengths of cinacalcet were manufactured. Patients receiving either 50-mg or 70-mg dosages were switched to a 60-mg dosage regimen. Thus, patients receiving 50 mg twice a day (BID) or 70 mg BID were switched to 60 mg BID, patients receiving 70 mg three times a day (TID) were switched to 60 mg TID, and patients receiving 70 mg four times a day (QID) were switched to 60 mg QID.
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) from baseline to the end of the titration phase. This was considered clinically relevant because it would be expected to result in an improvement in PHPT symptoms. This amount of reduction is similar to that observed in the treatment of acute hypercalcemia with iv infusion of saline and sc synthetic salmon calcitonin (15,16). Secondary efficacy end points included the proportion of patients experiencing a reduction in serum calcium into the normal range [≤10.3 mg/dl (2.6 mmol/liter)] and any significant changes in plasma iPTH, serum N-telopeptide (NTx), serum bone-specific alkaline phosphatase (BALP), and HRQOL scores.
Assessments
At baseline (d 1) and at the end of the titration phase, blood samples were obtained for measurement of serum calcium, serum bone turnover markers, serum phosphorus, and plasma iPTH after an overnight fast and before the morning dose of cinacalcet. Fasting serum calcium levels were determined weekly during the titration phase. At baseline and at the end of the titration phase, plasma iPTH and serum calcium were also obtained at 2 and 4 h after the dose. The end of titration phase visit occurred 2 wk after the final dose increase. During the maintenance phase, predose serum calcium and plasma iPTH were measured every 8 wk and serum bone turnover markers and serum phosphorus every 16 wk. Serum calcium concentrations were not corrected for albumin. PTH was measured using an immunoradiometric assay (coefficient of variation 4.2–6.4%) (Allegro PTH; Nichols Institute Diagnostics, San Juan Capistrano, CA). 1,25-Dihydroxyvitamin D and 25-hydroxyvitamin D were not measured. Urinary calcium excretion measurements were collected in a few patients, but because this was not part of the planned analysis and the data are incomplete, they are not reported here. Adverse events were recorded throughout the study. Endocrine Services (Calabasas, CA) analyzed samples for bone turnover markers. All other biochemical measurements were performed by Covance Central Laboratory Services (Indianapolis, IN, and Geneva, Switzerland).
Patients completed a HRQOL questionnaire at baseline, at the end of the titration phase, and every 16 wk thereafter. The questionnaire comprised the Medical Outcomes Study (MOS) Short Form 36 (SF-36), which has been extensively validated in the PHPT population (17,18), and the 6-item MOS Cognitive Functioning scale (19,20). Scores for the SF-36 scales were standardized using norm-based scoring so that the U.S. general population had a mean ± sd score of 50 ± 10. The MOS Cognitive Functioning scale was scored from 0 to 100. For all scales, a higher number indicates better or improved functioning. The minimum clinically important difference for the SF-36 scales was estimated to be with 3–5 points based on standardized scoring (21).
Statistical analysis
For the determination of efficacy end points, the last study visit was considered the end of titration for patients who withdrew from the study during the titration phase. Descriptive statistics were used to summarize study data. Results are expressed as mean ± sd, mean ± se, median, range, and the interquartile range. All adverse events were tabulated by body system affected, preferred term within body system (according to a modified World Health Organization Adverse Reaction Terminology directory), seriousness, and relationship to study drug. The Wilcoxon signed rank test was used to assess the significance (P < 0.05) of percent changes in calcium and PTH from baseline to the end of titration. At the end of the titration, the significance of change from predose to 2 and 4 h after the dose in calcium and PTH was also tested.
Results
Patient disposition and baseline characteristics
Seventeen patients with intractable PHPT were enrolled, of whom 14 (82%) completed the titration and entered the maintenance phase. The first patient was enrolled on April 4, 2001, and the last patient discontinued from the study on September 12, 2005. During the titration phase, one patient discontinued prematurely because of an adverse event (serious hypercalcemia), one patient was lost to follow-up, and one patient died. During the maintenance phase, one patient was lost to follow-up, one patient withdrew consent, and three patients discontinued prematurely because of adverse events [one patient because of nausea and vomiting, another because of muscle weakness, and the third because of parathyroid adenoma and HPT (clinical decision made by the investigator)]. Of the adverse events that led to discontinuation, only nausea and vomiting were considered treatment related. The median duration of cinacalcet treatment was 270 d (range 32–1105 d).
Demographic and baseline characteristics of patients are shown in Table 1. Contraindications to surgery in the three patients who had not previously undergone parathyroid surgery included coronary artery disease and multiple cerebrovascular accidents; hypertension and uncontrolled blood glucose levels; and presumed ectopic parathyroid adenoma in the mediastinum near the major blood vessels that made an operative approach extremely risky. The median cinacalcet dose was 70 mg twice daily at the end of the titration phase (range 30 mg twice daily to 90 mg four times daily) (n = 17) and 60 mg twice daily at the end of study (range 30 mg twice daily to 90 mg three times daily) (n = 17). Doses in individual patients are shown in the supplemental data (supplemental Table S3, published as supplemental data on The Endocrine Society’s Journals Online Web site at http://jcem.endojournals.org).
Table 1.
Demographic and baseline characteristics of patients (n = 17)
| Baseline parameter | Mean ± sd (range) |
|---|---|
| Age, yr | 65.7 ± 9.0 (52.0–88.0) |
| Gender: male/female, n | 8/9 |
| Race: white/black, n | 16/1 |
| Prior parathyroid surgery, n | 14 |
| Kidney stone history, n | 7 |
| Prior bisphosphonate use, n | 10 |
| Serum calcium, mg/dl | 12.7 ± 0.8 (11.8–14.5) |
| [3.2 ± 0.2 (3.0–3.6) mmol/liter] | |
| Plasma iPTH, pg/ml | 243 ± 105 (100–499) |
| [25.8 ± 11.1 (10.6–52.9) pmol/liter] |
Unless otherwise indicated.
Values less than 12.5 mg/dl (3.1 mmol/liter) were due to variation between screening and baseline values.
Changes in serum calcium
The primary end point of a 1 mg/dl or greater (0.25 mmol/liter) reduction in serum calcium concentration at the end of the titration phase was achieved in 15 patients (88%). A reduction in serum calcium to the normal range [≤10.3 mg/dl (2.6 mmol/liter)] at the end of the titration phase was achieved in nine patients (53%). During pharmacodynamic testing at the end of the titration phase, the mean ± se serum calcium predose concentration was reduced to 10.4 ± 0.3 mg/dl [2.60 ± 0.08 mmol/liter; range 8.5–12.7 mg/dl (2.1–3.2 mmol/liter)], and the 2 and 4 h postdose concentrations were 10.3 ± 0.3 mg/dl (2.58 ± 0.08 mmol/liter) (n = 15) and 10.2 ± 0.3 mg/dl (2.55 ± 0.08 mmol/liter) (n = 15), respectively; the change from predose to 4 h was significant (P = 0.04). The mean percentage change ± se in predose serum calcium from baseline to the end of the titration phase was −17.9% ± 2.3% (P < 0.0001). Mean ± se predose serum calcium concentrations at baseline, end of the titration phase, and during the maintenance phase are shown in Fig. 2A.
Figure 2.
Mean (± se) predose serum calcium concentration (A) and mean (± se) predose plasma iPTH concentration (B) at each visit are shown. The end of the titration phase (EOTP) was of variable duration (2–16 wk). The maintenance phase was 136 wk, but data are shown to wk 80 (i.e. where data were available for two or more patients). Shaded areas represent the normal ranges for serum calcium [8.4–10.3 mg/dl (2.1–2.6 mmol/liter)] (A) and iPTH [10–65 pg/ml (1.1–6.9 pmol/liter)] (B). B, Baseline.
During the maintenance phase, mean ± se predose serum calcium concentrations ranged from 9.9 ± 0.9 mg/dl (2.5 ± 0.2 mmol/liter) to 10.9 ± 0.7 mg/dl (2.7 ± 0.2 mmol/liter) (Fig. 2A). The proportion of patients with serum calcium reduced by 1 mg/dl or greater (0.25 mmol/liter) ranged from 67 to 83% of patients remaining in the study. The proportion of patients with serum calcium reduced to the normal range [≤10.3 mg/dl (2.6 mmol/liter)] ranged from 25 to 67% of patients remaining in the study. Serum calcium concentrations for individual patients at baseline, end of the titration phase, and last maintenance phase visit are listed in the supplemental data (supplemental Table S3).
Changes in plasma intact PTH
At baseline, the mean ± se predose plasma iPTH concentration was 243 ± 26 pg/ml (25.8 ± 2.8 pmol/liter) (n = 16). At the end of the titration phase, plasma iPTH concentrations were highly variable, with a mean ± se iPTH predose concentration of 396 ± 158 pg/ml (42.0 ± 16.8 pmol/liter) (n = 15) (Fig. 2B). At several study visits, the number of patients with plasma iPTH measurements was less than the number of patients with serum calcium measurements because patients were titrated on the basis of serum calcium, and it was possible to measure serum calcium for titration purposes without measuring plasma iPTH. The mean ± se percentage change in the iPTH of individual patients from baseline to the end of titration was −2.6 ± 13.7% and was not statistically significant. Median iPTH (interquartile range) decreased from 267 (136, 301) pg/ml [28.3 (14.4, 31.9) pmol/liter] at baseline to 173 (131, 295) pg/ml [18.3 (13.9, 31.3) pmol/liter] at the end of titration. At the end of titration during pharmacodynamic testing, mean ± se plasma iPTH values at 2 and 4 h after the dose [285 ± 137 pg/ml (30.2 ± 14.5 pmol/liter) and 254 ± 96 pg/ml (26.9 ± 10.2 pmol/liter), respectively] were lower than the mean predose concentration of 396 ± 158 pg/ml (P < 0.001 from before the dose to 4 h). Plasma iPTH concentrations continued to vary during the maintenance phase (Fig. 2B).
When a patient who developed renal failure was removed from the calculation of mean iPTH values at baseline and the end of the titration phase, the mean ± se iPTH concentration of the remaining patients was 226 ± 21.4 pg/ml (24.0 ± 2.3 pmol/liter) at baseline and 333 ± 155.5 pg/ml (35.3 ± 16.5 pmol/liter) at the end of titration. The mean ± se percentage change in the iPTH of the remaining individual patients from baseline to the end of titration was −15.0 ± 6.2%.
Changes in other biochemical values
Mean ± se serum phosphorus levels were in the hypophosphatemic range at baseline at 2.2 ± 0.1 mg/dl (0.7 ± 0.03 mmol/liter) and increased to 2.8 ± 0.1 mg/dl (0.9 ± 0.03 mmol/liter) at the end of titration. During the maintenance phase, mean serum phosphorus concentrations were similar to those observed at the end of titration and remained within the normal range (Table 2). There was no change in serum creatinine throughout the study (Table 2). Mean values for serum NTx and BALP showed large variability from baseline to wk 80, which was the last visit in which there were two or more patients in the maintenance phase. The median values are also shown in Table 2; a decrease (33%) in median BALP levels was observed at week 80 of the maintenance phase.
Table 2.
Other biochemical parameters during the study
| Parameter | Baseline | End of titration phase | Maintenance phase |
|---|---|---|---|
| Serum phosphorus | n = 17 | n = 15 | n = 3 (wk 80) |
| Mean ± se | 2.2 ± 0.1 mg/dl | 2.8 ± 0.1 mg/dl | 3.0 ± 0.5 mg/dl |
| 0.7 ± 0.03 mmol/liter | 0.9 ± 0.03 mmol/liter | 1.0 ± 0.2 mmol/liter | |
| Serum creatinine | n = 17 | n = 15 | n = 3 (wk 80) |
| Mean ± se | 1.1 ± 0.5 mg/dl | 1.0 ± 0.4 mg/dl | 1.1 ± 0.5 mg/dl |
| 97.2 ± 44 μmol/liter | 88.4 ± 35.4 μmol/liter | 97.2 ± 44.0 μmol/liter | |
| Serum N-telopeptide | n = 17 | n = 15 | n = 3 (wk 80) |
| Mean ± se | 78.8 ± 38.5 nm | 168 ± 119 nm | 21.8 ± 6.6 nm |
| Median (Q1, Q3) | 25 (15, 31) nm | 22 (16, 63) nm | 24 (9, 32) nm |
| Serum BALP | n = 16 | n = 15 | n = 3 (wk 80) |
| Mean ± se | 60.4 ± 27.7 ng/ml | 82.2 ± 37.0 ng/ml | 11.3 ± 5.3 ng/ml |
| Median (Q1, Q3) | 19 (12, 27) ng/ml | 21 (13, 94) ng/ml | 10 (3, 21) ng/ml |
Last visit where there were two or more patients in the maintenance phase.
Serum NTx reference range: premenopausal women = 6.2–19.0 nm bone collagen equivalent (BCE)/liter, postmenopausal women = no reference range, and males = 5.4–24.2 nm BCE/liter.
Serum BALP reference range: premenopausal women = 2.9–14.5 ng/ml, postmenopausal women = 3.8–22.6 ng/ml, and males = 3.7–20.9 ng/ml.
HRQOL
Fifteen of the 17 patients completed the HRQOL assessment at the end of titration. Scale scores at baseline indicated that patients had poor functional status (Table 3). The mean baseline values for six of the eight SF-36 scales, plus the Physical Component Summary and the Mental Component Summary scores, were all less than 40, which was greater than 1 sd below the mean for the U.S. general population. The mean MOS Cognitive Functioning score at baseline was less than the U.S. general population mean ± sd of 82.4 ± 16.5 (20). At the end of titration, the mean score improved in every SF-36 scale and in the MOS Cognitive Functioning scale (Table 3).
Table 3.
Changes in HRQOL scores from baseline to the end of the titration phase
| Scale | Baseline |
End of titration |
Difference |
||||
|---|---|---|---|---|---|---|---|
| n | Mean ± se | n | Mean ± se | n | Mean ± se | 95% CI | |
| SF-36 | |||||||
| Physical component summary | 16 | 36.9 ± 2.43 | 15 | 41.4 ± 3.09 | 14 | 3.1 ± 1.63 | (−0.44, 6.61) |
| Mental component summary | 16 | 39.4 ± 3.55 | 15 | 48.0 ± 2.80 | 14 | 7.3 ± 4.12 | (−1.60, 16.20) |
| Physical functioning | 17 | 34.3 ± 3.19 | 15 | 40.2 ± 3.73 | 15 | 4.6 ± 1.23 | (1.96, 7.24) |
| Role limitations, physical | 17 | 35.0 ± 2.64 | 15 | 39.3 ± 3.22 | 15 | 3.3 ± 2.06 | (−1.11, 7.71) |
| Body pain | 17 | 42.8 ± 3.05 | 15 | 47.4 ± 3.23 | 15 | 5.1 ± 2.08 | (0.68, 9.60) |
| General health perception | 17 | 40.9 ± 2.48 | 15 | 44.4 ± 2.74 | 15 | 3.0 ± 2.48 | (−2.33, 8.33) |
| Social functioning | 17 | 36.7 ± 3.56 | 15 | 45.6 ± 3.22 | 15 | 6.9 ± 4.19 | (−2.10, 15.86) |
| Vitality | 16 | 37.8 ± 2.61 | 15 | 45.1 ± 2.67 | 14 | 5.6 ± 3.81 | (−2.65, 13.81) |
| Role limitations, emotional | 17 | 37.4 ± 3.35 | 15 | 44.1 ± 2.99 | 15 | 7.7 ± 3.33 | (0.59, 14.9) |
| Emotional well-being | 16 | 38.5 ± 3.33 | 15 | 47.9 ± 2.98 | 14 | 7.5 ± 3.52 | (−0.14, 15.1) |
| MOS cognitive functioning | 17 | 61.2 ± 5.70 | 15 | 74.4 ± 5.92 | 15 | 11.8 ± 6.59 | (−2.35, 25.90) |
Higher values indicate better health status for all scales. CI, Confidence interval.
Number of patients with scale scores.
The minimum clinically important difference for each SF-36 scale was estimated to be 3–5 points [using norm-based scoring (21)]; all the mean improvements measured with the SF-36 scales were either within or above this range. Figure 3 shows the percentage of patients who had clinically improved or worsened SF-36 scores determined by achieving a minimum clinically important difference of 3 points. In all SF-36 scales, more patients improved than worsened. In all the SF-36 scales except the Role Limitations-Physical and Vitality scales, at least 50% of patients improved.
Figure 3.
Percentages of patients (rounded to the closest integer) with improvement or worsening in the eight SF-36 scales from baseline to the end of the titration period (n = 17). Improved, Increase in score from baseline of 3 or more points; same, increase or decrease in score from baseline of less than 3 points; worsened, decrease in score from baseline of 3 or more points.
Adverse events
All patients experienced at least one adverse event. Nausea, vomiting, and paresthesias were the most common adverse events, occurring in 10 (59%), six (35%), and five (29%) patients, respectively. Fifteen patients (88%) experienced treatment-related adverse events, none of which were serious. Nausea, vomiting, and paresthesias were considered to be treatment-related in nine (53%), four (24%), and three (18%) patients, respectively. Paresthesias occurred when serum calcium concentrations were within or above the normal range. Treatment-related hypocalcemia occurred in two patients (12%). One patient had a serum calcium of 12.4 mg/dl (3.1 mmol/liter) at baseline, which decreased to 7.2 mg/dl (1.8 mmol/liter) at 4 wk after the end of the titration phase and returned to within the normal range [8.4 mg/dl (2.1 mmol/liter)] by the end of the study. The episode of hypocalcemia required a decrease in dose from 60 mg four times daily to 60 mg three times daily. In the other patient, serum calcium decreased from 11.8 mg/dl (3.0 mmol/liter) at baseline to 7.8 mg/dl (2.0 mmol/liter) at wk 3. By wk 4, this patient’s serum calcium increased to within the normal range [8.5 mg/dl (2.1 mmol/liter)]. Cinacalcet therapy (30 mg twice daily) was not interrupted. This patient, who had a history of hypertension and chronic heart failure, died from arrhythmia, which was considered unrelated to cinacalcet treatment, 3 d after the wk 4 visit. No other patient died during the study. Four patients (24%) withdrew from the study because of adverse events (see Patient disposition and baseline characteristics above).
Discussion
This study demonstrates the ability of cinacalcet to substantially lower serum calcium concentrations and improve HRQOL in intractable PHPT in this sample of patients. There are few medical options available for patients with intractable PHPT. Hormone replacement therapy and the selective estrogen response modulator raloxifene have been studied in postmenopausal women with mild PHPT (22,23,24). In a randomized, placebo-controlled trial, hormone replacement therapy was associated with increased bone mineral density (BMD) in postmenopausal women with mild PHPT, but serum ionized calcium concentrations and PTH levels were unchanged (22). Raloxifene has been found to reduce serum calcium and bone turnover markers, with no effect on serum PTH, in two studies in postmenopausal women with mild PHPT (23,24). Alendronate has been shown to reduce bone turnover and increase BMD in PHPT patients, with no long-term effect on serum PTH and calcium (25). Thus, bisphosphonates may be a useful alternative to parathyroidectomy among PHPT patients with low BMD and mild hypercalcemia (but not symptomatic or intractable). Even if iv bisphosphonates may be recommended for the treatment of hypercalcemic crisis secondary to PHPT, they are not approved by the Food and Drug Administration for this indication. In the present study, most patients had markedly elevated serum calcium concentrations, despite previous parathyroidectomy and bisphosphonate use.
In this study, treatment with cinacalcet resulted in lower serum calcium concentrations as well as consistent reductions in iPTH 2–4 h after the morning dose, as has been shown in patients with mild PHPT (8). However, the reduction of serum iPTH was not sustained for the entire dosing period, and iPTH values obtained predose do not reflect the greater degree of reduction in iPTH that occurred during the 24-h dosing interval. Therefore, plasma iPTH reduction over the dosing period may be a more accurate reflection of efficacy than predose iPTH. Additionally, the modest reduction in iPTH concentration from baseline to the end of titration (−2.6 ± 13.7%) was primarily affected by a single patient who had a large increase in iPTH levels from a baseline value of 499 pg/ml (52.9 pmol/liter) to an end of titration value of 1290 pg/ml (136.9 pmol/liter). This patient gradually developed worsening renal failure and, as a consequence, overt SHPT. When this patient’s data were removed, the mean percent change from baseline was −15.0 ± 6.2%. Activation of renal CaSRs can reduce urine calcium reabsorption along the nephron independent of the effect of changes in serum PTH (8). The reduction in iPTH concentration from baseline is in line with previous findings from a larger group of patients with mild PHPT in which mean plasma predose iPTH fell by 7.6% from baseline to wk 24 (comprising 12 wk of dose titration and 12 wk of maintenance phase dosing), and predose PTH reductions were maintained during the 28-wk follow-up period (8). In the current study, an increase in serum phosphorus from baseline was observed at the end of the titration phase, indicating increased renal reabsorption of phosphorus due to reduced iPTH levels, also in line with prior observations in the cohort of patients with milder PHPT (8).
Reductions in bone turnover markers have been observed after parathyroidectomy in patients with PHPT (26,27). At the end of the titration phase, although mean values were highly variable, median serum NTx and BALP concentrations were generally similar to baseline levels. It is difficult to interpret the maintenance phase data due to the small number of patients. Additionally, BMD measurements were not available to allow us to appreciate the impact on bone mass, if any, of changes in bone turnover markers.
The poor functional status of patients in this study, as measured at baseline by the SF-36 scales, is not surprising, given the mean serum calcium, and matches the findings of other studies in which the SF-36 has been used in patients with PHPT to examine the impact of the disease on HRQOL before parathyroidectomy (28,29). In this study, HRQOL assessment using the SF-36 and MOS Cognitive Functioning scales provided preliminary evidence that cinacalcet treatment results in improved functional status and well-being in patients with intractable PHPT. The improvements in the Physical Component Summary and Mental Component Summary scores were comparable with the improvements observed in patients with PHPT after parathyroidectomy (30). Questionnaires covering more specific symptoms associated with PHPT, such as bone and joint pain, as well as specific neuropsychiatric symptoms and cognitive dysfunction, should be considered in future, larger studies.
Cinacalcet was generally well tolerated when titrated to as high as 90 mg four times daily, and the overall safety profile of cinacalcet observed in this study was generally similar to that observed in patients with SHPT (10,11,12) or parathyroid carcinoma (9). The rate of adverse events was higher than in the study of patients with milder PHPT (8) because the present study used higher cinacalcet doses. Nausea and vomiting were the most common adverse events, but only one patient withdrew from the study due to gastrointestinal events. The patient with parathyroid adenoma and HPT who discontinued treatment during the maintenance phase eventually underwent another parathyroidectomy, which was successful. Paresthesias in one patient may have been related to a rapid, concomitant decrease in serum calcium: 12.5 mg/dl (3.1 mmol/liter) on study d 1 to 10.5 mg/dl (2.6 mmol/liter) on d 8, with paresthesias noted on d 5.
An important but unavoidable limitation of this study is the single-arm design that raises the potential difficulty of distinguishing between the effects of the study drug and the effects of the natural progression of the disease. Ethical considerations, however, precluded enrollment of a control group because the patients we studied represent a group with an unmet medical need and potentially life-threatening disease. This cohort contained equal numbers of men and women, all with biochemically severe PHPT and further end-organ complications (e.g. 40% had renal stones). So it may be difficult to extrapolate these data to milder cases of PHPT.
In conclusion, the lack of therapeutic alternatives for patients with intractable PHPT and the demonstrated efficacy of cinacalcet in reducing (and even normalizing) serum calcium concentrations in these patients indicate that this intervention has the potential to improve metabolic parameters and fulfill an unmet medical need in this patient population.
Supplementary Material
Acknowledgments
All coauthors participated in the conception and design, acquisition of the data, or analysis and interpretation of the data and in the drafting of the article or revising it critically for intellectual content.
Footnotes
This work was supported by Amgen Inc. Writing assistance was provided by Reza Sayeed (Bioscript Stirling Ltd. supported by Amgen Europe) and Antonia Panayi [Amgen (Europe) GmbH]. This study was registered as a clinical trial (ClinicalTrials.gov identifier NCT00037518).
Disclosure Summary: C.M., J.B., L.F.-C., J.O., and C.H. have nothing to declare. P.C. has received a research grant from and consults for Amgen. D.S. is a consultant for Amgen and a speaker for Novartis, and has received honoraria from both. S.C., L.R.S., and J.L. are employed by Amgen. M.P. is a consultant for Amgen, Deltanoid, Genzyme, and Kirin.
First Published Online May 26, 2009
Abbreviations: BALP, Bone-specific alkaline phosphatase; BMD, bone mineral density; CaSR, calcium-sensing receptor; iPTH, intact PTH; HRQOL, health-related quality of life; MOS, Medical Outcomes Study; SF-36, Short Form 36; NTx, N-telopeptide; PHPT, primary hyperparathyroidism; SHPT, secondary hyperparathyroidism.
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