THE EFFECT OF CINACALCET (SENSIPAR®) ON INTRAOPERATIVE FINDINGS IN TERTIARY HYPERPARATHYROIDISM PATIENTS UNDERGOING PARATHYROIDECTOMY

Abstract

Introduction

Tertiary hyperparathyroidism (3HPTH) patients who undergo parathyroidectomy are often managed with calcium lowering medications such as cinacalcet (Sensipar®) preceding surgery. Here, we assess how cinacalcet (Sensipar®) treatment influences intraoperative PTH (IOPTH) kinetics and surgical findings in 3HPTH patients undergoing parathyroidectomy.

Methods

116 retrospectively reviewed 3HPTH patients underwent, parathyroidectomy of which 14 were on cinacalcet and 112 were on no drug. IOPTH levels fitted to linear curves vs. time were used to evaluate the role of cinacalcet.

Results

Cinacalcet did not significantly correlate with rates of cure (p=0.41) or recurrence (p=0.54). Patients on cinacalcet experienced a significantly steeper decline in IOPTH compared to those not on medication (p=0.005). Cinacalcet treatment was associated with a significant increase in rate of hungry bones (p=0.04). Weights of the heaviest glands resected (p=0.02) and preoperative PTH levels (p=0.0004) were significantly higher among patients on cinacalcet.

Conclusions

Perioperative cinacalcet treatment in 3HPTH patients alters IOPTH kinetics by causing a steeper IOPTH decline, but does not require modifying standard IOPTH protocol. Although cinacalcet use does not adversely affect cure rates, it is associated with higher preoperative PTH and an increased incidence of hungry bones, hence serving as an indicator of more severe disease. Cinacalcet does not need to be held prior to surgery.

INTRODUCTION

Tertiary hyperparathyroidism (3HPTH) is an endocrine disorder characterized by the persistent hypersecretion of parathyroid hormone (PTH) in patients with longstanding secondary hyperparathyroidism (2HPTH) who have undergone successful kidney transplantation to correct their chronic kidney disease^{1, 2}. While most transplant recipients experience a return to normal PTH secretion following restored renal functioning, up to 8% of patients retain abnormally functioning parathyroid tissue that fails to resolve^{3, 4}. Consequently, serum levels of PTH remain elevated. This persistent elevation of PTH raises serum calcium levels producing a constellation of debilitating symptoms including atherosclerosis, nephrolithiasis, osteopenia, osteoporosis and neuropsychiatric changes^3-7.

The mainstay curative approach for patients with 3HPTH is subtotal or total parathyroidectomy with forearm implantation of the remnant parathyroid^{3-5, 8-10}. Notably, medical management prior to surgical intervention often employs the use of calcimimetic agents to lower serum calcium¹¹. These agents exert their effect by allosterically activating the calcium sensing receptors of the parathyroid glands, thus directly suppressing PTH secretion¹². Prior interventions such as the use of sterols and Vitamin D supplementation proved to be effective in controlling PTH levels, but frequently resulted in hypercalcemia and hyperphosphatemia¹³. The advent of the calcimemetic agent known as cinacalcet (Sensipar ®, Amgen Inc.., Thousand Oaks, CA, USA) introduced a viable therapeutic option for effectively reducing plasma levels of PTH in patients with 2HPTH on dialysis, while simultaneously reducing calcium and phosphorous levels and avoiding associated symptoms^12-14. In addition to its registered indication for 2HPTH in patients with end-stage renal disease (ESRD) on maintenance dialysis, cinacalcet is also approved to reduce hypercalcemia in patients with parathyroid carcinoma and primary HPTH patients in whom surgery is contraindicated^{15, 16}. However, given its mechanism of action and favorable pharmacokinetics, cinacalcet has been increasingly prescribed for patients with 3HPTH as has been described in a number of reports^17-22. Since its introduction, many 3HPTH patients now opt for medical management with cinacalcet in place of surgery^{18, 23}. Accordingly, parathyroidectomy is often performed in conjunction with calcimimetics such as cinacalcet when managing symptomatic 3HPT patients²³. The purpose of this study was to investigate the influence of cinacalcet treatment on pre- and postoperative findings, intraoperative PTH (IOPTH) kinetics, and the etiology of disease in patients with 3HPTH.

METHODS

We retrospectively reviewed 116 3HPTH patients undergoing parathyroidectomy at our institution between March 2001 to March 2013. We defined 3HPTH patients as those who previously had 2HPTH and received successful renal transplantation. Patients who were undergoing reoperation parathyroidectomy from persistent or recurrent hyperparathyroidism were excluded. These patients were divided into two groups comprised of those on cinacalcet and those not on cinacalcet at the time of surgery. Those patients on cinacalcet prior to surgery but with whom it was discontinued were categorized in the non-treated group. Patients previously on cinacalcet but were considered in the non-treated group had an average duration of discontinuation prior to surgery of 428.13 days. Approval from the University of Wisconsin Institutional Review Board was granted for data collection and analysis. Patients underwent bilateral neck exploration with identification of all parathyroid glands. The number of glands excised depended on the disease etiology. Patients with hyperplasia underwent subtotal parathyroidectomy. IOPTH monitoring was performed according to our previous report²⁴. PTH lab values were drawn after anesthesia, and at 5, 10, and 15 minutes after excision of all hyperfunctioning glands. A drop in IOPTH of 50% was used as the criteria to end the operation. Trends in IOPTH monitoring within each group were assessed by calculating the average linear slope of IOPTH change based on the initial and final level drawn during the operation. Slopes between the two groups were then compared. Furthermore, we assessed the correlation between cinacalcet treatment and the number of glands discovered. We determined surgical cure as serum calcium <10.2 mg/dL at 6 months following parathyroidectomy. Persistence was defined as a return to calcium levels >10.2 mg/dL within 6 months after parathyroidectomy, while disease recurrence was defined as a resurgence of serum calcium levels >10.2 mg/dL after a period of normal calcium for 6 or more months after surgery. Hypocalcemia as a complication of surgery was specified in the setting of hypoparathyroidism with normal renal functioning retained. Such cases were defined as having a calcium level <8.5 mg/dL, and a PTH of <8 pg/mL, and a normal glomerular filtraiton rate and creatinine level within one week after surgery. If these labs did not resolve within 6 months these patients were classified as having permanent hypoparathyroidism. We diagnosed hungry bone syndrome in patients who had calcium levels <10.2mg/dL following parathyroidectomy beyond the 4^th postoperative day, and these determinations were initially made based on clinical manifestations of prolonged hypocalcemia. Statistical analysis was performed using SPSS software (version 10.0, SPSS Inc, Chicago, IL) using Pearson's Chi-square test, Fisher's exact test, and a 2-sided Student's T-Test for continuous variables. Statistical significance was specified based on a P-value of less than 0.05.

RESULTS

Patients and demographics

Among the 116 3HPTH patients undergoing parathyroidectomy, 14 (12%) were on cinacalcet at the time of operation, while 102 (88%) were on no calcimemetics. The median treatment time of cinacalcet was 26 months (1.9-56 months). The percentage of male patients was 64% among cinacalcet treated patients and 49% among patients on no drug, which appeared to be statistically similar (Table 1). Vitamin D levels among both groups were also similar, but were on the lower end of normal (Table 1). Furthermore, creatinine levels were significantly higher among those on cinacalcet compared to those taking no drug (Table 1). While preoperative calcium levels did not differ statistically between the two groups, those on cinacalcet exhibited significantly higher pre-operative PTH levels (681.4 pg/mL) versus those on no drug (270.6 pg/mL) (P=0.0004) (Table 1). Interestingly, while etiology was not significantly affected by cinacalcet treatment, all patients on cinacalcet had hyperplasia while 21% of those not on drug did not have hyperplasia (Table 1).

Table 1.

Patient Demographics and laboratory data

Demographics	Cinacalcet n=14 (12%)	No Drug n=102 (88%)	P value
Age (y)	47 ± 3	52 ± 1	0.19
Male patients§ (%)	9 (64)	50 (49)	0.39
Vitamin D (ng/mL)	29.1 ± 4.4	29.9 ± 0.89	0.89
Creatinine (mg/dL)	1.9 ± 0.22	1.5 ± 0.7	0.03*
Preoperative Ca (mg/dL)	10.5 ± 0.48	10.6 ± 0.12	0.86
Preoperative PTH (pg/mL)	681.4 ± 274.9	270.6 ± 20.2	0.0004*
Postoperative Ca (mg/dL)	8.5 ± 0.32	8.9 ± 0.1	0.22
Postoperative PTH (pg/mL)	118.7 ± 40.2	85.7 ± 11.14	0.37
Etiology§ (%)
Single adenoma	0	12	0.17
Double adenoma	0	9
Hyperplasia	14	81

Ca = Calcium

Continuous variables are represented as the mean ± SEM unless otherwise indicated

^*Statistically significant (P<0.05)

^§Denotes where Fisher's exact test was used

Cure, complications, and intraoperative findings

Parathyroidectomy in both patient groups resulted in high cure rates, (an overall rate of 97%), with a combined recurrence rate of 3.4%, indicating that surgical intervention is a successful curative approach regardless of cinacalcet treatment (Table 2). Cure rates within each group were 93% and 97% among those on cinacalcet and those on no calcimimetic respectively. Recurrence rates were also low in both groups and did not significantly differ.

Table 2.

Incidence of cure, recurrence and hypocalcemia

	Cinacalcet n=14	No Drug n=102	P value
Cure, n (%)	13 (93)	99 (97)	0.41
Recurrence, n (%)	1 (7)	5 (5)	0.54
Complications
Permanent hypoparathyroidism, n (%)	0 (0)	1 (1)	1.00
Transient hoarseness, n (%)	1 (7)	2 (2)	0.32
Hungry bone syndrome, n (%)	3 (21)	4 (4)	0.04*
Parasthesias, n (%)	2 (14)	4 (4)	0.15

^*Statistically significant (P<0.05)

All P values calculated based on Fisher's exact test

We also noted postoperative complications among cinacalcet treated patients and those on no drug. The overall rates of biochemical postoperative hypocalcemia from permanent hypoparathyroidism did not differ significantly between the two groups (Table 2). We also observed a significantly higher rate of certain postoperative complications among patients taking cinacalcet. Hungry bone syndrome occurred in 21% of patients taking cinacalcet and only 4% of patients on no drug (P=0.04) (Table 2). Other complications such as voice hoarseness and mild parasthesias did not differ between the two groups.

Finally, we compared the average weights of the heaviest resected parathyroid gland between those on cinacalcet and those on no drug. We found that the average weight of the heaviest gland among patients on cinacalcet, 1309.4 ± 330.1 grams, was significantly higher than that of those on no drug, whose average gland weight was 853.4 ± 58.5 (P=0.02).

IOPTH monitoring

To analyze the influence of cinacalcet on IOPTH kinetics, we plotted IOPTH draws over time, beginning with the pre-excision recording and followed by every reading thereafter. Notably, we found that pre-excision IOPTH values (0 minutes), were significantly higher among cinacalcet treated patients, with a value of 711.4 ± 277.3 pg/mL, versus non-cinacalcet patients whose pre-excision PTH average was 328.1 ± 50.4 pg/mL (P=0.03) (Table 3). This is aligned with the statistically significant findings from Table 1 showing a marked elevation in preoperative PTH levels taken prior to the day of surgery among cinacalcet treated patients. When comparing the patterns of the IOPTH monitoring between treatment and non-treatment groups, we found that cinacalcet altered IOPTH kinetics, correlating with a significantly steeper decline in IOPTH (Figure 1). The rate of IOPTH change, indicated by the average slope of linear fitted curves drawn between pre-excision IOPTH values from each patient and its paired final IOPTH recording were compared between the two groups. The rate of decline in IOPTH among patients on cinacalcet was represented by an average slope of −58.6 ± 34.1, while for those not on cinacalcet, the average downward slope of IOPTH levels was -17.3 ± 2.8 (P=0.005) (Table 3). Notably, there was no significant difference between the two groups in their average IOPTH percentage drops between the first and last IOPTH recordings (Table 3). Finally, we found that there was no difference in the number of patients achieving a 50% drop at any given interval of IOPTH recording between those taking and not taking cinacalcet. The distribution among those achieving surgical cure at 5, 10 and 15 minutes was statistically similar (Table 4). The number of PTH draws required to achieve a 50% drop also did not differ significantly between the two groups (Table 4).

Table 3.

IOPTH monitoring

	Cinacalcet n=14	No Calcimimetic n=102	P value
Pre-excision PTH (pg/mL)	711.4 ± 277.3	328.1 ± 50.4	0.03*
Percent drop (%)	77.2 ± 3.7	73.3 ± 2.6	0.59
Slope	−58.6 ± 34.1	−17.3 ± 2.8	0.005*

^*Statistically significant (P<0.05)

Figure 1.

Intraoperative PTH value plot for 3HPTH patients taking cinacalcet and not taking cinacalcet undergoing parathyroidectomy. The graph below shows a connected line of IOPTH values for those on cinacalcet (dotted line) and those on no drug (solid line), beginning with pre-excision (t=0) IOPTH levels and followed by every value recorded thereafter. Pre-excision IOPTH was significantly higher among those taking cinacalcet* (P=0.03). The slope and % reduction in IOPTH were determined using the pre-excision IOPTH (t=0 minutes) and the final IOPTH (t=15 minutes) as an endpoint. IOPTH levels declined at a significantly steeper slope among patients taking cinacalcet^§ (P=0.005). Standard error of the mean for each IOPTH reading is illustrated with error bars.

Table 4.

IOPTH monitoring

	Cinacalcet n=14	No Drug n=102	P value
50% drop achieved by§:
5 minutes, n (%)	1 (7)	4 (4)	0.48
10 minutes, n (%)	4 (28)	20 (20)	0.48
15 minutes, n (%)	14 (100)	93 (92)	0.60
Number of PTH draws to achieve 50% drop	2.64 ± 0.17	2.91 ± 0.08	0.23

Continuous variables are represented as the mean ± SEM unless otherwise indicated

*Statistically significant (P<0.05)

^§Denotes where Fisher's exact test was used

DISCUSSION

Parathyroidectomy has been well established as a curative approach for patients with hyperparathyroidism^{4, 7}. Nevertheless, medical management of tertiary hyperparathyroidism has become more widespread since the advent of safe and readily available calcimimetic agents^{12, 23}. Accordingly, medical therapy often precedes or accompanies surgical intervention. The calcimimetic cinacalcet was incorporated into 3HPTH management around 2005, and has since offered patients with severe disease the option of medical therapy in lieu of, and often preceding, surgery^{11, 23}. Although cinacalcet has been shown to resolve hypercalcemia and hyperphosphatemia in 3HPTH patients, most patients experience persistence of their hypercalcemic symptoms²³, necessitating parathyroidectomy. However, the impact of cinacalcet on IOTPH kinetics and intraoperative protocol has not been described in 3HPTH patients undergoing parathyroidectomy.

In this study, we report a series of 116 patients with 3HPTH who underwent parathyroidectomy. Among these patients, 12% were taking cinacalcet at the time of their surgery. Overall, cinacalcet treatment was significantly associated with a dramatically steeper decline in IOPTH during parathyroidectomy and did not alter the probability of surgical success. The percentage drop in IOPTH and number of IOPTH recordings required to achieve a 50% drop were not significantly different among the two groups. Collectively, these findings indicate that standardized IOPTH monitoring can still be used to confirm successful excavation of hyperfunctioning parathyroid tissue, regardless of perioperative cinacalcet therapy. Moreover, it demonstrates that surgical intervention is a highly curative approach with or without cinacalcet.

A previous study by Schneider et al. concluded that calcimimetic treatment at the time of parathyroidectomy among patients with primary HPTH also affected IOPTH kinetics by causing a steeper decline in the series of IOPTH readings with a lesser degree of recovery in IOPTH values. Our study found that pre-excision IOPTH values were significantly higher among cinacalcet-treated patients, accounting for the sharper drop in IOPTH levels that we observed. The significantly higher preoperative PTH levels may reflect salient distinctions in the biochemical severity of hyperparathyroidism in this group, as these patients warranted parathyroidectomy after previously requiring and failing a medical approach with cinacalcet. Schneider et al. went on to attribute a higher degree of postoperative hypocalcemia to multidrug calcimimetic therapy (1+ calcimimetics), but did not report a correlation with the use of only one calcimimetic²⁵. Similarly, our study did not see a correlation with cinacalcet monotherapy and the rate of overall biochemical postoperative hypocalcemia. Therefore, while cinacalcet alone may not drive postoperative hypocalcemia from hypoparathyroidism among 3HPH patients, its use may be an indicator of disease severity given these patients’ significantly higher pre-excision IOPTH and its subsequent effect on IOPTH kinetics²⁵.

It is thought that patients requiring calcium lowering medications like cinacalcet may exhibit a more extreme biochemical form of their disease²⁵. Studies have shown that higher rates of hypercalcemic complications such as fatigue, depression and altered mental status occur among 3HPTH patients who are referred for cinacalcet treatment versus those requiring no treatment²³. Likewise, previous reports have shown increased rates of postoperative hypocalcemia as well as associated complications among patients on calcium lowering medications such as cinacalcet. Consistent with this report, we found that 3HPTH patients on cinacalcet experienced higher rates of postoperative complications such as hungry bone syndrome. Furthermore, all of these patients needed to be managed medically with calcitriol and calcium phosphate supplementation to manage their symptomatology until resolution. The correlation between cinacalcet treatment and hypocalcemic complications such as hungry bone syndrome may be an indication of prolonged disease duration and severity from postponing parathyroidectomy in this patient group²⁵.

While cinacalcet may indeed serve as an index of disease severity, its direct effects on renal physiology and disease etiology may also contribute to the differences in pre- and postoperative findings between the two groups. In addition to their higher initial IOPTH levels, steeper drop in IOPTH, and increased incidence of hungry bone syndrome, we found that patients on cinacalcet had poorer renal function and heavier parathyroid glands. Whether these additional findings are a result of cinacalcet itself or are indicative of a more severe disease state that necessitated medicinal intervention is unclear. Calcimimetics have been suspected to increase the risk of kidney allograft failure or rejection, independent of the deleterious effects of prolonged hyperparathyroidism that may be associated with requiring cinacalcet²³. In this study, cinacalcet-treated 3HPTH patients did indeed have poorer creatinine clearance than those not on drug (Table 1). Additionally, studies have shown that calcimimetics may impair renal function, thus exacerbating the symptoms associated with abnormal parathyroid functioning¹⁸; the use of calcimimetics may therefore lead to direct and visible changes in 3HPT disease progression prior to surgery. Notably, we found a significant difference in the size of the largest resected gland among patients on cinacalcet versus the untreated group. The heaviest gland weights among the cinacalcet treated patients were significantly heaver than that of those not on cinacalcet. Furthermore, all patients on cinacalcet experienced four gland hyperplasia while this group only comprised 20% of those not on cinacalcet, further suggesting that cincacalcet is in indicator of a more severe disease state. Importantly, although cinacalcet was associated with an increase in parathyroid gland burden, it did not affect the etiology of disease, the number of glands excised, or the success of parathyroidectomy.

We recognize that our conclusions are drawn from a study with limitations, largely due to the our limited sample size, especially among patients on cinacalcet. We were only able to include 14 patients who were treated with cinacalcet perioperatively. We recognize that patients with whom cinacalcet was discontinued prior to surgery may still be physiologically affected by the after effects of therapy. In addition, we acknowledge that it was only after 2005 when cinacalcet became accepted as a therapeutic approach for use in tertiary hyperparathyroidism. This time period falls midway through our study's time frame. Presumably, if cinacalcet were available throughout the study period as an alternative to surgery, then a greater number of patients who would be considered as having a more severe disease burden would have at some point been placed on cinacalcet and included in the treated category. However, within our modest interpretation of this study's findings, our approach of classifying such patients given these limitations did not diminish from identifying significant differences in IOPTH kinetics, pre-operative creatinine levels, gland burden and complications. We do recognize that because our patient sample size is small and restricted to surveying a patient load at single institution, even drawing correlations between cinacalcet treated patients and their disease picture cannot be done with certitude.

We conclude that although cinacalcet treatment may be a determinant of a steeper decline in IOPTH, it does not alter operative protocol, does not impact operative success, and therefore does not diminish the effectiveness of parathyroidectomy. We maintain that those taking cinacalcet are comprised of patients with more long-standing HPTH whose surgical treatment has been delayed in an attempt to medically manage their symptomatology.

While cinacalcet alone is effective and safe for managing 3HPTH, patients’ hypercalcemic symptoms often persist. Therefore, regardless of medication status, patients experiencing symptomatic disease should opt for surgery to achieve a more immediate and permanent resolution of hypercalcemia and associated symptoms.