• Cinacalcet;
  • Parathyroid gland;
  • Secondary hyperparathyroidism;
  • Ultrasound


  1. Top of page
  2. Abstract

Cinacalcet efficacy is limited in severe secondary hyperparathyroidism (SHPT) and its effect on parathyroid gland (PTG) volume and morphology have not been sufficiently investigated. We evaluated the effect of cinacalcet treatment for one year on the laboratory parameters of calcium–phosphorus metabolism and PTG ultrasound (US) patterns in hemodialysis (HD) patients with severe SHPT and US results indicative of nodular hyperplasia. Thirteen HD patients with severe SHPT (intact parathyroid hormone >700 pg/mL), US/scintigraphic evidence of at least one PTG with a diameter >7 mm, and high surgical risk or refusal of surgery were included. The patients were treated with cinacalcet. The initial dose of 30 mg was increased up to 180 mg once daily. At baseline and after one year of cinacalcet treatment a neck US was performed, providing data on 22 parathyroid glands in eight patients. The mean diameter at baseline and at one year was 12.6 ± 5.9 and 13.0 ± 5.3 mm, respectively (P = 0.46). Similarly, the mean volume at baseline and at one year was 513.4 ± 416.3 and 556.8 ± 480.8 mm3, respectively (P = 0.18). The US structural score remained unchanged in 16 parathyroid glands and increased in 6 (P < 0.03), while the vascular score remained unchanged in 16 parathyroid glands and decreased in 6 (P = 0.25). Thus it can be concluded that cinacalcet treatment for one year in HD patients with severe SHPT is not associated with significant changes in parathyroid gland US patterns.

Secondary hyperparathyroidism (SHPT) is a common complication of chronic renal disease characterized by increased parathyroid hormone (PTH) and disorders of parathyroid cell proliferation. SHPT is responsible for metabolic bone disease and cardiovascular complications determining poor quality of life, fractures, and increased morbidity and mortality of hemodialysis (HD) patients (1,2). Currently, the prevention and treatment of SHPT is based on dietary phosphate restriction, administration of calcium or non-calcium-containing phosphate binders, phosphate removal by dialysis, maintenance of adequate serum calcium concentrations and the administration of calcitriol to suppress PTH. However, traditional calcitriol therapy allows the reduction of intact PTH (iPTH) to the recommended range in 25–30% of cases, but all four National Kidney Foundation Kidney Disease Outcomes Quality Initiative (NFK–KDOQI) targets (i.e. albumin-corrected calcium 8.4–9.5 mg/dL, phosphorus 3.5–5.5 mg/dL, iPTH 150–300 pg/mL) are achieved in only 6–8% of HD patients (3,4). The presence of nodular hyperplasia (NH) in the parathyroid glands (PTG) is the principal cause of medical therapy failure, including calcitriol pulses (5,6). In fact, once NH develops, the vitamin D and calcium sensing receptors are considerably reduced (7–9). Moreover, at this stage of PTG hyperplasia, prolonged calcitriol therapy may increase the risk of hypercalcemia and hyperphosphatemia (10).

To overcome these problems, new selective vitamin D receptor activators (calcitriol analogs), such as paricalcitol, have been developed. Paricalcitol in HD patients was more effective in suppressing PTH levels, but had minimal effects on serum calcium and phosphate levels, reduction of the risk of cardiovascular calcifications, or mortality (11–14).

Since vitamin D administration alone does not always allow the optimal iPTH target to be reached, new compounds such as calcimimetics (e.g. cinacalcet) have been recently introduced in the treatment of SHPT (15–18). Cinacalcet increases the sensitivity of the calcium sensing receptor located on the surface of parathyroid chief cells to extracellular calcium ions, inhibits the release of iPTH, and lowers the iPTH level within a few hours after administration (17). The results of clinical trials suggest that cinacalcet, in association with vitamin D, reduces plasma iPTH concentrations with a concomitant decrease in serum calcium and phosphorus (19–24). Recently, it has been shown that cinacalcet-treated subjects were more likely to achieve all NFK–KDOQI targets with a consequent reduction of the risk of bone fractures and the need for parathyroidectomy (22). Cinacalcet HCl has been recently approved by the US Food and Drug Administration and the European Medicines Agency for the treatment of SHPT in HD patients; however, a shared treatment algorithm using cinacalcet and vitamin D has not yet been defined (24,25). Moreover, in the calcimimetic era, the indications for parathyroidectomy still remain an open question (26,27).

Although the evidence of regression of PTG hyperplasia with calcitriol therapy is still contradictory (28,29), it is widely acknowledged that the PTG volume negatively influences the response to vitamin D treatment (30–32). Conversely, calcimimetics have been shown to prevent parathyroid hyperplasia in uremic rats; however, it has not been fully elucidated yet whether the patients with established NH can be controlled by calcimimetics.

The present study aims to evaluate the effect of cinacalcet treatment for one year on the metabolic parameters and PTG ultrasound patterns in HD patients with severe SHPT refractory to conventional therapy.


  1. Top of page
  2. Abstract

This study was a single center, prospective, non-randomized study, performed at the Hemodialysis Unit of the Università Cattolica del Sacro Cuore in Rome, Italy, between July 2005 and December 2008. The study was approved by the local ethics committee, and written informed consent was obtained from all patients before enrollment in the study. The recruitment criteria were: (i) stable clinical condition and hemodialysis regimen for at least 12 months; (ii) severe SHPT, defined as serum iPTH levels >700 pg/mL obtained in three consecutive measurements after one year of conventional i.v. vitamin D therapy (calcitriol 1–2 µg three times per week); (iii) US and scintigraphic evidence of at least one PTG with a diameter >7 mm; (iv) serum calcium levels >8.4 mg/dL; and (v) high surgical risk or refusal of surgery by the patient. The exclusion criteria were as follows: pregnancy, breastfeeding, use of cytochrome P450 (CYP) 3A4 inhibitors (e.g. ketoconazole, itraconazole, or erythromycin) or inducers (e.g. rifampin), and use of medications that are metabolized predominantly by CYP2D6 (e.g. flecainide, vinblastine, thioridazine, and most tricyclic antidepressants).


Ultrasonography was performed after one year of vitamin D therapy by a single experienced radiologist using the same ultrasound device and settings (Toshiba Aplio; Toshiba, Tokyo, Japan) connected to a multi-frequency high-resolution probe on the patient in the supine position with the neck slightly hyperextended. In the present study we identified the PTG as an oval, hypoechoic nodule, located close to the thyroid gland, but clearly separated by a well-defined echogenic line representative of its capsule. All nodular lesions located within the thyroid parenchyma were excluded from the analysis. For the purpose of the study, we included only parathyroid glands that were evident both at US and on Tc-99 sestamibi dual-phase scintigraphy. The sestamibi scan was considered positive for a PTG when a focal area was detected with increased uptake in the thyroid phase, showing a relative increase over time, and was not detectable in thyroid scintigraphy.

The structural patterns of a PTG on US were classified by the following structural scores: (1) hypoechoic, homogeneous or slightly heterogeneous; (2) highly heterogeneous; and (3) nodular. The US finding was classified as highly heterogeneous if the PTG showed a calcification, cystic change, fibrous band, or notch. The PTG size was defined in terms of its maximal longitudinal diameter (MLD) and volume, which is estimated using the formula: a × b × c × π/6 (where a, b, and c are the PTG dimensions).

Scanning the PTG in the longitudinal plane, the color Doppler blood flow signal was classified by the following vascular scores: (1) non- or hypo-vascularized pattern: an absent or very small peripheral/central blood flow signal; (2) mediumvascularized pattern: blood flow signal surrounding >30% of the PTG circumference and/or <30% of its surface; and (3) hypervascularized: high peripheral and central blood flow signal >30% of the PTG surface.

The PTG vascular pattern was defined retrospectively by the consensus of two observers who reviewed the complete video clip and set of images for each patient. The US of the PTG was repeated after cinacalcet treatment for one year.

Study design


After obtaining informed consent and initial evaluation, patients were treated with cinacalcet. The initial dose of cinacalcet was 30 mg, given orally once daily. The dose was increased sequentially every three weeks during the dose-titration phase to 60, 90, 120, or 180 mg once daily. Increases in the dose were permitted if the parathyroid hormone level remained >300 pg/mL and the serum calcium levels were ≥8.0 mg/dL. The dose was not increased if symptoms of hypocalcemia developed, if serum calcium levels were <8.0 mg/dL, or if patients had an adverse event that precluded an increase in the dose. Dose titration continued until the iPTH level was reduced to <300 pg/mL or until the highest dose of the drug (180 mg/day) was reached. Throughout the maintenance phase, the cinacalcet dose was reduced by 50% if iPTH levels were <150–300 pg/mL on two consecutive measurements within one month, if patients reported an adverse event requiring a reduction of the dose. Conversely, the dose was increased by 50% if the iPTH level was >300 pg/mL. If patients experienced symptoms secondary to hypocalcemia or an adverse event related to the medication, or if the iPTH levels were <150 pg/mL on two consecutive measurements in one month, cinacalcet was temporarily stopped.

Phosphate binders

Regardless of the serum phosphorus level and the weekly dose of vitamin D, a standard dose of a calcium-based phosphate binder (calcium carbonate or calcium acetate, expressed as grams of elemental calcium/day) was administered according to serum calcium levels: 3 g/day if calcium levels were 7.5–8.5 mg/dL; 2 g/day if calcium levels were 8.6–9.0 mg/dL; and 1 g/day if calcium levels were 9.1–9.5 mg/dL. The administration of calcium carbonate was stopped when serum calcium levels were >9.6 mg/dL.

In addition to the standard dose of calcium-based phosphate binders, sevelamer hydrochloride was administered if serum phosphorus levels were >6.0 mg/dL (1.6–9.6 g/day). The short-term administration of low doses of aluminum-containing phosphate-binding agents was used if the serum phosphorus levels remained >8.0 mg/dL despite the maximal dose of calcium carbonate and sevelamer hydrochloride being administered.

Vitamin D

A standard dose of i.v. paricalcitol was maintained according to serum calcium levels: 5 µg three times per week if calcium levels were 8–8.5 mg/dL; 5 µg two times per week if calcium levels were 8.6–9.5 mg/dL; and 5 µg weekly if calcium levels were 9.6–10.5 mg/dL. Vitamin D was not administered if calcium levels were >10.6 mg/dL, phosphorus levels were ≥7.5 mg/dL, or iPTH levels were <150 pg/mL.

Hemodialysis regimen

Patients were maintained on a regular hemodialysis regimen of three times a week, for 4 h per session. The blood flow ranged from 250 to 300 mL/min, with a dialysis rate flow of 500 mL/min. All patients were treated with low-permeability membranes. They were all maintained on a stable hemodialysis regimen, using a similar schedule of dialysis in all study periods. A 1.5 mmol/L dialysate calcium concentration was used in all patients.


Baseline clinical and laboratory data were recorded, including age, gender, underlying renal disease, hemodialysis regimen, duration on dialysis, Kt/V, urea, serum creatinine, serum phosphorus and calcium, alkaline phosphatase activities, osteocalcin, 25-hydroxycholecalciferol, and plasma iPTH levels. Serum iPTH levels were determined by the iPTH electrochemiluminescence immunoassay (Roche Modular E 70; F. Hoffmann-La Roche, Basel, Switzerland; normal range 10–65 pg/mL). Every two weeks during the dose-titration phase and every four weeks during the maintenance phase, the serum levels of phosphorus, calcium and iPTH were measured. The iPTH levels were measured 12–18 h following the cinacalcet dose. Alkaline phosphatase activities, osteocalcin, and 25-hydroxycholecalciferol levels were also determined at the end of the study. All biochemical measurements were performed at the Department of Clinical Chemistry, Catholic University of the Sacred Heart, Rome, Italy.

Statistical analyses

GraphPad Prism version 4.02003 for Microsoft Windows XP (GraphPad Software, La Jolla, CA, USA) was used for data analysis. Continuous variables are expressed as mean ± SD and categorical variables as frequencies. The appropriate test (paired t-test, Wilcoxon signed rank test, or two-way repeated measures analysis of variance [RM-anova]) was used when comparing group means or frequencies. A P value < 0.05 was considered statistically significant.


  1. Top of page
  2. Abstract

Patient characteristics

Thirteen patients were included in the study, six of whom were male. The mean age was 59 ± 22 years and the dialytic age was 50 ± 38 months. The primary causes of end-stage renal disease were as follows: glomerulonephritis in six patients, diabetes in two patients, interstitial nephritis in one case, and polycystic renal disease in two patients. The baseline mean urea and creatinine levels were 71.8 ± 12.8 mg/dL and 10.7 ± 1.9 mg/dL, respectively, and the baseline mean Kt/V was 1.34 ± 0.23. The patients had the following complications of SHPT: osteoarticular pain 84%, fractures 15.4%, subperiosteal bone resorption of phalanges or brown tumor (osteoclastomas) 38.5%, cardiovascular calcifications 76.9%, extra-skeletal calcifications 38.5%, calciphylaxis 15.4%, pruritus 61.5%, and refractory anemia secondary to erythropoiesis-stimulating agents 15.4%.

Two patients did not complete the study. One patient developed penile calciphylaxis and underwent parathyroidectomy four months after the start of cinacalcet treatment, and the other patient developed severe gastrointestinal symptoms (nausea and vomiting) and decided to stop the treatment.

During the maintenance phase of treatment, the mean (± SD) daily cinacalcet dose was 53.4 ± 15.6 mg (median 60, range 30–150 mg) and the mean weekly paricalcitol dose was 8.5 ± 5.2 µg (median 10, range 5–30 µg/week). The daily calcium carbonate dose was 1.5 ± 0.3 g. Nausea was documented in four patients, which led to the cessation of cinacalcet in one patient. No other side-effects were observed.

Laboratory parameters and clinical outcome

Between the baseline and one-year measurements, the iPTH (1145 ± 424 vs. 747 ± 517 pg/mL; P < 0.03) and osteocalcin (784.6 ± 526.4 vs. 537.5 ± 348.0 ng/mL; P < 0.007) levels changed significantly. Conversely, the concentrations of calcium, phosphorus and alkaline phosphatase did not differ significantly.

Overall, the median (±interquartile range) iPTH, calcium and phosphorus levels over time are detailed in Figure 1. Two-way RM-anova shows a significant difference in the calcium and iPTH serum levels (P < 0.001 for both) over time.


Figure 1. Changes in laboratory parameters over time. Median (±interquartile range) intact parathyroid hormone (iPTH), calcium and phosphorus levels over time (after 12 months of calcitriol therapy and 12 months of cinacalcet and paricalcitol therapy). The changes in iPTH and calcium serum levels (using two-way repeated measures analysis of variance) were significant (P < 0.001), whereas the change in the phosphorus level was not significant. Post, after one year of cinacalcet/paricalcitol therapy; Pre, at baseline.

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Comparing the median (±SEM) iPTH, calcium, and phosphorus levels of each patient during the year of vitamin D therapy and the year of cinacalcet/paricalcitol treatment, we found that in 8 out of 11 patients the median iPTH levels decreased, while they remained unchanged or increased in 3 patients. However, the median iPTH levels were reduced to levels <300 pg/mL in only 3 (27.2%) patients. In all patients the calcium levels decreased, remaining within optimal range values and <9.5 mg/dL. The phosphorus levels decreased in 7 out of 11 patients, but they remained within the recommended range in only six patients.

At the end of one year of cinacalcet treatment, three patients with persistent SHPT agreed to undergo parathyroidectomy. All eight parathyroid glands described by US and scintigraphy were surgically removed, and the pathology examination revealed the presence of nodular hyperplasia in seven (88%) of these.

Ultrasound findings

Of the 13 patients included in the study, two were excluded because they did not complete the follow-up. In the remaining 11 patients, 35 parathyroid glands were detected by ultrasound and/or scintigraphy. Of these, 22 were detected both at ultrasound and scintigraphy, and were analyzed for the purpose of the present study.

The maximal longitudinal diameters of the parathyroid glands detected by US, as well as the volume, and echo-structural and vascular scores, at baseline (pre) and after one year (post) of cinacalcet/paricalcitol therapy of the 11 patients who completed the study are detailed in Table 1. The mean PTG MLD and volume remained essentially unchanged.

Table 1. Maximum longitudinal diameter (MLD), volume, echo-structural score and vascular score of parathyroid glands detected in each patient before (pre) and after (post) one year of cinacalcet and paricalcitol therapy
PatientsMLD (mm)Volume (mm3)Structural scoreVascular score
  • *

    Parathyroid gland with histological evidence of nodular hyperplasia. The changes in the MLD, volume, and vascular score were not statistically significant. The worsening of the structural score was statistically significant (P < 0.031).



  1. Top of page
  2. Abstract

The present study shows that, in HD patients with severe SHPT refractory to conventional therapy and with ultrasound evidence of PTG nodular hyperplasia (21.24), treatment with cinacalcet associated with paricalcitol for one year did not change the ultrasound pattern, even in patients with a decrease in serum PTH level. However, the percentage of therapeutic response to cinacalcet associated with paricalcitol was similar to that observed in previous studies that included HD patients with serum iPTH levels >800 pg/mL (20–23). These studies suggest that the new compound may offer a therapeutic chance in HD patients with severe SHPT in whom the high surgical risk contraindicates parathyroidectomy (26,27,33–37). To the best of our knowledge, this is the first study to report such novel observations, and it may shed light on the role of cinacalcet in severe SHPT with ultrasound evidence of nodular hyperplasia of the parathyroid glands. The lack of macroscopic changes of PTG size (MLD and volume) and morphology after one year of therapy seems to exclude a regression of PTG hyperplasia, as well as a significant reduction in parathyroid cell proliferation or their relevant apoptosis.

So far, only two experimental studies have evaluated the efficacy of calcimimetics in the attenuation of established PTG hyperplasia (38,39). The study by Chin et al. evaluated the effects of oral or subcutaneous administration of the calcimimetic NPS R-568 for eight weeks on the progression of established mild or moderate-to-severe secondary hyperparathyroidism in uremic rats. Both oral and infused NPS R-568 completely prevented further hyperplasia, but did not reduce the total parathyroid cell number below that present at the initiation of treatment (38). Although, at least theoretically, PTG regression during calcimimetic treatment may also occur as a consequence of parathyroid cell apoptosis, the study by Colloton et al. failed to demonstrate DNA fragmentation through terminal dUTP nick-end labeling (TUNEL) examination in the parathyroid glands of calcimimetic-treated or untreated uremic rats (39). To explain these results, the authors suggested that if apoptosis was occurring, it was unlikely to be revealed because sampling occurred several weeks after cinacalcet administration and the process of apoptosis occurs very early. In addition, it is well known that few parathyroid cells undergo apoptosis in normal or uremic rats treated with vitamin D3 or with a phosphorus-restricted diet (40).

More recently, Terawaki et al. reported that a low dose of cinacalcet (25 mg/day) prescribed to a hemodialysis patient with SHPT from February to April 2008 was able to reduce the size of the right superior and inferior PTGs, but did not affect the size of the left superior PTG, and that the subsequent increase of the cinacalcet dose to 50 mg/day decreased the size of all PTGs (40).

However, the regression of NH still remains an unanswered question and a challenge for nephrologists. It is well known that PTGs with NH are characterized by cells more closely packed together than in purely diffuse hyperplasia (DH), a greater prevalence of cell cycle markers, more cycling cells by flow cytometry, lower numbers of vitamin D and calcium sensing receptors, and a higher calcium set point for PTH secretion. In addition, NH is more rapidly progressive, with a higher clonal proliferative activity than with purely DH (41). Thus, the opinion prevails that NH is an irreversible phenomenon currently difficult to treat with medical therapy (42).


  1. Top of page
  2. Abstract

In summary, the present study shows that one-year cinacalcet treatment in HD patients with SHPT is not associated with significant changes in the ultrasound patterns of parathyroid glands. However, further studies are needed to evaluate whether earlier or longer cinacalcet treatment may be able to prevent or reverse the nodular hyperplasia and to assess its therapeutic cost-effectiveness.


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  2. Abstract
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