http://www.kidney-international.org & 2006 International Society of Nephrology
The role of calcimimetics in chronic kidney disease A Gal-Moscovici1,2 and SM Sprague1 1
Division of Nephrology and Hypertension, Evanston Northwestern Healthcare, Northwestern University Feinberg School of Medicine, Evanston, Illinois, USA and 2Hadassah Hospital Medical Center, Hebrew University, Ein Keren, Jerusalem, Israel
Secondary hyperparathyroidism (SHPT) develops in chronic kidney disease as a consequence of impaired phosphate, calcium, and vitamin D homeostasis. Treatment strategies directed to reduce the parathyroid hormone (PTH) concentrations have included phosphate binders and active vitamin D compounds. The over zealous use of these agents may result in hypercalcemia or overt calcium overload. Severe SHPT, hyperphosphatemia, and total body calcium overload have been implicated in the pathophysiology of skeletal and extraskeletal calcification and associated with increased morbidity and mortality among the dialysis population. Cinacalcet, the recently approved agent to lower PTH, activates the calcium-sensing receptor of the parathyroid gland amplifying the glands’ sensitivity to extracellular ionized calcium concentration resulting in suppression of PTH secretion. Several clinical studies conducted in dialysis patients, have shown that cinacalcet in doses from 30 to 180 mg/day, significantly reduce PTH concentrations while simultaneously lowering calcium and phosphate levels. Respective to the National Kidney Foundation-Kidney Disease Outcomes and Quality Initiative (NKF-K/DOQI) recommended targets for bone and mineral metabolism, 41% of cinacalcet-treated patients achieved both PTH and calcium–phosphorus targets. The ability of cinacalcet to reduce PTH secretion, along with reductions in the serum calcium, phosphorus, and calcium–phosphorus product provide an alternative to the traditional treatment paradigm, and should be a welcomed addition to our therapeutic strategy in the management of SHPT. Kidney International (2006) 70, S68–S72. 10.1038/sj.ki.5001982 KEYWORDS: secondary hyperparathyroidism; vitamin D; cinacalcet; calcium sensing receptor
Correspondence: SM Sprague, Division of Nephrology and Hypertension, Evanston Northwestern Healthcare, 2650 Ridge Avenue, Evanston, Illinois 60201, USA. E-mail:
[email protected] S68
Secondary hyperparathyroidism (SHPT), owing to parathyroid gland hyperplasia and increase parathyroid hormone (PTH) secretion, develops early in chronic kidney disease (CKD), generally as the glomerular filtration rate drops below 60 ml/min/1.73 m2.1 Phosphate retention coupled with decreased production of calcitriol and hypocalcemia act both independently and additively to increase the production and release of PTH. Phosphorus exerts a stimulatory effect on the parathyroid cells leading to hyperplasia, increased pre-pro-PTH transcription, and PTH messenger RNA stability.2 Stimulation of the vitamin D receptor (VDR) by active vitamin D compounds decreases the synthesis of pre-pro-PTH, however, in the context of CKD where 1,25 dihydroxycholecalciferol (1,25D) production is severely impaired, PTH synthesis will be enhanced.3 Calcium is the main regulator of PTH secretion. Changes in its extracellular concentration are detected by the calcium sensing receptor (CaR) located on parathyroid cell surface. An increase in ionized serum calcium concentration leads to activation of the receptor resulting in an instantaneous and abrupt decrease in PTH secretion, whereas a fall in ionized serum calcium has the opposite effect, namely increased PTH secretion.4 Persistent hyperparathyroidism leads to severe skeletal and extraskelatal disorders associated with increased morbidity and mortality among CKD patients. PTH causes high bone turnover characterized by increased bone resorption, formation of woven bone, and fibrosis. These effects results in impaired bone quality resulting in increased fracture risk among the CKD population when compared to age match normal population.5 The extra-skeletal effects of elevated PTH concentrations have been associated with accelerated soft tissue and vascular calcification with increased cardiovascular mortality.6 Severe hyperparathyroidism is also associated with worsening hyperphosphatemia and hypercalcemia, factors which are also associated with vascular calcification and cardiovascular mortality.7 Thus, preventing and/or treating the development of SHPT is of paramount importance when approaching the management of patients with CKD. During the last few decades, reduction in serum phosphate level, normalization of calcium, calcium phosphate product, and calcitriol have been targeted to lower PTH level. Currently available phosphate binders are flawed by their side effects as in the case of aluminum and calcium Kidney International (2006) 70, S68–S72
A Gal-Moscovici and SM Sprague: Role of calcimimetics in CKD
containing binders.8 The use of calcitriol and alfacacidiol is limited because of hypercalcemia and its implication in vascular calcification and adverse cardiovascular outcome.9 The new non-calcium containing phosphate binders and vitamin D receptor activators (VDRA) which have a less calcemic and phosphatemic effect are promising therapeutic agents, but are not universally effective in controlling hyperparathyroidism, especially in those with the most severe disease.10 Cinacalcet, which is a CaR mimetic, has been approved for the treatment of SHPT in patients with CKD stage 5 and effectively suppresses PTH without causing hypercalcemia and hyperphosphatemia.11 It has demonstrated efficacy when used alone as well as with VDRA.12 However, its use has been limited by the high cost, and its approved indications are restricted to SHPT in CKD 5 patients undergoing dialysis. It remains unclear as to the optimal time to initiate cinacalcet therapy. Cinacalcet is a type II calcimimetic, which acts as a positive allosteric modulator of the CaR. It enhances the signal transduction of the CaR by presumably inducing conformational changes in the receptor and reducing the receptor’s threshold for Ca2 þ .13 In addition to this effect, the calcimimetic also upregulates the expression of the CaR.14 The maximum plasma concentration of cinacalcet is reached in approximately 2–6 h after oral administration. The half-life is 30–40 h and therefore steady state can be achieved in 7 days. Cinacalcet is highly protein bound, is metabolized by CYP3A4, CYP2D6, and CYP1A2 and its metabolites are excreted renally. The most prominent action of this calcimimetic is inhibition of PTH secretion from parathyroid cells in a dose-dependent manner. A single oral administration of cinacalcet decreases plasma PTH and calcium. This interesting effect on plasma calcium may be partially owing to a simultaneous stimulation of calcitonin.15 In addition, calcimimetics may also reduce cellular proliferation and arrest the progression to glandular hyperplasia.16 In a model of partially nephrectomized rats this effect was independent of changes in serum level of vitamin D or phosphorus. As activation of CaR seems to be linked to anti-proliferative effect on parathyroid cells it was also shown that long-term treatment with calcimimetics can suppress the parathyroid hyperplasia in rats with progressive CKD.16 However, there are no data showing that calcimimetics can regress parathyroid hyperplasia as they do not cause apoptosis in the parathyroid cells. As bone disease is one of the most concerning complications of SHPT, the effect of calcimimetics on bone in the context of CKD has been raised. This question has been addressed in animal studies where partially nephrectomized rats with mild osteitis fibrosa, received daily administration of the calcimimetic (NPS R-568 for 30 days had a doserelated decrease in serum PTH levels, marked reduction in peri-trabecular fibrosis, increased volumetric cortical bone mineral density and improved cortical bone stiffness at the femoral midshaft.17 A beneficial effect of NPS R-568 was Kidney International (2006) 70, S68–S72
also observed in a model of low turn-over bone disease. In this study, renal failure was induced by intravenous injections of adriamycin. Despite PTH elevation these rats developed osteomalacia with reduced turnover. Animals who received NPS R-568 orally on a daily intermittent basis, had a sustained suppression of serum PTH and increased cancellous bone volume by normalizing the trabecular thickness whereas those who received a continuous subcutaneous infusion did not have normalization of bone, in spite of a decrease in serum PTH.18 Evidence that calcimimetics may benefit bone in humans was demonstrated in a small trial in CKD stage 4 and 5 patients treated for 26 weeks with cinacalcet. Increased bone mineral density of the proximal femoral but not of the lumbar spine was observed at the end of the study.19 Clinical trials on the effect of calcimimetics on bone are presently under evaluation in humans. Whether the calcimimetic affects the bone metabolism indirectly by lowering the serum PTH level or directly by activating the CaR on osteoblasts or both, has yet to be determined. Vascular calcifications, as previously mentioned, is another threatening complication in CKD patients, associated predominantly with hyperphosphatemia and excessive calcium loading. Recent animal studies showed a beneficial effect of calcimmetics on this complication. Henley et al.20 treated 5/6 nephrectomized rats for 26 days with either daily 1,25(OH)2D3, cinacalcet, or the combination. They demonstrated an increased serum calcium, Ca P product and marked aortic calcification in 1,25(OH)2D3-treated rats whereas no significant calcifications and even decreased serum calcium were observed in the cinacalcet-treated animals despite a similar reduction in serum PTH concentrations in both groups. More interesting is the finding that co-administration of cinacalcet with calcitriol did not attenuate neither the calcitriol-mediated increase in Ca P product nor the calcitriol-mediated aortic calcification. The recently published results by Lopez et al.21, which performed a similar study, contrast these of Henley et al.20 by showing not only a significant effect of R-568 on preventing calcitriolinduced vascular calcifications but also a significant decreased mortality. CLINICAL EXPERIENCE WITH CALCIMIMETICS
Multiple clinical trials with different protocols have been performed in the last several years in order to assess the efficacy of calcimimetics. Table 1 summarizes the main features of the early trials that were of short duration and tested the effect of a single or multiple doses of calcimimetics on PTH plasma level in dialysis patients.22–24 PTH plasma level dropped in all the studies, even in cases of severe hyperparathyroidism. The maximal effect was observed within 4–6 h with a dose-dependent decrease in PTH. Utilizing the first generation agent, R-568, severe hypocalcemia that lead to withdrawal in seven patients23 whereas the second generation agent, cinacalcet, was accompanied by a mild reduction in calcium level. S69
A Gal-Moscovici and SM Sprague: Role of calcimimetics in CKD
Table 1 | Short-term clinical trials with single and multiple calcimimetic doses in HD No. of patients
Duration
PTH
CaXP
Ca
PO4
Severity SPTH
Dose/day
Antonsen et al.22
Author
7 CKD 5
2d
k
—
—
—
Mild
R-568 40–80 mg 120–200
Goodman et al.23
21 HD
15 d
k
—
kk
—
Severe
R-568 100 mg
Goodman et al.24
52 HD
28 h
k
—
k Only 75–100 mg
—
Severe
Single dose 5–100 mg cinacalcet
Goodman et al.24
23 HD
8d
k
k 20–35%
k 5–10%
—
Severe
25–50 mg cinacalcet
d, day; HD, hemodialysis; PTH, parathyroid hormone. The percentages are given as decrease from baseline value.
Table 2 | Phase 2 double-blind, prospective, randomized studies on the effect of cinacalcet-HCl on PTH levels in dialysis patients (HD) Author
No. of patients
Duration
PTH
CaXP
25
Drueke et al.
215 HD
12 w
k 24%
k 7%
Quarles et al.26
71 HD 78 HD 82 HD
18 w
k 33% k 26% k 30%
k 8% k 11.9% k 13%
Lindberg et al.27 Block et al.28
18 w
9–12 w
Ca
PO4
k 5% —
k 3% — k 7.5%
Severity SHPT
Dose/day
Mild
Mild-moderate
AMG 073 20–25 mg 50–100 mg AMG 073 25, 50, 75, and 100 mg AMG 073 up to 50 mg
Uncontrolled
AMG 073 50–180 mg
Severe uncontrolled
HD, hemodialysis; PTH, parathyroid hormone; W, week. The percentages are given as a decrease from baseline value.
Table 3 | Long-term treatment of SHPT with cinacalcet-HCl: effect on plasma PTH, calcium, phosphate, and CaXP product in hemodialysis patients (HD) Author
No. of patients
Moe et al.32
59 HD
2y
Moe et al.34
60 HD
3y
Duration PTH
CaXP o55 mg2/dl2
k 53% of patients *430% in 66% of achieved target patients *30% in 70% of k patients
Calcium 8.4–9.5 mg/dl
PO4 3.5–5.5 mg/dl
37% of patients achieved target
37% of patients achieved target
Severity SPTH
Dose/day
Mild-moderate
30–180 mg median 70 mg
Mild-moderate
d, day; HD, hemodialysis; PTH, parathyroid hormone; y, years. *The reduction in percentage from the baseline value.
The relevant findings of the phase II studies utilizing cinacalcet are summarized in Table 2.25–28 In these studies patients continued on their phosphate binders and/or vitamin D compounds. Following a titration period the dose of cinacalcet was adjusted based on changes on PTH and calcium level. PTH level and Ca P product decreased significantly and significantly more patients in the calcimimetic group achieved a PTH level less than 300 pg/ml when compared to placebo. In three phase III placebo-controlled, double-blind, randomized studies, 1100 hemodialysis and peritoneal dialysis patients with uncontrolled HPT were treated for S70
26 weeks with cinacalcet (30–180 mg/day). In these studies cinacalcet significantly reduced PTH concentrations with the majority of treated patients achieving a PTH o250 pg/ml. This reduction in PTH was paralleled by significant reduction in serum calcium, phosphorus and Ca P product.29–31 Moe et al. investigated the long-term use of cinacalcet in patients with SPTH undergoing hemodialysis; data summarized in Table 3. The 2-year study included patients who had completed a qualifying phase II study and subsequently enrolled in an open label extension study.31 The 3-year study included patients that received cinacalcet in a 1-year phase II study and then 2 years in an open-label extension study. PTH Kidney International (2006) 70, S68–S72
A Gal-Moscovici and SM Sprague: Role of calcimimetics in CKD
Table 4 | Achieving NFK-K/DOQI goals of bone metabolism with cinacalcet-HCl Moe et al.32
No. of patients
IPTH 150–300 pg/ml (%)
CaXP o55 mg2/dl2 (%)
Calcium 8.4–9.5 mg/dl (%)
PO4 3.5–5.5 mg/dl (%)
205 205 165 166 294 101
60 10 60 11 51 10
63 34 67 35 66 43
54 26 55 23 43 24
40 32 48 30 48 42
A Cinacalcet treated A Placebo treated B Cinacalcet treated B Placebo treated C Cinacalcet treated C Placebo treated
A United States and Canada December 2001–December 2002: B European Community and Australia Feb 2002-Jan 2003: C United States, Canada and Australia May 2002–March 2003. The percentage represents the patients who achieved the K/DOQI target
lower that 300 pg/ml was achieved in 59% of the patients at the end of 2 years. Ninety-two percent of the patients received VDRAs and 90% received phosphate binders at some time during the study. However, in those receiving cinacalcet, the mean dose of calcium-containing phosphate binders dropped from 3.1 (at 52 weeks) to 2.4 (at 100 weeks) tablets per meal. The most frequent adverse effects were mildto-moderate nausea and vomiting observed in 34 and 44% of patients, respectively. Moe et al.32 analyzed the ability of cinacalcet therapy to achieve the National Kidney Foundation’s Kidney Disease Outcomes Quality Initiative (NFK-K/DOQI) bone metabolism goals by combining the data from the three placebocontrolled, double-blind, randomized studies of 1136 hemodialysis patients (Table 4). The treatment dose ranged from 30–180 mg/day following a titration period. It is worthy to note that in a subgroup of patients with PTH level above 800 pg/ml (a level at which parathyroidectomy is recommended) and Ca P product greater than 70 mg2/dl2, 22, and 37%, respectively, of the cinacalcet treated patients achieved the established goal for these markers. The efficacy of cinacalcet was also evaluated in patients with CKD stages 3 and 4 in a placebo-controlled study of 18-week duration. Treatment with cinacalcet resulted in 56% of the subjects achieving a 30% or greater reduction in PTH levels compared to 19% in the placebo group (P ¼ 0.006). Mean PTH levels decreased by 32% in the cinacalcet group, as opposed to a 6% increase in the control group (Po0.001).33 However, there was an 18% increase in serum phosphorus associated with a 13% decrease in urinary phosphorus and a 151% increase in urinary calcium. The ramifications of these changes requires further investigation.
tives, (d) cinacalcet significantly reduces the Ca P product potentially providing a beneficial effect on preventing and combating vascular calcifications, and (e) to the present no serious adverse effect of cinacalcet have been remarked. REVISING CINACALCET INDICATIONS
The current treatment paradigm includes the use of high dose calcium containing phosphate binders and a VDRA as first-line therapy, leaving cinacalcet in the role of rescuetreatment in resistant hyperthyroidism. This implies that patients will be treated with cinacalcet only after have being exposed for a prolonged period of time to the deleterious effects of hyperphosphatemia, hyperparathyroidism as well as the potential adverse effects of excessive calcium overload and very high doses of VDRAs. Unfortunately at this moment many patients will have already developed significant end organ damage resulting in increased morbidity and mortality. Thus, in patients with severe or resistant hyperphosphatemia, which is a major driving force in the initiation and perpetuation of kidney–bone–parathyroid axis disturbances, severe hyperparathyroidism should be anticipated when indication to initiate cinacalcet therapy early seems prudent. Future indications for cinacalcet treatment should consider to balance continuing the ‘traditional’ treatments in safe doses where the adverse side effects and clinical outcome are well established, with the addition of treatment which may enhance therapeutic and clinical outcomes. REFERENCES 1. 2.
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