Treatment of Secondary Hyperparathyroidism in CKD Patients with Cinacalcet And/Or Vitamin D Derivatives

In-Depth Review

Treatment of Secondary Hyperparathyroidism in CKD Patients with Cinacalcet and/or Vitamin D Derivatives

Tilman B. Dru¨eke* and Eberhard Ritz† *INSERM Unite´845 and Service de Ne´phrologie, Hoˆpital Necker, Assistance Publique-Hoˆpitaux de Paris, and Faculte´ de Me´decine Rene´Descartes Paris 5, Paris, France; and †Department of Internal Medicine (Nierenzentrum), Ruperto- Carola University, Heidelberg, Germany

The discovery of the calcium-sensing receptor (CaR) 15 yr ago was rapidly followed by the development of drugs modulating its activity, the so-called calcimimetics (increasing the CaR signal) and calcilytics (decreasing the CaR signal). The indication for calcimimetics is treatment of primary and secondary hyperparathyroidism, whereas calcilytics have potential for treatment of osteoporosis. A large number of clinical studies has shown that cinacalcet, the only presently available calcimimetic, effectively reduces serum parathyroid hormone in dialysis patients with secondary hyperparathyroidism. In contrast to the effect of active vitamin D derivatives, it simultaneously decreases serum calcium and phosphorus. Experimental studies showed a concomitant decrease in parathyroid hyperplasia. In the treatment of secondary hyperparathyroidism of dialysis patients, important questions remain unresolved, for example, whether there are reasons to prefer calcimimetics to active vitamin D derivatives and whether combined administration offers advantages compared with calcimimetics or active vitamin D given in isolation. For lowering parathyroid hormone, available evidence from recent studies suggests that combination therapy should be preferred to single drug treatment because of less side-effects and greater efficacy in controlling parathyroid overfunction. Future randomized controlled trial must answer whether calcimimetics impact on cardiovascular events or survival and whether in this respect there are differences between vitamin D sterols and calcimimetics. Clin J Am Soc Nephrol 4: 234–241, 2009. doi: 10.2215/CJN.04520908

Discovery and Function of Calcium-Sensing netically old. It has been detected in lower prevertebrate spe- Receptor cies such as the worm Caenorhabditis elegans and even plants ϩ ntracellular Ca2 has long been known to play a major role such as Arabidopsis (2). A highly homologous CaR gene has as second messenger in signal transduction across the also been identified in fishes, which use hormones distinct ϩ I extracellular membrane, in response to a large number of from PTH, such as stanniocalcin, to maintain extracellular Ca2 activators and inhibitors outside the cell. Subsequently, it has homeostasis (3). The CaR, however, mediates olfactory sensi- ϩ ϩϩ become apparent that extracellular Ca2 itself is one of these tivity to changes in the environmental Ca in the freshwater activators and inhibitors because a variety of tissues and cell teleosts (4). ϩ types were capable of sensing and responding to changes in the CaR activation occurs at surprisingly high extracellular Ca2 ϩ concentration of extracellular Ca2 . This is also true for endo- concentrations, compared with activator concentrations needed ϩ ϩ crine cells. In most of them, extracellular Ca2 stimulates hor- for the majority of other extracellular receptors. Ca2 is the mone secretion, for instance, in the ␤-cells of the pancreas or the main activator, although not the only one. It binds to specific C-cells of the thyroid, where it increases insulin and calcitonin sites on the extracellular domain of the CaR, with relatively secretion, respectively. Not so in the principal cells of the para- high affinity. The receptor can be stimulated by many other thyroid or the juxtaglomerular cells of the kidney, where extra- cationic agents, including magnesium, aluminum, gadolinium, ϩ cellular Ca2 inhibits parathyroid hormone (PTH) and renin and organic compounds such as aminosides. The CaR is part of secretion, respectively. a large G-protein–coupled receptor family. Signal transduction ␣ The observation that cells could sense the extracellular con- occurs via several pathways (5). It interacts with G q11 subunits ϩ centration of Ca2 led Brown et al. to search for the existence of of heterotrimeric G proteins, resulting in the activation of phos- a calcium sensor located in the cell membrane. They were pholipases C and A2 and activation of protein kinase C. It successful in cloning such a sensor 15 yr ago and called it activates phosphatidylinositol 4-kinase (PI4K), which catalyzes “calcium-sensing receptor” (CaR) (1). The receptor is phyloge- the first step of the inositol lipid biosynthesis, independently of the G proteins, by a ␳-dependent mechanism. In some cells, ␣ CaR interacts with protein G i, which results in inhibition of Published online ahead of print. Publication date available at www.cjasn.org. adenylate cyclase-mediated cAMP production. The expression of the CaR is practically ubiquitous. In addi- Correspondence: Tilman B. Dru¨eke, MD FRCP, INSERM Unite´ 845, Hoˆpital 2ϩ Necker, Tour Lavoisier, 161 rue de Se`vres, F-75743 Paris Cedex 15, France. Phone: tion to the classic organs involved in extracellular Ca ho- ϩ33 1 44 49 52 43; Fax: ϩ33 1 45 66 51 33; E-mail: [email protected] meostasis, namely the kidney, the parathyroid gland, and the

C-cells of the thyroid gland, it also is present in tissues as Several studies in experimental animals with chronic renal different as the brain, the intestinal tract, vascular tissue includ- failure showed beneficial effects of calcimimetics in terms of ing endothelium, smooth muscle cells, and perivascular neu- disturbed calcium and phosphate metabolism and beyond. rons (6). Whether the same CaR also is expressed in bone Thus, the use of calcimimetics led to a decrease in PTH synthe- remains a matter of debate. The observation that osteoblasts sis and PTH release (17); modulated the regulation of genes isolated from CaR-deficient mice retained responsiveness to involved in these processes, including upregulation of CaR (18) ϩ extracellular Ca2 led to the identification of another receptor, and VDR (19); reduced parathyroid cell proliferation (20); at- namely, GPRC6A. This is another member of the G-protein– tenuated progression of parathyroid hyperplasia (21,22); and coupled receptor family and mediates calcium sensing in os- enhanced parathyroid cell apoptosis (23). In experimental ani- Ϫ Ϫ teoblasts and possibly other tissues even in CaR / mice (7). mals, calcimimetics attenuated or even halted the progression In humans, both inactivating and activating mutations of the of osteitis fibrosa (24). They also have been shown to reduce the CaR have been shown to lead to distinct clinical diseases with progression of arterial calcification or prevent their appearance contrasting phenotypes. In heterozygotes, inactivating CaR in uremic rats (25,26) and mice (22). mutations cause familial benign hypocalciuric hypercalcemia, Because CaR are expressed in many tissues unrelated to and in homozygotes, severe neonatal primary hyperparathy- mineral metabolism, calcimimetics have numerous, so-called roidism (8,9). In contrast, activating CaR mutations result in pleiotropic effects. In experimental models, they have been autosomal dominant hypocalcemia (10,11). The latter may be reported to cause a short-term increase, but a long-term de- sometimes associated with hypercalciuria and a Bartter-like crease, in BP and to reduce cardiac pathology at the micro- syndrome (12,13), explained by the fact that the CaR is also scopic level (27,28). They also caused reduction in serum LDL expressed by epithelial cells of Henle’s loop. Corresponding cholesterol concentration (28); slowing of CKD progression phenotypes have been reproduced in genetically modified an- with less albuminuria and less morphologic abnormalities of imal models. the kidney (28), comparable to the effect of calcitriol (29); and improved survival (26). In this context, it is of interest that CaR Development of Calcimimetics and polymorphisms in human subjects have been shown to be Calcilytics related to cardiovascular morbidity and mortality (30). The ϩ In addition to the activation of the CaR by extracellular Ca2 observation that cataracts and ectopic calcification develop in and other cations, called “type I calcimimetics,” its sensitivity to the Nuf mouse, caused by an activating CaR mutation (31), has these direct receptor agonists can be increased by CaR modu- been of some concern because this phenotypic feature was lators, called “type II calcimimetics.” They act as positive allo- suggestive of similar complications in human patients treated steric activators. The protoype is cinacalcet. Alternatively, the with calcimimetics. This finding probably reflects the conse- sensitivity of the CaR to extracellular cations can be reduced by quences of profound hypocalcemia (cataract) and hyperphos- so-called calcilytics. The CaR modulators act through differing phatemia (ectopic calcification) in the Nuf mouse model (32). conformational changes of the tertiary structure of the receptor. The main clinical interest of the calcimimetics resides in the Clinical Use of Cinacalcet treatment of parathyroid overfunction, whereas that of the The vast majority of experimental and clinical studies have calcilytics is its potential for the treatment of osteoporosis (14). been limited to the exploration of effects of calcimimetics on Of note, the increase in the sensitivity of the parathyroid CaR serum biochemistry, that is, PTH, calcium, and phosphorus. ϩ to extracellular Ca2 brought about by the calcimimetics is Some of them also examined effects on vascular calcification approximately 100 times higher than that of the C-cell of the and bone. Only a small number of reports dealt with pleiotropic thyroid gland (15). This probably explains why relatively low effects, as alluded to above. Currently, there are no prospective doses of cinacalcet generally allow control of secondary hyper- randomized trials available to document the effect on patient parathyroidism in patients receiving dialysis therapy without outcome (see below). inducing major side effects at other tissue sites, except initial It is noteworthy mentioning that the targets of the major hypocalcemia and gastrointenstinal symptoms such as nausea biochemical parameters to which clinicians should be treating and vomiting. These adverse effects can be avoided in the according to the guidelines of the National Kidney Foundation majority of patients by using cautious cinacalcet dose incre- Kidney Disease Outcomes Quality Initiative (K/DOQI) of 2003 ments at treatment initiation. The administration of calcimimet- (33) have recently become a matter of lively debate. This is ics to patients with chronic kidney disease (CKD) before the particularly true for PTH. Studies from Brazil and Portugal stage of dialysis, however, may lead to increased urinary cal- have questioned the previously held assumption of a good cium excretion and phosphate retention via direct effects on the correlation between serum intact PTH and bone turnover kidney and indirect effects through inhibition of PTH. Recently, (34,35). Moreover, a variety of methodological problems with the group of the late Steve Hebert showed that modulation of PTH assays have been identified (36–39), which make the rec- intestinal CaR activity by calcimimetics leads to a reduction of ommendation of optimal targets even more difficult. excessive fluid secretion into the gut lumen upon stimulation In patients with primary parathyroid adenomas and normal by cAMP- and cGMP-dependent secretagogues (16). Calcimi- renal function (40) or in chronic hemodialysis patients with metics could thus represent a new tool in the control of cholera end-stage kidney disease (41), the acute effects of cinacalcet toxin- and Escherichia coli endotoxin-induced diarrhea. administration consist of a rapid decrease of serum PTH within 236 Clinical Journal of the American Society of Nephrology Clin J Am Soc Nephrol 4: 234–241, 2009

2 to 4 h, closely followed by a decrease of serum calcium within associated with the progression of chronic renal failure (51,52). 4to8hinpatients with renal disease, but not in patients with These treatments are equally effective in CKD 5D patients with parathyroid adenoma. Long-term administration of cinacalcet moderate to severe hyperparathyroidism (53–56). Although to patients with primary hyperparathyroidism induces a pro- this is the case in the majority of patients, it is not true in all of gressive decrease in serum calcium toward the normal range them, as shown in a recent prospective study from Japan: 120 and an increase in serum phosphorus, despite only minor dialysis patients with secondary hyperparathyroidism were changes in serum PTH (42). In contrast, predialysis serum treated de novo with intravenous calcitriol for up to 48 wk. The values of PTH, calcium, and phosphorus all decrease progres- treatment goal of decreasing serum intact PTH to levels Ͻ300 sively with time in ESRD patients in response to cinacalcet, pg/ml could be achieved only in 79 patients (57). when given in addition to optimal standard treatment consist- The administration of excessive amounts of calcitriol or alfa- ing of active vitamin D derivatives and phosphate binders calcidol may induce adynamic bone disease and arterial calci- alone (32). Importantly, in ESRD patients cinacalcet effectively fication, as do excessive oral doses of calcium salts (58). It controls secondary hyperparathyroidism over prolonged time remains to be demonstrated in patients with CKD whether periods, up to at least 3 yr (43). Of note, the pathologic right- treatment with high doses of the novel active vitamin D deriv- ϩ ward shift of the Ca2 -PTH curve seen in many dialysis pa- atives such as paricalcitol has similar adverse effects on bone, or tients with secondary hyperparathyroidism can be reversed by whether, on the contrary, it is useful to prevent bone loss (in cinacalcet treatment (44,45). part by stimulating bone formation) and to prevent vascular calcification. The latter claims are based on experimental data Role of Cinacalcet and Vitamin D Derivatives in the obtained in cell cultures and experimental animals (59–61). Management of Hyperparathyroidism in Patients with ESRD It has recently been widely appreciated that administration Both active vitamin D derivatives and cinacalcet allow long- of native vitamin D or its hepatic metabolite, 25 OH vitamin D term control of secondary hyperparathyroidism in patients (calcifediol), may be useful in CKD patients with vitamin D with ESRD. An important question is whether there are reasons deficiency (33,62). Insufficient or deficient levels of circulating to prefer one to the other, and whether combined administra- 25(OH) vitamin D and/or 1,25(OH) vitamin D in CKD patients tion offers advantages compared with each drug (or drug class) 2 are associated with an increased prevalence of vascular calcifi- given in isolation. Potential arguments for the latter approach, cation (63) and arterial stiffness (64), as well as with higher which has been proposed by Levi and Silver (17), may be the ϩϩ mortality (63,65 to 67). For many years, some authors had findings that active vitamin D increases Ca sensitivity of the advised that calcifediol should be administered early in the parathyroid (46) and that the CaR is regulated by vitamin D but course of CKD to hyperparathyroid patients with CKD, even not by calcium (47). when they are vitamin D replete (68). In recent years, it has In terms of PTH control, the efficacy of the two drug classes become apparent that most, if not all, patients with advanced can be considered equal, although a recent meta-analysis cast stages of CKD have vitamin D insufficiency or deficiency (69), some doubt on the consistent efficacy of vitamin D compounds and the same is true even in the general population (70). There- in reducing PTH levels in patients with CKD (48). Vitamin D fore, some authors recommend supplementation with native and its active derivatives attenuate the severity of secondary hyperparathyroidism, often, however, at the price of an in- vitamin D in all CKD patients. This advice is based on patho- crease in serum calcium and phosphorus, resulting from en- physiological considerations and numerous observations of hanced intestinal absorption (49,50). In contrast, cinacalcet gen- pleiotropic vitamin D effects, including cardiovascular, antipro- erally decreases both serum calcium and phosphorus, in liferative, and immunomodulatory actions (71). Recently, cir- addition to a reduction of PTH (see below). culating 25(OH)D and 1,25(OH)2D levels have been found to be related to cardiac outcome and survival even in nonrenal patients with coronary heart disease (65). Case in Favor of Vitamin D or Active Vitamin D Derivatives Alone In line with this concept, in several retrospective studies, The hypercalcemic and hyperphosphatemic effect of thera- treatment with calcitriol, alfacalcidol, or paricalcitol has been peutic doses of active vitamin D derivatives is generally not a reported to be associated with beneficial effects on survival in major problem in early stages of CKD, which are already char- CKD patients, both before (72) and after (73–77) the initiation of acterized by progressive impairment of renal calcitriol synthe- dialysis treatment. Moreover, the results of one of these obser- sis. This effect may constitute an advantage when serum cal- vational studies in hemodialysis patients suggested a survival cium and phosphorus are at the lower end of the normal range advantage with paricalcitol as compared with calcitriol (74), but or below. In addition, one has to point out that the only cur- another failed to identify such a difference (76). These effects rently available calcimimetic, cinacalcet, is licensed for use in appeared to be independent of changes in serum calcium and patients with CKD stage 5D. In patients with CKD stages 2 to phosphorus. A major problem with historical cohort analyses of 5, clinicians have to rely on the use of calcitriol, its analog drug effects, however, is the risk of residual and unmeasured 1-alpha 25 OH vitamin D (alfacalcidol), or other active vitamin confounding by indication (48,76,78). Unfortunately, definite D sterols, either alone or in combination with oral calcium controlled, prospective evidence for the benefit of administra- supplements and/or non–calcium containing phosphate bind- tion of native vitamin D or vitamin D derivatives in CKD ers, to arrest or retard the steady increase in plasma PTH levels patients on outcome, that is, morbidity or mortality, is not yet Clin J Am Soc Nephrol 4: 234–241, 2009 Secondary Hyperparathyroidism: Cinacalcet versus Vitamin D 237 available, as pointed out in a recent meta-analysis (48). This sible dose of 180 mg/d. At the end of the study, K/DOQI issue has become a matter of continued debate (79–82). targets for biointact PTH were achieved in 85% of patients, and It may well be that the outcome of vitamin D therapy— for Ca ϫ P in 72% of patients. Concurrent achievement of both whether benefit or side effects—will turn out to be a matter of targets occurred in 47% of patients. Thus cinacalcet enabled dose. If not closely supervised, prolonged high-dose supple- improved control of mineral metabolism with a combination of ments of vitamin D or its active derivatives may lead to hyper- low-dose active vitamin D derivatives. calcemia and hyperphosphatemia and induce adverse effects such as vascular calcification (83–85). Of interest, both vitamin Adverse Effects of Vitamin D Derivatives and Cinacalcet D deficiency and vitamin D excess have been shown to be Vitamin D, both its natural active derivatives and its active associated with an increased prevalence of vascular calcifica- analogs, are generally better tolerated than cinacalcet and cause tion (63). fewer gastrointestinal side effects. Thus in a recent double- blind, placebo-controlled, multicenter study aimed to evaluate Case in Favor of Cinacalcet Alone the long-term safety and efficacy of cinacalcet, nausea was The main theoretical advantage of cinacalcet over active vi- observed in 13% patients receiving cinacalcet versus 5% patients tamin D derivatives in dialysis patients is that it decreases not on standard therapy alone, vomiting in 9% versus 2%, dyspep- only serum PTH, but also serum calcium and phosphorus and sia in 5% versus 4%, and diarrhea in 5% versus 2% (91). hence the Ca ϫ P product. Investigator-reported hypocalcemia was seen in 11% of cina- A recent study in chronic hemodialysis patients with mod- calcet-treated patients, but in only 1% of patients on standard erate to severe secondary hyperparathyroidism addressed the therapy (91). In contrast, active vitamin D sterols often induce issue of whether treatment with cinacalcet combined with low hypercalcemia and/or hyperphosphatemia (83–85). The fre- doses of vitamin D sterols improves control of both serum PTH quency of these side effects may be less with so-called nonhy- and Ca ϫ P (86). The results documented that combined ther- percalcemic active vitamin D derivatives such as paricalcitol apy with cinacalcet and low-dose vitamin D sterols improved (92) or doxercalciferol (93), but it clearly has not been reduced achievement of the biochemical targets for CKD-related min- to zero (94,95). eral and bone disorder (CKD-MBD) recommended by the In a recent uncontrolled clinical trial in hemodialysis pa- K/DOQI guidelines. Moreover, the study provided evidence in tients, cinacalcet treatment was associated with an increase in favor of cinacalcet being equivalent to combined treatment in serum osteoprotegerin and a decrease in serum fetuin-A levels those patients whose serum values of PTH and Ca ϫ P product (96). Because in CKD, both fetuin-A and osteoprotegerin play could be well controlled according to K/DOQI guidelines. This an important role in the pathogenesis of vascular calcification, might be particularly true for ESRD patients with mild to mod- the changes induced by cinacalcet could be interpreted as con- erate degrees of hyperparathyroidism. ferring an increased risk of vascular calcification. Alternatively, they could reflect a reduced demand for feedback defense Case in Favor of Combination of Vitamin D and Cinacalcet mechanisms, which may be secondary to improved mineral Several controlled trials documented that in patients with metabolism (97). ESRD, the addition of cinacalcet treatment on top of optimal standard therapy with active vitamin D derivatives and phos- Perspectives phate binders provides better control of secondary hyperpara- A major problem remains in assessing the effectiveness of thyroidism than standard therapy alone (32,87). The K/DOQI cinacalcet/vitamin D treatment, namely the absence of pro- treatment goals were achieved in a higher proportion of dial- spective randomized trials to document that in CKD patients, ysis patients with elevated serum PTH and Ca ϫ P levels in one better control of secondary hyperparathyroidism translates into such study (88). The superiority of the combination of standard fewer hard end-points such as fractures, cardiovascular mor- therapy with cinalcalcet was also demonstrated in the OPTIMA bidity, and mortality. trial, in which dialysis patrients with poorly controlled hyper- As outlined above, several observational studies point to a parathyroidism were randomly allocated to receive either con- survival advantage in CKD patients receiving vitamin D treat- ventional care or a cinacalcet-based regimen (89). Again, a ment. This concerned mostly active derivatives. Some studies higher proportion of patients receiving cinacalcet in addition to showed better survival with the more recently developed vita- conventional therapy versus conventional care alone achieved min D analogs than with the parent substance, that is, calcitriol. the targets for serum PTH, calcium, and phosphorus. More- It must not be forgotten, however, that observational, retro- over, cinacalcet treatment allowed a 22% reduction of the vita- spective studies show association but do not prove causality min D dose in patients who had received vitamin D at baseline. (78). The outcome of direct, head-on comparisons would be of Another trial was conducted in hemodialysis patients with considerable interest. controlled PTH and elevated Ca ϫ P to evaluate whether Of note, two randomized controlled trials (RCT) are under- treatment with low-dose active vitamin D derivatives plus way that examine the question of whether cinacalcet is superior cinacalcet enhanced the proportion of patients achieving to optimal standard treatment. The first trial (ADVANCE), a K/DOQI serum PTH and Ca ϫ P targets (90). At the start of the randomized, open label, parallel assignment, efficacy study, is study, the dose of active vitamin D derivatives was lowered aimed at reducing the progression of aortic valve calcification and cinacalcet was titrated from 30 mg/d to a maximum pos- in a cohort of 330 dialysis patients (http://clinicaltrials.gov/ 238 Clinical Journal of the American Society of Nephrology Clin J Am Soc Nephrol 4: 234–241, 2009 ct2/show/record/NCT00379899). 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