Pharmacotherapy of chronic kidney disease and mineral bone disorder

1. Introduction

2. Phosphate binders

3. Vitamin D

4. Calcimimetics

5. Conclusion

6. Expert opinion

Review

Pharmacotherapy of chronickidney disease and mineral bonedisorderFellype Carvalho Barreto, Rodrigo Azevedo de Oliveira,Rodrigo Bueno Oliveira & Vanda Jorgetti†

Universidade de Sao Paulo, Nephrology Division, Department of Internal Medicine,

Sao Paulo, Brazil

Introduction:Disturbances of the bone andmineral metabolism are a common

complication of chronic kidney disease (CKD); these disturbances are known

as CKD--mineral bone disorder (CKD-MBD). A better understanding of the

pathophysiological mechanisms of CKD-MBD, along with its negative impact

on other organs and systems, as well as on survival, has led to a shift in the

treatment paradigm of this disorder. The use of phosphate binders changed

dramatically over the last decade when noncalcium-containing phosphate

binders, such as sevelamer and lanthanum carbonate, becamepossible alterna-

tive treatments to avoid calcium overload. Vitamin D receptor activators, such

as paricalcitol and doxercalciferol, with fewer calcemic and phosphatemic

effects, have also been introduced to control parathormone production and

the interest in native vitamin D supplementation has grown. Furthermore,

a new drug class, the calcimimetics, has recently been introduced into the

therapeutic arsenal for treating secondary hyperparathyroidism.

Areas covered: This review discusses the advantages and disadvantages of the

above pharmacological options to treat CKD-MBD.

Expert opinion: The individual-based use of phosphate binders, vitamin D and

calcimimetics, separately or in combination, constitute a reasonable approach

to treat CKD-MBD. These treatments aim to achieve a rigorous control of

phosphorus and parathormone levels, while avoiding calcium overload.

Keywords: calcimimetic, calcium, chronic kidney disease, CKD-MBD, parathormone,

phosphate binders, phosphorus, renal osteodystrophy, vitamin D, vitamin D receptor activators

Expert Opin. Pharmacother. (2011) 12(17):2627-2640

1. Introduction

Mineral homeostasis presents early alterations in chronic kidney disease (CKD)compromising phosphorus (P) excretion capacity and calcitriol synthesis. Theresulting accumulation of P, increased production of fibroblast growth factor 23(FGF-23) and decreased intestinal absorption of calcium (Ca) favor the develop-ment of secondary hyperparathyroidism (SHP). It has been recognized thatderanged mineral homeostasis, including SHP, is associated not only with bonediseases but also with a higher mortality risk [1,2]. These disturbances have tradi-tionally been termed renal osteodystrophy. Recently, a new term, “CKD--mineraland bone disorders (CKD-MBD)”, has been proposed to describe the broaderclinical syndrome encompassing mineral, bone and cardiovascular abnormalitiesthat develop as a complication of CKD [3]. The currently available drug-basedtreatment options for CKD-MBD include phosphate binders, vitamin Dcompounds and calcimimetics.

10.1517/14656566.2011.626768 © 2011 Informa UK, Ltd. ISSN 1465-6566 2627All rights reserved: reproduction in whole or in part not permitted

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2. Phosphate binders

Within the theme of CKD-MBD, serum P control is one ofthe greatest problems faced by nephrologists. Block et al. [4]

observed that hyperphosphatemia was independently associ-ated with increased mortality in end-stage renal disease(ESRD) and Isakova et al. [5] noted that the use of P binderswas associated with improved survival among incident hemo-dialysis (HD) patients. In-vitro studies have demonstratedthat P, at concentrations that are commonly observed inpatients with CKD, induces phenotypic transformation of vas-cular smooth-muscle cells into cells that resemble osteoblasts,resulting in vascular calcification [6]. High P levels are also astimulus for the development of SHP, which is also associatedwith high mortality [1,2]. Palmer et al. recently published ameta-analysis assessing studies that analyzed the degree of evi-dence for the association between serum levels of Ca, P andparathormone (PTH) and the risk of cardiovascular mortality,nonfatal cardiovascular events and death risk in CKDpatients [7]. This study further confirmed the importance ofadequate control of P levels. The risk of death increased 18%for every 0.32 mmol/L increase in serum P [relative risk (RR)1.18; 95% confidence interval (C)1.12 -- 1.25].

In 2003, the Kidney Disease Outcomes Quality Initiative(K-DOQI) guidelines recommended that the target range forserum P levels for the dialysis population should be between1.12 and 1.77 mmol/L [8]. More recently, faced with growingevidence of the deleterious potential of hyperphosphatemiaderived from observational studies, the Kidney DiseaseImproving Global Outcomes (KDIGO) recommended amore rigorous control of P that should be kept within the nor-mal range for the general population, i.e., between 0.80 and1.45 mmol/L [3].

There are three strategies to control hyperphosphatemia inCKD: i) dietary restriction; ii) dialysis removal; and iii) reduc-tion of intestinal absorption by using P binders. An adequatenutritional orientation is very important for P control, as60 -- 70% of ingested P is absorbed. However, restricting Pintake by rigorous diet is very difficult and usually results inmalnutrition, poor compliance or both. Additives should bestrictly avoided because they present a form of P that is easilyabsorbed and is less nutritious. Moreover, there are many diffi-culties in obtaining information on the real P content of manyconserved foods because the amount of P in food additives andpreservatives is not usually specified [9]. The classic HDmethod(4 h three times per week) is insufficient to promote an adequateP balance in most patients. Nocturnal HD (8 -- 10 h six timesper week) and short daily HD (3 h six times per week) are inter-esting alternatives. The first promotes a better P control, elimi-nating the need for binders or diet inmost cases. However, thesemethods are not routinely applied worldwide [10,11].

P binders therefore remain an essential component of Pmanagement. An ideal P binder should have the followingcharacteristics: minimum adverse events; high efficiency,regardless of pH; good palatability; no absorption in the diges-tive tract preventing deposit in tissues; long-lasting action, thusrequiring minimum daily doses; and -- finally -- low cost.Table 1 summarizes the characteristics of the main drugs usedto treat hyperphosphatemia.

2.1 Aluminum-based phosphate bindersAluminum hydroxide is a powerful and cheap P binder andwas used extensively in the CKD population until approxi-mately 1980, since when its use worldwide has declined sig-nificantly because of serious hematological (microcyticanemia), neurological (encephalopathy) and skeletal (osteo-malacia) adverse events linked to aluminum deposition [12].However, Mudge et al. have recently observed that in manycountries aluminum-based P binders are still used withoutthe adverse effects mentioned above [13]. In Australia, forexample, 32.4% of the dialysis population use aluminumhydroxide. This observation suggests that the side effectsmay be related more to the quality of water used in dialysisthan to the aluminum ingested orally.

2.2 Calcium-based phosphate bindersCalcium-based P binders (Ca carbonate and acetate) havelargely replaced aluminum-based binders and are the main

Article highlights.

. Chronic kidney disease (CKD) and mineral bonedisorders are common and early complications of CKD.They comprise the broader clinical syndromeencompassing mineral, bone and cardiovascularabnormalities that develop as a complication of CKD.

. Hyperphosphatemia has been associated not only withsecondary hyperparathyroidism (SHP) but also withcardiovascular disease and greater mortality. The limitedefficacy of dietary restriction and dialysis therapy tocontrol phosphorous (P) levels generally requires the useof P binders. The choice between calcium (Ca)-basedand Ca-free P binders constitutes one of the maindilemmas faced by nephrologists.

. Vitamin D insufficiency and deficiency are highlyprevalent in CKD patients. Even though data are scarce,vitamin D supplementation by either ergocalciferol orcholecalciferol seems to be associated with a bettercontrol of mineral metabolism in this population.

. The use of vitamin D receptor activators (VDRAs) tocontrol SHP has been advocated for almost threedecades. VDRAs, such as paricalcitol and doxercalciferol,can suppress parathormone (PTH) production whilehaving less impact on calcemia and phosphatemia andpreserving the pleiotropic effects of the VDRAs;they have progressively replaced calcitriol in theclinical practice.

. Cinacalcet is the only available agent for clinical use of anew class of drug called calcimimetics that acts directlyon the calcium receptor, increasing its sensitivity toextracellular calcium. It has been demonstrated to be aneffective treatment for controlling SHP with minimalside effects.

This box summarizes key points contained in the article.

Pharmacotherapy of chronic kidney disease and mineral bone disorder

2628 Expert Opin. Pharmacother. (2011) 12(17)

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binders used in many countries [14]. Studies comparing thesetwo types of Ca-based P binder for the control of serum Pin the HD population have demonstrated that Ca acetate ade-quately controls mineral metabolism with significantly lessabsorption of elemental Ca than occurs with Ca carbon-ate [15,16]. However, this did not result in a lower incidenceof hypercalcemia.

Although Ca-based P binders are relatively free of adversereactions, increasing evidence has suggested that intestinalabsorption of large doses of Ca may contribute to Ca over-load, development of adynamic bone disease and, conse-quently, diminished bone buffer capacity, which have beenshown to potentially increase the risk of soft-tissue calcifica-tion and cardiovascular mortality [17,18]. Based on the previousobservations, the KDIGO guidelines recommend avoidingCa-based P binders in patients with low bone turnover,vascular calcification and hypercalcemia [3].

2.3 Magnesium-based phosphate bindersMagnesium-based P binders (Mg hydroxide and carbonate)have been used as alternative or adjunct therapy for the man-agement of hyperphosphatemia. However, there are few stud-ies on their effectiveness and safety [19]. Their main advantageis the avoidance of Ca overload and their main disadvantagesare the gastrointestinal side effects and low efficacy [12,20].

Observational data suggest higher serum levels of Mg as apossible protective factor in the progression of vascular calci-fication [21]. This observation is in agreement with experi-mental findings that demonstrated that adding Mg to anenvironment saturated with Ca and P prevents the growthof crystals of hydroxyapatite [22]. However, it remains to beshown whether chronic administration of oral Mg is safe forbone health as, due to its renal excretion, a positive Mgbalance may occur in CKD and high Mg bone content

(secondary to hypermagnesemia) could interfere with themineralization process. In fact, Gonella et al. showedan improvement in bone mineralization defects associatedwith normalization of serum Mg levels by reducing theconcentration of Mg in dialysis solution [23].

2.4 SevelamerSevelamer hydrochloride (sevelamer HCl) is a non-Ca, non-metal, nonabsorbable P binder that acts ideally at pH 6 -- 7 inthe small intestine. It has been demonstrated to be as effectiveas Ca-based P binders in controlling P and its great advantageis that it does not promote Ca overload [12,24-26]. Sevelamer-HCl also reduces low-density lipoprotein cholesterol (LDL),a known cardiovascular risk factor [25-27].

Some studies have also reported that sevelamer may attenu-ate the progression of arterial calcification in CKD patientswhen compared with Ca-based salts. Russo et al. have reporteda lower progression of coronary calcification in predialysispatients (n = 90; CKD stage 3 -- 5) using sevelamer comparedwith those on a low-P diet alone or those taking Ca carbon-ate [28]. Chertow et al. have found a similar result in the dialysispopulation [29]. However, these findings have not been repro-duced by other studies [25,30]. Of note, few studies have simul-taneously evaluated the effects of sevelamer and Ca acetate oncoronary calcification and bone remodeling over 1 year oftreatment [25,27]. A study conducted by our group found no dif-ferences between these two P binders, neither in the progres-sion of coronary calcification nor in bone remodeling.Some particularity of the study designs may have accountedfor the different results, such as population characteristicand avoidance of high doses of Ca-containing binders, aswell as the concomitant use of fixed or flexible vitamin Dtreatment [25,30]. Table 2 summarizes the main studiescomparing sevelamer and Ca-based P binders.

Table 1. Main drugs used to treat hyperphosphatemia in patients with CKD.

Drug Potential advantages Potential disadvantages

Aluminum hydroxide Very effective; inexpensive Aluminum toxicity (anemia, dementia, ABD)Calcium carbonate Effective and inexpensive Ca overload and its possible risks (vascular

calcification and ABD)Calcium acetate Effective; less Ca exposure than Ca

carbonateCa overload and its possible risks (vascularcalcification and ABD)

Magnesium carbonate No Ca exposure Low efficacy; GI side effectsSevelamer-HCl No Ca exposure; not absorbed;

reduces LDL cholesterol;might attenuate the progression of VC

Acidosis; GI side effects; high cost

Sevelamer carbonate Similar to sevelamer-HCl without therisk of acidosis

GI side effects; cost

Lanthanum carbonate Effective; no Ca exposure GI side effects; cost; potential accumulationon tissues

Niacin (nicotinic acid) Once daily use; different site of action(Na/P2b) than P binders

GI side effects; flush

Nicotinamide (niacinamide) Once daily use; different site of action(Na/P2b) than P binders

GI side effects; thrombocytopenia

ABD: Adynamic bone disease; Ca: Calcium; GI: Gastrointestinal; HCl: Hydrocloride; LDL: Low-density lipoprotein; P: Phosphate; VC: Vascular calcification.

Barreto, de Oliveira, Oliveira & Jorgetti

Expert Opin. Pharmacother. (2011) 12(17) 2629

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Recent studies have documented that sevelamer has theability to reduce levels of FGF-23 in the CKD population [31].FGF-23 is a hormone that regulates serum P levels by modulat-ing urinary P excretion and calcitriol synthesis in the kid-ney [5,31,32]. Small elevations in FGF-23 levels may have abeneficial effect by preventing hyperphosphatemia in earlyCKD. However, over the long term, high FGF-23 levels canfavor the development of SHP because FGF-23 inhibits thesynthesis of calcitriol. Its levels are usually increased in CKDand have been reported to be independently associated withmortality among incident patients initiating HD treatment.Mortality risk associated with elevated FGF-23 is substantiallylarger than that reported for serum P [33]. The current under-standing of the role of FGF-23 is still emerging. It is not clearlyunderstood how much the increased levels of FGF-23 in CKDrepresent a compensatory mechanism for maintaining a normalP balance or a secondarymarker indicating a reduced peripheraleffect due to Klotho deficiency. Furthermore, in addition tosevelamer, treatment with lanthanum carbonate or treatmentof hyperparathyroidism with parathyroidectomy or withcalcimimetics can also reduce levels of FGF-23 [34-36].The greatest problems related to sevelamer are the cost,

gastrointestinal side effects, the high pill burden to achieve

an adequate chelating power and metabolic acidosis [37,38].Recently, a new formulation of sevelamer was developed toprevent acidosis: the sevelamer carbonate. Comparative stud-ies between this new presentation and sevelamer hydrochlo-ride show the same efficacy and less acidosis favoring thefirst group [14,39].

2.5 Lanthanum carbonateIn 2004 a new P binder was approved to be used in CKD:lanthanum carbonate. This non-Ca, metal-based drug is aseffective as Ca carbonate, and has the advantage of resultingin fewer episodes of hypercalcemia [40]. A characteristic of lan-thanum carbonate that facilitates adherence to medication isthe need for fewer pills per day compared with sevelamer [37].The main side effects described are nausea, vomiting andmyalgia [37,41].

Like aluminium, lanthanum is a naturally occurring metal.Many experts question the safety of the long-term use of lan-thanum in humans [41,42]. Slatopolsky et al. demonstratedliver deposition of lanthanum in an animal model of CKD.However, prospective clinical trials in humans have shownits safe use over a period of 6 years [42,43]. Intestinal absorptionof lanthanum carbonate is minimal and its elimination occurs

Table 2. Main studies comparing Ca-containing P binders � Sevelamer-HCl in adult CKD patients.

Author [Ref.] Year Technical features Outcome 1 Outcome 2

Suki et al. [119](DCOR Trial)

2007 2103 prevalent HD patients atbaseline; 1068 patients at theend of the studyFollow up: 44 months

No difference in all-cause mortality. Suggestedbenefit for patients > 65 yearsin the sevelamer group

No difference incardiovascular mortality andhospitalization

Block et al. [26](RIND Study)

2005 148 incident HD patients.Follow up: 18 months

Median increase in CAC scorehigher in Ca-treated group

Equivalent serum P control;lower LDL in the sevelamergroup; more isolatedepisodes of hypercalcemia inCa group

Russo et al. [28] 2007 90 predialysis patientsrandomized to receive low-P diet, sevelamer-HCl + diet orCa carbonate + dietFollow up: 2 years

Less CAC progression in Ca-based P binders group than indiet group. No CAC progressionin sevelamer group

Total and LDL cholesteroland triglycerides reduction insevelamer group

Chertow et al. [29](treat to goal)

2002 RCT in 200 HD patientsFollow up: 52 weeks

Lower progression of VC in thesevelamer group

Equivalent control of serumP; higher serum Ca andlower serum PTH in theCa- group

Qunibi et al. [30](CARE 2 study)

2008 203 prevalent HD patients.Atorvastatin was used asadjunctive therapy in bothgroupsFollow up: 12 months

Similar progression of CAC inboth groups

Similar P control in bothgroups

Barreto et al. [25](BRiC Study)

2008 101 HD patientsFollow up: 12 months

No difference in CACprogression

No changes in boneremodeling

Ferreira et al. [27] 2008 119 HD patientsFollow up: 54 weeks

No changes in bone turnover ormineralization, but boneformation increased andtrabecular architecture improvedwith sevelamer

Reduction of total and LDLcholesterol in the sevelamergroup

Ca: Calcium; CAC: Coronary artery calcification; HCl: Hydrocloride; HD: Hemodialysis; LDL: Low-density lipoprotein; P: Phosphorus; PTH: Parathyroid hormone;

VC: Vascular calcification.



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via the liver; thus, unlike aluminum, lanthanum eliminationis not dependent on renal function [44]. To date, lanthanumhas demonstrated no evidence of any of the side effects ofaluminum. In fact, a prospective, randomized study withbone biopsy before and after the use of lanthanum carbo-nate vs. Ca carbonate for 1 year showed no predisposition tolow bone remodeling disease in the lanthanum group.Malluche et al. [45] not only corroborated these findings butalso noted an improvement in bone remodeling in patientstreated with lanthanum [46]. However, it is worth mentioninga recent isolated case report of a 59-year-old man with anacute confusional state who was being treated with lanthanumcarbonate. Serum and cerebral spinal fluid lanthanum dosagewere elevated and clinical symptoms reversed after discontin-uation of the drug [47].

Despite the isolated case report cited above and the disas-trous experience with aluminum-based P binders -- which isworrisome -- clinical evidence has demonstrated that lantha-num carbonate may be an interesting therapeutic option forthe treatment of hyperphosphatemia in CKD.

2.6 Future perspectivesNew P binders under study include magnesium iron hydrox-ycarbonate (fermagate), MCI-196 (colestilan) and a chitosanchewing gum [14]. The last has been effective in loweringserum P levels in parallel with reductions in salivary Plevels [48].

Vitamin B3 -- niacin (nicotinic acid) and nicotinamide(niacinamide) -- have the ability to reduce P absorption inthe digestive tract. They act by inhibiting the intestinal co-transporter sodium/phosphorus (Na/P2b). As more than50% of the intestinal P absorption takes place via this co-transporter, vitamin B3 has become an interesting therapeuticoption [49]. It can be used safely once daily and associated withthe traditional P binders, as demonstrated by Cheng et al. in awell-conducted, placebo-controlled study [50]. Another prop-erty of vitamin B3 is the modulation in lipid profile (reducingLDL and enhancing HDL cholesterol levels), although theclinical importance of these effects is unclear in the dialysispopulation. The main adverse effects of nicotinamide arediarrhea and thrombocytopenia, and the main adverse effectof niacin is flushing [49-51].

Larger prospective, double-blind studies with longerfollow-up periods and clinical outcomes as end points arerequired before these new agents can be recommended forclinical use.

3. Vitamin D

3.1 Native vitamin D compounds25-hydroxyvitamin D (25(OH)D) insufficiency and defi-ciency are highly prevalent and associated with SHP andadverse outcomes in CKD patients [52-54]. Given that dietarysources of vitamin D are scarce, vitamin D supplementationhas been recommended to correct 25(OH)D levels.

KDOQI guidelines recommend that stage 3 -- 4 CKDpatients should be given weekly bolus oral doses of eitherergocalciferol (vitamin D2) or cholecalciferol (vitamin D3)aiming to raise serum 25(OH)D levels > 75 nmol/L [8].However, few studies have evaluated the efficacy of thisapproach. Although a complementary effect of vitamin Dsupplementation on mineral metabolism has been demon-strated in CKD predialysis patients, its use as a sole therapyis not sufficient to promote a pronounced reduction inPTH levels, being less effective in the later stages ofCKD [55-57]. In HD patients, vitamin D supplementationhas been associated with a better control of mineralmetabolism parameters [58-60] as well as with a beneficialimpact on inflammation, cardiac function and response toerythropoietin stimulating agents [58,59].

In summary, the use of vitamin D supplementation hasbeen shown to be safe with minimal risk of toxicity acrossall stages of CKD. However, one should take into accountthat the studies currently available either enrolled a smallnumber of patients or had a short follow-up (or both).Thus, the current recommendation cannot be considered asevidence-based and a real benefit on and beyond CKD-MBD remains to be shown. Larger and better-designedclinical studies to examine the effect of vitamin D supplemen-tation on mineral metabolism (preferably with bone biopsy)and on the cardiovascular system are required.

3.2 Vitamin D receptor activatorsSecondary hyperparathyroidism is a major component ofCKD-MBD. The use of vitamin D receptor activators(VDRA), such as calcitriol, to control this disorder has beenadvocated for almost three decades [61]. Investigations overthe past years have elucidated many of the mechanisms ofaction of calcitriol on the parathyroid glands. Calcitriol actson parathyroid by a direct effect on PTH gene transcription,increasing the expression of vitamin D and Ca sensor recep-tors and decreasing parathyroid cell proliferation [62,63]. Calci-triol therefore has direct effects on the parathyroid, and sodecreases PTH production and secretion and influences glandgrowth. In addition, the effects of calcitriol on bone and intes-tine leading to an increase in serum Ca levels help to suppressPTH secretion [64]. Therapy with thrice-weekly doses of calci-triol has been shown to effectively reduce PTH levels andbone turnover [65,66]. However, this form of therapy isassociated with some undesirable effects leading to the devel-opment of adynamic bone disease [65], hypercalcemia and/orhyperphosphatemia [67], as well as vascular calcification [68].

Due to this myriad of harmful effects of calcitriol, newVDRAs that are more selective for suppressing PTH secretionand have less impact on Ca and P levels have been developed.The most commonly used are paricalcitol (19-nor-1a,25(OH)2D2) and doxercalciferol (1a,25(OH)D2). Paricalcitolbinds directly to the vitamin D receptor (VDR) and is, conse-quently, an active compound, whereas doxercalciferol is aprodrug that requires hepatic 25-hydroxylation activation.



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Several studies have demonstrated that doxercalciferol,given both by oral or intravenous routes, is effective in thetreatment of SHP in HD [69-71] and CKD stage 3 -- 4patients [70]. More recently, Wesseling-Perry et al. have dem-onstrated that doxercalciferol is as effective as calcitriol in con-trolling bone disease in pediatric patients with CKD. Nodifferences in serum levels of Ca and/or P, or in episodes ofhypercalcemia and/or hyperphosphatemia, were detectedbetween calcitriol and doxercalciferol therapies [72].Maung et al. reported an overall prevalence of hypercalcemia(Ca levels > 2.62 mmol/Ll) of up to 15%, whilst serum Plevels > 2.22 mmol/L were noted in 13.5 and 16.5%, respec-tively, of the measurements during intravenous and oral ther-apy with doxercalciferol [73]. Considering that a strictercontrol of P levels is currently recommended [3], the numberof hyperphosphatemia episodes observed in this study wouldprobably need to be greater. Experimental studies using amodel of ovariectomized rats also argue against the bone selec-tivity of doxercalciferol. Calcitriol and doxercalciferol haveboth been shown to be capable of preventing bone loss inthis rat model, with generally equal effects on Ca, P andPTH levels at all doses studied [74]. Although doxercalciferolcan be considered a safe and efficient option for the manage-ment of SHP, it remains to be proved whether this agent hasan advantage over calcitriol therapy.Paricalcitol was the first VDRA approved for treating SHP.

Several studies have shown that paricalcitol effectively controlsPTH levels with smaller calcemic and phosphatemic effectsthan calcitriol [75-77]. Although the mechanisms of this selec-tivity are not completely understood, this may be due to theability of paricalcitol to: i) reduce intestinal VDR expres-sion [78]; ii) lessen stimulation of the expression of proteinsinvolved in the regulation of intestinal Ca and P absorp-tion [79]; and iii) be less effective in mobilizing Ca and Pfrom the skeleton [80]. In fact, clinical studies have repeatedlyconfirmed the less calcemic effect of paricalcitol. In a12-week, double-blind, placebo-controlled study in 78 HDpatients, PTH levels in the paricalcitol treatment groupdecreased progressively by more than 50% over the courseof treatment [76]. Importantly, patients experienced only afew episodes (27 over 414 determinations) of hypercalcemia,defined as Ca levels > 2.62 mmol/L and no significantchanges in P [76]. Studies have also compared the effects ofparicalcitol and calcitriol on mineral metabolism control inCKD patients. A double-blind, randomized, multicenterstudy that enrolled 263 HD patients demonstrated that intra-venous paricalcitol reduces PTH concentrations faster andwith fewer sustained episodes of hypercalcemia and/or increased Ca-P product than calcitriol [81]. Interestingly,paricalcitol and calcitriol seem to have the opposite effect onthe PTH(1 -- 84) : large carboxy-terminal-PTH fragmentsratio. Paricalcitol therapy was associated with a higher ratio,which suggests that this compound can control SHP withoutmajor suppression of bone remodeling [82]. Paricalcitol hasalso been shown to successfully suppress PTH levels in HD

patients resistant to calcitriol therapy at an initial conversiondose rate of 1 : 3 [77]. The initial dose of paricalcitol canalso be based on PTH concentration (intact PTH/80) orbody weight (0.04 µg/kg of dry body weight) [83]. The formerformula is associated with fewer requirements of doseadjustment, faster PTH suppression and no difference inhypercalcemia episodes.

In recent years, increasing attention has been paid to thenonclassical effects of vitamin D therapy and its potentialimpact on cardiovascular disease and survival. Epidemiologi-cal studies have reported that HD patients treated with pari-calcitol have a better survival rate and a lower rate ofhospitalization than calcitriol-treated patients [84]. Severalclues that may at least in part explain the outcome advantagesfavoring paricalcitol therapy have been provided by clinicaland experimental studies. In a recent 2-year, single-center study comparing long-term calcitriol with paricalcitoltreatment in the same 59 HD patients, conversion from calci-triol to paricalcitol resulted in significantly lower serum Ca, Pand PTH levels and in a better compliance [85]. In uremic rats,calcitriol and doxercalciferol promoted vascular calcificationand the expression of bone-related markers Runx2 and osteo-calcin in the aorta, whereas paricalcitol did not [86,87].Increased calcification of vascular smooth-muscle cells cul-tured in calcification media with calcitriol, but not with pari-calcitol, has also been reported [86]. In addition, Becker et al.found a favorable effect of paricalcitol on aortic wall remodel-ing in uninephrectomized ApoE knockout mice [88]. Con-versely, one should bear in mind that: i) experimental datashow that even new VDRAs may induce vascular calcification,although to a lesser extent than calcitriol; and ii) there is as yetno clinical study that demonstrates that selective VDRAs areless prone to inducing vascular calcification.

It should also be noted that although paricalcitol seemedbetter than calcitriol for patient survival, there are also studiesdemonstrating that other VDRAs, including calcitriol, have asurvival benefit compared to no VDRA use [89-91]. A recentstudy evaluated the associations of oral calcitriol use withmortality and dialysis requirement in 1418 nondialysispatients with CKD and hyperparathyroidism during a medianfollow-up of 1.9 years. After adjustment for confounders,such as kidney function and baseline levels of PTH, Caand P, oral calcitriol was associated with a 26% lower riskfor death (p < 0.016) and a 20% lower risk for death or dial-ysis (p < 0.038) [89]. A survival benefit of oral calcitriol has alsobeen demonstrated in hemodialysis patients from six LatinAmerican countries followed for a median of 16 months incomparison to patients who did not receive vitamin D [90].Furthermore, Tentori et al. have shown that mortality rates(deaths/100 patient years) were similar in doxercalciferol-and paricaltol-treated patients and higher in patients receivingcalcitirol (p < 0.0001). In adjusted models, this difference wasno more statistically significant whereas mortality was higherfor patients who did not receive vitamin D than for thosewho did [91]. Altogether, these findings suggest that the



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survival benefit in patients with CKD seems to be better withthe use of VDRAs, including calcitriol, and that the worstsurvival is associated with no VDRA use.

Finally, the evidence that the less calcemic and phosphate-mic properties of selective VDRAs could have an advan-tageous impact on the outcome in CKD patients hasstimulated the development of new agents of this class. Theadministration of VS-105, a novel VDRA, in 5/6 nephrectom-ized male Sprague--Dawley rats with established uremia effec-tively suppressed serum PTH without raising serum Ca or P.Furthermore, 2 weeks of treatment with VS-105 improvedendothelium-dependent aortic relaxation and attenuated leftventricular abnormalities [92].

Taken all together, selective VDRAs, such as doxercalci-ferol and paricalcitol, seem to be safer than calcitriol for treat-ing SHP, presenting less calcemic and phosphatemic effectsand a similar PTH-lowering action, while preserving the non-classical effects of the VDRA. The available data showing apotential benefit of paricalcitol therapy in the survival rateof HD patients might suggest an advantage of using thisagent. Nevertheless, randomized, controlled clinical trials(RCTs) with a large number of patients to evaluate the benefitof VDRA in hard outcomes as well as the superiority of oneVDRA over the other are still required.

4. Calcimimetics

Calcimimetics are a new class of drug that act directly on thecalcium receptor (CaR), increasing its sensitivity to extracellu-lar Ca. The CaR was cloned and characterized by Brown et al.in 1993 from parathyroid bovine glands [93]. This receptorconsists of three segments: an N-terminal segment of extracel-lular location, a central domain consisting of seven segmentsthat cross the plasma membrane and a C-terminal intracyto-plasmatic segment. The extracellular domain has a predomi-nance of negative charges and thus binds to Ca and othermolecules with positive charges. This receptor acts as a sensorof extracellular Ca concentrations in various tissues, includingparathyroid glands, where it also translates the signals insidecells, regulating the synthesis and release of PTH.

The action of calcimimetics in the CaR of parathyroid cellsis reflected by a decreased synthesis and secretion of PTH.There are two groups of calcimimetics with distinct mecha-nisms of action: type 1 calcimimetics are organic or nonor-ganic polycations that act as receptor agonists, stimulatingits activity regardless of the concentration of extracellularCa. Type 2 calcimimetics act as positive allosteric modulators,i.e., they induce changes in receptor conformation by increas-ing its sensitivity to extracellular Ca and consequently decreas-ing the serum concentration of PTH [94]. Cinacalcet, atype 2 calcimimetic, is the only available agent of the classof calcimimetics for clinical use. In 2002, a controlled clinicalstudy with 52 patients on HD revealed that 8 days treatmentwith cinacalcet decreased levels of PTH, Ca and P. This effectwas observed by treatment day 3 and was dose dependent [95].

A year later, a randomized, controlled, double-blind study waspublished, in which 78 HD patients with SHP were followedfor 18 weeks. Those treated with cinacalcet presented a signif-icant reduction of PTH, Ca and P compared to those receiv-ing placebo [96]. These two studies were crucial to demonstratethe safety of the drug, especially on serum Ca levels.

In 2004, Block et al. published a study of 741 HD patientswho were followed for 26 weeks. The cinacalcet patient group(n = 371) received escalating doses of the medication(30 -- 180 mg/day), which were well tolerated. The resultsalso revealed that 43% reached target levels of PTH(< 250 pg/mL) versus 5% in the control group, regardless ofthe severity of SHP or doses of VDRA [97]. Other studieshave demonstrated the effectiveness of cinacalcet in the treat-ment and control of SHP in HD and peritoneal dialysispatients [98-100]. The OPTIMA study included 11 Europeancenters (n = 552 patients) and compared the treatment ofpoorly controlled SHP with cinacalcet or conventional ther-apy (VDRA and P binders). A greater percentage ofpatients (71%) on cinacalcet reached target levels of PTH(£ 300 pg/mL) than those receiving conventional treatment(22%) [99]. The ECHO observational study involved1865 patients from 12 countries with SHP that was not con-trolled with conventional therapy (median PTH 721 pg/mL).At 12 months after cinacalcet initiation, 28% of the patientsachieved the target range of PTH recommended by KDOQIcompared to only 4% at baseline [100].

The effects of cinacalcet were also studied on bone andparathyroid tissues [101-104]. Wada et al. observed that cinacal-cet attenuated osteitis fibrosa in rats with CKD [101].Malluche et al. studied 32 patients with SHP, randomizedto receive either cinacalcet (n = 19) or conventional therapycombined with placebo (n = 13) [102]. Histomorphometricanalysis of bone tissue was performed before and after 1 yearof treatment. No marked changes in bone remodeling, miner-alization and volume were observed in the two groups, prob-ably due to the small number of patients [102]. Meola et al.used high-definition ultrasound Doppler to evaluate the para-thyroid glands of nine patients with SHP treated with cinacal-cet for a period of 24 -- 30 months. Cinacalcet led to asignificant reduction in glandular volume (233 ± 115 mm3

at baseline vs. 102 ± 132 mm3 at the end of follow-up; p < 0.007) in glands < 500 mm3, as well as diminishedvascularization. In cinacalcet-treated patients, PTH levelsdecreased from 1196 ± 381 pg/mL to 256 ± 160 pg/mL atthe end of the study (p < 0.0001) [103].

Recently, the parathyroid glands obtained from 24 dialysispatients with SHP who underwent parathyroidectomy werestudied. Areas of cystic degeneration, hemorrhagic foci andhemosiderin deposition were observed in patients who werepreviously treated with cinacalcet. These histological changesof involution of parathyroid lesions suggest a direct effect ofcinacalcet in this tissue. However, it is noteworthy that fivepatients who showed significant decrease of PTH, or of thevolume of the gland during treatment, presented increased



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levels of PTH caused by the discontinuation of cinacalcet for2 weeks [104].Despite several studies demonstrating the effectiveness of

cinacalcet in the control of SHP [95-104], few have evaluatedits effect on mortality [105-107]. A post-hoc analysis of fourRCTs with follow-up ranging from 6 to 12 months, involving1184 patients with CKD and SHP, showed that treatmentwith cinacalcet led to a significant reduction in the risk of para-thyroidectomy, fractures and hospitalization, in addition toimprovement in physical well-being and pain when comparedto conventional treatment (VDRA and P binders). However,mortality was not statistically different between the two groups(RR 0.81, 95% CI 0.45 -- 1.45) [105]. In 2010, Block et al. pub-lished the results of an observational prospective study with19,186 patients followed for 26 months, which comparedthe mortality rate between patients treated with cinacalcet(n = 5976) and those receiving conventional therapy. All-cause and cardiovascular mortality rates were significantlylower for those treated with cinacalcet than for those withoutcinacalcet, even after adjustment for confounders [106]. How-ever, in the FARO Study, in which dialysis patients werefollowed-up for 18 months, cinacalcet use (with or withoutVDRAs) was not associated with a further benefit on mortalitycompared with paricalcitol monotherapy [107]. So far there arestill no conclusive studies on the role of cinacalcet in reducingmortality rates of patients with CKD.There is little information on the role of calcimimetics in

vascular calcification. Recent in-vitro and in-vivo studies sug-gest that the CaR plays a role in the process of vascular calci-fication. The calcimimetic R-568 delayed the progression ofboth aortic calcification and atherosclerosis in uremic ApoEknockout mice [108]. In addition, in a uremic rat model, calci-mimetics attenuated media calcification and proliferation ofvascular smooth muscle and endothelial cells [109].Despite this experimental evidence, clinical evidence is

scarce. The ADVANCE Study, an RCT, compared the pro-gression of vascular and cardiac valve calcification in 360 prev-alent HD patients with HPS, treated with either cinacalcetplus low-doses of vitamin D or flexible doses of vitamin Dalone. The patients in the former group presented a 24%increase in calcification score whereas patients in the othergroup presented a 31% increase (p = 0.073) [110].Few studies have evaluated the effects of cinacalcet in the

treatment of patients with CKD at earlier stages (3, 4 and5 not on dialysis) [111,112]. In 2005, a randomized, double-blind, placebo-controlled, 18-week study enrolled adultswith an estimated glomerular filtration rate of 15 -- 50 mL/min/1.73 m2 and a PTH level > 130 pg/ml. Cinacalcet (orplacebo) was titrated from 30 to 180 mg once daily to obtaina 30% or greater reduction in PTH levels from baseline.Cinacalcet-treated patients had a significantly decreasedPTH concentrations compared with controls: 56 vs. 19% ofsubjects achieved a 30% or greater reduction in PTH levels(p = 0.006) and mean PTH levels decreased by 32% inthe cinacalcet group, but increased by 6% in the control

group (p < 0.001) [111]. Chonchol et al. evaluated 404 patientswith CKD stage 3 or 4 with high PTH levels (PTH ‡ 100 pg/ml, stage 3; and ‡ 160 pg/mL, stage 4) followed for 32 weeks.Those treated with cinacalcet had a much greater reduction inPTH levels then the untreated patients (43 vs. 1%, respec-tively) and presented a reduction in serum Ca and an increasein serum P [112].

Cinacalcet has also been studied in patients with hypercal-cemia or persistent hyperparathyroidism after kidney trans-plantation (Tx) [113-117]. In 2005, a study was publishedinvolving 11 Tx patients with persistent hyperparathyroidismtreated with cinacalcet. All patients presented normalizationof serum Ca levels and there was a 21.8% decrease in PTHby the end of the study [113]. In the same year, a study with14 Tx patients with persistent hyperparathyroidism demon-strated that the use of cinacalcet, 30 mg daily for 3 months,was effective in reducing calcemia in almost all patients,although no reduction in PTH and P levels was observed [114].

An observational study involving 58 Tx patients followedup for 12 months showed that cinacalcet normalized Ca,decreased PTH and increased bone-specific alkaline phospha-tase. The authors also observed a reduction in renal function,probably mediated by PTH, similar to the effects observedafter parathyroidectomy [115]. The use of cinacalcet in Txpatients with persistent hyperparathyroidism has been associ-ated with improvement in bone mineral density [116]. Anothereffect associated to cinacalcet use is better systemic arterialblood pressure control in Tx patients with persistent hyper-parathyroidism [117]. Currently, there is no consistent infor-mation regarding the effects of cinacalcet on bone histologyof Tx patients.

With regard to the side effects of cinacalcet, it is worth not-ing that 9 -- 15% of patients discontinue treatment due toadverse events. Nausea, vomiting and hypocalcemia are themost frequent symptoms [97-99]. Sprague et al. showed thatonly 3% of patients treated with cinacalcet for more than3 years presented severe adverse effects [118].

5. Conclusion

Disturbances of the mineral metabolism contribute toincreased mortality and morbidity in patients with CKD.Understanding the pathophysiological mechanisms involvedand using an individualized treatment aimed at fixing eachof the disturbances should not help to improve survival butalso the quality of life of these patients.

6. Expert opinion

In the last few years, new drugs and treatment strategies havebeen developed and introduced into clinical practice. The addi-tional effects (beneficial or otherwise) of these drugs on boneand mineral metabolism have become a matter of constantdebate. Not surprisingly, it is a challenge for nephrologists tochoose the best therapeutic approach to CKD-MBD.



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Patients should be evaluated and treated on a case-by-casebasis, and nephrologists should not rely exclusively on drugtherapy. In the authors’ opinion, the presence of a nutritionistin the medical team is of paramount importance to encouragepatients to change their dietary habits from an inappropriatelyhigh phosphorus intake to an adequate nutrient intake, whichincludes the lowest possible phosphate intake, a limitedprotein intake and a caloric intake that is sufficiently high toprevent malnutrition.

Dialysis should be prescribed on a case-by-case basis. Fre-quent or longer dialysis sessions should be prescribed to controlhyperphosphatemia. Because both strategies seem to be equiv-alent in terms of phosphorus removal, we usually choose theone that best suits the patient, taking into consideration his/her everyday activities. Other dialysis modalities, suchas short daily hemodialysis and nocturnal hemodialysis, arenot routinely used. The choice of Ca dialysate concentrationis another important aspect of the nonpharmacologicaltreatment for CKD-MBD. Although a concentration of1.5 mmol/L seems to be adequate for the majority ofpatients on hemodialysis, lower (1.25 mmol/L) or higher(1.75 mmol/L) concentrations can be recommended in certaincircumstances. A low-Ca dialysate (1.25 mmol/L) should beused in patients with low PTH levels and adynamic bonedisease. Two common clinical situations in which higherCa concentrations can be recommended are as follows:

. patients with SHP taking Ca-free phosphate bindingagents for PTH suppression

. patients with hungry bone syndrome followingparathyroidectomy.

The pharmacological treatment of CKD should be startedearly in the course of the disease and be based primarily onthe levels of Ca, P and PTH. Ca-based P binders shouldbe avoided in patients with low PTH levels to prevent Caoverload and further suppression of bone remodeling. Inpatients with SHP and hyperphosphatemia, the use ofVDRAs, Ca salts (or both) might be a reasonable initialapproach if Ca levels are low or low normal and if there isno evidence of vascular calcification. However, if Ca levelsare high normal or high, Ca-free P binders and calcimimeticsconstitute the first choice of initial pharmacotherapy. In fact,since calcimimetics became available, the role of VDRAs inthe treatment of SHP has been the subject of much debate.In our opinion, because the two classes of drug have distincteffects on parathyroid function, they are clearly complemen-tary and allow us to control SHP more safely (with feweradverse effects on calcium and phosphorus levels). In addi-tion, they can have a beneficial effect on the cardiovascularsystem, as well as on survival.

It is likely that future treatment options will be aimed atmolecular targets in order to modulate the synthesis of pro-teins produced by bone and vascular tissues. Finally, in theauthors’ experience, the use of native vitamin D compoundsin CKD patients allows a better control of mineral metabo-lism parameters, which is why we advocate the use of nativevitamin D supplementation in this population.

Declaration of interest

V Jorgetti is a consultant for Abbot, Amgen & Genzyme. Theother authors declare no conflict of interest.



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AffiliationFellype Carvalho Barreto MD PhD,

Rodrigo Azevedo de Oliveira MD,

Rodrigo Bueno Oliveira MD PhD &

Vanda Jorgetti† MD PhD†Author for correspondence

Universidade de Sao Paulo,

Nephrology Division,

Department of Internal Medicine,

Av. Dr. Arnaldo, 455, 3rd floor,

room 3342, 01246 903,

Sao Paulo, Brazil

Tel: +55 11 3061 8351; Fax: +55 11 3061 7261;

E-mail: [email protected]



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Pharmacotherapy of chronic kidney disease and mineral bone disorder

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