How Do Calcimimetics Fit Into the Management of Parathyroid Hormone, Calcium, and Phosphate...

226

Address correspondence to

: Albert Fournier, Service deNéphrologie – Médecine Interne, Chu Amiens, Hôpital Sud,80054 Amiens Cedex 1, France, or e-mail: [email protected].

Seminars in Dialysis

—Vol 18, No 3 (May–June) 2005pp. 226–238

Viewpoint

Blackwell Publishing, Ltd.

How Do Calcimimetics Fit Into the Management of Parathyroid Hormone, Calcium, and Phosphate Disturbances in Dialysis Patients?

Irina Shahapuni, Janet Mansour, Laïd Harbouche, Bechir Maouad, Mohamed Benyahia, Khelifa Rahmouni, Roxana Oprisiu, Jean-François Bonne, Matthieu Monge, Najeh El Esper, Claire Presne, Philippe Moriniere, Gabriel Choukroun, and Albert Fournier

Nephrology Department, University Hospital, University Jules Verne, Amiens, France

ABSTRACT

As suggested by its American brand name (Sensipar), the calci-mimetic cinacalcet sensitizes the parathyroid cells to the extra-cellular calcium signal, suppressing parathyroid hormone(PTH) release and synthesis and preventing parathyroid cellproliferation. This primary PTH suppression decreases therelease of calcium and phosphate from bone without increasingintestinal absorption of calcium and phosphate. Thereforecinacalcet decreases the risk of hypercalcemia and hyper-phosphatemia in contrast to 1

α

-OH vitamin D derivatives.Compared with calcium-containing oral phosphate binder(OPB), it increases the risk of hypocalcemia and may decreasethe PTH-mediated phosphaturia in predialysis patients. Thisjustifies its combined use with calcium-containing OPB inorder to prevent hypocalcemia and enhance the hypophos-phatemic effect of the latter, while improving PTH suppres-sion. The National Kidney Foundation (NKF) Kidney DiseaseOutcomes Quality Initiative (K/DOQI) has recommendedrestriction of supplemental elemental calcium to 1.5 g/day, arecommendation that we believe should be revised. No patho-

physiologic or randomized trial data have yet evidenced theabsolute necessity for systematically using 1

α

-OH vitamin Dderivatives and noncalcium-containing OPB rather than higherdoses of calcium-containing OPB alone in uremic patientswithout vitamin D insufficiency. In patients with hyperparathy-roidism as severe as in the “Treat to Goal Study,” the Durhamstudy showed that a calcium carbonate dose more thanthree times the K/DOQI limit could decrease PTH into therecommended range, with the advantage of a lower calcium-phosphate product compared with the combination of calcitrioland noncalcium OPB. Besides the efficient PTH suppressionassociated with lower calcium-phosphate product and a goodgastrointestinal tolerance, long-term data suggest that cinacalcetmay decrease the risk of parathyroidectomy and fracture, whilehigh bone turnover lesions are improved. However, no long-term data on bone mineral density and cardiovascular calcifica-tion and complications are yet available. Such studies, alongwith those comparing cinacalcet and 1

α

-OH vitamin D-basedapproaches to hyperparathyroidism, are needed.

Address correspondence to: Albert Fournier, Service de Néphrologie – Médecine Interne, Chu Amiens, Hôpital Sud, 80054 Amiens Cedex 1, France, or e-mail: [email protected].

Calcimimetics are substances that activate the extra-cellular calcium signal at the level of the calcium sensorreceptor (CaR) present on the parathyroid, thyroid, renal,intestinal, osteoblastic, chondrocytic, and neuronal cells.Other substances, including inorganic cations, polyamines,and aminosides, activate this receptor in the absence ofcalcium and constitute class I calcimimetics. The class IIcalcimimetics used for parathyroid hormone (PTH) sup-pression are organic products that increase the sensitivityof the CaR to calcium and therefore need the presence ofcalcium to be active. These class II calcimimetics act bychanging the spatial conformation of the receptor and arebetter called “positive allosteric modulators of calciumreceptor” (1,2). Cinacalcet hydrochloride (AMG-073),developed by Amgen, has a more favorable pharmaco-

kinetic profile than the first generation of class II calci-mimetics (NPS R-567 and R-568). Its action on theparathyroid cells, in the presence of calcium, leads toPTH secretion inhibition through a signaling cascadeinvolving stimulation of the Gi protein, phospholipase C,inositide triphosphate, intracellular calcium mobiliza-tion, and protein kinase, together with inhibition of ade-nylyl cyclase and protein kinase A (1).

As evidenced by the results of two identical random-ized, double-blind, placebo-controlled trials recentlyperformed in the United States, Europe, and Australia,and published in combination (3), cinacalcet is an effi-cient and well-tolerated treatment of hyperparathyroid-ism in hemodialysis patients. These trials comparedcinacalcet to placebo in a population of 741 patientstreated thrice weekly by hemodialysis for at least 3months. The inclusion criteria were a baseline “intact”PTH level (Allegro IRMA, Nichols Institute, San Juan,CA) greater than 300 pg/ml in spite of “standard” ther-apy and a serum calcium (SCa) greater than 8.4 mg/dl.After a titration period of 12 weeks (once daily doseincreasing from 30 to 180 mg), cinacalcet was able to

CALCIMIMETICS IN THE MANAGEMENT OF PTH, CALCIUM, AND PHOSPHATE DISTURBANCES

227

maintain a PTH level of 250 pg/ml or less in 53% ofpatients (compared with 5% in the placebo population)for the next 14 weeks. Overall, mean PTH leveldecreased from 643 pg/ml to 360 pg/ml in the cinacalcetgroup, whereas it did not significantly decrease in theplacebo group. This was associated with a 15% decreasein the calcium-phosphate product (from 62 mg

2

/dl

2

to53 mg

2

/dl

2

) due to moderate reductions in SCa and serumphosphate (SPO

4

) averaging 6.8% and 8.4%, respec-tively. No significant change was observed in the placebogroup. Furthermore, this drug was relatively well toler-ated, the main side effects being nausea and vomiting(reported in 32% versus 19% and 30% versus 16% oftreated and placebo patients, respectively). Thesegastrointestinal side effects were mild to moderate, moti-vating cinacalcet withdrawal in only 5% of patients. A2-year study of cinacalcet in 59 patients recently confirmedits long-term effect on PTH suppression (4).

As already mentioned by Curhan (5) in his editorial forthe cinacalcet combined trials, the availability of this power-ful and well-tolerated drug raises a number of issues thatwe wish to comprehensively discuss in relation to the recentKidney Disease Outcomes Quality Initiative (K/DOQI)recommendations of the National Kidney Foundation(NKF) (6). The following issues will be addressed:

What is the optimal target PTH range with calcimi-metic use?

What is the optimal phosphate binder to use in associ-ation with a calcimimetic?

What is the optimal dialysate calcium concentration tobe used with a calcimimetic?

Will calcimimetics help prevent the need for surgicalparathyroidectomy?

Will calcimimetics help prevent bone remodelingabnormalities, osteopenia, and fracture risk?

Will calcimimetics help prevent vascular calcifica-tions and cardiovascular complications?

Should calcimimetics be used in association with 1

α

-OH vitamin D metabolites or instead of them?

When and how long will calcimimetics be necessary,and at what cost?

What is the Optimal Target PTH Range With Calcimimetic Use?

Before directly answering this question, the issue ofoptimal PTH range will be discussed based on differenttherapeutic strategies and the selectivity of the methodfor measuring true PTH 1-84. According to the K/DOQI(6) (pp. S12 and S53) for patients with stage 5 chronickidney disease (CKD) (glomerular filtration rate [GFR]< 15 ml/min or dialysis), the recommended range forserum “intact” PTH (SPTH) (Allegro IRMA) is 150–300 pg/ml (16.5–33.0 pmol/L), that is, 2.5–5 times theupper limit of normal (ULN), whereas the optimal rangefor SPO

4

is 3.5–5.5 mg/dl (1.13–1.78 mmol/L; thoughothers suggest

≤

5 mg/dl or 1.6 mmol/L) (7) and that ofSCa is 8.4–9.5 mg/dl (2.10–2.37 mmol/L). The recom-mendation for SCa was said (in 2003) to be only opinionbased, while those for SPO

4

and SPTH were said to beevidence based.

The evidence for the recommended PTH range isbased on bone remodeling data and is relatively shakysince it represents a significant upward shift when com-pared with the results of the receiver operating character-istics (ROC) analysis. According to the latter (see p. S54of the K/DOQI) (6), the best threshold for high boneturnover disease was between 150 and 200 pg/ml (2.5–3times the ULN), whereas that for low bone turnover dis-ease was 60 pg/ml, that is, the actual ULN. Furthermore, itshould be pointed out that this diagnostic meta-analysiswas based on bone biopsy studies performed before 1991,that is, before Sherrard, in his

New England Journal ofMedicine

editorial, acknowledged the toxicity of a “lowsafe dose” of aluminum phosphate binders (8). As aresult, most of these biopsies were overloaded with alu-minum, even though those with heavy accumulationswere generally excluded.

Regarding cardiovascular risk, the latest U.S. RenalData System (USRDS) evaluation (7) suggests that thereis no increase in risk when PTH levels are less than150 pg/ml when the analysis is multivariate adjusted.However, this adjusted death risk increases when SCa(corrected for albumin) is greater than 9.5 mg/dl, SPO

4

is greater than 5 mg/dl, or the calcium-phosphate productis greater than 45 mg

2

/dl

2

. In the British Columbia cohort(9), the multivariate mortality risk was higher in thegroup with high SCa and SPO

4

and low PTH comparedto the group with low SCa and SPO

4

but high PTH. Thismay be due to the fact that aluminum phosphate binderuse was still widespread and the serum aluminum levelswere not taken into account in this analysis.

This was not the case with our 1991 study (10)

10

inwhich aluminum-phosphate binders had been excludedin 1980 (11), an important point since, independent ofthe PTH level, aluminum overload per se suppresses boneremodeling (12). This lack of aluminum intoxication isone explanation why our optimal PTH range (based onnormal bone formation rate assessed by double tetracy-cline labeled bone biopsies) was lower (one to two timesthe upper limit of normal). In fact, our optimal range wasonly 30–60 pg/mL because the IRMA used to measurePTH was that of Roger Bouillon, which uses two anti-bodies, the first binding to the middle of the 7-84 C-terminus and the second on the 1-7 N-terminus fragments(10,13). Since C-terminal fragments like the 7-84 oneswere not measured (unlike the Nichols Allegro kit for“intact” PTH), the ULN of this assay was about half thatfor the Nichols Allegro IRMA; this ratio was confirmedin the 410 patients from the American cinacalcet trial (3).

Another reason why our proposed optimal range wasso low is our parsimonious use of 1

α

-OH vitamin D.Calcitriol down-regulates the PTH/PTHrP receptor inosteoblast-like cell cultures (14), suggesting that vitaminD creates PTH resistance. The alfacalcidol trial by Hamdyet al. (15) supports this idea, since this study showed nochange in PTH levels, while bone turnover (assessed onbone biopsies) significantly decreased. This concept isalso supported by Urena et al. (16), who reported thatdialysis patients receiving 1

α

-OH vitamin D had a greatersuppression of bone alkaline phosphatase than PTH andfound no measurable bone formation rate in four of thesix patients who had a bone biopsy.

228 Shahapuni et al.

Our PTH suppression policy is based on 1) a dialysatecalcium concentration of 6.0 mg/dl (1.5 mmol/L), whichyields an approximately neutral intradialysis calciumbalance; 2) prevention of native vitamin D insufficiency.[Plasma 25-hydroxyvitamin D

3

levels of 30–40 ng/ml(17) are now recommended by the K/DOQI for predia-lysis patients since with values below 25 ng/ml, serumPTH rises sharply in the general population. True vitaminD deficiency with mineralization defect usually occursin nonuremic patients when serum 25-hydroxyvitaminD

3

is less than 10 ng/ml (18)]; and 3) use of a relativelylarge dose of calcium carbonate given as a phosphatebinder (mean daily dose 6–9 g, equal to 2.4–3.6 g of ele-mental calcium).

The clinical justification for our lower optimal PTHrange is supported by our observation that patients hav-ing a PTH one to two times the ULN have a lower fre-quency of hypercalcemia and hyperphosphatemia with ahigher bone mineral density than those whose PTH valueis more than four times the ULN (19). In addition, wesaw no link between arterial calcification and PTH levelor bone mineral density (BMD) in our patients.

The limited need for aluminum-phosphate bindersshould diminish even further in the future. This isbecause of the advent of new phosphate binders (anioncomplexants (20,21), iron hydroxide (22), lanthanumcarbonate (23)) and active inhibitors of intestinal phos-phate absorption (nicotinamide (24)), and because calci-mimetics will increase the need for calcium-containingOPDs. The use of an optimal PTH range based on thecriterion of a normal bone formation rate (or activationfrequency) evaluated on aluminum-overloaded bonebiopsies will therefore soon become quite irrelevant.

The largest recent study evaluating PTH level as a bio-chemical marker of bone turnover on the basis of bonehistodynamic data of uremic patients never exposed toaluminum is that of Monier-Faugère et al. (25). However,these authors did not define an optimal range, since theyonly differentiated patients with adynamic bone diseaseand normal SCa and phosphate from a mixture of uremicpatients with normal and high bone turnover and hyper-phosphatemia. They reported that the ratio of the full-length PTH 1-84 on the PTH 7-84 segment was clinicallyuseful, an observation not confirmed by other groups(26,27); this issue remains controversial. Unfortunatelythese last two studies also did not define an optimal PTHrange corresponding with normal bone turnover.

The issue of determining the optimal PTH range withcalcimimetics is further complicated by the much shorterduration of PTH suppression with these drugs than withcalcium-containing oral phosphate binders (OPBs) and1

α

-OH vitamin D metabolites. This raises the questionof the optimal blood sampling schedule after calcimi-metic administration. For patients on hemodialysis,sampling 24 hours after the last cinacalcet dose (as per-formed in a recent trial (3)) appears to be the most appro-priate, in our opinion, for practical reasons.

In the study by Malluche et al. (28), adynamic bonedisease was found in 3 of 19 cinacalcet-treated patients,2 of whom had an intact PTH less than 100 pg/mL. Thissuggests that the lower limit of 150 pg/mL proposed bythe NKF seems quite appropriate when cinacalcet is

used. Further evaluation of bone histomorphometric datais needed to precisely define the upper limit of the opti-mal PTH range with cinacalcet. At present, a PTH levelof 250 pg/mL can be considered a good guess (3). Con-sidering that the physiologic nycthemeral oscillations ofPTH have a bone anabolic effect, the K/DOQI recom-mended ULN of 300 pg of intact PTH may also be quiteappropriate.

Longer follow-up studies are needed in order to showthe level of PTH that is optimal, both for the skeleton(not only by assessing bone turnover markers or bonebiopsy, but also by bone mineral density and fracturerisk) and for the cardiovascular system (by evaluatingnot only vascular calcification, but also cardiovascularcomplications).

What is the Optimal Phosphate Binder to Use in Association with a Calcimimetic?

Calcimimetics reduce SCa levels by suppressing PTHand decreasing bone calcium release. The introduction of(or increase in) calcium-containing OPB would appearto be the most logical early therapy for hypocalcemia[SCa decreases below 9.0 mg/dl (2.25 mmol/L)] in thissetting. This measure was not formally recommended inthe protocol of either the American or the European–Australian trials, since “no restrictions were imposed onthe dose or type of phosphate binder.” Rather, an increasein 1

α

-OH vitamin D was prescribed if SCa fell below8.4 mg/dl or if the patient had symptoms of hypocalcemia;an increase in dialysate calcium concentration was pro-hibited. The net results of these recommendations were a6.8% decrease in SCa and an 8.4% decrease in SPO

4

.Considering that 1

α

-OH vitamin D metabolites increaseintestinal absorption of both phosphate and calcium,it may be speculated that the much desired decreasein SPO

4

would have been greater had this alternativerecommendation (i.e., calcium-containing OPB increase)been made. As we pointed out in a letter (29), cinacalcetat 100 mg/day showed similar PTH and SCa suppres-sion, but (paradoxically) less of a decrease in SPO

4

(2.6% versus 7.5%) than cinacalcet at 50 mg/day. The onlyexplanation for these paradoxical results was the morefrequent use of calcitriol or paricalcitol in the 100 mgcinacalcet study than in the 50 mg study.

This increase in calcium-containing phosphate binderdose may lead to ingestion of more than the K/DOQIrecommended maximal binder dose of elementalcalcium (1500 mg). This recommendation was, however,only opinion based and was formulated by Americanexperts living in a country where the federal reimburse-ment policy has favored widespread use of intravenous1

α

-OH vitamin D metabolites (30). Since these metabo-lites increase calcium absorption, the restriction of oralcalcium intake is logical for the prevention of hyper-calcemia. However, with the advent of calcimimetics,whose main risk is hypocalcemia, any need for increasedintestinal calcium absorption is probably best achievedby increasing the oral calcium intake rather than byincreasing active (1

α

-OH vitamin D-mediated) calciumabsorption. The reason, of course, is that the latter also


229

enhances phosphate absorption, worsening hyperphos-phatemia and limiting PTH suppression. Only whenhypophosphatemia occurs is an increase of 1

α

-OH vita-min D justified. Such an event is exceptional with cina-calcet, even in patients with severe hyperparathyroidismand decreased bone mineral density.

The limitation of calcium supplements to 1.5 g of ele-mental calcium per day does not take into account sub-stantial differences between calcium acetate and calciumcarbonate. Mai et al. (31) showed, with a single mealgastrointestinal balance measurement, that the phosphatebinding capacity of calcium acetate was twice that of cal-cium carbonate, at the same dose of elemental calcium,with a comparable amount of calcium absorbed. Asa result, Slatopolsky et al. (32) and our group (33) inde-pendently performed a crossover study to see whethercomparable control of hyperphosphatemia could beachieved in dialysis patients with a dose of calcium ace-tate (expressed in elemental calcium) half that of calciumcarbonate. Although control of hyperphosphatemia wascomparable, the incidence of hypercalcemia was thesame with both salts, suggesting that the bioavailabilityof calcium acetate was higher than with calcium carbon-ate, not only for phosphate chelation, but also for cal-cium absorption. This challenged the long-term clinicalrelevance of Mai et al.’s observations on a single meal.Therefore, if the recommended maximal oral calciumdose of the K/DOQI is valid for calcium acetate, itshould probably be twofold higher for calcium carbon-ate. Thus our usual dose of calcium carbonate in dialysispatients (6–9 g/day or 2.4–3.6 g of elemental calcium)would correspond to 1.2 and 1.8 g of elemental calciumgiven as acetate when the risk of hypercalcemia is con-sidered. These doses only marginally exceed the maxi-mal dose of elemental calcium recommended by the K/DOQI (1.5 g/day), at least on an absorptive basis.

The main justification for the K/DOQI restriction ofcalcium supplementation has been the “Treat to Goal”study (20), with its questionable design. This studyrandomized dialysis patients in the United States andEurope with a mean baseline PTH of 200 pg/mL in theglobal study and 150 pg/mL in the European study aftera 2-week phosphate binder washout. Dialysate calciumconcentration was 5 mg/dl in the United States and 6 mg/dl in Europe, and 1

α

-OH vitamin D treatment was givento more than 60% of patients in the United States, butonly 23% of the European patients. One year after intro-duction of either sevelamer or a calcium-phosphatebinder [(4.6 g/day of calcium acetate in the United Statesand 3.9 g/day of elemental calcium carbonate inEurope)], coronary and aortic calcification was greater inthe calcium group than in the sevelamer group in boththe global and European studies (20,34). However, thiswas associated with an oversuppression of PTH in thecalcium group (to 138 pg/mL and 110 pg/mL in theglobal and European study, respectively); in the seve-lamer group, PTH averaged 100 pg/mL higher. Therewas also a significantly higher frequency of hypercalce-mia (greater than 2.6 mmol/L) in the calcium groups(43% and 46%) than in the sevelamer groups (17% and16%), while SPO

4

was comparably controlled. Thecalcium-phosphate product was not significantly different,

in contrast to the expectation of a 10 mg

2

/dl

2

lower prod-uct with sevelamer.

Thus the targeted serum levels for PTH, calcium, andphosphate were not achieved; this may well explain thegreater progression of vascular calcification extensionand raises questions about the appropriateness of thetherapeutic design and/or its execution. It had alreadybeen established that for mild PTH elevations (300 pg/mL in patients on a dialysate calcium of 5 mg/dl, taking2.3 g elemental calcium as carbonate) increasing thedose of calcium carbonate (to 5.4 g) suppresses PTH(to 160 pg/mL) and controls SCa (9.2 mg/dl) and SPO

4

(3.5 mg/dl) better than oral or intravenous calcitriol withaluminum hydroxide (35). These outcome data based oncalcium-phosphate parameters suggest (according thelatest USRDS evaluation (7)) that the high-dose calciumcarbonate monotherapy is potentially more cardiovascu-larly protective than the calcitriol + sevelamer bitherapy.Therefore the results of the “Treat to Goal” study (20) donot shake our skepticism about the fear that oral calciumloading alone may be a dialysis patient killer.

A recent systematic review of the determinants of cor-onary vascular calcifications in patients with CKD andend-stage renal disease (ESRD) is notable (36). Only3 of 30 studies found that oral calcium load was inde-pendently associated with vascular calcifications; the maindeterminants were age, length of time on dialysis, andpossibly, dyslipidemia. This review did not include asmall, but interesting study using computed tomographyto compare 13 hemodialysis patients with slow progres-sion of aortic calcification to 13 others with rapid pro-gression. This study found that rapid progression wasassociated not only with a higher dose of calcium, butalso with a SCa above the optimal upper limit (9.8 versus8.6 mg/dl), an oversuppressed PTH (98 versus 250 pg/mL), higher blood glucose, lower albumin, and higherC-reactive protein; multivariate regression did not findan independent link between oral calcium load and aorticcalcification extension (37). Furthermore, this review hasnot tested serum aluminum as a calcification risk factor,even though aluminum overload may be an independentdeterminant of hypercalcemia (38) and vascular calcifi-cation (39). While London et al. (40) reported a linkbetween oral calcium load and arterial media calcifica-tion, as well as between calcification and total mortalityrisk, an independent link was never shown between oralcalcium load and cardiovascular mortality. In any case,the small size of their dialysis population (202 patientswith 46 cardiovascular deaths) precludes any safe con-clusion on the mortality causality issue.

It should be recalled that the only study that used hardclinical outcomes to evaluate the prognostic significanceof coronary calcifications in hemodialysis patients sub-jected to coronary dilatation found, paradoxically, thatcalcification was associated with better cardiovascularoutcomes, possibly due to lower total cholesterol levels(41). This dissociation is reassuring, since a recent arti-cle has shown an association between coronary calcifica-tion and the severity of coronary occlusive disease onangiography, but not with clinical complications (42).

Along with Coladonato and Ritz (43), we consider itquite premature to advocate the wholesale abandonment


of calcium-containing OPBs, and fully agree with thefive following reasons given by these authors to supporttheir statement: 1) the flawed causal pathway linking cal-cium ingestion to intimal calcifications; 2) the occur-rence of coronary artery calcifications in patients notexposed to calcium salts given as phosphate binders; 3)the inconsistent association between changes in divalention concentration, PTH levels, and vascular calcifica-tions; 4) the design limitations in studies reporting a linkbetween calcification and calcium intake; and 5) theunjustified assumption that coronary artery calcificationevaluation by electron beam computed tomography(EBCT) is a suitable surrogate parameter for clinicalcardiovascular outcomes.

In conclusion, evidence is lacking to link oral calciumload with cardiovascular morbidity or mortality. There-fore the arbitrary 1.5 g calcium restriction, especially whencalcium carbonate is used instead of calcium acetate, andwhen 1

α

-OH vitamin D is not associated, should bereconsidered. What probably matters is only the effect ofan oral calcium load on serum concentrations of calcium,phosphate, and PTH. Interestingly, the recommendedtarget ranges for these parameters (based on USRDSprognostic evaluations) were achieved more often withcalcium acetate than with sevelamer in the CARE study(44,45) (in which 1

α

-OH vitamin D was given in both arms),and with high-dose calcium carbonate than with cal-citriol + low-dose calcium + aluminum hydroxide in theDurham study (35). Only head-to-head comparison intrials evaluating not only biochemical, but also hard clin-ical outcomes will settle the cardiovascular risks at issue.As stressed in the recent comprehensive review on vas-cular calcification by Goldsmith et al. (46), dyslipidemiawill need to be comparably controlled in both arms.

What is the Optimal Dialysate Calcium Concentration to be Used with

a Calcimimetic?

For therapeutic purposes, increasing dialysate calciumconcentration would be logical when an increase in calcium-phosphate binder dose is insufficient to correct hypocal-cemia. Compared with administration of 1

α

-OH vitaminD, this has the advantages of not increasing intestinalabsorption of phosphate and improving hemodynamicstability during dialysis (47). It is conceivable that theadvent of calcimimetics will revive the use of a dialysatecalcium of 7 mg/dl (1.75 mmol/L), at least at the begin-ning of cinacalcet treatment, when high doses are neces-sary because of severe hyperparathyroidism with highbone alkaline phosphate and low bone mineral density.Indeed, too rapid PTH suppression will possibly unmask(as after surgical parathyroidectomy) “hungry bone syn-drome,” with both hypocalcemia and hypophosphatemia,necessitating intravenous calcium rather than oral cal-cium in order to prevent worsening hypophosphatemia.

Unless high doses of 1

α

-OH vitamin D metabolitesare used (by habit rather than necessity, as discussed pre-viously), the use of a dialysate calcium concentrationless than 1.5 mmol/L is not advised, especially when cal-cimimetic use is considered. Indeed, since 1971 (48,49),

it has been known that such a low calcium concentrationstimulates PTH secretion and is associated with moresevere hyperparathyroid bone disease. This worsening ofhyperparathyroidism was demonstrated by Argiles et al.(50) in a 1-year randomized controlled study duringwhich PTH increased by 100% in the 5.0 mg/dl calciumdialysate group compared to the 6.0 mg/dl group. Thelatter dialysate calcium concentration is the one usuallyadvocated in Europe (47), while the former level is widelyused in the United States, a practice explained by the useof calcium-phosphate binder together with routine intra-venous calcitriol in the 1990s and of paracalcitol afterthe millennium change. This is the only justification forthe 5 mg/dl dialysate calcium concentration recommendedby K/DOQI guidelines, a recommendation recognized asonly opinion based and the result of a “best guess” takinginto account this specific U.S. environment.

Will Calcimimetics Help Prevent the Need for Surgical Parathyroidectomy?

Cinacalcet can probably both prevent parathyroidhyperplasia and induce its regression, as evidenced bylower parathyroid weights and proliferating cell nuclearantigens in 5/6 nephrectomized rats treated with the drug(51). If we accept that a mean of three intact PTH leveldeterminations greater than 800 pg/mL associated withserum levels of calcium and phosphate above the recom-mended range is an indication for parathyroidectomy,then the results of the post hoc analysis of three com-bined cinacalcet trials reported by Frazao et al. (52) areencouraging. Of the 53 patients having a baseline PTHbetween 800 and 1000 pg/mL, approximately half hadvalues less than 600 pg/mL 36 weeks later. However, forthe 111 patients having a baseline PTH greater than1000 pg/mL, ultimate surgical parathyroidectomy maybe more likely, since about half had a posttreatment PTHgreater than 900 pg/mL.

A post hoc analysis (53) of safety data collected in1184 patients also suggests that the parathyroidectomymay be prevented with cinacalcet. The rate of parathy-roidectomy for 100 subject-years was 0.3 in the cinacal-cet group versus 4.1 in the placebo group, yielding asignificantly lower hazard ratio of 0.07. The power ofthis study is low, however, since the total number of par-athyroidectomies could be estimated at 2 in the cinacal-cet group and 16 in the placebo group. More data aretherefore needed to delineate the PTH range (or otherfactors) for which the cinacalcet approach is likely to beeffective in avoiding surgery.

Will Calcimimetics Help Prevent Bone Remodeling Abnormalities, Osteopenia, and

Fracture Risk?

At the last European Renal Association (ERA) Con-gress in Lisbon in May 2004, Malluche et al. (28) pre-sented a preliminary report on the effect of cinacalceton bone. Patients had two sequential bone biopsieswith double tetracycline labeling at 1-year intervals. At


231

baseline 16 of 19 patients in the cinacalcet group and 11 of13 patients in the placebo group had elevated bone turnoverwith increased osteoblasts and osteoclasts, marrow fibro-sis, and woven bone. Adynamic bone was present in onepatient in each group.

Treatment with cinacalcet reduced PTH by 51%, bonealkaline phosphatase by 18%, and N-telopeptide (a markerof resorption) by 24%. After treatment, activation fre-quency, bone formation rate/bone surface, marrow fibro-sis, and the number of osteoblasts and osteoclasts werereduced. In the placebo group activation frequency wasreduced, but less, as well as the number of osteoclasts.

At baseline, and at the end of the study, the mineraliza-tion parameters were normal in both treatment groups.Curiously, at the end of the study, a “mixed uremicosteodystrophy” (implying an associated mineralizationdisorder) was reported in 4 of 13 patients in the placebogroup versus 2 of 19 in the cinacalcet group. Adynamic bonedisease developed in three patients treated by cinacalcet,two of whom had a PTH less than 100 pg/mL. No dataon bone volume and aluminum staining are available.

Altogether these results show the efficiency of cina-calcet in correcting high bone turnover and bone marrowfibrosis. However, it is difficult to understand why sixpatients were said to have mixed uremic osteodystrophywhile the mineralization parameters seem normal.

No long-term bone density study is presently avail-able, but the fracture risk, evaluated in the study reportedby Cunningham et al. (53) was 0.46 (

p

= 0.04). Never-theless, here again the power of the study is low, the totalnumber of fractures being estimated at 28 in the placebogroup and 18 in the cinacalcet group. More data aretherefore necessary to delineate cinacalcet’s effect onfracture risk as well as the comparative benefits of cina-calcet and surgical parathyroidectomy.

Will Calcimimetics Help Prevent Vascular Calcifications and Cardiovascular

Complications?

The study reported by Cunningham et al. (53) didn’tfind any reductions in hospitalization rate or mortalitywith cinacalcet. However, to draw a safe conclusion(

p

= 0.05 and a power of 90%), 844 cardiovascular eventswould be needed, far more than the 163 cardiovascularhospitalizations and 59 deaths that were observed.

No studies have yet evaluated the impact on vascularcalcifications of cinacalcet versus placebo or versus 1

α

-OH vitamin D metabolites. The results of these studiesare awaited with great interest.

Should Calcimimetics be Used in Association with 1αααα

-OH Vitamin D Metabolites or Instead of Them?

Teaching of High Ca Rescue Diet in Animals with Deletion of Vitamin D and Ca-related Genes

The routine use of 1

α

-OH vitamin D derivatives inaddition to calcium-containing OPBs has long been

common practice. It has been based on the observationsthat in uremic patients, calcitriol synthesis as well asvitamin D receptor (VDR) expression are reduced. Fur-ther, in experimental uremia, toxins prevent the bindingof the 1,25-dihydroxyvitamin D

3

/RXR heterodimeron the vitamin D responsive element of the prepro-PTHgene and therefore limit the physiologic suppression ofPTH at the transcription level (54).

Regardless of its pathogenesis, the presence of auremia-induced vitamin D resistance does not provethat supraphysiologic doses of 1

α

-OH vitamin D derivativesare required to control hyperparathyroidism in uremia.Indeed, in nonuremic mice with ablation of the 25-hydroxyvitamin D

3

1

α

-hydroxylase gene or of the VDRgene, normalization of extracellular calcium alone bya “rescue” high-calcium diet (increasing the calcium/phosphate intake ratio to two) is sufficient to normalizePTH secretion, though not to prevent parathyroid hyper-plasia (55–57). In uremic rats (58), however, a high cal-cium diet, low phosphate diet, as well as 1

α

-OH vitaminD decrease PTH hypersecretion and prevent parathyroidhyperplasia. The latter is mediated by mechanisms com-mon to the three treatments: increased cyclin-dependentkinase inhibitor p27 and decreased transforming growthfactor (TGF)-

α

(58). Suppression of PTH synthesis ismediated by treatment-specific mechanisms: suppres-sion of prepro-PTH gene transcription not only by 1

α

-OHvitamin D derivatives but also by increased extracel-lular calcium, and decreased stability of prepro-PTHmRNA by a high calcium or low phosphate diet (59–61).In order to better suppress hyperparathyroidism and pre-vent soft tissue calcification, both decreased phosphateintake and increased calcium intake are needed in uremicrats (62,63).

The critical role of the CaR in preventing hyper-parathyroidism in nonuremic animals is evidenced by theoccurrence of a fatal hyperparathyroidism in CaR geneablated mice. These mice can be rescued only by adouble gene ablation: either that of the prepro-PTH gene(64) or that of the glial cells missing 2 gene (65) (thelatter gene being required for parathyroid gland develop-ment). In uremic rats, cinacalcet, unlike calcitriol, cannot only prevent parathyroid hyperplasia, but can alsoinduce regression of this hyperplasia (Martin et al.EDTA Lisbon Conference 2004, abstract, in press).

Regarding the issue of the necessity of 1

α

-OH vitaminD for bone mineralization, this latter can be normalizedby a high-calcium rescue diet in both VDR gene ablatedmice and 25-hydroxyvitamin D

3

1

α

-hydroxylase mice(55–57). Paradoxically, excessive VDR activation byhigh calcitriol levels has a negative effect on bone miner-alization (66,67). Only epiphyseal cartilage developmentand longitudinal skeletal growth cannot be rescued byjust a high-calcium diet (56).

These experimental data show that in spite of a uremia-induced vitamin D-resistant state, hyperparathyroidismcan be suppressed, bone can be well mineralized, andsoft tissue calcification can be prevented without a supra-physiologic dose of 1

α

-OH vitamin D, provided thatphosphate intake is reduced and calcium intake isincreased sufficiently to raise the calcium/phosphateintake ratio to two.


Preventing vitamin D insufficiency will still facilitateprevention of hyperparathyroidism and improve bonemineralization. This issue has been obscured by earlierexperimental data reporting a ratio of 2000 in the VDRbinding capacity of 1,25-dihydroxyvitamin D

3

versusthat of 25-hydroxyvitamin D

3

. More recent reports haveshown that the power ratio of calcitriol versus calcitriolfor controlling synthesis of vitamin D-sensitive hor-mones actually was 500, suggesting that physiologicconcentrations of 25-hydroxyvitamin D

3

1000 timeshigher than those of 1,25-dihydroxyvitamin D

3

, couldactually play a physiologic role in calcium absorptionand PTH suppression (17,68).

Fig. 1 integrates the effect of all the main factors influ-encing PTH secretion (69). Review of these factorssuggests that commonsense prevention of vitamin Dinsufficiency in uremic patients, together with calcium-containing OPBs to decrease phosphate absorptionand increase calcium absorption, constitute a more cost-effective treatment of hyperparathyroidism and osteo-malacia or rickets in uremia than pharmacologic doses of1

α

-OH vitamin D derivatives and noncalcium OPBs.

Review of the Clinical Data in Uremic Patients

In elderly patients without overt renal disease (70,71),the efficiency of calcium and native vitamin D supple-ments has been proven repeatedly to improve bonemineral density and decrease fracture risks. However, thiswell-validated treatment has rarely been used as a com-

parison for the evaluation of 1

α

-OH vitamin D deriva-tives in uremic patients, despite their usual vitamin Dinsufficiency or even deficiency (72) and their calcium-deficient diet.

This is all the more regrettable, since as long ago as1943, Liu and Chu (73) showed that just decreasingphosphate intake (and preventing phosphate absorptionby ferric ammonium citrate) while increasing calciumintake induced a positive calcium-phosphate balance inpredialysis patients. More recently, in 1975, Llach et al.(74) showed that phosphate restriction decreased PTHlevels in these patients. In the late 1980s, we showedthat nonhypercalcemic doses of 25-hydroxyvitamin Dtogether with oral calcium supplements suppressed PTHhypersecretion and improved osteitis fibrosa in predialy-sis patients. Finally, in the early 1990s, Lafage et al. (75)showed that phosphate restriction with physiologic cal-cium and vitamin D

2

supplements not only suppressedPTH, but also cured osteitis fibrosa and osteomalaciawithout changing of the parathyroid calcium set point(76). The efficiency of this approach has even been evi-denced by the occurrence of adynamic bone disease (77).

In contrast, 1

α

-OH vitamin D derivatives (inappropri-ately considered to be the only active vitamin D sterol inuremia) are not consistently efficient in suppressing highPTH, particularly in predialysis patients. PTH levels didnot decrease in the Hamdy et al. trial (15) with a hyper-calcemic hyperphosphatemic dose of alfacalcidol nor inthe Schomig and Ritz trial (78) using a nonhypercalce-mic dose of calcitriol. It is only in uremic patients with

Fig. 1. Interventions designed to prevent or control hyperparathyroidism in renal failure and promote osteoid mineralization.


233

vitamin D deficiency (25-hydroxyvitamin D

3

≤

8 ng/ml)and without calcium supplementation that 1

α

-OH vita-min D derivatives have been shown to decrease PTH andprevent osteopenia (79).

In dialysis patients, the effectiveness of calcitriol oralfacalcidol in suppressing PTH and improving histologicor radiologic osteitis fibrosa has also been inconsistentlyproven, depending largely on the level of hyperphos-phatemia control by (mainly) aluminum hydroxide (80–82). Since aluminum hydroxide alone suppresses PTH(49) and improves osteitis fibrosa (83), the therapeuticeffect could not be ascribed exclusively to calcitriol.

In 1980, we realized that our patients most commoncomplaint with aluminum hydroxide was developingosteomalacia despite a dialysate that was not highly con-taminated with aluminum (unlike that in the Newcastleupon Tyne study (84)). Therefore we began treatingrenal osteodystrophy only by preventing vitamin Dinsufficiency, preventing dialysate aluminum overload,and using exclusively higher dose calcium carbonate as aphosphate binder (11). Increasing calcium carbonatefrom 1.2 to 3.6 g/day of elemental calcium allowed dis-continuation of aluminum hydroxide and decreasedserum aluminum, while maintaining the same control ofPTH, SCa, and SPO

4

(85). To assess whether addingalfacalcidol would be beneficial, we performed a ran-domized study in 1985 comparing patients maintainedat 3.6 g calcium elemental carbonate with patients receiv-ing 1.2 g calcium elemental carbonate plus alfacalcidoland a small dose of aluminum hydroxide (86). Control ofSPTH, SCa, and SPO

4

was comparable, but serum alumi-num increased in the aluminum hydroxide group.

The long-term effectiveness of a predominantlycalcium carbonate-based approach in suppressing SPTHwas evidenced by the publication of the first cases ofadynamic bone disease not related to aluminum, but onlyto calcium carbonate and vitamin D insufficiency pre-vention (87); good prevention of cortical bone loss at themidshaft radius has also been shown (19). Furthermore,the risk of aortic calcification was assessed in two cross-sectional studies: one in 1988, which found progressionrelated only to male gender, age, triglycerides, and bloodpressure (88), and one in 1996, which linked it only toage and duration on dialysis (19). In neither study wasthere a significant link between vascular calcificationand SCa, SPO

4

, or with calcium carbonate dose. Unlikethe Framingham (89) and Braun et al. (90) studies, whichshowed an inverse correlation between vascular calcifi-cations and bone mineral density, we found no correla-tion (positive or negative) between vascular calcificationand BMD, suggesting that our therapeutic approach pre-vents the senile shift of calcium from bone to artery.Since the Framingham study (91) found aortic calcifica-tion extension to be an independent risk factor for coro-nary disease and the study of Taal et al. (92) reported thatmortality risk was increased 3.3-fold with osteopenia (

Z

score < 1.5) and 4.3-fold with osteoporosis (

Z

score <

−

2.5), our bone and vascular data are rather reassuring.Besides our 6-month comparison of 3.6 g calcium car-

bonate versus 1.2 g alfacalcidol and aluminum hydro-xide in 1985, the only studies that have compared thishigh calcium carbonate approach to 1

α

-OH vitamin D

with a non-calcium-phosphate binder are those ofIndridason and Quarles (35) and Sadek et al. (93).The Durham study group (35) found that, compared withcalcitriol (oral or intravenous) plus aluminum hydroxide,calcium carbonate (up to 2.3–5.4 g/day elemental cal-cium) had the advantage of adequately suppressing PTHfor 9 months with a SCa below the K/DOQI (9.5 mg/dl)threshold and with a much lower SPO

4

(3.5 versus5.2 mg/dl). With the advent of sevelamer, our group hascompared, in an open label randomized trial, calciumcarbonate versus sevelamer plus measures to preventhypocalcemia (1

α

-OH vitamin D when SPO

4

was lessthan 1.7 mmol/L; increase in dialysate calcium whenSPO

4

was greater than 1.7 mmol/L). After 5 months thePTH, SCa, and SPO

4

were comparable, with lower LDLcholesterol and bicarbonate (transiently) with sevelamer.

Thus there is no long-term comparison of the strategybased on relatively high-dose calcium-containing OPBuse versus that based on combined 1

α

-OH vitamin D plussevelamer. The Genzyme sponsored trials (20,90) comparedcalcium carbonate and/or calcium acetate with sevelamer,both with 1

α

-OH vitamin D, in patients with an alreadyoptimal baseline PTH. This resulted in the oversuppres-sion of PTH and a higher incidence of hypercalcemia inthe calcium group, contributing to a greater increase invascular calcification.

That the combined use of calcium-containing OPBand intravenous 1

α

-OH vitamin D and low dialysate cal-cium can successfully suppress PTH has been demon-strated by many authors including ourselves (94). Thesetrials (95) gave conflicting results regarding the superiorityof the intravenous over the oral route, but a recent meta-analysis (6) has suggested an edge for the intravenousroute because it suppresses PTH with less risk of hypercal-cemia and hyperphosphatemia. The intravenous route may,however, increase the risk of stunting growth in children (96).

The reduction in parathyroidectomy rate (97) duringthe 1990s has been ascribed to the use of intravenouscalcitriol. However, calcium-containing OPB use alsoincreased during this period (after the toxicity of low-dose aluminum was finally recognized (8)), making thedecrease in parathyroidectomy rates potentially attribut-able to both therapeutic interventions. The recent Tenget al. (98) study showed that after 1 year of intravenouscalcitriol administration, PTH decreased by only 5%, butSCa and SPO

4

increased by 8.2% and 13.9%, respec-tively, raising doubts as to the value and safety of thispractice. In particular, a higher vascular calcification riskcan be expected, since in dialysis patients, an indepen-dent link has been found between serum calcitriol andvascular calcification (46).

Greater safety from the so-called nonhypercalcemicand nonhyperphosphatemic vitamin D derivatives is notyet established. Compared with calcitriol, maxacalcitoldid not reduce the risk of hypercalcemia and hyperphos-phatemia (99) and according to the Teng et al. (98) study,paricalcitol reduced the absolute risk of hypercalcemiaby 1.5% and hyperphosphatemia by 2% compared withcalcitriol. In the randomized trial of Sprague et al. (100),paricalcitol reduced the rate of hypercalcemia and hyper-phosphatemia (expressed per 100 patient-years) by only0.25 and 3, respectively.


In regards to the 4% lower mortality in the paracalcitol-treated cohort compared with the calcitriol-treatedcohort reported by Teng et al., the results of an ongoingrandomized trial evaluating these two drugs are greatlyanticipated. If there is lower mortality with paricalcitolthat is unexplained by differences in SCa and SPO

4

, anew road to increasing longevity will be opened. It willbe quite exciting to see whether any benefits will bedemonstrated through prevention of cardiovascular,infectious, or neoplasic diseases.

If a lower cardiovascular mortality with paricalcitol isconfirmed in association with less cardiovascular calcifi-cation, hypercalcemia, and hyperphosphatemia, thiswould support the preferential use of paricalcitol overthat of calcitriol, but not necessarily its routine adminis-tration with noncalcium-containing OPB and a lowdialysate calcium. Actually, the changes in SCa andSPO

4

will probably be close to those previously observedin the cohort study (i.e., an increase of 6% and 12%,respectively). This would suggest that the best approachwould be no use of 1

α

-OH vitamin D, but rather the useof a 6 mg/dl dialysate calcium concentration with thehighest nonhypercalcemic (SCa < 9.5 mg/dl) dose ofcalcium-containing OPB plus, if PTH remains above300 pg/mL, introduction of cinacalcet.

At the present time, we share the skeptical view ofStanley Goldfarb (reported in a syllabus on renal osteo-dystrophy (101)) regarding major breakthroughs in clinicaluses of nonhypercalcemic and nonhyperphosphatemicvitamin D derivatives. However, as also suggested bythis author, the new 2 methylene-19 nor-(205)-1

α

25(OH)

2

D

3

may be an exception, given its remarkable pro-motion of bone formation (both in vivo and in vitro) inassociation with a much stronger mobilization of cal-cium at the osteoblast than at the intestine level (102).

Firm conclusions on 1

α

-OH vitamin D derivatives useare difficult due to the absence of long-term trialsassessing hard clinical outcomes. This review stronglysuggests that in dialysis patients without vitamin Dinsufficiency, relatively high doses of oral calcium alonehave comparable efficacy to noncalcium OPB combinedwith 1

α

-OH vitamin D metabolites in the control of dia-lysis hyperparathyroidism. However, 1

α

-OH vitamin Dmetabolites have a poor safety profile (more hypercalcemia,hyperphosphatemia, and vascular calcifications risk)when they are used with calcium-containing OPB, espe-cially when PTH oversuppression results.

Therefore it is logical to suggest that cinacalcet shouldprobably replace rather than be added to 1

α

-OH vitaminD. While discontinuation of 1

α

-OH vitamin D willaccentuate the hypocalcemic effect of cinacalcet, anincrease of calcium-containing OPB and, if necessary,the dialysate calcium will prevent this problem. Thisapproach is further justified by trials showing that when1

α

-OH vitamin D doses were decreased rather thanincreased, cinacalcet was equally effective for PTHsuppression, but associated with better control of hyper-phosphatemia. Indeed, while PTH suppression (

−

44%and

−

50%, respectively) and SCa decrease (

−

7.1% and6.8%, respectively) were comparable, SPO

4

decreasedmore when vitamin D dose decreased (

−13.5% and −7.2%,respectively) (103).

When and How Long Will Calcimimetics be Necessary, and at What Cost?

Surgical parathyroidectomy, the definitive treatmentof uremic parathyroid hyperplasia and hyperfunction(104), is generally considered when intact PTH levels aregreater than 800 pg/mL. In Frazao et al. (52), cinacalcetcan decrease PTH levels to less than 600 pg (the thresh-old for increased morbidity/mortality) in only half ofthe patients with an initial PTH level between 800 and1000 pg/mL, and none when PTH levels were greaterthan 1000 pg/mL. Thus cinacalcet should be consideredonly when, on “standard” therapy, the PTH levels arebetween 300 and 800 pg/mL.

Regarding the duration of this treatment, it may belife-long, unless surgical parathyroidectomy or a suc-cessful kidney transplantation is performed. Sinceinvolution of parathyroid hyperplasia is very slow, dis-continuation of cinacalcet after kidney transplantationshould be gradual and carefully monitored by repetitivemeasurement of serum concentrations of calcium, phos-phate, and PTH in order to prevent a hypercalcemic crisisthat would be hazardous for the graft. Unfortunately,no data are yet available concerning the SCa, SPO4, andPTH levels in cinacalcet-treated patients receiving akidney graft and discontinuing cinacalcet.

Because of the life-long potential duration of thistreatment, its cost-effectiveness versus surgical parathy-roidectomy should be estimated. A major difficulty inthis evaluation is the variability of “standard” therapyamong countries. This is reflected in the differencesbetween American K/DOQI recommendations of 2003and those made by European experts in 2000, especiallyregarding the use of 1α-OH vitamin D (104), low dialy-sate calcium (105), and the proposed maximal dose ofcalcium-containing OPB (2.4 g instead of 1.5 g of ele-mental calcium) (106). Furthermore the cost of standardtherapy is also influenced by country-specific economicrules and insurance policies. There is obviously a needfor more data to allow a rational evaluation of the alter-native therapeutic approaches available since the intro-duction of cinacalcet.

The former (precinacalcet) K/DOQI recommendedstrategy was:

• The use of a dialysate calcium concentration of5.0 mg/dl (2.5 mEq/L or 1.25 mmol/L) but onlywhen SCa is greater than 8.4 mg/dl.

• The use of calcium-containing OPB (maximaldose 1.5 g of elemental calcium) combined withnoncalcium-containing OPD (sevelamer hydro-chloride, lanthanum carbonate) in order to maintainSPO4 at less than 5.5 mg/dl.

• No routine correction of 25-hydroxyvitamin D3

insufficiency (recommended only for predialysisuremic patients).

• Use of intravenous 1α-OH vitamin D for PTHgreater than 300 pg/mL, while SCa is less than9.5 mg/dl and SPO4 is less than 5 mg/dl.

It has been estimated (107) that 66% of U.S. patientshad at least one criterion to be switched to sevelamer,with an estimated cost of this switch of $781 million/year, assuming an average dose of 6.5 g/day. To provide

CALCIMIMETICS IN THE MANAGEMENT OF PTH, CALCIUM, AND PHOSPHATE DISTURBANCES 235

perspective on this expense, hospitalization costs forESRD patients would need to be reduced by more than45% to offset this additional cost.

It may be argued, however, that the K/DOQI criteriafor switching to a noncalcium OPB are not fully justified.The PTH less than 100–150 pg/mL criterion may bewarranted based on the associated risks of hypercalce-mia and calcification, but not because of a higher mor-bidity/mortality risk (7). Arbitrarily limiting calciumsupplements to 1.5 g/day prevents use of higher dosesthat are as effective as calcitriol on PTH suppression,with the advantage of less hyperphosphatemia and lesshypercalcemia than with calcitriol and non-calcium-phosphate binders (35). Thus, a potentially less hazard-ous and cheaper treatment is restricted ($463 for calciumacetate; $154 for calcium carbonate, $3644 for seve-lamer per patient-year).

The availability of cinacalcet gives a promising alter-native treatment to the combination of sevelamer and 1α-OH vitamin D when the serum mineral parameters are abovetheir optimal range. For a rational evaluation of cinaca-lcet, it is first necessary to agree on appropriate baselinepreventive treatment of dialysis hyperparathyroidism.

For this baseline treatment we propose:• Normalization of serum 25-hydroxyvitamin D3

(greater than 30 ng/ml).• Use of dialysate calcium of 6 mg/dl (1.5 mmol/L)

as recommended by European experts rather thanthe 5 mg/dl (1.25 mmol/L) recommended by the K/DOQI.

• Use of calcium-containing OPB taken with mealswith the maximal dose restricted only by the K/DOQI upper limit of optimal SCa (9.5 mg/dl or2.37 mmol/L).

• Use of nicotinamide in doses up to 1750 mg/day.Nicotinamide is a cheap and well-tolerated treatment

that efficiently controls hyperphosphatemia (24). In ourexperience, 1.4 tablets of 500 mg had the same effect as4 tablets of 800 mg sevelamer. Furthermore, it increaseshigh-density lipoprotein (HDL) cholesterol by 42% anddecreases LDL by 11% (24). Considering the poor per-formance of the statin-like atorvastatin in diabetic dialysispatients (an insignificant 8% decrease in cardiovascularrisk in spite of a 45% decrease in LDL cholesterol), thiseffect of nicotinamide may be quite relevant, sinceincreases in HDL cholesterol are the strongest predictorsof risk reduction in lipid intervention trials (108).

When, with this cost-effective baseline treatment,PTH remains above 300 pg/mL while SCa is between9.0 and 9.5 mg/dl, but SPO4 is greater than 5 mg/dl and/or calcium-phosphate product is greater than 45 mg2/dl2,one of the following two strategies should be considered:

Strategy I: cinacalcet with increased dose of calcium-containing OPB and, if necessary, dialysate calciumincrease in order to prevent hypocalcemia.

Strategy II: sevelamer or lanthanum carbonate (whiledecreasing oral calcium to 1.5 g/day) and introduc-tion of paricalcitol.

Considering that the treatment duration will be life-long for the majority of patients, a clinically meaningfulevaluation of these strategies is worth performing inorder to properly evaluate the effectiveness and tolerance

of the two strategies. A trial should ideally last at least5 years, although for surrogate endpoint evaluationssuch as bone density and vascular calcification exten-sion, a 2- to 3-year follow-up would suffice. When seve-lamer is used in strategy II, a statin should be added instrategy I. Indeed, Goldsmith et al. (46) have stressed theimportance of comparable dyslipidemia treatment toclarify the issue of whether measures for preventingbone disease in uremic patients actually aggravate theirarterial disease.

Conclusion

Cinacalcet is an effective and well-tolerated drug forsuppressing PTH hypersecretion and thus improvingosteitis fibrosa and preventing fracture risk and parathy-roidectomy. It offers the advantage over 1α-OH vitaminD derivatives of decreasing SCa and SPO4. Thishypophosphatemic effect is further enhanced by a doseincrease of calcium-containing OPB, often necessarybecause of the drug’s hypocalcemic effect. Correctinghypocalcemia by calcium instead of 1α-OH vitamin D ispreferable; a revision of the current K/DOQI recommen-dation limiting oral elemental calcium supplements to1.5 g/day should be considered. The only justified limitto oral calcium load is a SCa greater than 9.5 mg/dl,because of it association with a higher mortality risk.

Cinacalcet has a cost ranging between $296 and $1778per month according to the dose needed. As a result,cost /clinical effectiveness studies should be performedin patients whose serum concentrations of PTH, calcium,and phosphate are above the K/DOQI recommendedthresholds, despite treatment with a cost-effective base-line approach. For this latter we suggest prevention ofnative vitamin D insufficiency, the use of a dialysate cal-cium of 6 mg/dl (and not 5 mg/dl in order to prevent PTHstimulation) together with calcium-containing OPBwithout arbitrary dose limitation other than a correctedSCa greater than 9.5 mg/dl. If SPO4 remains above5 mg/dl, nicotinamide should be used as an inhibitor ofintestinal absorption of phosphate (and HDL cholesterolenhancer). Patients whose serum concentrations ofPTH and/or phosphate remain above the recommendedrange should be considered for one of two therapeuticstrategies: paricalcitol and sevelamer hydrochloride orlanthanum carbonate; or cinacalcet and a higher dose ofcalcium-containing OPB. The relative value of thesetwo approaches should be addressed in a randomizedtrial.

Dedication

Albert Fournier dedicates this review of 35 year devel-opment in hyperparathyroidism treatment for dialysispatients to his former Mayo Clinic teachers: Dr W. J.Johnson, Claude Arnaud and Ralph Goldsmith withwhom he enjoyed a fruitful collaboration during his fellow-ship in 1968–69 as well as to the memory of demisedfriends: Dr Philipper Bordier, Jean-Luc Sebert and JackCoburn.


Acknowledgment

The authors thank Professor Tilman Drüeke, DoctorsGerard London and Pablo Ureha from France andProfessor Chonchol from Denver—Colorado USA, fortheir constructive comments. They also appreciate thededicated work of their secretaries for typing the manu-script: Mrs Anne Duputel, Perrine Delaire, PamelaCadran, Nathalie Bontemps, Sabine Darret, Nathalie Pletand Chistel Fournet.

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APPENDIX

CLINICALLY RELEVANT PHARMACOKINETIC INTERACTIONS WITH CINACALCET (SENSIPAR®)

A. Drugs leading to change of cinacalcet dose because of metabolising enzyme changes

Cytochrome P450 related liver enzyme

metabolising cinacalcet

Inhibiting drugs →→→→ cinacalcet increase→→→→ dose decrease

Stimulating drugs →→→→ cinacalcet decrease

→→→→ dose increase

CYP3A4

ketoconazole rifampicineitraconazolevoriconazole

telithromycineritonavir

CYP1A2fluvoxamine

ciprofloxacine smoking

B. Drugs which dose should be decreased when cinacalcet is added because they are metabolised by CYP 2D6 enzyme which is strongly inhibited by cinacalcet. —drugs used for heart disorders:

flecaïnide (Flecaïne®), propafenone (Rythmol®), metoprolol (Seloken®)—drugs used of psychiatric disorders:

desipramine, nortriptyline, clomipramine (Anafranil®)

C. No dose modification with cinacalcet of drugs metabolised by CYP1A2, CYP2C9, CYP2C19 and CYP3A4.

D. No pharmacokinetic interference of cinacalcet with Ca phosphate binder, sevelamer, inhibitors of gastric proton pump, warfarin derivatives.

E. Note that concomitant food intake compared to fasting state improves cinacalcet bioavailability by 50/80%, regardless of the fat intake. Dose increase induces a linear increase of cinacalcet absorption up to 200 mg. Cinacalcet plasma half life is biphasic, the initial one being 6 hours and the final one 30–40 hours.

How Do Calcimimetics Fit Into the Management of Parathyroid Hormone, Calcium, and Phosphate...

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