Old and new calcimimetics for treatment of secondary hyperparathyroidism: Impact on biochemical and relevant clinical outcomes

CKJ REVIEW Old and new calcimime ics o ea men o seconda y hype pa a hy oidism: impac on biochemical and ele an clinical ou comes Luciano Pe ei a 1,2,3,4 , Ca a ina Meng 1,2,3 , Daniela Ma ques 5 and Jo~ ao M. F az~ ao 1,2,3,4 1 Ins i u e o In es iga ion and Inno a ion in Heal h, Uni e si y o Po o, Po o, Po ugal, 2 Neph ology and In eciology g oup, INEB—Na ional Ins i u e o Biomedical Enginee , Uni e si y o Po o, Po o, Po ugal, 3 Depa men o Neph ology, S~ ao Jo~ ao Hospi al Cen e , Po o, Po ugal, 4 DaVi a Kidney Ca e, Po o, Po ugal and 5 School o Medicine o Uni e si y o Po o, Po o, Po ugal Co espondence and o p in eques s o: Jo~ ao M. F az~ ao; E-mail: [email p o ec ed] Abs ac Seconda y hype pa a hy oidism (SHPT) is associa ed wi h inc eased bone u no e , isk o ac u es, ascula calci ica ions, and ca dio ascula and all-cause mo ali y. The classical ea men o SHPT includes ac i e i amin D compounds and phospha e binde s. Howe e , achie ing he op imal labo a o y a ge s is o en di icul because i amin D s e ols supp ess pa a hy oid ho mone (PTH) sec e ion, while also p omo ing calcium and phospha e in es inal abso p ion. Calcimime ics inc ease he sensi i i y o he calcium-sensing ecep o , so ha e en wi h lowe le els o ex acellula calcium a signal can s ill exis , leading o a dec ease o he se -poin o sys emic calcium homeos asis. This enables a dec ease in plasma PTH le els and, consequen ly, o calcium le els. Cinacalce was he i s calcimime ic o be app o ed o clinical use. Mo e han 10 yea s since i s app o al, cinacalce has been demons a ed o e ec i ely educe PTH and imp o e biochemical con ol o mine al and bone diso de s in ch onic kidney pa ien s. Th ee andomized con olled ials ha e analysed he e ec s o ea men wi h cinacalce on ha d clinical ou comes such as ascula calci ica ion, bone his ology and ca dio ascula mo ali y and mo bidi y. Howe e , a inal conclusion on he e ec o cinacalce on ha d ou comes emains elusi e. E elcalce ide is a new second-gene a ion calcimime ic wi h a pha macokine ic p o ile ha allows h ice-weekly dosing a he ime o haemodialysis. I was ecen ly app o ed in Eu ope, and is ega ded as a second oppo uni y o imp o e ou comes by op imizing ea men o SHPT. In his e iew, we summa ize he impac o cinacalce wi h ega d o biochemical and clinical ou comes. We also discuss he possible implica ions o he new calcimime ic e elcalce ide in he ques o imp o e ou comes. Key wo ds: calcimime ic agen s, ch onic kidney disease, cinacalce , e elcalce ide, seconda y hype pa a hy oidism In oduc ion Ch onic kidney disease (CKD) is apidly becoming a public heal h issue, wi h inc easing incidence and es ima ed wo ldwide p e alence o 8–16% [1]. Du ing he cou se o CKD, he decline in enal unc ion is accompanied by he de elopmen o diso de s o calcium and phospha e me abolism, leading o he well- known condi ion ‘Mine al Bone Disease associa ed wi h CKD’ Recei ed: July 6, 2017. Edi o ial decision: Augus 18, 2017 V CThe Au ho 2017. Published by Ox o d Uni e si y P ess on behal o ERA-EDTA. This is an Open Access a icle dis ibu ed unde he e ms o he C ea i e Commons A ibu ion Non-Comme cial License (h p://c ea i ecommons.o g/ licenses/by-nc/4.0/), which pe mi s non-comme cial e-use, dis ibu ion, and ep oduc ion in any medium, p o ided he o iginal wo k is p ope ly ci ed. Fo comme cial e-use, please con ac [email p o ec ed] 80 Clinical Kidney Jou nal, 2018, ol. 11, no. 1, 80–88 doi: 10.1093/ckj/s x125 Ad ance Access Publica ion Da e: 8 Decembe 2017 CKJ Re iew Downloaded om h ps://academic.oup.com/ckj/a icle-abs ac /11/1/80/4711103 by Uni e sidade do Po o use on 23 Decembe 2019 (CKD-MBD) [2]. This condi ion de elops due o he inabili y o he kidney o exc e e phospha e p ope ly, leading o i s e en ion and accumula ion, which s imula es ib oblas g ow h ac o 23 (FGF- 23) and se um pa a hy oid ho mone (PTH) [3]. FGF-23, a pep ide ho mone p oduced mainly in he os eocy es, is able o educe phospha e le els using h ee di e en pa hways: inc eased enal exc e ion, PTH s imula ion and calci iol syn hesis inhibi ion. The la e p omo es dec eased gas oin es inal abso p ion o phospha e and calcium, leading o hypocalcaemia. The low calci- iol le els and hypocalcaemia also s imula e PTH sec e ion in he pa a hy oid glands and induce he de elopmen o pa a hy- oid gland hype plasia and seconda y hype pa a hy oidism (SHPT). SHPT is associa ed wi h inc eased bone u no e , isk o ac u es, ascula calci ica ions and, mos impo an ly, isk o ca dio ascula and all-cause mo ali y [4]. Recen obse a ional da a indica e ha PTH >600 pg/mL is associa ed wi h a highe isk o ca dio ascula mo ali y as well as all-cause ca dio as- cula hospi aliza ion [5]. I is in e es ing o no e ha pa ien s ha e be e ou comes he longe he ime ha hey ha e PTH wi hin ecommended le els. Indeed, consis en con ol o bone me abolism pa ame e s, including PTH, wi hin published ec- ommended a ge s is a s ong p edic o o su i al in haemo- dialysis pa ien s [6]. The classical ea men o SHPT includes ac i e i amin D compounds and phospha e binde s ( o limi i s gas oin es inal phospha e abso p ion) [7]. Howe e , achie emen o op imal labo a o y a ge s is o en di icul because i amin D s e ols supp ess PTH sec e ion, bu also p omo e calcium and phos- pha e in es inal abso p ion. Calcium-sensing ecep o (CaSR) is essen ial o he main e- nance o sys emic calcium homeos asis, and has become an excellen a ge o he ea men o bone and mine al diso - de s. I s ligands a e called calcimime ics and can be classi ied as Type 1 (agonis s), such as ionized calcium and o he di alen anions ha di ec ly s imula e CaSR, o Type 2 (posi i e allos- e ic modula o s), which bind o a si e ha is dis inc om he physiological ligand and inc ease he sensi i i y o CaSR o ion- ized calcium, leading o he dec ease o he se -poin o sys- emic calcium homeos asis (homeos asis is achie ed wi h lowe concen a ions o ionized calcium). [8]. This enables a dec ease in plasma PTH le els, and consequen ly o calcium le els (Table 1). Addi ionally, lowe le els o phospho us and calcium phospho us a e also seen [9], demons a ing he capabili y o calcimime ics o imp o e he ou c i ical disease bioma ke s associa ed wi h SHPT ( he phospho us- and cal- cium-lowe ing e ec dis inguishes calcimime ics om ac i e i amin D) [10]. Fi s -gene a ion compounds include phenylalkylamines R- 567 and R-568, which we e es ed in haemodialysis pa ien s, bu pha macokine ics issues hal ed u he clinical de elopmen [7]. Second-gene a ion calcimime ic d ugs include cinacalce and o he s ha ha e ne e achie ed clinical use, such as calin- dol and AC-265347. Cinacalce hyd ochlo ide was he i s Type 2 calcimime ic o be app o ed o clinical use [11]. T ea men wi h cinacalce e ec i ely educes PTH, calcium and phospho us [12]. Mo e han 10 yea s since i s app o al, cinacalce has been demons a ed o e ec i ely educe PTH and imp o e biochemical con ol o CKD-MBD. E elcalce ide is a new second-gene a ion calcimime ic. As a no el in a enous o mula ion wi h a pha macokine ic p o ile ha allows h ice-weekly dosing (a he ime o haemodialysis), e elcalce ide was de eloped o imp o e e icacy and adhe ence, and educe gas oin es inal ad e se e ec s ela i e o cinacalce . I was ecen ly app o ed in Eu ope, and is ega ded as a second oppo uni y o imp o e ou comes in CKD-MBD pa ien s by op imizing ea men o SHPT using his p omising new calcimime ic [13]. In his e iew, we summa ize he impac o cinacalce in bio- chemical and ele an clinical ou comes such as ca dio ascula mo ali y, ascula calci ica ions and ac u es. We also discuss he possible implica ions o he new calcimime ic e elcalce ide in he ques o imp o e ou comes o CKD pa ien s. Cinacalce e ec i ely con ols SHPT Cinacalce ’s e icacy and sa e y has been es ed in se e al andomized con olled ials (RCTs) [11,12,14]. Cinacalce ea - men in addi ion o ac i e i amin D in pa ien s wi h SHPT ha is inadequa ely con olled despi e s anda d he apy e ec i ely dec eases PTH le els, while also educing se um calcium and phospho us. Pos hoc analysis has demons a ed ha ea men wi h cinacalce imp o es he achie emen o biochemical a - ge s ecomended by in e na ional socie ies [15]. In a me a- analysis [16] in ol ing eigh ials (1429 pa ien s) compa ing cinacalce ea men plus s anda d he apy wi h placebo plus s anda d he apy, end-o - ea men alues o PTH [290.49 pg/ mL, 95% con idence in e al (CI) 359.91 o 221.07], calcium (0.85 mg/dL, 95% CI 1.14 o 0.56), phospho us (0.29 mg/dL, 95% CI 0.50 o 0.08) and calcium phospho us p oduc (7.90 mg 2 /dL 2 , 95% CI 10.25 o 5.54) we e signi ican ly lowe wi h cinacalce compa ed wi h placebo. To allow an objec i e assessmen o he e ec o cinacalce on lowe ing PTH, he i amin D ac i a o ecep o agonis (VDRag) dose was kep cons an . Howe e , subsequen clinical s udies ha e con i med he PTH-lowe ing e ec o cinacalce used in a ying o cons an doses o VDRags. This is an impo - an inding conside ing ha , in clinical p ac ice, cinacalce is used o en wi h VDRags [17]. Ad e se e ec s o cinacalce a e desc ibed in Table 2. Besides i s supp essi e e ec on PTH le els, da a sugges ha cinacalce ea men can induce a olume educ ion o he enla ged pa a hy oid glands wi h nodula hype plasia seen in SHPT pa ien s [18]. Cinacalce educes FGF-23 le els FGF-23 le els ha e been associa ed wi h ad e se clinical ou - comes [19–24] such as p og ession o CKD, a e ial calci ica ion, le en icle hype ophy, ca dio ascula e en s and inc eased mo ali y. Pha macologic in e en ion capable o educing FGF- 23 would hold he p omise o ha ing a bene icial e ec on hese impo an clinical ou comes. CUPID (Cinacalce S udy o Pe i oneal Dialysis Pa ien s in Double A m On he Lowing E ec o iPTH le el), a p ospec i e RCT ha e alua ed he e ec o cinacalce on FGF-23 le els [25], en olled pa ien s ha had been on pe i oneal dialysis o >3 mon hs and had PTH >300 pg/mL. Pa ien s we e andomized o Table 1. E ec o PTH-supp essi e he apies on biochemical pa ame e s PTH Calcium Phospho us FGF-23 Vi amin D analogues #" " " Cinacalce ## # # E elcalce ide ## ## # ## Old and new calcimime ics |81 Downloaded om h ps://academic.oup.com/ckj/a icle-abs ac /11/1/80/4711103 by Uni e sidade do Po o use on 23 Decembe 2019 cinacalce he apy o i amin D. The cinacalce g oup had a educ ion in FGF-23 le els (3960–2325 RU/mL), whe eas he con- ol g oup had an inc ease in FGF-23 concen a ion (2085–2415 RU/mL). ACHIEVE (ACHIEVE: Op imizing he T ea men o SHPT: A Compa ison o Sensipa and Low Dose Vi amin D s Escala ing Doses o Vi amin D Alone)—a Phase 4, open-label, placebo-con olled, mul icen e, RCT—was designed o compa e ea men esul s wi h escala ing doses o cinacalce plus ixed low-dose calci iol (cinacalce -D g oup) e sus calci iol alone (Flex-D g oup) [26]. Using he da a o 91 subjec s om his s udy, We mo e e al. e i ied ha he pe cen age change o FGF-23 be ween he wo g oups di e ed signi ican ly (P ¼0.002) [27]. In he cinacalce -D g oup, he pe cen age change dec eased (9.7 618.2; P ¼0.021), while an inc ease was ound in he Flex- D g oup; howe e , he esul s we e no signi ican (4.1 616.5). The mechanism unde lying he abili y o cinacalce o dec ease FGF-23 le els emains o be cla i ied. The CUPID in es- iga o s concluded ha cinacalce ea men was independen ly associa ed wi h FGF-23 educ ion, and no ela ed o he d ug’s e ec s on PTH, calcium and phospho us se um le els. O he s ha e obse ed ha he dec ease o FGF-23 le els is concomi an wi h he dec ease in phospho us le els (bu no o PTH o cal- cium le els) [28]. We mo e e al. sugges ed ha calcium and phospho us a e esponsible o cinacalce ’s e ec on FGF-23 le - els [27]. Fu he in es iga ion is needed in o de o unde s and exac ly how cinacalce he apy esul s in a g ea e educ ion o se um FGF-23 when compa ed wi h adi ional d ugs. Recen ly, a pos hoc e alua ion o he EVOLVE (E alua ion o Cinacalce Hyd ochlo ide The apy oLowe Ca dio ascula E en s) s udy added some mo e in o ma ion o he FGF-23 issue [29]. When analysing he esul s om he cinacalce - ea ed pa ien g oup (n¼1338), a dec ease in FGF-23 le els was seen (5555–2255 pg/mL; P <0.001), in con as o he con ol g oup (n¼1264), whe e le els emained unchanged (5600–5580 pg/mL). Mo eo e , when compa ed wi h he con ol g oup, a la ge p opo ion o pa ien s in he cinacalce g oup had a meaning ul decline (30%) o FGF-23 (28% e sus 64%; P <0.001). This inding is ele an because he 30% educ ion o FGF-23 le els was associa ed wi h a dec eased isk o ca dio ascula mo ali y (P <0.001), sudden dea h (P < 0.001) and hea ailu e (P ¼0.04). Cinacalce and ac u es Pa ien s wi h CKD ha e inc eased isk o ac u es compa ed wi h he gene al popula ion [30,31]. The e is also a high a e o dea h and hospi aliza ion ollowing bone ac u e among hae- modialysis pa ien s [32]. Abno mali ies in bone s uc u e, which a ec bone quali y, a e obse ed in pa ien s wi h CKD-MBD. Malluche e al. demons a ed ha bone wi h high u no e had ma e ial and nanomechanical abno mali ies such as a educed mine al o ma ix a io [33]. Such u no e - ela ed al e a ions in bone quali y may con ibu e o he diminished mechanical compe ence o bone in CKD. In hei single cen e coho s udy, Iimo i e al. [34] demon- s a ed a U-shaped co ela ion be ween PTH le el and isk o ac u e; only dec eased [PTH <150 pg/mL; haza d a io (HR) 3.27] o inc eased le els we e ela ed o a supe io haza d o clinical ac u e (PTH >300 pg/mL; HR 2.69). To da e, no RCT has been speci ically designed o e alua e whe he any compounds used in he ea men o SHPT (phos- pha e binde s, i amin D analogues o calcimime ics) dec ease he isk o ac u e in CKD pa ien s. Howe e , ea men wi h cinacalce has been associa ed wi h educed isk o ac u es. A combined pos hoc analysis o sa e y da a om ou Phase 3 RCTs en olling 1184 pa ien s wi h end-s age enal disease (ESRD) and uncon olled SHPT (de ined as PTH >300 pg/mL) showed ha andomiza ion o cinacalce , in addi ion o con en- ional ea men wi h ac i e i amin D, esul ed in a signi ican educ ion in he isk o ac u e [ ela i e isk (RR) 0.46, 95% CI 0.22–0.95, P ¼0.04] compa ed wi h placebo and con en ional ea men [35]. In he EVOLVE ial, in he in en ion- o- ea (ITT) analysis, cinacalce did no signi ican ly educed he isk o ac u es [36]. Du ing he s udy, mo e han wo- hi ds o pa ien s in bo h g oups discon inued he ea men , so a p ede e mined lag- censo ing analysis (censo ing ime >6 mon hs a e s opping he s udy d ug) was pe o med and a ela i e haza d o ac u e Table 2. La e al e ec s o calcimime ic agen s and sugges ed ac ions o ake Side e ec F equency P oposed ac ion Gas oin es inal e en s Nausea Ve y common Gi e cinacalce wi h main meal a e dialysis/in he e ening Dec ease o ac iona e he dose i symp oms appea a e a dose inc ease Cau ion is ad ised wi h an i-eme ics, including me oclop amide (QT p olonga ion) Vomi ing Ve y common Dia hoea and dyspepsia Uncommon Ano exia Common Hypocalcaemia and ne ous sys em diso de s Hypocalcaemia Common Wi hhold o educe cinacalce un il se um calcium le els each 8 mg/ dL o symp oms ha e esol ed Use o calcium-based phospha e binde s, i amin D s e ols o adjus - men s o dialysis luid calcium ha e been sugges ed by some au ho s, acco ding o clinical judgemen Dizziness and pa aes hesia Common Seizu es Uncommon O he s Skin and cu aneous diso de s, ash Common Seek o he causes; conside discon inuing d ug Musculoskele al, connec i e issue and bone diso de s, myalgia Common Seek o he causes; conside discon inuing d ug Immune sys em diso de s, hype sensi i i y eac ions Uncommon Seek o he causes; conside discon inuing d ug 82 | L. Pe ei a e al. Downloaded om h ps://academic.oup.com/ckj/a icle-abs ac /11/1/80/4711103 by Uni e sidade do Po o use on 23 Decembe 2019 o 0.72 (95% CI 0.58–0.90; P ¼0.003) was ob ained. When pa ici- pan s we e censo ed a he ime o co-in e en ions, such as pa a hy oidec omy and kidney ansplan , he ela i e haza d was 0.71 (95% CI 0.58–0.87; P ¼0.001). Mo eo e , when conside - ing he isk o all clinical ac u es (no only he i s , bu also subsequen ones) he mul i a iable-adjus ed ela i e haza d was 0.83 (95% CI 0.72–0.98; P ¼0.02). They concluded ha , when conside ing e en s p omp ing discon inua ion o he s udy d ug, such as co-in e en ions and cumula i e clinical ac- u es, cinacalce educed he a e o clinical ac u e by 17–29% [36]. These da a p o ide sugges i e e idence ha cinacalce educes he isk o ac u e in pa ien s wi h SHPT. This e ec o cinacalce in educing ac u es is no a su - p ising one conside ing wo epo s ha used bone his omo ph- ome y om di e en g oups o desc ibe imp o ed his ology in pa ien s ea ed wi h cinacalce [37,38]. In he BONAFIDE (Bone Biopsy S udy o Dialysis Pa ien s wi h SHPT o End S age Renal Disease) s udy [38], dialysis pa ien s wi h PTH >300 pg/mL and biopsy-p o en high- u no e bone disease we e ea ed wi h cinacalce and a second bone biopsy was pe o med a e 6–12 mon hs o cinacalce ea men . Bone o ma ion and bone eab- so ion indices we e imp o ed; mos imp essi e was ha he numbe o pa ien s wi h no mal bone his ology inc eased om none a baseline o 20 a 12 mon hs. The ole o bone mine al densi y (BMD) e alua ion in ch onic kidney pa ien s is e ol ing. Unlike p e ious e sions, he cu - en KDIGO (Kidney Disease: Imp o ing Global Ou comes) guidelines sugges ha BMD es ing is unde aken in pa ien s wi h CKD G3a-G5D wi h CKD-MBD and/o isk ac o s o os eo- po osis i esul s will impac he apeu ic decisions [39]. E idence-based in o ma ion is sca ce abou he e ec o cina- calce on BMD in CKD pa ien s. Some o he a ailable da a ha e shown a posi i e e ec o cinacalce on BMD, namely on he emo al neck [40] and p oximal emu [41]. Howe e , o he s ha e e ealed ha cinacalce he apy shows no e ec on BMD o he lumba spine [41] o has a de imen al e ec wi h associ- a ed bone loss on he emo al neck and lumba spine [42]. The e ec and signi icance o cinacalce on BMD emains o be cla i ied. Cinacalce and ascula calci ica ion SHPT is associa ed wi h ascula calci ica ion. Once es ablished in haemodialysis pa ien s, i gene ally p og esses much as e han in he gene al popula ion, leading o inc eased isk o all- cause and ca dio ascula mo ali y [2]. In a single-cen e p ospec i e coho s udy (n¼23), Nakayama e al. [43] e alua ed he impac o cinacalce on abdominal ao ic calci ica ion by calcula ing he ao ic calci ica- ion a ea index (ACAI) be o e and a e ea men (12, 0, 12, 24 and 36 mon hs). The mean ACAI alues we e no dec eased du - ing he obse a ion pe iod (21.4% a baseline, 23.9% a 12 mon hs, 23.7% a 24 mon hs and 24.3% a 36 mon hs). In addi- ion, Tsu u a e al. [44] compa ed co ona y a e y calci ica ion (CAC) in cinacalce (n¼8) and con ol (n¼60) g oups, e i ying a dec ease (0.094/yea ) in he CAC sco e when cinacalce was used, while opposi e was seen in he con ol g oup he (þ0.034/ yea ). Howe e , he esul s we e no s a is ically signi ican (P ¼0.102). The ADVANCE (A Randomized S udy o E alua e he E ec s o Cinacalce Plus Low Dose Vi amin D on Vascula Calci ica ion in Subjec s wi h CKD) s udy [45] compa ed ascula and ca diac al e calci ica ion p og ession in 360 adul haemodialysis pa ien s wi h SHPT, ea ed ei he wi h cinacalce plus low-dose i amin D (n¼180) o lexible doses o i amin D alone (n¼180). The p ima y endpoin was a change in he Aga s on To al CAC sco e (which uses he concep o plaque densi y and he e o e e lec s he amoun o calcium deposi ed wi hin a cal- ci ied lesion). The median pe cen inc ease in Aga s on o al CAC sco e was 24% o he cinacalce plus i amin D g oup and 31% o in he i amin D g oup (s a i ied median ea men di - e ence ¼10.3%; 95% CI 22.6% o 0.8%; P ¼0.073). Simila ly, Aga s on sco e changes in he ho acic ao a and mi al al e we e no s a is ically signi ican . The ao ic al e, on he o he hand, had a s a i ied median ea men di e ence o 44.7% (95% CI 85.8% o 6.1%; P ¼0.014). The ADVANCE s udy had some limi a ions. A subs an ial numbe o pa ien s assigned o he cinacalce g oup ecei ed doses o i amin D ha we e highe han speci ied in he p o o- col. A pos hoc analysis [46] compa ing CAC p og ession among p o ocol-adhe en pa ien s ea ed wi h cinacalce showed ha he pe cen age inc ease in CAC and ao ic al e calci ica ion was signi ican ly slowe in he cinacalce g oup. O he limi a ions included he open-label design and sho pe iod o ollow-up (12 mon hs, which is unlikely o be su icien o he de ec ion o subs an ial changes in ascula calci ica ion). Finally, he educed obse ed calci ica ion p og ession could no be solely a ibu ed o cinacalce ; he lowe doses om i a- min D s e ols in he cinacalce g oup also ha e o be conside ed. Cinacalce , ca dio ascula disease and all-cause mo ali y Ele a ed se um le els o phospho us, calcium, PTH and FGF-23 ha e been linked o dea h and ca dio ascula ou comes [47–49]. In a pos hoc analysis, Cunningham e al. [35] combined da a on clinical ou comes om ou Phase 3 RCTs and showed ha ea men wi h cinacalce esul ed in a signi ican educ ion in he isk o ca dio ascula hospi aliza ion (HR 0.61; 95% CI 0.43– 0.86) and a non-signi ican endency o educe all-cause mo al- i y. Ano he obse a ional s udy, including 19 186 haemodialy- sis pa ien s om a la ge dialysis p o ide [50] ecei ing in a enous i amin D analogues (as a su oga e o he diagno- sis o SHPT), ound ha ea men wi h cinacalce was associ- a ed wi h signi ican educ ions in all-cause and ca dio ascula mo ali y, wi h mo e p onounced su i al bene i s ound in pa ien s wi h SHPT o g ea e se e i y. In a p ospec i ely obse - a ional s udy, Block e al.[50] desc ibed a signi ican su i al bene i associa ed wi h cinacalce p esc ip ion. These obse a- ions and hose o o he s [51,52] led o he de elopmen o a p ospec i e RCT e alua ing he e ec o cinacalce ea men on ca dio ascula mo ali y. The EVOLVE [53] s udy was an RCT ha en olled 3883 haemodialysis pa ien s wi h mode a e o se e e SHPT (median PTH 693 pg/mL) assigned o ecei e cina- calce (n¼1948) o placebo (n¼1935). All pa ien s we e eligible o ecei e con en ional ea men including phospha e binde s and i amin D s e ols. The p ima y composi e endpoin was ime un il dea h, myoca dial in a c ion, hospi aliza ion o uns able angina, hea ailu e o a pe iphe al ascula e en . In an unadjus ed ITT analysis, he p ima y endpoin was eached in 48.2% o pa ien s in he cinacalce g oup and 49.2% in he pla- cebo g oup ( ela i e HR in he cinacalce g oup 0.93; 95% CI 0.85– 1.02; P ¼0.11). A e adjus ing o baseline cha ac e is ics, he ela i e HR o he p ima y composi e endpoin was 0.88 (95% CI 0.79–0.97; P ¼0.008). In ac , despi e andomiza ion, he e was an unexpec ed 1-yea di e ence in age be ween g oups (median age 55 yea s in he cinacalce g oup and 54 yea s in he placebo Old and new calcimime ics |83 Downloaded om h ps://academic.oup.com/ckj/a icle-abs ac /11/1/80/4711103 by Uni e sidade do Po o use on 23 Decembe 2019 g oup). As age is one o he s onges p edic ions o dea h, his di e ence may ha e a ec ed he esul s. Also, he s a is ical powe o he EVOLVE s udy was a ec ed by high a es o ea - men c osso e because o discon inua ion in he cinacalce g oup (d opou ) and use o comme cially a ailable cinacalce in he placebo g oup (d op-in). A p especi ied lag-censo ing analy- sis, in which da a was censo ed 6 mon hs a e pa ien s s opped cinacalce , was pe o med. This analysis ound a signi ican educ ion in he isk o p ima y composi e endpoin (HR 0.85; 95% CI 0.76–0.95; P ¼0.003) and isk o dea h (HR 0.83; 95% CI 0.73–0.96; P ¼0.009) in he cinacalce g oup. Ano he p ede e mined p o ocol analysis compa ed younge (<65 yea s) and olde pa ien s (65 yea s) [54]. Cinacalce educed he isk o dea h and majo ca dio ascula e en s in olde bu no younge pa ien s (HR 0.70; 95% CI 0.60–0.81 o olde subjec s and HR 0.97; 95% CI 0.86–1.09 o younge subjec s). Al hough he p ima y analysis o he EVOLVE ial was nega- i e, p especi ied addi ional analysis showed signi ican educ- ion o he isk o dea h o ca dio ascula ou comes, which sugges s a po en ial bene i o cinacalce . Palme e al. [55] ha e published a me a-analysis o andom- ized ials ha e alua ed he e ec s o calcimime ic he apy on mo ali y and ad e se e en s in adul s wi h CKD. Including 18 ials and a o al o 7446 pa ien s, hey ound ha cinacalce had li le o no e ec on all-cause mo ali y (RR 0.97; 95% CI 0.89–1.05) and an imp ecise e ec on ca dio ascula mo ali y (RR 0.67; 95% CI 0.16–2.87). The esul s o his me a-analysis should be in e p e ed wi h cau ion. Mo e han hal o he pa ien s we e de i ed om he EVOLVE ial and his me a- analysis only included he esul s om p ima y analysis, wi h he po en ial se backs discussed abo e. Also, all o ials included, excep he EVOLVE ial, we e small and no speci i- cally designed o assess clinically ele an ou comes such as mo ali y o ca dio ascula e en s. New calcimime ics: e elcalce ide, a s ep o wa d E elcalce ide is a no el second-gene a ion calcimime ic agen ha was ecen ly app o ed o he ea men o SHPT [13]. E elcalce ide is a eigh amino acid pep ide agonis o CaSR, which binds o CaSR by a co alen disulphide bond ha esul s in he allos e ic ac i a ion o CaSR and consequen ly educes he ci cula ing le els o PTH and calcium [56]. In con as o cinacalce , e elcalce ide unc ions as a di ec agonis o CaSR, sligh ly ac i a ing CaSR e en unde calcium- ee condi ions (Table 3). Howe e , downs eam signalling is s onge in he p esence o calcium; hus, he main ac ion o e elcalce ide is media ed h ough i s e ec s as an allos e ic ac i a o [57]. E elcalce ide has a a ou able pha macokine ic p o ile, wi h a longe elimina ion hal -li e han cinacalce , and hal -li e elim- ina ion ha exceeds 7 days in ESRD pa ien s [58]. I is adminis- e ed in a enously a he end o a haemodialysis session; he plasma concen a ion o e elcalce ide dec eases o e ime bu emains ela i ely cons an om 24 h pos -dose o he nex dialysis session [13]. I is a molecule ha is dialysable du ing haemodialysis and, wi h he doses o e elcalce ide eaching Table 3. Compa ison be ween cinacalce and e elcalce ide Cinacalce E elcalce ide Class Calcimime ic Calcimime ic Yea o app o al (Eu ope) 2004 2016 Mechanism o ac ion In e ac s wi h memb ane-spanning segmen s o CaSR and enhances signal ansduc ion, he eby educing PTH sec e ion Pep ide agonis o he CaSR ha in e ac s wi h and ac i a es he ecep o , he eby educing PTH sec e ion Mode o adminis a ion Daily o al IV a he end o dialysis Hal -li e 30–40 h >7 days Exc e ion Renal (80%), aecal (15%) Renal In e ac ion wi h CYPs Me abolized by CYP3A4, and o a lesse ex en CYP1A2; inhibi s CYP2D6 (cau ion is ad ised when p esc ibing po en ially in e ac ing d ugs) No signi ican in e ac ions Daily dosing (s a ing; maximal) 30–180 mg 2.5–15 mg/dialysis E icacy endpoin s >30% educ ion om baseline in mean se um PTH le el du ing he EAP 63.9 77.9 >50% educ ion om baseline in mean se um PTH du ing he EAP 40 52 (P ¼0.001) Ad e se e ec s Nausea 22.6 18.3 Vomi ing 13.8 13.3 Dia hoea 10.3 6.2 Headache 7.0 6.5 Hype ension 6.7 6.2 Hypo ension 2.9 6.8 Muscle spasms 5.9 6.5 Pain in ex emi y 4.1 5.0 Asymp oma ic hypocalcaemia 59.8 68.9 Symp oma ic hypocalcaemia 2.3 5.0 Values a e exp essed as pe cen age unless indica ed o he wise. EAP, e icacy assessmen phase. 84 | L. Pe ei a e al. Downloaded om h ps://academic.oup.com/ckj/a icle-abs ac /11/1/80/4711103 by Uni e sidade do Po o use on 23 Decembe 2019 be ween 2.5 and 5 mg a he end o a dialysis session, plasma concen a ions o e elcalce ide each s eady-s a e by week 4. Al hough clinical expe ience is o cou se cu en ly limi ed, in i o da a show ha e elcalce ide is no an inhibi o , induce o subs a e o hepa ic cy och ome (CYP) enzymes, no is i an inhibi o o subs a e o common e lux and up ake human anspo p o eins such as P-glycop o ein [59]. Thus, e elcalce- ide is expec ed o ha e a low isk o CYP o anspo e - media ed d ug in e ac ions. The immunogenici y isk o e elcalce ide has been e alua ed [60]. While bo h p eexis ing an i-e elcalce ide an ibodies and hose ha de eloped a e ea men we e de ec ed, no conse- quences ha e been epo ed ega ding he clinical exposu e, e icacy o sa e y o e elcalce ide. Pi o al ials es ing e elcalce ide in he ea men o SHPT we e ecen ly published [61,62]. Two pa allel Phase 3 placebo- con olled ials we e conduc ed in 1023 haemodialysis pa ien s wi h mode a e o se e e hype pa a hy oidism. In a enous adminis a ion o e elcalce ide (n¼503) o placebo (n¼513) a e each haemodialysis session o 26 weeks was pe o med. Pa ien s andomized o e elcalce ide we e signi ican ly mo e likely o achie e he p ima y e icacy endpoin (a educ ion >30% in baseline PTH: 74.0–75.3% in he e elcalce ide g oup e - sus 8.3–9.6% in he placebo g oup). In addi ion, pa ien s andomized o e elcalce ide we e signi ican ly mo e likely o achie e a PTH le el o 300 pg/mL o lowe (49.6–53.3% in he e elcalce ide g oup e sus 4.6–5.1% in he placebo g oup). The median dose o e elcalce ide du ing he e icacy assessmen phase was 5.0 and 7.1 mg, espec i ely. Pa ien s andomized o e elcalce ide we e mo e likely o expe ience subs an ial lowe - ing o FGF-23 despi e mo e equen p o ision o calcium and i amin D. T ea men wi h e elcalce ide dec eased bone- speci ic alkaline phospha ase and collagen Type 1 c oss-linked C- elopep ide. Pa ien s andomized o e elcalce ide had mo e muscle spasms, nausea and omi ing han he placebo g oup. Hypocalcaemia occu ed in 63.8% o pa ien s, bu symp oma ic hypocalcaemia was epo ed in only 7% o pa ien s assigned o e elcalce ide. Simila esul s we e ob ained in a placebo- con olled ial om Japan, which es ed he e icacy and sa e y o e elcalce ide [63]. A andomized double-bind, double-dummy ac i e clinical ial has been conduc ed ha compa ed in a enous e elcalce- ide e sus o al placebo and o al cinacalce e sus in a enous placebo in 683 haemodialysis pa ien s wi h PTH highe han 500 pg/mL [62]. The p ima y e icacy endpoin was non-in e io i y o e elcalce ide a achie ing mo e han a 30% educ ion om baseline in mean p edialysis PTH concen a ion, and seconda y endpoin s included supe io i y in achie ing biochemical Fig. 1. Pa a hy oid ho mone, calcium and phospha e concen a ions in pa ien s ecei ing cinacalce o e elcalce ide. Rep oduced wi h pe mission om Block e al. [62]. Old and new calcimime ics |85 Downloaded om h ps://academic.oup.com/ckj/a icle-abs ac /11/1/80/4711103 by Uni e sidade do Po o use on 23 Decembe 2019 endpoin s (>50% and >30% educ ion in PTH) and sel - epo ed nausea o omi ing. E elcalce ide was no in e io o cinacalce in educing PTH concen a ion and also me supe io c i e ia. The p opo ion o pa ien s who achie ed >30% PTH educ ion was 68.2% in he e elcalce ide g oup and 57.7% in he cinacalce g oup (Figu e 1). The e was also a signi ican di e ence in he p opo ion o pa ien s who achie ed >50% educ ion o PTH. Hypocalcaemia was mo e equen in e elcalce ide g oup (68.9% e sus 59.8%) and he mean numbe o days o omi ing o nau- sea we e no signi ican ly di e en . O e all sa e y and ole abil- i y be ween e elcalce ide and cinacalce we e simila . The e was a nume ically highe numbe o hea ailu e episodes in he e elcalce ide g oup, bu o e all he e en a es we e e y low and simila o hose obse ed in he EVOLVE ial. The e ec o e elcalce ide on FGF-23 le els is also no ewo - hy. E elcalce ide ea men yielded a mo e p onounced educ ion in FGF-23 le els han cinacalce . As discussed abo e, FGF-23 is ele a ed in CKD pa ien s and has been associa ed wi h ad e se ou comes such as le en icula hype ophy and ca diac ailu e. In he EVOLVE ial, a 30% educ ion o FGF-23 le els was associa ed wi h signi ican educ ion o he p ima y composi e endpoin , hea ailu e and dea h [29]. This p omis- ing inding in he e elcalce ide g oup aises he possibili y o a mo e p onounced impac on ca dio ascula ou comes. The e a e some impo an clinical aspec s conside ing he esul s o he ials men ioned abo e ha we wan o highligh . E elcalce ide is supe io o cinacalce in achie ing a educ ion o PTH and FGF-23 concen a ions in ESRD pa ien s; howe e , i also leads o mo e equen episodes o hypocalcaemia. Da a sugges ha his hypocalcaemic e ec could be mo e p o- nounced a he beginning o ea men when PTH is highes . Indeed, in a mul ina ional placebo-con olled ial, he calcium- lowe ing e ec o e elcalce ide was e iden ea ly a e ea - men ini ia ion and eached a nadi by weeks 10–12. This calcium-lowe ing e ec was obse ed despi e inc eased use o o al calcium-con aining binde s and ac i e i amin D ana- logues, and inc eases in dialysa e calcium concen a ion in an impo an p opo ion o pa ien s. This obse a ion aises legi i- ma e conce ns ega ding he possible cumula i e posi i e cal- cium balance. E elcalce ide is gi en a he end o haemodialysis sessions, which imp o es medica ion adhe ence and educes pill bu den. E elcalce ide does no seem o esul in ewe gas- oin es inal symp oms ela ed o calcimime ic ea men despi e in a enous adminis a ion, in con as o wha was p e iously an icipa ed. The nausea and omi ing induced by cinacalce and e elcalce ide appea s o be a sys emic e ec a he han a local gas oin es inal class e ec . Finally, i is emp ing o specula e ha he longe elimina- ion hal -li e o e elcalce ide could lead o mo e s able con ol o biochemical pa ame e s like PTH and calcium phospha e, and ha such a sus ained supp ession o PTH could ansla e in o imp o ed bone u no e and me abolism, dec eased ascula calci ica ion and, ul ima ely, imp o ed ca dio ascula pa ien ou comes. Any impac on such impo an ou comes emains o be iden i ied. Conclusion In conclusion, SHPT is associa ed wi h inc eased bone u no e , isk o ac u es, ascula calci ica ions, and ca dio ascula and all-cause mo ali y. Cinacalce , he i s calcimime ic app o ed o clinical use, e ec i ely educes PTH and imp o es biochemi- cal con ol o mine al and bone diso de s in CKD pa ien s. Howe e , he e ec o cinacalce on ha d ou comes emains o be p o ed. E elcalce ide, a new second-gene a ion calcimime ic, is supe io o cinacalce in achie ing he educ ion o PTH and FGF-23 concen a ions in ESRD pa ien s, bu also leads o mo e equen episodes o hypocalcaemia ha could be mo e p o- nounced a beginning o ea men . E elcalce ide is gi en a he end o haemodialysis sessions, which imp o es medica ion adhe ence and educes pill bu den. Howe e , e elcalce ide does no seem o cause ewe gas oin es inal symp oms despi e in a enous adminis a ion. In ou iew, e elcalce ide ep esen s a signi ican ad ance in he ea men o SHPT, ia be e con ol o PTH and FGF-23 le - els and imp o ed adhe ence. Howe e , whe he his imp o ed biochemical con ol ansla es in o imp o ed clinical ou comes such as bone ac u e a e and ca dio ascula mo bidi y and mo ali y emains o be elucida ed by p ospec i e andomized ials. Con lic s o in e es s a emen None decla ed. Re e ences 1. Jha V, Ga cia-Ga cia G, Iseki K e al. Ch onic kidney disease: global dimension and pe spec i es. Lance 2013; 382: 260–272 2. KDIGO clinical p ac ice guideline o he diagnosis, e alua- ion, p e en ion, and ea men o Ch onic Kidney Disease- Mine al and Bone Diso de (CKD-MBD). Kidney In Suppl 2009; 113: S1–S130 3. Diniz H, F azao JM. The ole o ib oblas g ow h ac o 23 in ch onic kidney disease-mine al and bone diso de . Ne ologia 2013; 33: 835–844 4. Kalan a -Zadeh K, Kuwae N, Regido DL e al. Su i al p e- dic abili y o ime- a ying indica o s o bone disease in main enance hemodialysis pa ien s. Kidney In 2006; 70: 771–780 5. Ten o i F, Wang M, Biebe BA e al. Recen changes in he a- peu ic app oaches and associa ion wi h ou comes among pa ien s wi h seconda y hype pa a hy oidism on ch onic hemodialysis: he DOPPS s udy. Clin J Am Soc Neph ol 2015; 10: 98–109 6. Danese MD, Beloze o V, Smi nakis K e al. Consis en con- ol o mine al and bone diso de in inciden hemodialysis pa ien s. Clin J Am Soc Neph ol 2008; 3: 1423–1429 7. Rod iguez M, Goodman WG, Liakopoulos V e al. The use o calcimime ics o he ea men o seconda y hype pa a- hy oidism: a 10 yea e idence e iew. Semin Dial 2015; 28: 497–507 8. Ha ing on PE, Fo sch C. Calcium sensing ecep o ac i a- o s: calcimime ics. Cu Med Chem 2007; 14: 3027–3034 9. S Pe e WL, Li Q, Liu J e al. Cinacalce use pa e ns and e ec on labo a o y alues and o he medica ions in a la ge dialy- sis o ganiza ion, 2004 h ough 2006. Clin J Am Soc Neph ol 2009; 4: 354–360 10. F azao J, Rod iguez M. Seconda y hype pa a hy oidism dis- ease s abiliza ion ollowing calcimime ic he apy. NDT Plus 2008; 1: i12–i17 11. Lindbe g JS, Culle on B, Wong G e al. Cinacalce HCl, an o al calcimime ic agen o he ea men o seconda y hype pa - a hy oidism in hemodialysis and pe i oneal dialysis: a andomized, double-blind, mul icen e s udy. J Am Soc Neph ol 2005; 16: 800–807 86 | L. Pe ei a e al. Downloaded om h ps://academic.oup.com/ckj/a icle-abs ac /11/1/80/4711103 by Uni e sidade do Po o use on 23 Decembe 2019 12. Block GA, Ma in KJ, de F ancisco AL e al. Cinacalce o sec- onda y hype pa a hy oidism in pa ien s ecei ing hemo- dialysis. N Engl J Med 2004; 350: 1516–1525 13. Blai HA. E elcalce ide: i s global app o al. D ugs 2016; 76: 1787–1792 14. Goodman WG, Hladik GA, Tu ne SA e al. The Calcimime ic agen AMG 073 lowe s plasma pa a hy oid ho mone le els in hemodialysis pa ien s wi h seconda y hype pa a hy oid- ism. J Am Soc Neph ol 2002; 13: 1017–1024 15. Moe SM, Che ow GM, Cobu n JW e al. Achie ing NKF-K/ DOQI bone me abolism and disease ea men goals wi h cinacalce HCl. Kidney In 2005; 67: 760–771 16. S ippoli GF, Palme S, Tong A e al. Me a-analysis o bio- chemical and pa ien -le el e ec s o calcimime ic he apy. Am J Kidney Dis 2005; 47: 715–726 17. S ubbs JR, We mo e JB. Does i ma e how pa a hy oid ho - mone le els a e supp essed in seconda y hype pa a hy oid- ism? Semin Dial 2011; 24: 298–306 18. Komaba H, Nakanishi S, Fujimo i A e al. Cinacalce e ec- i ely educes pa a hy oid ho mone sec e ion and gland ol- ume ega dless o p e ea men gland size in pa ien s wi h seconda y hype pa a hy oidism. Clin J Am Soc Neph ol 2010; 5: 2305–2314 19. Isako a T, Xie H, Yang W e al. Fib oblas g ow h ac o 23 and isks o mo ali y and end-s age enal disease in pa ien s wi h ch onic kidney disease. JAMA 2011; 305: 2432–2439 20. Flise D, Kolle i s B, Neye U e al. Fib oblas g ow h ac o 23 (FGF23) p edic s p og ession o ch onic kidney disease: he Mild o Mode a e Kidney Disease (MMKD) S udy. J Am Soc Neph ol 2007; 18: 2600–2608 21. Nas allah MM, El-Shehaby AR, Salem MM e al. Fib oblas g ow h ac o -23 (FGF-23) is independen ly co ela ed o ao ic calci ica ion in haemodialysis pa ien s. Neph ol Dial T ansplan 2010; 25: 2679–2685 22. Gu ie ez OM, Januzzi JL, Isako a T e al. Fib oblas g ow h ac o 23 and le en icula hype ophy in ch onic kidney disease. Ci cula ion 2009; 119: 2545–2552 23. Seile S, Reicha B, Ro h D e al. FGF-23 and u u e ca dio as- cula e en s in pa ien s wi h ch onic kidney disease be o e ini ia ion o dialysis ea men . Neph ol Dial T ansplan 2010; 25: 3983–3989 24. Nakano C, Hamano T, Fujii N e al. In ac ib oblas g ow h ac o 23 le els p edic inciden ca dio ascula e en be o e bu no a e he s a o dialysis. Bone 2012; 50: 1266–1274 25. Kim HJ, Kim H, Shin N e al. Cinacalce lowe ing o se um ib oblas g ow h ac o -23 concen a ion may be independ- en om se um Ca, P, PTH and dose o ac i e i amin D in pe i oneal dialysis pa ien s: a andomized con olled s udy. BMC Neph ol 2013; 14: 112 26. Fishbane S, Shapi o WB, Co y DB e al. Cinacalce HCl and concu en low-dose i amin D imp o es ea men o sec- onda y hype pa a hy oidism in dialysis pa ien s compa ed wi h i amin D alone: he ACHIEVE s udy esul s. Clin J Am Soc Neph ol 2008; 3: 1718–1725 27. We mo e JB, Liu S, K ebill R e al. E ec s o cinacalce and concu en low-dose i amin D on FGF23 le els in ESRD. Clin J Am Soc Neph ol 2010; 5: 110–116 28. Kucze a, P, Adamczak M, Wiecek A. Cinacalce ea men dec eases plasma ib oblas g ow h ac o 23 concen a ion in haemodialysed pa ien s wi h ch onic kidney disease and seconda y hype pa a hy oidism. Clin Endoc inol (Ox ) 2014; 80: 607–612 29. Moe SM, Che ow, GM, Pa ey PS. Cinacalce , ib oblas g ow h ac o -23, and ca dio ascula disease in hemodialy- sis: he E alua ion O Cinacalce HCl The apy To Lowe Ca dio ascula E en s (EVOLVE) T ial. Ci cula ion 2015; 132: 27–39 30. Nickolas TL, McMahon DJ, Shane E. Rela ionship be ween mode a e o se e e kidney disease and hip ac u e in he Uni ed S a es. J Am Soc Neph ol 2006; 17: 3223–3232 31. Kaji H, Suzuki M, Yano S e al. Risk ac o s o hip ac u e in hemodialysis pa ien s. Am J Neph ol 2002; 22: 325–331 32. Ten o i F, McCullough K, Kilpa ick RD e al. High a es o dea h and hospi aliza ion ollow bone ac u e among hemodialysis pa ien s. Kidney In 2014; 85: 166–173 33. Malluche HH, Po e DS, Monie -Fauge e MC. Di e ences in bone quali y in low- and high- u no e enal os eodys o- phy. J Am Soc Neph ol 2012; 23: 525–532 34. Iimo i S, Mo i Y, Aki a W e al. Diagnos ic use ulness o bone mine al densi y and biochemical ma ke s o bone u no e in p edic ing ac u e in CKD s age 5D pa ien s—a single- cen e coho s udy. Neph ol Dial T ansplan 2012; 27: 345–351 35. Cunningham J, Danese M., Olson K. E ec s o he calcimi- me ic cinacalce HCl on ca dio ascula disease, ac u e, and heal h- ela ed quali y o li e in seconda y hype pa a- hy oidism. Kidney In 2005; 68: 1793–1800 36. Moe SM, Abdalla S, Che ow GM e al. E ec s o cinacalce on ac u e e en s in pa ien s ecei ing hemodialysis: he EVOLVE T ial. J Am Soc Neph ol 2015; 26: 1466–1475 37. Malluche HH, Monie -Fauge e MC, Wang G e al. An assess- men o cinacalce HCl e ec s on bone his ology in dialysis pa ien s wi h seconda y hype pa a hy oidism. Clin Neph ol 2008; 69: 269–278 38. Behe s GJ, Spaso ski G, S e ling LR e al. Bone his omo ph- ome y be o e and a e long- e m ea men wi h cinacalce in dialysis pa ien s wi h seconda y hype pa a hy oidism. Kidney In 2015; 87: 846–856 39. Ke ele M, Block GA, E enepoel P e al. Execu i e summa y o he 2017 KDIGO Ch onic Kidney Disease-Mine al and Bone Diso de (CKD-MBD) Guideline Upda e: wha ’s changed and why i ma e s. Kidney In 2017; 92: 26–36 40. Tsu u a Y, Okano K, Kikuchi K e al. E ec s o cinacalce on bone mine al densi y and bone ma ke s in hemodialysis pa ien s wi h seconda y hype pa a hy oidism. Clin Exp Neph ol 2013; 17: 120–126 41. Lien YH, Sil a AL, Whi man D. E ec s o cinacalce on bone mine al densi y in pa ien s wi h seconda y hype pa a hy - oidism. Neph ol Dial T ansplan 2005; 20: 1232–1237 42. Mi sopoulos E, Ginikopoulou E, Economidou D e al. Impac o long- e m cinacalce , iband ona e o e ipa a ide he apy on bone mine al densi y o hemodialysis pa ien s: a pilo s udy. Am J Neph ol 2012; 36: 238–244 43. Nakayama K, Nakao K, Taka o i Y e al. Long- e m e ec o cinacalce hyd ochlo ide on abdominal ao ic calci ica ion in pa ien s on hemodialysis wi h seconda y hype pa a hy - oidism. In J Neph ol Reno asc Dis 2013; 7: 25–33 44. Tsu u a Y, Ohbayashi T, Fujii M e al. Change in co ona y a e y calci ica ion sco e due o cinacalce hyd ochlo ide adminis a ion. The Aphe Dial 2008; 12: S34–S37 45. Raggi, P, Che ow GM, To es PU e al. The ADVANCE s udy: a andomized s udy o e alua e he e ec s o cinacalce plus low-dose i amin D on ascula calci ica ion in pa ien s on hemodialysis. Neph ol Dial T ansplan 2011; 26: 1327–1339 46. U ena-To es PA, Floege J, Hawley CM e al. P o ocol adhe - ence and he p og ession o ca dio ascula calci ica ion in Old and new calcimime ics |87 Downloaded om h ps://academic.oup.com/ckj/a icle-abs ac /11/1/80/4711103 by Uni e sidade do Po o use on 23 Decembe 2019 he ADVANCE s udy. Neph ol Dial T ansplan 2013; 28: 146–152 47. Block GA, Klassen PS, Laza us JM. Mine al me abolism, mo - ali y, and mo bidi y in main enance hemodialysis. J Am Soc Neph ol 2004; 15: 2208–2218 48. Floege J, Kim J, I eland E e al. Se um iPTH, calcium and phos- pha e, and he isk o mo ali y in a Eu opean haemodialysis popula ion. Neph ol Dial T ansplan 2011; 26: 1948–1955 49. Gu ie ez OM, Manns ad M, Isako a T e al. Fib oblas g ow h ac o 23 and mo ali y among pa ien s unde going hemodialysis. N Engl J Med 2008; 359: 584–592 50. Block GA, Zaun D, Smi s G e al. Cinacalce hyd ochlo ide ea men signi ican ly imp o es all-cause and ca dio ascu- la su i al in a la ge coho o hemodialysis pa ien s. Kidney In 2010; 78: 578–589 51. Akizawa T, Ku i a N, Mizobuchi M e al. PTH-dependence o he e ec i eness o cinacalce in hemodialysis pa ien s wi h seconda y hype pa a hy oidism. Sci Rep 2016; 6: 19612 52. Gillespie IA, Floege J, Gioni I e al. P opensi y sco e ma ching and pe sis ence co ec ion o educe bias in compa a i e e ec i eness: he e ec o cinacalce use on all-cause mo - ali y. Pha macoepidemiol D ug Sa 2015: 24: 738–747 53. Che ow GM, Block GA, Co ea-Ro e R e al. E ec o cina- calce on ca dio ascula disease in pa ien s unde going dial- ysis. N Engl J Med 2012: 367: 2482–2494 54. Pa ey PS, D ueke TB, Block GA e al. The e ec s o cinacal- ce in olde and younge pa ien s on hemodialysis: The E alua ion o Cinacalce HCl The apy o Lowe Ca dio ascula E en s (EVOLVE) T ial. Clin J Am Soc Neph ol 2015; 10: 791–799 55. Palme SC, Nis o I, C aig JC e al. Cinacalce in pa ien s wi h ch onic kidney disease: a cumula i e me a-analysis o andomized con olled ials. PLoS Med 2013; 10: e1001436 56. Alexande ST, Hun e T, Wal e S e al. C i ical cys eine esi- dues in bo h he calcium-sensing ecep o and he allos e ic ac i a o amg 416 unde lie he mechanism o ac ion. Mol Pha macol 2015; 88: 853–865 57. Wal e S, Ba uch A, Dong J e al. Pha macology o AMG 416 (Velcalce ide), a no el pep ide agonis o he calcium- sensing ecep o , o he ea men o seconda y hype pa a- hy oidism in hemodialysis pa ien s. J Pha macol Exp The 2013, 346: 229–240 58. Chen P, Melhem M, Xiao J e al. Popula ion pha macokine ics analysis o AMG 416, an allos e ic ac i a o o he calcium- sensing ecep o , in subjec s wi h seconda y hype pa a hy - oidism ecei ing hemodialysis. J Clin Pha macol 2015; 55: 620–628 59. Sub amanian R, Zhu X, Ke SJ e al. Nonclinical pha macoki- ne ics, disposi ion, and d ug-d ug in e ac ion po en ial o a no el d-amino acid pep ide agonis o he calcium-sensing ecep o AMG 416 (e elcalce ide). D ug Me ab Dispos 2016; 44: 1319–1331 60. K oenke MA, Wee a a ne DK, Deng H e al. Clinical immuno- genici y o he d-amino acid pep ide he apeu ic e elcalce- ide: me hod de elopmen challenges and an i-d ug an ibody clinical impac assessmen s. J Immunol Me hods 2017; 445: 37–44 61. Block GA, Bushinsky DA, Cunningham J e al. E ec o e el- calce ide s placebo on se um pa a hy oid ho mone in pa ien s ecei ing hemodialysis wi h seconda y hype pa a- hy oidism: wo andomized clinical ials. JAMA 2017; 317: 146–155 62. Block GA, Bushinsky DA, Cheng S e al. E ec o e elcalce ide s cinacalce on se um pa a hy oid ho mone in pa ien s ecei ing hemodialysis wi h seconda y hype pa a hy oid- ism: a andomized clinical ial. JAMA 2017; 317: 156–164 63. Fukagawa M, Yokoyama K, Shigema su T e al. A Phase 3, mul icen e, andomized, double-blind, placebo-con olled, pa allel-g oup s udy o e alua e he e icacy and sa e y o e elcalce ide (ONO-5163/AMG 416), a no el in a enous cal- cimime ic, o seconda y hype pa a hy oidism in Japanese haemodialysis pa ien s. Neph ol Dial T ansplan 2017; 32: 1723–1730 88 | L. Pe ei a e al. Downloaded om h ps://academic.oup.com/ckj/a icle-abs ac /11/1/80/4711103 by Uni e sidade do Po o use on 23 Decembe 2019