Severe Symptomatic Hypocalcemia after Denosumab Administration in an End-Stage Renal Disease Patient on Peritoneal Dialysis with Controlled Secondary Hyperparathyroidism

___________________________________________________________________________________________ *Co esponding au ho : Email: maga [email protected]; B i ish Jou nal o Medicine & Medical Resea ch 3(4): 1398-1406, 2013 SCIENCEDOMAIN in e na ional www.sciencedomain.o g Se e e Symp oma ic Hypocalcemia a e Denosumab Adminis a ion in an End-S age Renal Disease Pa ien on Pe i oneal Dialysis wi h Con olled Seconda y Hype pa a hy oidism Mohi Aga wal 1* , É a Csong ádi 1,2 , Ch is ian A. Koch 1 , Luis A. Juncos 1 , Vonda Echols 1 , Mihály Tapolyai 3 and Tibo Fülöp 1 . 1 Depa men o Medicine, Uni e si y o Mississippi Medical Cen e , Jackson, MS, USA. 2 Depa men o Medicine, Medical and Heal h Science Cen e Uni e si y o Deb ecen, Hunga y. 3 F esenius Medical Ca e, Semmelweis Uni e si y, Budapes , Hunga y. Au ho s’ con ibu ions This wo k was ca ied ou in collabo a ion be ween all au ho s. Au ho s TF and MA designed and w o e mos o he case epo . Au ho s MA and VE collec ed he da a. Au ho MA, TF, MT and ÉC managed he li e a u e sea ches. Au ho s CAK, ÉC, MT and LAJ p o ided in ellec ual inpu s. All au ho s ead and app o ed he inal manusc ip . Recei ed 31 s Decembe 2012 Accep ed 17 h Ma ch 2013 Published 23 d Ap il 2013 ABSTRACT We epo he 1 s case o se e e, symp oma ic hypocalcemia a e denosumab (RANKL inhibi o ) ea men in a pe i oneal dialysis pa ien wi h seconda y hype pa a hy oidism and os eopo osis. A 58-yea -old Caucasian emale has been ecei ing ch onic ambula o y pe i oneal dialysis o ou yea s seconda y o polycys ic kidney disease. Labo a o y s udies e ealed: albumin-co ec ed calcium 9.0 mg/dL, phospho us 5 mg/dL, alkaline phospha ase (ALP) 58 U/L [no mal, 40-105], albumin 3.4 gm/dL [no mal, 3.6-5.4] and in ac pa a hy oid ho mone (PTH) 315 pg/mL [no mal, 40-72]. Ma ked os eopo osis was no ed on he DXA scan, p e en ing he om enal ansplan a ion conside a ions. She had ailed con en ional medical ea men , including pe os calcium, mon hly e gocalci e ol (50,000 uni s/mon h), ac i a ed i amin-D analog (doxe calci e ol) and Case S udy B i ish Jou nal o Medicine & Medical Resea ch, 3(4): 1398-1406, 2013 1399 enal- ailu e adjus ed alend ona e (70 mg wice a mon h). She was s a ed on subcu aneous denosumab 60 mg e e y 6 mon hs. A e he i s dose, she de eloped a p og essi e d op o calcium, phospho us, bica bona e and magnesium, in spi e o massi e escala ion o doxe calci e ol and calcium supplemen a ion. Hypocalcemia nadi ed a 6.3 mg/dL wi h symp oma ic e any, equi ing a b ie hospi aliza ion app oxima ely 7 weeks a e denosumab ea men . He ele a ed PTH ose u he ansien ly (647 pg/mL), along wi h ALP (123 U/L). Bone-mine al pa ame e s no malized app oxima ely 3 mon hs a e denosumab adminis a ion. The obse ed phenomenon esembled he pheno ype o “hung y bone synd ome” obse ed a e su gical pa a hy oidec omy. Conclusion: T ea men decisions based on bone densi ome y esul s alone a e no ansposable be ween pa ien s wi h o wi hou end-s age enal disease. Denosumab may lead o c i ical hypocalcemia in dialysis pa ien s and u he agg a a e exis ing seconda y hype pa a hy oidism. Keywo ds: Denosumab; end-s age enal disease; hung y bone synd ome; hypocalcemia; os eopo osis; RANK ligand inhibi o ; e any. 1. INTRODUCTION Bisphosphona es bind bone mine als and a e abso bed by ma u e os eoclas s, inducing os eoclas apop osis and supp essing eso p ion [1,2]. Due o he po en ial enal oxici y o bisphosphona es, he e has been some in e es in he use o denosumab, a ecep o ac i a o o nuclea ac o (NF-κB) ligand (RANKL) inhibi o o ea men o os eopo osis in pa ien s wi h enal impai men . Un il ecen ly, denosumab, as pe he manu ac u e 's ins uc ions, did no equi e dosage adjus men s o enal impai men [3]. Published expe ience o he use o denosumab in end-s age enal disease (ESRD) is, howe e , e y scan . One p elimina y s udy o 8 hemodialysis pa ien s [4] and ano he case epo ha e aised conce ns abou se e e hypocalcemia in hemodialysis pa ien s [5]. We epo he 1 s case o se e e symp oma ic hypocalcemia seconda y o denosumab in a pe i oneal dialysis- dependen pa ien wi h con olled seconda y hype pa a hy oidism. 2. CASE STUDY Ou index pa ien was a 58-yea -old Caucasian emale wi h end-s age enal disease (ESRD) seconda y o polycys ic kidney, who had been on ch onic ambula o y pe i oneal dialysis (CAPD) o 4 yea s and doing well on enal eplacemen he apy, excep o a p og essi e heigh loss. A dual-ene gy x- ay abso p iome y (DXA) scan was ob ained in Augus o 2011, e ealing signi ican os eopo osis (Table. 2). She denied a p io his o y o os eopo osis o any ac u e. Excep o con inued obacco abuse, she denied isk ac o s such as glucoco icoid use, seizu e medica ions o a amily his o y o os eopo osis. She had been on a i amin D supplemen 50,000 In e na ional Uni s once a mon h and was p e iously on o e - he coun e calcium-ca bona e as phospho us binde ; howe e , she de eloped ansien hype calcemia and calcium ca bona e was discon inued. She was placed on alend ona e (Fosamax®) which she had been aking wi hou any di icul y. B i ish Jou nal o Medicine & Medical Resea ch, 3(4): 1398-1406, 2013 1400 Table 1. Changes o bone-mine al me abolism pa ame e s a e denosumab adminis a ion Da e (Days Since Denosumab dosage) 04/10/12 (-73) 06/21/12 (-1) 07/26/12 (34) 08/14/12 (53) 08/23/12 (62) 09/11/12 (81) 10/09/12 (109) 11/01/12 (132) 12/06/12 (167) Re . Range Calcium 9.2 8.5 6.9 6.6 9.6 10.0 8.9 9.7 9.3 8.2-10.1 mg /dL Calcium (Adjus ed o albumin) 9.5 9.0 7.4 7.0 10.6 9.5 10.3 9.8 8.2-10.1 mg/dL Phospho us 5.0 5.0 3.4 4.6 2.6 4.2 5.7 7.5 7.6 2.5-5.0 mg/dL Alkaline Phospha ase 58 85 123 122 62 50 43 40-105 IU/L iPTH 315 647 117 14-72 pg/mL Table 2. DXA esul s summa y (Augus 2011) Region A ea (cm 2 ) BMC (g) BMD (g/cm 2 ) T - sco e Z - sco e Neck 5.27 2.53 0.480 -3.3 -2.2 To al 32.05 20.68 0.645 -2.4 -1.7 L1 13.38 8.79 0.657 -3.0 -2.0 L2 14.24 9.48 0.666 -3.3 -2.1 L3 16.94 12.42 0.734 -3.2 -2.0 L4 16.09 10.52 0.654 -3.7 -2.4 To al 60.65 41.22 0.680 -3.3 -2.1 B i ish Jou nal o Medicine & Medical Resea ch, 3(4): 1398-1406, 2013 1401 Howe e , she no ed u he heigh loss o e he ensuing mon hs and was also ejec ed by he enal ansplan eam, ci ing he se e e os eopo osis uling ou conside a ions o enal ansplan eligibili y. Co-mo bid issues associa ed wi h he ESRD included seconda y hype pa a hy oidism and hype phospha emia, enal anemia wi h unc ional i on de iciency and ch onic hypoalbuminemia and hypokalemia associa ed wi h pe i oneal dialysis. O he co-mo bidi ies included a p io ce eb o ascula acciden wi h no esidual de ici , well- con olled hype ension, alle gic hini is, ch onic anxie y, his o y o colonic polyps and a e io enous mal o ma ions and i amin-D de iciency equi ing eplacemen . Fo ch onic me abolic acidosis, she was aking po assium-ci a e on a long- e m basis. Fig. 1. Calcium, adjus ed calcium and phospho us changes a e denosumab adminis a ion. Denosumab ini ia ed on day '0', alend ona e discon inued on day '-31' (31 days p io o denosumab ini ia ion) In e ms o ESRD, she had done easonably well on a CAPD egimen o 2 li e s x 4 exchanges wi h 1.5% dex ose solu ion. Re u n olumes we e always sa is ac o y, esul ing in a ne ul a il a ion o 300-800 mL pe exchange. Comp ehensi e dialysis low shee s e ealed excellen K /V’s be ween 2.2-2.8 pe week bu a p og essi e loss o c ea inine clea ance o e he yea s, mos ecen ly 52 L/week/1.73 m 2 . He esidual u ine ou pu was e y limi ed (30-40 mL/day) and con ibu ed li le o he o e all clea ance. Labo a o y s udies (Table. 1) a baseline e ealed: albumin-co ec ed calcium 9.0 mg/dL, phospho us 5 mg/dL, alkaline phospha ase (ALP) 58 U/L [no mal, 40-105], albumin 3.4 gm/dL [no mal, 3.6-5.4] and in ac pa a hy oid ho mone (PTH) 315 pg/mL [no mal, 40-72]. The 25-hyd oxy i amin-D le el was no mal a 31.3 ng/ml [no mal, 20-100], 1,25 di-hyd oxy Vi amin D was 25 pg/mL [no mal, 18-78]. Fou yea s ea lie , se um p o ein and u ine elec opho esis e ealed only non-selec i e p o einu ia and no e idence o mul iple B i ish Jou nal o Medicine & Medical Resea ch, 3(4): 1398-1406, 2013 1402 myeloma. Baseline medica ions included doxe calci e ol (2.5 mcg wice weekly), se elame (2400 mg TID wi h meals and 1600 mg a bed ime), e gocalci e ol (50,000 IU once a mon h) and alend ona e (70 mg wice a mon h). Rheuma ology consul an s ecommended o discon inue he alend ona e and o s a denosumab e e y 6 mon hs. The i s dose was gi en on 06/22/12 along wi h ins uc ions o ake daily o e - he-coun e 500 mg calcium ca bona e. A e he i s dose, she de eloped a p og essi e d op o calcium (Fig. 1), phospho us, bica bona e and magnesium, in spi e o massi e escala ion o bioac i e i amin-D analog and calcium supplemen a ion (calcium ace a e 2001 mg (elemen al calcium 507 mg) h ee imes daily, calcium ca bona e 2250 mg a bed ime (elemen al calcium 898.2 mg), doxe calci e ol 2.5 mcg daily) and inc eased calcium con en o pe i oneal luid o 3.0 mEq/L. Wi h p og essi e hypocalcemia, calcium d opped o 6.3 mg/dL, wi h symp oma ic e any equi ing a b ie hospi aliza ion locally app oxima ely 7 weeks a e denosumab ea men . As expec ed, PTH ose ansien ly du ing his pe iod (647 pg/mL), along wi h ALP (123 U/L). A e a sho pe iod o ansien hype calcemia, bone-mine al pa ame e s, including calcium, phospho us and ALP no malized app oxima ely 3 mon hs a e denosumab adminis a ion. Inciden ally, she had an episode o back pain a e sudden je king mo emen s o he ex emi ies and o so in July 2012 leading o an x- ay in es iga ion (8/14/12) showing igh supe io and in e io pubic ami ac u es which demons a ed healing on ollow-up X- ays. 3. DISCUSSION Denosumab is he i s Fede al D ug Adminis a ion (FDA) app o ed RANK Ligand inhibi o . As P olia® (Thousand Oaks, CA, USA), i was ini ially app o ed in June 2010 o ea men o pos menopausal os eopo osis wi h high isk o ac u es. This app o al was based on a h ee-yea , andomized, double-blind, placebo-con olled ial o 7,808 os eopo o ic pos menopausal women ages 60 o 91 yea s (F ac u e Reduc ion E alua ion o Denosumab in Os eopo osis E e y 6 Mon hs o FREEDOM S udy), in which denosumab educed he incidence o e eb al, non- e eb al, and hip ac u es [6]. Indica ions since hen ha e been expanded o include inc easing bone mass in pa ien s a high isk o ac u e ecei ing and ogen dep i a ion he apy o non-me as a ic p os a e cance o adju an a oma ase inhibi o he apy o b eas cance (App o al Sep embe 2011), and o inc ease bone mass in men wi h os eopo osis a high isk o ac u e (App o al Sep embe 2012). As Xge a®, Denosumab is also app o ed o p e en ion o skele al- ela ed e en s in pa ien s wi h bone me as ases om solid umo s wi h he excep ion o Mul iple Myeloma (App o al No embe 2010). Os eoclas di e en ia ion ac o , also called ecep o ac i a o o nuclea ac o (NF-κB) ligand (RANKL), s imula es he di e en ia ion o os eoclas p ogeni o s in o os eoclas s. Os eop o ege in ac s as a na u al soluble decoy ecep o o bind RANKL and hus, educing RANKL binding o RANK and educing bone eso p ion. Denosumab is a ull leng h human monoclonal an ibody o IgG2 sub ype mimicking he ac ion o na u al os eop o ege in by binding o and inhibi ing RANKL. I exhibi s a nonlinea , dose dependen pha macokine ics a e subcu aneous injec ion, wi h le els peaking in 7-21 days [7]. As expec ed o an IgG an ibody, i is no clea ed by he kidneys and, he e o e, does no equi e dosage adjus men s o enal impai men [4]. Denosumab adminis a ion esul s in apid and sus ained dec ease o ma ke s o bone eso p ion; in one s udy, an 85% educ ion in se um C- elopep ide o ype I collagen (a bone eso p ion ma ke e lec ing os eoclas ac i i y) was seen in 3 days, wi h a peak educ ion in one mon h [3]. The e o e, his po en and long las ing e ec on bone emodeling aises he conce ns o hypocalcemia. This was clinically no ed in he FREEDOM ial in which wi hin one mon h, 1.7% o subjec s om he d ug a m B i ish Jou nal o Medicine & Medical Resea ch, 3(4): 1398-1406, 2013 1403 expe ienced calcium alues below 8.5 mg/dl as opposed o 0.4% in he placebo a m [6,8]. I should be no ed ha in he FREEDOM T ial, only 73 women had a calcula ed c ea inine clea ance 15 o 29 mL/min and none had end-s age enal dys unc ion (< 15 mL/min) and, he e o e, i was unde powe ed o s udy he hypocalcemic e ec s o denosumab in se e e CKD o e minal enal ailu e [9]. In pa ien s wi h no mal kidney unc ion, nadi in se um calcium is no ed on day 10 [3]. This hypocalcemic e ec appea s o be mo e p onounced in pa ien s wi h enal insu iciency. In he FREEDOM Ex ension s udy o 4,550 subjec s, a mo e ma ked educ ion in se um calcium was no ed in subjec s wi h enal insu iciency: -5.5% educ ion in mean se um calcium in subjec s wi h c ea inine clea ance < 30 mL/min s. - 3.1% in subjec s wi h c ea inine clea ance ≥ 30 mL/min a app oxima ely day 10 [3,10]. In ano he s udy o 55 pa ien s wi h a ious deg ees o enal impai men , se e e and pe sis en hypocalcemia was no ed in subjec s wi h se e e CKD (GFR <30 mL/min/1.73 m 2 ), which was especially p o ound wi h kidney ailu e equi ing hemodialysis. 5 ou o 8 dialysis dependen pa ien de eloped hypocalcemia (se um calcium < 8 mg/dL) and calcium d opped below 7.5 mg/dL in 2 o hem [4]. Addi ionally, McCo mick e al. also ecen ly epo ed a case o se e e hypocalcemia wi h denosumab in a hemodialysis pa ien [5]. In e es ingly, a ecen case epo men ioned success ul ea men o immobiliza ion- ela ed hype calcemia wi h denosumab in a pa ien wi h ad anced enal insu iciency [11]. In a boy wi h ib ous dysplasia, denosumab did no impai healing o a emo al ac u e ha occu ed while on ea men du ing which, simila o ou case p esen ed he e, seconda y hype pa a hy oidism de eloped [12]. Clinical expe ience hus a sugges s ha denosumab can esul in a apid and sus ained educ ion in se um calcium in he p esence o se e e enal insu iciency o enal ailu e. This e ec may be mo e p onounced in pa ien s wi h a his o y o seconda y hype pa a hy oidism, pe haps as a unc ion o a la ge os eoblas mass in hese pa ien s. Inhibi ion o os eoclas ic ac i i y by denosumab may esul in excess unopposed os eoblas ic ac i i y and esul an se e e sus ained hypocalcemia, analogous o wha we obse e as “hung y bone synd ome” a e su gical pa a hy oidec omy [13,14]. This sus ained hypocalcemia can also ( u he ) ele a e PTH and agg a a e exis ing seconda y hype pa a hy oidism. O no e, ou pa ien wi h exis ing seconda y hype pa a hy oidism had p e iously been ea ed wi h a bisphosphona e (alend ona e) be o e denosumab had been adminis e ed while 1,25- dihyd oxy i amin D and 25-OH i amin D le els we e wi hin no mal ange, possibly sugges ing an addi i e e ec o bo h an i eso p i e agen s. Ou pa ien had PTH in he a ge ange, no mal calcium and i amin D le els a baseline, and was al eady ecei ing calcium supplemen a ion and ac i a ed i amin D analog (doxe calci e ol) o seconda y hype pa a hy oidism. While hypocalcemia was expec ed, he magni ude and he leng h o he p ocess we e ce ainly su p ising o us. O no e, Heal h Canada placed a hypocalcemia ale on denosumab in June o 2012 (h p://www.hc-sc.gc.ca/dhp-mps/mede /ad iso ies- a is/public/_2012/xge a_pc-cp-eng.php). Addi ionally, he manu ac u e (Amgen) also issued addi ional wa ning in he US in Sep embe o 2012 (h p://www.p oliahcp.com/pd /dea _heal hca e_p o essional_le e .pd ), including indica ing he isk o se e e hypocalcemia. Ou pa ien was ea ed o p esumed os eopo osis wi h denosumab pe ecommenda ion by he Rheuma ologis on he basis o an abno mal DXA scan. As opposed o non-CKD pa ien s in whom os eopo osis is he p edominan cause o bone disease and ac u es, enal os eodys ophy is a he e ogenous diso de . S anda d imaging diagnos ic c i e ia o os eopenia/os eopo osis de eloped o use wi h he gene al popula ion a e some imes ex apola ed o pa ien s wi h ad anced CKD wi h less han sa is ac o y esul s. Bone mine al densi y (BMD) ob ained om he widely used es DXA scan is a p ime example. A low bone B i ish Jou nal o Medicine & Medical Resea ch, 3(4): 1398-1406, 2013 1404 densi y no iced on DXA is ou inely labeled as os eopenia/os eopo osis based upon Wo d Heal h O ganiza ion (WHO) de ini ions, bu i may be oo simple o a label o a pa ien wi h ad anced CKD [15,16]. DXA scan is a wo-dimensional p ojec ion ha indi ec ly ep esen s BMD h ough X- ay abso p ion and as h ee-dimensional s uc u es a e in isible, his imaging modali y canno dis inguish be ween a ully mine alized po ous bone and an unde mine alized bone wi h less po osi y. Fu he , DXA scans ha e no been alida ed o be a eliable es in dialysis ela ed, o seconda y hype pa a hy oidism- ela ed bone disease [17]. Disease spec um in hese pa ien s can a y om a high u no e disease wi h ue seconda y hype pa a hy oidism o a low u no e s a es wi h adynamic bone disease and he co ec diagnosis in he absence o a bone biopsy emains a challenge. Adynamic bone diseases is o pa icula conce n as he s anda d an i eso p i e ea men p esc ibed o os eopo osis ea men (bisphosphona es, denosumab) has heo e ical po en ial o exace ba e adynamic bone disease. E en an inc ease in measu ed bone densi y may no esul in educ ion in ac u e isk i he bone is o poo quali y. Because o his complex in e play, no all CKD pa ien s a e likely o bene i om he s anda d an i eso p i e ea men p esc ibed o he p esumed diagnosis o os eopenia/os eopo osis based upon WHO de ini ion and indeed s udies ha e demons a ed his he e ogenei y [18,19]. Cu en ly, we do no ha e any cu en guidelines abou e.g. adjus ing he ini ial dose o denosumab du ing he i s ea men s. Denosumab should be bes a oided, o he ime being, in pa ien s wi h ESRD and signi ican seconda y hype pa a hy oidism un il u he clinical expe ience is been ga he ed on how o p e en o manage hypocalcemia. E en when pa ien s a e adequa ely eple ed on i amin-D (no mal 25-hyd oxy i amin-D and 1,25 di-hyd oxy i amin D le els), la ge doses o calcium supplemen s a e equi ed. We would like o ad oca e he use o IV calcium glucona e, sup aphysiologic dialysa e calcium concen a ion, and high doses o o al calcium supplemen s (6-12 g ams pe day) oge he wi h Vi amin D eple ion and educing denosumab dose unde hese ci cums ances. None heless, a blank elimina ion o his medica ion om he he apeu ic a mamen a ium may no be he bes long- e m policy a e all; i so doing, we would ne e expose pa ien s o su gical pa a hy oidec omy o he ea o hypocalcemia and hung y bone synd ome. The e y ac ha ou pa ien de eloped such se e e deg ee o hypocalcemia may se e as a p edic o o an excellen po en ial o bone mine aliza ion and success ul u u e ou comes o bone in eg i y. We also so ely need bone his ology da a in hese pa ien s, whe e local expe ise on ob aining and in e p e ing bone biopsy specimens a e a ailable. Whe he denosumab has any ole in ea ing hype calcemia in dialysis pa ien s, beyond cance - induced hype calcemia [20], is unclea a his ime. Po en ially, a pa ien wi h os eopo osis and hype calcemia may be he ideal candida e, bu his issue is clea ly no well s udied o unde s ood a his poin . 4. CONCLUSION T ea men decisions based on bone densi ome y esul s alone ( a he han bone biopsy) a e no ansposable be ween pa ien s wi h o wi hou end-s age enal disease. An an i eso p i e agen such as denosumab may lead o c i ical and p olonged hypocalcemia in dialysis pa ien s as obse ed in his case and u he agg a a e exis ing seconda y hype pa a hy oidism. Addi ional esea ch is needed o iden i y he highes isk pa ien s and e ec i e s a egies o minimize his se ious side e ec . B i ish Jou nal o Medicine & Medical Resea ch, 3(4): 1398-1406, 2013 1405 CONSENT W i en in o med consen was ob ained om he pa ien o publica ion o his case epo , who had an oppo uni y o ead and e iew his pape and ecei ed a copy o i . ETHICAL APPROVAL This case epo is no an animal expe imen o expe imen al s udy. The Uni e si y o Mississippi’s Ins i u ional Re iew Boa d e iewed his p ojec and de e mined ha would no quali y as esea ch (IRB File #2013-0016). In o med consen was ob ained om he pa ien and we ha e a copy o he pa ien ’s w i en consen on ou iles, a ailable o inspec ion upon eques . ACKNOWLEDGEMENT We wish o hank Ilena S. Aga wal, who has wo ked closely wi h he i s au ho and who c i ically ead he manusc ip in e e y d a and helped p epa e i o publica ion. COMPETING INTERESTS Au ho s ha e decla ed ha no compe ing in e es s exis . REFERENCES 1. 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