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1 , f,osteoporos nt (2014) 25: EO to.007/s r 1r; f Distinctive role of 6-month teriprtide tretment on intrctle isphosphonte-relted osteonecrosis of the jw (. M. Kim W. Prk S. Oh H...J. Kim W. Nm S.-K. Lim Rhee L H. Ch,. Rc:ceived; 11 Septemer 2013 /Accepted: 9 Jnury 2014 /Pulished online: 20 Feruiy 2014 nterntionl Osteopor08is Foundtion nd Ntion.nl Osteoporosis Foundtion 2014 Astrct Summry The dministrtion of teriprtide {TPTD) in conjunction with periodontl cre coujd provide fster nd more fvorle clinicl outcomes in previously refrctory isphosphonte-relted osteooecrosis of the jws (BRONJ) cses compred to conventionj dentl cre, comintion of surgery nd ntimicroil tretment We Jso found tht underlying vitmin D levels might influence the response to TPTD tretment. ntroduction Tretment of BRONJ is quite chllenging nd there re no stndrd tretment modlities. n this retrospective, longitudinl study, we exmined wheth dditionl TPTD dministrtion could e eneficij for the resolution of BRONJ lesions compred to conservtive mngement, such s ntimicroil tretment with or without surgery, nd lso studied the fctors influencing the response to TPTD. Methods Twenty-four cses of intrctle BRONJ were included: 15 sujects were ssigned to the TPTD group nd the other 9 sujects, who refused TPTD dministrtion, were K. M. Kim nd W. Pck contriuted eqully to this study. K. M. Kim Deprtment of nternl Medicine, Seoul Ntionl University Bundng Hospitl, Seongnm, South Kore W. Prk S. Y. Oh Deprtment of Advnced Generl Dentistry, Severnce Dentl Hospitl, Yonsei University College of Dentistry, Seoul, South Kore H.-J. Kim W. Nm. H. Ch (8) Deprtment of Orl nd Mxillofcil Surgery, Severnce Dentl Hospitl, Yonsei University College ofdentistry, Seoul, South Kore e-mil: CHA8764@yuhs.c S.-K. Lim Y. Rhee (181) Deprtment of nternl Medicine, Severnce Hospitl, Endocrine Reserch nstitute, Brin Kore 21 Project for Medicl Science, Yoosei University College of Medicine, Seoul, South Kore e-mil: yumie@yuhs.c ssigned to the non-tptd group. All sujects in oth groups continued cjcium nd vitmin D supplementtion nd the TPTD group dditioojjy received dily sucutneous injection of20 µg TPTD for 6 months. Results While 60.0 % of the oon-tptd group showed one stge of improvement in BRONJ, 40.0 % of the group did not show ny improvement in disese sttus. n the TPTD group, 62.5 % of the treted sujects showed one stge of improvement nd the other 37.5 % demonstrted mrked improvement, including two stges of improvement or complete heling, nd there ws not single cse tht did not improve. The clinicl improvement ofbronj ws sttisticjly etter in the TPTD group fter the 6-mooth tretment (p<0.05). Moreover, ptients with higher seline serum 25(0H)D levels showed etter clinicl therpeutic outcomes with TPTD. Conclusions We oserved the eneficij effects of TPTD on BRONJ, nd sujects with optimj serum vitmin D concentrtions seemed to rep the mximum therpeutic effects of TPTD. A prospective, rndomized, controlled tril shoujd e needed to further evlute the therpeutic efficcy oftptd in the resolution ofbronj. Keywords Bisphosphonte Jw Osteonecrosis Teriprtide Vitmin D Arevitions BRONJ Bisphosphonte-relted osteonecrosis of the jws BMD Bone minerj density BM Body mss index TPTD Teri pr tide CTX C-telopeptide of type collgen OCN OsteocJcin PTH 25(0H)D Prthyroid honnone 25-Hydroxyvitmin D v. Springu

2 tteoporos nt (2014) 25: J J0.1007/s ,,, Distinctive role of 6-month teriprtide tretment on intrctle isphosphonte-relted osteonecrosis of the jw }(. M. Kim W. Prk S. Oh. Kim \V. Nm s.-k- Lim \-: Rhee. H. Ch Rived: 11 Sepll:mer 2013 / Accep: 9 Jnury 2014 /Pulished onlinc: 20 Ferury 2014 nterntionl Osteoporosis Foundtion nd Ntionl Osteoporosis Foundtion 2014! 1 Astrct Summ,y The dministrtion ofteriprtide (TPTD) in conjunction with periodontl cre could provide fster nd more fvorle clinicl outcomes in previously refrctory isphosphonte-reltcd osteonecrosis of the jws (BRONJ) cses compred to conventionl dentl cie, comintion of surgery nd ntimicroil tretment We lso found tht underlying vitmin D levels might influence the response to TPTD tretment. ntroduction Tretment of BRONJ is quite chllenging nd there re no stndrd tretment modlities. n this retrospective, longitudinl study, we exmined whether dditionl TPTD dministrtion could e eneficil for the resolution of BRONJ lesions compred to conservtive mngement, such s ntimicroil tretment with or without surgery, nd lso studied the fctors influencing the response to TPTD. Methods Twenty-four cses of intrctle BRONJ were included: 15 sujects were ssigned to the TPTD group nd the other 9 sujects, who refused TPTD dministrtion, were K. M. Kim nd W. Prk contriuted eqully to this study. K. M. Kim Depr1rnent oflntcml Medicine, Seoul Ntionl University Bundnog Hospitl, Seongnm, South Kore W. Prk S. Y. Oh Deprtment of Advnced Generl Dentistry, Severnce Dentl Hospitl, Yonsei University College ofdencistry, Seoul, South Kore H.-J. Kim W. Nm. H. Ch (12l) Depnment of Orl nd Mxillofcil Surgery, Severnce Dentl Hospitl, Yonsei University College ofdentistry, Seoul, South Kore e-mil: CRA8764@yuhs.c S.-K. Lim Y. Rhee (12l) Deprtment of nternl Medicine, Severnce Hospitl, Endocrine Reserch nstitute, Brin Kore 21 Project for Medicl Science, Yonsci University College of Medicine, Seoul, South Kore e-mil: yumie@yuhs.c ssigned to the non-tptd group. All sujects in oth groups continued clcium nd vitmin D supplementtion nd the TPTD group dditionlly received dily sucutneous injection of 20 µg TPTD for 6 months. Results While 60.0 % of the non-tptd group showed one stge of improvement in BRONJ, 40.0 % ofte group did not show ny improvement in iliscsc stus. ln the TPTD group, 62.5 % of the treted sujects showed one stge of improvement nd the other 37.5 % demonstrted mrked improvement, including two stges of improvement or complete heling, nd there ws not single cse tht did not improve. The clinicl improvement of BRONJ ws sttisticlly etter in the TPTD group fter the 6-month tretment (p<0.05). Moreover, ptients with higher seline serum 25(OH)D levels showed etter clinicl therpeutic outcomes with TPTD. Conclusions We oserved the eneficil effects oftptd on BRONJ, nd sujects with optiml serum vitmin D concentrtions seemed to rep the mximum therpeutic effects of TPTD. A prospective, rndomized, controlled tril should e needed to further evlute the therpeutic efficcy of TPTD in the resolution ofbronj. Keywords Bisphosphonte Jw Osteonecrosis Teriprtid Vitmin D Arevitions BRONJ Bisphosphonte-relted osteonecrosis of the jws BMD Bone minerl density BM Body mss index TPTD Teriprtide CTX C-telopeptide of type collgen OCN Osteoclcin PTH Prthyroid hormone 25(OH)D 25-Hydroxyvitrnin D Springtt.

3 1626 Ostoporos nt (2014) 25: ntroduction Osteoporosis nd relted frctures re seiious, worldwide hehh prolem in ged societies, cusmg incresed moridity nd mortlity; so treting osteoporosis nd preventing relted osteoporotic frctures re urgent tsks in cring for the helth of the elderly [, 2): Bone loss resulting from negtive one lnce etween resorption nd fonntion is n inevitle chnge ssocited with ging [3]. Therefore, ntiresorptive therpy hs een one of the min effe ctive strtegies for treting osteoporosis [ 4 J. Among severl ntiresorprive gents, isphosphontes hve een widely used over the pst decdes s mjor drug for osteoporosis. They hve demonstrted superior effects in incresing one minerl density (BMD) nd decresing the numer of frctures, ultimtely ecoming fundmentl, therpeutic pproch for osteoporosis (5). Bisphosphcinte-relted osteonecrosis of the jws (BRONJ) ws defined s condition of exposed one in the mxillofcil region tht did not hel within 8 weeks in ptient who hd een exposed to isphosphontes y the Americn Society for Bone nd Minerl Reserch [6] nd emerged s grve side effect of isphosphonte use fter the first report y Mrx et l. in 2003 [7]. The risk fctors nd clmicl stge ccording to symptom nd sign hd een lso defined y the Americn Assocition of Orl nd Mxillofcil Surgeons (AAOMS) [8]. BRONJ occurs more.frequently in ptients receiving higher doses of intrvenous isphosphonte, ut lso hppens in ptients dministered with lower doses in orl forms [6, 9]. The current consensus on treting ptients with BRONJ is conservtive mngement with ntiiotics, nlgesics, nd occsioolly surgicl intervention [8]. However, mnging BR,ONJ {n=r1t9) Referred to riclocilnoldgy Al (n=24). tt t y Conventlonl dentl cre Dentl check up Bone Turnover Mrkers 25(0HJD, PTH, BMD Fig. 1 Srudy prticipnts nd tretment schedule. Among the 119 BRONJ cses, 24 dvnced cses were included, with 15 sujects ssigned to the TPTD group od 9 sujects to the non-tptd group. Assessment oflhe resolution ofbronj ws ssessed mont.ly nd ooe Springer BROJ is quite chllenging nd n idel stndrd tretment modlity does not yet exist. The condition in muner of ptients thus persists or progresses to severe stge, even fter long-tenn, conventionl tretment [5). Teriprtide (TPTD), drug composed of the first 34 mino cids of recominnt humn prthyroid honnone initilly stimultes one formtion y osteolsts nd susequently one resol})tion y osteoclsts nd thus cn rectivte suppressed one remodeling nd exert nolic effects on one (10). Becuse of this mechnism, it hs een necdotlly suggested s eneficil drug in situtions tht need stimultion of one remodeling. TPTD hs cliniclly demonstrted greter resolution of lveolr one defects nd ccelerted osseous wound heling in the orl cvity of chronic periodontitis cses [11). Moreover, severl cse reports hve disclosed fvorle therpeutic outcomes with TPD in BRONJ [ 12-14]. The ims of this study were to detennine whether the ddition of TPD to conventionl tretment could provide etter outcomes in mnging intrctle cses ofbronj nd to investigte ny predictive fctors on therpeutic effects oftptd. Mterils nd methods Study design nd prticipnts The study design nd tretment schedules for oth groups re shown in Fig. l, _. This ws retrospective, longitudinl study nd included dvnced BRONJ cses dignosed etween Jnury nd Decemer 2011 t Severnce Hospitl. We included ptients with intrctle BRONJ whose condition did not recover fter few months or up to more thn TPTD therpy seline 1mo. 2mo. 3mo. 4mo. Smo. 6mo. 1...J...J turnover mrlcers were checked t seline, 1 month, 3 months, nd 6 months. BRONJ, isphosphontes-relted ostconecrosis of the jws; TPTD, teriprtide; 25{0H)D, 25-hydroxyvitmin D; PTH, prthyroid hormone; BMD, one minerl density t!! j

4 1626 ntroduction Osteoporosis nd relted frctures rc serious, worldwide helth prolem in ged societies, cusing incresed moridity nd mortlity; so treting osteoporosis nd preventing relted osteoporotic frctures re urgent tsks in cring for the helth of the elderly [, 2]. Bone loss resulting from negtive one lnce etween resorptio,n nd fonntion is n inevitle chnge ssocited with ging (3]. Therefore, ntiresorptive therpy hs een one of the min effective strtegies for treting osteoporosis ( 4]. Among severl ntiresorptive gents, isposphontes hve een widely used over the pst decdes s mjor drug for osteoporosis. They hve demonstrted superior t:ffects in incresing one minerl density (BMD) nd decresing the numer of frctures, ultimtely ecoming fi.mdmentl, therpeutic pproch for osteoporosis [5]. Bisphosphonte-relted osteonecrosis of the jws (BRONJ) ws defined s condition of exposed one in the mxillofcil region tht did not hel within 8 weeks in ptient who hd een exposed to isphosphontes y the Americn Society for Bone nd Minerl Reserch r61 nd emerzen ls c1 grve side effect of i3phosphonte use flt:r the first report y Mrx et l. in 2003 [7]. The risk fctors nd clinicl stge ccording to symptom od sign hd een lso defined y the Americn Assocition of Orl nd Mxillofcil Surgeons (AAOMS) (8]. BRONJ occurs more frequently in ptients receiving higher doses of intrvenous isposphonte, ut lso hppens in ptients dministered with lower doses in orl forms [6, 9]. The current consensus on treting ptients with BRONJ is conservtive mngement with ntiiotics, nlgesics, nd occsionlly surgicl intervention [8]. However, mnging Osteoporos nt (2014) 25: BRONJ is quite chllenging nd n idel stndrd tretment modlity does not yet exist. The condition in numer of ptients thus persists or progresses to severe stge, even fter long-tenn, conventionl tretment [5]. Teriprtide (TPTD), drug composed of the first 34 mino cids of recominnt humn prthyroid hormone initilly stimultes one fonntion y osteolsts nd suse quently one resorption y osteoclsts And thus cn rectivl1: suppressed one remodeling nd exert nolic effects on one [ OJ. Becuse of this mechnism, it s een necdotlly suggested s eneficil drug in situtions tht need stimuf, tion of one remodeling. TPTD hs cliniclly demonstrted greter resolution of lveolr one defects nd ccelerted osseous wound heling in the orl cvity of chronic periodontitis cses [11 ]. Moreover, severl cse reports hve disclosed fvorle therpeutic outcomes with TPTD in BRONJ [ 2- l 4]. The ims of this study were to detennine whether e ddition of TP1D to conventionl tretment could provide etter outcomes in mnging intrctle cses of BRONJ nd to investigte ny predictive fctors on therpeutic effocts oftptd. Mterils nd methods Study design nd prticipnts The study design nd tretment schedules for oth groups re shown in Fig. l,. This ws retrospective, longttudinl study nd included dvnced BRONJ cses dignosed etween Jnury nd Decemer 2011 t Severnce Hospitl. We included ptients with intrctle BRONJ whose condition did not recover fter few months or up to more thn t it y Conventionl dentl cre (months) TPTO therpy seline 1mo. 2mo. 3mo. 4mo. 5mo. 8mo. Dentl check up Bone Turnover Mrkers 25(0H)O, PTH, BMO Fig. Stu_dy prticipnts nd tretment schedule. Among tlte 119 BRONJ cses, 24 dvnced cses were included, with 15 sujects ssigned to the TPD group nd 9 sujects to the non-tptd group. Assessment of the resolution ofbronj ws ssessed monthly nd one..j , ::,_ / ],;-. f"i turnover mrkers were checked t seline, 1 month, 3 months, nd 6 months. BRONJ, isphosphontcs-rclted osteouecrosis of the jws; TPTD, tcriprtide; 2S(OH)D, 25-hydroxyvitmin D; PH, prthyroid honnonc; BMD, one minerl density Springer

5 Osteoporos nt (2014) 25: yers of conventionl cre with or without sequestrectornies fter the dignosis ofbronj. All ptients enrolled hd een recommended for TPTD tretment for 6 months. The sujects who greed to the TPTD therpy received dily sucutneous injection of 20 µg TPTD (Forsteo, Eli Lilly, ndinpolis, N, USA) with clcium nd vitmin D supplementtion for 6 months, nd this group ws design_!.ed s the TPTD group. The remining sujects, who refused the use oftptd, were only prescried clcium nd vitmin D upplernenttion nd were designted then s non-tptd group. Periodic follow-up visits were the sme for oth groups nd scheduled l J, 3, nd 6 months fter the initition of therpy. "All prticipnts underwent monthly dentl exmintion including pnormic rdiogrphs, during the entire tretment period. Associted clinicl spects of the lesions, including size, site, nd signs of secondry infection were monitored nd recorded. We only included primry osteoporosis ptients nd excluded the sujects who hd other contriutle fctors for developing BRONJ including glucocorticoid exposure or chemotherpy. Therefore, indictions for previous isphosphonte usge y the study sujects were postmenopusl osteoporosis for lj femle sujects nd ge-relted mle osteoporosis for the two mle sujects. This study protocol ws reviewed nd pproved y the lnstitutionl Review Bord of Yonsei University College of Medicine, Severnce Hospitl ( ). Assessment of BRONJ resolution The clinicl rid rdiogrphic resolution of the lesion t ech scheduled visit ws lindly reviewed y two seprte dentists. Stge ofbronj ws defmed ccording to the definition of the AAOMS (8). Heling sttus t the finl sixth month visit ws ssessed s the primry endpoint. The outcome vrile ws the improvement ofbronj stge, nd the evolution of the disese er 6 months of tretment ws strtified s follows (Fig. 2): "No improvement"-no improvement or worsening of BRONJ sttus (Fig. 2) "Moderte improvement"-one stge of improvement of BRONJ sttus (Fig. 2) "Mrked improvement-improvement of two stges of BRONJ or complete heling (Fig. 2c) Assessment for one-relted mrkers nd BMD Bone turnover mrkers, including c-telopeptide of type collgen (CTX, Roche Dignostics, ndinpolis, N, USA), osteoclcin (OCN, Roche Dignostics, ndinpolis, N, USA), 25-hydroxyvitmin D (25(0H)D, D 3 -RA-CT, Biosource, Belgium, Europe), nd prthyroid hormone....! t 1627 t - t c Fig. 2 Assessment ofbronj resolution. A cse from the no improvement group. nitil dignosis ws stge with one exposure in 1he mndiulr right posterior region fter implnt plcement (white rmw, ). Though implnt removl rid sequestrectomy were performed, symptoms such s pin nd dischrge of pus ecme worse nd osteonecrosis spred to the djcent teet nd inferior lveolr nerve, which ws dignosed s stge 3 (while rjt>ws, OJ. A cse from the moderte improvement group. nitil dignosis ws stge 2 with one exposure in the mndiulr right posterior region fter implnt plcement (white nvw.r, ). After TPTD injection, implnt removl, nod sequestrectomy, no further progress of osteonecrosis ws oserved nd mucos! heling ws chieved finlly down to stge (whitenvw.. J. ca cse from the mrked improvement group. nitil dignosis ws stge 3 in the mndiulr right posterior lower region fter implnt plcement (while n-0111s, c). Even though sequestrectornies hd een performed severl times, osteonecrosis extended to the inferior order of the mndile (flrrowhed, c). After TPTO injection, one heling ws oserved rdiogrphicnlly, mucos! heling ws chieved, nd inflmmtion ws not oseived cliniclly, indicting n improvement of more thn two stges (white rrows, c) (PTH) (Elecsys System; Roche, Mnnheim, Germny), were checked t seline (visit 0). The one turnover mrkers were then regulrly monitored t the 1-, 3-, nd 6-month follow-up l;l i 1 J 1 Springer