ORIGINAL ARTICLE JBMR Differing Effects of PTH 1 34, PTH 1 84, nd Zoledronic Acid on Bone Microrchitecture nd Estimted Strength in Postmenopusl Women With Osteoporosis: An 18-Month Open-Leled Oservtionl Study Using HR-pQCT Stinus Hnsen, 1, Ellen M Huge, 3 Jens-Erik Beck Jensen, 4 nd Kim Brixen 1, 1 Deprtment of Endocrinology, Odense University Hospitl, Odense, Denmrk Institute of Clinicl Reserch, University of Southern Denmrk, Odense, Denmrk 3 Deprtment of Rheumtology, Arhus University Hospitl, Arhus, Denmrk 4 Osteoporosis Reserch Clinic, Hvidovre University Hospitl, Hvidovre, Denmrk ABSTRACT Wheres the eneficil effects of intermittent tretment with prthyroid hormone (PTH) (intct PTH 1 84 or frgment PTH 1 34, teriprtide) on verterl strength is well documented, tretment my not e eqully effective in the peripherl skeleton. We used highresolution peripherl quntittive computed tomogrphy (HR-pQCT) to detil effects on comprtmentl geometry, density, nd microrchitecture s well s finite element (FE) estimted integrl strength t the distl rdius nd tii in postmenopusl osteoporotic women treted with PTH 1 34 ( mg sc dily, n ¼ 18) or PTH 1 84 (1 mg sc dily, n ¼ ) for 18 months in n open-lel, nonrndomized study. A group of postmenopusl osteoporotic women receiving zoledronic cid (5 mg infusion once yerly, n ¼ 33) ws lso included. Anolic therpy incresed corticl porosity in rdius (PTH 1 34 3 37%, PTH 1 84 39 3%, oth p <.1) nd tii (PTH 1 34 13 7%, PTH 1 84 15 %, oth p <.1) with corresponding declines in corticl density. With PTH 1 34, increses in corticl thickness in rdius (. 3.8%, p <.5) nd tii (3.8 1.4%, p <.1) were found. Treculr numer incresed in tii with oth PTH 1 34 (4. 7.1%, p <.5) nd PTH 1 84 (5.3 8.3%, p <.1). Zoledronic cid did not impct corticl porosity t either site ut incresed corticl thickness (3. 3.5%, p <.1), totl (.7.5%, p <.1) nd corticl density (1.5.%, p <.1) in tii s well s treculr volume frction in rdius (.5 5.1%, p <.5) nd tii (..%, p <.1). FE estimted one strength ws preserved, ut not incresed, with PTH 1 34 nd zoledronic cid t oth sites, wheres it decresed with PTH 1 84 in rdius (.8 5.8%, p <.5) nd tii ( 3.9 4.8%, p <.1). Conclusively, divergent tretment-specific effects in corticl nd treculr one were oserved with nolic nd zoledronic cid therpy. The finding of decresed estimted strength with PTH 1 84 tretment ws surprising nd wrrnts confirmtion. ß 13 Americn Society for Bone nd Minerl Reserch. KEY WORDS: HR-PQCT; OSTEOPOROSIS; ANTI-OSTEOPOROTIC TREATMENT; PTH 1 34; PTH 1 84; ZOLEDRONIC ACID Introduction The 1 to 34 mino-cid N-terminl prthyroid hormone (PTH) frgment teriprtide (PTH 1 34) nd the intct 1 to 84 mino-cid PTH peptide (PTH 1 84) re used s one nolic gents for the tretment of postmenopusl osteoporosis. By preferentilly incresing one formtion over one resorption, these gents stimulte, in intermittent use, the formtion of new one. (1) The mechnisms involved include modeling-sed one formtion on quiescent one surfces s well s remodelingsed one formtion. () Bone minerl density (BMD) in the spine s ssessed y dul-energy X-ry sorptiometry (DXA) increses 7% to 1% fter 18 months of tretment. (3,4) Both PTH 1 34 nd PTH 1 84 reduce the risk of new verterl frctures, wheres efficcy ginst new nonverterl frctures ws documented with PTH 1 34 (4) ut not with PTH 1 84. (3) Both gents re used widely, lthough PTH 1 84 is not pproved y the Food nd Drug Administrtion in the United Sttes. Received in originl form July 5, 1; revised form Septemer 17, 1; ccepted Octoer 1, 1. Accepted mnuscript online Octoer 8, 1. Address correspondence to: Stinus Hnsen, MD, Deprtment of Endocrinology, Institute of Clinicl Reserch, Odense University Hospitl, University of Southern Denmrk, Kloevervenget 6.1.sl, DK-5 Odense C, Denmrk. E-mil: sthnsen@ddlnet.dk Journl of Bone nd Minerl Reserch, Vol. 8, No. 4, April 13, pp 736 745 DOI: 1.1/jmr.1784 ß 13 Americn Society for Bone nd Minerl Reserch 736
PTH 1 34 s n nolic gent ws proposed y Reeve nd collegues in 198. (5) Although the formtion of new cncellous one ws convincing, it ws oserved tht PTH 1 34 my hve n unfvorle effect in corticl one. Since then, this corticl stel phenomenon hs een widely studied. (6) In primtes, it hs een shown tht intermittent PTH 1 34 or PTH 1 84 exposure cuses n increse in corticl porosity. (7,8) This ws, however, shown not to decrese integrl one strength, s the pores were preferentilly locted ner the endostel surfce, where their iomechnicl impct ws limited, nd this effect ws outweighed s tretment lso incresed the corticl re. (7) With the development of newer one-imging devices tht contrry to DXA methodology llow three-dimensionl one imging, ssessment of tretment effects on one geometry nd comprtmentl chrcteristics hs ecome fesile in ptients. With the ltest genertion high-resolution peripherl quntittive computed tomogrphy (HR-pQCT) devices, imge resolution hs een mrkedly refined nd now permits detiled one microrchitecture evlution. (9) Noninvsive ssessment of oth corticl nd treculr microrchitecture t the distl rdius nd tii is now possile in vivo with n isotropic imge voxel size of 8 mm. Mesurement of selected microrchitecturl chrcteristics hitherto limited to evlution in one iopsies hs ecome cliniclly ville with this technique. Bone strength my lso e estimted using finite element (FE) nlysis sed on the HRpQCT imges. (1) Such FE strength estimtes hve een shown to e more closely correlted to rdius iomechnicl competence thn BMD y DXA. (1) In recent longitudinl study using HR-pQCT in 11 postmenopusl women, tretment with 18 months of PTH 1 34 decresed corticl BMD t rdius nd tii, wheres nonsignificnt increse ws seen in corticl porosity in rdius. (11) Treculr thinning nd reduced treculr one volume frction were lso found in rdius, wheres FE estimted one strength ws preserved t oth sites. In comprison, quntittive computed tomogrphy (QCT) studies with intermittent PTH 1 84 or PTH 1 34 hve shown lrge increses in verterl cncellous BMD nd estimted verterl strength. (1,13) Tretment my thus not e eqully effective in the peripherl skeleton. To ddress this issue further, the effects of 18 months of one nolic therpy with PTH 1 34 or PTH 1 84 were chrcterized in detil using HR-pQCT. A group of postmenopusl women with osteoporosis treted with zoledronic cid, ie, potent ntiresorptive gent, ws lso included for comprison. Mterils nd Methods Prticipnts This 18-month prospective, open-lel, nonrndomized study involved women (Tle 1) from single clinicl site (Deprtment of Endocrinology, Odense University Hospitl, Odense, Denmrk), who were prescried tretment for postmenopusl osteoporosis with PTH ( mg PTH 1 34 [teriprtide] sucutneous dily [Eli Lilly, Indinpolis, IN, USA] or 1 mg PTH 1 84 sucutneous dily [Tked Nycomed, Zurich, Switzerlnd]) or zoledronic cid 5 mg infused once yerly (Novrtis Europhrm, Horshm, UK) from April 9 to Decemer 1 s prt of routine clinicl cre. Inclusion criteri were postmenopusl sttus ( > 1 yer from lst menstrution) nd ility to provide informed consent. Reimursement of PTH 1 34 nd PTH 1 84 tretment in Denmrk required two or more verterl frctures or one verterl frcture nd lumr spine (L 1 to L 4 ) or totl hip T-score 3. SD. Reimursement of zoledronic cid required lumr spine (L 1 to L 4 ) or totl hip T-score.5 SD nd clinicl risk fctor for osteoporosis. Exclusion criteri were tretment with glucocorticoids (equivlent to more thn 5 mg prednisone dily > 3 months), kidney or liver disese, clcium-metolic or endocrine diseses ffecting one metolism, or current exposure to drugs with known effect on one. At lest 1 month pssed from cesstion of previous isphosphonte tretment (lendronte, etidronte, or orl indronte) until initition of Tle 1. Bseline Anthropometrics, Biochemistry, nd DXA BMD in Study Prticipnts With t Lest One Follow-up Visit Zoledronic cid (n ¼ 33) PTH 1 34 (n ¼ 18) PTH 1 84 (n ¼ ) p Vlue Age (yers) 7 (54 86) 7 (59 8) 7 (61 86).45 Height (cm) 16 6 159 5 159 7.7 Weight (kg) 63 9 64 1 64 11.83 Age t menopuse (yers) 47 6 48 5 49 6.4 Prior isphosphonte tretment, n (%) 16 (48) 5 (8) 9 (45).66 Durtion of prior isphosphonte tretment (months) 18 33 17 39 13 9.89 Individuls with prior verterl frcture, n (%) 11 (33) 18 (1) (1).4 No. of prior verterl frctures 33 36 39.7 Individuls with prior nonverterl frcture, n (%) 11 (37) 9 (5) 7 (39).77 No. of prior nonverterl frctures 19 14 9.55 Dily clcium supplements (mg) 76 39 75 39 637 38.17 5(OH)D3 (mmol/l) 94 34 96 35 8 3.39 Spine BMD (g/cm ).7.11.71.13.7.13.93 Totl hip BMD (g/cm ).7.11.6.13.66.1.7 1/3 Distl forerm BMD (g/cm ).5.7.49.11.48.8.18 Ultrdistl forerm BMD (g/cm ).6.4.4.7.6.6.55 The p vlues re derived from one-wy nlysis of vrince. Journl of Bone nd Minerl Reserch EFFECTS OF PTH 1 34, PTH 1 84, AND ZOLEDRONIC ACID ON BONE MICROARCHITECTURE 737
tretment with PTH (PTH 1 34 medin months, rnge 1 to 13 months; PTH 1 84 medin 4 months, rnge 1 to 6 months) or zoledronic cid (medin 3 months, rnge 1 to 14 months). Bsed on their diet intke, ll prticipnts were recommended supplements with (up to) 1 mg clcium dily nd (up to) mg vitmin D3 dily. Ptients prescried nolic therpy were presented PTH 1 34 nd PTH 1 84 injection pens y study nurse nd were ssigned to either PTH tretment sed on personl preference. Trining ws provided regrding selfdministrtion of PTH, nd prticipnts hd their first injection supervised y study nurse. Susequent injections were selfdministered. Ptients were scheduled for visits t.5, 3, 6, nd 1 months for supervision of injection technique, serum ionized clcium, nd ssessment of dverse events. Clcium nd vitmin D supplements were discontinued if cliniclly significnt hyperclcemi developed during tretment. PTH dosing frequency ws reduced if the hyperclcemi persisted. Women treted with zoledronic cid hd kidney sttus nd serum clcium evluted efore their first nd second infusion. Historicl nonverterl frctures were ssessed using interviews, wheres verterl frctures ( > % reduction in ny verterl height) were ssessed on rdiogrphs. Prevlence nd durtion of prior isphosphonte tretment were ssessed using interviews nd chrt reviews. Prticipnts were informed orlly nd in writing efore informed consent were otined. The study ws pproved y the locl Ethics Review Bord (file no. 8 19). HR-pQCT Imges of the nondominnt distl rdius nd tii (or dominnt side in cse of previous frcture t the desired site) were otined using high-resolution peripherl quntittive computed tomogrphy (XtremeCT, Scnco Medicl, Brüttisellen, Switzerlnd) t seline, 6 months, nd 18 months. Imges were evluted to otin mesures of 1) one geometry, ) corticl morphology, 3) treculr morphology, nd 4) overll iomechnicl competence. The stndrd ptient protocol for imge cquisition ws pplied s descried previously. (9) Using n offset from the endplte of 9.5 mm nd.5 mm in rdius nd tii, respectively, 9. mm xil one representtions comprising 11 slices were otined providing imges with n isotropic voxel size of 8 mm. Imge qulity ws grded fter reconstruction y one uthor (SH) using five-step scle s suggested y the mnufcturer (1 ¼ est, 5 ¼ worst), nd imges with grde < 3 were disregrded. (14) An utosegmenttion pproch using periostel nd endostel thresholds ws pplied for imge segmenttion. (15) All contours were visully checked on screen nd corrected mnully if necessry y one uthor (SH). Totl nd corticl one densities were derived from the respective volumes, clirted using scn phntom, nd expressed in mg/cm 3. Corticl prmeters included corticl thickness (Ct.Th), mesured directly s the endostel-periostel distnce using distnce trnsformtion method, nd corticl porosity mesured s void corticl volume divided y totl corticl volume. (16,17) Treculr re ws derived from treculr volume; scn height nd voxel size using n nnulr pproch. Metric treculr prmeters were extrcted using the mnufcturer s defult method fter fixed threshold segmenttion. Bone volume per tissue volume (BV/TV) ws derived from treculr density, wheres treculr numer (T.N) ws directly mesured using distnce trnsformtion method. Treculr thickness (T.Th) nd treculr spcing (T.Sp) were derived from T.N nd BV/TV in nlogy to stndrd histomorphometry. (9) An utomtic common region mtching procedure sed on vrition in one cross-sectionl re ws pplied to ensure tht only volumes common to scns otined t seline, 6 months, nd 18 months were used for extrction of the ove prmeters. (18) Finlly, rdius nd tii filure lod ws estimted using unmtched imges with micro-finite element nlysis solver provided y the mnufcturer (Finite Element Anlysis Softwre version 1.15, Scnco Medicl), where ll one mterils were given Young s Modulus of 1 GP nd Poisson s rtio of.3. From the models, n estimte of filure lod in compression is clculted sed on the ssumption tht one filure occurs if > % of the elements re strined eyond.7% strin. (1) Qulity control ws ssessed y dily nd weekly scn of phntoms (QRM, Möhrendorf, Germny). Bsed on repeted mesurement of 13 individuls fter repositioning (men ge 64 yers, rnge 33 to 79 yers), the root men squre coefficient of vrition (RMSCV) for rdius nd tii prmeters in our unit rnged from.4% to.8% for densities, 3.5% to 5.% for treculr microrchitecture prmeters, 1.% to 7.% for extended corticl mesures, nd 1.% to 1.7% for FE estimted filure lod. This is in greement with the reproduciility reported y others. (9,16) DXA Arel BMD ws mesured t the spine (L 1 to L 4 ), totl hip, nd forerm (1/3 distl nd ultrdistl regions), using DXA (Hologic, Wlthm, MA, USA) t seline, 6 months, nd 18 months. In our unit, the RMSCV ws 1.5% t oth the hip nd spine. Biochemicl nlysis Blood smples were drwn in fsting stte nd stored t 88C until nlysis of one turnover mrkers. Serum 5 (OH) vitmin D levels were mesured using EZChrom Elite chromtogrphy (Agilent Technologies, Snt Clr, CA, USA). Amino-terminl propeptide of type 1 collgen (PINP) nd c-telopeptide of type 1 collgen (CTX-1) were mesured using n electrochemiluminescent method (Roche Dignostics, Mnnheim, Germny). Sttisticl nlysis No reports regrding the effects of nolic or ntiresorptive gents on HR-pQCT prmeters were ville t the time of study plnning. Forml hypothesis testing ws therefore not preplnned. We did, however, estimte smple sizes required to show significnt etween-group differences in tii BV/TV sed on the ssumption tht the effect with either PTH therpy would resemle tht of PTH 1 34 in the ilic crest ( þ 14% in BV/TV fter 18 months of tretment), (19) wheres the effect with zoledronic cid would resemle tht of risedronte ( 9.5% in BV/TV fter 3 yers of tretment with 5 mg risedronte dily). () Bsed on these ssumptions nd n estimte of tii BV/TV in osteoporotic women of 9.7%.5% (9) nd similr SD post-tretment, 19 prticipnts in ech therpy group would suffice to demonstrte 738 HANSEN ET AL. Journl of Bone nd Minerl Reserch
significnt etween-group tretment differences with lph ¼.5 nd et ¼.8. Dt from prticipnts with t lest one follow-up visit were nlyzed. Dt re presented s men SD or medin (rnge) s pproprite. Between-group differences t seline were quntified using one-wy nlysis of vrince. The percentge chnge from seline in DXA nd HR-pQCT prmeters for ech prticipnt ws determined nd the three tretments were compred in longitudinl nlysis y using liner mixedeffect model with fixed effects for visit, tretment group, nd visit y tretment-group interction. From the models, the fitted men percentge chnges from seline within ech tretment group t months 6 nd 18 were determined, nd the differences in tretment response etween groups t month 18 were quntified. Chnges in iochemicl mrkers of one turnover hd non-norml distriution. The chnge within groups ws therefore quntified using Wilcoxon s mtch-pirs signed rnk test. Between-group differences were quntified using Kruskl- Wllis test, nd if significnt, pirwise comprisons were specified using Mnn-Whitney two-smple test. Becuse the ojective of the study ws hypothesis-generting rther thn to confirm etween-tretment differences, we did not pply correction for multiple testing. The p vlues re two-sided nd thus considered sttisticlly significnt if elow.5. Results Study recruitment nd completion re outlined in Fig. 1. Of those prescried nolic therpy (n ¼ 78) or zoledronic cid (n ¼ 68) during study recruitment, 35 met one or more exclusion criteri (PTH, n ¼ 18; zoledronic cid, n ¼ 17), wheres 3 refused to prticipte (PTH, n ¼ 16; zoledronic cid, n ¼ 16). Of the 79 women included, 71 (9%) completed the month 6 visit nd 66 (84%) completed the month 18 visit. Min resons for discontinution were no wish to continue nd dverse events. Becuse of hyperclcemi, reduction of PTH dosing frequency ws necessry in two ptients (PTH 1 34 ¼ 1, PTH 1 84 ¼ 1). More prticipnts prescried nolic therpy hd prior verterl frctures compred with those prescried zoledronic cid (p ¼.4), wheres no differences etween groups were oserved regrding ge, height, weight, yers from menopuse, numer of nonverterl frctures, clcium supplements, 5(OH)D3, BMD y DXA (Tle 1), or HR-pQCT prmeters in rdius (Tle ). In tii, HR-pQCT prmeters did not differ etween groups except tht those prescried PTH 1 34 hd smller CSA compred with those prescried PTH 1 84 nd zoledronic cid (oth p <.5) nd lower totl density compred with those prescried zoledronic cid (p <.5). A similr frction in ech tretment group hd received prior isphosphonte tretment (zoledronic cid 16/33, PTH 1 34 ¼ 5/18, PTH 1 84 ¼ 9/, p ¼.66). All prticipnts were white. Effects of tretment on BMD y DXA Zoledronic cid incresed BMD in the spine, totl hip, 1/3 distl, nd ultrdistl forerm fter 18 months of tretment (Fig. ). Similrly, PTH 1 34 incresed BMD in the spine nd totl hip ut decresed BMD t the 1/3 distl forerm site. No chnge t the ultrdistl site ws oserved t month 18. PTH 1 84 incresed BMD in the spine, did not chnge BMD t the totl hip, wheres Fig. 1. Digrm showing numer of sujects screened for study prticiption nd numer of prticipnts in ech tretment group t seline, 6 months, nd 18 months with designtion of resons for erly discontinution. Journl of Bone nd Minerl Reserch EFFECTS OF PTH 1 34, PTH 1 84, AND ZOLEDRONIC ACID ON BONE MICROARCHITECTURE 739
Tle. Rdius nd Tii HR-pQCT Prmeters t Bseline, Month 6 (M6), nd Month 18 (M18) s Well s Men Percentge Chnges SD t M6 nd M18 in Ptients Treted With Zoledronic Acid, PTH 1 34, or PTH 1 84 Zoledronic cid PTH 1 34 PTH 1 84 Bseline M6 M18 Bseline M6 M18 Bseline M6 M18 Rdius No. of imges 33 33 8 18 18 18 19 17 CSA (mm ) ~(%) 5 5 5 51 5 5 77 48 78 48 78 48 61 46 6 47 61 49.3..3..9.. W..7..1. Treculr re (mm ) ~(%) 9 53 1 53 11 5 35 5 33 5 33 49 47 47 49.3.7.3.9.5 W 1...6.13.6.4 W.9 m Corticl thickness (mm) ~(%).7.16.7.18.71 15.67..69 1.68 1.65.13.65 13.64 11.9.8 1..9.8 W 5.6. W 3.8 h. 4.3. 5.4 Corticl porosity (%) ~(%).6 1..6 1.1.6 1..6 1.3 3. 1.4 3.3 1.3.5 1.3.9 1.6 3.4 1.7 4.6..6 4. g 19.1 W 9.7 3.4 W 37. 13.9 W.4 39.4 W 3.4 m Totl density (mg/cm 3 ) ~(%) 35 71 35 71 34 7 198 66 69 196 67 11 6 11 6 6 61.8.1 1..5,f.4 3. 1.1 5.4 i. 3.1 4.1 W 6. m Corticl density (mg/cm 3 ) ~(%) 96 56 96 57 936 55 98 6 89 68 886 75 915 53 96 53 885 56.5..9.7,g. W 3..4 W 4.5.7 1.5 3.5 W 3.3 m BV/TV (%) ~(%) 7.8.9 7.8.9 7.9.9 6.1.9 6.3 3. 6. 3. 7.4 3.5 7.5 3.6 7.6 3.6 1.6 3..5 W 5.1.7 5.6.7 1.,h 1.7 6. 1.6 9.8 k Treculr numer (mm 1 ) ~(%) 1.37.43 1.41.45 1.44.36 1.16.5 1..49 1.17.48 1.4.46 1..46 1.3.45 3. W 8. 4.3 W 11.5 5. W 1..7 8.1 h 1.7 6.1.9 6.8 m Treculr thickness (mm) ~(%).6..6.3.5.1.5.1.5.1.5.1.6.1.6.1.6.1 1. 7..8 9.6 1.7 6.1.4 9.3 4. W 6.7 1.6 9.8 Treculr spcing (mm) ~(%).79.4.78.45.71.3 1..5.95.48.97.48.9.56.93.54.9.58.6 7.8 3.1 11.6 4.1 W 9.4.1 7.6 h.1 6.7 3.7 7.8,l FE filure lod (N) ~(%) 561 37 573 38 556 347 55 634 5 634 481 614 5 64 54 68 58 597.9 5.1 1.1 7..8 4.4.7 5.7.5 4.5.8 W 5.8 l Tii No. of imges 33 33 3 18 18 18 18 CSA (mm ) ~(%) 79 13 c 71 13 78 11 85 1e 85 1 85 1 71 14 71 14 717 15..9.4.7..1.1.1..7.5.5 Treculr re (mm ) ~(%) 6 19 d 64 13 617 17 76 16 e 73 14 75 13 68 15 69 15 64 17..96.5 W.7.8 W 1.6.6 W 1.4 i.6.4.1.5 k Corticl thickness (mm) ~(%).86.19.87..9.19.73.16.74.15.75.14.85.18.83.18.8.18.5 3.4 3. W 3.5 3. W 6.4 3.8 W 1.4 j.8 3.3.8 W 4.7 m Corticl porosity (%) ~(%) 9.1.9 8.7.7 9. 3. 9.9 3. 11. 3.3 11. 3.1 8.5 3.3 8.8 3.4 1.1 3.4 1.9 11.8.9 11.1 f 1.5 W 4.5 13. W 7.1 5.3 13.6 14.9 W 1.5 m Totl density (mg/cm 3 ) ~(%) 197 58 c 199 58 8 58 156 4 16 43 158 41 179 4 178 43 174 47 1.1.3.7 W.5 3. W 6.9.1 W 7.1 j.9 3.1 3.9 W 5.4 m Corticl density (mg/cm 3 ) ~(%) 794 63 799 58 811 61 75 88 746 89 739 89 797 73 785 7 754 73.7. 1.5 W. g.8.4 1.6 W 4.4 1.6 W.5 4.7 W 4.5 m BV/TV (%) ~(%) 9.8 3.6 9.8 3.6 1.4 3.5 7.9.5 8..5 8.1.5 8.6 3.1 8.6 3.1 8.9 3.3 1.4 5.. W..1 W 4.7 3.3 W 5.7 j.4 3.7.4 5.3 l Treculr numer (mm 1 ) ~(%) 1.47.48 1.48.45 1.6.45 1.9.41 1.34.46 1.35.46 1.4.34 1.8.39 1.36.36.5 11.9 4.3 W 8.1 3.4 5.7 4. W 7.1.9 7.8 5.3 W 8.3 Treculr thickness (mm) ~(%).7..7..7.1.6..6..6.1.7..7..7..3 8.5 1.5 7.1.8 5.7.3 7.3 h.5 8.5 5.1 W 5.5 k Treculr spcing (mm) ~(%).75.54.7.36.6.3.8.31.78.3.78 35.8.33.8.3.73.3 1.5 1.3 3.9 W 7.4 3. 5.4 3.7 W 6.5.5 7. 4.6 W 7.7 FE filure lod (N) ~(%) 698 1117 6997 115 7188 177 649 1184 66 19 6548 113 68 1517 6768 1534 6587 1685 1.3 5. 1.7 5.3. 6.8 1. 6.8 j.4 4.9 3.9 W 4.8 m Note: Prmeters printed old indicte significnt chnge from seline within tretment group with p <.5. ~ ¼ chnge from seline; CSA ¼ cross-sectionl re; BV/TV ¼ treculr one volume per tissue volume; FE ¼ finite element. Outcomes otined fter utosegmenttion lgorithm. p <.1 compred with seline within tretment group. c p <.5. d p <.1 zoledronic cid versus PTH 1 34 t seline. e p <.5 PTH 1 34 versus PTH 1 84 t seline. f p <.1. g p <.1 zoledronic cid versus PTH 1 34 t follow-up. h p <.5. i p <.1. j p <.1 PTH 1 34 versus PTH 1 84 t follow-up. k p <.5. l p <.1. m p <.1 PTH 1 84 versus zoledronic cid t follow-up. The p vlues re derived from one-wy nlysis of vrince for seline comprisons nd mixed-effects models for longitudinl chnges. 74 HANSEN ET AL. Journl of Bone nd Minerl Reserch
15 1 5 A Lumr spine 3 1 1 B Totl hip Medin (5 75 Percentiles) (µg/l) 4 4 1.5 1..5 C 1/3 Distl forerm E CTX1 PTH 1 34 PTH 1 84 Medin (5 75 Percentiles) (µg/l) 4 4 6 3 1 D Ultr distl forerm F P1NP Zoledronic Acid Fig.. Chnge over time in one minerl density y DXA t the lumr spine (A), totl hip (B), 1/3 distl forerm (C), nd ultrdistl forerm (D) nd for iochemicl mrkers of one turnover including c-telopeptide of type 1 collgen (CTX1) (E) nd mino-terminl propeptide of type 1 collgen (P1NP) (F). Ptients treted with PTH 1 34 re shown s lck solid lines, PTH 1 84 s gry solid lines, nd zoledronic cid s lck dshed lines. The p vlues for longitudinl chnges in DXA vlues re derived from mixed-effects models. The p vlues etween groups for chnges in P1NP nd CTX1 re derived from Mnn-Whitney two-smple test. ¼ p <.1 for zoledronic cid versus PTH 1 34; ¼ p <.1 for PTH 1 84 versus zoledronic cid. declines were seen oth t the 1/3 distl nd ultrdistl forerm sites t month 18. Effects of tretment on iochemicl mrkers of one turnover Zoledronic cid decresed mrkers of one formtion nd resorption t oth months 6 nd 18 (Fig. ). Conversely, mrkers of formtion nd resorption incresed with PTH 1 84 t months 6 nd 18, wheres PTH 1 34 incresed P1NP t months 6 nd 18 nd incresed CTX1 t month 6 nd nonsignificntly so t month 18 (p ¼.8). Effects of tretment on one morphology y HR-pQCT HR-pQCT dt re shown in Tle. One imge t month 6 (PTH 1 84, n ¼ 1) nd three imges t month 18 (PTH 1 84 ¼ 1, zoledronic cid ¼ ) were disregrded ecuse of excessive motion rtifcts. The verge common region in rdius ws 85%. In rdius, zoledronic cid incresed BV/TV nd treculr numer t month 18, wheres CSA, corticl thickness, corticl porosity, nd totl nd corticl densities were unchnged (Fig. 3). PTH 1 34 incresed CSA t month 18 long with corticl thickness nd corticl porosity t months 6 nd 18. Corticl density ws decresed t month 18. Treculr numer ws incresed t month 6 ut ws unchnged from seline t month 18. PTH 1 84 incresed corticl porosity t month 6 nd month 18, wheres CSA nd corticl thickness were unchnged. Corticl density ws decresed t month 18. No significnt chnges in the cncellous comprtment were oserved t month 18. The response in severl prmeters differed etween tretment groups (Tle ). Most notly, the increse in corticl porosity with PTH 1 34 nd PTH 1 84 differed significntly from the response to zoledronic cid (p <.1 nd p <.1). In tii, ll imges hd dequte qulity, nd the verge common region ws 91%. In tii, zoledronic cid incresed corticl thickness, totl nd corticl densities, treculr BV/TV, nd treculr numer t month 18, wheres CSA ws unchnged. PTH 1 34 incresed corticl thickness nd corticl porosity t months 6 nd 18, wheres CSA ws unchnged. Totl density incresed t month 18, despite decrese in corticl density. In the cncellous comprtment, BV/TV nd treculr numer incresed with no chnge in treculr thickness. PTH 1 84 decresed corticl thickness nd incresed corticl porosity t month 18 with no chnge in CSA. Totl nd corticl densities decresed. In the cncellous comprtment, treculr numer incresed, wheres treculr thickness decresed t month 18. The increse in corticl porosity ws unique to PTH 1 34 nd PTH 1 84 tretments (p <.1 nd p <.1), wheres the decrese in corticl thickness nd BV/TV oserved with PTH 1 84 t month 18 ws significnt compred with the responses seen with zoledronic cid (p <.1 nd p <.1) nd PTH 1 34 (oth p <.1). Treculr thinning ws solely oserved with PTH 1 84 (p <.5 compred with PTH 1 34 or zoledronic cid). Journl of Bone nd Minerl Reserch EFFECTS OF PTH 1 34, PTH 1 84, AND ZOLEDRONIC ACID ON BONE MICROARCHITECTURE 741
RADIUS 6 4 Corticl thickness c 6 4 Corticl porosity e TIBIA 5 5 Corticl thickness d e 1 1 Corticl porosity e PTH 1 34 PTH 1 84 Zoledronic Acid Fig. 3. Percent chnges from seline y HR-pQCT in corticl thickness (left column) nd corticl porosity (right column) in rdius (top row) nd tii (ottom row). Ptients treted with PTH 1 34 shown s lck solid lines, PTH 1 84 s gry solid lines, nd zoledronic cid s lck dshed lines. Predicted men nd 95% CI from mixed effects models. ¼ p <.1, ¼ p <.1 for zoledronic cid versus PTH 1 34; c ¼ p <.1, d ¼ p <.1 for PTH 1 34 versus PTH 1 84; e ¼ p <.1 for PTH 1 84 versus zoledronic cid. Effects on FE estimted strength In rdius, FE estimted strength ws preserved with zoledronic cid nd PTH 1 34, wheres it decresed from seline with PTH 1 84 (Fig. 4). This decline ws significntly different from the response with zoledronic cid (p <.1) ut not PTH 1 34 (p ¼.16). In tii, estimted filure lod ws mintined with zoledronic cid t month 6 with trend towrd n increse t month 18. Estimted strength ws preserved with PTH 1 34, wheres it declined from seline with PTH 1 84 t month 18. This decline ws significnt compred with the response with oth zoledronic cid (p <.1) nd PTH 1 34 (p <.1). Discussion In this longitudinl HR-pQCT study, we found tht 18 months of tretment with PTH 1 34 or PTH 1 84 ws ssocited with n increse in corticl porosity nd decline in corticl density in oth rdius nd tii. Also, treculr numer in tii incresed with oth nolic gents s did corticl thickness in oth rdius nd tii with PTH 1 34. Conversely, with 18 months of tretment with zoledronic cid, rdius nd tii corticl porosity ws unchnged, wheres treculr one volume frction incresed. Bone strength estimted y FE nlysis ws preserved RADIUS 4 4 6 Filure lod TIBIA 4 4 6 Filure lod c PTH 1 34 PTH 1 84 Zoledronic Acid Fig. 4. Percent chnges from seline in HR-pQCT-sed finite element (FE) estimted filure lod in rdius (left) nd tii (right). Ptients treted with PTH 1 34 shown s lck solid lines, PTH 1 84 s gry solid lines, nd zoledronic cid s lck dshed lines. Predicted men nd 95% confidence intervls from mixed effects models. ¼ p <.1, ¼ p <.1 for PTH 1 84 versus zoledronic cid; c ¼ p <.1 for PTH 1 84 versus PTH 1 34. 74 HANSEN ET AL. Journl of Bone nd Minerl Reserch
with PTH 1 34 nd zoledronic cid, wheres it decresed with PTH 1 84 t oth rdius nd tii. Anolic therpy incresed corticl porosity with corresponding decrese in corticl density in oth rdius nd tii. The decline in corticl density is in ccordnce with findings from smller 18-month study on the effects of PTH 1 34 using HR-pQCT (n ¼ 11), which lso reported (nonsignificnt) increses in corticl porosity. (11) The cellulr mechnisms underlying these findings cnnot e ddressed using HR-pQCT. Consistent with the mode of ction of nolic gents documented in nimls, (7,8,1) PTH my, however, ccelerte intrcorticl remodeling s well s endostel remodeling with net positive lnce etween one formtion nd resorption on the endostel surfce. () We lso found slight ut significnt increse in rdius CSA with PTH 1 34. As the chnge in CSA long the extremity length is used for common region mtching in HRpQCT methodology, (18) it is uncertin if this increse reltes to the pplied imge hndling or represents pposition of new one on the periostel surfce. An increse in rdius CSA with 18 months of PTH 1 34 ( mg) tretment compred with plceo-treted control sujects ws similrly found using peripherl QCT. (3) However, the extent to which intermittent PTH exposure increses one dimeter in humns remins unsettled. No chnges in cncellous microrchitecture prmeters with either nolic gent were oserved in rdius. In tii, oth nolic gents cused significnt increse in treculr numer. PTH 1 34 lso incresed BV/TV, wheres significnt treculr thinning ws oserved with PTH 1 84. Treculr thinning ws lso reported y McDonld nd collegues (11) during PTH 1 34 tretment using HR-pQCT. The underlying cellulr mechnism cnnot e ddressed using HR-pQCT ut my include intrtreculr tunneling. This phenomenon hs een oserved t multiple skeletl sites in nimls treted with intermittent PTH 1 84 (4) nd lso in the humn ilic crest during tretment with PTH 1 34. (5) Tretment with zoledronic cid incresed corticl density nd corticl thickness in tii with similr nonsignificnt trends in rdius. No chnges in corticl porosity were oserved. This is in ccordnce with previous findings on the effects of the isphosphontes lendronte nd indronte using HRpQCT. (6 9) The response in the cncellous comprtment with zoledronic cid in our study, with n increse in treculr numer in tii, is in ccordnce with findings with lendronte in some (9) ut not ll studies. (7) Indronte did not exert significnt effects on cncellous rchitecture compred with plceo fter yers of tretment. (8) Wheres the oserved increse in corticl thickness my e cused y closure of the endostel remodeling spce, the mechnism underlying the oserved increse in treculr numer is not in ccordnce with the ntiresorptive mode of ction of isphosphontes. (3) Treculr tunneling hs not een descried with isphosphonte tretment, nd with ge the numer of trecule in rdius nd tii decrese rther thn increse. (31) The oserved increse in treculr numer in our nd other studies with isphosphontes my thus relte to imge segmenttion nd structure extrction on the endostel surfce. Neither nolic nor ntiresorptive therpy resulted in n increse in FE estimted one strength compred with seline. For zoledronic cid, this is in ccordnce with HR-pQCT study ssessing the effects of yers of tretment with lendronte on FE estimted one strength in rdius nd tii. (7) An importnt limittion to the FE nlysis pplied in our nd in the ovementioned study is tht it ssumes fixed, homogeneous mteril properties. The oserved chnges in estimted strength re therefore solely ttriutle to chnges in geometry nd microrchitecture. This my hve underestimted the iomechnicl response with zoledronic cid ecuse prt of the frcture-reducing efficcy with isphosphontes is thought to e conveyed through n increse in one minerliztion. (3) Increses in FE estimted verterl strength up to 3% hve een found fter 1 yer of PTH 1 34 tretment. (1) In the totl hip, FE estimted strength ws found to e preserved with 18 months of PTH 1 34 tretment, (33) wheres % increse ws found fter 1 months of PTH 1 84. (34) In our study, FE estimted one strength ws preserved with PTH 1 34, wheres it decresed from seline with PTH 1 84 in rdius nd tii. In postmenopusl women, corticl pores hve een estimted to cuse.6% nd.6% decrement in FE estimted filure lod in rdius nd tii, respectively. (35) The oserved increses in corticl porosity in our study my therefore prtly underlie the decreses in estimted strength found with PTH 1 84. In the cse of PTH 1 34, the increse in corticl porosity ws to lrger extent counterlnced y eneficil effects on corticl geometry nd cncellous mss nd rchitecture wherey overll one strength ws preserved. It should, however, e emphsized tht the FE models used in this study were unscled. The effects on one strength of new, underminerlized one tissue formed during nolic therpy my therefore not hve een ppropritely ccounted for. The finding tht PTH 1 34 nd PTH 1 84 pper to hve different profiles ws, however, surprising nd wrrnts confirmtion. The extent to which differences in phrmcokinetic profiles etween the two gents (36,37) or ctions through seprte receptor for the C-terminl end of the PTH peptide, proposed to e expressed in cells of osteolst linege, (38,39) cuse diverse skeletl effects is unknown. Lrger, long-term cohort studies directly compring frcture rtes etween ptients treted with the two nolic gents re needed to clrify the clinicl significnce of these oservtions. This study hs some importnt strengths. To our knowledge, this is the first study to directly compre nolic tretment with PTH 1 34 nd PTH 1 84 in postmenopusl osteoporotic women in hed-to-hed oservtionl study. Also, group of prticipnts prescried isphosphonte therpy ws included, llowing comprisons of tretment effects of oth nolic nd ntiresorptive therpy within the sme study. However, we cknowledge tht our study hs limittions. First, frction of prticipnts in ech tretment group hd received prior isphosphonte tretment, which hs een oserved to lunt the response to nolic therpy in the spine nd hip. (4,41) There ws no consistent pttern to suggest lunting of the response in BTM, DXA, or HR-pQCT prmeters in the cse of previous isphosphonte use in those treted with PTH 1 34 nd PTH 1 84 (dt not shown). Becuse the frction of previous isphosphonte users in those treted with PTH 1 34 (8%) ws Journl of Bone nd Minerl Reserch EFFECTS OF PTH 1 34, PTH 1 84, AND ZOLEDRONIC ACID ON BONE MICROARCHITECTURE 743
(nonsignificntly) lower compred with PTH 1 84 (45%), we cnnot, however, exclude tht this difference hs impcted findings. Second, this ws n open-lel, nonrndomized study. Becuse of differences in reimursement criteri for nolic therpy nd zoledronic cid, those prescried nolic therpy hd more severe skeletl disese illustrted y lrger frction with verterl frctures. Also, totl density in tii ws lower in those prescried PTH 1 34. Tretment groups did not, however, differ significntly in terms of BMD y DXA or microrchitecture prmeters in either rdius or tii. Third, the complince with nolic therpy nd supplements ws not scertined through drug ccountility ut ws ddressed through numer of clinicl visits throughout the study nd susequent chrt review. To conclude, this 18-month, open-lel, oservtionl HRpQCT study found divergent tretment-specific effects in corticl nd treculr one with nolic nd zoledronic cid therpy. Anolic therpy incresed corticl porosity nd decresed corticl density, which for PTH 1 34 ws ccompnied y n increse in corticl thickness t oth sites. With oth nolic gents nd with zoledronic cid, treculr numer incresed in tii. FE estimtes of one strength ws mintined with zoledronic cid nd PTH 1 34 ut decresed with PTH 1 84. The decline in FE filure lod with PTH 1 84 ws significntly inferior to the response with zoledronic cid in oth rdius nd tii nd to PTH 1 34 in tii ut not in rdius. The different responses with PTH 1 34 nd PTH 1 84 ws surprising nd wrrnts confirmtion. Disclosures All uthors stte tht they hve no conflicts of interest. Acknowledgments We re grteful to Mrs. Steffnie Anthony Christinsen for study coordintion nd Clire Gudex, MD, for lnguge support. Authors roles: Study design: SH nd KB. Study conduct: SH. Dt collection: SH. Dt nlysis: SH. Dt interprettion: SH, KB, EH, nd JEBJ. Drfting mnuscript: SH. Revising mnuscript: KB, JEBJ, nd EH. Approving finl version of mnuscript: SH, KB, EH, nd JEBJ. SH tkes responsiility for the integrity of the dt nlysis. References 1. Lindsy R, Cosmn F, Zhou H, Bostrom MP, Shen VW, Cruz JD, Nieves JW, Dempster DW. A novel tetrcycline leling schedule for longitudinl evlution of the short-term effects of nolic therpy with single ilic crest one iopsy: erly ctions of teriprtide. J Bone Miner Res. 6 Mr; 1(3):366 73.. M YL, Zeng Q, Donley DW, Ste-Mrie LG, Gllgher JC, Dlsky GP, Mrcus R, Eriksen EF. Teriprtide increses one formtion in modeling nd remodeling osteons nd enhnces IGF-II immunorectivity in postmenopusl women with osteoporosis. J Bone Miner Res. 6 Jun; 1(6):855 64. 3. Greenspn SL, Bone HG, Ettinger MP, Hnley DA, Lindsy R, Znchett JR, Blosch CM, Mthisen AL, Morris SA, Mrriott TB. Effect of recominnt humn prthyroid hormone (1 84) on verterl frcture nd one minerl density in postmenopusl women with osteoporosis: rndomized tril. Ann Intern Med. 7 Mr 6; 146(5):36 39. 4. Neer RM, Arnud CD, Znchett JR, Prince R, Gich GA, Reginster JY, Hodsmn AB, Eriksen EF, Ish-Shlom S, Gennt HK, Wng O, Mitlk BH. Effect of prthyroid hormone (1 34) on frctures nd one minerl density in postmenopusl women with osteoporosis. N Engl J Med. 1 My 1; 344(19):1434 41. 5. Reeve J, Meunier PJ, Prsons JA, Bernt M, Bijvoet OL, Courpron P, Edourd C, Klenermn L, Neer RM, Renier JC, Slovik D, Vismns FJ, Potts JT Jr. Anolic effect of humn prthyroid hormone frgment on treculr one in involutionl osteoporosis: multicentre tril. Br Med J. 198 Jun 7; 8(68):134 4. 6. Dempster DW, Cosmn F, Prisien M, Shen V, Lindsy R. Anolic ctions of prthyroid hormone on one. Endocr Rev. 1993 Dec; 14(6):69 79. 7. Burr DB, Hirno T, Turner CH, Hotchkiss C, Brommge R, Hock JM. Intermittently dministered humn prthyroid hormone(1 34) tretment increses intrcorticl one turnover nd porosity without reducing one strength in the humerus of ovriectomized cynomolgus monkeys. J Bone Miner Res. 1 Jn; 16(1):157 65. 8. Fox J, Miller MA, Newmn MK, Recker RR, Turner CH, Smith SY. Effects of dily tretment with prthyroid hormone 1 84. for 16 months on density, rchitecture nd iomechnicl properties of corticl one in dult ovriectomized rhesus monkeys. Bone. 7 Sep; 41(3):31 3. 9. Boutroy S, Bouxsein ML, Munoz F, Delms PD. In vivo ssessment of treculr one microrchitecture y high-resolution peripherl quntittive computed tomogrphy. J Clin Endocrinol Met. 5 Dec; 9(1):658 15. 1. Pistoi W, Vn Rietergen B, Lochmuller EM, Lill CA, Eckstein F, Ruegsegger P. Imge-sed micro-finite-element modeling for improved distl rdius strength dignosis: moving from ench to edside. J Clin Densitom. 4;7():153 6. 11. Mcdonld HM, Nishiym KK, Hnley DA, Boyd SK. Chnges in treculr nd corticl one microrchitecture t peripherl sites ssocited with 18 months of teriprtide therpy in postmenopusl women with osteoporosis. Osteoporos Int. 11 Jn; (1):357 6. 1. Greff C, Chevlier Y, Chrleois M, Vrg P, Phr D, Nickelsen TN, Morlock MM, Gluer CC, Zysset PK. Improvements in verterl ody strength under teriprtide tretment ssessed in vivo y finite element nlysis: results from the EUROFORS study. J Bone Miner Res. 9 Oct; 4(1):167 8. 13. Buer DC, Grnero P, Bilezikin JP, Greenspn SL, Ensrud KE, Rosen CJ, Plermo L, Blck DM. Short-term chnges in one turnover mrkers nd one minerl density response to prthyroid hormone in postmenopusl women with osteoporosis. J Clin Endocrinol Met. 6 Apr; 91(4):137 5. 14. Puchrd Y, Liphrdt AM, Mcdonld HM, Hnley DA, Boyd SK. Qulity control for one qulity prmeters ffected y suject motion in high-resolution peripherl quntittive computed tomogrphy. Bone. 1 Jun; 5(6):134 1. 15. Buie HR, Cmpell GM, Klinck RJ, McNeil JA, Boyd SK. Automtic segmenttion of corticl nd treculr comprtments sed on dul threshold technique for in vivo micro-ct one nlysis. Bone. 7 Oct; 41(4):55 15. 16. Burghrdt AJ, Buie HR, Li A, Mjumdr S, Boyd SK. Reproduciility of direct quntittive mesures of corticl one microrchitecture of the distl rdius nd tii y HR-pQCT. Bone. 1 Sep; 47(3):519 8. 17. Nishiym KK, Mcdonld HM, Buie HR, Hnley DA, Boyd SK. Postmenopusl women with osteopeni hve higher corticl porosity nd thinner cortices t the distl rdius nd tii thn women with norml BMD: n in vivo HR-pQCT study. J Bone Miner Res. 1 Apr; 5(4):88 9. 18. Li A, Huselmnn HJ, Ruegsegger P. In vivo high resolution 3D-QCT of the humn forerm. Technol Helth Cre. 1998 Dec; 6(5 6):39 37. 744 HANSEN ET AL. Journl of Bone nd Minerl Reserch
19. Jing Y, Zho JJ, Mitlk BH, Wng O, Gennt HK, Eriksen EF. Recominnt humn prthyroid hormone (1 34) [teriprtide] improves oth corticl nd cncellous one structure. J Bone Miner Res. 3; Nov; 18(11):193 41.. Eriksen EF, Melsen F, Sod E, Brton I, Chines A. Effects of long-term risedronte on one qulity nd one turnover in women with postmenopusl osteoporosis. Bone. Nov; 31(5):6 5. 1. Hirno T, Burr DB, Cin RL, Hock JM. Chnges in geometry nd corticl porosity in dult, ovry-intct rits fter 5 months tretment with LY333334 (hpth 1 34). Clcif Tissue Int. Jun; 66(6):456 6.. Lindsy R, Zhou H, Cosmn F, Nieves J, Dempster DW, Hodsmn AB. Effects of one-month tretment with PTH(1 34) on one formtion on cncellous, endocorticl, nd periostel surfces of the humn ilium. J Bone Miner Res. 7 Apr; (4):495 5. 3. Znchett JR, Bogdo CE, Ferretti JL, Wng O, Wilson MG, Sto M, Gich GA, Dlsky GP, Myers SL. Effects of teriprtide [recominnt humn prthyroid hormone (1 34)] on corticl one in postmenopusl women with osteoporosis. J Bone Miner Res. 3 Mr; 18(3):539 43. 4. Miller MA, Bre SP, Recker RR, Smith SY, Fox J. Intrtreculr tunneling increses treculr numer throughout the skeleton of ovriectomized rhesus monkeys treted with prthyroid hormone 1 84. Bone. 8 Jun; 4(6):1175 83. 5. Joke B, Muche B, Burghrdt AJ, Semler J, Link TM, Mjumdr S. Teriprtide in isphosphonte-resistnt osteoporosis: microrchitecturl chnges nd clinicl results fter 6 nd 18 months. Clcif Tissue Int. 11 Aug; 89():13 9. 6. Seemn E, Delms P.D, Hnley D.A, Sellmeyer D, Cheung A.M, Shne E, Kerns A, Thoms T, Boyd S.K, Boutroy S, Bogdo C, Mjumdr S, Fn M, Linti C, Znchett J. Microrchitecturl deteriortion of corticl nd treculr one: differing effects of denosum nd lendronte. J Bone Miner Res. 1; Aug; 5(8):1886 94. 7. Burghrdt AJ, Kzki GJ, Sode M, de Ppp AE, Link TM, Mjumdr S. A longitudinl HR-pQCT study of lendronte tretment in postmenopusl women with low one density: reltions mong density, corticl nd treculr microrchitecture, iomechnics, nd one turnover. J Bone Miner Res. 1 Dec; 5(1):8 95. 8. Chpurlt RD, Lroche M, Thoms T, Rounet S, Delms PD, De Vernejoul MC. Effect of orl monthly indronte on one microrchitecture in women with osteopeni rndomized plceo-controlled tril. Osteoporos Int. 1 Mr 9. [Epu hed of print]. 9. Rizzoli R, Chpurlt RD, Lroche JM, Krieg MA, Thoms T, Frieling I, Boutroy S, Li A, Bock O, Felsenerg D. Effects of strontium rnelte nd lendronte on one microstructure in women with osteoporosis. Results of -yer study. Osteoporos Int. 1 Jn; 3(1):35 15. 3. Estell R, Wlsh JS, Wtts NB, Siris E. Bisphosphontes for postmenopusl osteoporosis. Bone. 11 Jul; 49(1):8 8. 31. Mcdonld HM, Nishiym KK, Kng J, Hnley DA, Boyd SK. Agerelted ptterns of treculr nd corticl one loss differ etween sexes nd skeletl sites: popultion-sed HR-pQCT study. J Bone Miner Res. 11 Jn; 6(1):5 6. 3. Boivin GY, Chvssieux PM, Sntor AC, Ytes J, Meunier PJ. Alendronte increses one strength y incresing the men degree of minerliztion of one tissue in osteoporotic women. Bone. Nov; 7(5):687 94. 33. Keveny TM, McClung MR, Wn X, Kopperdhl DL, Mitlk BH, Krohn K. Femorl strength in osteoporotic women treted with teriprtide or lendronte. Bone. 1 Jn; 5(1):165 7. 34. Keveny TM, Hoffmnn PF, Singh M, Plermo L, Bilezikin JP, Greenspn SL, Blck DM. Femorl one strength nd its reltion to corticl nd treculr chnges fter tretment with PTH, lendronte, nd their comintion s ssessed y finite element nlysis of quntittive CT scns. J Bone Miner Res. 8 Dec; 3(1):1974 8. 35. Burghrdt AJ, Kzki GJ, Rmchndrn S, Link TM, Mjumdr S. Age- nd gender-relted differences in the geometric properties nd iomechnicl significnce of intrcorticl porosity in the distl rdius nd tii. J Bone Miner Res. 1 My; 5(5):983 93. 36. Europen Medicines Agency. Forteo. Aville t: www.eme. europ.eu. Accessed 1 My 3. 37. Europen Medicines Agency. Preotct. Aville t: www.eme. europ.eu. Accessed 1 My 3. 38. Divieti P, Inomt N, Chpin K, Singh R, Juppner H, Bringhurst FR. Receptors for the croxyl-terminl region of pth(1 84) re highly expressed in osteocytic cells. Endocrinology. 1 Fe; 14():916 5. 39. Sutherlnd MK, Ro LG, Wylie JN, Gupt A, Ly H, Sodek J, Murry TM. Croxyl-terminl prthyroid hormone peptide (53 84) elevtes lkline phosphtse nd osteoclcin mrna levels in SOS- cells. J Bone Miner Res. 1994 Apr; 9(4):453 8. 4. Oermyer-Pietsch BM, Mrin F, McCloskey EV, Hdji P, Frrerons J, Boonen S, Audrn M, Brker C, Anstsilkis AD, Frser WD, Nickelsen T. Effects of two yers of dily teriprtide tretment on BMD in postmenopusl women with severe osteoporosis with nd without prior ntiresorptive tretment. J Bone Miner Res. 8; Oct; 3(1): 1591 6. 41. Greff C, Timm W, Nickelsen TN, Frrerons J, Mrin F, Brker C, Gluer CC. Monitoring teriprtide-ssocited chnges in verterl microstructure y high-resolution CT in vivo: results from the EUROFORS study. J Bone Miner Res. 7 Sep; (9):146 33. Journl of Bone nd Minerl Reserch EFFECTS OF PTH 1 34, PTH 1 84, AND ZOLEDRONIC ACID ON BONE MICROARCHITECTURE 745