Effects of Odanacatib on the Radius and Tibia of Postmenopausal Women: Improvements in Bone Geometry, Microarchitecture, and Estimated Bone Strength

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1 ORIGINL RTICLE JMR Effects of Odanacatib on the Radius and Tibia of Postmenopausal Women: Improvements in one Geometry, Microarchitecture, and Estimated one Strength ngela M Cheung, Sharmila Majumdar, Kim rixen, 3 Roland Chapurlat, 4 Thomas Fuerst, 5 Klaus Engelke, 6 ernard Dardzinski, 7 ntonio Cabal, 8 Nadia Verbruggen, 9 Shabana ther, 8 Elizabeth Rosenberg, 8 and nne E de Papp 8 University of Toronto, Ontario, Canada University of California, San Francisco, C, US 3 University of Southern Denmark, Odense, Denmark 4 INSERM, Lyon, France 5 Synarc, Inc., Newark, C, US 6 Synarc, Inc., Hamburg, Germany 7 Children s Hospital, The University of Pennsylvania, Philadelphia, P, US 8 Merck Sharp & Dohme, Whitehouse Station, NJ, US 9 Merck Sharp & Dohme, russels, elgium STRCT The cathepsin K inhibitor odanacatib (ODN), currently in phase 3 development for postmenopausal osteoporosis, has a novel mechanism of action that reduces bone resorption while maintaining bone formation. In phase studies, odanacatib increased areal bone mineral density (amd) at the lumbar spine and total hip progressively over 5 years. To determine the effects of ODN on cortical and trabecular bone and estimate changes in bone strength, we conducted a randomized, double blind, placebo controlled trial, using both quantitative computed tomography (QCT) and high resolution peripheral (HR p)qct. In previously published results, odanacatib was superior to placebo with respect to increases in trabecular volumetric MD (vmd) and estimated compressive strength at the spine, and integral and trabecular vmd and estimated strength at the hip. Here, we report the results of HR pqct assessment. total of 4 postmenopausal women (mean age years and baseline lumbar spine T score.8.83) were randomized to oral ODN 5 mg or placebo, weekly for years. With ODN, significant increases from baseline in total vmd occurred at the distal radius and tibia. Treatment differences from placebo were also significant (3.84% and.63% for radius and tibia, respectively). t both sites, significant differences from placebo were also found in trabecular vmd, cortical vmd, cortical thickness, cortical area, and strength (failure load) estimated using finite element analysis of HR pqct scans (treatment differences at radius and tibia ¼.64% and.66%). t the distal radius, odanacatib significantly improved trabecular thickness and bone volume/total volume (V/TV) versus placebo. t a more proximal radial site, odanacatib attenuated the increase in cortical porosity found with placebo (treatment difference ¼ 7.7%, p ¼.66). t the distal tibia, odanacatib significantly improved trabecular number, separation, and V/TV versus placebo. Safety and tolerability were similar between treatment groups. In conclusion, odanacatib increased cortical and trabecular density, cortical thickness, aspects of trabecular microarchitecture, and estimated strength at the distal radius and distal tibia compared with placebo. 4 merican Society for one and Mineral Research KEY WORDS: VOLUMETRIC MD; OSTEOPOROSIS; ODNCTI Introduction Odanacatib (ODN) is a selective and reversible inhibitor of cathepsin K, the principal collagenase secreted by osteoclasts. () Odanacatib is currently in late stage development for treatment of postmenopausal osteoporosis, a disease characterized by low bone density and microarchitectural deterioration. (,3) oth bone density and microarchitecture contribute to bone strength. However, routine clinical imaging of bone is generally limited to areal bone mineral density (amd) assessment, a measurement that does not always accurately identify women who will experience fragility fractures. Received in original form October, 3; revised form January 4, 4; accepted February, 4. ccepted manuscript online February,, 4. ddress correspondence to: ngela M Cheung, MD, PhD, FRCPC, CCD, Lillian Love Chair in Women s Health, University of Toronto and University Health, Elizabeth Street, 7EN, Toronto ON M5G C4, Canada. E mail: angela.m.cheung@uhn.ca Journal of one and Mineral Research, Vol. 9, No. 8, ugust 4, pp DOI:./jbmr.94 4 merican Society for one and Mineral Research 786

2 Previously, bone microarchitecture was generally assessed in humans with an iliac crest bone biopsy using histomorphometry. Quantitative computed tomography (QCT) and high resolution peripheral (HR p)qct now allow in vivo assessment of bone microstructure within the trabecular and cortical bone compartments, without the need for bone biopsy. (4) Despite the availability of effective treatments for osteoporosis, these treatments have limitations in real world effectiveness and tolerability. Furthermore, the majority of women sustaining osteoporotic fractures remain untreated. New therapeutic options with novel mechanisms of action are desirable. In a randomized, placebo controlled, phase study in postmenopausal women with osteoporosis, 5 years of ODN 5 mg once weekly progressively increased amd at the lumbar spine and total hip (by.9% and 8.5% from baseline, respectively). (5) ODN treatment resulted in sustained reductions in bone resorption markers, but reductions in bone formation markers were transient and returned to baseline levels after approximately years of treatment. (6,7) The absence of a sustained effect on bone formation with odanacatib treatment is supported by histomorphometric analyses at the iliac crest in humans, showing no difference in activation frequency compared with placebo after years of treatment. (7,8) This finding differs from the sustained reduction in bone formation markers and the reduction of activation frequency observed by histomorphometry with estrogen, bisphosphonates, and the RNK ligand antibody denosumab. (9) one formation by osteoblasts is dependent on the maintenance of osteoclast activity. () The preservation of bone formation with odanacatib is likely the result of the maintenance or increase in osteoclast number that occurs with treatment. In the global odanacatib dose finding phase clinical trial, the osteoclast marker TRP 5b was noted to increase with odanacatib treatment. (5,6) In addition, odanacatib treatment of ovariectomized primates dose dependently increased osteoclast number at the lumbar vertebral trabecular surface. () Odanacatib differs from currently available antiresorptive treatments, which either reduce the number of mature osteoclasts and/or interfere with differentiated osteoclast functions. The result of these treatments is a reduction of bone resorption and an indirect reduction of bone formation owing to the communication between osteoclasts and osteoblasts. (9) phase 3 study of odanacatib in postmenopausal women with low bone mass that utilized detailed imaging methodologies, QCT and QCT based finite element analysis (FE) showed increases in volumetric MD (vmd) and estimated strength at the lumbar spine and femur with odanacatib relative to placebo treatment. (7) In addition, the analysis suggested that odanacatib increased endocortical apposition of bone at the femoral neck, without evidence of periosteal expansion. In ovariectomized nonhuman primates, odanacatib increased MD and strength (ultimate load) at the femoral neck and increased cortical thickness and periosteal bone formation at the femoral neck and proximal femur. () In this model, odanacatib also improved bone density and geometry at the radius and tibia, as determined by HR pqct. (3,4) t these peripheral sites, odanacatib treatment led to increases in bone strength estimated using HR pqct based FE, and these estimated increases were validated ex vivo by mechanical compression testing (r ¼.95 and.85 in the two studies, respectively). In the second study, odanacatib demonstrated significantly greater gains in vmd, cortical thickness, bone volume/total volume (V/TV), and estimated bone strength at the distal radius compared with alendronate. (4) ased upon these observations in the nonhuman primate model, HR pqct was used in exploratory endpoints, described in the current report, to determine the effects of odanacatib compared with placebo on cortical and trabecular bone density, microarchitecture, and geometry at the distal radius and distal tibia in postmenopausal women. Furthermore, HR pqct based FE was used to compare changes in estimated bone strength at these skeletal sites after years of treatment. Materials and Methods Study design Detailed methods of this study (registered under www. clinicaltrials.gov [NCT7983]) have been published previously. (7) Postmenopausal women generally naïve to prior boneactive agents and with low normal to moderately osteoporotic bone density (MD T scores at the lumbar spine, total hip, femoral neck, or trochanter.5 but > 3.5) were enrolled in a year randomized trial to receive either placebo or ODN 5 mg weekly. Women were excluded if they had ever had a hip fracture or had a non hip fragility fracture with 4 months of entry (unless they were not candidates for any currently approved osteoporosis therapy). Lumbar spine MD at year was the primary endpoint. Secondary endpoints included QCT at the total hip and biochemical markers of bone turnover. Exploratory endpoints, reported herein, included QCT analysis at the spine and hip subregions and QCT based FE at the spine and hip. HR pqct parameters and HR pqct based FE at the distal radius and distal tibia are the exploratory endpoints included in the current study. High resolution peripheral quantitative computed tomography HR pqct images were acquired using a Scanco XtremeCT (Scanco Medical, rüttisellen, Switzerland) in both the radius and tibia of each patient. Images were acquired at the standard XtremeCT locations 9.5 mm from the distal radial endplate and.5 mm from distal tibial endplate. Specifically in this study, a second set of scans were performed mm further proximal in both the tibia and radius for the assessment of cortical porosity. Fig. shows the position of the standard and more proximal volumes of interest for the radius. For the purpose of this article, the standard locations will be denoted as distal and the more proximal locations as more proximal. ll scans were acquired with an isotropic voxel size of 8 microns. For the analysis of the distal scans, the standard fixed attenuation threshold segmentation technique implemented on the scanner was used (Scanco analysis software version 5.7b). This software reports vmd in various compartments as well as cortical thickness; however, it does not provide a measure of cortical porosity. Experimental advanced cortical segmentation described by urghardt and colleagues (5) for the standard distal sites was applied to our novel more proximal sites. This technique allows for an extensive characterization of cortical pores and provides a measure of cortical porosity by using an improved segmentation. t the time of the initial data analysis, the advanced cortical segmentation was not available from Scanco for the standard distal location. Since then, we have performed blinded post hoc analyses using the Scanco cortical porosity software at the standard distal location. Centralized quality control and analyses were performed by Synarc, Inc. (Hamburg, Germany). Cross calibration of HR pqct scanners was performed using a European forearm Journal of one and Mineral Research ODNCTI IMPROVES VOLUMETRIC MD IN POSTMENOPUSL WOMEN 787

3 between the two methods were compared, a regression analysis showed that with the exception of Tb.Th (r ¼.4), all standard HR pqct parameters were highly correlated (r >.8) to similar mct parameters. Of note, correlation was high for cortical thickness (r ¼.93) but lower for cortical porosity (r ¼.6) (at the standard distal site). Finite element analysis Fig.. () Schematic illustrating the two distal radius bone regions scanned in the study. Similar regions were scanned in the tibia. () Left: Three dimensional (3D) distribution of von Mises stresses in the distal radius bone tissue. Right: Two dimensional (D) view of center slice for the same bone section. (C) Left: 3D distribution of von Mises stresses in the distal tibia bone tissue. Right: D view of center slice for the same bone section. phantom (QRM, Möhrendorf, Germany). Further details of the analysis method and the multicenter short term precision obtained in a subset of scans from the study were previously reported by Engelke and colleagues. (6) In brief, the HR pqct scans were analyzed using the Scanco software to provide results for total, trabecular, and cortical vmd, cortical thickness, trabecular number, thickness, and separation, and V/TV. t both the more proximal site and the standard distal site, cortical porosity was measured as the proportion of cortical volume occupied by pores detected in the HR pqct image. ccuracy of HR pqct has recently been investigated by comparing HR pqct with mct measurements of the same samples. (7) lthough for all parameters of trabecular structure there were significant differences when absolute measurements ll FE was performed using the methodology proposed by Pistoia and colleagues, (8) used previously in several clinical studies. (9 3) FE analysis was only applied to the distal locations. Patient specific FE models generated from the HR pqct scans were tested in silico to estimate axial compression bone strength at baseline,, and 4 months after randomization. The FE methodology has been validated for ODN treatment using the ovariectomized (OVX) nonhuman primates (NHPs) osteoporosis model. (3,4) Fig. shows representative FE analyses of 3D reconstructed scans from a distal radius and distal tibia from this trial. The HR pqct images had an 8 mm voxel size, resulting in more than million elements per FE model too many for reasonable processing times with available processing power. To save computation time, images were down sampled to within % of those of the original images by adaptive thresholds, (3) resulting in less than million elements. We used a subject specific adaptive threshold that preserved the V of the original images (see details in Jayakar and colleagues). (3) Two different test thresholds were first applied: a lower one that gave an FE volume with a V above that for parent images and a higher one that gave an FE volume below the original V. The threshold corresponding to the FE volume with V of the parent image was then determined from a linear interpolation of the two test thresholds. The resulting FE volume matched within % of the V of the original parent image. This allowed us to run each FE simulation in a realistic time frame of a few hours, as opposed to a number of days with the original resolution, using 6 nodes of a 3 node dual core 64 bit Linux cluster with.66 GHz processors, 48 G of RM on the master node, and 6 G RM per processor node. FE models were created from the down sampled images using NSYS Mechanical (NSYS, Inc., Canonsburg, P, US) assuming a homogeneous linear elastic isotropic material (Young s modulus E ¼ 8 GPa; Poisson s ratio a c ¼.3). fixed displacement was applied at the distal end of the slab while keeping the proximal end clamped. We assumed bone failure was initiated when % of the total bone tissue was strained beyond.7%, as proposed by Pistoia and colleagues. (8) Statistical analysis ll results obtained from the HR pqct data were exploratory endpoints, analyzed using methods similar to those used for areal MD. (7) In the full analysis set population (treated participants with baseline and at least one on treatment measurement), a longitudinal analysis of covariance (NCOV) model was used with terms for treatment, time, geographic region, and the interaction of time by treatment, with the corresponding baseline value as a covariate. Results total of 4 postmenopausal women were enrolled into the study. The women who received ODN 5 mg or placebo weekly 788 CHEUNG ET L. Journal of one and Mineral Research

4 had similar characteristics at baseline (Table ). (7) Fifty three women (6 in the ODN group, 7 in the placebo group) had a history of any clinical (all nonvertebral) fractures since menopause. HR pqct data showed significant increases at 6 months, year, and years in total vmd at both the distal radius (Fig. ) and the distal tibia (Fig. 3) with odanacatib. Decreases in total vmd were observed in the placebo group. The differences (95% confidence interval [CI]) between ODN and placebo after years in least squares mean percent changes from baseline were significant at the radius and tibia: 3.84% (.9 to 4.77) and.63% (.8 to 3.46), respectively (p <. for each). When vmd was examined separately in the trabecular and cortical compartments, significant treatment differences favoring odanacatib occurred at both the radius and tibia (Fig. and Fig. 3). Relative to placebo, odanacatib increased vmd in the trabecular compartments and prevented a decline in vmd in the cortical compartments. Odanacatib improved several measures of bone structure. Whereas cortical thickness at the radius and tibia significantly decreased in the placebo group over the course of the trial, cortical thickness increased with odanacatib at the distal radius and tibia (Fig. 4). t the distal radius, odanacatib treatment also led to increases in trabecular thickness and trabecular V/TV relative to placebo. t the distal tibia, there were significant treatment differences favoring odanacatib in trabecular number, trabecular separation, and trabecular V/TV (Fig. 5) but not trabecular thickness. trend toward significant reduction relative to placebo in cortical porosity was observed at the more proximal radial site (p ¼.66), although treatment differences in cortical porosity were not observed at the tibia (Fig. 5). Post hoc analyses of cortical porosity at the standard distal locations produced similar results (Fig. 5). There were no significant treatment differences in total area. Significant gains in cortical area, relative to placebo, were observed at both the Table. aseline Characteristics Characteristic ODN 5 mg OW (n ¼ 9) a Placebo OW (n ¼ 5) a ge (years), mean (SD) 63.9 (7.3) 64. (6.) Ethnicity: White, n (%) (93) 98 (93) real MD T score, mean (SD) Lumbar spine.7 (.74).9 (.9) Total hip.3 (.64).8 (.7) Femoral neck.78 (.53).76 (.55) HR pqct, mean (SD) Distal radius Volumetric MD (mg/cm 3 ) Total 68 (59) 73 (57) Trabecular 8 (33) 8 (3) Cortical 87 (75) 83 (7) Cortical thickness (mm).63 (.8).65 (.8) Trabecular thickness (mm).6 (.).6 (.) Trabecular number (per mm 3 ).69 (.3).67 (.33) Trabecular separation (mm).55 (.).56 (.5) Trabecular V/TV. (.3). (.3) Cortical porosity Proximal radius.3 (.).34 (.) Distal radius.4 (.).6 (.4) Distal tibia Volumetric MD (mg/cm 3 ) Total 45 (45) 4 (48) Trabecular 4 (3) 37 (3) Cortical 797 (57) 8 (66) Cortical thickness (mm).9 (.).9 (.4) Trabecular thickness (mm).7 (.).7 (.) Trabecular number (per mm 3 ).6 (.3).6 (.3) Trabecular separation.57 (.5).58 (.4) Trabecular V/TV. (.3). (.3) Cortical porosity Proximal tibia.83 (.35).77 (.3) Distal tibia.76 (.6).73 (.4) Estimated strength by HR pqct based FE (Newtons), mean (SD) Radius 34 (47) 338 (466) Tibia 89 (8) 87 (6) ODN ¼ odanacatib; OW ¼ once weekly; SD ¼ standard deviation; MD ¼ bone mineral density; HR pqct ¼ high resolution peripheral quantitative computed tomography; FE ¼ finite element analysis. a Numbers are for primary endpoint (lumbar spine areal MD). Other numbers may vary. Of 4 randomized, 6 had baseline HR pqct at the radius and 3 at the tibia. Of the 74 women who completed year follow up, 46 had HR pqct at the radius and 66 at the tibia. Journal of one and Mineral Research ODNCTI IMPROVES VOLUMETRIC MD IN POSTMENOPUSL WOMEN 789

5 C Total vmd aseline Trabecular vmd aseline Cortical vmd aseline 6 4 ODN 5 mg OW n=7 Placebo OW n= P vs Placebo. P vs Placebo <. 95% CI for % change from baseline excludes zero. Fig.. Volumetric MD (vmd) at the distal radius. Percent changes from baseline in () total vmd, () trabecular vmd, and (C) cortical MD. LS ¼ least squares. radius and tibia. Treatment differences were significant as early as 6 months, with the placebo group showing progressive losses in cortical area over time. t 4 months, there was a 6.95% difference between odanacatib and placebo at the radius and a 5.9% difference at the tibia (p <.; Fig. 5). Over years, FE estimated bone strength increased with odanacatib treatment at the radius and tibia but decreased in the placebo group (Fig. 6). Treatment differences after years in least squares mean percent change from baseline were.64% at the radius and.66% at the tibia compared with placebo (p <. C Total vmd aseline Trabecular vmd aseline aseline 6 4 ODN 5 mg OW n=79 Placebo OW n=87 Cortical vmd P vs Placebo <. P vs Placebo <. P vs Placebo <.5 95% CI for % change from baseline excludes zero. Fig. 3. Volumetric MD (vmd) at the distal tibia. Percent changes from baseline in () total vmd, () trabecular vmd, and (C) cortical MD. LS ¼ least squares. for both). Of note, FE analysis at the tibia was not specified in the protocol and was performed post hoc. Odanacatib was generally well tolerated with no treatment differences in overall adverse experiences or specifically in adverse effects of the skin or respiratory tract. Clinical fractures, captured as adverse experiences, occurred in patients (9.5%) 79 CHEUNG ET L. Journal of one and Mineral Research

6 Distal Radius Cortical Thickness Distal Tibia Cortical Thickness aseline 6 4 aseline 6 4 ODN 5 mg OW n=7 Placebo OW n=74 ODN 5 mg OW n=79 Placebo OW n=87 C Proximal Radius Cortical Thickness Proximal Tibia Cortical Thickness aseline 6 4 aseline 6 4 ODN 5 mg OW n=53 Placebo OW n=64 ODN 5 mg OW n=7 Placebo OW n=8 D P vs Placebo <.; P vs Placebo <.; P vs Placebo <.5; 95% CI for % change from baseline excludes zero. Fig. 4. Percent changes from baseline in cortical thickness at () the distal radius, () the distal tibia, (C) the more proximal radius, and (D) the more proximal tibia. LS ¼ least squares. receiving placebo and 3 (.8%) receiving odanacatib. The previous report from this study provides a more detailed presentation of safety results. (7) Discussion In this randomized, double blind, placebo controlled, year trial of odanacatib 5 mg weekly, HR pqct assessment showed significant improvements compared with placebo in total, cortical, and trabecular vmd, cortical thickness, cortical area, and estimated strength at the distal radius and distal tibia. HRpQCT at the radius and tibia also showed improvements in trabecular microarchitecture. The results of these exploratory endpoints are congruent with QCT based assessments of vmd and FE estimated strength at the hip and spine, (7) as well as areal MD results at hip and spine in this trial and in a previous odanacatib phase study. (5,7) HR pqct is a noninvasive means to assess the density and microstructure of trabecular and cortical skeletal compartments. The validity of HR pqct assessment and FE modeling of bone strength is supported by the finding of lower vmd, cortical thickness, and estimated bone strength in the distal radius in women with forearm fractures compared with a matched group without fracture, (4) by an association between HR pqct based FE estimates of failure load and wrist fracture in a cohort of the OFELY study, () by the association of estimated bone strength at the radius and tibia with all types of fragility fractures among postmenopausal women, () and by correlations between HRpQCT parameters and torque failure assessed mechanically in cadaveric tibia. (5) In addition, as mentioned previously, HRpQCT based FE estimates of bone strength correlated closely with biomechanical compression testing of bone strength in nonhuman primates treated with odanacatib. (3,4) HR pqct assessment has been used to evaluate treatment effects of several anti osteoporosis medications. (6) s with odanacatib in the current investigation, vmd at the radius and/ or tibia has been reported to be greater in comparison to placebo with alendronate, (9,7) ibandronate, (8) denosumab, (7) and estrogen/progestin therapy. (9) Comparing overall HR pqct measurement of density and microstructure between anatomic sites, greater treatment effects were found in the weight bearing tibia than the radius in some, (9,8) but not all, (7) studies of bisphosphonates. In general, differences in weight bearing did not appear to influence odanacatib treatment effects at different anatomic sites relative to placebo in this investigation. Changes in the radius mostly mirrored those in the tibia. Exceptions included an apparent increase in trabecular thickness found only in the radius and increases in trabecular number and separation found only in the tibia. These differences might be because of chance, as the trabecular microarchitecture parameters are derived results and affected by the resolution of the HR pqct Journal of one and Mineral Research ODNCTI IMPROVES VOLUMETRIC MD IN POSTMENOPUSL WOMEN 79

7 LS Mean %Change From aseline (95% CI) ODN PO Radius P =.66 P = Distal Radius Estimated Strength LS Mean %Change From aseline (95% CI) ODN PO Tibia P =.66 P =.74 aseline 6 4 ODN 5 mg OW n=7 Placebo OW n= Distal Tibia Estimated Strength P vs Placebo = <. P vs Placebo <. P vs Placebo =.5 Fig. 5. Two year percent changes from baseline in other HR pqct parameters at () radius and () tibia. The distal radius and tibia (to the left of the vertical line) were scanned for trabecular number, trabecular separation, trabecular thickness, trabecular bone volume/total volume (V/TV), cortical area, and cortical porosity. The more proximal regions (to the right of the vertical line) were scanned for assessment of cortical porosity. LS ¼ least squares. scanner. In the cortex, the attenuation of the increase in cortical porosity observed in the placebo group seemed to differ between the radius and tibia with a stronger effect at the radius, although the effect was not statistically significant at either site. In the OVX primate model, one of the most striking features of odanacatib treatment was a large increase in cortical thickness of the radius as measured by HR pqct. (4) Cortical thickness increased by 4.4% with odanacatib compared with.% with alendronate in that trial. In the current clinical trial, odanacatib treatment increased cortical thickness, cortical area, and cortical vmd at the distal radius and distal tibia, showing a favorable effect on the cortical compartment. The observed increases in cortical thickness are likely owing to endocortical apposition of aseline 6 4 ODN 5 mg OW n=8 Placebo OW n=8 P vs Placebo <. P vs Placebo <. Fig. 6. Percent changes from baseline in estimated strength at () the distal radius and () the distal tibia, based on finite element analysis of HRpQCT scans. LS ¼ least squares. bone (as suggested by QCT analysis of the femoral neck in the same study (7) ) and an increase in cortical area. ecause of coregistration of the baseline and follow up scans, it is not possible to determine whether the increase in cortical thickness is due to periosteal apposition (as documented by histomorphometry in nonhuman primates treated with odanacatib () ). The percent gains in cortical thickness and estimated strength in our study were of a lesser magnitude than those observed in nonhuman primates but similar to the denosumab and alendronate study using similar techniques. (7) Doses of odanacatib in primates were selected to approximate the exposure obtained with the 5 mg once weekly oral clinical dose in humans. However, the OVX nonhuman primates were treated in a prevention rather than treatment mode (ie, treated before they experienced reductions in bone mass) and were 79 CHEUNG ET L. Journal of one and Mineral Research

8 dosed daily because of their more rapid metabolism of odanacatib. These differences may account in part for the lack of translation of the primate data to the clinic. iomechanically, cortical bone bears a considerable share of the skeletal load, and maintenance of cortical bone structure is important for the maintenance of bone strength. (3,3) In the current trial, significant differences between treatment with odanacatib and treatment with placebo were observed in cortical thickness, cortical area, and cortical vmd. The significant increases in estimated bone strength that occurred at both the radius and tibia with odanacatib were likely influenced by the positive treatment effects on both cortical and trabecular bone. Our study has several limitations. Women in this study had low normal to moderately osteoporotic bone density; treatment effects reported here may not translate to women with more severe osteoporosis or women with greater cortical porosity. priori, we chose to measure cortical porosity at a more proximal site in the radius and tibia because the cortex is thicker there and less prone to partial volume artifacts (6) and motion artifacts. However, the measurement of cortical porosity by HR pqct at both the more proximal site and the standard distal site likely underestimates true cortical porosity because only large pores are counted, and the relationship of pore size with treatment effects is unknown. Thus, our results on cortical porosity should be interpreted with caution. Similar to other clinical studies using FE to estimate bone strength, we used a homogeneous linear model in this study. lthough a heterogeneous model may result in more robust estimates, it requires more intense computation. (3) In conclusion, in this study, odanacatib improved bone density, structure, and estimated strength not only at central sites as previously reported (7) but also at peripheral sites as well, as demonstrated by HR pqct and HR pqct based finite element analysis. n ongoing, large, randomized, phase 3 trial of odanacatib will provide detailed information on the antifracture efficacy of this novel formation sparing resorption inhibitor. Disclosures MC has received consulting fees from or been a consultant on advisory boards for Merck, mgen, Warner Chilcott, and Eli Lilly; speaker fees from Merck and mgen; and grants or grants pending from Merck, mgen, Eli Lilly, and Novartis. SM has been a consultant for Samumed Pharm and received research support from Merck. K has received research support from Merck, Osteologic, Servier, mgen, Natural Product Sciences, and Eli Lilly; consulting fees from or been a consultant on advisory boards for Merck, Osteologic, Servier, mgen, and Novartis; travel support from mgen, Eli Lilly, Servier, and Novartis; speaker fees from Servier, mgen, Novartis, and GlaxoSmithKline; and provided expert testimony for Osteologic. RC has been a consultant on advisory boards for Merck, Novartis, ioiberica, Savient, and mgen; received speaker fees from Chugai Roche, Pfizer, Eli Lilly, and Servier; and received travel support from Merck, Novartis, and Servier. KE and TF have received consulting fees and support for travel from Merck as employees of Synarc Inc. D, C, NV, S, ER, and EdP are current or former employees of Merck & Co. Inc., Whitehouse Station, NJ, US, and may own stock or stock options in the company. cknowledgments The authors thank Jennifer Pawlowski (Merck & Co., Inc.) for her administrative support and submission of the manuscript. uthors roles: Cheung, Majumdar, rixen, Chapurlat were all clinical investigators who enrolled patients in this clinical trial. Fuerst, Engelke both work for Synarc and were the central imaging vendor for this multisite clinical trial.. Darzinski and Tony Cabal are Merck employees responsible for imaging and performing FE. N Verbruggen was the project statistician. Shaban ther was the Merck clinical scientist responsible for all administrative aspects of this trial. E Rosenberg was the Merck medical writer and depapp was the Merck Medical monitor, a physician responsible for the oversite of this trial for Merck. References. Lewiecki EM. 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