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This is a repository copy of Use of high resolution dual-energy x-ray absorptiometry-region free analysis (DXA-RFA) to detect local periprosthetic remodeling events..

White Rose Research Online URL for this paper: http://eprints.whiterose.ac.uk/85663/

Version: Accepted Version

Article: Wilkinson, J.M., Morris, R.M., Martin-Fernandez, M.A. et al. (4 more authors) (2015) Use of high resolution dual-energy x-ray absorptiometry-region free analysis (DXA-RFA) to detect local periprosthetic bone remodeling events. Journal of Orthopaedic Research, 33 (5). 712 - 716. https://doi.org/10.1002/jor.22823

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[email protected] https://eprints.whiterose.ac.uk/ Journal of Orthopaedic Research

Use of High Resolution Region-Free Bone Densitometry (DXA-RFA) To Detect Local Periprosthetic Bone Remodeling Events

For Peer Review Journal: Journal of Orthopaedic Research

Manuscript ID: JOR-14-0531.R1

Wiley - Manuscript type: Research Article (Member)

Date Submitted by the Author: n/a

Complete List of Authors: Wilkinson, J; University of Sheffield, Academic Unit of Bone Metabolism; Morris, Richard Martin-Fernandez, Miguel Pozo, Jose Frangi, Alex Maheson, Marci Yang, Lang; University of Sheffield, Division of Clinical Sciences

Keywords: DXA, bone remodeling

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1 2 3 Use of High Resolution Dual-energy X-ray Absorptiometry-Region Free 4 5 6 Analysis (DXA-RFA) To Detect Local Periprosthetic Bone Remodeling 7 8 Events 9 10 11 12 JM Wilkinson[1], RM Morris[1], MA Martin-Fernandez[2], JM Pozo [2], AF Frangi[2], 13 14 Marci Maheson[3], L Yang[1] 15 16

17 18 For Peer Review 19 20 [1]University of Sheffield, Academic Unit of Bone Metabolism, Northern General Hospital, 21 22 Sheffield, UK; [2]University of Sheffield, Centre for Computational Imaging & Simulation 23 24 Technologies in Biomedicine (CISTIB), Department of Mechanical Engineering, Sheffield, 25 26 27 UK; [3] University Hospital of Wales, Department of Trauma and Orthopaedics, Cardiff, UK. 28 29 30 31 32 33 Correspondence and reprint requests to: 34 35 36 Prof J Mark Wilkinson 37 38 39 Department of Human Metabolism, University of Sheffield, DU24, The Medical School, 40 41 Beech Hill Road, Sheffield, S10 2RX, United Kingdom 42 43 44 Email: [email protected] 45 46 47 Telephone +44 114 271 4705 48 49 50 Fax +44 114 2618775 51 52 53 54 55 56 57 58 59 60 1

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1 2 3 ABSTRACT 4 5 6 Dual energy x-ray absorptiometry (DXA) is the gold standard method for measuring 7 8 periprosthetic bone remodeling, but relies on a region of interest (ROI) analysis approach. 9 10 Whilst this addresses issues of anatomic variability it is insensitive to bone remodeling events 11 12 13 at the sub-ROI level. We have validated a high-spatial resolution tool, termed DXA-Region- 14 15 Free Analysis (DXA-RFA) that uses advanced image processing approaches to allow 16 17 quantitation of bone mineral density (BMD) at the individual pixel (data-point) level. Here 18 For Peer Review 19 we compared the resolution of bone remodeling measurements made around a stemless 20 21 22 femoral in 18 subjects over 24 months using ROI-based analysis versus that made 23 24 using DXA-RFA. Using the ROI approach the regional pattern of BMD change varied by 25 26 region, with greatest loss in ROI5 (20%, P<0.001), and largest gain in ROI4 (6%, P<0.05). 27 28 Analysis using DXA-RFA showed a focal zone of increased BMD localized to the prosthesis- 29 30 bone interface (30-40%, P<0.001) that was not resolved using conventional DXA analysis. 31 32 33 The 20% bone loss observed in ROI5 with conventional DXA was resolved to a focal area 34 35 adjacent to the cut surface of the infero-medial (up to -40%, P<0.0001). DXA- 36 37 RFA enables high resolution analysis of DXA datasets without the limitations incurred using 38 39 ROI-based approaches. 40 41 42 Keywords: bone mineral density, , total , dual energy x-ray 43 44 45 absorptiometry region-free analysis. 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 2

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1 2 3 INTRODUCTION 4 5 Dual energy x-ray absorptiometry (DXA) is the gold standard method for measuring bone 6 7 remodeling events that occur following total hip arthroplasty (THA). However, current 8 9 10 analysis approaches express BMD as an average value within a given region of interest 11 1 12 (ROI). . This value is calculated as the mean BMD value derived from large numbers of 13 14 pixels contained within the defined ROI. However, bone remodeling events occurring after 15 16 prosthesis insertion are spatially-complex and may not be uniform across a given ROI,2 For 17 18 For Peer Review 19 example, within a large ROI the BMD change occurring over a given time at the bone-

20 2 21 prosthesis interface may differ substantially to that occurring at the bone periosteal surface. 22 23 Such differences cannot be resolved using ROI-based DXA analysis technology, whilst the 24 25 alternate computed tomography-based approach is accompanied with a higher radiation 26 27 exposure dose.3; 4 Further, different ROI models may also be required to measure BMD 28 29 5-7 30 change around prostheses with differing geometries, making quantitative comparisons of 31 32 bone remodeling between prostheses challenging. 33 34 35 In order to solve these issues we recently developed and validated a high-spatial 36 37 resolution tool for measuring femoral periprosthetic BMD change events, termed DXA- 38 39 Region-Free Analysis (DXA-RFA).8 This analysis approach uses the data contained within a 40 41 42 standard DXA acquisition and applies contemporary image processing techniques to allow 43 9; 10 44 full statistical use of the spatial information contained within each DXA scan, shedding 45 46 this limitation of ROI-based analysis approaches. 47 48 49 In this study we compared and contrasted the sensitivity of DXA-RFA versus ROI- 50 51 based DXA analysis to detect BMD change over 24 months in the setting of a stemless, 52 53 54 hydroxyapatite-coated femoral prosthesis (The Silent hip prosthesis, DePuy International Ltd, 55 56 Leeds, UK). Specifically, we aimed to determine whether DXA-RFA provides greater 57 58 analysis resolution of local bone remodeling events. 59 60 3

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1 2 3 METHODS 4 5 Study design, recruitment, and randomization 6 7 8 The DXA scans were collected as part of a single-center, prospective cohort study of 18 9 10 patients undergoing primary THA using the Silent Hip. The study was approved by the South 11 12 West National Health Service Research Ethics Committee, UK (05/WSE02/133), and all 13 14 patients provided written, informed, consent prior to inclusion. The inclusion criteria were 15 16 adult males and females with of the hip requiring THA, and considered suitable 17 18 For Peer Review 19 for a cementless prosthesis. The exclusion criteria were pregnancy, known drug or alcohol 20 21 abuse or psychological disorders that could affect care or treatment outcomes, participation in 22 23 clinical trials of an investigational medical product within the last 6 months, osteonecrosis of 24 25 the femoral neck, Paget‘s disease, significant bone loss or gross deformity in the region of the 26 27 28 femoral neck identified on pre-operative radiographs, and patients with Charnley C functional 29 30 classification. All operations were performed through a posterior approach with the patient in 31 32 the lateral position. The femoral and acetabular components were inserted with a press-fit 33 34 technique in accordance with the manufacturer‘s instructions. All patients were mobilized on 35 36 the first or second post-operative day with unrestricted weight bearing. 37 38 39 Patient monitoring and assessments 40 41 A Harris Hip Score and an Oxford hip score were assessed pre-operatively, and 3, 6, 12, and 42 43 24 months post-operatively.11; 12 Patients underwent DXA of the operated hip at post- 44 45 operative baseline within 10 days of , and at months 3, 6, 12, and 24 thereafter. All 46 47 48 acquisitions were made using the same Hologic Discovery fan beam densitometer (Hologic 49 50 Inc, Bedford, MA, USA) using the —metal-removal hip“ scanning mode. 51 52 53 DXA scan analysis using conventional ROI approach 54 55 56 57 58 59 60 4

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1 2 3 A 5 ROI analysis model similar to that described by Albanese et al was applied,13 but adapted 4 5 for the shorter length of the Silent Hip (Figure 1). The inter-observer repeatability of this ROI 6 7 model was evaluated by comparison of 54 scan acquisitions by 2 independent, experienced 8 9 10 DXA analysis technicians, and precision expressed as the coefficient of variation (CV%) 11 14 12 using a formula described previously. The inter-observer CV% was 0.3, 1.0, 0.5, 1.6, and 13 14 4.3 for ROIs 1 to 5, respectively, and similar to that described by Albanese et al (1.9 to 15 16 3.4%).13 17 18 For Peer Review 19 DXA scan analysis using DXA-RFA 20 21 22 DXA scan analysis using DXA-RFA was implemented in Matlab v6.11.0.584r2010b 23 24 8 25 (Mathworks Inc, Cambridge, MA), and performed as previously described. The DXA-RFA 26 27 bone map data extraction algorithm was written using proprietary Hologic technical 28 29 information provided under a non-disclosure agreement between the University of Sheffield 30 31 and Hologic Inc, and is based on the Hologic Inc algorithm APEX 3.2. A BMD image of 32 33 each proximal femur was extracted from each archived Hologic scan file using DXA-RFA. 34 35 36 The raw x-ray attenuation images were read from the scan files then segmented into 37 38 prosthesis, bone, and soft tissue compartments using automated edge-detection, intensity 39 40 thresholding, and morphological operations. The BMD at each pixel within the bone 41 42 compartment was then calculated using the DXA-RFA algorithm. A single scan template was 43 44 45 generated from the full population of acquired scans using the Generalized Procrustes 46 47 Alignment method from a set of anatomical landmarks located automatically around the 48 49 femur.10 The individual scans were then registered to the template using thin plate splines.15 50 51 The accuracy of the method was quantitated in an independent study using a hip phantom and 52 53 8 54 was within 2% of that measured using the Hologic APEX 3.2 proprietary algorithm. The 55 56 NET clinical repeatability of the method (CV%), assessed previously in 29 independent 57 58 patients undergoing repeated scan acquisitions on the same day after repositioning, was 1.7%. 59 60 5

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1 2 3 The median CV% of the method at the individual datapoint level was 13.6% (interquartile 4 5 range 11.9 to 15.6). 6 7 8 Statistical analysis 9 10 11 Categorical data were analyzed using the chi-squared test. Continuous data were analyzed 12 13 within-group by paired t-test or by Wilcoxon test, as appropriate, comparing each follow-up 14 15 16 time-point with the baseline data. All analyses were made 2-tailed with a critical P-value of 17 18 0.05. For DXA-RFAFor measurements Peer change versus Review baseline for each BMD datapoint was 19 20 analyzed using the paired t-test and presented as heatmaps of BMD change (%) together with 21 22 its statistical significance. 23 24 25 RESULTS 26 27 28 29 Patient characteristics, clinical and patient reported outcomes 30 31 Eighteen patients (13 male, 5 female) with a mean age of 54.4 years (standard deviation 6.4) 32 33 and body mass index of 28.1Kg/m2 (standard deviation 3.5) participated in the study. All 34 35 36 patients received the Silent Hip prosthesis (median length 55mm, range 45 to 70). All patients 37 38 completed baseline post-operative, 3 month and 6 month clinical assessments and DXA 39 40 measurements. Sixteen patients had assessments at 12 months. Two patients failed to attend 41 42 the 12 month follow up appointments and were excluded from this analysis. Fifteen patients 43 44 underwent assessments at 24 months. Three patients failed to attend at 24 months, and were 45 46 47 excluded from the analyses of this time-point. 48 49 50 Clinical and patient reported outcomes, measured by Harris hip score and Oxford hip score, 51 52 respectively, were consistent with expected improved physical function over 24 months after 53 54 THA (Table 1, P<0.001, both scores). These improvements were most rapid over the first 3 55 56 months following surgery, with a slower rate of improvement continuing to 24 months. 57 58 59 60 6

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1 2 3 4 5 6 DXA scan results for conventional ROI approach 7 8 9 The regional distribution of periprosthetic BMD at baseline varied from 0.70 to 1.34g/cm2 10 11 (Figure 1). Higher BMD was observed in diaphyseal versus metaphyseal ROIs consistent 12 13 with the overall average of the relative amount of cortical and cancellous bone within each 14 15 16 ROI. 17 18 For Peer Review 19 Post-operatively, the NET ROI showed a transient fall in BMD of 4% (P<0.001) at 3 20 21 months, which recovered to approximately baseline levels by 24 months. ROI3 showed no 22 23 change in BMD at any time-point. An increase in BMD of 6% (P<0.05) in ROI4 was 24 25 identified at 24 months. Falls in BMD were measured in ROIs 1, 2, and 5 (P<0.05). In ROI1 26 27 28 and ROI2 these falls had nadirs of 8 and 7%, respectively (P<0.01), and were followed by 29 30 partial recovery in BMD. In ROI5 BMD loss commenced early after surgery and continued 31 32 throughout follow-up, with a 20% decrease in BMD by 24 months (P<0.001). 33 34 35 DXA scan results using DXA-RFA 36 37 In contrast to the ROI-based analyses, quantitation using DXA-RFA resolved a baseline 38 39 BMD distribution consistent with the anatomic macro-architecture of the proximal femur, 40 41 42 with high bone mass recorded in anatomic cortical areas, and lower mass in the cancellous 43 44 bone areas of the metaphysis and trochanters (Figures 2A and B). This baseline post- 45 46 operative analysis also showed a focal area of high BMD at the superolateral border of the 47 48 prosthesis tip (>4.0±2.5g/cm2) that may represent bone compaction during prosthesis 49 50 51 insertion. 52 53 54 Post-operative BMD change measured by DXA-RFA was observed in discrete, focal 55 56 areas of the proximal femur over the duration of the study (Figures 3A to 3D). The majority 57 58 of BMD change events occurred over the first 6 months following surgery. The reduction in 59 60 7

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1 2 3 bone mass observed in ROI5 using the conventional approach was visualized as a highly 4 5 discrete area at the most supero-medial aspect of the inferior femoral neck (>30% over 24 6 7 months, P<0.0001). Site-specific increases in bone mass were visualized at the prosthesis- 8 9 10 bone interface over 24 months (up to 40%, P<0.001). The pattern of BMD change at the 11 12 was heterogeneous over the first 3 months. The dominant remodeling 13 14 pattern following this timepoint was one of increased BMD, initially in the most proximal 15 16 trochanter, and moving distally over time, with a general trend towards increased BMD 17 18 For Peer Review 19 throughout the region by 24 months. The dominant remodeling pattern at the femoral 20 21 diaphysis was one of a small reduction in bone mass over the 24 month period, but the 22 23 discrete, focal nature of the changes remained a characteristic feature. 24 25 26 DISCUSSION 27 28 29 We compared bone remodeling events using conventional ROI-based analysis versus that 30 31 made using an ROI-free computational approach (DXA-RFA) over 24 months after hip 32 33 replacement using a stemless femoral prosthesis. Analysis using DXA-RFA demonstrated 34 35 baseline post-operative spatial distribution of bone mass and subsequent BMD change at 36 37 38 higher resolution than that observed using ROI-based analysis. BMD change that was 39 40 observed as -20% BMD loss at 24 months in ROI5 using the conventional approach was 41 42 resolved using DXA-RFA as a highly focal area adjacent to the neck resection site, and 43 44 clearly defined within the first 6 months post-operatively. The DXA-RFA method was also 45 46 able to resolve bone remodeling events at the prosthesis-bone interface that were not 47 48 49 visualized using ROI-based DXA analysis. 50 51 52 These data confirm previous observations that BMD distribution at the proximal 53 16 54 femur is spatially-complex, and that the quantitation of remodeling events after prosthesis 55 56 insertion is best made using high resolution approaches.2 DXA-RFA provides a low-radiation 57 58 59 60 8

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1 2 3 dose alternative to computed tomography for such imaging. This approach may provide a 4 5 novel opportunity to study non-invasively in clinical trials the effect of investigational drugs 6 7 or surface modifications suggested in animal studies to modulate prosthesis 8 9 17-20 10 . This interface is less easily visualized using CT or MRI because of 11 12 beam hardening, metal susceptibility and magnetic field artifacts, despite recent advances in 13 14 data analysis using these modalities.21 15 16 17 DXA-RFA also has limitations. The generation of a common template and elastic 18 For Peer Review 19 registration of all images to this template causes some image distortion, resulting in poorer 20 21 22 precision at the individual datapoint level than that observed at ROI level with conventional 23 24 DXA. However, the precision error incurred is outweighed by the additional resolution 25 26 achieved. The method also requires that all the scans analyzed in a series are included in the 27 28 template generation. Thus far we have only applied the method to Hologic densitometer 29 30 datasets. However, the DXA acquisition algorithms used in other manufacturer‘s 31 32 33 densitometers also utilize a pixel bone map that may be extracted in a similar fashion. 34 35 Finally, DXA is a 2-dimensional method used to resolve events that occur in 3 dimensions. 36 37 However, this is a limitation of the acquisition technology, rather than the analytical 38 39 approach, which may also be applied to cross-sectional imaging datasets.9 40 41 42 43 44 45 ACKNOWLEDGEMENT 46 47 48 This study was funded by DePuy International Ltd, Leeds, UK. JM Wilkinson acted as a paid 49 50 51 consultant to DePuy International Ltd for the dataset on which the presented work is based, 52 53 the other authors have no conflict of interest. 54 55 56 57 58 59 60 9

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1 2 3 REFERENCES 4 5 1. Gruen TA, McNeice GM, Amstutz HC. 1979. Modes of failure of cemented stem-type femoral 6 7 components. A radiographic analysis of loosening. Clin Orthop 141:17-27. 8 2. Shim VB, Pitto RP, Anderson IA. 2012. Quantitative CT with finite element analysis: towards a 9 predictive tool for bone remodelling around an uncemented tapered stem. Int Orthop 10 36:1363-1369. 11 3. Damilakis J, Adams JE, Guglielmi G, et al. 2010. Radiation exposure in X-ray-based imaging 12 techniques used in osteoporosis. European radiology 20:2707-2714. 13 4. Baumann BM, Chen EH, Mills AM, et al. 2011. Patient perceptions of computed tomographic 14 imaging and their understanding of radiation risk and exposure. Annals of emergency 15 medicine 58:1-7 e2. 16 5. Munting E, Smitz P, Van Sante N, et al. 1997. Effect of a stemless femoral implant for total 17 hip arthroplasty on the bone mineral density of the proximal femur. Journal of Arthroplasty 18 12:373-379. For Peer Review 19 20 6. Lerch M, Kurtz A, Stukenborg-Colsman C, et al. 2012. Bone remodeling after total hip 21 arthroplasty with a short stemmed metaphyseal loading implant: finite element analysis 22 validated by a prospective DEXA investigation. J Orthop Res 30:1822-1829. 23 7. Niinimaki T, Junila J, Jalovaara P. 2001. A proximal fixed anatomic femoral stem reduces 24 stress shielding. Int Orthop 25:85-88. 25 8. Morris RM, Yang L, Martin-Fernandez MA, et al. 2014. High-Spatial-Resolution Bone 26 Densitometry with Dual-Energy X-ray Absorptiometric Region-free Analysis. 27 Radiology:140636. 28 9. Astrakas LG, Argyropoulou MI. 2010. Shifting from region of interest (ROI) to voxel-based 29 analysis in human brain mapping. Pediatr Radiol 40:1857-1867. 30 10. Goodall C. 1991. Procrustes methods in the statistical analysis of shape. J R Stat Soc [B] 31 53:285-339. 32 33 11. Harris WH. 1969. Traumatic of the hip after dislocation and acetabular fractures: 34 Treatment by mold arthroplasty. An end-result study using a new method of result 35 evaluation. Journal of Bone and Surgery 51-A:737-755. 36 12. Dawson J, Fitzpatrick R, Carr A, et al. 1996. Questionnaire on the perceptions of patients 37 about total . Journal of Bone and Joint Surgery 78-B:185-190. 38 13. Albanese CV, Santori FS, Pavan L, et al. 2009. Periprosthetic DXA after total hip arthroplasty 39 with short vs. ultra-short custom-made femoral stems: 37 patients followed for 3 years. Acta 40 Orthop 80:291-297. 41 14. Wilkinson JM, Peel NFA, Elson RA, et al. 2001. Measuring bone mineral density of the pelvis 42 and proximal femur after total hip arthroplasty. J Bone Joint Surg 83-B:283-288. 43 15. Rohr K, Stiehl HS, Sprengel R, et al. 2001. Landmark-based elastic registration using 44 approximating thin-plate splines. IEEE Trans Med Imaging 20:526-534. 45 46 16. Yang L, Udall WJ, McCloskey EV, et al. 2014. Distribution of bone density and cortical 47 thickness in the proximal femur and their association with in postmenopausal 48 women: a quantitative computed tomography study. Osteoporos Int 25:251-263. 49 17. Virdi AS, Liu M, Sena K, et al. 2012. Sclerostin antibody increases bone volume and enhances 50 implant fixation in a rat model. J Bone Joint Surg Am 94:1670-1680. 51 18. Tengvall P, Skoglund B, Askendal A, et al. 2004. Surface immobilized bisphosphonate 52 improves stainless-steel screw fixation in rats. 25:2133-2138. 53 19. Tanzer M, Karabasz D, Krygier JJ, et al. 2005. The Otto Aufranc Award: bone augmentation 54 around and within porous implants by local bisphosphonate elution. Clin Orthop Relat Res 55 441:30-39. 56 57 58 59 60 10

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1 2 3 20. Eberhardt C, Habermann B, Muller S, et al. 2007. The bisphosphonate ibandronate 4 accelerates osseointegration of hydroxyapatite-coated cementless implants in an animal 5 model. J Orthop Sci 12:61-66. 6 21. Prell D, Kyriakou Y, Kachelrie M, et al. 2010. Reducing metal artifacts in computed 7 tomography caused by hip endoprostheses using a physics-based approach. Investigative 8 radiology 45:747-754. 9 10 11 12 13 14 15 16 17 18 For Peer Review 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 11

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1 2 3 4 5 Harris Hip Score Oxford Hip Score 6 7 Pre-operative baseline 48 (40 to 51) 21 (17 to 27) 8 9 3 months (n=18) **96 (90 to 100) **47 (38 to 48) 10 11 12 6 months (n=18) ***100 (93 to 100) ***48 (44 to 48) 13 14 12 months (n=16) ***100 (100 to 100) ***48 (48 to 48) 15 16 24 months (n=15) ***100 (99 to 100) ***48 (48 to 48) 17 18 For Peer Review 19 20 21 22 Table 1. Harris hip score and Oxford hip score measured over 24 months. Data are 23 24 median (interquartile range). Data in parentheses adjacent to follow up date are number of 25 26 complete respondents at each timepoint. Analysis is within-group by Wilcoxon test, 27 28 comparing completers at each follow-up time-point with their baseline data, *P<0.05, 29 30 **P<0.01, ***P<0.001. 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 12

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1 2 3 FIGURE LEGEND 4 5 6 Figure 1. Baseline and mean percentage change in BMD in each region versus baseline 7 8 analyzed using a conventional analysis approach. Inset image shows the distribution of the 9 10 5 analysis regions of interest. Baseline value is mean±standard deviation. Analysis is by 11 12 13 absolute change at each timepoint versus absolute baseline value by paired t-test. *P<0.05, 14 15 **P<0.01, ***P<0.001. 16 17 18 Figure 2. BaselineFor BMD measurements Peer made Review using DXA-RFA. A) Mean BMD (g/cm2) at 19 20 each pixel, and B) standard deviation (std BMD) of the BMD at each pixel. Colorbars 21 22 indicate values for each parameter. 23 24 25 Figure 3. Average post-operative BMD change (%) and its statistical significance 26 27 28 analyzed using DXA-RFA. BMD change is shown at 3A) 3 months, 3B) 6 months, 3C) 12 29 30 months, and 3D) 24 months post operatively. Analysis is in completers versus baseline at 31 32 each timepoint by paired t-test. Colorbars indicate values for each parameter. 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 13

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1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 For Peer Review 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 Figure 1 44 79x87mm (300 x 300 DPI) 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 John Wiley & Sons, Inc. Page 15 of 16 Journal of Orthopaedic Research

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 For Peer Review 19 20 21 22 23 24 25 26 27 28 29 30 Figure 2 55x37mm (300 x 300 DPI) 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 John Wiley & Sons, Inc. Journal of Orthopaedic Research Page 16 of 16

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 For Peer Review 19 20 21 22 23 24 25 26 27 28 29 30 Figure 3 31 115x78mm (300 x 300 DPI) 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 John Wiley & Sons, Inc.