Internal validation of modified Mirels' scoring system for pathologic femur fractures.

BACKGROUND: The proximal femur is a common site of bone metastasis. The Mirels' score is a frequently utilized system to identify patients at risk for pathologic fracture and while it has consistently demonstrated strong sensitivity, specificity has been relatively poor. Our group previously developed a Modified Mirels' scoring system which demonstrated improved ability to predict cases at risk of fracture in this patient population through modification of the Mirels' location score. The purpose of the present study is to internally validate this newly developed scoring system on an independent patient series. METHODS: Retrospective review was performed to identify patients who were evaluated for proximal femoral bone lesions. Patients were stratified into one of two groups: 1) those who went on to fracture within 4 months after initial evaluation (Fracture Group) and 2) those who did not fracture within 4 months of initial evaluation (No Fracture Group). Retrospective chart review was performed to assign an Original Mirels' (OM) Score and Modified Mirels' (MM) score to each patient at the time of initial evaluation. Descriptive statistics, logistic regression, receiver operating curve, and net benefit analyses were performed to determine the predictability of fractures when utilizing both scoring systems. RESULTS: The use of the MM scoring improved fracture prediction over OM scoring for patients observed over a 4 month follow up based on logistic regression. Decision curve analysis showed that there was a net benefit using the MM score over the OM scoring for a full range of fracture threshold probabilities. Fracture prevalence was similar for current internal validation dataset when compared to the dataset of our index study with a comparable reduction in misclassification of fracture prediction when utilizing the modified scoring system versus the original. CONCLUSIONS: Use of MM scoring was found to improve fracture prediction over OM scoring when tested on an internal validation set of patients with disseminated metastatic lesions to the proximal femur. The improvement in fracture prediction demonstrated in the present study mirrored the results of our index study during which the MM system was developed.

Peri-operative zoledronic acid attenuates peri-prosthetic osteolysis in a rat model of cemented knee replacement.

Progressive osteolysis can occur at the cement-bone interface of joint replacements and the associated loss of fixation can lead to clinical loosening. We previously developed a rat hemiarthroplasty model that exhibited progressive loss of fixation with the development of cement-bone gaps under the tibial tray that mimicked patterns found in human arthroplasty retrievals. Here we explored the ability of a bisphosphonate (zoledronic acid, ZA) to attenuate cement-bone osteolysis and maintain implant stability. Sprague-Dawley rats (n = 59) received a poly(methylmethacrylate) cemented tibial component and were followed for up to 12 weeks. Treatment groups included peri-operative administration of ZA (ZA group), administration of ZA at 6 weeks postop (late ZA group), or vehicle (Veh group). There was a 60% reduction in the rate of cement-bone gap formation for the ZA group (0.15 mm3/week) compared to Veh group (0.38 mm3/week, p = 0.016). Late ZA prevented further progression of gap formation but did not reverse bone loss to the level achieved in the ZA group. Micromotion from five times body weight toggle loading was positively correlated with cement-bone gap volume (p = 0.009) and negatively correlated with the amount of cement in the metaphysis (p = 0.005). Reduced new bone formation and enduring nonviable bone in the epiphysis for the ZA group were found. This suggests that low bone turnover in the epiphysis may suppress the early catabolic response due to implantation, thereby maintaining better fixation in the epiphysis. This preclinical model presents compelling supporting data documenting improved maintenance of the cement-bone fixation with the use of peri-operative bisphosphonates.

Modification to Mirels scoring system location component improves fracture prediction for metastatic disease of the proximal femur.

BACKGROUND: Correctly identifying patients at risk of femoral fracture due to metastatic bone disease remains a clinical challenge. Mirels criteria remains the most widely referenced method with the advantage of being easily calculated but it suffers from poor specificity. The purpose of this study was to develop and evaluate a modified Mirels scoring system through scoring modification of the original Mirels location component within the proximal femur. METHODS: Computational (finite element) experiments were performed to quantify strength reduction in the proximal femur caused by simulated lytic lesions at defined locations. Virtual spherical defects representing lytic lesions were placed at 32 defined locations based on axial (4 axial positions: neck, intertrochanteric, subtrochanteric or diaphyseal) and circumferential (8 circumferential: 45-degree intervals) positions. Finite element meshes were created, material property assignment was based on CT mineral density, and femoral head/greater trochanter loading consistent with stair ascent was applied. The strength of each femur with a simulated lesion divided by the strength of the intact femur was used to calculate the Location-Based Strength Fraction (LBSF). A modified Mirels location score was next defined for each of the 32 lesion locations with an assignment of 1 (LBSF > 75%), 2 (LBSF: 51-75%), and 3 (LBSF: 0-50%). To test the new scoring system, data from 48 patients with metastatic disease to the femur, previously enrolled in a Musculoskeletal Tumor Society (MSTS) cross-sectional study was used. The lesion location was identified for each case based on axial and circumferential location from the CT images and assigned an original (2 or 3) and modified (1,2, or 3) Mirels location score. The total score for each was then calculated. Eight patients had a fracture of the femur and 40 did not over a 4-month follow-up period. Logistic regression and decision curve analysis were used to explore relationships between clinical outcome (Fracture/No Fracture) and the two Mirels scoring methods. RESULTS: The location-based strength fraction (LBSF) was lowest for lesions in the subtrochanteric and diaphyseal regions on the lateral side of the femur; lesions in these regions would be at greatest risk of fracture. Neck lesions located at the anterior and antero-medial positions were at the lowest risk of fracture. When grouped, neck lesions had the highest LBSF (83%), followed by intertrochanteric (72%), with subtrochanteric (50%) and diaphyseal lesions (49%) having the lowest LBSF. There was a significant difference (p < 0.0001) in LBSF between each axial location, except subtrochanteric and diaphyseal which were not different from each other (p = 0.96). The area under the receiver operator characteristic (ROC) curve using logistic regression was greatest for modified Mirels Score using site specific location of the lesion (Modified Mirels-ss, AUC = 0.950), followed by a modified Mirels Score using axial location of lesion (Modified Mirels-ax, AUC = 0.941). Both were an improvement over the original Mirels score (AUC = 0.853). Decision curve analysis was used to quantify the relative risks of identifying patients that would fracture (TP, true positives) and those erroneously predicted to fracture (FP, false positives) for the original and modified Mirels scoring systems. The net benefit of the scoring system weighed the benefits (TP) and harms (FP) on the same scale. At a threshold probability of fracture of 10%, use of the modified Mirels scoring reduced the number of false positives by 17-20% compared to Mirels scoring. CONCLUSIONS: A modified Mirels scoring system, informed by detailed analysis of the influence of lesion location, improved the ability to predict impending pathological fractures of the proximal femur for patients with metastatic bone disease. Decision curve analysis is a useful tool to weigh costs and benefits concerning fracture risk and could be combined with other patient/clinical factors that contribute to clinical decision making.

Potential for supraphysiologic fluid shear stresses in a rat cemented knee replacement model.

The mechano-biologic environment associated with aseptic loosening of cemented joint replacements is not fully understood. The goal of this study was to use a preclinical rat knee arthroplasty model to explore the changes in cement-bone morphology and micromotion that occur with in vivo service. Narrow gaps between cement and bone under the tibial tray were present at early time points, and with even small magnitude micromotion, resulted in large micromotion-to-gap width ratios. These data were then used to develop models of fluid flow in the cement-bone gaps to estimate potential for high fluid shear stress (FSS). Modeling results revealed supraphysiologic (>4 Pa) FSS were possible, particularly for cases in which eccentric loading applied to the implant and if the fluid in the gap consisted of marrow or synovial fluid. The early, high FSS environment, could cause fluid-induced periprosthetic osteolysis locally, resulting in progressive loss of cement-bone fixation.

Orchestrated delivery of PTH [1-34] followed by zoledronic acid prevents radiotherapy-induced bone loss but does not abrogate marrow damage.

Postradiotherapy bone fragility fractures are a frequent late-onset complication in cancer survivors. There is a critical need to develop preventative interventions, and the use of Food and Drug Administration-approved drugs remains an attractive option. Prior data from our lab and others have shown that parathyroid hormone [1-34] mitigates radiotherapy-induced bone loss, but only for the duration of drug delivery. Utilizing a murine hindlimb radiotherapy model, we investigated whether orchestrated delivery of single-dose zoledronic acid could extend these anabolic benefits after cessation of parathyroid hormone delivery. We then explored the potential use of parathyroid hormone as a bone marrow radioprotectant. While the addition of zoledronic acid to parathyroid hormone increased irradiated bone mass, there was no increase in femur bending strength. In this model, the parathyroid hormone was not effective as a marrow radioprotectant, although this could be due to the short course of parathyroid hormone treatment. Marrow repopulation kinetics differed from those in total body irradiation, with hematopoietic stem cell repopulation occurring relatively early at four weeks postirradiation. Furthermore, we found radiation induced a loss of marrow stromal cells and an increase in inflammatory monocytes. Statement of Clinical Significance: Staged delivery of parathyroid hormone and zoledronic acid shows promise as an off-the-shelf intervention to mitigate post-radiotherapy bone damage in cancer patients, but parathyroid hormone is unlikely to function as a broad-spectrum marrow radioprotectant.

Effect of Stem Positioning on Biomechanical Performance of a Novel Cementless Short-Stem Canine Total Hip Implant.

OBJECTIVE: The aim of this study was to evaluate the effect of stem positioning on the biomechanical performance of a novel, collared, short-stem total hip implant under compression and torsion ex vivo. STUDY DESIGN: Six canine cadaveric femurs were implanted with a collared short-stem femoral implant. Canal flare index (CFI), stem angle, absolute and relative cut heights and relative size were measured radiographically and used as independent variables. Biomechanical performance of the construct was evaluated using physiologic loading (loading) and supraphysiologic loading (failure) protocols. RESULTS: During loading protocols, compressive stiffness was influenced by absolute cut height (p = 0.018). During failure protocols, peak torque was influenced by CFI (p = 0.004) and craniocaudal relative size (p = 0.005). Peak load and torsional stiffness were not impacted by any of the radiographic variables (p > 0.05). Three of six femurs developed longitudinal fractures originating at the medial calcar at the time of failure. CONCLUSION: The biomechanical performance of the collared short-stem implant was positively impacted by preserving more of the femoral neck, having a higher CFI and using a smaller implant size relative to the femoral neck isthmus.

Predicting Fracture Risk in Patients with Metastatic Bone Disease of the Femur: A Pictorial Review Using Three Different Techniques.

One of the key roles of an orthopedic surgeon treating metastatic bone disease (MBD) is fracture risk prediction. Current widely used impending fracture risk tools such as Mirels scoring lack specificity. Two newer methods of fracture risk prediction, CT-based structural rigidity analysis (CTRA) and finite element analysis (FEA), have each been shown to be more accurate than Mirels. This case series illustrates comparative Mirels, CTRA, and FEA for 8 femurs in 7 subjects. These cases were selected from a much larger data set to portray examples of true positives, true negatives, false positives, and false negatives as defined by CTRA relative to the fracture outcome. Case illustrations demonstrate comparative Mirels and FEA. This series illustrates the use, efficacy, and limitations of these tools. As all current tools have limitations, further work is needed in refining and developing fracture risk prediction.

Progressive loss of implant fixation in a preclinical rat model of cemented knee arthroplasty.

Aseptic loosening of total knee arthroplasty continues to be a challenging clinical problem. The progression of the loosening process, from the initial well-fixed component, is not fully understood. In this study, loss of fixation of cemented hemiarthroplasty was explored using 9-month-old Sprague-Dawley rats with 0, 2, 6, 12, 26 week end points. Morphological and cellular changes of cement-bone fixation were determined for regions directly below the tibial tray (epiphysis) and distal to the tray (metaphysis). Loss of fixation, with a progressive increase in cement-bone gap volume was found in the epiphysis (0.162 mm3 /week), but did not progress appreciably in the metaphysis (0.007 mm3 /week). In the epiphysis, there was an early and sustained elevation of osteoclasts adjacent to the cement border and development of a fibrous tissue layer between the cement and bone. There was early formation of bone around the cement in the metaphysis, resulting in a condensed bone layer without osteoclastic bone resorption or development of a fibrous tissue layer. Implant positioning was also an important factor in the cement-bone gap formation, with greater gap formation for implants that were placed medially on the tibial articular surface. Loss of fixation in the rat model mimicked patterns found in human arthroplasty where cement-bone gaps initiate under the tibial tray, at the periphery of the implant. This preclinical model could be used to study early biological response to cemented fixation and associated contributions of mechanical instability, component alignment, and periprosthetic inflammation.

Altered mechanical behavior of demineralized bone following therapeutic radiation.

Post-radiotherapy (RTx) bone fragility fractures are a late-onset complication occurring in bone within or underlying the radiation field. These fractures are difficult to predict, as patients do not present with local osteopenia. Using a murine hindlimb RTx model, we previously documented decreased mineralized bone strength and fracture toughness, but alterations in material properties of the organic bone matrix are largely unknown. In this study, 4 days of fractionated hindlimb irradiation (4 × 5 Gy) or Sham irradiation was administered in a mouse model (BALB/cJ, end points: 0, 4, 8, and 12 weeks, n = 15/group/end point). Following demineralization, the viscoelastic stress relaxation, and monotonic tensile mechanical properties of tibiae were determined. Irradiated tibiae demonstrated an immediate (day after last radiation fraction) and sustained (4, 8, 12 weeks) increase in stress relaxation compared to the Sham group, with a 4.4% decrease in equilibrium stress (p < .017). While tensile strength was not different between groups, irradiated tibiae had a lower elastic modulus (-5%, p = .027) and energy to failure (-12.2%, p = .012) with monotonic loading. Gel electrophoresis showed that therapeutic irradiation (4 × 5 Gy) does not result in collagen fragmentation, while irradiation at a common sterilization dose (25 kGy) extensively fragmented collagen. These results suggest that altered collagen mechanical behavior has a role in postirradiation bone fragility, but this can occur without detectable collagen fragmentation. Statement of Clinical Significance: Therapeutic irradiation alters bone organic matrix mechanics and which contribute to diminished fatigue strength, but this does not occur via collagen fragmentation.

Radiographic and Biomechanical Assessment of Three Implant Designs for Canine Cementless Total Hip Replacement.

OBJECTIVE: The aim of this study was to evaluate the relationship between radiographic fit/fill measurements and biomechanical performance of three canine cementless total hip implant designs using an in vitro biomechanical testing protocol that replicates compression and torsion. STUDY DESIGN: Eighteen (six/group) canine cadaveric femurs were implanted with one of three cementless total hip implant designs: (1) collarless, (2) collared or (3) lateral bolt stems. Femoral length, canal flare index (CFI), canal fill, stem fit, stem level and stem angle were measured as independent variables. Biomechanical performance was tested using physiological, non-destructive gait loading (loading protocols) and destructive testing (failure protocols). RESULTS: During loading protocols, compressive stiffness was influenced by stem level (p < 0.05) and torsional stiffness was influenced by stem level and CFI for collarless stems (p < 0.05). During failure protocols, peak load was influenced by mediolateral (ML) stem angle (p < 0.05) and CFI (p < 0.01) for collarless stems and CFI for lateral bolt stems (p < 0.05). Peak torque was influenced by ML stem angle, craniocaudal stem angle and CFI for collarless stems (p < 0.05) and average ML fill for collared stems (p < 0.05). CONCLUSION: Biomechanical performance of collarless stems in cementless hip arthroplasty is more impacted by radiographic fit/fill than lateral bolt and collared stems. As a result, collarless stems may be more dependent on preoperative fit and intraoperative precision.

Radiation-induced changes to bone composition extend beyond periosteal bone.

BACKGROUND: Cancer patients receiving radiotherapy for soft tissue sarcomas are often at risk of post-irradiation (post-RTx) bone fragility fractures, but our understanding of factors controlling radiation-induced bone injury is limited. Previous studies have evaluated post-RTx changes to cortical bone composition in the periosteum of irradiated tibiae, but have not evaluated effects of irradiation in deeper tissues, such as endosteal or mid-cortical bone, and whether there are differential spatial effects of irradiation. In this study, we hypothesize that post-RTx changes to cortical bone composition are greater in endosteal compared to mid-cortical or periosteal bone. METHODS: A pre-clinical mouse model of limited field hindlimb irradiation was used to evaluate spatial and temporal post-RTx changes to the metaphyseal cortex of irradiated tibiae. Irradiation was delivered unilaterally to the hindlimbs of 12-wk old female BALB/cJ mice as 4 consecutive daily doses of 5 Gy each. RTx and non-RTx tibiae were obtained at 0, 2, 4, 8, and 12 wks post-RTx (n = 9 mice/group/time). Raman spectroscopy was used to evaluate spatial and temporal post-RTx changes to cortical bone composition in age-matched RTx and non-RTx groups. RESULTS: Significant early spatial differences in mineral/matrix and collagen crosslink ratios were found between endosteal and periosteal or mid-cortical bone at 2-wks post-RTx. Although spatial differences were transient, mineral/matrix ratios significantly decreased and collagen crosslink ratios significantly increased with post-RTx time throughout the entire tibial metaphyseal cortex. CONCLUSIONS: Irradiation negatively impacts the composition of cortical bone in a spatially-dependent manner starting as early as 2-wks post-RTx. Long-term progressive post-RTx changes across all cortical bone sites may eventually contribute to the increased risk of post-RTx bone fragility fractures.

Similitude of cement-bone micromechanics in cemented rat and human knee replacement.

A preclinical rat knee replacement model was recently developed to explore the biological and mechanobiological changes of trabecular resorption for cement-bone interdigitated regions. The goal here was to evaluate the relevance of this model compared with human knee replacement with regards to functional micromechanics. Eight nonsurvival, cemented knee replacement surgeries were performed, the interdigitated gap morphology was quantified, and interface micromotion between cement and bone was measured for 1 to 5 bodyweight loading. Computational fluid dynamics modeling of unit cell geometries with small gaps between trabeculae and cement was used to estimate fluid flow. Gap width (3.6 µm) was substantially smaller compared with cement-bone gaps reported in human knee replacement (11.8 µm). Micromotion at the cement-bone border was also decreased for the rat knee replacement (0.48 µm), compared with human (1.97 µm), for 1 bodyweight loading. However, the micromotion-to-gap width ratio (0.19 and 0.22 for, rat and human), and estimated fluid shear stress (6.47 and 7.13 Pa, for rat and human) were similar. Replicating the fluid dynamic characteristics of cement-bone interdigitated regions in human knee replacements using preclinical models may be important to recapitulate trabecular resorption mechanisms due to proposed supraphysiologic fluid shear stress. Statement of clinical significance: local cement-bone micromotion due to joint loading may contribute to the process of clinical loosening in total joint replacements. This work shows that while micromotion and gap morphology are diminished for the rat knee model compared to human, the motion-to-gap ratio, and corresponding fluid shear stress are of similar magnitudes.

Fracture risk assessment and clinical decision making for patients with metastatic bone disease.

Metastatic breast, prostate, lung, and other cancers often affect bone, causing pain, increasing fracture risk, and decreasing function. Management of metastatic bone disease (MBD) is clinically challenging when there is potential but uncertain risk of pathological fracture. Management of MBD has become a major focus within orthopedic oncology with respect to fracture and impending fracture care. If impending skeletal-related events (SREs), particularly pathologic fracture, could be predicted, increasing evidence suggests that prophylactic surgical treatment improves patient outcomes. However, current fracture risk assessment and radiographic metrics do not have high accuracy and have not been combined with relevant patient survival tools. This review first explores the prevalence, incidence, and morbidity of MBD and associated SREs for different cancer types. Strengths and limitations of current fracture risk scoring systems for spinal stability and long bone fracture are highlighted. More recent computed tomography (CT)-based structural rigidity analysis (CTRA) and finite element (FE) analysis methods offer advantages of increased specificity (true negative rate), but are limited in availability. Other fracture prediction approaches including parametric response mapping and positron emission tomography/computed tomography measures show early promise. Substantial new information to inform clinical decision-making includes measures of survival, clinical benefits, and economic analysis of prophylactic treatment compared to after-fracture stabilization. Areas of future research include use of big data and machine learning to predict SREs, greater access and refinement of CTRA/FE approaches, combination of clinical survival prediction tools with radiographically based fracture risk assessment, and net benefit analysis for fracture risk assessment and prophylactic treatment.

Early Changes in Cement-Bone Fixation Using a Novel Rat Knee Replacement Model.

Trabecular resorption from interdigitated regions between cement and bone has been found in postmortem-retrieved knee replacements, but the viability of interdigitated bone, and the mechanism responsible for this bone loss is not known. In this work, a Sprague-Dawley (age 12 weeks) rat knee replacement model with an interdigitated cement-bone interface was developed. Morphological and cellular changes in the interdigitated region of the knee replacement over time (0, 2, 6, or 12 weeks) were determined for ovariectomy (OVX) and Sham OVX treatment groups. Interdigitated bone volume fraction (BV/TV) increased with time for Sham OVX (0.022 BV/TV/wk) and OVX (0.015 BV/TV/wk) group, but the rate of increase was greater for the Sham OVX group (p = 0.0064). Tissue mineral density followed a similar increase with time in the interdigitated regions. Trabecular resorption, when it did occur, started at the cement border with medullary-adjacent bone in the presence of osteoclasts. There was substantial loss of viable bone (~80% empty osteocyte lacunae) in the interdigitated regions. Pre-surgical fluorochrome labels remained in the interdigitated regions, and did not diminish with time, indicating that the bone was not remodeling. There was also some evidence of continued surface mineralization in the interdigitated region after cementing of the knee, but this diminished over time. Statement of clinical significance: Interdigitated bone with cement provides mechanical stability for success of knee replacements. Improved understanding of the fate of the interdigitated bone over time could lead to a better understanding of the loosening process and interventions to prevent loss of fixation. © 2019 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 37:2163-2171, 2019.

A Biomechanical Comparison of Four Hip Arthroplasty Designs in a Canine Model.

OBJECTIVE: The aim of this study was to develop an in vitro biomechanical protocol for canine cementless hip arthroplasty that represents physiological gait loading (compression and torsion) and to evaluate if three alternative implant designs improve fixation compared with the traditional collarless, tapered stem in the clinically challenging case of moderate canal flare index. STUDY DESIGN: Twenty-four (six/group) laboratory-prepared canine constructs were tested using a simulated gait and overload (failure) protocol. Construct stiffness, failure load/displacement and migration were measured as outcome variables. RESULTS: Simulated gait loading did not show any significant differences between implant types for peak displacement, peak rotation, torsional stiffness, subsidence or inducible displacement. The collared and collarless stem groups were stiffer in compression compared with the collarless with a lateral bolt and short-stem groups. Increasing the loading above simulated gait showed significant reductions in compressive and torsional stiffness for all implant constructs. Despite the reductions, the short-stem group showed significantly higher stiffness compared with the other three groups. CONCLUSION: Peak failure loads (compressive and torsional) in this study were approximately four to seven times the simulated gait loading (430 N, 1.6 Nm) regardless of implant type and highlight the importance of limiting activity level (trotting, jumping) following hip replacement in the postoperative period and during the osseointegration of the implant.

Mechanical Loading Promotes the Expansion of Primitive Osteoprogenitors and Organizes Matrix and Vascular Morphology in Long Bone Defects.

Elucidating the effects of mechanical stimulation on bone repair is crucial for optimization of the healing process. Specifically, the regulatory role that mechanical loading exerts on the osteogenic stem cell pool and vascular morphology during healing is incompletely understood. Because dynamic loading has been shown to enhance osteogenesis and repair, we hypothesized that loading induces the expansion of the osteoprogenitor cell population within a healing bone defect, leading to an increased presence of osteogenic cells. We further hypothesized that loading during the repair process regulates vascular and collagen matrix morphology and spatial interactions between vessels and osteogenic cells. To address these hypotheses, we used a mechanobiological bone repair model, which produces a consistent and reproducible intramembranous repair response confined in time and space. Bilateral tibial defects were created in adult C57BL/6 mice, which were subjected to axial compressive dynamic loading either during the early cellular invasion phase on postsurgical days (PSDs) 2 to 5 or during the matrix deposition phase on PSD 5 to 8. Confocal and two-photon microscopy was used to generate high-resolution three-dimensional (3D) renderings of longitudinal thick sections of the defect on PSD 10. Endomucin (EMCN)-positive vessels, Paired related homeobox 1 (Prrx1+) stem cell antigen-1 positive (Sca-1+) primitive osteoprogenitors (OPCs), and osterix positive (Osx+) preosteoblasts were visualized and quantified using deep tissue immunohistochemistry. New bone matrix was visualized with second harmonic generation autofluorescence of collagen fibers. We found that mechanical loading during the matrix deposition phase (PSD 5 to 8) increased vessel volume and number, and aligned vessels and collagen fibers to the load-bearing direction of bone. Furthermore, loading led to a significant increase in the proliferation and number of Prrx1+ Sca-1+ primitive OPCs, but not Osx+ preosteoblasts within the defect. Together, these data illustrate the adaptation of both collagen matrix and vascular morphology to better withstand mechanical load during bone repair, and that the mechanoresponsive cell population consists of the primitive osteogenic progenitors. © 2019 American Society for Bone and Mineral Research.

Evidence of Negative Effects of Defect Size and Older Patient Age by Quantitative CT-Based 3D Image Analysis in Ultraporous Beta-Tricalcium Phosphate Grafted Extremity Bone Defects at One Year.

INTRODUCTION: Synthetic bone graft materials are commonly used to fill defects after curettage of benign bone lesions. Ultraporous beta tricalcium phosphate (TCP) is a popular synthetic compound used in this situation. Prior clinical studies based on plain X-ray analysis suggest incorporation of TCP is incomplete, even when combined with bone marrow (BMA). PURPOSE: The purpose was to analyze volumetric CT-based changes in defects grafted with TCP with/without BMA in a completed prospective RCT to objectively determine (1) relationship between size and age versus TCP incorporation and (2) whether there is an advantage to addition of BMA. METHODS: Twenty-one patients with CT scans at ≥1 year follow-up available for digital analysis (TCP=10, TCP w/BMA =11) form the study population. CT image stacks were evaluated by creating volumetric masks using MIMICS imaging software for total defect, graft remaining, and graft incorporated volumes graft incorporation endpoints. RESULTS: Overall, there was significant (p=0.0029) negative correlation (r2 = 0.38) between defect size and ratio of incorporated bone to defect size. This relationship remained strong (r2 = 0.56) particularly for defects > 20 cc but not for smaller defects. Bone width was also a significantly related factor (r2 = 0.94), with less graft incorporation in larger bone sites, in part likely due to the linear relationship between defect size and bone width. Relationship with age was complex and closely tied to defect volume. For larger defect volumes, younger patients were more successful at graft incorporation. Although age itself was not an independently significant factor, as defect volume increased, advanced age more negatively impacted new bone formation. CONCLUSIONS: Larger size defect and affected bone and advancing age appear to be important negative factors in synthetic graft incorporation. Results showed no advantage to addition of BMA to TCP.

Limited field radiation therapy results in decreased bone fracture toughness in a murine model.

Fragility fractures are a well-known complication following oncologic radiotherapy, and it is suspected that radiation-induced embrittlement of bone within the treatment field may contribute to fracture risk. To explore this phenomenon, a mouse model (BALB/cJ) of fractionated, limited field, bilateral hindlimb irradiation (4x5 Gy) was used. The effects of radiation on femoral (cortical) bone fracture toughness, morphology, and biochemistry-including advanced glycation end products (AGEs)-were quantified and compared to Sham group samples prior to irradiation and at 0, 4, 8, and 12 weeks post-irradiation. Additionally, alterations to bone fracture toughness mediated directly by radiation (independent of cellular mechanisms) were determined using devitalized mouse cadaver femurs. Finally, the contribution of AGEs to reduced fracture toughness was examined by artificially ribosylating mouse femurs ex vivo. These data demonstrate that in vivo irradiation results in an immediate (-42% at 0 weeks, p < 0.001) and sustained (-28% at 12 weeks, p < 0.001) decrease in fracture toughness with small changes in morphology (-5% in cortical area at 12 weeks), and minimal changes in bone composition (tissue mineral density, mineral:matrix ratio, and AGE content). Irradiation of devitalized femurs also reduced fracture toughness (-29%, p < 0.001), but to a lesser extent than was seen in vivo. While artificial ribosylation decreased fracture toughness with time, the extent of glycation needed to induce this effect exceeded the AGE accumulation that occurred in vivo. Overall, hindlimb irradiation induced a substantial and sustained decrease in bone fracture toughness. Approximately half of this decrease in fracture toughness is due to direct radiation damage, independent of cellular remodeling. Collagen glycation in vivo was not substantially altered, suggesting other matrix changes may contribute to post-radiotherapy bone embrittlement.

Effects of mechanical loading on cortical defect repair using a novel mechanobiological model of bone healing.

Mechanical loading is an important aspect of post-surgical fracture care. The timing of load application relative to the injury event may differentially regulate repair depending on the stage of healing. Here, we used a novel mechanobiological model of cortical defect repair that offers several advantages including its technical simplicity and spatially confined repair program, making effects of both physical and biological interventions more easily assessed. Using this model, we showed that daily loading (5N peak load, 2Hz, 60 cycles, 4 consecutive days) during hematoma consolidation and inflammation disrupted the injury site and activated cartilage formation on the periosteal surface adjacent to the defect. We also showed that daily loading during the matrix deposition phase enhanced both bone and cartilage formation at the defect site, while loading during the remodeling phase resulted in an enlarged woven bone regenerate. All loading regimens resulted in abundant cellular proliferation throughout the regenerate and fibrous tissue formation directly above the defect demonstrating that all phases of cortical defect healing are sensitive to physical stimulation. Stress was concentrated at the edges of the defect during exogenous loading, and finite element (FE)-modeled longitudinal strain (εzz) values along the anterior and posterior borders of the defect (~2200µÎµ) was an order of magnitude larger than strain values on the proximal and distal borders (~50-100µÎµ). It is concluded that loading during the early stages of repair may impede stabilization of the injury site important for early bone matrix deposition, whereas loading while matrix deposition and remodeling are ongoing may enhance stabilization through the formation of additional cartilage and bone.

Longitudinal Effects of Single Hindlimb Radiation Therapy on Bone Strength and Morphology at Local and Contralateral Sites.

Radiation therapy (RTx) is associated with increased risk for late-onset fragility fractures in bone tissue underlying the radiation field. Bone tissue outside the RTx field is often selected as a "normal" comparator tissue in clinical assessment of fragility fracture risk, but the robustness of this comparison is limited by an incomplete understanding of the systemic effects of local radiotherapy. In this study, a mouse model of limited field irradiation was used to quantify longitudinal changes in local (irradiated) and systemic (non-irradiated) femurs with respect to bone density, morphology, and strength. BALB/cJ mice aged 12 weeks underwent unilateral hindlimb irradiation (4 × 5 Gy) or a sham procedure. Femurs were collected at endpoints of 4 days before treatment and at 0, 1, 2, 4, 8, 12, and 26 weeks post-treatment. Irradiated (RTx), Contralateral (non-RTx), and Sham (non-RTx) femurs were imaged by micro-computed tomography and mechanically tested in three-point bending. In both the RTx and Contralateral non-RTx groups, the longer-term (12- to 26-week) outcomes included trabecular resorption, loss of diaphyseal cortical bone, and decreased bending strength. Contralateral femurs generally followed an intermediate response compared with RTx femurs. Change also varied by anatomic compartment; post-RTx loss of trabecular bone was more profound in the metaphyseal than the epiphyseal compartment, and cortical bone thickness decreased at the mid-diaphysis but increased at the metaphysis. These data demonstrate that changes in bone quantity, density, and architecture occur both locally and systemically after limited field irradiation and vary by anatomic compartment. Furthermore, the severity and persistence of systemic bone damage after limited field irradiation suggest selection of control tissues for assessment of fracture risk or changes in bone density after radiotherapy may be challenging. © 2017 American Society for Bone and Mineral Research.