Kenneth A. Mann

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.

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.

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.

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.

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.

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.

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.

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.

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.