Staphylococcus aureus persistence in osteocytes: weathering the storm of antibiotics and autophagy/xenophagy.

Staphylococcus aureus is a major causative pathogen of osteomyelitis. Intracellular infections of resident bone cells including osteocytes can persist despite gold-standard clinical intervention. The mechanisms by which intracellular S. aureus evades antibiotic therapy are unknown. In this study, we utilised an in vitro S. aureus infection model of human osteocytes to investigate whether antibiotic-mediated dysregulation of autophagy contributes to this phenomenon. Infected or non-infected osteocyte-like cells were exposed to combinations of rifampicin, vancomycin, and modulators of autophagy. Intracellular bacterial growth characteristics were assessed using colony-forming unit (CFU) analysis, viable bacterial DNA abundance, and the rate of escape into antibiotic-free medium, together with measures of autophagic flux. Rifampicin, alone or in combination with vancomycin, caused a rapid decrease in the culturability of intracellular bacteria, concomitant with stable or increased absolute bacterial DNA levels. Both antibiotics significantly inhibited autophagic flux. However, modulation of autophagic flux did not affect viable bacterial DNA levels. In summary, autophagy was shown to be a factor in the host-pathogen relationship in this model, as its modulation affected the growth state of intracellular S. aureus with respect to both their culturability and propensity to escape the intracellular niche. While rifampicin and vancomycin treatments moderately suppressed autophagic flux acutely, this did not explain the paradoxical response of antibiotic treatment in decreasing S. aureus culturability whilst failing to clear bacterial DNA and hence intracellular bacterial load. Thus, off-target effects of rifampicin and vancomycin on autophagic flux in osteocyte-like cells could not explain the persistent S. aureus infection in these cells.

Patient-Related Predictors of Treatment Failure After Two-Stage Total Hip Arthroplasty Revision for Periprosthetic Joint Infection: A Systematic Review and Meta-Analysis.

BACKGROUND: Periprosthetic joint infection (PJI) treatment has high failure rates even after 2-stage revision. Risk factors for treatment failure (TF) after staged revision for PJI are not well defined, nor is it well established how they correlate with the risks of developing an index PJI. Identifying modifiable risk factors may allow preoperative optimization, while identifying nonmodifiable risk factors can influence surgical options or advise against further surgery. We performed a systematic review and meta-analysis to better define predictors of TF in 2-stage revision for PJI. METHODS: The PubMed, Embase, and Scopus databases were searched from their inception in December 1976 to April 15, 2023. Studies comparing patient-related variables between patients successfully treated who had 2-staged revision total hip arthroplasty (THA) and patients with persistent infections were included. Studies were screened, and 2 independent reviewers extracted data, while a third resolved discrepancies. Meta-analysis was performed on these data. There were 10,052 unique studies screened, and 21 studies met the inclusion criteria for data extraction. RESULTS: There was good-quality evidence that obesity, liver cirrhosis, and previous failed revisions for PJI are nonmodifiable risk factors, while intravenous drug use (IVDU) and smoking are modifiable risk factors for TF after 2-stage revision for hip PJI. Reoperation between revision stages was also significantly associated with an increased risk of TF. Interestingly, other risk factors for an index PJI including male gender, American Society of Anesthesiology score, diabetes mellitus, and inflammatory arthropathy did not predict TF. Evidence on Charlson Comorbidity Index was limited. CONCLUSIONS: Patients with a smoking history, obesity, IVDU, previous failed revision for PJI, reoperation between stages, and liver cirrhosis are more likely to experience TF after 2-stage revision THA for PJI. Modifiable risk factors include smoking and IVDU and these patients should be referred to services for cessation as early as possible before 2-stage revision THA.

Virtual biomechanical assessment of porous tantalum and custom triflange components in the treatment of patients with acetabular defects and pelvic discontinuity.

Aims: The aim of this study was to compare the biomechanical models of two frequently used techniques for reconstructing severe acetabular defects with pelvic discontinuity in revision total hip arthroplasty (THA) - the Trabecular Metal Acetabular Revision System (TMARS) and custom triflange acetabular components (CTACs) - using virtual modelling. Methods: Pre- and postoperative CT scans from ten patients who underwent revision with the TMARS for a Paprosky IIIB acetabular defect with pelvic discontinuity were retrospectively collated. Computer models of a CTAC implant were designed from the preoperative CT scans of these patients. Computer models of the TMARS reconstruction were segmented from postoperative CT scans using a semi-automated method. The amount of bone removed, the implant-bone apposition that was achieved, and the restoration of the centre of rotation of the hip were compared between all the actual TMARS and the virtual CTAC implants. Results: The median amount of bone removed for TMARS reconstructions was significantly greater than for CTAC implants (9.07 cm3 (interquartile range (IQR) 5.86 to 21.42) vs 1.16 cm3 (IQR 0.42 to 3.53) (p = 0.004). There was no significant difference between the median overall implant-bone apposition between TMARS reconstructions and CTAC implants (54.8 cm2 (IQR 28.2 to 82.3) vs 56.6 cm2 (IQR 40.6 to 69.7) (p = 0.683). However, there was significantly more implant-bone apposition within the residual acetabulum (45.2 cm2 (IQR 28.2 to 72.4) vs 25.5 cm2 (IQR 12.8 to 44.1) (p = 0.001) and conversely significantly less apposition with the outer cortex of the pelvis for TMARS implants compared with CTAC reconstructions (0 cm2 (IQR 0 to 13.1) vs 23.2 cm2 (IQR 16.4 to 30.6) (p = 0.009). The mean centre of rotation of the hip of TMARS reconstructions differed by a mean of 11.1 mm (3 to 28) compared with CTAC implants. Conclusion: In using TMARS, more bone is removed, thus achieving more implant-bone apposition within the residual acetabular bone. In CTAC implants, the amount of bone removed is minimal, while the implant-bone apposition is more evenly distributed between the residual acetabulum and the outer cortex of the pelvis. The differences suggest that these implants used to treat pelvic discontinuity might achieve short- and long-term stability through different biomechanical mechanisms.

Supervised machine learning for the prediction of post-operative clinical outcomes of hip and knee replacements: a review.

Prediction models are being increasingly used in the medical field to identify risk factors and possible outcomes. Some of these are presently being used to develop guidelines for improving clinical practice. The application of machine learning (ML), comprising a powerful set of computational tools for analysing data, has been clearly expanding in the role of predictive modelling. This paper reviews the latest developments of supervised ML techniques that have been used to analyse data related to post-operative total hip and knee replacements. The aim was to review the most recent findings of relevant published studies by outlining the methodologies employed (most-widely used supervised ML techniques), data sources, domains, limitations of predictive analytics and the quality of predictions.

What Is the Most Appropriate Comparator to Use in Assessing the Comparative Performance of Primary Total Knee Prostheses? A Registry-Based Study.

Background: The Australian Orthopedic Association National Joint Replacement Registry has developed a standardized multi-stage approach to identify prostheses with a higher-than-anticipated rate of revision when comparing a prosthesis of interest to all other prostheses within the same broad class. However, the approach does not adequately differentiate between the conventional and complex design prostheses, and the comparator classes need to be re-evaluated. This study aimed to identify a more relevant comparator to better reflect conventional and complex surgical practices according to the stability design and also explore how the rate of revision estimated in the comparator groups affects the identification of "prosthesis outliers." Methods: The cumulative percent revision (CPR) was calculated for 640,045 primary total knee replacements (TKRs) undertaken for Osteoarthritis from 1 January 2003 to 31 December 2019. At first, survivorship analyses were undertaken to calculate the rate of revision for primary TKR by stability design. A modified TKR comparator group was developed by excluding the "complex" group of prostheses with fully stabilized and hinged designs. The effectiveness of the modified comparator groups, including cruciate retaining and posterior stabilized designs, was evaluated based on the ability to detect additional prostheses by performing the Australian Orthopedic Association National Joint Replacement Registry standardized method for identifying prosthesis outliers. Results: The modified comparator to include only conventional designs had a 10-year CPR of 5.2% (5.1, 5.3). When the fully stabilized and hinged design groups were combined as a comparator group of complex devices to reflect devices used only for specific purposes in primary TKR, the CPR at 10 year was 10.3% (8.6, 12.0). Conclusions: The use of modified comparator groups led to identifying additional conventional prostheses but fewer complex designs as being at risk and has the potential to improve the early assessment of TKR prostheses.

Corroboration of coupled musculoskeletal model and finite element predictions with in vivo RSA migration of an uncemented acetabular component.

While finite element (FE) models have been used extensively in orthopedic studies, validation of their outcome metrics has been limited to comparison against ex vivo testing. The aim of this study was to validate FE model predictions of the initial cup mechanical environment against patient-matched in vivo measurements of acetabular cup migration using radiostereometric analysis (RSA). Tailored musculoskeletal and FE models were developed using a combination of three-dimensional (3D) motion capture data and clinical computerized tomography (CT) scans for a cohort of eight individuals who underwent primary total hip replacement and were prospectively enrolled in an RSA study. FE models were developed to calculate the mean modulus of cancellous bone, composite peak micromotion (CPM), composite peak strain (CPS) and percentage area of bone ingrowth. The RSA cup migration at 3 months was used to corroborate the FE output metrics. Qualitatively, all FE-predicted metrics followed a similar rank order as the in vivo RSA 3D migration data. The two cases with the lowest predicted CPM (<20 µm), lowest CPS (<0.0041), and high bone modulus (>917 MPa) were confirmed to have the lowest in vivo RSA 3D migration (<0.14 mm). The two cases with the largest predicted CPM (>80 µm), larger CPS (>0.0119) and lowest bone modulus (<472 MPa) were confirmed to have the largest in vivo RSA 3D migration (>0.78 mm). This study enabled the first corroboration between tailored musculoskeletal and FE model predictions with in vivo RSA cup migration. Investigation of additional patient-matched CT, gait, and RSA examinations may allow further development and validation of FE models.

What is the most appropriate comparator group to use in assessing the performance of primary total hip prostheses within the community?

BACKGROUND: There are variations in the performance of individual prostheses used in hip replacements. Some of which have unexpectedly higher revision rates - outliers. The Australian Orthopaedic Association National Joint Replacement Registry (AOANJRR) has established a standardised multi-stage approach for identifying these devices. This is done by comparing the revision rates of individual prostheses to all other prostheses in class, with the exception of large head metal-on-metal (LHMoM) prostheses. However, improvements in device design and performance over time have required a need to reconsider the comparator group. This study aimed to identify a more specific comparator to better reflect contemporary surgical practice. METHODS: The time to first revision was estimated on the data of 413,417 primary total conventional hip replacements undertaken for osteoarthritis (OA) from 01 January 2003 to 31 December 2019. Survivorship analyses with stepwise exclusions were undertaken. The first exclusion was LHMoM, followed by other non-modern bearing surfaces (defined as all the bearing couples except metal or ceramic heads on cross-linked polyethylene and mixed ceramic-on-ceramic), and then devices with modular neck-stem design or used for specific purposes (incl. constrained, dual-mobility, and head size <28 mm). Lastly, all remaining prostheses previously identified as having a higher than anticipated rate of revision (HTARR) were also excluded. RESULTS: These exclusions progressively reduced the cumulative percent revision (CPR) rate. The final comparator, which only includes satisfactory-performed prostheses of contemporary design and use, has a 10-year CPR of 4.30% (95% CI, 4.2-4.41) which is lower than 4.93% (95% CI, 4.84-5.02) for the current comparator used by the AOANJRR (all prostheses excluding LHMOM). Over the study period, 13 additional components were identified utilising the modified comparator. CONCLUSIONS: The calculation of the comparator revision rate should be re-evaluated to include only modern prosthesis constructs to ensure that poorly performing prostheses are identified early.

Migration patterns of acetabular cups: a systematic review and meta-analysis of RSA studies.

BACKGROUND AND PURPOSE: We conducted a systematic review and meta-analysis of RSA studies to investigate the early and long-term migration patterns of acetabular cups and the influence of implant factors on cup migration over time. METHODS: We performed a systematic search of PubMed, Embase, and Scopus databases to identify all RSA studies of cup migration following primary total hip replacement (THR). Proximal migration at 3 and 6 months, 1, 2, 5, and 10 years were considered for analysis. Implant factors investigated included fixation type, head size, bearing surface, uncemented coating design, and the decade of RSA introduction. RESULTS: 47 studies reported the proximal migration of 83 cohorts (2,328 cups). Besides 1 threaded cup design, no implant factor investigated was found to significantly influence proximal migration. The mean pooled 2-year proximal migration of cemented cups (0.14 mm, 95% confidence interval [CI] 0.08-0.20) was not significantly different from uncemented cups (0.12 mm, CI 0.04-0.19). The mean pooled proximal migration at 6 months was 0.11 mm (CI 0.06-0.16) and there was no significant increase between 6 months and 2 years (0.015 mm, CI 0.000-0.030). 27 of 75 cohorts (36%) reported mean proximal migration greater than 0.2 mm at 2 years, which has previously been identified as a predictor of implants at risk of long-term loosening. CONCLUSION: Our meta-analysis demonstrated that the majority of cup migration occurs within the first 6 months. With one exception, no implant factors influenced the 2-year proximal migration of acetabular cups. 36% of studies with 2-year migration were considered at risk of long-term loosening. Further investigation and comparison against long-term survivorship data would validate 6-month and/or 1-year proximal migration measurements as an earlier predictor of long-term loosening than the current 2-year threshold.

Saos-2 cells cultured under hypoxia rapidly differentiate to an osteocyte-like stage and support intracellular infection by Staphylococcus aureus.

The intracellular infection of osteocytes represents a clinically important aspect of osteomyelitis. However, few human osteocyte in vitro models exist and the differentiation of immature osteoblasts to an osteocyte stage typically takes at least 4-weeks of culture, making the study of this process challenging and time consuming. The osteosarcoma cell line Saos-2 has proved to be a useful model of human osteoblast to mature osteocyte differentiation. Culture under osteogenic conditions in a standard normoxic (21% O2 ) atmosphere results in reproducible mineralization and acquisition of mature osteocyte markers over the expected 28-35 day culture period. In order to expedite experimental assays, we tested whether reducing available oxygen to mimic concentrations experienced by osteocytes in vivo would increase the rate of differentiation. Cells cultured under 1% O2 exhibited maximal mineral deposition by 14 days. Early (COLA1, MEPE) and mature (PHEX, DMP1, GJA1, SOST) osteocyte markers were upregulated earlier under hypoxia compared to normoxia. Cells differentiated under 1% O2 for 14 days displayed a similar ability to internalize Staphylococcus aureus as day 28 cells grown under normoxic conditions. Thus, low oxygen accelerates Saos-2 osteocyte differentiation, resulting in a useful human osteocyte-like cell model within 14 days.

Microstructural and cellular characterisation of the subchondral trabecular bone in human knee and hip osteoarthritis using synchrotron tomography.

OBJECTIVE: It is unclear if different factors influence osteoarthritis (OA) progression and degenerative changes characterising OA disease in hip and knee. We investigated the difference between hip OA and knee OA at the subchondral bone (SCB) tissue and cellular level, relative to the degree of cartilage degeneration. DESIGN: Bone samples were collected from 11 patients (aged 70.4 ± 10.7years) undergoing knee arthroplasty and 8 patients (aged 62.3 ± 13.4years) undergoing hip arthroplasty surgery. Trabecular bone microstructure, osteocyte-lacunar network, and bone matrix vascularity were evaluated using synchrotron micro-CT imaging. Additionally, osteocyte density, viability, and connectivity were determined histologically. RESULTS: The associations between severe cartilage degeneration and increase of bone volume fraction (%) [- 8.7, 95% CI (-14.1, -3.4)], trabecular number (#/mm) [- 1.5, 95% CI (-0.8, -2.3)], osteocyte lacunar density (#/mm3) [4714.9; 95% CI (2079.1, 7350.6)] and decrease of trabecular separation (mm) [- 0.07, 95% CI (0.02, 0.1)] were found in both knee and hip OA. When compared to knee OA, hip OA was characterised by larger (µm3) but less spheric osteocyte lacunae [47.3; 95% CI (11.2, 83.4), - 0.04; 95% CI (-0.06, -0.02), respectively], lower vascular canal density (#/mm3) [- 22.8; 95% CI (-35.4, -10.3)], lower osteocyte cell density (#/mm2) [- 84.2; 95% CI (-102.5, -67.4)], and less senescent (#/mm2) but more apoptotic osteocytes (%) [- 2.4; 95% CI (-3.6, -1.2), 24.9; 95% CI (17.7, 32.1)], respectively. CONCLUSION: SCB from hip OA and knee OA exhibits different characteristics at the tissue and cellular levels, suggesting different mechanisms of OA progression in different joints.

Impact of computed tomography metal artifact reduction protocol on periprosthetic tissue characterization after total hip arthroplasty: A cadaveric study.

Metal artifact reduction (MAR) has improved computed tomography (CT) imaging of total hip arthroplasty (THA) but the assessment of osteolysis and implant to bone contact relies on the accurate depiction of bone defects, cancellous bone, and cement. This study evaluates the impact of available single and dual-energy protocols on periprosthetic tissue characterization in a cadaveric phantom. Bilateral THA was performed on a fresh frozen cadaveric pelvis with simulated osteolytic cavities. CT acquisitions with projection-based MAR and noise equivalence were performed using single energy 140 kVp, single energy 150 kVp with 0.6 mm tin filtration, and dual-energy at 100/150 kVp with 0.6 mm tin filtration, from which simulated energies were extracted. Image subtraction, segmentation, region of interest histograms, and line profiles were used to characterize tissue density and separation. Tissue densities were heavily dependent on the energy profile of the protocol. Cancellous bone ranged from 182 to 45 HU and cement from 1012 to 131 HU using 140 kVp compared to dual-energy with weighted high energy tube, respectively. Spectral separation between cancellous bone, osteolytic defect, and cement was reduced for all protocols compared with 140 kVp. Spectral overlap was most severe using dual-energy with heavily weighted high-energy tubes. Dual-energy algorithms reduced trabecular contrast within the cancellous bone and cortical edge response. Although the dual-energy acquisition has been proposed as an additive to projection-based MAR techniques in THA, reduced density and contrast in clinically relevant periprosthetic tissue compared to 140 kVp single energy may limit its use in characterizing periprosthetic tissues.

The effect of surgical change to hip geometry on hip biomechanics after primary total hip arthroplasty.

The aim of this study was to determine the effect of surgical change to the acetabular offset and femoral offset on the abductor muscle and hip contact forces after primary total hip arthroplasty (THA) using computational methods. Thirty-five patients undergoing primary THA were recruited. Patients underwent a computed tomography scan of their pelvis and hip, and underwent gait analysis pre- and 6-months postoperatively. Surgically induced changes in acetabular and femoral offset were used to inform a musculoskeletal model to estimated abductor muscle and hip joint contact forces. Two experiments were performed: (1) influence of changes in hip geometry on hip biomechanics with preoperative kinematics; and (2) influence of changes in hip geometry on hip biomechanics with postoperative kinematics. Superior and medial placement of the hip centre of rotation during THA was most influential in reducing hip contact forces, predicting 63% of the variance (p < 0.001). When comparing the preoperative geometry and kinematics model, with postoperative geometry and kinematics, hip contact forces increased after surgery (0.68 BW, p = 0.001). Increasing the abductor lever arm reduced abductor muscle force by 28% (p < 0.001) and resultant hip contact force by 17% (0.6 BW, p = 0.003), with both preoperative and postoperative kinematics. Failure to increase abductor lever arm increased resultant hip contact force 11% (0.33 BW, p < 0.001). In conclusion, increasing the abductor lever arm provides a substantial biomechanical benefit to reduce hip abductor and resultant hip joint contact forces. The magnitude of this effect is equivalent to the average increase in hip contact force seen with improved gait from pre-to post-surgery.

Assigning trabecular bone material properties in finite element models simulating the pelvis before and after the development of peri-prosthetic osteolytic lesions.

Estimating strain distribution in the acetabulum before and after the development of peri-prosthetic osteolytic lesions secondary to total hip arthroplasty may assist with understanding the pathogenesis of this condition. This could be achieved by performing patient-specific finite element analysis of (1) total hip arthroplasty recipients with developed acetabular osteolytic lesions, and (2) models simulating the patient's pelvis and implant immediately after primary surgery. State of the art patient-specific total hip arthroplasty finite element analysis simulations obtain trabecular bone material properties from Hounsfield units within computed tomography (CT) scans of patients. However, this is not feasible when an implant is already in situ due to metal artefact disruption and, in turn, incorrectly reproduced Hounsfield units. Therefore, alternative methods of assigning trabecular bone material properties within such models were tested and strain results compared. It was found that assigning set material properties throughout the trabecular bone geometry was sufficient for the desired application. Simulating the primary implant and pelvis requires geometric and material based assumptions. Therefore, comparisons were made between strain values obtained from simulated primary models, from state of the art methods using material properties obtained from intact bone within a CT scan, and from models with osteolytic lesions. Strain values found using the finite element models simulating the pelvis before osteolytic lesion developed were considerably closer to those found using state of the art methods than those found for the bone loss models. These models could be used to determine relationships between strain distribution and factors such as bone loss.

A Mild Case of Autosomal Recessive Osteopetrosis Masquerading as the Dominant Form Involving Homozygous Deep Intronic Variations in the CLCN7 Gene.

Osteopetrosis is a heterogeneous group of rare hereditary diseases characterized by increased bone mass of poor quality. Autosomal-dominant osteopetrosis type II (ADOII) is most often caused by mutation of the CLCN7 gene leading to impaired bone resorption. Autosomal recessive osteopetrosis (ARO) is a more severe form and is frequently accompanied by additional morbidities. We report an adult male presenting with classical clinical and radiological features of ADOII. Genetic analyses showed no amino-acid-converting mutation in CLCN7 but an apparent haploinsufficiency and suppression of CLCN7 mRNA levels in peripheral blood mononuclear cells. Next generation sequencing revealed low-frequency intronic homozygous variations in CLCN7, suggesting recessive inheritance. In silico analysis of an intronic duplication c.595-120_595-86dup revealed additional binding sites for Serine- and Arginine-rich Splicing Factors (SRSF), which is predicted to impair CLCN7 expression. Quantitative backscattered electron imaging and histomorphometric analyses revealed bone tissue and material abnormalities. Giant osteoclasts were present and additionally to lamellar bone, and abundant woven bone and mineralized cartilage were observed, together with increased frequency and thickness of cement lines. Bone mineralization density distribution (BMDD) analysis revealed markedly increased average mineral content of the dense bone (CaMean T-score + 10.1) and frequency of bone with highest mineral content (CaHigh T-score + 19.6), suggesting continued mineral accumulation and lack of bone remodelling. Osteocyte lacunae sections (OLS) characteristics were unremarkable except for an unusually circular shape. Together, our findings suggest that the reduced expression of CLCN7 mRNA in osteoclasts, and possibly also osteocytes, causes poorly remodelled bone with abnormal bone matrix with high mineral content. This together with the lack of adequate bone repair mechanisms makes the material brittle and prone to fracture. While the skeletal phenotype and medical history were suggestive of ADOII, genetic analysis revealed that this is a possible mild case of ARO due to deep intronic mutation.

A semiautomated method to quantitatively assess osteolytic lesion volume and bone mineral density within acetabular regions of interest from CT.

The objectives of this study were to (1) develop a semiautomated method to obtain lesion volume and bone mineral density (BMD) in terms of Hounsfield units from pelvic computed tomography (CT) scans in three regions of interest, and (2) assess accuracy and reliability of the method based on cadaveric CT scans. Image artefacts due to metal implants reduce CT clarity and are more severe with more than one implant in situ. Therefore, accuracy and reliability tests were performed with varying numbers of total hip arthroplasties implanted. To test the accuracy of lesion size measurements, microcomputed tomography was used as a reference. Mean absolute error ranged from 36 to 284 mm3 after five measurements. Intra- and inter-operator reliability of the entire method was measured for a selection of parameters. All coefficient of variation values were good to excellent for CT scans of the native pelvic anatomy and a CT scans of the same pelvis with one and two implants in situ. Accuracy of quantifying lesion volume decreased with decreasing CT image clarity by 0.6%-3.6% mean absolute relative error. Reliability of lesion volume measurement decreased with decreasing CT clarity. This was also the case for reliability of BMD measurements in the region most disrupted by metal artefact. The presented method proposes an approach for quantifying bone loss which has been proven to be accurate, reliable, and clinically applicable.

Relationships between tibial articular cartilage, in vivo external joint moments and static alignment in end-stage knee osteoarthritis: A micro-CT study.

Biomechanical factors (e.g., joint loading) have a significant role in the progression of osteoarthritis (OA). However, some relationships between in vivo joint loading indices and tibial cartilage thickness are conflicting. This study investigated relationships between pre-operative in vivo external knee joint moments, joint alignment and regional tibial cartilage thickness using micro-CT in subjects with end-stage knee OA. Tibial plateaus from 25 patients that underwent knee replacement for OA were micro-CT scanned (17 µm/voxel). Prior to surgery, subjects underwent gait analysis to calculate external knee moments. The mechanical axis deviation (MAD) was obtained from pre-operative radiographs. Cartilage thickness (Cart.Th) was analyzed from micro-CT images, in anteromedial, anterolateral, posteromedial and posterolateral subregions of interest. Medial-to-lateral Cart.Th ratios were also explored. Relationships between Cart.Th and joint loading indices were examined using Pearson's correlations. Significant correlations were found between Cart.Th and joint loading indices, positive anteromedially with the first peak knee adduction moment (r = 0.55, p < 0.01) and external rotation moment (ERM; r = 0.52, p < 0.01), and negative with MAD (r = -0.76, p < 0.001). In the lateral regions, these correlations had opposite signs. The medial-to-lateral Cart.Th ratio correlated strongly with ERM (r = 0.63, p = 0.001) and MAD (r = -0.75, p < 0.001). Joint loading indices correlated with regional cartilage thickness values and their medial-to-lateral ratios in end-stage knee OA subjects, with higher regional loads corresponding to thinner cartilage. These relationships have the opposite sign compared to the subchondral bone microarchitecture found in our previous study on the same specimens, which may suggest a complementary bone-cartilage interplay in response to loading.

A Human Osteocyte Cell Line Model for Studying Staphylococcus aureus Persistence in Osteomyelitis.

Infectious osteomyelitis associated with periprosthetic joint infections is often recalcitrant to treatment and has a high rate of recurrence. In the case of Staphylococcus aureus, the most common pathogen in all forms of osteomyelitis, this may be attributed in part to residual intracellular infection of host cells, yet this is not generally considered in the treatment strategy. Osteocytes represent a unique cell type in this context due to their abundance, their formation of a syncytium throughout the bone that could facilitate bacterial spread and their relative inaccessibility to professional immune cells. As such, there is potential value in studying the host-pathogen interactions in the context of this cell type in a replicable and scalable in vitro model. Here, we examined the utility of the human osteosarcoma cell line SaOS2 differentiated to an osteocyte-like stage (SaOS2-OY) as an intracellular infection model for S. aureus. We demonstrate that S. aureus is capable of generating stable intracellular infections in SaOS2-OY cells but not in undifferentiated, osteoblast-like SaOS2 cells (SaOS2-OB). In SaOS2-OY cells, S. aureus transitioned towards a quasi-dormant small colony variant (SCV) growth phenotype over a 15-day post-infection period. The infected cells exhibited changes in the expression of key immunomodulatory mediators that are consistent with the infection response of primary osteocytes. Thus, SaOS2-OY is an appropriate cell line model that may be predictive of the interactions between S. aureus and human osteocytes, and this will be useful for studying mechanisms of persistence and for testing the efficacy of potential antimicrobial strategies.

Assessment of the primary stability of revision tibial trays augmented with a cementless sleeve in AORI Type III defects.

BACKGROUND: Previous studies have evaluated the initial stability of uncemented tibial components in revision total knee replacement (rTKR) in the presence of an Anderson Orthopaedic Research Institute (AORI) Type II tibial defect. This study sought to evaluate similar metrics in the severe Type III (AORI TIII) defects with combined uncemented stem and sleeve fixation, specifically, the effect of varying the stem's length and tibial canal engagement upon stability and bone strain. METHOD: Finite element models generated from the CT scans of 4 tibias with Type III defects were used to investigate the primary stability, in terms of the bone-implant composite peak micromotion (CPM) and microstrains (CPS), achieved after virtual implantations with and without stems. RESULTS: A stemless rTKR had increased metaphyseal CPM and CPS compared to all stemmed implants. Significant area of the bone supporting the stemless rTKR had CPS greater than bone yield (7000 µÎµ). Short engaging stems (≤150 mm construct length), could not achieve reliable engagement in the diaphysis (canal fill ≤ 50%), leading to insufficient reduction of CPS (≥5000 µÎµ). Longer engaging stems (170-220 mm construct length), were able to reliably engage the diaphysis (fill ratio ≥ 75%) resulting in CPS ≤ 5000 µÎµ. Although, non-engaging stems resulted in increased CPM and CPS compared to engaging stems, long non-engaging stems (170-220 mm construct) appeared to provide additional stability to the rTKR compared to stemless rTKR. CONCLUSION: The results indicate a likely correlation between uncemented stem engagement and metaphyseal CPS in Type III defects. Excessive strain within the supporting metaphyseal bone is likely to lead to rTKR migration and loosening.

Cognitive decline is associated with an accelerated rate of bone loss and increased fracture risk in women: a prospective study from the Canadian Multicentre Osteoporosis Study.

Cognitive decline and osteoporosis often coexist and some evidence suggests a causal link. However, there are no data on the longitudinal relationship between cognitive decline, bone loss and fracture risk, independent of aging. This study aimed to determine the association between: (i) cognitive decline and bone loss; and (ii) clinically significant cognitive decline (≥3 points) on Mini Mental State Examination (MMSE) over the first 5 years and subsequent fracture risk over the following 10 years. A total of 1741 women and 620 men aged ≥65 years from the population-based Canadian Multicentre Osteoporosis Study were followed from 1997 to 2013. Association between cognitive decline and (i) bone loss was estimated using mixed-effects models; and (ii) fracture risk was estimated using adjusted Cox models. Over 95% of participants had normal cognition at baseline (MMSE ≥ 24). The annual % change in MMSE was similar for both genders (women -0.33, interquartile range [IQR] -0.70 to +0.00; and men -0.34, IQR: -0.99 to 0.01). After multivariable adjustment, cognitive decline was associated with bone loss in women (6.5%; 95% confidence interval [CI], 3.2% to 9.9% for each percent decline in MMSE from baseline) but not men. Approximately 13% of participants experienced significant cognitive decline by year 5. In women, fracture risk was increased significantly (multivariable hazard ratio [HR], 1.61; 95% CI, 1.11 to 2.34). There were too few men to analyze. There was a significant association between cognitive decline and both bone loss and fracture risk, independent of aging, in women. Further studies are needed to determine mechanisms that link these common conditions. © 2021 American Society for Bone and Mineral Research (ASBMR).