Elevated proinflammatory cytokines in response to mechanical stimulus are associated with reduced knee loading 2 years after anterior cruciate ligament reconstruction.

BACKGROUND: The aim of this study was to test the hypothesis that proinflammatory cytokines correlate with knee loading mechanics during gait following a mechanical walking stimulus in subjects 2 years after anterior cruciate ligament reconstruction. Elevated systemic levels of proinflammatory cytokines can be sustained for years after injury. Considering roughly 50% of these patients progress to Osteoarthritis 10-15 years after injury, a better understanding of the role of proinflammatory cytokines such as tumor necrosis factor-α and Interleukin-1ß on Osteoarthritis risk is needed. METHODS: Serum proinflammatory cytokines concentrations were measured in 21 subjects 2 years after unilateral ACLR from blood drawn at rest and 3.5 h after 30 min of walking. An optoelectronic system and a force plate measured subjects' knee kinetics. Correlations were tested between inflammatory marker response and knee extension and knee adduction moments. FINDINGS: Changes in proinflammatory cytokines due to mechanical stimulus were correlated (R = 0.86) and showed substantial variation between subjects in both cytokines at 3.5 h post-walk. Knee loading correlated with 3.5-h changes in tumor necrosis factor-α concentration (Knee extension moment: R = -0.5, Knee adduction moment: R = -0.5) and Interleukin-1ß concentration (Knee extension moment: R = -0.44). However, no significant changes in concentrations were observed in tumor necrosis factor-α and Interleukin-1ß when comparing baseline and post walking stimulus conditions. INTERPRETATION: The significant associations between changes in serum proinflammatory markers following a mechanical stimulus and gait metrics in subjects at risk for developing Osteoarthritis underscore the importance of investigating the interaction between biomarkers and biomechanical factors in Osteoarthritis development.

Diverse parameters of ambulatory knee moments differ with medial knee osteoarthritis severity and are combinable into a severity index.

Objective: To characterize ambulatory knee moments with respect to medial knee osteoarthritis (OA) severity comprehensively and to assess the possibility of developing a severity index combining knee moment parameters. Methods: Nine parameters (peak amplitudes) commonly used to quantify three-dimensional knee moments during walking were analyzed for 98 individuals (58.7 ± 9.2 years old, 1.69 ± 0.09 m, 76.9 ± 14.5 kg, 56% female), corresponding to three medial knee osteoarthritis severity groups: non-osteoarthritis (n = 22), mild osteoarthritis (n = 38) and severe osteoarthritis (n = 38). Multinomial logistic regression was used to create a severity index. Comparison and regression analyses were performed with respect to disease severity. Results: Six of the nine moment parameters differed statistically significantly among severity groups (p ≤ 0.039) and five reported statistically significant correlation with disease severity (0.23 ≤ |r| ≤ 0.59). The proposed severity index was highly reliable (ICC = 0.96) and statistically significantly different between the three groups (p < 0.001) as well as correlated with disease severity (r = 0.70). Conclusion: While medial knee osteoarthritis research has mostly focused on a few knee moment parameters, this study showed that other parameters differ with disease severity. In particular, it shed light on three parameters frequently disregarded in prior works. Another important finding is the possibility of combining the parameters into a severity index, which opens promising perspectives based on a single figure assessing the knee moments in their entirety. Although the proposed index was shown to be reliable and associated with disease severity, further research will be necessary particularly to assess its validity.

Vertical ground reaction force 2 years after anterior cruciate ligament reconstruction predicts 10-year patient-reported outcomes.

Disruptions in knee biomechanics during walking following anterior cruciate ligament (ACL) injury have been suggested to lead to the development of premature knee osteoarthritis (OA) and to be potential markers of OA risk and targets for intervention. This study investigated if side-to-side differences in early stance peak vertical ground reaction force (vGRF) during walking 2 years after ACL reconstruction are associated with longer-term (10 years post-reconstruction) changes in patient-reported outcomes. Twenty-eight participants (mean age: 28.7 ± 6.4 years) with primary unilateral ACL reconstruction underwent gait analysis for assessment of peak vGRF and completed Knee Injury and Osteoarthritis Outcome Score (KOOS) and International Knee Documentation Committee (IKDC) surveys at 2 years post-surgery (2.2 ± 0.3 years) and completed surveys at follow-up 10 years post-surgery (10.5 ± 0.9 years). Associations between changes (10-2 years) in patient-reported outcomes and between limb-differences in vGRF were assessed with Pearson or Spearman's ρ correlation coefficients and exploratory backwards elimination multiple linear regression analyses. Differences in vGRF between symptomatic progressors and non-progressors were also assessed. The side-to-side difference in vGRF was related to the variability in longer-term changes in patient-reported outcome metrics and distinguished symptomatic progressors from non-progressors. Participants with higher vGRF in the reconstructed (ACLR) limb versus the contralateral limb had worsening of IKDC (R = -0.391, p = 0.040), KOOS pain (ρ = -0.396, p = 0.037), KOOS symptoms (ρ = -0.572, p = 0.001), and KOOS quality of life (R = -0.458, p = 0.014) scores at follow-up. Symptomatic progressors had greater vGRF in the ACLR limb as compared to the contralateral limb at baseline than non-progressors (p = 0.023). These data highlight associations between a simple-to-measure gait metric and the development of long-term clinical symptoms after an ACL injury.

Cartilage oligomeric matrix protein responses to a mechanical stimulus associate with ambulatory loading in individuals with anterior cruciate ligament reconstruction.

Mechanical factors have been implicated in the development of osteoarthritis after anterior cruciate ligament (ACL) reconstruction. This study tested for associations between ambulatory joint loading (total joint moment [TJM] and vertical ground reaction force [vGRF]) and changes in serum levels of cartilage oligomeric matrix protein (COMP) in response to a mechanical stimulus (30-min walk) in individuals with ACL reconstruction. Twenty-five subjects (mean age: 34.5 ± 9.8 years; 2.2 ± 0.2 years post-surgery) with primary unilateral ACL reconstruction underwent gait analysis for assessment of peak vGRF and TJM first (TJM1) and second (TJM2) peaks. Serum COMP concentrations were measured by enzyme-linked immunosorbent assay immediately before, 3.5 h, and 5.5 h after a 30-min walk. Pearson correlation coefficients and backward stepwise multiple linear regression analysis, with adjustments for age, sex, body mass index, and between-limb speed difference, assessed associations between changes in COMP and between-limb differences in joint loading parameters. Greater TJM1 (R = 0.542, p = 0.005), TJM2 (R = 0.460, p = 0.021), and vGRF (R = 0.577, p = 0.003) in the ACL-reconstructed limb as compared to the contralateral limb were associated with higher COMP values 3.5 h following the 30-min walk. Change in COMP at 5.5 h became a significant predictor of the between-limb difference in TJM1 and vGRF in multivariate analyses after accounting for the between-limb speed difference. These results demonstrate that higher TJM and vGRF in the ACLR limb as compared to the contralateral limb are associated with higher relative COMP levels 3.5 and 5.5 h after a 30-min walk. Future work should investigate the effect of therapies to alter joint loading on the biological response in individuals after ACL reconstruction.

Kinematic Comparison between Medially Congruent and Posterior-Stabilized Third-Generation TKA Designs.

Background: This study compares knee kinematics in two groups of patients who have undergone primary total knee arthroplasty (TKA) using two different modern designs: medially congruent (MC) and posterior-stabilized (PS). The aim of the study is to demonstrate only minimal differences between the groups. Methods: Ten TKA patients (4 PS, 6 MC) with successful clinical outcomes were evaluated through 3D knee kinematics analysis performed using a multicamera optoelectronic system and a force platform. Extracted kinematic data included knee flexion angle at heel-strike (KFH), peak midstance knee flexion angle (MSKFA), maximum and minimum knee adduction angle (KAA), and knee rotational angle at heel-strike. Data were compared with a group of healthy controls. Results: There were no differences in preferred walking speed between MC and PS groups, but we found consistent differences in knee function. At heel-strike, the knee tended to be more flexed in the PS group compared to the MC group; the MSKFA tended to be higher in the PS group compared to the MC group. There was a significant fluctuation in KAA during the swing phase in the PS group compared to the MC group, PS patients showed a higher peak knee flexion moment compared to MC patients, and the PS group had significantly less peak internal rotation moments than the MC group. Conclusions: Modern, third-generation TKA designs failed to reproduce normal knee kinematics. MC knees tended to reproduce a more natural kinematic pattern at heel-strike and during axial rotation, while PS knees showed better kinematics during mid-flexion.

Visualizing pre-osteoarthritis: Integrating MRI UTE-T2* with mechanics and biology to combat osteoarthritis-The 2019 Elizabeth Winston Lanier Kappa Delta Award.

Osteoarthritis (OA) is a leading cause of pain and disability for which disease-modifying treatments remain lacking. This is because the symptoms and radiographic changes of OA occur after the onset of likely irreversible changes. Defining and treating earlier disease states are therefore needed to delay or to halt OA progression. Taking this concept a step further, studying OA pathogenesis before disease onset by characterizing potentially reversible markers of increased OA risk to identify a state of "pre-osteoarthritis (pre-OA)" shifts the paradigm towards OA prevention. The purpose of this review is to summarize the 42 studies comprising the 2019 Kappa Delta Elizabeth Lanier Award where conceptualization of a systems-based definition for "pre-osteoarthritis (pre-OA)" was followed by demonstration of potentially reversible markers of heightened OA risk in patients after anterior cruciate ligament (ACL) injury and reconstruction. In the process, these efforts contributed a new magnetic resonance imaging method of ultrashort echo time (UTE) enhanced T2* mapping to visualize joint tissue damage before the development of irreversible changes. The studies presented here support a transformative approach to OA that accounts for interactions between mechanical, biological, and structural markers of OA risk to develop and evaluate new treatment strategies that can delay or prevent the onset of clinical disease. This body of work was inspired by and performed for patients. Shifting the paradigm from attempting to modify symptomatic radiographic OA towards monitoring and reversing markers of "pre-OA" opens the door for transforming the clinical approach to OA from palliation to prevention.

Intermittent vibrational stimulation enhances mobility during stair navigation in patients with knee pain.

BACKGROUND: Reduced quadriceps function and proprioception can cause decreased mobility during stair navigation in patients with knee pain. Patients can benefit from interventions to mitigate pain and restore quadriceps function. Activating the somatosensory system via intermittent vibrational stimulation has the potential to improve stair navigation mobility in patients with knee pain by moderating quadriceps inhibition and enhancing proprioception. RESEARCH QUESTION: What are the effects of intermittent vibrational stimulus synchronized to stair ambulation on muscle activity, kinematics, kinetics, and pain using a randomized controlled clinical trial design. METHODS: Thirty-eight patients with knee pain were enrolled into a blinded cross-over study, and twenty-nine patients completed all assessments and analyses. Subjects were randomly assigned sequentially to both an active Treatment A (active) and passive Treatment B (passive) worn at the knee during ambulation for 4 weeks with a 2-week washout period between treatments. RESULTS: Knee pain during stair navigation was significantly reduced only with Treatment A (P = 0.007). During ascent, Treatment A (active) significantly increased vastus lateralis activation (P = 0.01), increased knee flexion moment (P = 0.04) and decreased trunk flexion angles (P = 0.015) between baseline and 4-week follow-up. After using passive Treatment B, there were no significant differences in pain (P = 0.19), knee flexion moment (P = 0.09), and trunk flexion angles (P = 0.23). Changes in muscle function correlated significantly with changes in knee flexion moment and trunk flexion with Treatment A (P < 0.015). Descending differed from ascending in response to Treatment A with significantly decreased knee flexion moment(P = 0.04), hip(P = 0.02) and ankle(P = 0.04) flexion angles. Treatment B significantly reduced hip flexion angles (P = 0.005) but not knee flexion moment (P = 0.85). SIGNIFICANCE: The results of this study suggest that intermittent vibration can improve joint motion and loading during stair navigation by enhancing quadriceps function during stair ascent and improving movement control during stair descent by modifying an adaptive flexed movement pattern in the lower limb.

Analyzing Femorotibial Cartilage Thickness Using Anatomically Standardized Maps: Reproducibility and Reference Data.

Alterations in cartilage thickness (CTh) are a hallmark of knee osteoarthritis, which remain difficult to characterize at high resolution, even with modern magnetic resonance imaging (MRI), due to a paucity of standardization tools. This study aimed to assess a computational anatomy method producing standardized two-dimensional femorotibial CTh maps. The method was assessed with twenty knees, processed following three common experimental scenarios. Cartilage thickness maps were obtained for the femorotibial cartilages by reconstructing bone and cartilage mesh models in tree-dimension, calculating three-dimensional CTh maps, and anatomically standardizing the maps. The intra-operator accuracy (median (interquartile range, IQR) of -0.006 (0.045) mm), precision (0.152 (0.070) mm), entropy (7.02 (0.71) and agreement (0.975 (0.020))) results suggested that the method is adequate to capture the spatial variations in CTh and compare knees at varying osteoarthritis stages. The lower inter-operator precision (0.496 (0.132) mm) and agreement (0.808 (0.108)) indicate a possible loss of sensitivity to detect differences in a setting with multiple operators. The results confirmed the promising potential of anatomically standardized maps, with the lower inter-operator reproducibility stressing the need to coordinate operators. This study also provided essential reference data and indications for future research using CTh maps.

Patient-Reported Outcomes and Knee Mechanics Correlate With Patellofemoral Deep Cartilage UTE-T2* 2 Years After Anterior Cruciate Ligament Reconstruction.

BACKGROUND: Patellofemoral joint degeneration and dysfunction after anterior cruciate ligament reconstruction (ACLR) are increasingly recognized as contributors to poor clinical outcomes. PURPOSE: To determine if greater deep cartilage matrix disruption at 2 years after ACLR, as assessed by elevated patellofemoral magnetic resonance imaging (MRI) ultrashort echo time-enhanced T2* (UTE-T2*), is correlated with (1) worse patient-reported knee function and pain and (2) gait metrics related to patellofemoral tracking and loading, such as greater external rotation of the tibia at heel strike, reduced knee flexion moment (as a surrogate of quadriceps function), and greater knee flexion angle at heel strike. STUDY DESIGN: Cross-sectional study; Level of evidence, 3. METHODS: MRI UTE-T2* relaxation times in patellar and trochlear deep cartilage were compared with patient-reported outcomes and ambulatory gait metrics in 60 patients with ACLR at 2 years after reconstruction. ACLR gait metrics were compared with those of 60 uninjured reference patients matched by age, body mass index, and sex. ACLR UTE-T2* values were compared with those of 20 uninjured reference patients. RESULTS: Higher trochlear UTE-T2* values were associated with worse Knee injury and Osteoarthritis Outcome Scores (KOOS) Sport/Recreation subscale scores (rho = -0.32; P = .015), and showed a trend for association with worse KOOS Pain subscale scores (rho = -0.26; P = .045). At 2 years after ACLR, greater external rotation of the tibia at heel strike was associated with higher patellar UTE-T2* values (R = 0.40; P = .002); greater knee flexion angle at heel strike was associated with higher trochlear UTE-T2* values (rho = 0.39; P = .002); and greater knee flexion moment showed a trend for association with higher trochlear UTE-T2* values (rho = 0.30; P = .019). Patellar cartilage UTE-T2* values, knee flexion angle at heel strike, and external rotation of the tibia at heel strike were all elevated in ACLR knees as compared with reference knees (P = .029, .001, and .044, respectively). CONCLUSION: Patellofemoral deep cartilage matrix disruption, as assessed by MRI UTE-T2*, was associated with reduced sports and recreational function and with gait metrics reflective of altered patellofemoral loading. As such, the findings provide new mechanistic information important to improving clinical outcomes related to patellofemoral dysfunction after ACLR.

Changes in knee adduction moment wearing a variable-stiffness shoe correlate with changes in pain and mechanically stimulated cartilage oligomeric matrix levels.

This study aimed to determine if changes in knee adduction moment (KAM) after 6 months of variable-stiffness shoe wear are associated with changes in symptoms or serum levels of cartilage oligomeric matrix protein (COMP) following a mechanical stimulus in subjects with medial knee osteoarthritis (OA). Twenty-five subjects were enrolled in the study and assigned a variable-stiffness shoe, and 19 subjects completed the 6-month follow-up. At baseline and follow-up subjects underwent gait analysis in control and variable-stiffness shoes, completed Western Ontario and McMaster Universities (WOMAC) questionnaires, and serum COMP concentrations were measured immediately before, 3.5 and 5.5 hours after a 30-minute walking activity. Relationships between changes in KAM (first peak and impulse) and changes in (a) COMP levels in response to the 30-minute walking activity and (b) WOMAC scores from baseline to 6-month follow-up were assessed by Pearson correlation coefficients. Changes in first peak KAM were associated with changes in COMP levels 5.5 hours postactivity from baseline to follow-up (R = .564, P = .045). Subjects with greater reductions in KAM had larger decreases in COMP (expressed as a percent of preactivity levels) at follow-up. Subjects with greater reductions in KAM impulse had significantly greater improvements in WOMAC Pain (R = -.56, P = .015) and Function (R = -.52, P = .028) scores at follow-up. The study results demonstrated the magnitude of reduction in the KAM wearing a variable-stiffness shoe is associated with decreases in mechanically stimulated COMP levels and pain/function. This work suggests that interactions between COMP and joint loading during walking should be further investigated in future studies of treatment outcomes in OA.

Utilizing the somatosensory system via vibratory stimulation to mitigate knee pain during walking: Randomized clinical trial.

BACKGROUND: Pain and proprioception deficits are often associated with knee pathologies and resultant quadriceps muscle inhibition. There is a need for new approaches to mitigate active knee pain and restore muscle function during walking. Activating properties of the somatosensory system with common pain and sensory pathways offers a novel opportunity to enhance quadriceps function during walking. RESEARCH QUESTION: Conduct a controlled clinical trial that investigates the effects of applying intermittent vibrational cutaneous stimulation during walking on knee pain and symptoms and their correlations to gait parameters. METHODS: This longitudinal controlled cross-over clinical study included thirty-two patients randomly and blindly assigned to active Treatment A and passive Treatment B for 4 weeks with a 2-week washout period between treatments. RESULTS: Subjects when wearing active Treatment A for 4 weeks had significant (p = 0.04) improvement in patient reported outcomes, while they had no significant differences with passive Treatment B (p > 0.7) compared to the no treatment condition. For Treatment A, subjects with low knee flexion moment and knee flexion angle in no-treatment condition exhibited the greatest increase in knee flexion moment/angle in the active treatment condition (R > 0.57, p < 0.001). These changes in gait measures were correlated significantly to changes in pain. SIGNIFICANCE: This clinical trial indicates that knee pain can be reduced, and gait improved in a manner that enhances quadriceps function by applying intermittent cutaneous stimulation during gait in patients following knee injury or disease. The correlation between decreased pain and improved gait suggests that rehabilitation and exercise therapy may benefit from this treatment.

Bridging Disciplines as a pathway to Finding New Solutions for Osteoarthritis a collaborative program presented at the 2019 Orthopaedic Research Society and the Osteoarthritis Research Society International.

Objective: To stimulate future research directions that seek solutions for osteoarthritis (OA) at the interface between diverse disciplines and address osteoarthritis (OA) as a serious disease with a complexity that has presented a barrier to finding safe effective solutions. Methods: Sessions were conducted at the 2019 meetings of the Orthopaedic Research Society (ORS) and Osteoarthritis Research Society International (OARSI) that included presentations and questions/comments submitted from leading OA researchers representing imaging, mechanics, biomarkers, phenotyping, clinical, epidemiology, inflammation and exercise. Results: Solutions for OA require a paradigm shift in research and clinical methods in which OA is contextualized as a complex whole-body/person disease. New OA definition(s)/phenotype(s) and OA markers/signals are needed to address the interplay between genetic and environmental factors of the disease as well as capture the mechanosensitivity of the disease. The term "Mechanokines" was proposed to highlight the importance of incorporating whole body mechanics as a marker of early OA. New interventions and apparent paradoxical observations/questions (e.g. exercise vs. load modification) were also discussed in the context of considering OA as a complex system. Conclusion: To advance new OA treatments that are safe and effective, OA should be considered as a "Whole Person" disease. This approach requires a concerted effort to bridge disciplines and include interactions across scales from the molecule to the whole body, including psychosocial aspects.

New insight on the subchondral bone and cartilage functional unit: Bone mineral density and cartilage thickness are spatially correlated in non-osteoarthritic femoral condyles.

Objective: This study aimed to improve our understanding of the relationship between bone and cartilage by characterizing the morphological coupling between these mechanosensitive tissues exposed to the same mechanical environment within each knee. Specifically, it reanalyzed a prior dataset to test the hypothesis that the locations of thickest cartilage and densest subchondral bone are correlated in non-osteoarthritic femoral condyles. Method: Anatomically standardized maps of cartilage thickness (CTh) and subchondral bone mineral density (sBMD) were calculated for 50 non-osteoarthritic distal femurs based on computed tomography arthrography examinations. The locations of thickest CTh and densest sBMD were identified in the load-bearing region of the medial and lateral compartments, and correlation analyses were performed to quantify the associations between these locations, with inclusion of age, gender, femoral bone size and femorotibial angle as cofounding variables. Paired Student's t-tests were also performed to compare CTh and sBMD locations. Results: Locations of thickest CTh and densest sBMD were positively correlated along the anteroposterior direction in both compartments (r ≥ 0.45, p ≤ 0.001). Furthermore, thickest CTh was more posterior than densest sBMD in the medial (p = 0.014) and lateral (p < 0.001) compartments, and more lateral than densest sBMD in the lateral compartment (p < 0.001). On average, these location differences were of 1.3, 5.3 and 2.1% of the subchondral bone size. Conclusion: The positive spatial relationship between the locations of thickest CTh and densest sBMD supports the idea of a functional cartilage/subchondral bone unit with morphological coupling conditioned by the individual loading pattern.

Changes in stair ascent biomechanics two to eight years after ACL reconstruction are associated with patient-reported outcomes.

BACKGROUND: Anterior cruciate ligament (ACL) injury is often followed by quadriceps deficits that are apparent with gait analysis. The deficit frequently remains after ACL reconstruction (ACLR). As such, evaluation of ACLR patients could be enhanced by a simple method to detect quadriceps deficits. Analyzing forward trunk flexion during stair ascent has been suggested as an assessment of quadriceps function that can be visualized with relatively simple instrumentation. AIM: The purpose of this study was to determine if trunk flexion angle (TFA) during stair ascent is associated with quadriceps function (as measured by the peak knee flexion moment (KFM)) at 2 and 8 years post-ACLR and if changes are associated with patient-reported outcomes (PRO). METHODS: Fourteen subjects with unilateral primary ACLR performed three stair-ascending trials at two-time periods: 2 years (baseline) and 8 years (follow-up) post-ACLR. Paired Student t-tests determined differences in KFM and TFA. Associations between KFM, TFA, and PRO were determined through Pearson correlations. RESULTS: Peak KFM during stair ascent significantly increased from baseline to follow-up (p = 0.01). Though there was no significant difference in TFA (p = 0.84) compared to baseline, 50% of subjects showed decreases in TFA. Further, subjects with reduced TFA during stair ascent at follow-up had significantly increased peak KFM (p = 0.029) and improvements in PRO (p = 0.001). DISCUSSION: The results suggest that TFA during stair ascent can provide a simple method to assess changes in quadriceps function and pain over time following ACLR. Further analysis is needed to draw conclusions between knee osteoarthritis development and increases in TFA.

Activating the somatosensory system enhances net quadriceps moment during gait.

Quadriceps muscle rehabilitation following knee injury or disease is often hampered by pain, proprioception deficits or instability associated with inhibition of quadriceps activation during walking. The cross-modal plasticity of the somatosensory system with common sensory pathways including pain, pressure and vibration offers a novel opportunity to enhance quadriceps function during walking. This study explores the effectiveness of an active knee brace that used intermittent cutaneous vibration during walking to enhance the peak knee flexion moment (KFM) during early stance phase as a surrogate for net quadriceps moment (balance between knee extensor and flexor muscle moments). The stimulus was turned on prior to heel strike and turned off at mid-stance of the gait cycle. Twenty-one subjects with knee pathologies known to inhibit quadriceps function were tested walking under three conditions: control (no brace), a passive brace, and an active brace. Findings show that compared to the control, subjects wearing an active brace during gait exhibited a significant (p < 0.001) increase in peak KFM and no significant difference when wearing a passive brace (p = 0.17). Furthermore, subjects with low KFM and knee flexion angle (KFA) in control exhibited the greatest increase in KFA at loading response in the active brace condition (R = 0.47, p < 0.05). Intermittent cutaneous stimulation during gait, therefore, provides an efficient method for increasing the KFM in patients with knee pathologies. This study's results suggest that intermittent vibration stimulus can activate the cross-modalities of the somatosensory system in a manner that gates pain stimulus and possibly restores quadriceps function in patients with knee pain.

Changes in the total knee joint moment in patients with medial compartment knee osteoarthritis over 5 years.

Progression of medial compartment knee osteoarthritis (OA) has been associated with repetitive mechanical loading during walking, often characterized by the peak knee adduction (KAM) and knee flexion moments (KFM). However, the relative contributions of these components to the knee total joint moment (TJM) can change as the disease progresses since KAM and KFM are influenced by different factors that change over time. This study tested the hypothesis that the relative contributions of KAM, KFM, and the rotational moment (KRM) to the TJM change over time in subjects with medial compartment knee OA. Patients with medial compartment knee OA (n = 19) were tested walking at their self-selected speed at baseline and a 5-year follow-up. For each frame during stance, the TJM was calculated using the KAM, KFM, and KRM. The peaks of the TJM and the relative contributions of the moment components at the time of the peaks of the TJM were tested for changes between baseline and follow-up. The percent contribution of KFM to the first peak of the TJM (TJM1) significantly decreased (p < 0.001) and the percent contribution of KAM to TJM1 significantly increased (p < 0.001), while the magnitude of the TJM1 did not significantly change over the 5-year follow-up. These gait changes with disease progression appear to maintain a constant TJM1, but the transition from a KFM to a KAM dominance appears to reflect gait changes associated with progressing OA and pain. Thus, the TJM and its component analysis captures a comprehensive metric for total loading on the knee over time. Published 2018. This article is a U.S. Government work and is in the public domain in the USA. 36:2373-2379, 2018.

Cartilage Subsurface Changes to Magnetic Resonance Imaging UTE-T2* 2 Years After Anterior Cruciate Ligament Reconstruction Correlate With Walking Mechanics Associated With Knee Osteoarthritis.

BACKGROUND: Anterior cruciate ligament (ACL) injury increases risk for posttraumatic knee osteoarthritis (OA). Quantitative ultrashort echo time enhanced T2* (UTE-T2*) mapping shows promise for early detection of potentially reversible subsurface cartilage abnormalities after ACL reconstruction (ACLR) but needs further validation against established clinical metrics of OA risk such as knee adduction moment (KAM) and mechanical alignment. HYPOTHESIS: Elevated UTE-T2* values in medial knee cartilage 2 years after ACLR correlate with varus alignment and higher KAM during walking. STUDY DESIGN: Cohort study (diagnosis); Level of evidence, 2. METHODS: Twenty patients (mean age, 33.1 ± 10.5 years; 11 female) 2 years after ACLR underwent 3.0-T knee magnetic resonance imaging (MRI), radiography, and gait analysis, after which mechanical alignment was measured, KAM during walking was calculated, and UTE-T2* maps were generated. The mechanical axis and the first and second peaks of KAM (KAM1 and KAM2, respectively) were tested using linear regressions for correlations with deep UTE-T2* values in the central and posterior medial femoral condyle (cMFC and pMFC, respectively) and central medial tibial plateau (cMTP). UTE-T2* values from ACL-reconstructed patients were additionally compared with those of 14 uninjured participants (mean age, 30.9 ± 8.9 years; 6 female) using Mann-Whitney U and standard t tests. RESULTS: Central weightbearing medial compartment cartilage of ACL-reconstructed knees was intact on morphological MRI. Mean UTE-T2* values were elevated in both the cMFC and pMFC of ACL-reconstructed knees compared with those of uninjured knees ( P = .003 and P = .012, respectively). In ACL-reconstructed knees, UTE-T2* values of cMFC cartilage positively correlated with increasing varus alignment ( R = 0.568). Higher UTE-T2* values in cMFC and cMTP cartilage of ACL-reconstructed knees also correlated with greater KAM1 ( R = 0.452 and R = 0.463, respectively) and KAM2 ( R = 0.465 and R = 0.764, respectively) and with KAM2 in pMFC cartilage ( R = 0.602). CONCLUSION: Elevated deep UTE-T2* values of medial knee cartilage 2 years after ACLR correlate with 2 clinical markers of increased risk of medial knee OA. These results support the clinical utility of MRI UTE-T2* for early diagnosis of subsurface cartilage abnormalities. Longitudinal follow-up of larger cohorts is needed to determine the predictive and staging potential of UTE-T2* for posttraumatic OA.

Mechanically stimulated biomarkers signal cartilage changes over 5 years consistent with disease progression in medial knee osteoarthritis patients.

Using serum biomarkers to assess osteoarthritis (OA) disease state and risks of progression remain challenging. This study tested the hypothesis that changes to serum biomarkers in response to a mechanical stimulus in patients with medial knee OA signal cartilage thickness changes 5 years later. Specifically, serum concentrations of a collagen degradation marker (C1,2C) and a chondroitin sulfate synthesis marker (CS846) were measured 0.5 and 5.5 hours after a 30-min walk in 16 patients. Regional cartilage thickness changes measured from magnetic resonance images obtained at study entry and at 5-year follow-up were tested for correlations with baseline biomarker changes after mechanical stimulus, and for differences between groups stratified based on whether biomarker levels increased or decreased. Results showed that an increase in the degradation biomarker C1,2C correlated with cartilage thinning of the lateral tibia (R = -0.63, p = 0.009), whereas an increase in the synthesis marker CS846 correlated with cartilage thickening of the lateral femur (R = 0.76, p = 0.001). Changes in C1,2C and CS846 were correlated (R2 = 0.28, p = 0.037). Subjects with increased C1,2C had greater (p = 0.05) medial tibial cartilage thinning than those with decreased C1,2C. In conclusion, the mechanical stimulus appeared to metabolically link the biomarker responses where biomarker increases signaled more active OA disease states. The findings of medial cartilage thinning for patients with increases in the degradation marker and correlation of cartilage thickening in the less involved lateral femur with increases in the synthetic marker were consistent with progression of medial compartment OA. Thus, the mechanical stimulus facilitated assessing OA disease states using serum biomarkers. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:891-897, 2018.

Longitudinal changes in knee gait mechanics between 2 and 8 years after anterior cruciate ligament reconstruction.

The purpose of this study was to longitudinally investigate changes in knee joint kinematics and kinetics from 2 to 8 years post-ACLR. Seventeen subjects with primary unilateral transtibial ACLR performed bilateral gait analysis approximately 2 years and 8 years post-ACLR. Seventeen matched healthy control subjects were also analyzed. Kinematic and kinetic comparisons between the ACLR and contralateral limbs over time were completed using a 2 × 2 (time, limb) repeated-measures ANOVA. Unpaired Student's t-tests were used to compare the ACLR and contralateral kinematics and kinetics to the control group. The ACLR and contralateral limbs had similar gait changes over time. Kinetic changes over time included a reduction in first (p = 0.048) and second (p < 0.001) peak extension moments, internal rotation moment (p < 0.001), adduction moment (first peak: p = 0.002, second peak: p = 0.009, impulse: p = 0.004) and an increase in peak knee flexion moment (p = 0.002). Kinematic changes over time included increases in peak knee flexion angle in the first half of stance (p = 0.026), minimum knee flexion angle in the second half of stance (p < 0.001), and average external rotation angle during stance (p = 0.007), and a reduction in average anterior femoral displacement during stance (p = 0.006). Comparison to healthy controls demonstrated improvement in some gait metrics over time. The results demonstrated longitudinal changes from 2 to 8 years after ACLR in knee joint kinetics and kinematics that have been related to clinical outcome after ACLR and the progression of knee OA, and support future larger and comprehensive investigations into long-term changes in joint mechanics in the ACLR population. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:1478-1486, 2018.

Sensitivity of serum concentration of cartilage biomarkers to 21-days of bed rest.

The objective of the study was to test the hypothesis that serum levels of cartilage oligomeric matrix protein (COMP) would decrease and serum levels of tumor-necrosis factor alpha (TNF-α) and selected matrix metalloproteinases (MMPs) would increase in response to bed rest (BR) and that these changes are unaffected by the intake of potassium bicarbonate or whey protein. Seven and nine healthy male subjects participated in two 21-day 6° head down tilt crossover BR-studies with nutrition interventions. Serum samples were taken before, during, and after BR and biomarker concentrations were measured using commercial enzyme-linked immunosorbent assays. MMP-3 during BR was significantly lower than at baseline (reduction greater 20%; p < 0.001). MMP-3 increased significantly from 14 to 21 days of BR (+7%; p = 0.049). COMP during BR was significantly lower than at baseline (reduction greater 20%; p < 0.001). MMP-3 and COMP returned to baseline within 1 day after BR. MMP-9 on day 3 of BR was significantly lower than at baseline (-31%; p < 0.033) and on days 3, 5, and 14 of BR significantly lower than at the end of and after BR (reduction greater 35%; p < 0.030). The nutritional countermeasures did not affect these results. The observed changes in cartilage biomarkers may be caused by altered cartilage metabolism in response to the lack of mechanical stimulus during BR and inflammatory biomarkers may play a role in changes in biomarker levels. CLINICAL RELEVANCE: Immobilization independently from injury can cause altered cartilage biomarker concentration. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:1465-1471, 2018.