Classification of inertial sensor-based gait patterns of orthopaedic conditions using machine learning: A pilot study.

Elderly patients often have more than one disease that affects walking behavior. An objective tool to identify which disease is the main cause of functional limitations may aid clinical decision making. Therefore, we investigated whether gait patterns could be used to identify degenerative diseases using machine learning. Data were extracted from a clinical database that included sagittal joint angles and spatiotemporal parameters measured using seven inertial sensors, and anthropometric data of patients with unilateral knee or hip osteoarthritis, lumbar or cervical spinal stenosis, and healthy controls. Various classification models were explored using the MATLAB Classification Learner app, and the optimizable Support Vector Machine was chosen as the best performing model. The accuracy of discrimination between healthy and pathologic gait was 82.3%, indicating that it is possible to distinguish pathological from healthy gait. The accuracy of discrimination between the different degenerative diseases was 51.4%, indicating the similarities in gait patterns between diseases need to be further explored. Overall, the differences between pathologic and healthy gait are distinct enough to classify using a classical machine learning model; however, routinely recorded gait characteristics and anthropometric data are not sufficient for successful discrimination of the degenerative diseases.

Gait function assessed using 3D gait analysis in patients with cervical spinal myelopathy before and after surgical decompression: a systematic review and meta-analysis.

BACKGROUND: Degenerative cervical myelopathy (DCM) is the most common cause of cervical spinal cord dysfunction in adults and the result of chronic degenerative changes of the cervical spine. The compression of the spinal cord can lead to ischemia, inflammation, and neuronal apoptosis with a consequent impairment of the neurological function. Gait impairment is one of the most frequent signs of DCM. PURPOSE: To investigate the changes in spatio-temporal gait parameters assessed using 3D gait analysis in patients affected by DCM compared with healthy controls and the effect of surgical decompression on these parameters. STUDY DESIGN/SETTING: Systematic review and meta-analysis. PATIENT SAMPLE: The meta-analysis included 267 patients with DCM and 276 healthy controls. OUTCOME MEASURES: Spatio-temporal parameters of gait were assessed. The primary outcome was gait speed; the secondary outcomes were cadence, stride length, step width, stride time, single-limb support time, and double-limb support time. METHODS: Studies reporting spatial and/or temporal gait parameters measured using 3D gait analysis in patients with DCM were included. Data sources were Embase, Medline, and the Core Collection of Web of Science. Meta-analyses were performed to investigate the influence of surgical decompression in patients measured before and after surgery as well as to compare gait parameters of patients with DCM with controls. RESULTS: Thirteen studies reporting on 267 patients with DCM and 276 healthy controls met the inclusion criteria. Seven studies compared patients with DCM with healthy controls, three studies compared gait in patients with DCM before and after surgical decompression, and three studies performed both comparisons. Compared with healthy controls, patients with DCM had slower gait speed (Standardized Mean Difference (SMD), -1.49; 95% confidence interval (CI) [-1.86; -1.13]; p<.001), lower cadence (SMD, -0.78; 95%CI [-1.00; -0.56]; p<.001), shorter stride length (SMD, -1.27; 95%CI [-1.53, -1.01]; p<.001), greater step width (SMD, 0.98; 95%CI [0.42, 1.54]; p=.003), longer stride time (SMD, 0.77; 95%CI [0.37, 1.16]; p=.009), single-limb support phase (SMD, -0.68; 95%CI [-1.06; -0.29]; p=.011), and double-limb support phase (SMD 0.84; 95%CI [0.35, 1.32]; p=.012). After surgical decompression, patients with DCM showed an improvement in gait speed (SMD, 0.57 (95%CI [0.29; 0.85]; p=.003) and no significant differences in other spatio-temporal parameters. CONCLUSIONS: Patients with DCM have clearly different spatio-temporal gait parameters than healthy controls. Gait speed is the only spatio-temporal gait parameter that improves significantly after surgical decompression suggesting that gait speed may be an important clinical outcome parameter in patients with DCM.

Is Age a Risk Factor for Early Postoperative Cage Subsidence After Transforaminal Lumbar Interbody Fusion? A Retrospective Study in 170 Patients.

STUDY DESIGN: Retrospective observational study. OBJECTIVES: We aim to evaluate whether age is a risk factor for cage subsidence, and whether other patient characteristics, preoperative radiological or imaging parameters are associated with cage subsidence and the need for revision surgery in patients undergoing transforaminal lumbar interbody fusion (TLIF). METHODS: Patient demographics and surgery-related information were extracted. Cage subsidence was evaluated using upright standing sagittal plane X-rays and defined as more than 2 mm migration of the cage into the adjacent vertebral body. Patients who received revision surgery within 1 year for any reason were recorded. Radiographic parameters were measured. Univariable logistic regression models were used to evaluate the risk factors for cage subsidence and need for revision surgery. RESULTS: At 3-month and 1-year follow-up, cage subsidence was observed in 28 patients (16.5%) and 58 patients (34.1%), respectively. Twenty-seven patients received revision surgery within the first year after TLIF. Age (odds ratio (OR): 1.07 per year) and male sex (OR: 2.76) had a significantly increased odds ratio for cage subsidence 3 months after TLIF. Male sex (OR: 2.55) but not age was a significant risk factor for cage subsidence 1 year after TLIF. Of all assessed risk factors, only BMI (OR: 1.11 per kg/m2) had a significantly increased risk for the need of revision surgery. CONCLUSIONS: Age was associated with cage subsidence 3 months but not 1 year after TLIF suggesting that age is only a risk factor for early cage subsidence and not in a longer follow-up.

The role of muscle degeneration and spinal balance in the pathophysiology of lumbar spinal stenosis: Study protocol of a translational approach combining in vivo biomechanical experiments with clinical and radiological parameters.

OBJECTIVE: To describe a study protocol for investigating the functional association between posture, spinal balance, ambulatory biomechanics, paraspinal muscle fatigue, paraspinal muscle quality and symptoms in patients with symptomatic lumbar spinal stenosis (sLSS) before and 1-year after elective surgical intervention. DESIGN: Single-centre prospective, experimental, multimodal (clinical, biomechanical, radiological) study with three instances of data collection: baseline (study visit 1), 6-month follow-up (remote) and 1-year follow-up (study visit 2). Both study visits include an in vivo experiment aiming to elicit paraspinal muscle fatigue for postural assessment in a non-fatigued and fatigued state. EXPERIMENTAL PROTOCOL: At baseline and 1-year follow-up, 122 patients with sLSS will be assessed clinically, perform the back-performance scale assessment and complete several patient-reported outcome measure (PROMs) questionnaires regarding overall health, disease-related symptoms and kinesiophobia. Posture and biomechanical parameters (joint kinematics, kinetics, surface electromyography, back curvature) will be recorded using an optoelectronic system and retroreflective markers during different tasks including overground walking and movement assessments before and after a modified Biering-Sørensen test, used to elicit paraspinal muscle fatigue. Measurements of muscle size and quality and the severity of spinal stenosis will be obtained using magnetic resonance imaging (MRI) and sagittal postural alignment data from EOS radiographies. After each study visit, physical activity level will be assessed during 9 days using a wrist-worn activity monitor. In addition, physical activity level and PROMs will be assessed remotely at 6-month follow-up. CONCLUSION: The multimodal set of data obtained using the study protocol described in this paper will help to expand our current knowledge on the pathophysiology, biomechanics, and treatment outcome of degenerative sLSS. The results of this study may contribute to defining and/or altering patient treatment norms, surgery indication criteria and post-surgery rehabilitation schedules. TRIAL REGISTRATION: The protocol was approved by the regional ethics committee and has been registered at clinicaltrials.gov (NCT05523388).

Perception of frailty in spinal metastatic disease: international survey of the AO Spine community.

OBJECTIVE: Frailty has not been clearly defined in the context of spinal metastatic disease (SMD). Given this, the objective of this study was to better understand how members of the international AO Spine community conceptualize, define, and assess frailty in SMD. METHODS: The AO Spine Knowledge Forum Tumor conducted an international cross-sectional survey of the AO Spine community. The survey was developed using a modified Delphi technique and was designed to capture preoperative surrogate markers of frailty and relevant postoperative clinical outcomes in the context of SMD. Responses were ranked using weighted averages. Consensus was defined as ≥ 70% agreement among respondents. RESULTS: Results were analyzed for 359 respondents, with an 87% completion rate. Study participants represented 71 countries. In the clinical setting, most respondents informally assess frailty and cognition in patients with SMD by forming a general perception based on clinical condition and patient history. Consensus was attained among respondents regarding the association between 14 preoperative clinical variables and frailty. Severe comorbidities, extensive systemic disease burden, and poor performance status were most associated with frailty. Severe comorbidities associated with frailty included high-risk cardiopulmonary disease, renal failure, liver failure, and malnutrition. The most clinically relevant outcomes were major complications, neurological recovery, and change in performance status. CONCLUSIONS: The respondents recognized that frailty is important, but they most commonly evaluate it based on general clinical impressions rather than using existing frailty tools. The authors identified numerous preoperative surrogate markers of frailty and postoperative clinical outcomes that spine surgeons perceived as most relevant in this population.

Kinematics and paraspinal muscle activation patterns during walking differ between patients with lumbar spinal stenosis and controls.

BACKGROUND: The narrowing of the spinal canal due to degenerative processes may lead to symptomatic lumbar spinal stenosis (sLSS) and impairments in the patients' gait. Changes in lower extremity joint kinematics and trunk flexion angles have been reported, yet less is known about muscle activation patterns of paraspinal and gluteal muscles in patients with sLSS compared to healthy participants. RESEARCH QUESTION: Do muscle activation patterns together with sagittal joint kinematics differ between patients with sLSS and healthy controls and do these differences-quantified using gait scores-correlate with clinical scores? METHODS: In 20 patients with sLSS scheduled for surgery and 19 healthy participants, gait was assessed using seven inertial sensors and muscle activation of gluteus medius, erector spinae and multifidus using wireless surface electromyography (EMG). Differences in joint kinematics and EMG patterns were assessed using statistical parametric mapping with non-parametric independent sample t tests (P < 0.05). Gait scores that describe the overall deviation in joint angles (mGPS) and muscle activation patterns (EMG-Profile Score) were calculated as root mean square distances between patients and healthy participants and their associations with clinical scores (pain, Oswestry Disability Score (ODI)) were analyzed using Spearman's correlation coefficients rho (P < 0.05). RESULTS: Patients had larger mGPS (+1.9°) and EMG-Profile Scores (+50%) and walked on average slower (-0.26 m/s) than controls. EMG patterns revealed higher activation of multifidus, erector spinae and gluteus medius during midstance in patients compared to controls. Clinical scores (pain, ODI) did not correlate with mGPS or EMG-Profile Scores within patients. SIGNIFICANCE: Observed differences in gait and muscle activation patterns and in the summary scores of gait and EMG deviations between patients with sLSS and healthy controls may represent additional functional outcomes reflecting the functional status of patients that can be measured using wearable sensors and hence is suitable for application in clinical practice.

Systemic considerations for the surgical treatment of spinal metastatic disease: a scoping literature review.

Systemic assessment is a pillar in the neurological, oncological, mechanical, and systemic (NOMS) decision-making framework for the treatment of patients with spinal metastatic disease. Despite this importance, emerging evidence relating systemic considerations to clinical outcomes following surgery for spinal metastatic disease has not been comprehensively summarised. We aimed to conduct a scoping literature review of this broad topic. We searched MEDLINE, Embase, Scopus, Cochrane Central Register of Controlled Trials, Web of Science, and CINAHL databases from Jan 1, 2000, to July 31, 2021. 61 articles were included, accounting for a total of 22 335 patients. Preoperative systemic variables negatively associated with postoperative clinical outcomes included demographics (eg, older age [>60 years], Black race, male sex, low or elevated body-mass index, and smoking status), medical comorbidities (eg, cardiac, pulmonary, hepatic, renal, endocrine, vascular, and rheumatological), biochemical abnormalities (eg, hypoalbuminaemia, atypical blood cell counts, and elevated C-reactive protein concentration), low muscle mass, generalised motor weakness (American Spinal Cord Injury Association Impairment Scale grade and Frankel grade) and poor ambulation, reduced performance status, and systemic disease burden. This is the first comprehensive scoping review to broadly summarise emerging evidence relevant to the systemic assessment component of the widely used NOMS framework for spinal metastatic disease decision making. Medical, surgical, and radiation oncologists can consider these findings when prognosticating spinal metastatic disease-related surgical outcomes on the basis of patients' systemic condition. These factors might inform a shared decision-making approach with patients and their families.

Localization of Nerve Growth Factor Expression to Structurally Damaged Cartilaginous Tissues in Human Lumbar Facet Joint Osteoarthritis.

Purpose: Nerve Growth Factor (NGF) is a pivotal mediator of chronic pain and plays a role in bone remodelling. Through its high affinity receptor TrkA, NGF induces substance P (SP) as key downstream mediator of pain and local inflammation. Here we analysed NGF, TrkA and SP tissue distribution in facet joint osteoarthritis (FJOA), a major cause of chronic low back pain. Methods: FJOA specimens (n=19) were harvested from patients undergoing intervertebral fusion surgery. Radiologic grading of FJOA and spinal stenosis, followed by immunohistochemistry for NGF, TrkA and SP on consecutive tissue sections, was performed in ten specimens. Explant cultures (n=9) were used to assess secretion of NGF, IL-6, and SP by FJOA osteochondral tissues under basal and inflammatory conditions. Results: NGF was predominantly expressed in damaged cartilaginous tissues (80%), occasionally in bone marrow (20%), but not in osteochondral vascular channels. NGF area fraction in cartilage was not associated with the extent of proteoglycan loss or radiologic FJOA severity. Consecutive sections showed that NGF and SP expression was localized at structurally damaged cartilage, in absence of TrkA expression. SP and TrkA were expressed in subchondral bone marrow in both presence and absence of NGF. Low level NGF, but not SP secretion, was detected in four out of eighteen FJOA explants under both basal or inflammatory conditions (n=2 each). Conclusion: NGF is associated with SP expression and structural cartilage damage in osteoarthritic facet joints, but not with radiologic disease severity. NGF tissue distribution in FJOA differs from predominant subchondral bone expression reported for knee OA.

Open-Label Placebo Treatment for Acute Postoperative Pain (OLP-POP Study): Study Protocol of a Randomized Controlled Trial.

Introduction: Open-label placebos have been proposed as way of using long recognized analgesic placebo effects in an ethical manner. Recent evidence shows efficacy of open-label placebos for clinical conditions, but there is need for more research on open-label placebos in acute pain. In the treatment of acute postoperative pain, minimization of opioid related side effects remains one of the key challenges. Therefore, this study aims at investigating the potential of adding unconditioned open-label placebos to treatment as usual as a means of reducing opioid consumption and its related side effects in patients with acute postoperative pain. Methods and Analysis: This is the protocol of an ongoing single site randomized controlled trial. The first patient was enrolled in May 2020. In total, 70 patients suffering from acute postoperative pain following dorsal lumbar interbody fusion are randomized to either a treatment as usual group or an experimental intervention group. The treatment as usual group consists of participants receiving a patient-controlled morphine pump. On day 1 and 2 post-surgery, patients in the intervention group receive, in addition to treatment as usual, two open-label placebo injections per day along with an evidence-based treatment rationale explaining the mechanisms of placebos. The primary outcome is measured by means of self-administered morphine during day 1 and 2 post-surgery. Several other outcome measures including pain intensity and adverse events as well as potential predictors of placebo response are assessed. Analysis of covariance will be used to answer the primary research question and additional statistical techniques such as generalized linear mixed models will be applied to model the temporal course of morphine consumption. Discussion: This study will provide valuable insights into the efficacy of open-label placebos in acute pain and will potentially constitute an important step toward the implementation of open-label placebos in the clinical management of acute postoperative pain. In addition, it will shed light on a cost-efficient and patient-centered strategy to reduce opioid consumption and its related side effects, without any loss in pain management efficacy. Ethics and Dissemination: The "Ethikkommission Nordwest- und Zentralschweiz" (BASEC2020-00099) approved the study protocol. Results of the analysis will be submitted for publication in a peer-reviewed journal. Clinical Trial Registration: The study is registered at ClinicalTrials.gov (NCT04339023) and is listed in the Swiss national registry at kofam.ch (SNCTP000003720).

Assessing Fatty Infiltration of Paraspinal Muscles in Patients With Lumbar Spinal Stenosis: Goutallier Classification and Quantitative MRI Measurements.

Objective: Fatty infiltration of paraspinal muscle is associated with spinal disorders. It can be assessed qualitatively (i.e., Goutallier classification) and quantitatively using image processing software. The aims of this study were to compare paraspinal muscle fatty infiltration as assessed using the Goutallier classification vs. quantitative magnetic resonance images (MRI) measurements and to investigate the association between anthropometric parameters and paraspinal muscle morphology and fatty infiltration in patients with symptomatic lumbar spinal stenosis (LSS). Methods: Patients affected by symptomatic LSS scheduled for surgery with available MRI of the lumbar spine were included in this retrospective cross-sectional study. Fatty infiltration at each lumbar level was rated qualitatively according to the Goutallier classification and quantified based on the cross-sectional area (CSA) of the paraspinal muscle, of its lean fraction (LeanCSA), and the ratio between LeanCSA and CSA and the CSA relative to the CSA of vertebral body (RCSA). Considering the muscle as a single unit, overall fatty infiltration according to Goutallier, overall CSA, LeanCSA, LeanCSA/CSA, and RCSA were computed as averages (aGoutallier, aCSA, aLeanCSA, aLeanCSA/aCSA, and aRCSA). Associations among parameters were assessed using Spearman's respective Pearson's correlation coefficients. Results: Eighteen patients, with a mean age of 71.3 years, were included. aGoutallier correlated strongly with aLeanCSA and aLeanCSA/aCSA (R = -0.673 and R = -0.754, both P < 0.001). There was a very strong correlation between values of the left and right sides for CSA (R = 0.956, P < 0.001), LeanCSA (R = 0.900, P < 0.001), and LeanCSA/CSA (R = 0.827, P < 0.001) at all levels. Among all anthropometric measurements, paraspinal muscle CSA correlated the most with height (left: R = 0.737, P < 0.001; right: R = 0.700, P < 0.001), while there was a moderate correlation between vertebral body CSA and paraspinal muscle CSA (left: R = 0.448, P < 0.001; right: R = 0.454, P < 0.001). Paraspinal muscle CSA correlated moderately with body mass index (BMI; left: R = 0.423, P < 0.001; right: R = 0.436, P < 0.001), and there was no significant correlation between aLeanCSA or aLeanCSA/CSA and BMI. Conclusions: The Goutallier classification is a reliable yet efficient tool for assessing fatty infiltration of paraspinal muscles in patients with symptomatic LSS. We suggest taking body height as a reference for normalization in future studies assessing paraspinal muscle atrophy and fatty infiltration.

Association between fatty infiltration of paraspinal muscle, sagittal spinopelvic alignment and stenosis grade in patients with degenerative lumbar spinal stenosis.

INTRODUCTION: Sagittal balance and fatty infiltration of paraspinal muscle are important factors in patients with lumbar spinal stenosis (LSS) that may affect patients' quality of life. Sagittal spinopelvic parameters and fatty infiltration may be associated with the severity of LSS. The purpose of this study was to test the hypothesis that severity of fatty infiltration correlates with severity of LSS and with sagittal pelvic alignment independent of age. METHODS: Age and body mass index (BMI) were extracted. Fatty infiltration was rated according to Goutallier classification and the severity of LSS was graded according to Schizas at five intervertebral disc levels. Overall fatty infiltration was computed as average fatty infiltration (aFI) and severity of LSS was defined as the highest severity of LSS of all segments. The sagittal spinopelvic parameters pelvic incidence (PI), pelvic tilt (PT), sacral slope (SS), lumbar lordosis (LL) and PI-LL were measured. Associations among parameters were assessed using Spearman correlation coefficients adjusted for age (α = 0.05). RESULTS: 165 LSS patients with a median age of 69 years were included. All parameters correlated with age (R>0.162, P<0.05) except BMI and LL (R<0.007, P>0.05). aFI correlated with PI, PT and PI-LL before (R>0.371, P<0.05) and after (R>0.180, P<0.05) adjusting for age. Severity of LSS correlated with PI, PT and PI-LL before (R>0.187, P<0.05) but not after (R<0.130, P>0.05) adjusting for age. aFI correlated with severity of LSS before (R=0.349, P<0.05) but not (R=0.114, P>0.05) after adjusting for age. CONCLUSIONS: The correlation of aFI with sagittal spinopelvic parameters indicates that there might be a relationship between muscle characteristics and the sagittal alignment. Sagittal spinopelvic parameters and fatty infiltration of paraspinal muscles are not associated with radiological severity of LSS. Whether they are associated with clinical manifestation of LSS remains to be investigated.

Severity of degenerative lumbar spinal stenosis affects pelvic rigidity during walking.

BACKGROUND CONTEXT: To understand the role of compensation mechanisms in the development and treatment of symptomatic degenerative lumbar spinal stenosis (DLSS), pelvic stability during walking should be objectively assessed in the context of clinical parameters. PURPOSE: To determine the association among duration of symptoms, lumbar muscle atrophy, disease severity, pelvic stability during walking, and surgical outcome in patients with DLSS scheduled for decompression surgery. STUDY DESIGN/SETTING: Prospective observational study with intervention. PATIENT SAMPLE: Patients with symptomatic DLSS. OUTCOME MEASURES: Oswestry Disability Index score; duration of symptoms; lumbar muscle atrophy; severity grade; pelvis rigidity during walking. METHODS: Patients with symptomatic DLSS were analyzed on the day before surgery and 10 weeks and 12 months postoperatively. Duration of symptoms was categorized as: <2years, <5years, and >5years. Muscle atrophy at the stenosis level was categorized according to Goutallier. Bilateral cross-sectional areas of the erector spinae and psoas muscles were quantified from magnetic resonance imaging. Stenosis grade was assessed using the Schizas classification. Pelvic tilt was measured in standing radiographs. Pelvic rigidity during walking was assessed as root mean square of the pelvic acceleration in each direction (anteroposterior, mediolateral, and vertical) normalized to walking speed measured using an inertial sensor attached to the skin between the posterior superior iliac spine. RESULTS: Body mass index but not duration of symptoms, lumbar muscle atrophy, pelvic rigidity, and stenosis grade explained changes in Oswestry Disability Index from before to after surgery. Patients with greater stenosis grade had greater pelvic rigidity during walking. Lumbar muscle atrophy did not correlate with pelvic rigidity during walking. Patients with lower stenosis grade had greater muscle atrophy and patients with smaller erector spinae and psoas muscle cross-sectional areas had a greater pelvis tilt. CONCLUSIONS: Greater pelvic rigidity during walking may represent a compensatory mechanism of adopting a protective body position to keep the spinal canal more open during walking and hence reduce pain. Pelvic rigidity during walking may be a useful screening parameter for identifying early compensating mechanisms. Whether it can be used as a parameter for personalized treatment planning or outcome prognosis necessitates further evaluation.

Inertial Sensor-Based Gait and Attractor Analysis as Clinical Measurement Tool: Functionality and Sensitivity in Healthy Subjects and Patients With Symptomatic Lumbar Spinal Stenosis.

Objective: To determine if the attractor for acceleration gait data is similar among healthy persons defining a reference attractor; if exercise-induced changes in the attractor in patients with symptomatic lumbar spinal stenosis (sLSS) are greater than in healthy persons; and if the exercise-induced changes in the attractor are affected by surgical treatment. Methods: Twenty-four healthy subjects and 19 patients with sLSS completed a 6-min walk test (6MWT) on a 30-m walkway. Gait data were collected using inertial sensors (RehaGait®;) capturing 3-dimensional foot accelerations. Attractor analysis was used to quantify changes in low-pass filtered acceleration pattern (δM) and variability (δD) and their combination as attractor-based index (δF = δM* δD) between the first and last 30 m of walking. These parameters were compared within healthy persons and patients with sLSS (preoperatively and 10 weeks and 12 months postoperatively) and between healthy persons and patients with sLSS. The variability in the attractor pattern among healthy persons was assessed as the standard deviation of the individual attractors. Results: The attractor pattern differed greatly among healthy persons. The variability in the attractor between subjects was about three times higher than the variability around the attractor within subject. The change in gait pattern and variability during the 6MWT did not differ significantly in patients with sLSS between baseline and follow-up but differed significantly compared to healthy persons. Discussion: The attractor for acceleration data varied largely among healthy subjects, and hence a reference attractor could not be generated. Moreover, the change in the attractor and its variability during the 6MWT differed between patients and elderly healthy persons but not between repeated assessments. Hence, the attractor based on low-pass filtered signals as used in this study may reflect pathology specific differences in gait characteristics but does not appear to be sufficiently sensitive to serve as outcome parameter of decompression surgery in patients with sLSS.

Novel Ex Vivo Human Osteochondral Explant Model of Knee and Spine Osteoarthritis Enables Assessment of Inflammatory and Drug Treatment Responses.

Osteoarthritis of the knee and spine is highly prevalent in modern society, yet a disease-modifying pharmacological treatment remains an unmet clinical need. A major challenge for drug development includes selection of appropriate preclinical models that accurately reflect clinical phenotypes of human disease. The aim of this study was to establish an ex vivo explant model of human knee and spine osteoarthritis that enables assessment of osteochondral tissue responses to inflammation and drug treatment. Equal-sized osteochondral fragments from knee and facet joints (both n = 6) were subjected to explant culture for 7 days in the presence of a toll-like receptor 4 (TLR4) agonist and an inhibitor of transforming growth factor-beta (TGF-β) receptor type I signaling. Markers of inflammation, interleukin-6 (IL-6) and monocyte chemoattractant protein-1 (MCP-1), but not bone metabolism (pro-collagen-I) were significantly increased by treatment with TLR4 agonist. Targeting of TGF-β signaling resulted in a strong reduction of pro-collagen-I and significantly decreased IL-6 levels. MCP-1 secretion was increased, revealing a regulatory feedback mechanism between TGF-β and MCP-1 in joint tissues. These findings demonstrate proof-of-concept and feasibility of explant culture of human osteochondral specimens as a preclinical disease model, which might aid in definition and validation of disease-modifying drug targets.

Decompression surgery improves gait quality in patients with symptomatic lumbar spinal stenosis.

BACKGROUND CONTEXT: We aimed to fully understand the extent of limitations associated with symptomatic lumbar spinal stenosis (LSS) and the functional outcome of its treatment, including not only function during daily activities (eg, using the 6-minute walk test [6MWT]) but also the quality of function that should be objectively assessed. PURPOSE: This study was performed to test the hypothesis that the Oswestry Disability Index (ODI) score, the walking distance during the 6MWT (6-minute walking distance [6MWD]), and gait quality (spatiotemporal parameters and gait asymmetry) will improve postoperatively and achieve normal values; to determine if changes in gait parameters correlate with changes in Oswestry Disability Index (ODI) score; and to ascertain if patients' gait quality will diminish during the 6MWT, reflected by changes in gait parameters during the 6MWT. STUDY DESIGN/SETTING: This is a prospective observational study with intervention. PATIENT SAMPLE: The sample comprised patients with symptomatic LSS. OUTCOME MEASURES: The ODI score, gait quality (spatiotemporal and asymmetry), and walking performance (walking distance during the 6MWT) were the outcome measures. METHODS: Patients with symptomatic LSS were analyzed on the day before surgery and 10 weeks and 12 months postoperatively. Functional disability in daily life was assessed by the ODI. Spatiotemporal and kinematic gait parameters were recorded with an inertial sensor system during the 6MWT, and the 6MWD was determined. Gait asymmetry was defined as 100*|right-left|/(0.5*(|right+left|)). RESULTS: The ODI decreased by 17.9% and 23.9% and 6MWD increased by 21 m and 26 m from baseline to 10-week and 12-month follow-up, respectively. Gait quality did not change during the 6MWT at any assessment or between assessments. Compared with the control group, patients walked less during the 6MWT, and gait quality differed between patients and the control group at baseline and 10-week follow-up but not at 12-month follow-up. Change in gait quality explained 39% and 73% of variance in change in ODI from baseline to 10-week and to 12-month follow-up, respectively. CONCLUSIONS: Changes in gait quality explained a large portion of variance in changes in the ODI, indicating that patients with symptomatic LSS perceive their compromised gait quality as functional limitations. Gait data obtained by instrumented gait analysis contain information on gait quality that can be helpful for evaluating functional limitations in patients with LSS, the outcome of decompression surgery, and the development of patient-specific rehabilitation regimens.

Comparative Analysis of Bone Structural Parameters Reveals Subchondral Cortical Plate Resorption and Increased Trabecular Bone Remodeling in Human Facet Joint Osteoarthritis.

Facet joint osteoarthritis is a prominent feature of degenerative spine disorders, highly prevalent in ageing populations, and considered a major cause for chronic lower back pain. Since there is no targeted pharmacological therapy, clinical management of disease includes analgesic or surgical treatment. The specific cellular, molecular, and structural changes underpinning facet joint osteoarthritis remain largely elusive. The aim of this study was to determine osteoarthritis-related structural alterations in cortical and trabecular subchondral bone compartments. To this end, we conducted comparative micro computed tomography analysis in healthy (n = 15) and osteoarthritic (n = 22) lumbar facet joints. In osteoarthritic joints, subchondral cortical plate thickness and porosity were significantly reduced. The trabecular compartment displayed a 42 percent increase in bone volume fraction due to an increase in trabecular number, but not trabecular thickness. Bone structural alterations were associated with radiological osteoarthritis severity, mildly age-dependent but not gender-dependent. There was a lack of association between structural parameters of cortical and trabecular compartments in healthy and osteoarthritic specimens. The specific structural alterations suggest elevated subchondral bone resorption and turnover as a potential treatment target in facet joint osteoarthritis.

Alterations of Subchondral Bone Progenitor Cells in Human Knee and Hip Osteoarthritis Lead to a Bone Sclerosis Phenotype.

Subchondral bone tissue plays a key role in the initiation and progression of human and experimental osteoarthritis and has received considerable interest as a treatment target. Elevated bone turnover and remodeling leads to subchondral bone sclerosis that is characterized by an increase in bone material that is less mineralized. The aim of this study was to investigate whether perturbations in subchondral bone-resident progenitor cells might play a role in aberrant bone formation in osteoarthritis. Colony formation assays indicated similar clonogenicity of progenitor cells from non-sclerotic and sclerotic subchondral trabecular bone tissues of osteoarthritic knee and hip joints compared with controls from iliac crest bone. However, the osteogenic potential at the clonal level was approximately two-fold higher in osteoarthritis than controls. An osteogenic differentiation assay indicated an efficient induction of alkaline phosphatase activity but blunted in vitro matrix mineralization irrespective of the presence of sclerosis. Micro-computed tomography and histology demonstrated the formation of de novo calcified tissues by osteoblast-like cells in an ectopic implantation model. The expression of bone sialoprotein, a marker for osteoblast maturation and mineralization, was significantly less in sclerotic progenitor cells. Perturbation of resident progenitor cell function is associated with subchondral bone sclerosis and may be a treatment target for osteoarthritis.

GEORG-SCHMORL-PRIZE OF THE GERMAN SPINE SOCIETY (DWG) 2016: Comparison of in vitro osteogenic potential of iliac crest and degenerative facet joint bone autografts for intervertebral fusion in lumbar spinal stenosis.

PURPOSE: The promotion of spinal fusion using bone autografts is largely mediated by the osteoinductive potential of progenitors/mesenchymal stem cells (MSC) that reside in the marrow spaces of cancellous bone. Iliac crest is the common autograft donor site, but its use presents an increased risk for donor site pain, morbidity and infection. Degenerative bone samples harvested during facetectomy might provide an alternative viable source of osteoinductive autografts. In this study, we conducted an intra-individual comparison of the osteogenic potential of isolated low passage MSC from both sources. METHODS: Iliac crest and degenerative facet joints were harvested from eight consecutive patients undergoing transforaminal lumbar interspinal fusion due to lumbar spinal stenosis. MSC were isolated by collagenase digestion, selected by plastic adherence and minimally expanded for downstream assays. Clonogenic and osteogenic potential was evaluated by colony formation assays in control and osteogenic culture medium. Osteogenic properties, including alkaline phosphatase (ALP) induction, matrix mineralization and type I collagen mRNA and protein expression were characterized using quantitative histochemical staining and reverse transcription PCR. Spontaneous adipogenesis was analysed by adipocyte enumeration and gene expression analysis of adipogenic markers. RESULTS: Average colony-forming efficiency in osteogenic medium was equal between iliac crest (38 ± 12%) and facet joint (36 ± 11%). Osteogenic potential at the clonal level was 55 ± 26 and 68 ± 17% for iliac crest and facet joint MSC, respectively. Clonogenic and osteogenic potential were significantly negatively associated with donor age. Osteogenic differentiation led to significant induction of ALP activity in iliac crest (sixfold) and facet joint (eightfold) MSC. Matrix mineralization quantified by Alizarin red staining was increased by osteogenic differentiation, yet similar between both MSC sources. Protein expression of type I collagen was enhanced during osteogenesis and significantly greater in iliac crest MSC. Correspondingly, COL1A2 mRNA expression was higher in osteogenically differentiated MSC from iliac crest. Adipocyte numbers showed significant differences between iliac crest (63 ± 60) and facet joint (18 ± 15) MSC under osteogenic conditions. Negative (GREM1) and positive (FABP4) adipogenic markers were not differentially expressed between sources. CONCLUSION: MSC from iliac crest and degenerative facet joints largely display similar clonogenic and osteogenic properties in vitro. Differences at the molecular level are not likely to impair the osteoinductive capacity of facet joint MSC. Bone autografts from facetectomy would be viable alternatives as bone autografts for intervertebral spinal fusion in lumbar spinal stenosis.

Effect of gait retraining for reducing ambulatory knee load on trunk biomechanics and trunk muscle activity.

The purpose of this study was to test the hypothesis that walking with increased medio-lateral trunk sway is associated with lower external knee adduction moment and lower extremity muscle activation, and higher external ipsilateral trunk moment and trunk muscle activity than walking with normal trunk sway in healthy participants. Fifteen participants performed walking trials with normal and increased medio-lateral trunk sway. Maximum trunk sway, first maximum knee adduction moment, lateral trunk bending moment, and bilateral vastus medialis, vastus lateralis, gluteus medius, rectus abdominis, external oblique and erector spinae muscle activity were computed. Walking with increased trunk sway was associated with lower maximum knee adduction moment (95% confidence interval (CI): 0.50-0.62Nm/kg vs. 0.62-0.76Nm/kg; P<.001) and ipsilateral gluteus medius (-17%; P=.014) and erector spinae muscle activity (-24%; P=.004) and greater maximum lateral trunk bending moment (+34%; P<.001) and contralateral external oblique muscle activity (+60%; P=.009). In all participants, maximum knee adduction moment was negatively correlated and maximum trunk moment was positively correlated with maximum trunk sway. The results of this study suggest that walking with increased trunk sway not only reduces the external knee adduction moment but also alters and possibly increases the load on the trunk. Hence, load-altering biomechanical interventions should always be evaluated not only regarding their effects on the index joint but on other load-bearing joints such as the spine.

Characterization of subchondral bone histopathology of facet joint osteoarthritis in lumbar spinal stenosis.

Facet joint osteoarthritis may be a cause of low back pain in degenerative spine diseases including lumbar spinal stenosis. Subchondral bone is regarded as a potential therapeutic target for osteoarthritis treatment. The goal of this study was to characterize subchondral bone histopathology in osteoarthritic facet joints from lumbar spinal stenosis patients. Fifteen patients with degenerative spinal stenosis scheduled for transforaminal lumbar interbody fusion surgery were recruited for this study. Osteoarthritis severity was graded on T1- and T2-weighted MRI images using Weishaupt scoring system. Dissected osteoarthritic facet joints were subjected to histological and immunohistochemistry analyses to study relative abundance of osteoblast, osteoclasts, and macrophages using van Gieson's, tartrate-resistant acid phosphatase and CD68-antibody staining, respectively. Presence of nerve fibers was evaluated by PGP9.5-antibody staining. Differential bone histopathology, independent from radiological osteoarthritis grade, was observed in facet joints. Extensive de novo bone formation was found in subchondral bone tissues of eight of fifteen specimens. Regions of bone formation showed high abundance of blood vessels and CD68-positive macrophages, but were devoid of multinucleated osteoclasts. Additional pathological changes in subchondral marrow spaces, including inflammatory infiltration and enhanced osteoclast activity, were characterized by macrophage-rich tissues. PGP9.5-positive nerve fibers were detected near arterioles, but not in regions displaying bone pathology. Individual histopathological parameters did not associate with clinical features or radiological osteoarthritis severity. Subchondral bone histopathology of facet joint osteoarthritis in lumbar spinal stenosis is characterized by marrow infiltration by macrophage-rich tissues and enhanced de novo bone formation. © 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 34:1475-1480, 2016.