Network-based cytokine inference implicates Oncostatin M as a driver of an inflammation phenotype in knee osteoarthritis.

Inflammatory cytokines released by synovium after trauma disturb the gene regulatory network and have been implicated in the pathophysiology of osteoarthritis. A mechanistic understanding of how aging perturbs this process can help identify novel interventions. Here, we introduced network paradigms to simulate cytokine-mediated pathological communication between the synovium and cartilage. Cartilage-specific network analysis of injured young and aged murine knees revealed aberrant matrix remodeling as a transcriptomic response unique to aged knees displaying accelerated cartilage degradation. Next, network-based cytokine inference with pharmacological manipulation uncovered IL6 family member, Oncostatin M (OSM), as a driver of the aberrant matrix remodeling. By implementing a phenotypic drug discovery approach, we identified that the activation of OSM recapitulated an "inflammatory" phenotype of knee osteoarthritis and highlighted high-value targets for drug development and repurposing. These findings offer translational opportunities targeting the inflammation-driven osteoarthritis phenotype.

Network-based systematic dissection of exercise-induced inhibition of myosteatosis in older individuals.

Accumulated fat in skeletal muscle (i.e. myosteatosis), common in sedentary older individuals, compromises skeletal muscle health and function. A mechanistic understanding of how physical activity levels dictate fat accumulation represents a critical step towards establishment of therapies that promote healthy ageing. Using a network medicine paradigm that characterized the transcriptomic response of aged muscle to exercise versus immobilization protocols, this study explored the shared molecular cascade that regulates the fate of fibro-adipogenic progenitors (FAPs), the cell population primarily responsible for fat accumulation. Specifically, gene set enrichment analyses with network propagation revealed Pgc-1α as a functional hub of a large gene regulatory network underlying the regulation of FAPs by physical activity in aged muscle, but not in young counterparts. Integrated in silico and in situ approaches to induce Pgc-1α overexpression in aged muscle promoted mitochondrial fatty acid oxidation and inhibited FAP adipogenesis. These findings suggest that the Pgc-1α-mitochondrial fatty acid oxidation axis is a shared mechanism by which physical activity regulates age-related myosteatosis. The network medicine paradigm introduced provides mechanistic insight into exercise adaptation in elderly skeletal muscle and offers translational opportunities to advance exercise prescription for older populations. KEY POINTS: Fat accumulation is a quintessential feature of aged skeletal muscle. While increasing physical activity levels has been proposed as an effective strategy to reduce the fat in skeletal muscle (i.e. myosteatosis), the molecular cascade underlying these benefits has been poorly defined. This study implemented a series of network medicine approaches and uncovered Pgc-1α as a mechanistic driver of the regulation of fibro-adipogenic progenitors (FAPs) by physical activity. Integrated in silico and in situ approaches to induce Pgc-1α overexpression promoted mitochondrial fatty acid oxidation and inhibited FAP adipogenesis. Together, the findings of the current study suggest a novel hypothesis that physical activity reduces myosteatosis via upregulation of Pgc-1α-mediated mitochondrial fatty acid oxidation and subsequent inhibition of FAP adipogenesis.

Exploring the role of mechanical forces on tendon development using in vivo model: A scoping review.

Tendons transmit the muscle contraction forces to bones and drive joint movement throughout life. While extensive research have indicated the essentiality of mechanical forces on tendon development, a comprehensive understanding of the fundamental role of mechanical forces still needs to be impaerted. This scoping review aimed to summarize the current knowledge about the role of mechanical forces during the tendon developmental phase. The electronic database search using PubMed, performed in May 2023, yielded 651 articles, of which 16 met the prespecified inclusion criteria. We summarized and divided the methods to reduce the mechanical force into three groups: loss of muscle, muscle dysfunction, and weight-bearing regulation. In contrast, there were few studies to analyze the increased mechanical force model. Most studies suggested that mechanical force has some roles in tendon development in the embryo to postnatal phase. However, we identified species variability and methodological heterogeneity to modulate mechanical force. To establish a comprehensive understanding, methodological commonality to modulate the mechanical force is needed in this field. Additionally, summarizing chronological changes in developmental processes across animal species helps to understand the essence of developmental tendon mechanobiology. We expect that the findings summarized in the current review serve as a groundwork for future study in the fields of tendon developmantal biology and mechanobiology.

Compensatory gait mechanics in person with multiple toe amputation: A single case report.

This case highlights the biomechanical influence of toe amputation on contralateral limb force elevation, possibly through reduced ipsilateral plantar flexor torque production. These findings provide insight into toe amputation-related compensatory gait mechanics with greater inter-limb asymmetry, which may increase the risk of musculoskeletal comorbidities, including osteoarthritis in contralateral limb.

Exercise-primed extracellular vesicles improve cell-matrix adhesion and chondrocyte health.

Extracellular vesicles (EVs) have been suggested to transmit the health-promoting effects of exercise throughout the body. Yet, the mechanisms by which beneficial information is transmitted from extracellular vesicles to recipient cells are poorly understood, precluding a holistic understanding of how exercise promotes cellular and tissue health. In this study, using articular cartilage as a model, we introduced a network medicine paradigm to simulate how exercise facilitates communication between circulating EVs and chondrocytes, the cells resident in articular cartilage. Using the archived small RNA-seq data of EV before and after aerobic exercise, microRNA regulatory network analysis based on network propagation inferred that circulating EVs activated by aerobic exercise perturb chondrocyte-matrix interactions and downstream cellular aging processes. Building on the mechanistic framework identified through computational analyses, follow up experimental studies interrogated the direct influence of exercise on EV-mediated chondrocyte-matrix interactions. We found that pathogenic matrix signaling in chondrocytes was abrogated in the presence of exercise-primed EVs, restoring a more youthful phenotype, as determined by chondrocyte morphological profiling and evaluation of chondrogenicity. Epigenetic reprograming of the gene encoding the longevity protein, α-Klotho, mediated these effects. These studies provide mechanistic evidence that exercise transduces rejuvenation signals to circulating EVs, endowing EVs with the capacity to ameliorate cellular health even in the presence of an unfavorable microenvironmental signals.

Dynamical modeling reveals RNA decay mediates the effect of matrix stiffness on aged muscle stem cell fate.

Loss of muscle stem cell (MuSC) self-renewal with aging reflects a combination of influences from the intracellular (e.g., post-transcriptional modifications) and extracellular (e.g., matrix stiffness) environment. Whereas conventional single cell analyses have revealed valuable insights into factors contributing to impaired self-renewal with age, most are limited by static measurements that fail to capture nonlinear dynamics. Using bioengineered matrices mimicking the stiffness of young and old muscle, we showed that while young MuSCs were unaffected by aged matrices, old MuSCs were phenotypically rejuvenated by young matrices. Dynamical modeling of RNA velocity vector fields in silico revealed that soft matrices promoted a self-renewing state in old MuSCs by attenuating RNA decay. Vector field perturbations demonstrated that the effects of matrix stiffness on MuSC self-renewal could be circumvented by fine-tuning the expression of the RNA decay machinery. These results demonstrate that post-transcriptional dynamics dictate the negative effect of aged matrices on MuSC self-renewal.

Exploring the modification factors of exercise therapy on biomechanical load in patients with knee osteoarthritis: a systematic review and meta-analysis.

The objective of this systematic review and meta-analysis is to clarify the effect of exercise therapy on the first peak knee adduction moment (KAM), as well as other biomechanical loads in patients with knee osteoarthritis (OA), and identify physical characteristics that influence differences in biomechanical load after exercise therapy. The data sources are PubMed, PEDro, and CINAHL, from study inception to May 2021. The eligibility criteria include studies evaluating the first peak (KAM), peak knee flexion moment (KFM), maximal knee joint compression force (KCF), or co-contraction during walking before and after exercise therapy in patients with knee OA. The risk of bias was independently assessed by two reviewers using PEDro and NIH scales. Among 11 RCTs and nine non-RCTs, 1119 patients with knee OA were included (average age: 63.7 years). As the results of meta-analysis, exercise therapy tended to increase the first peak KAM (SMD 0.11; 95% CI: -0.03-0.24), peak KFM (SMD 0.13; 95% CI: -0.03-0.29), and maximal KCF (SMD 0.09; 95% CI -0.05-0.22). An increased first peak KAM was significantly associated with a larger improvement in knee muscle strength and WOMAC pain. However, the quality of evidence regarding the biomechanical loads was low-to-moderate according to the GRADE approach. The improvement in pain and knee muscle strength may mediate the increase in first peak KAM, suggesting difficulty in balancing symptom relief and biomechanical load reduction. Therefore, exercise therapy may satisfy both aspects simultaneously when combined with biomechanical interventions, such as a valgus knee brace or insoles. Registration: PROSPERO (CRD42021230966).

Ankle instability as a prognostic factor associated with the recurrence of ankle sprain: A systematic review.

DESIGN: Systematic review using PRISMA guidelines. PURPOSE: To explore Relationship between ankle instability and ankle sprain recurrence in preventing recurrence of ankle sprains and to provide appropriate treatment. METHODS: MEDLINE (the Cochrane Library) and the Physiotherapy Evidence Database (PEDro) were explored using key words related to ankle instability and ankle sprains in for April 2022. According to the inclusion criteria, studies that 1) targeted patients with ankle sprains, 2) assessed ankle instability, and 3) investigated ankle sprain recurrence rates, were extracted. The author names, publication year, patient characteristics, comparison groups, intervention methods, and outcome data (ankle instability and recurrence) were extracted. A correlation analysis between recurrence rate and ankle instability was conducted. In addition, A meta-analysis was performed on the correlation coefficients within each article. RESULTS: Eight studies were extracted from 149 studies. A correlation analysis was conducted on five studies and meta-analysis was on three studies with the same post-intervention follow-up period and the same assessment methods for ankle instability and recurrence rate. Strong positive correlations were found for the same follow-up periods (r = 0.95: 95%CI [0.62-0.99]; 3-month, r = 0.97: 95%CI [0.75-0.10]; 1 year, p < .05). The correlation became stronger as the follow-up period increased. Furthermore, the meta-analysis showed that ankle instability as well as the main symptoms of sprain, such as pain and swelling, tended to be positively correlated with the recurrent rate of ankle sprains. These results suggest that ankle instability is strongly related to recurrence, and the longer the time since onset, the stronger the relationship. CONCLUSIONS: Ankle instability was a prognostic factor associated with recurrence of ankle sprains in patients with ankle sprains. Therefore, ankle instability is one of important factor in preventing recurrence of ankle sprains.

Age-related matrix stiffening epigenetically regulates α-Klotho expression and compromises chondrocyte integrity.

Extracellular matrix stiffening is a quintessential feature of cartilage aging, a leading cause of knee osteoarthritis. Yet, the downstream molecular and cellular consequences of age-related biophysical alterations are poorly understood. Here, we show that epigenetic regulation of α-Klotho represents a novel mechanosensitive mechanism by which the aged extracellular matrix influences chondrocyte physiology. Using mass spectrometry proteomics followed by a series of genetic and pharmacological manipulations, we discovered that increased matrix stiffness drove Klotho promoter methylation, downregulated Klotho gene expression, and accelerated chondrocyte senescence in vitro. In contrast, exposing aged chondrocytes to a soft matrix restored a more youthful phenotype in vitro and enhanced cartilage integrity in vivo. Our findings demonstrate that age-related alterations in extracellular matrix biophysical properties initiate pathogenic mechanotransductive signaling that promotes Klotho promoter methylation and compromises cellular health. These findings are likely to have broad implications even beyond cartilage for the field of aging research.

Bioengineered 3D Skeletal Muscle Model Reveals Complement 4b as a Cell-Autonomous Mechanism of Impaired Regeneration with Aging.

A mechanistic understanding of cell-autonomous skeletal muscle changes after injury can lead to novel interventions to improve functional recovery in an aged population. However, major knowledge gaps persist owing to limitations of traditional biological aging models. 2D cell culture represents an artificial environment, while aging mammalian models are contaminated by influences from non-muscle cells and other organs. Here, a 3D muscle aging system is created to overcome the limitations of these traditional platforms. It is shown that old muscle constructs (OMC) manifest a sarcopenic phenotype, as evidenced by hypotrophic myotubes, reduced contractile function, and decreased regenerative capacity compared to young muscle constructs. OMC also phenocopy the regenerative responses of aged muscle to two interventions, pharmacological and biological. Interrogation of muscle cell-specific mechanisms that contribute to impaired regeneration over time further reveals that an aging-induced increase of complement component 4b (C4b) delays muscle progenitor cell amplification and impairs functional recovery. However, administration of complement factor I, a C4b inactivator, improves muscle regeneration in vitro and in vivo, indicating that C4b inhibition may be a novel approach to enhance aged muscle repair. Collectively, the model herein exhibits capabilities to study cell-autonomous changes in skeletal muscle during aging, regeneration, and intervention.

Aging Affects the Efficacy of Platelet-Rich Plasma Treatment for Osteoarthritis.

OBJECTIVE: Despite the increased use of platelet-rich plasma in the treatment of osteoarthritis, whether and how age of the platelet-rich plasma donor affects therapeutic efficacy is unclear. DESIGN: In vitro, male osteoarthritic human chondrocytes were treated with platelet-rich plasma from young (18-35 yrs) or old (≥65 yrs) donors, and the chondrogenic profile was evaluated using immunofluorescent staining for two markers of chondrogenicity, type II collagen and SOX-9. In vivo, we used a within-subjects design to compare Osteoarthritis Research Society International scores in aged mouse knee joints injected with platelet-rich plasma from young or old individuals. RESULTS: In vitro experiments revealed that platelet-rich plasma from young donors induced a more youthful chondrocyte phenotype, as evidenced by increased type II collagen ( P = 0.033) and SOX-9 expression ( P = 0.022). This benefit, however, was significantly blunted when cells were cultured with platelet-rich plasma from aged donors. Accordingly, in vivo studies revealed that animals treated with platelet-rich plasma from young donors displayed a significantly improved cartilage integrity when compared with knees injected with platelet-rich plasma from aged donors ( P = 0.019). CONCLUSIONS: Injection of platelet-rich plasma from a young individual induced a regenerative effect in aged cells and mice, whereas platelet-rich plasma from aged individuals showed no improvement in chondrocyte health or cartilage integrity.

Identification of Early Knee Osteoarthritis Based on Knee Joint Trajectory during Stair Climbing.

Patients with knee osteoarthritis show low stair climbing ability, but a diagnosis of stair performance time is not enough to identify the early stages of knee osteoarthritis. Therefore, we developed an indicator named range of the knee joint trajectory (RKJT) as a kinematic parameter to express more detailed characteristics than stair performance time. To achieve this, we used our developed "IR-Locomotion", a markerless measurement system that can track the knee joint trajectory when climbing stairs. This study aimed to test whether the RKJT effectively identifies patients with early knee osteoarthritis even after controlling stair performance time. Forty-seven adults with moderate to severe knee pain (mean age 59.2 years; 68.1% women) underwent the radiographic examination (Kellgren and Lawrence grade) of both knees and a stair climbing test on 11 stairs. The RKJT during the stair climbing test was calculated by "IR-Locomotion". A generalized linear mixed model was used to evaluate the discriminative capability of RKJT on early knee osteoarthritis (i.e., Kellgren and Lawrence grade of 1). As expected, patients with early knee osteoarthritis showed larger RKJT than non-radiographic controls (95% confidence interval: 1.007, 1.076). Notably, this finding was consistent even after adjusting stair performance time.

Functional manifestations of early knee osteoarthritis: a systematic review and meta-analysis.

Early detection of knee osteoarthritis (KOA) can improve treatment outcomes and prevent its progression. The aim of this systematic review was to identify the functional changes in early KOA. Electronic journal databases and platforms, including PubMed, the Physiotherapy Evidence Database, the Cochrane Central Register of Controlled Trials, and Scopus were searched. The inclusion criteria were as follows: (1) studies comparing patients with early KOA with an age-matched control group and (2) studies with objectively measured functional changes as outcomes. Studies that included individuals with Kellgren and Lawrence (K/L) grades > 2- were excluded. A random-effects model was constructed to calculate pooled standardized mean differences (SMDs). A total of nine articles were included in this systematic review. Seven studies used classification criteria to define early KOA, including knee pain; a K/L grade of 0, 1, or 2- (osteophytes only) for the medial compartment; and the presence of two out of four MRI criteria. The remaining two studies included K/L grade 1 confirmed by radiography. Early KOA participants had a significantly longer timed up-and-go test (TUG) time (pooled SMD: 0.57; 95% confidence interval: 0.15, 0.98). The two groups had similar knee extension muscle strength at 90° knee flexion. The quality of evidence for each measured outcome was "very low." In this review, longer TUG was identified as a functional manifestation of early KOA. Further studies involving functional assessments are needed to develop a screening method to detect early KOA. Key Points • There is a need for diagnostic criteria that include functional changes in patients with early knee osteoarthritis, since radiographic facilities are not available everywhere. • In this review, a long timed up-and-go test time was identified as a functional manifestation of early knee osteoarthritis. • If the findings of this study can be replicated, measurement of TUG may allow for earlier detection of knee osteoarthritis outside the hospital and in routine clinical practice without the use of MRI or X-rays.

Rate of force development in the quadriceps of individuals with severe knee osteoarthritis: A preliminary cross-sectional study.

Knee osteoarthritis (KOA) is a leading cause of knee pain and disability due to irreversible cartilage degeneration. Previous studies have not identified modifiable risk factors for KOA. In this preliminary cross-sectional study, we aimed to test the following hypotheses: individuals with severe KOA would have a significantly lower quadriceps rate of force development (RFD) than individuals with early KOA, and the decrease in quadriceps RFD would be greater than the decrease in maximum quadriceps strength in individuals with severe KOA. The maximum isometric strength of the quadriceps was assessed in individuals with mild (Kellgren and Lawrence [K&L] grade 1-2) and severe KOA (K&L grade 3-4) using a handheld dynamometer. The RFD was analyzed at 200 ms from torque onset and normalized to the body mass and maximum voluntary isometric contraction torque. To test whether the quadriceps RFD was lowered and whether the lower in the quadriceps RFD was greater than the lower in maximum quadriceps strength in individuals with severe knee OA, the Mann-Whitney U-test and analysis of covariance were performed, respectively. The effect size (ES) based on Hedges' g with a 95% confidence interval (CI) was calculated for the quadriceps RFD and maximum quadriceps strength. Sixty-six participants were analyzed. Individuals with severe KOA displayed significantly lower quadriceps RFD (p = 0.009), the lower being greater than the lower in maximum quadriceps strength (between-group difference, ES: 0.88, -1.07 vs. 0.06, -0.22). Our results suggest that a decreased quadriceps RFD is a modifiable risk factor for progressive KOA. Our finding could help in the early detection and prevention of severe KOA.

Meta-analysis Integrated With Multi-omics Data Analysis to Elucidate Pathogenic Mechanisms of Age-Related Knee Osteoarthritis in Mice.

Increased mechanistic insight into the pathogenesis of knee osteoarthritis (KOA) is needed to develop efficacious disease-modifying treatments. Though age-related pathogenic mechanisms are most relevant to the majority of clinically presenting KOA, the bulk of our mechanistic understanding of KOA has been derived using surgically induced posttraumatic OA (PTOA) models. Here, we took an integrated approach of meta-analysis and multi-omics data analysis to elucidate pathogenic mechanisms of age-related KOA in mice. Protein-level data were integrated with transcriptomic profiling to reveal inflammation, autophagy, and cellular senescence as primary hallmarks of age-related KOA. Importantly, the molecular profiles of cartilage aging were unique from those observed following PTOA, with less than 3% overlap between the 2 models. At the nexus of the 3 aging hallmarks, advanced glycation end product (AGE)/receptor for AGE (RAGE) emerged as the most statistically robust pathway associated with age-related KOA. This pathway was further supported by analysis of mass spectrometry data. Notably, the change in AGE-RAGE signaling over time was exclusively observed in male mice, suggesting sexual dimorphism in the pathogenesis of age-induced KOA in murine models. Collectively, these findings implicate dysregulation of AGE-RAGE signaling as a sex-dependent driver of age-related KOA.

Analysis of Spastic Gait in Patients With Cervical Myelopathy Using the Timed Up and Go Test With a Laser Range Sensor.

STUDY DESIGN: Cross-sectional study. OBJECTIVE: This study aimed to objectively evaluate spastic gait and reveal its novel characteristics via analysis of gait in patients with cervical myelopathy (CM) using the Timed Up and Go (TUG) test with a laser range sensor. SUMMARY OF BACKGROUND DATA: Among patients with CM, spastic gait is a common diagnostic symptom; thus, objective assessments of spastic gait would be useful for the diagnosis of CM and recognition of disease status. Although spastic gait has been objectively evaluated in previous studies, the methods employed in those studies are not suitable for clinical settings. METHODS: In total, 37 and 24 participants were recruited for a control group and CM group, respectively. CM was diagnosed by spine surgeons. We developed a laser TUG test, in which the position and velocity of both the legs were captured. The parameter values for both groups were statistically compared, and odds ratios were calculated using logistic regression analyses. RESULTS: The total TUG-test time, time to stand up, time to first step, number of steps, and trajectory error for the CM group were significantly higher than those for the control group, whereas the average velocity and average stride length for the CM group were significantly lower than those for the control group. There was a significant independent association between the total TUG-test time and CM. The optimal cutoff point of the total test time for CM risk was approximately 9 seconds. CONCLUSION: Through the use of the laser TUG test, we were able to identify characteristics of spastic gait, which leads to difficulty in standing and taking the first step, wobbling while walking, and an increased risk of falling. We found that the risk of CM was higher if the individual took longer than 9 seconds to complete the TUG test.Level of Evidence: 4.

Increased recurrent falls experience in older adults with coexisting of sarcopenia and knee osteoarthritis: a cross-sectional study.

BACKGROUND: Sarcopenia and knee osteoarthritis (OA) are two major risk factors for falls in older adults. The coexistence of these two conditions may exacerbate the risk of falls. This cross-sectional study aimed to test the hypothesis that older adults with coexisting sarcopenia and knee OA displayed an increased risk of falls experience. METHODS: Participants recruited from an orthopedic clinic were divided into four groups according to the presence of sarcopenia and radiographic knee OA: isolated sarcopenia, isolated knee OA, sarcopenia + knee OA, and control (i.e., non-sarcopenia with non-OA) groups. We used questionnaires to assess falls experience in the prior 12 months. We performed logistic regression analyses to evaluate the relationship between the four groups and falls experience. RESULTS: Of 291 participants (age: 60-90 years, 78.7% women) included in this study, 25 (8.6%) had sarcopenia + knee OA. Participants with sarcopenia + knee OA had 4.17 times (95% confidence interval: 0.84, 20.6) higher odds of recurrent falls (≥2 falls) than controls after adjustment for age, sex, and body mass index. The increased recurrent falls experience was not clearly confirmed in participants with isolated sarcopenia and isolated knee OA. CONCLUSIONS: People with coexisting of sarcopenia and knee OA displayed increased recurrent falls experience. This study suggests a new concept, "sarcopenic knee OA", as a subgroup associated with higher risk of falls, which should be validated in future large cohort studies. TRIAL REGISTRATION: Not applicable.

Microcurrent Therapy as a Therapeutic Modality for Musculoskeletal Pain: A Systematic Review Accelerating the Translation From Clinical Trials to Patient Care.

OBJECTIVE: To summarize the level of knowledge regarding the effects of microcurrent therapy (MCT) on musculoskeletal pain in adults. DATA SOURCES: The PubMed, Physiotherapy Evidence Database, Cumulative Index to Nursing Allied Health Literature, Cochrane Central Register of Controlled Trials, and Igaku Chuo Zasshi database were searched from the time of their inception to December 2020. STUDY SELECTION: Randomized controlled trials (RCTs) investigating the effects of MCT on musculoskeletal pain were included. Additionally, non-RCTs were included to assess the adverse events. DATA EXTRACTION: The primary outcomes were pain and adverse events related to MCT. To assess the reproducibility of MCT, we evaluated the completeness of treatment description using the Template for Intervention Description and Replication (TIDieR) checklist. We also assessed the quality of evidence using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE). DATA SYNTHESIS: A comprehensive assessment of 4 RCTs and 5 non-RCTs that met the inclusion criteria revealed that MCT significantly improved shoulder pain (1 study, 40 patients) and knee pain (1 study, 52 patients) compared with sham MCT without any severe adverse events. MCT has clinically significant benefits for knee pain. This study also revealed a clinically significant placebo response in treating knee pain. This evidence highlights the substantial effect of placebo response in clinical care. These treatment effects on knee pain are further supported by the high quality of evidence in GRADE with high reproducibility in TIDieR. CONCLUSIONS: The findings of this meta-analysis highlight the effect of placebo response in treating knee pain. MCT is a potential, core nonpharmacologic treatment option in clinical care with minimal adverse events and should be further investigated. This study proposes a framework for the future investigation of the effect of MCT on musculoskeletal pain to enhance the study quality and reproducibility.

Low Back Pain as a Risk Factor for Recurrent Falls in People With Knee Osteoarthritis.

OBJECTIVE: Knee osteoarthritis (OA) has been suggested to increase the risk of falls. Low back pain (LBP) is a potential risk factor for falls in people with knee OA, but this issue has not been addressed adequately in previous studies. The objective of this study was to investigate the relationship between LBP and falls in people with knee OA in a 12-month period. METHODS: Participants with knee OA (Kellgren/Lawrence [K/L] grade ≥1) completed questionnaires for LBP and falls that occurred in the preceding 12 months. Binary and ordinal logistic regression analyses were performed to assess the relationship between LBP or moderate-to-severe LBP (numeric rating scale ≥4 points) and any fall (≥1 fall) or recurrent falls (≥2 falls) after adjustment for age, sex, K/L grade, knee pain severity, and quadriceps strength. Sensitivity analyses were performed excluding people with sciatica, nonchronic LBP, K/L grade 1, and those receiving pain medications. RESULTS: We included 189 participants (ages 61-90 years, 78.3% women) in this study. Of these participants, 41 (21.6%) reported falls in the preceding 12 months. People with any LBP (n = 101) and those with moderate-to-severe LBP (n = 45) had 2.7- and 3.7-times higher odds of recurrent falls, respectively. Sensitivity analyses revealed a strong correlation between moderate-to-severe LBP and recurrent falls. CONCLUSION: Thorough investigation of LBP as a risk factor for recurrent falls in people with knee OA may provide a novel insight into the pathomechanics of recurrent falls in this population.