Biomarkers and longitudinal changes in lumbar spine degeneration and low back pain: the Johnston County Osteoarthritis Project.

OBJECTIVE: To determine if baseline biomarkers are associated with longitudinal changes in the worsening of disc space narrowing (DSN), vertebral osteophytes (OST), and low back pain (LBP). DESIGN: Paired baseline (2003-2004) and follow-up (2006-2010) lumbar spine radiographs from the Johnston County Osteoarthritis Project were graded for severity of DSN and OST. LBP severity was self-reported. Concentrations of analytes (cytokines, proteoglycans, and neuropeptides) were quantified by immunoassay. Pressure-pain threshold (PPT), a marker of sensitivity to pressure pain, was measured with a standard dolorimeter. Binary logistic regression models were used to estimate odd ratios (OR) and 95% confidence intervals (CI) of biomarker levels with DSN, OST, or LBP. Interactions were tested between biomarker levels and the number of affected lumbar spine levels or LBP. RESULTS: We included participants (n = 723) with biospecimens, PPT, and paired lumbar spine radiographic data. Baseline Lumican, a proteoglycan reflective of extracellular matrix changes, was associated with longitudinal changes in DSN worsening (OR = 3.19 [95% CI 1.22, 8.01]). Baseline brain-derived neuropathic factor, a neuropeptide, (OR = 1.80 [95% CI 1.03, 3.16]) was associated with longitudinal changes in OST worsening, which may reflect osteoclast genesis. Baseline hyaluronic acid (OR = 1.31 [95% CI 1.01, 1.71]), indicative of systemic inflammation, and PPT (OR = 1.56 [95% CI 1.02, 2.31]) were associated with longitudinal increases in LBP severity. CONCLUSION: These findings suggest that baseline biomarkers are associated with longitudinal changes occurring in structures of the lumbar spine (DSN vs OST). Markers of inflammation and perceived pressure pain sensitivity were associated with longitudinal worsening of LBP.

International Foot and Ankle Osteoarthritis Consortium review and research agenda for diagnosis, epidemiology, burden, outcome assessment and treatment.

OBJECTIVE: To summarise the available evidence relating to the diagnosis, epidemiology, burden, outcome assessment and treatment of foot and ankle osteoarthritis (OA) and to develop an agenda to guide future research. METHOD: Members of the International Foot and Ankle Osteoarthritis Consortium compiled a narrative summary of the literature which formed the basis of an interactive discussion at the Osteoarthritis Research Society International World Congress in 2021, during which a list of 24 research agenda items were generated. Following the meeting, delegates were asked to rank the research agenda items on a 0 to 100 visual analogue rating scale (0 = not at all important to 100 = extremely important). Items scoring a mean of 70 or above were selected for inclusion. RESULTS: Of the 45 delegates who attended the meeting, 31 contributed to the agenda item scoring. Nineteen research agenda items met the required threshold: three related to diagnosis, four to epidemiology, four to burden, three to outcome assessment and five to treatment. CONCLUSIONS: Key knowledge gaps related to foot and ankle OA were identified, and a comprehensive agenda to guide future research planning was developed. Implementation of this agenda will assist in improving the understanding and clinical management of this common and disabling, yet relatively overlooked condition.

Epidemiology of osteoarthritis.

OBJECTIVE: To summarize the current state of the evidence regarding osteoarthritis (OA) prevalence, incidence and risk factors at the person-level and joint-level. DESIGN: This was a narrative review that took a comprehensive approach regarding inclusion of potential risk factors. The review complements prior reviews of OA epidemiology, with a focus on new research and emerging topics since 2017, as well as seminal studies. RESULTS: Studies continue to illustrate the high prevalence of OA worldwide, with a greater burden among older individuals, women, some racial and ethnic groups, and individuals with lower socioeconomic status. Modifiable risk factors for OA with the strongest evidence are obesity and joint injury. Topics of high interest or emerging evidence for a potential association with OA risk or progression include specific vitamins and diets, high blood pressure, genetic factors, metformin use, bone mineral density, abnormal joint shape and malalignment, and lower muscle strength/quality. Studies also continue to highlight the heterogenous nature of OA, with strong interest in understanding and defining OA phenotypes. CONCLUSIONS: OA is an increasingly prevalent condition with worldwide impacts on many health outcomes. The strong evidence for obesity and joint injury as OA risk factors calls for heightened efforts to mitigate these risks at clinical and public health levels. There is also a need for continued research regarding how potential person- and joint-level risk factors may interact to influence the development and progression of OA.

Individual and cumulative measures of knee joint load associate with T2 relaxation times of knee cartilage in young, uninjured individuals: A pilot study.

BACKGROUND: Articular cartilage structure and chondrocyte health are sensitive and reliant on dynamic joint loading during activities. The purpose of this pilot study was to determine the association between measures of individual and cumulative knee joint loading with T2 relaxation times in the knee cartilage of young individuals without knee injury. METHODS: Twelve participants (17-30 years old) without history of knee injury or surgery completed MRI, physical activity (PA), and biomechanical gait testing. T2 relaxation times were calculated in the cartilage within the patella and lateral and medial compartments. Accelerometry was used to measure mean daily step counts, minutes of PA, and % sedentary time over 7 days. Vertical ground reaction force, external knee joint moments and peak knee flexion angle were measured during stance phase of gait using three-dimensional motion capture. Cumulative knee joint loading was calculated as daily step count by external knee joint moment impulse. The relationship between measures of knee joint loading and T2 relaxation times was assessed using Pearson correlations. RESULTS: Higher T2 relaxation times in the femoral and tibial cartilage were consistently correlated to greater body mass, daily step counts, moderate and vigorous PA, and peak knee joint moments (r = 0.10-0.84). Greater cumulative knee flexion and adduction loading was associated with higher T2 relaxation times in the femoral and tibial cartilage (r = 0.16-0.65). CONCLUSION: Preliminary findings suggest that individual loading factors and cumulative knee joint loading are associated with higher T2 relaxation times in the articular cartilage of young, healthy knees.

The association between walking speed from short- and standard-distance tests with the risk of all-cause mortality among adults with radiographic knee osteoarthritis: data from three large United States cohort studies.

OBJECTIVE: Adults with radiographic knee OA (rKOA) are at increased risk of mortality and walking difficulty may modify this relation. Little is known about specific aspects of walking difficulty that increase mortality risk. We investigated the association of walking speed (objective measure of walking difficulty) with mortality and examined the threshold that best discriminated this risk in adults with rKOA. METHODS: Participants with rKOA from the Johnston County Osteoarthritis Project (JoCoOA, longitudinal population-based cohort), Osteoarthritis Initiative and Multicenter Osteoarthritis Study (OAI and MOST, cohorts of individuals with or at high risk of knee OA) were included. Baseline speed was measured via 2.4-meter (m) walk test (short-distance) in JoCoOA and 20-m walk test (standard-distance) in OAI and MOST. To examine the association of walking speed with mortality risk over 9 years, hazard ratios (HR) and 95% confidence intervals (CI) were calculated from Cox regression models adjusted for potential confounders. A Maximal Likelihood Ratio Chi-square Approach was utilized to identify an optimal threshold of walking speed predictive of mortality. RESULTS: Deaths after 9 years of follow-up occurred in 23.3% (290/1244) of JoCoOA and 5.9% (249/4215) of OAI + MOST. Walking 0.2 m/s slower during short- and standard-distance walk tests was associated with 23% (aHR [95%CI]; 1.23 [1.10, 1.39]) and 25% (1.25 [1.09, 1.43]) higher mortality risk, respectively. Walking <0.5 m/s on short-distance and <1.2 m/s standard-distance walk tests, best discriminated those with and without mortality risk. CONCLUSION: Slower walking speed measured via short- and standard-distance walk tests was associated with increased mortality risk in adults with rKOA.

Incidence and progression of hand osteoarthritis in a large community-based cohort: the Johnston County Osteoarthritis Project.

OBJECTIVE: To describe the incidence and progression of radiographic and symptomatic hand osteoarthritis (rHOA and sxHOA) in a large community-based cohort. DESIGN: Data were from the Johnston County OA Project (1999-2015, 12 ± 1.2 years follow-up, age 45+). Participants had bilateral hand radiographs each visit, read for Kellgren-Lawrence grade (KLG) at 30 joints. We defined rHOA as KLG ≥2 in ≥1 joint. SxHOA was defined in a hand/joint with rHOA and self-reported symptoms or tenderness on exam. Incidence was assessed in those without, while progression was assessed in those with, baseline rHOA. Proportions or medians are reported; differences by sex and race were assessed using models appropriate for dichotomous or continuous definitions, additionally adjusted for age, education, body mass index (BMI), and weight change. RESULTS: Of 800 participants (68% women, 32% African American, mean age 60 years), 327 had baseline rHOA and were older, more often white and female, than those without rHOA (n = 473). The incidence of HOA was high, for rHOA (60%) and for sxHOA (13%). Women were more likely than men to have incident HOA, particularly for distal interphalangeal joint radiographic osteoarthritis (DIP rOA) (adjusted odds ratios (aOR) 1.60 95% confidence intervals (95% CI) [1.03, 2.49]) and sxHOA (aOR 2.98 [1.50, 5.91]). Progressive HOA was more similar by sex, although thumb base rOA progressed more frequently in women than in men (aOR 2.56 [1.44, 4.55]). Particularly HOA incidence, but also progression, was more frequent among whites compared with African Americans. CONCLUSION: This study provides much needed information about the natural history of HOA, a common and frequently debilitating condition, in the general population.

Osteoarthritis in England: Incidence Trends From National Health Service Hospital Episode Statistics.

OBJECTIVE: It is typical in epidemiological research of osteoarthritis (OA) to collect data for the hand, hip, and knee. However, little population-based data exist for this disease in the foot. Thus, we addressed patterns of OA for the foot compared with the hand, hip, and knee spanning 2000/2001 to 2017/2018 in England. METHODS: Secondary-care data from 3 143 928 patients with OA of the foot, hand, hip, and knee were derived from the National Health Service (NHS) Hospital Episode Statistics (HES) database. Distribution, population prevalence, and incidence of joint-specific OA were stratified by age and sex. RESULTS: OA incidence increased significantly at the foot [3.8% (95% confidence interval [CI] 3.0, 4.6)], hand [10.9% (10.1, 11.7)], hip [3.8% (2.9, 4.7)], and knee [2.9% (2.2, 3.6)] per year from 2000/2001 to 2017/2018. A higher proportion of women were diagnosed with OA, whereas greater incidence in men was estimated for the hand and hip. Foot OA presented comparable diagnosis numbers to the hand. More recently during 2012/2013 to 2017/2018, a significant rise in hip OA was estimated among younger adults, whereas knee OA decreased across all age groups. Incidence of OA in the foot and hand were particularly significant among the 75 or older age group, though bimodal age distributions were observed for both sites. CONCLUSION: The significant increase in secondary care records for OA in England underscores the importance of exploring possible causative factors and identifying groups most at risk. Further detailed data may be particularly important for the hip, which represents significant incidence among younger adults. Greater incidence of OA in the foot compared with the knee emphasizes the need for well-conducted epidemiological research in this area. Monitoring the performance of surgical outcomes at the population-level for this frequently affected yet understudied site could have substantial potential to reduce the socioeconomic burden it represents to the NHS.

Physical therapy vs internet-based exercise training for patients with knee osteoarthritis: results of a randomized controlled trial.

OBJECTIVE: To compare the effectiveness of physical therapy (PT, evidence-based approach) and internet-based exercise training (IBET), each vs a wait list (WL) control, among individuals with knee osteoarthritis (OA). DESIGN: Randomized controlled trial of 350 participants with symptomatic knee OA, allocated to standard PT, IBET and WL control in a 2:2:1 ratio, respectively. The PT group received up to eight individual visits within 4 months. The IBET program provided tailored exercises, video demonstrations, and guidance on progression. The primary outcome was the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC, range 0 [no problems]-96 [extreme problems]), assessed at baseline, 4 months (primary time point) and 12 months. General linear mixed effects modeling compared changes in WOMAC among study groups, with superiority hypotheses testing differences between each intervention group and WL and non-inferiority hypotheses comparing IBET with PT. RESULTS: At 4-months, improvements in WOMAC score did not differ significantly for either the IBET or PT group compared with WL (IBET: -2.70, 95% Confidence Interval (CI) = -6.24, 0.85, P = 0.14; PT: -3.36, 95% (CI) = -6.84, 0.12, P = 0.06). Similarly, at 12-months mean differences compared to WL were not statistically significant for either group (IBET: -2.63, 95% CI = -6.37, 1.11, P = 0.17; PT: -1.59, 95% CI = -5.26, 2.08, P = 0.39). IBET was non-inferior to PT at both time points. CONCLUSIONS: Improvements in WOMAC score following IBET and PT did not differ significantly from the WL group. Additional research is needed to examine strategies for maximizing benefits of exercise-based interventions for patients with knee OA. TRIAL REGISTRATION: NCT02312713.

Clinical algorithms to aid osteoarthritis guideline dissemination.

BACKGROUND: Numerous scientific organisations have developed evidence-based recommendations aiming to optimise the management of osteoarthritis (OA). Uptake, however, has been suboptimal. The purpose of this exercise was to harmonize the recent recommendations and develop a user-friendly treatment algorithm to facilitate translation of evidence into practice. METHODS: We updated a previous systematic review on clinical practice guidelines (CPGs) for OA management. The guidelines were assessed using the Appraisal of Guidelines for Research and Evaluation for quality and the standards for developing trustworthy CPGs as established by the National Academy of Medicine (NAM). Four case scenarios and algorithms were developed by consensus of a multidisciplinary panel. RESULTS: Sixteen guidelines were included in the systematic review. Most recommendations were directed toward physicians and allied health professionals, and most had multi-disciplinary input. Analysis for trustworthiness suggests that many guidelines still present a lack of transparency. A treatment algorithm was developed for each case scenario advised by recommendations from guidelines and based on panel consensus. CONCLUSION: Strategies to facilitate the implementation of guidelines in clinical practice are necessary. The algorithms proposed are examples of how to apply recommendations in the clinical context, helping the clinician to visualise the patient flow and timing of different treatment modalities.

OARSI Clinical Trials Recommendations: Design and conduct of clinical trials of lifestyle diet and exercise interventions for osteoarthritis.

The objective was to develop a set of "best practices" for use as a primer for those interested in entering the clinical trials field for lifestyle diet and/or exercise interventions in osteoarthritis (OA), and as a set of recommendations for experienced clinical trials investigators. A subcommittee of the non-pharmacologic therapies committee of the OARSI Clinical Trials Working Group was selected by the Steering Committee to develop a set of recommended principles for non-pharmacologic diet/exercise OA randomized clinical trials. Topics were identified for inclusion by co-authors and reviewed by the subcommittee. Resources included authors' expert opinions, traditional search methods including MEDLINE (via PubMed), and previously published guidelines. Suggested steps and considerations for study methods (e.g., recruitment and enrollment of participants, study design, intervention and assessment methods) were recommended. The recommendations set forth in this paper provide a guide from which a research group can design a lifestyle diet/exercise randomized clinical trial in patients with OA.

OARSI Clinical Trials Recommendations: Design and conduct of implementation trials of interventions for osteoarthritis.

Rigorous implementation research is important for testing strategies to improve the delivery of effective osteoarthritis (OA) interventions. The objective of this manuscript is to describe principles of implementation research, including conceptual frameworks, study designs and methodology, with specific recommendations for randomized clinical trials of OA treatment and management. This manuscript includes a comprehensive review of prior research and recommendations for implementation trials. The review of literature included identification of seminal articles on implementation research methods, as well as examples of previous exemplar studies using these methods. In addition to a comprehensive summary of this literature, this manuscript provides key recommendations for OA implementation trials. This review concluded that to date there have been relatively few implementation trials of OA interventions, but this is an emerging area of research. Future OA clinical trials should routinely consider incorporation of implementation aims to enhance translation of findings.

Osteoarthritis-related biomarkers following anterior cruciate ligament injury and reconstruction: a systematic review.

OBJECTIVE: There is an increased risk of developing knee osteoarthritis (OA) following anterior cruciate ligament (ACL) injury. Biomarkers may provide diagnostic, prognostic, or burden of disease indicators of OA before radiographic changes become apparent. Unfortunately, there has been no systematic review to clarify which biomarkers may be most informative following injury. Therefore, this review critically investigated existing studies of OA-related biomarkers in ACL-deficient (ACL-D) and reconstructed (ACL-R) patients to summarize the current evidence and identify knowledge gaps. DESIGN: A systematic review of the literature in Web of Science and PubMed databases (1960-June 2014) was performed. All English-language case-control and longitudinal studies assessing OA-related biomarkers in ACL-D and ACL-R patients were considered. Data regarding biomarker changes over time within ACL-D and ACL-R patients as well as differences in ACL-D/ACL-R patients compared with a control group were extracted from pertinent studies. RESULTS: A descriptive summary of 20 included studies was produced. In ACL-D patients compared with controls, synovial fluid biomarkers indicated elevated collagen turnover, while the inflammatory cytokine response was inconclusive. In ACL-R patients, serum concentrations indicated decreased collagen breakdown, but urine concentrations were indicative of greater collagen breakdown when compared to controls. Compared to preoperative values, the overall inflammatory cytokine response measured with synovial fluid biomarkers increased while plasma biomarkers did not change following reconstruction. CONCLUSION: Patients with ACL-D or ACL-R have altered biomarkers indicative of OA. More research with standardized reporting is needed to effectively determine which biomarkers are the most indicative for OA development and progression following ACL injury.

Serum transforming growth factor-beta 1 is not a robust biomarker of incident and progressive radiographic osteoarthritis at the hip and knee: the Johnston County Osteoarthritis Project.

PURPOSE: To test whether serum transforming growth factor-beta 1 (TGF-beta1) predicts incident and progressive hip or knee radiographic OA (rOA). METHODS: Serum TGF-beta1 was measured for 330 participants aged 45 years and older in the Johnston County Osteoarthritis Project, with paired longitudinal films available for 618 hips and 658 knees. Incident and progressive rOA were defined using Kellgren-Lawrence (K-L) grade as well as osteophyte (OST) and joint space narrowing (JSN) scores. Natural logarithm transformation was used to produce near-normal distributions for continuous TGF-beta1 (lnTGF-beta1). Separate multivariable Weibull regression models were used to provide hazard ratios (HRs) for a 1-unit increase lnTGF-beta1 with each rOA outcome, accounting for variable follow-up times and clustering by individual, adjusted for age, race, gender, and body mass index (BMI). Interaction terms were considered statistically significant at P<0.10. RESULTS: The mean (+/-SD) age of the sample was 61.9+/-9.7 years, the mean BMI was 30.3+/-6.9 kg/m(2), with 60.6% women and 42.4% AA. The mean (+/-SD) TGF-beta1 was 17.8+/-6.1 ng/ml; follow-up time was 6.1+/-1.3 years. There were no significant interactions by race or gender. HRs showed no significant relationship between lnTGF-beta1 and incident or progressive rOA, OST, or JSN, at the knee or the hip. CONCLUSIONS: Levels of TGF-beta1 do not predict incident or progressive rOA, OST, or JSN at the hip or knee in this longitudinal, population-based study, making it unlikely that TGF-beta1 will be a robust biomarker for rOA in future studies.

Daily pain variations among patients with hand, hip, and knee osteoarthritis.

OBJECTIVE: This study examined within-day osteoarthritis (OA)-related pain patterns and associated patient characteristics. METHODS: Participants with physician diagnoses and self-reported symptoms of hand (N=40), hip (N=32), and knee (N=85) OA recorded pain using a handheld computer on one weekday and one weekend day, with ratings beginning immediately after waking, then approximately every 2h following. Pain was rated on a sliding visual analog scale with hidden coding of 1-100. Multivariable linear mixed models examined associations of patient demographic characteristics, enrollment site (Durham VA Medical Center vs Duke University Medical Center), joint site, body mass index, and pain medication use with within-day pain range (maximum minus minimum pain rating) and area under the curve (AUC) of pain ratings, which incorporates the magnitude of all pain measurements. RESULTS: Pain patterns differed substantially across individuals. The sample means of the average, maximum, and minimum weekday pain scores were 35.3, 54.4, and 17.9, respectively. The mean pain range was 36.4, and the mean pain AUC was 564.3 (possible range: 16-1600). Pain scores were similar on weekends. In multivariable mixed models, both knee and hip OA were associated with a greater within-day pain range than hand OA. Only VA enrollment site was associated with a significantly greater pain AUC. CONCLUSION: There is substantial within-day range in OA-related pain. Both pain range and overall within-day magnitude vary according to patient characteristics. Patients' records of within-day pain patterns could be used in clinical encounters to tailor recommendations for the timing of medication use and behavioral strategies.

Symptoms of the knee and hip in individuals with and without limb length inequality.

OBJECTIVE: This cross-sectional study examined the association of limb length inequality (LLI) with chronic joint symptoms at the hip and knee in a large, community-based sample, adjusting for the presence of radiographic osteoarthritis (OA) and other confounders. METHODS: The total study group comprised 3012 participants with complete knee symptoms data, 3007 participants with complete hip symptoms data, and 206 with LLI>or=2 cm. Presence of chronic knee symptoms was defined as report of pain, aching, or stiffness (symptoms) of the knee on most days. Presence of chronic hip symptoms was defined as hip pain, aching, or stiffness on most days or groin pain. Multiple logistic regression models were used to examine the relationship of LLI with knee and hip symptoms, while adjusting for demographic and clinical factors, radiographic knee or hip OA and history of knee or hip problems (joint injury, fracture, surgery, or congenital anomalies). RESULTS: Participants with LLI were more likely than those without LLI to have knee symptoms (56.8% vs 43.0%, P<0.001), and hip symptoms (49.5% vs 40.0%, P=0.09). In adjusted models, knee symptoms were significantly associated with presence of LLI (adjusted odds ratio [aOR]=1.41, 95% confidence interval, [95% CI] 1.02-1.97), but the relationship between hip symptoms and LLI (aOR=1.20, 95% CI 0.87-1.67) was not statistically significant. CONCLUSION: LLI was moderately associated with chronic knee symptoms and less strongly associated with hip symptoms. LLI may be a new modifiable risk factor for therapy of people with knee or hip symptoms.

Relationship of limb length inequality with radiographic knee and hip osteoarthritis.

OBJECTIVE: This study examined the relationship of limb length inequality (LLI) with radiographic hip and knee osteoarthritis (OA) in a large, community-based sample. METHODS: The total study group comprised 926 participants with radiographic knee OA, 796 with radiographic hip OA, and 210 (6.6%) with LLI >or=2cm. The presence of radiographic OA was defined as Kellgren/Lawrence (K/L) grade >or=2. Multiple logistic regression models were used to examine the relationship of LLI with hip and knee OA, while controlling for age, gender, race, body mass index, and history of hip or knee problems (joint injury, fracture, surgery, or congenital anomalies). RESULTS: In unadjusted analyses, participants with LLI were more likely than those without LLI to have radiographic knee OA (45.1% vs 28.3%, P<0.001) and radiographic hip OA (35.2% vs 28.7%, P=0.063). In multiple logistic regression models, knee OA was significantly associated with presence of LLI (adjusted Odds Ratio [aOR]=1.80, 95% Confidence Interval [95% CI] 1.29-2.52), but there was no significant relationship between hip OA and LLI (aOR=1.20, 95% CI 0.86-1.67). Among participants with LLI, right hip OA was more common when the contralateral limb was longer than when the ipsilateral limb was longer (30.3% vs 17.5%, P=0.070). CONCLUSION: LLI was associated with radiographic knee OA, controlling for other important variables. Future research should examine the relationship of LLI with hip or knee OA incidence, progression, and symptom severity, as well as the efficacy for LLI corrective treatments in OA.